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Oral drugs: final formulation in phase II. Final product considerations: size, s
hape, color, taste, skin feel, viscosity, physical appearance, production equipm
ent / site.
Product line extensions:
Dosage forms with change in physical form or strength but not use or indication.
Usually occurs during Phases III, IV, V. Regulatory approval: based on stabilit
y, analytical / manufacturing controls, bioequivalence studies, clinical trials
Solid products: Different strength in a tablet or capsule form
only bioequivalen
ce required (simplest case). Easier if in vitro dissolution / in vivo bioavailab
ility correlation exists. Modified release: clinical trials required. If new ind
ication
new NDA and new efficacy studies. Liquid products: If an extension of a
liquid same as above for solids If an extension of a solid
if big difference in
extent / rate of absorption
new clinical trials.
Preapproval inspections
Manufacturing facility is inspected prior to NDA / ANDA approval or after a majo
r reported change to NDA / ANDA. Includes: general cGMP inspection, reviews docu
mentation, verifies traceability of information to documentation, consults the c
hemistry / manfucaturing / control (CMC) section of NDA / ANDA, make a final rec
ommendation.
Scale-up and post-approval changes (SUPAC)
Guidelines to # of manufacutring changes that require preapproval by the FDA. Ex
amples: minor formulation changes, change site of manufacture, batch size
or , ch
ange manufacturing process / equipment. 1. Very minor changes not requiring appr
oval are reported in an annual report. Examples: compliance with guidance, label
description, deletion of colorant, expiration date extension, container / closu
re type (not size), analytical method 2. Changes being effected supplement: mino
r changes but require some validation, documentation. A supplement but no pre-ap
proval is required. Examples: new specs, label changes on clinical info, differe
nt cGMP manufacturing facility but same process. 3. Preapproval supplement: majo
r changes require specific preapproval. Examples: adding or deleting an ingredie
nt, relaxing specs, deleting a spec or method, method of manufacture, in-process
controls. Therapeutic and Bio-equivalence: must be shown for any change. Minor
change comparable dissolution profiles. Major change
in vivo bioequivalence stud
y.
GMPs
Minimum requirements for manufacturing, processing, packing, or holding drugs. I
nclude criteria for personnel, facilities, processes to ensure final product has
the correct identity, strength, quality, purity. Quality Control (QC): departme
nt responsible for establishing process and product specifications. The QC dept
test the product and verifies specs are met. This includes acceptance / rejectio
n of incoming raw materials, packaging components, water, drug products, environ
mental conditions. Quality Assurance (QA): a department that determines that the
systems and facilities are adequate and that written procedures are followed.
When the negative pole of a dipole approach the positive pole of another
molecul
ar attraction called dipole-dipole interaction. If similar poles approach
molecula
r repulsion (intermolecular repulsive forces)
Types of intermolecular forces of attraction
Van der Waals forces (liquids) Induced dipole induced dipole (London dispersion
force): when a transient dipole in a nonpolar molecule induces another transient
dipole in another molecule. Force = 0.5-1 Kcal/mole Dipole-induced dipole (Deby
e induction force): A transient dipole is induced by a permanent dipole. Force =
2 Kcal/mole Permanent dipole (Keesom orientation force): 4 Kcal/mole Hydrogen b
onds Hydrogen ions are small and have a large electrostatic field, so it approac
hes highly electronegative atoms (O, F, Cl, N, S) and interact electrostatically
to form a hydrogen bond. Force = 5 Kcal/mole. Ion-ion, ion-dipole, ion-induced
dipole Force of positive-negative ion interaction in the solid state = 150 Kcal/
mole. Covalent and ionic forces are much stronger than van der Waals forces.
States of matter
Gases Molecules move in straight path at high speed until they randomly collide
with another molecule, creating pressure. Intermolecular forces ~ zero. Ideal ga
s law: Pressure (P) x Volume (V) = number of moles (n) X Molar Gas Constant (R)
X Temperature (T) Gases in pharmacy: anesthetics (nitrous oxide, halothane), com
pressed oxygen, liquefiable aerosol propellants (nitrogen, CO2, hydrocarbons, ha
lohydrocarbons), ethylene oxide for sterilization of heat labile objects. Volati
le liquids (ether, halothane, methoxyfurane) are used as anesthetics. Amyl nitri
te (volatile liquid) is inhaled as a vasodilator in acute angina. Sublimation: a
solid is heated directly to the gaseous or vapor state (or vice versa, also cal
led deposition) without passing through the liquid state. Examples: camphor, iod
ine. Liquids Van der Waals intermolecular forces are sufficient to impose some o
rdering. Hydrogen bonding cohesion in liquids. Surface and interfacial tension M
olecules at the surface of the liquid experience a net inward pull from the inte
rior and they tend to contract. This makes liquids assume a spherical shape as i
t is the volume with minimum surface and least free energy. Surface free energy
/ surface tension: the work required to
the surface area A of the liquid by 1 un
it area. Example: SFE for water = 72 mN/m. Interfacial tension: at the surface o
f two immiscible liquids. Viscosity Viscosity = shear stress / shear rate Non-Ne
wtonian viscosity: exhibit shear dependent or time dependent (apparent) viscosit
y. Shear dependent viscosity: Shear thickening (dilatancy) as in suspensions of
small deflocculated particles with high solid content. Shear thinning (pseudopla
stic): as in polymer solutions. Plastic (Bingham body): as in flocculated partic
les in concentrated suspensions that have yield value. Time dependent viscosity:
yield value of plastic systems may be time dependent. Thixotropic systems are s
hear thinning but they do not recover viscosity after shear is removed, i.e., st
ructural recovery is slow
Buffer: a mixture of salt with acid or base that resists changes in pH when smal
l quantities of acid or salt are added. Buffer is a combination of weak acid and
its conjugate base (salt) (more common), or a weak base and its conjugate acid
(salt). Buffer capacity: is the number of gram equivalents in an acid or base th
at changes the pH of 1 liter buffer by 1 unit. Maximum buffer capacity occurs wh
en pH = pKa. Higher concentration of buffer constituents
buffer capacity due to
the acid or base reserve.
Heterogenous (disperse) systems:
Suspension: two phas system that is composed of solid material dispersed in a li
quid. Particle size is > 0.5 mm. Emulsion: heterogeneous system that consists of
one immiscible liquid dispersed in another as droplets. Droplets diameter > 0.1
micron. Emulsions are inherently unstable because the droplet tend to coalesce.
An emulsifying agent is used to prevent coalescence. In ideal (not real) disper
sion, the dispersed particles are uniform in size and do not interact. Stokess la
w defines Sedimentation rate. The rate
with
particle size and the difference in
density between particles and medium. The rate with
medium viscosity. High parti
culate (dispersed phase) concentration leads to particle collision and aggregati
on, coalsecnce, instability. Avoidance of particle-particle interactions: if par
ticles have similar electrical charge (e.g. from the surfactant). Zeta potential
(magnitude of the charge) is the difference in electrical potential between the
particle charged surface and dispesion medium. When zeta potential is high (<25
mV), interparticulate repulsive forces > attractive forces, which results in de
flocculation and stability. Coalescence of droplets in O/W emulsions is
by elect
rostatic repulsion of similarly charged particles. Creaming: is the reversible s
eparation of a layer of emulsified particles. Mixing or shaking may be sufficien
t to reconstitute the emulsion. Phase inversion: from o/w to w/o emulsion or vic
e versa.
IV Chemical kinetics and drug stability
Degradation rate depends on concentration, temperature, pH, solvents, additives,
light, radiation, catalysts (polyvalent cations), surfactants, buffers, complex
ing agents. Order of reaction: the way in which the concentration affects rate.
Zero order: rate is independent of concentration, e.g., 5 mg/hr, i.e., straight
line concentration vs. time. First order: rate depends on the first power of con
centration, e.g., 5% / hr. Concentration exponentially with time. Straight line
log concentration vs. time. t1/2 = 0.693/k, t90% = 0.104/k. Half life is concent
ration independent. Temperature: T
reaction rate (Arrenius equation). Solvent: m
ay change pKa, surface tension, viscosity, reaction rate, etc. Additional reacti
on pathways may be created (e.g. aspirin in ethanol). pH: H+ catalysis occurs at
pH, OH- catalysis occurs to
pH. Rate constant at intermediate pH range is usual
ly lower than at or
pH. pH of optimum stability (point of inflection) is measure
d. Aromatic esters (benzocaine, procaine, tetracaine)
t1/2 is presence of caffei
ne due to complex formation.
Modes of pharmaceutical degradation:
Hydrolysis: most common. Occurs for esters, amides, lactams. H+ and OH- are the
most common catalysts. Esters easily hydrolize and should be avoided in liquids.
Oxidation: by oxygen in the air or in solvent. Oxidizable compounds should be p
acked in an inert atmosphere (nitrogen or CO2). Oxidation involves free radical
mechanism and chain reaction. Free radicals take electrons from other compounds.
Antioxidants react with free radicals by providing electrons. Antioxidants incl
ude: ascorbic acid, tocopherols, sodium bisulfite, sodium sulfite, butylated hyd
roxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate. Photolysis: d
egradation in sunlight or room light. Molecules may absorb the proper wavelenght
of light (usually <400 nm) and acquire sufficient energy to undergo reaction. P
revent by using opaque container or amber glass bottle. Examle: sodium nitroprus
side in water.
Geometric dilution: used for mixing potent drugs with large amount of diluent. F
irst mix equal amounts of drug and diluent in a mortar by trituration, repeat un
til diluent is used up. Sifting: powders are passed through sifters similar to f
lour sifters, resulting in a light fluffy product. Not suitable for potent drugs
. Tumbling: mix powders in a large container rotated by motor. Use and packaging
of powders: As bulk powders or divided powders. For bulk powders, a perforated
sifter can is used for external dusting or an aerosol container is used for spra
ying onto skin. Powders dispensed in bulk: antacids and laxatives (e.g. PEG is m
ixed with a drink). Douches are mixed with water and applied vaginally. Dentifri
ces and dental cleansing powders. Powders for ear, nose, throat, tooth sockets,
vagina. Non potent substances. Divided powders: dispensed usually in folded pape
r (chartulae). If drug is not potent, approximate portions by block and divide m
ethod (do not weight). Special problems: volatile substances (camphor, menthol,
essential oils)
use sealed containers. Liquids added to divided powders in small
amounts. Hygroscopic substances become moist
divide, add diluent, double wrap.
Eutectic mixtures.
Capsules
Hard gelatin capsules Storage: contain 15% water, so when humidity capsules beco
me brittle, when humidity
capsules become shapeless. Size: empty capsules are nu
mbered (000 largest / 600 mg, 5
smallest / 30 mg). Large capsules are for veteri
nary use. May add lubricant to flow or wetting agent to dissolution. Filling: by
the punch method. Powder is placed on paper and the capsule is pressed into pow
der until filled. Soft gelatin capsules Preparation: from gelatin shells. Glycer
in or polyhydric alcohol (sorbitol) is added to make shells more elastic. Contai
n preservatives (sorbic acid, parabens). Uniformity and disintegration Uniformit
y is demonstrated by weight variation or content uniformity. Disintegration are
usually not requires unless they are enteric coated. Contents may be designed fo
r sprinkling on food (e.g. Theo-Dur Sprinkle).
Tablets
Advantages of solid dosage forms: accurate dose, easy shipping / handling, less
shelf space, no preservative, no taste masking problems, more stable / longer ex
piration. Advantages of liquid dosage forms: more effective (antacids, adsorbent
s), easier to swallow. Advantages of tablets; precise dose, content variability,
manufacturing cost, easy packaging and shipping, easy to identify, easy to swal
low, specific release forms, stable, tamperproof. Disadvantages of tablets: diff
icult compression, difficult formulation / bioavailability (poor wetting, dissol
ution, dose). Ideal tablet: free of defects, strong / durable, stable, predictab
le drug release. Tablet design and formulation (excipients) Diluents: fillers to
make up the tablet bulk of dose drugs. May cohesion, flow, or direct compressio
n. Examples: kaolin, lactose, mannitol, sugar, starch, microcrystalline cellulos
e, calcium phosphate. Do not use calcium salts with tetracycline ( absorption). B
inders / adhesives: added dry or liquid to granulation or direct compression. Ex
amples: cornstarch, glucose, molasses, natural gum (acacia, may be contaminated)
, celluloses (methylcellulose, CMC, microcrystalline cellulose), gelatins, provi
de (PVP). Liquid binders are more effective.
too hard, dissolution.
soft crumblin
tablets. Disintegrants: disintegration on gastric fluid contact (critical for d
issolution and bioavailability). They draw water to tablet, swell and burst. Exa
mples: cornstarch, potato starch, sodium starch glycolate, celluloses (sodium CM
C), clays (veegum, bentonite), cation exchange resins.
A portion can be added with the diluent and another with the lubricant after gra
nulation
double disintegration. Lubricants / antiadherents / glidants: lubricant
s friction between tablet and die upon ejection (talc, magnesium stearate, calci
um stearate). Anti-adherents
sticking, adhesion of granules to the punches or di
e. Glidants
particle friction
powder / granule flow. Colors / dyes: disguise off
-color drugs, product ID. FDC dyes are applied in solution. Lakes are dyes absor
bed on a hydrous oxide (dry powder). Flavoring agents: only for chewable or mout
h dissolving tablets. Flavor oils or powders are stable, water soluble flavor ar
e stable. Maximum: 0.75%. Artificial sweeteners: only for chewable or mouth diss
olving tablets. May come with diluent (mannitol, lactose). Other agents; sacchar
in, aspartame. Adsorbents: hold fluid in apparently dry state. Example: magnesiu
m oxide, magnesium carbonate, bentonite. Tablet types and classes For oral inges
tion: May be mask taste, color, odor, control release, enteric coating, incorpor
ate another drug, avoid incompatibility, appearance. Compressed: from powders, c
rystals or granules with or without excipients. No coating. Multiple compressed:
layered compress tablet granules around previously compressed granules, then re
peat. Compression coated / dry coated
made by feeding previously compressed tabl
et to a machine that compresses an shell around it separate incompatible drugs,
provide repeat action / prolonged action. Repeat-action: multiple compressed tab
let where the outer shell rapidly disintegrates in the stomach. Example: Repetab
s, Extentabs. The components of the inner layer are insoluble in the stomach but
soluble in the intestine. Delayed action / enteric coated: delays drug release
to prevent stomach destruction, prevent stomach irritation, or better stomach ab
sorption. Enteric: intact in stomach, release in intestine (e.g. Ecotrin). Sugar
/ chocolate-coated: to protect drug from air / humidity, mask taste / odor. Pro
cess includes seal coating (waterproofing), subcoating, syrup coating (for smoot
hing, coloring), polishing. Disadvantage: time consuming, require expertise, bul
ky coats. Film coated: compressed tablets coated with water soluble or insoluble
polymer (HPMC, povidone, PEG). Film is colored, durable, chipping, bulky (3% wt
), time consuming than sugar coating. May contain film former, plasticizer, surf
actant, opacifier, sweetner, color, flavor, glossant, volatile solvent. Air-susp
ension coated: fed into vertical cylinder and supported by air column (Wurster p
rocess) where the coating solution is applied. Chewable: disintegrate rapidly wh
en showed or dissolved. Contains flavored and colored mannitol. Used for childre
n, multivitamins, antacids, antibiotics. Used in oral cavity Buccal / sublingual
: allow absorption through oral mucosa after dissolution. Avoid gastric destruct
ion or intestinal absorption. Examples: sublingual nitroglycerin, buccal progest
erone. Troches / lozenges / dental cones: dissolves slowly in the mouth and prov
ide local effect. Used to prepare solutions: Effervescent: made by compressing g
ranular effervescent salts (citric acid, tartaric acid, sodium bicarbonate) that
release CO2 when contacting water. Example: alkalinizing analgesics (Alka-Seltz
er, dissolution, absorption). Other tablets to prepare solution: dispensing tabs
, hypodermic tabs, tab triturates. Processing problems Capping: separation of th
e top or bottom crown from main body of tab. Lamination: separation of tab into
two or layers. Usually due to air entrapment. Picking: removal of the surface ma
terial by a punch. Sticking: adhesion of material to the die wall. Due to excess
moisture or melting ingredient. Mottling: unequal color distribution. Due to di
fferent color drug vs. excipient or drug degradation.
Tablet evaluation and control General appearance: size, shape, color, odor, tast
e, surface, texture, physical flaws, consistency, marking legibility. Hardness /
friability resistance: Hardness affects dissolution / disintegration. Slow diss
olved tabs are harder, vice versa. Hardness tester measure force required to bre
ak tab. Friabilators measure weight loss when tabs roll and fall (<1%). Chewable
/ effervescent tabs are highly friable, require special packaging. Weight varia
tion: USP standards apply to tabs containing >50 mg drug where drug is > 50% of
total weight. Content uniformity: USP standards apply if drug <50 mg. Disintegra
tion: USP test is conducted in vitro. Disintegration time: nitroglycerin (2 min)
, aspirin (5 min), most other drugs (<30 min), buccal tabs (4hr), enteric coated
(none in 1 hr is simulated gastric fluid, within 2 hr in simulated intestinal f
luid). Dissolution: standards in USP. Increased emphasis on dissolution replaced
disintegration for many drugs.
Aerosols
Pressurized dosage forms that deliver drugs topically or systemically with the a
id of liquefied or propelled gas (propellant). Valve allows pressurized product
to be expelled continuously or intermittently when the actuator is pressed. Dip
tube conveys the formulation for the containers bottom to the valve. Metered dose
inhalers (MDIs): aerosol systems for systemic or pulmonary delivery. They conta
in fine drug mist solution or dispersion. 1 Actuation = 1 dose. Propellants: com
pressed gases (CO2, N2, NO), pressure with time due to head space. Liquefiable g
ases: saturated hydrocarbons, hydrofluorocarbons, dimethyl ether, chlorofluoroca
rbons (CFC). CFC are banned now. Advantages: push-button dispensing convenience,
stability of closed container (protects from light, moisture, air, microbes), t
ampering, wide product range. Disadvantage: propellants are environmental hazard
.
Controlled release dosage forms
They release drug slowly. Also known as delayed-release, sustained-action, prolo
nged-action, sustainedrelease, prolonged-release, timed-release, slow-release, e
xtended-action, extended-release. Advantages: compliance, total drug used, local
or systemic SE, drug accumulation / potentiation / loss of activity with prolon
ged use, treatment efficiency, rapid condition control, bioavailability, level f
luctuation, cost. Coated beads or granules: Examples: Theo-Dur Sprinke, Spansule
s, Sequels,. Produce drug level similar to multiple dosing. Non-aqueous (e.g. al
cohol) drug solution is coated onto small inert beads or granules (starch/sugar)
. Beads may be made of drug if dose is . Some granules take no further coating to
give immediate release. Otherwise, coats of a lipid (e.g. beeswax) or cellulosi
c (e.g. ethylcellulose) material are applied. Thickness is varied by varying # o
f coats to provide SR. Microencapsulation Example: Bayer time-release aspirin. S
olids, liquids or gases are encased in microscopic capsules. Coacervation: most
common method of encapsulation. A hydrophilic substance is added to a colloidal
drug dispersion and causes layering and formation of microcapsules. Film forming
substances for coating (natural or synthetic) include shellacs, waxes, gelatin,
starches, cellulose acetate phthalate, ethylcellulose. After the coating dissol
ves, the drug is immediately available. Matrix tablets: Examples: Gradumet, Lont
abs, Dospan, Slow-K Use hydrophilic polymers (methyl cellulose, HPMC), insoluble
plastics (polyethylene, polyvinyl acetate, polymethacrylate), fatty compounds (
waxes, glyceryl tristearate). The drug is mixed with matrix material then compre
ssed.
The immediate dose is coated as a top layer. Osmotic systems: Example: Oros syst
em (Alza) Oral osmotic pump composed of a core tablet and semipermeable coating
that has a small hole (0.4 mm) produced by laser beam for drug exit. The system
requires only osmotic pressure to be effective and is independent of pH. Drug re
lease rate is controlled by changing surface area, membrane nature, or hole diam
eter. Ion-exchange resins: Example: biphenamine (amphetamine and dextroamphetami
ne), lonamin (phentermine), Pennkinetic system. Ion exchange resins are complexe
d with drugs by passage of a cationic drug solution through a column that contai
ns the resin. The drug is complexed to the resin by replacement of hydrogen atom
s. Then the resin-drug complex is washed and tableted. Release is dependent on i
onic environment in GI and resin properties ( pH
release). Complex formation: Exa
mple: hydroxypropyl-beta-cyclodextrin forms a chemical complex slowly dissolves
depending on pH. Hydrocolloid systems: Example: Valrelease (SR diazepam) include
s hydrodynamically balanced system (HBS). HBS contains a matrix that is dense th
an gastric acid, so it remains buoyant. Multiple hydrocolloid layers swell when
contacting gastric acid and slowly erode releasing the drug.
4. Biopharmaceutics and Drug Delivery Systems
Drug transport and absorption
Transport across cell membranes
Cell membrane: is a semipermeable structure composed of lipids and proteins. Pro
teins, protein bound drugs and macromolecules do not cross cell membranes easily
. Nonpolar lipid soluble and smaller molecular weight drugs diffuse through cell
membranes faster. Passive diffusion / partitioning: passive diffusion is domina
nt within the cytoplasm or in interstitial fluid (Ficks law). Passive transport a
cross cell membranes involves successive partitioning of solute between aqueous
and lipid phase as well as diffusion within phases. Nonionized drugs are more li
pid soluble and partition better across cell membranes. Carrier-mediated transpo
rt: Active transport: drug moves against concentration gradient, requires energy
, carrier may be selective for drugs that resemble natural substrates, system ma
y saturate at concentrations, process may be competitive. Facilitated diffusion:
carrier mediated transport that occurs with a concentration gradient and does n
ot require energy. Paracellular transport: drug transport across tight junction
between cells or channels. It involves diffusion and convective (bulk) flow of w
ater and dissolved molecules Vesicular transport: the process of engulfing parti
cles by a cell. Only mechanism that does not require water solubility for absorp
tion. Pinocytosis: engulfment of small solute or fluid volumes. Phagocytosis: en
gulfment of large particles or macromolecules by macrophages. Endo/Exo-cytosis:
movement of macromolecules in and out of the cell. Transport proteins: (e.g. P-g
lycoprotein) are embedded in the lipid bilayer of cell membranes. These are ATP
energy dependent pumps. Work closely with cytochrome P450 3A4 to intracellullar
drug concentration. Substrates: cyclosporin, nifedipine, digoxin.
Routes of drug administration
Parenteral: IV Bolus is directly injected to the blood stream, very quick action
/ SE. IV infusion: constant input rate maintains constant plasma concentration.
Intra-arterial: to achieve
concentration in specific tissue before systemic dru
g absorption, mostly diagnostic and chemotherapy. IM: rate of
tion is the rate limiting step. For CR or SR, release from the delivery system i
s the rate limiting step.
Tetracycline
accumulate in bone (calcium Complexation). Plasma protein binding:
results in a big complex
cant cross membranes. Albumin: major plasma protein for
drug binding. Alpha1-glycoprotein: binds basic drugs (e.g. propranolol) in the p
lasma. bound drugs (e.g. phenytoin) can be displaced by other bound drug
free un
bound drug in effect / toxicity.
One-compartment model
Intravenous bolus injection
Very rapid drug entry. Rate of absorption is negligible. Entire body is one comp
artment
all tissue equilibrate rapidly. Drug elimination: first order kinetics.
Elimination rate constant = renal excretion rate constant + metabolism (biotrans
formation) rate constant Some controlled release oral drugs have zero absorption
rate constant. Apparent volume of distribution (Vd): hypothetical volume of bod
y fluid in which drug is dissolved. Vd is needed to estimate amount of drug in t
he body (Db) relative to concentration in plasma (Cp). Cp = Db / Vd More drug di
stribution into tissues
Cp Vd
Single oral dose
Rapid absorption then elimination, both with first order kinetics. Time to reach
max concentration (tmax) depends only on absorption and elimination rate consta
nts but not on Vd or Db. AUC: calculated using trapezoidal rule by integrating t
he plasma drug concentration over time. AUC depends on Do, Vd, elimination K but
not absorption K. Lag time: at the beginning of systemic drug absorption, e.g.
due to delay in gastric emptying.
Intravenous infusion
Absorption: zero order. Elimination: first order (when infusion stops) Steady st
ate concentration (Css): target plateau drug concentration where fraction of dru
g absorbed = fraction of drug eliminated. Loading dose (DL): initial IV bolus do
se to produce Css as rapidly as possible. Start IV infusion at the same time. DL
: amount of drug that, when dissolved in the apparent Vd, produces the desired D
ss. Reaching 07% of Css without DL takes ~ t1/2. Time to reach Css depends on th
e drug elimination half life. IV infusion: ideal for drugs with narrow therapeut
ic window (controls Cp).
Intermittent intravenous infusion
Drug is infused for short periods to prevent accumulation and toxicity. Used for
aminoglycosides (e.g. gentamicin).
Multiple doses
Drug is given intermittently in multiple-dose regimen for continuous or prolonge
d therapeutic activity to treat chronic disease. Give new dose before previous d
ose completely eliminated
Cp accumulation
to Css. At steady state: Cp fluctuatio
ns between a max and a min (C min-max). Superposition principle: assumes that pr
evious drug doses have no effect on subsequent doses total Cp = cumulative resid
ual Cp from each previous dose. Dosing rate = dose size (Do) / dose interval (e.
g. X mg/hr). Same dosing rate
same average Css but may be different (C min-max).
Some AB multiple rapid IV bolus injections. Oral immediate release drug product
s (multiple doses)
rapid absorption, slow elimination. Maintenance dose (DM): af
ter loading dose to maintain Cp at Css. If DM dosing interaval = elimination t1/
2 DL = 2 x DM
Multi-compartment models
Drug distributes into different tissue groups at different rates. Tissues with b
lood flow equilibrate rapidly with the drug. Two-compartment model (IV bolus): F
irst, rapid distribution into highly perfused tissue (central compartment)
rapid
decline in Cp (distribution phase). Both are first-order processes. Then, slow
distribution into peripheral tissues (tissue compartment)
slow decline in Cp aft
er equilibration (elimination phase). Vd = Vd at steady state + central + tissue
compartment volumes. Two-compartment model (oral): two-compartment ONLY if abso
rption is rapid but distribution is slow. Models with additional compartments: e
xample of a third compartment: deep tissue space. If frequent interval dosing
th
ird compartment accumulation. Elimination rate constant: two constants; one for
elimination from central compartment, the other for elimination after complete d
istribution.
Nonlinear pharmacokinetics
Also known as capacity-limited, dose-dependent, or saturation PK. Result from th
e saturation of an enzyme of carrier-mediated system. Do not follow first-order
kinetics as the dose . AUC or drug excreted in urine are not proportional to dose
Elimination t1/2 may at doses. Michaelis-Menten equation: describe velocity of
enzyme reactions in nonlinear PK. It described rate of change of Cp after IV bol
us. If Cp is the equation is a zero-order rate of elimination. If Cp is
first-ord
er. Note that first-order PK = linear PK
Clearance
Total body clearance (ClT)
ClT = drug elimination rate /
T1/2 is a dependent variable.
dy per unit time. First order
earance ClT
t1/2. Vd
Hepatic clearance
Volume of drug-containing plasma cleared by the liver per unit time. Measurement
of hepatic clearance (ClH) Main mechanism for non-renal clearance. Measured ind
irectly (difference between total and renal clearance). ClH = hepatic blood flow
x extraction ratio. Extraction ratio: drug fraction irreversibly removed by an
organ or tissue as the drug-containing plasma perfuses the tissue. Blood flow, i
ntrinsic clearance, protein binding All these factors affect hepatic clearance.
Blood flow: to the liver is ~ 1.5 L/min. After oral GI absorption
to mesenteric
vessels to hepatic portal vein through the liver
to hepatic vein
to systemic cir
culation. Intrinsic clearance: ability of the liver to remove the drug independe
nt of blood flow due to inherent ability of the biotransformation enzymes (oxida
ses) to metabolize the drug as it enters the liver. This is affected by enzyme i
nducers (Phenobarbital, tobacco) and inhibitors (cimetidine, lead). Protein bind
ing: bound drugs are not easily cleared by the liver or kidney. Only free drug c
rosses the membrane into the tissue and is available to metabolizing enzymes. Bi
liary drug excretion Active transport (secretion) process. Separate systems for
weak acids and weak bases. Excretes MWt drugs (>500) or polar drugs (digoxin, re
serpine, glucuronide conjugates). Drugs may be recycled by enterohepatic circula
tion. GI absorption
mesenteric vessels hepatic portal veins
liver
secrete to the
bile store in gallbladder empty into the GI through the bile duct (recirculatio
n). First pass effect (pre-systemic elimination) Portion of oral drugs may be el
iminated before systemic absorption due to rapid drug biotransformation by liver
enzymes. Measure absolute bioavailability (F). If F < 1
some drug was eliminate
d before systemic absorption. Common for drug with high liver extraction ratio.
If first-pass effect dose (e.g. propranolol, penicillin), different route (e.g.
nitroglycerin, insulin), or modified dosage form (e.g. mesalamine).
Non-compartment models
Some PK parameters can be estimated with non-compartment methods using compariso
n of the AUCs. Mean residence time (MRT): average time for the drug molecules to
reside in the body. Called Mean Transit Time or Sojourn Time. It depends on the
route of administration. Assumes elimination from the central compartment. MRT
= total residence time of all drug molecules in the body / total number of drug
molecules. Mean absorption time (MAT): difference between MRT and MRTIV and an e
xtravascular route. Clearance: volume of plasma cleared of the drug per unit tim
e. Steady-state volume of distribution (Vss): amount of drug in the body at stea
dy sate and the average steady-state drug concentration.
Clinical pharmacokinetics
The application of PK principles to the rational design of an individualized dos
age regimen. Objectives: maintenance of an optimum drug concentration at the rec
eptor site to produce effect for the desired period, and minimization of SE.
Toxicokinetics
Application of PK principles to the design, conduct, and interpretation of drug
sate evaluation studies. Used to validate dose-related exposures in animals in p
reclinical drug development to predict human toxicity.
Therapeutic substitution
The process of dispensing a therapeutic alternative. For example: dispensing amo
xicillin for ampicillin. The substituted drug is usually in the same therapeutic
class (e.g. calcium channel blockers) and is expected to have a similar clinica
l profile.
Formulary issues
A formulary is a list of drugs. Positive formulary: lists all drugs that may be
substituted. Negative formulary: lists drugs which cant be substituted. Restricti
ve formulary: lists only drugs that may be reimbursed without justification by t
he prescriber. States provide guidance for drug product selection through formul
ary. FDA annually publishes Approved Drug Products with Therapeutic Equivalence
Evaluations (the Orange Book). It is also published in the USP/DI Volume III. Oran
ge Book Codes: A Rated: drug products that are considered therapeutically equiva
lent. B Rated: drug products that are not considered therapeutically equivalent.
AB Rated: products meeting bioequivalence requirements.
8. Organic Chemistry and Biochemistry
Organic chemistry
Functional groups affect hydrophilicity, lipophilicity, reactivity, shelf life,
stability, biotransformation, metabolism.
Alkanes
Also called paraffins, saturated hydrocarbons. General formula: R-CH2-CH3. Lipid
soluble. Common reactions: halogenation, combustion. Chemically inert to air, h
eat, light, acids, bases. Stable in vivo.
Alkenes
Also called olefins, unsaturated hydrocarbons. General formula: R-CH=CH2. Lipid
soluble. Common reactions: addition of hydrogen or halogen, hydration (to form g
lycols), oxidation (to form peroxides). Volatile alkenes and peroxides may explo
de in presence of O2 and spark Stable in vivo. Hydration, peroxidation, reductio
n may occur.
Aromatic hydrocarbons
Based on benzene. Exhibit multicenter bonding. Lipid soluble. Common reactions:
halogenation, alkylation, nitration, sulfonation. Chemically stable. In vivo: hy
droxylation, diol formation.
Alkyl halides
Halogenated hydrocarbons. General formula: R-CH2-X. Lipid soluble. degree of hal
ogenation
Solubility. Common reactions: dehyro-halogenation, nucleophilic substi
tution. Stable on the shelf. Not readily metabolized in vivo.
Alcohols
Contains OH group. May be primary (R-CH2-OH), secondary (R1/R2-CH-OH), or tertia
ry (R1/R2/R3-COH). Alcohols are lipid soluble. Low molecular weight alcohols are
water soluble. hydrocarbon chain length water solubility.
Amides
General formula: R-CONH2 or R-CONR1/R2 (lactam form). Lipid soluble. Low molecul
ar weight amides are slightly water soluble. No common reactions. Very stable on
shelf. In vivo: enzymatic hydrolysis by amidases in the liver.
Biochemistry
Amino acid and proteins
Monomeric units of protein (peptide bonds). Formula: NH2-CH-R/-COOH. Proteins ar
e made of 20 AA, differ in R side chain (alpha (C)). Protein hydrolysis to AAs b
y acids, bases, enzymes. + AA ionize (depending on pH) to zwitterions structure
(NH3 -CH-COO /R)
water solubility, melting point. Levels of protein structure: p
rimary, secondary (alpha/beta), 3ry, 4ry.
Carbohydrates
Polyhydroxy aldehydes or ketones Monosaccharides: simple single unit sugars, e.g
., glucose, fructose. Oligosaccharides: short chains of monosaccharides joined c
ovalently, e.g. sucrose (has to convert into glucose, fructose before GI absorpt
ion), maltose (hydrolyzed by maltase into 2x glucose), lactose (milk sugar, has
to convert into galactose, glucose before GI absorption). Polysaccharides: long
chains of monosaccharides, e.g., cellulose, glycogen.
Pyrimidines and purines
Bases
bond with ribose nucleosides
bond with phosphoric acid
nucleotides
g blocks of nucleic acid. Exhibit tautomerism (isomerism): can be keto or enol.
Pyrimidines bases: cytosine, uracil, thymine. Purine bases: adenine, guanine DNA
bases: thymine, cytosine, adenine, guanine RNA bases: uracil, cytosine, adenine
, guanine.
buildin
Biopolymers
Enzymes Linked amino acid chains (proteins)
catalysts for biological reactions.
They reactions activation energy but do not change reaction equilibrium point, ar
e used up or changed in the reaction. May require cofactors or coenzymes. Cofact
or: inorganic (metal ion) or nonprotein organic molecule. Prosthetic group: cofa
ctor firmly bound to apoenzyme (protein portion of a complex enzyme). Coenzymes:
organic cofactor that is not firmly bound but actively involved in catalysis. H
oloenzyme: complete catalytically active enzyme system. Lyases: removes function
al group (deaminase, decarboxylase). Ligases: bind two molecules (e.g. DNA ligas
e 2 nucleotides). Isomerases: change D L, cis trans, vice versa. Polysaccharides Als
o called glycans. Long chain polymers of carbohydrates. Homopolysaccharides: Con
tains one type of monomeric units. Starch
plants reserve food, two glucose polyme
rs (linear water soluble amylose, and branched water insoluble amylopectin), enz
ymatic hydrolysis maltose (glucose disaccharide). Glycogen branched D-glucose ch
ain, polysaccharide storage in animal cells (liver, muscles). Cellulose
water so
luble, in plant cell wall, linear D-glucose chain, cant be digested (hydrolyzed)
by humans.
Lipid metabolism
Catabolism Triglycerides stores in fat cells (adipocytes) are hydrolyzed by horm
one-sensitive lipases into three fatty acids and glycerol Fatty acids: broken do
wn by beta oxidation to acetyl CoA
to Krebs cycle
breaks down to CO2, water and
energy release. Ketogenesis: very rapid break down of fatty acids leading to for
mation of ketone bodies (as in DM). Glycerol: enters glycolysis
oxidized to pyru
vate to Krebs cycle
CO2 and water. Steroids: may be converted to bile acids, vit
amin D, hormones. Anabolism Fatty acids: formed in the cytoplasm. Unsaturation o
ccurs I the mitochondria or endoplasmic reticulum. Essential fatty acids: linole
ic acid (can not be synthesized, diet is only sources). Terpenes: derived from a
cetyl CoA. Include: cholesterol, steroids, fat soluble vitamins (ADEK), bile aci
ds. Sphingolipids: forms a ceramide backbone with fatty acids. Joins with other
compounds to form cerebrosides, sphingomyelin Phosphatidyl compounds: i.e. phosp
hatidyl choline (lecithin), ethanolamine.
Nitrogen metabolism
Catabolism Amino acids: amino group is removed by transaminase. Carbon skeleton
is broken down to acetyl CoA or citric acid derivatives
oxidized to CO2 and wate
r for energy. Glycogenic amino acids form glucose as needed by guconeogenesis. P
urines: 90% is salvaged, 10% degrade to uric acid using xanthine oxidase. Pyrimi
dines: breaks down to B-alanine, ammonia, CO2 Anabolism Amino acids: from citric
acid cycle intermediates. Essential AA: TIM (threonine, isoleucine, methionine)
, HALL (histidine, arginine, lysine, leucine), PVT (phenylalanine, valine, trypt
ophan) PVT TIM HALL Purines / Pyrimidines: from aspartate, carbamoyl phosphate,
CO2, other AA.
Nitrogen excretion
Excess nitrogen is toxic
must be eliminated, mainly as urea. Urea synthesis: in
the liver using the Krebs-Henseleit pathway. Amino acid
AA transferases (transam
inases) + pyridoxine (vitamin B6) as coenzyme Ammonia
+ glutamate
glutamine
+ CO
2 carbamoyl phosphate
urea cycle urea. Uric acid synthesis: most purines are sal
vages. Remaining purines are excreted as uric acid.
9.
Microbiology
Taxonomy and nomenclature
Taxonomy
Classification or ordering into groups based on degree of relatedness. Bacteria
are named using the Linnaean or binomial system (genus species = homo sapiens =
human)
Morphology
Cultural morphology Based on size, shape and texture or colonies grown inj axeni
c (pure) cultures Each colony originates from a Colony Forming Unit (CFU) consis
ting of a single cell or group of adherent cells
Partial agonists: interact with same receptors but with similar affinity but low
er intrinsic activity
response. Pharmacologic antagonists: bind to the same rece
ptor as the agonist but with no intrinsic activity. Can be reversible, irreversi
ble, competitive, noncompetitive (like enzyme inhibitors). Chemical antagonists:
two compounds react inactivation of both. Example: heparin (acidic polysacchari
de) with protamine (basic protein), chelating agents as metal poisoning antidote
s (EDTA for calcium / lead, penicillamine for copper, dimercaprol for mercury /
gold / arsenic). Functional / physical antagonists: produce antagonistic physiol
ogic actions by binding at separate receptors. Example: acetylcholine, NEp.
Interaction with enzymes
Activation Due to enzyme protein synthesis. Examples: barbiturates, antiepilepti
cs (phenytoin), rifampin, antihistamines, griseofulvin, oral contraceptives. Mec
hanism: by allosteric binding or coezymes such as vitamins (esp vitamin B comple
x), cofactors (Na, , Mg, Ca, Zn, Fe). Inhibition Due to interaction with the apo
enzyme, coenzyme or enzyme. Reversible inhibition: results from non-covalent int
eraction. Equilibrium exists between bound and free drug. Irreversible inhibitio
n: results from covalent stable interaction. Competitive inhibition: occurs when
there is a mutually exclusive binding of the substrate and inhibitor. Noncompet
itive inhibition: occurs when the drug binds to an allosteric site on the enzyme
.
Interaction with DNA/RNA
Inhibition of nucleotide biosynthesis: caused by folate, purine, pyrimidine anti
metabolites. Folic acid analogs: e.g. methotrexate, trimetrexate, dihydrofolate
reductase
purine, thymidylate. Purine analogs: e.g. 6-mercaptopurine, thioguanin
e, act as antagonists in the purine bases synthesis. Pyrimidine analog: e.g. 5-f
luorouracil, thymidine synthase. Inhibition of RNA/DNA biosynthesis: due to inte
rference with nucleic acid synthesis. Use mainly as antineoplastic agents (Cance
r chapter).
Inhibition of protein synthesis
Tetracyclines: tRNA binding to ribosomes and block release of completed peptides
from ribosomes. Erythromycin, chloramphenicol: bind to ribosomes, peptidyl tran
sferase, formation of peptide bond, peptide chain formation Aminoglycosides: bin
ding to ribosomes
formation of abnormal protein, addition of AAs to peptide chai
n, misreading of mRNA tempelate
incorporation of incorrect AAs in peptide chain.
Interaction with cell membranes
Digitalis glycosides: cell membrane Na-K pump
K influx, Na outflow. Quinidine: p
rolong polarized and depolarized states of membrane potential in myocardial memb
ranes. Local anesthetics: interfere with membrane permeability to Na-K block imp
ulse conduction in nerve cell membranes. Polyene antifungals: e.g. nystatin, amp
hotericin B, alter membrane permeability. Antibiotics: e.g. polymyxin B, colisti
n, alter membrane permeability Acetylcholine: membrane permeability to cations.
Proton pump inhibitors: H+/K+ pump in parietal cell membranes
efflux of protons
to the stomach.
Nonspecific action
Form monomolecular layer over entire areas of cells. Large dose is given. Exampl
es: volatile general anesthetic gases (ether, nitrous oxide), some depressants (
ethanol, chloral hydrate), antiseptics (phenol, rubbing alcohol).
do
Anxiolytics / sedative-hypnotics
Examples: BZD (diazepam, alprozlam, flurazepam, halazepam, oxazepam, prazepam, l
orazepam, chlordiazepoxide, clorazepate), buspirone, zolpidem. Old drugs: barbit
urates, hydroxyzine no longer used due to risk of tolerance, dependence, withdra
wal reactions, and SE ( CNS depression). Diazepam: not basic enough to form water
soluble salt with acid
dissolve in propylene glycol for IV, may ppt if mixed wi
th water. Barbiturates: derivatives of barbituric acid. Long / branched / unsatu
rated side chain lipid solubility
metabolism, onset, duration of action, potenc
. Phenobarbital (barbiturates) strong enzyme inducer. Weak acids, in overdose
al
kalinize the urine excretion. BZD: Mechanism: GABA-ergic, chloride channel openi
ng chloride conduction
membrane hyperpolarization. Also CNS depression (hypnotic
, anesthetic, anticonvulsant, muscle relaxant, alcohol depression). Use: anxiety
, insomnia, pre-anesthesia, during acute alcohol withdrawal. SE: CNS depression,
ataxia, confusion, abuse / dependence. Buspirone (x-pirone): Mechanism: bind to
central dopamine, serotonin receptors. No CNS depression (hypnosis, anti-convul
sion, alcohol interaction, no abuse, no rebound anxiety). Use: anxiolytic (effec
t takes a week). SE: headache, dizziness. Zolpidem (Ambien): Mechanism: strong s
edation but anxiolytic effect (for insomnia). Use: insomnia. No abuse, rebound i
nsomnia, or respiratory depression.
Menotropin: produce ovarian follicular growth and induce ovulation by FSH and LH
-like actions. Use: induce ovulation and pregnancy in anovulatory infertile wome
n, spermatogenesis in men. SE: gynecomastia in men, hypersensitivity, thromboemb
olism, ovary enlargement.
Gonadal hormones
Estrogen
Estrogen receptors: in the nucleus in the vagina, uterus, mammary glands, anteri
or pituitary, hypothalamus
alter mRNA. Uses: oral contraceptives (with progestin
s), menopause symptoms, acne, osteoporosis, prostate cancer. SE: edema / fluid r
etention, weight gain, triglycerides, hypertension, thromboembolism, M I, stroke
, GI upset, endometrial cancer. Estradiol: principal estrogenic hormone, in equi
librium with estrone. Estradiol esters are used as IM injections in oil for depo
t action (valerate, cypionate). The esters hydrolyze slowly in muscle tissue bef
ore absorption (prodrugs). Synthetic estrogens: resist first pass metabolism
ora
l efficacy. Examples: ethinyl estradiol, 3methyl ether mestranol (contraceptives
), quinestrol (ERT). Non-steroidal synthetic estrogens: e.g. diethylstilbestrol.
Estrogen antagonists: e.g. clomiphene, tamoxifen citrate, toremifene citrate. U
ses: clomiphene
induce ovulation, tamoxifen
breast cancer. Aromatase inhibitors:
anastrozole, letrozole (non-steroidal) conversion of androgens to estrogens. Us
e: advanced breast cancer. Selective estrogen receptor modulators (SERM): raloxi
fene bone resorption, bone turnover. Estrogen effect on bone and lipids but estr
ogen antagonist effect on uterus and breast. Use: prevention of osteoporosis.
Progestins
Progesterone: C-21 natural steroidal progestin. Synthetic progestins: 17alpha-hy
droxyprogesterones, 17alpha-ethinylandrogens. lipid solubility, first pass metab
olism, oral effect Mechanism: similar to estrogens (intracellular receptors
mRNA
). Uses: oral contraceptives (alone or with estrogens), uterine bleeding, dysmen
orrhea, endometriosis. SE: irregular period, breakthrough bleading, amenorrhea,
weight gain, edema. 17alpha-hydroxyprogesterones: e.g. medroxyprogesterone aceta
te, megestrol acetate 17alpha-ethinylandrogens: e.g. norethindrone, norgestrel,
androgens with progesterone activity. Used as oral contraceptives.
Androgens / anabolic steroids
Testosterone: C-19 steroid natural androgen / anabolic agent. Androgens: testost
erone 17-enanthate (ester with long IM action), fluoxymesterone (oral). Anabolic
s: oxandrolone, dromostanolone. Mechanism: testosterone 5alpha-reductase (in cyt
oplasm) dihydrotestosterone
bind to androgen receptor in nucleus mRNA Uses: andr
ogen replacement, breast cancer, endometriosis, female hypopituitarism (with est
rogens), treating ve nitrogen balance, anemia. SE: fluid retention, LDL, HDL, fem
ale masculinity, female fertility. Anti-androgens: flutamide, bicalutamide, nilu
tamide (all non-steroids)
competitive androgen inhibition by receptor binding. U
se: prostate cancer (with luteinizing hormone releasing hormone). 5alpha-reducat
se inhibitors: finasteride conversion of testosterone to dihydrotestosterone. Us
e: BPH, androgenic alopecia.
Adrenocorticosteroids
Synthesis: in the adrenal cortex. All steroids have fused reduced 17-carbon-atom
ring. Most natural steroids have some mineralo- and gluco- effect. All require
cytoplasmic receptors to transfer to the nuclei of target tissue cells.
Uses: replacement therapy (adrenal insufficiency), last resort for severe disabl
ing arthritis, severe allergic reactions, ulcerative colitis, kidney disease, ce
rebral edema, topical anti-inflammatory. SE: peptic ulcer, GI bleeding, intraocu
lar / intracranial pressure, headache, muscle weakness, skin atrophy, edema, wei
ght gain, excitation, irritability, hypertension, hyperglycemia, osteoporosis, f
lushing, hirsutism, cushingoid moon face / buffalo hump, immunity, infections. M
ineralocorticoids: Na retention, K excretion. Glucocorticoids: anti-inflammatory
, protein-catabolic, immunosuppressant. Cortisone / hydrocortisone: natural gluc
ocorticoids. Synthetic and semi-synthetic glucocorticoids try to mineralocortico
id activity. Examples: prednisone, prednisolone, triamcinolone, betamethasone, d
examethasone. Aldosterone: natural mineralocoritoid. Synthetics: fludrocortisone
acetate, desoxycoriticosterone acetate.
Antianemic agents
Iron
Iron preparations: ferrous salts are better absorbed from GI than ferric salts.
Examples: ferrous sulfate, ferrous gluconate, ferrous fumarate. Iron dextran (IV
) = colloidal complex of ferric hydroxide and low molecular weight dextrans. Iro
n (ferrous salts): easy GI absorption
stored in bone marrow, liver, spleen as fe
rritin and hemosiderin incorporate into hemoglobin
iron reversibly binds molecul
ar oxygen. Iron (ferrous salts): iron deficiency anemia (hypochromic, microcytic
RBCs
poor oxygen transport). Cyanbocobalamin (Vit B12): nucleotide-like macro-m
olecule. Includes cyanide and cobalt. Iron (ferrous salts): GI distress, constip
ation, diarrhea, heartburn
Vitamin B12 (cyanocobalamin)
Vit B12: easy GI absorption in the presence of intrinsic (Castles) factor (glycop
rotein produced by gastric parietal cells). Deficiency causes megaloblastic anem
ia and demyelination of nerve cells
irreversible CNS damage. Important for cell
growth. Vit B12: megaloblastic anemia due to vit B12 deficiency (hyperchromic, m
acrocytic, immature RBCs). Vit B12: no common SE
Folic acid
Folic acid: structure includes PABA, glutamic acid. Folic acid: easy GI absorpti
on, stored intracellularly. Precursor for several coenzymes (derivatives of tetr
ahydrofolic acid). Deficiency causes megaloblastic anemia but not neurologic dam
age. Folic acid: megaloblastic anemia due to folic acid deficiency. Folic acid:
rare allergy if taken parenterally.
Thyroid hormones / inhibitors (52)
Synthesis of thyroid hormones
Concentration of iodide in thyroid gland iodination of tyrosine residues on thyr
ogobulin (glycoprotein)
proteolysis of thyroglobulin into T4 (thyroxine, levothy
roxine), and T3 (triiodothyronine, liothyronine). T4 is less potent but has long
er duration than T3. T4 converts to T3 by peripheral deiodination. Control: invo
lves hypothalamic-pituitary-thyroid feedback. TRH is secreted by hypothalamus
re
lease of TSH (thyrotropin) by the anterior pituitary production of T4/T3 in thyr
oid.
Thyroid preparations
Action: mimic the activity of endogenous thyroid hormones
regulate growth and de
velopment, calorigenic and metabolic activity, positive inotropic / chronotropic
effects (sensitize beta receptors). Use: hypothyroidism (e.g. Myxedema), Myxede
ma coma, cretinism, simple goiter, endemic goiter. SE: rare, palpitations, nervo
usness, insomnia, weight loss. Sodium salts of T4/T3. T4 can be given alone (con
verts to T3).
urine
protein diet
glycine, oxidative drug metabolism capacity. Diet in essential fatt
y acids (linoleic acid)
synthesis of certain enzymes metabolism of hexobarbital.
Diet in minerals (Ca, Mg, Zn) metabolism. Fe
metabolism. Diet in vitamins (A,
, C, E): C oxidation. E
dealkylation, hydroxylation.
Age
Metabolic enzyme systems are not fully developed at birth
doses in infants / chi
ldren to avoid SE, especially for glucuronide conjugation. Older children
liver
develops faster than in body weight efficacy. Elderly
metabolizing enzymes
nation Cp
SE
Gender
Due to androgen, estrogen, adrenocorticoid activity
idative metabolism is faster in men.
elim
Administration route
Oral: first-pass effect oral dose IV: by pass first-pass effect
dose compared to
oral dose. Sublingual / rectal: also bypass first-pass effect. Variable absorpti
on from rectal administration.
Chemical structure
Presence of certain functional groups influences drugs metabolic pathway (route,
extent, degree of metabolism).
Circadian rhythm
Nocturnal Cp of theophylline, diazepam are than diurnal Cp.
Extra-hepatic metabolism
Plasma: contains esterases (hydrolyze esters). Simple esters (procaine, succinyl
choline) are rapidly hydrolyzed in the blood. Esterases can also activate prodr
ugs. Intestinal mucosa: microsomal oxidation, conjugation (glucuronide, sulfate)
first pass effect of lipid soluble drugs during absorption. Intestinal bacteria
l flora: secrete metabolizing enzymes. Ulcerative colitis
flora. Diarrhea, antib
iotics flora. Flora secrete beta glucuronidase
hydrolyze polar glururonide conju
gates of bile
reabsorption of free nonpolar bile acids eneterohepatic circulatio
n. Flora convert vitamin K to active form, and cyclamate (sweetener) to cyclohex
ylamine (carcinogen). Flora produce azoreductase converts sulfasalazine to 5-ami
nosalicylic acid (anti-inflammatory) and sulfapyridine (antibacterial). Stomach
acidity: degradation of penicillin G, carbenicillin, erythromycin, tetracycline,
peptides / proteins (insulin). Nasal mucosa: CYP450 activity and metabolism on
nasal decongestants, anesthetics, nicotine, cocaine. Lung: first pass metabolism
of IV, IM, transdermal, SC drugs but to degree than the liver. Also, second pas
s metabolism for drugs leaving the liver. Placenta: if drug is lipid soluble eno
ugh to get to circulation
pass through the placenta too. Placenta is not a physi
cal or metabolic barrier to xenobiotics. Very little metabolism occurs. Smoking
induce certain enzymes in pregnant women carcinogens from polycyclic HC. Fetus:
depends on fetal age, glucuronic acid conjugation. Chloramphenical
glucuronidatio
n gray baby syndrome. bilirubin glucuronide
neonatal hyperbilirubinemia.
Site specificity
Methyldopa: structurally similar to L-dopa
transported to CNS
metabolized to act
ive alphamethyldopamine central alpha-2 agonist Omeprazole: activated at acidic
pH < 1 inhibition of H+/K+ATPase. Formaldehyde: effective urinary tract antisept
ic. Orally
toxicity. Methenamine
non-toxic prodrug
hydrolyzes to formaldehyde an
d ammonium ions in acidic urine (pH<5.5). Use enteric coating to prevent activat
ion in the stomach. Olsalazine: polar dimer of 5-aminosalisalyic acid
poor oral
absorption. In large intestine colonic bacteria cleave azo bond
free active. Die
thylstilbestrol: synthetic estrogen for prostate cancer feminizing SE. Diethylst
ilbestrol diphosphate (ester prodrug) activated by acid phosphatase in prostate
tumor cells local action, systemic SE.
shelf-life
Cefamandole: 2 generation cephalosporin, unstable in solid dosage forms. Cefaman
dole nafate: stable formic acid ester
hydrolyzed by plasma esterases. Cyclophosp
hamide: stable prodrug in vivo oxidation + nonenzymatic decomposition
active pho
sphoramide mustard.
nd
Drug interactions
Types of interactions: drug-drug, drug-food, drug-chemical, drug-laboratory. Pre
cipitant: drug, food or chemical causing the interaction. Object: drug affected
by the interaction. Epinephrine, erythromycin decompose in IV alkaline pH
do not
mix with aminophylline (alkaline).
PK interactions
Due to in absorption, distribution (protein / tissue binding), elimination (excr
etion / metabolism).
Absorption
Epinephrine (vasoconstrictor) percutaneous absorption of lidocaine (local anesth
etic). CHF GI blood flow
drug absorption MAO inhibitors + foods w/ tyramine metab
olism hypertensive crisis Antibiotics (erythromycin)
intestinal flora digoxin mic
robial deactivation
bioavailability. Antacids / H2 antagonists GI pH
ketoconazol
e dissolution intestinal motility (anticholinergics
, laxatives )
absorption Chol
styramine / kaolin digoxin adsorption
bioavailability Complexation by divalent c
ations tetracycline bioavailability
Distribution
Due to in plasma protein binding / displacement or tissue / cellular interaction
s. Valproic acid displaces phenytoin and its liver metabolism
phenytoin. Quinidin
e displaces digoxin and digoxin clearance digoxin.
Elimination / clearance
Due to in kidney or liver clearance (enzyme induction / inhibition, enzyme subst
rate competition, blood flow) . Grapefruit juice is a powerful inhibitor of CYP3
A4. Enzyme inducers: tobacco (polycyclic aromatic HC), barbiturates, rifampin, c
arbamazepine, phenytoin, omeprazole, troglitazone. Enzyme inhibitors: cimetidine
, ketoconazole, ciprofloxacin, erythromycin, ritonavir / nelfinavir, clopidrogel
.
Food-drug interactions
drug absorption. Example: Complexation of tetracycline + calcium
Names
USP Dictionary Unlisted Drugs USP DI Index Medicus X X X X
Search strategies
Is it a clinical or research-related question? Define as specifically as possibl
e. Identify appropriate index search terms (keywords, descriptors). Determine qu
antity and quality of needed information. Ascertain as much as possible about th
e drug and the inquirer. What is the drug indication? Is the drug approved or no
t? Patient information (age, sex, weight, medical conditions, other drugs, signs
of SE, allergies, etc).
Guidelines for responding to information requests
Do NOT guess Intended use of information (abuse, misuse). Organize information a
nd response first. Tailor to the inquirers background (e.g. public vs. profession
al).
Evaluating a clinical study
Study objective: was the objective clearly stated? One or more objectives? Study
subjects: profile of study population. Healthy subjects or patients? Degree of
disease severity if patients? Volunteers? Number / ID of subjects (sex, age, rac
e, etc)? Co-morbidities? Inclusion / exclusion criteria? Stratification can be u
sed in case of inter-patient variability. Administration of drug treatment: dose
, frequency, time of day, route, drug source, dosage form, timing vs. factors af
fecting absorption (e.g. food), duration. Study setting: environment, dates, typ
e of professionals making observations, inpatient vs. outpatient, length of stud
y. Study methods / design: are methods and design clearly described? Retrospecti
ve vs. prospective: Retrospective
examination of past events to find links betwe
en variables, relies on patient memory and accurate records, used for rare disea
se, may lead to a decision to conduct prospective study. Prospective looks forwa
rd in time, can be observational or experimental (clinical trials). Treatment al
location: Parallel different patient groups are studied concurrently, identical
treatment for all groups except for one variable. Crossover
good control of inte
r- / intra-patient variability, each group undergoes each treatment, with the se
quence reversed for one group vs. the other, includes a washout period. Control
measures: own control (crossover design), concurrent controls, stratification, m
atched subgroups, run-in period. Controls: blind assessment / blind patients (do
uble blind vs. open label (non-blind)), randomization, matching dummies (placebo
s), comparison (to placebo or standard drug). Analysis: appropriate statistical
methods should be used
22. Clinical Toxicology
Overview
Definitions
Clinical toxicology: studies the effects of substances on patients caused by acc
idental poisoning or intentional overdose of medications, abuse drugs, household
products or other chemicals. Intoxication: toxicity associated with any chemica
l substance Poisoning: clinical toxicity secondary to accidental exposure Overdo
se: intentional exposure to cause self-injury or death
Information resources
Computerized databases: Poisindex: CD database updated quarterly and used by poi
son control centers. TOMES: Toxicologic, Occupational Medicine and Environmental
Series
info on industrial chemicals. Printed publications: textbooks and manual
s are useful but suffer a lag time of information published in primary literatur
e. Internet: Center for Disease Control and Prevention, FDA, and National Librar
y of Medicine websites. Poison control centers: accredited by the AAPCC. Provide
s info for the public and health care providers. Most reliable and up to date so
urces of information.
General management
Supportive care
Evaluate and support vital functions as a first step until patient is stabilized
. Airway, Breathing, Circulation (ABC).
Patients with depressed mental status
Hypoglycemia: to rule out or treat 50 ml of 50% dextrose IV Glucose can ppt Wern
icke-Korsakoff syndrome in thiamine-deficient patients
give IV thiamine push. Op
iate: give naloxone IV push.
History of exposure
Identity: of ingested substance, route of exposure, quantity ingested, time sinc
e ingestion, symptoms of overdose, associated illness / injury. Neurologic exami
nation: seizures, altered consciousness, confusion, ataxia, slurred speech, trem
or, headache, syncope. Cardiopulmonary examination: syncope, palpitations, cough
, chest pain, shortness of breath, upper airway burning / irritation. GI examina
tion: abdominal pain, nausea, vomiting, diarrhea, difficulty swallowing. Past me
dical history: Rx/OTC drugs, herbal medicines, alcohol / drug abuse, psychiatric
history, allergies, occupational / hobby exposures, travel, domestic violence /
neglect. Routine lab assessment: Complete blood count (CBC), serum electrolytes
, BUN, serum creatinine, BG, urinalysis, ECG
Toxicology lab tests
Advantages: confirm or determine substance identity, predict severity of toxic e
ffects, may help guide therapy Disadvantages: diagnosis is not always specific,
not available for all poisons, supportive care is the first priority. Generally,
only qualitative determination is need. However, quantitative determination is
required for some substances (e.g metals, lithium, methanol, APAP, salicylate, t
heophylline, ethylene glycol)
Skin decontamination
Required when skin absorption may cause systemic toxicity or when contamination
substance may produce toxic effects (e.g. acid burns). Remove clothes, irrigate
area with plenty of water. DO NOT neutralized (exothermic reaction).
Gastric decontamination
Emesis Contraindications: children < 6 months, CNS depression, seizures, strong
acids / alkali, sharp object, compromised airway, coma, convulsions, HC or petro
leum distillates, patients already vomiting, substance that are very fast acting
.
Syrup of ipecac: consider only if within 60 (even 30) minutes since ingestion, o
therwise, no benefit. Onset of emesis: within 30 minutes, 3 vomiting episodes in
1 hour. SE: diarrhea, drowsiness, lethargy Gastric lavage Use: if patient is no
t alert or has gag reflex, if quantity was ingestion short while ago or if not re
sponding to ipecac Procedure: aspire gastric contents
instill 250 ml tap water o
r saline aspire
repeat until content is clear for 2 liters. Activated charcoal A
dsorbs the majority of substances. Always give ASAP. Exceptions: iron, lead, mer
cury, cyanide, lithium, ethanol, methanol, organic solvents, strong acids / alka
li. Form: colloidal dispersion with water or sorbitol. Avoid multiple doses of c
athartics may cause electrolyte imbalance, dehydration. SE: charcoal aspiration
avoid if vomiting, bowel obstruction with multiple doses.
Whole bowel irrigation
Effective when charcoal is not available / effective. Use osmotic cathartic solu
tion (e.g. PEG (Golytely, Colyte). Continue until rectal effluent is clear.
Forced diuresis / urine pH manipulation
Use: for substance with kidney elimination, Vd, protein binding Alkaline diuresi
s: ionization of weak acids (aspirin, long-acting barbiturates (phenobarbital))
kidney reabsorption elimination. Use IV sodium bicarbonate urine pH at 8.0, main
tain adequate urine output. SE: metabolic alkalosis, hypernatremia, hyperosmolar
ity, fluid overload. Acid diuresis: ionization of weak alkali (amphetamines, phe
ncyclidine, quinidine) kidney reabsorption
elimination. Use ascorbic acid (vitam
in C) or ammonium chloride urine pH at 5.0.
Dialysis
Last resort for decontamination. Hemodialysis or peritoneal dialysis. Hemodialys
is: used for water soluble substances with Vd, MWt, protein binding. Use for lif
e threatening ingestions of ethylene glycol, methanol. Can correct fluid and ele
ctrolyte abnormalities.
Hemoperfusion
Anticoagulated blood is passed through (perfused) a column containing activated
charcoal or resin particles. Quicker than hemodialysis. Can NOT correct electrol
yte / fluid abnormalities. Less effective for methanol / ethanol. SE: thrombocyt
openia, leukopenia, hypoglycemia, hypocalcemia.
Management of specific ingestions
Acetaminophen
Toxicokinetics: mostly metabolized in the liver (Cytochrome P450) toxic metabolit
e liver toxicity, especially in alcoholics / elderly. Symptoms: phase I (1 day):
nausea, vomiting, phase II (2 days): no symptoms, phase III (3 days): abdominal
pain, coma, death. Treatment: ipecac or gastric lavage (within 2 hr), N-acetylc
ystein (specific antidote, oral / IV). Metoclopramide: emesis during / absorptio
n of N-acetylcysteine therapy.
Alcohols
Ethylene glycol Forms: antifreeze, windshield deicing. Colorless, sweet taste.
Theophylline
Toxicokinetics: liver metabolism
highly variable (depends on age, other drugs, d
isease). Symptoms: nausea, vomiting, seizures, dysrhythmias. Acute toxicity
hype
rglycemia, hypokalemia. SE are due to cAMP. Treatment: supportive (maintain airw
ays, treat seizures, beta blocker (esmolol) treats tachycardia, disrhythmia), ip
ecac (if within minutes), repeated activated charcoal, whole bowel irrigation (i
f quantitiy), charcoal hemoperfusion or hemodialysis. Dosage forms: Toxicokineti
cs: Symptoms: Lab data: Treatment:
23. Federal Pharmacy Law
Federal Controlled Substances Act
Schedules of controlled substances
Drugs that have potential for abuse leading to physical or psychological depende
nce. Lists are published annually. US attorney general has the authority to modi
fy lists. Schedules II-V have accpeted medical uses but schedule I does not. Sch
edule II has the highest potential for abuse / severe dependence and Schedule V
has the least. Schedule I: drugs can not be kept in the pharmacy or dispensed ex
cept for authorized research or investigative reasons. Drugs with abuse potentia
l but no accepted medical use or esablished safety record. Examples: heroin, mar
ijuana, LSD, ecstacy, Schedule II: Highly restricted. Examples: morphine, oxycod
one, methyphenidate, amphetamine, methamphetamine, cocaine, opium, fentanyl, sho
rt acting barbiturates. Schedule III: Less potential for abuse / dependence than
CI or CII. Examples: anabolic steroids (testosterone, androgens), hydrocodone /
codeine with APAP / aspirin, intermediate acting barbiturates (talbutal). Sched
ule IV: Examples: BZD (diazepam, chlordiazepoxide, alprazolam, long acting barbi
turates (phenobarbital), propoxyphene, pentazocine, pemoline Schedule V: May be
available w/o Rx but sales are documented. Examples: small amounts of opium or c
odeine.
Registration requirements
All handlers of controlled drugs have to register with the DEA. DEA issues an Or
der To Show Cause to allow the registrant to appeal. Entities that must register
: wholesalers (annual renewals), dispensers (pharmacies, practitioners) (renew e
very 3 years). Pharmacists / pharmacy employees do not have to register. Registr
ation for separate activities: certain activies require separate registartion. E
xamples: manufacturing, distributing, dispensing, conducting research, narcotic
treatment programs, chemical analysis, importing / exporting, maintenance, dispo
sal, detoxification, packaging. Registration for separate locations: separate re
gistration for each pharmacy, pharmacy chain, clinic, hospital. Wholesalers do n
ot have to register if distributing to a registered location. Registration proce
dure: submit application to DEA by individual, partners, corporate officer, or p
erson with power of attorney. Registration action by the DEA: certificate of reg
istration is granted by DEA if appropriate, otherwise it may be denied. Modifica
tion of registration: e.g. for change of name, address, extension of authorized
activities, etc. Transfer of registration: not allowed except in case of pharmac
y ownership transfer.
Package inserts
Manufacturers insert: full disclosure is required by the manufacturer. Enclosed w
ith every commercial container. Contains essential informative and accurate scie
ntific information for safe and effective drug use. It cant be promotional in ton
e, false or misleading. Patient package insert: due to certain SE with certain p
roducts, patient inserts must be dispensed, including refills. That includes the
following: Oral contraceptives, IUDs, Estrogen products, Porgestational product
s, Isoproterenol inhalation products, Miscellaneous (e.g. Isotretinoin
serious f
etal harm if pregnant). For isoproterenol, label with Do not exceed prescribed do
se. Contact physician if difficult persists.
Prescription drug samples
Currently, sample distribution is very restricted. All sale, purchase, trade of
samples are banned. Sample records are maintained by the manufacturer for 3 year
s. Pharmacies can not accept samples. Importation after exporting is illegal.
Medical devices
Safety and effectiveness are required. Class I: reasonable assurance of safety a
nd quality Class II: no reasonable assurance of safety and quality, but has suff
icient info to establish controls to ensure safety and quality Class III: no rea
sonable assurance of safety and quality (generally, they can not be marketed). M
edical device tracking: required if failure may lead to serious SE. Tracking all
ows recalls. Manufacturers reports: manufacturer, hospitals, pharmacies, etc are
required to report to the FDA potential link to death or adverse SE. Misbranding
and adulteration: same as drugs
Poison Prevention Packaging Act
The Act (1970) require child-resistant containers for all drugs (difficult for c
hildren under age of 5 to open easily within short period of time). Enforced by
the Consumer Product Safety Comission. Requests for non-child resistant containe
r: request can be made by the prescriber in a specific prescription, but a blank
et request cant be made. Patient can request that for one or all Rx (does not hav
e to be in writing). Reuse of child-resistant containers: generally prohibited.
Allowed for glass containers when a new child resistant cap is used. Manufacture
rs packaging: no child-resistant container if the product will be repackaged by t
he pharmacist, but is required if product will be dispensed directly to the pati
ent. Exemptions for easy access: OTC non-child-resistant packaged can be sold as
long as child-resistant alternative is offered. Label For Households Withouth Ch
ildren or Package Not Child Resistant. Hospitals and institutions: the Act applies
to houshold substances (any substance produced or distributed for sale for consum
ption or use by individuals in the household). Act does not apply if drug is give
n by hosptial personnel and not directly dispensed to the patient. Miscellaneous
special packaging: such as furniture polish containing petroleum distillates, d
rain pipe cleaners, turpentine, pain solvents, lighter fluid.
Exceptions
Sublingual nitroglycerin and sublingual / chewable isosorbide dinitrate at low d
oses. Erythromycin ethylsuccinate granules for oral suspension ( doses). Oral co
ntracpetives / conjugated estrogen / norethindrone acetate in memory-aid (mnemon
ic) packages ( dose). Medroxyprogesterone acetate tablets. Anhydrous cholestyrami
ne powder. Colestipol powder ( dose) Potassium supplements (effervescent tablets,
liquid, powder) ( dose). Sodium fluoride (tablet / liquid,
dose). Betamethasone
tablets in dispenser packages ( dose).
Anti-Tampering Act
Act passed in 1984 due to death from OTC capsules containing cyanide. Applies to
consumer products (food, drug, device, cosmetic, other articles). OTC tamper-re
sistant packaging: required from some products (contact lens, ophthalmic solutio
ns). Contain a visible indicator of breach or tampering. Product / tamper-resist
ant technology design must be distinct to avoid easy duplication by commonly ava
ilable processes. OTC tamper-resistant labeling: clearly alert consumers to spec
ific tamper-resistant feature on the package. Medical devices and cosmetics: req
uired for certain products Violations: include tampering, false communication or
conspiracy for either.
Mailing Prescription Medications
All drugs, including narcotics, can be mailed by the physician or pharmacist. Pl
ace drugs in a plain outer container or securely wrap in plain paper. Make no ou
tside markings that indicate nature of content. Exception: do not mail flammable
liquids or alcoholic beverages.
Omnibus Budget Reconciliation Act (OBRA)
The US Constitution states that the federal government has no authority to regul
ate the practice of pharmacy (done by the states). Federal government can indire
ctly affect practice by attaching conditions of participation and reimbursement
for federally funded programs. Medicaid: Rx are paid jointly by federal and stat
e governments. Federal reimbursement require the pharmacist to get a patient and
medication history, conduct DUR, offer counseling to the patient. Manufacturers
best price: for manufacturers to participate in Medicaid, they must offer best pri
ce (lowest price for the purchaser).
Narcotic Treatment Programs
Methadone can be used as part of a total narcotic addition treatment program. Re
gulations were established by the FDA and DEA. It is used for maintenance or det
oxification. Facility has to be approved by the FDA, DEA and state authority. De
toxification treatment: dispensing a narcotic drug in
doses to withdrawal physio
logic or psychologic symptoms. Maximum period: 6 months. Maintenance treatment:
dispensing a narcotic drug at stable dosage levels to treat heroin or morphineli
ke dependence. Requirments for patient admittance: has been physiologically depe
ndent on a narcotic for one year and still is. Patient participation must be vol
untary. Patient has to sign Conset to Methadone Treatment after being infomred pro
perly. Take home methadone: only to patients, judged by the physician, are respo
nsible in handling narcotic drugs. Patient must come to the clinic for observati
on at least 6 days a week, then gradually
observations to once a week. Dispense
methadone as any CII drug.
24. Reviewing and dispensing prescriptions
Definitions
Prescriptions: orders for medications, non-drug products, and services. Practiti
oners may prescribe medications only in their field of practice. Information in
the Rx: patient name and address, date, name and dosage form of the product, pro
duct strength, quantity (directly or indirectly), directions to the pharmacist (
preparation, labeling), directions for the patient (quantity, schedule, duration
, avoid as directed), refill information (as needed means one year), prescriber info
rmation (signature, DEA if controlled). Medical orders: orders for medications i
ntended for use by patients in an institutional setting.
Information in medication order: patient information, date and time, name and do
sage form, product strength, route of administration, signature, directions to t
he pharmacist, instructions for administration.
Understanding the Rx
Understanding the order: all info must be understood and consistent, including d
isease condition, reason for treatment, type of units used. Evaluating appropria
teness: follow up if incomplete info was provided. Evaluate allergies, route of
administration, drug-drug / food / disease interactions, safety for intended use
, proper quantity and dosage, incompatibilities, legitimate prescriber. Discover
ing inappropriate Rx: Drug Utilization Review: review medication profiles to ens
ure appropriateness. Therapeutic intervention: calling the prescriber to discuss
concerns regarding the Rx. Following the intervention, the Rx may be dispensed
as written, with changes or not at all.
Processing the Rx
Involves use of technicians and automation, save pharmacists time for patient cou
nseling and education. Record Rx number, original date of filling, product and
quantity dispensed, pharmacists initials. Product selection: involves generic sub
stitution, formulary / therapeutic substitution policies. Product preparation st
eps: obtain proper medication amount, reconstitute if necessary, extemporaneous
compounding, assembly of delivery unit, selection of proper package or container
. Labeling: contains name and address of pharmacy, patients name, original date o
f filling, Rx number, directions for use, product name and manufacturer, product
strength, quantity dispensed, prescriber name, expiration date, pharmacist init
ials. Unit-dose packages: contain one dose or unit of medication, label identifi
es drug name, strength, lot#, expiration date. Auxiliary labels: to ensure prope
r medication use, storage, federal transfer of narcotics, etc. Record-keeping: i
nclude patient profile system that includes demographic information (allergies,
DOB, disease, weight, occupation, OTC use) and record of all medications.
Dispensing medication and counseling
Counseling patients: evaluate patients understanding, supply additional informati
on, proper use, storage, appearance, name, route of administration, duration of
use, reason for the Rx, SE (frequency, severity, actions to manage and minimize)
, OTC or food interactions. Counseling health professionals: especially in insti
tutional setting where the professional administers the drug. Other information:
cost, drug-drug or nutrition interactions, physical incompatibilities, interfer
ence with lab tests,
Patient monitoring
Pharmaceutical care plan: to frequency and benefits of desired outcomes. Include
s: assessment (review medical conditions and symptoms), plan (decision on approp
riate therapy), monitoring (review outcome goals and endpoints). Drug-related pr
oblems: unnecessary therapy, wrong drug, wrong dose, SE, poor compliance, need f
or additional therapy.
25. Sterile Products and Parenterals
Introduction
Sterile products: parenterals, irrigating solutions, ophthalmics Aseptic techniq
ue: preparation procedures to maintain sterility Pyrogens: metabolic byproducts
of live and dead microorganisms that cause fever upon injection. Tonicity: relat
ed to osmotic pressure. Hypotonic solution: osmotic pressure than blood or 0.9%
NaCl. Cause cells to expand
hemolysis, pain. Isotonic: exert same osmotic pressu
re as blood or 0.9% NaCl. Hypertonic: must be administered through a large vein
to avoid phlebitis and ensure rapid dilution. Clean rooms: areas constructed and
maintained to probability of environmental contamination of sterile products. T
hey have the following:
High-efficiency particulate air (HEPA) filters: used to clean the air entering t
he room. Remove all particulates < 0.3 mm with efficiency ~ 100%. HEPA filtered
rooms are Federal Class 10,000, i.e., they contain <10,000 particles 0.5 mm or l
arger per cubic foot of air. Positive-air pressure flow: used to prevent contami
nated air from entering a clean room. Counters: in the clean room are made of ea
sily cleaned nonporous material, e.g., stainless steel. Wall / floors: free from
cracks / crevices, rounded corners, made of nonporous material, easily disinfec
ted. Air flow: air moved with uniform velocity (90 fpm) along parallel lines. La
minar flow hoods: clean air work benches in clean rooms designed as aseptic envi
ronment for making sterile products (Class 100). Horizontal: air flow moves acro
ss the surface of the work area (disadvantage: no protection for the operator).
Vertical: advantages: air flows down on the work space, which protects the opera
tor, portion of the air is circulated a second time. Inspection / certification:
for clean rooms and laminar flow hoods is done annually or when moved. The dioc
tyl phthalate (DOP) smoke test ensures that no particle > 0.3 mm passes through
HEPA filter. Anemometer is used to measure air flow velocity and a particle coun
ter is used to count particles.
Sterilization methods and equipment
Thermal: using either moist or dry heat. Moist heat (autoclave): most reliable a
nd widely used. Microorganisms are destroyed by cellular protein coagulation. Mi
nimum 121 C for 15 minutes. Dry heat: minimum 160 C for 120 minutes. More potent
ial damage to product due to temperature. Chemical (gas): used for surfaces and
porous materials (e.g. surgical dressings). Ethylene oxide is used with gas and
moisture. Residual gas must be dissipated before product use. Radioactive: for i
ndustrial sterilization of products in sealed packages that can not be heated (e
.g. surgical equipment, ophthalmic ointments). Use either electromagnetic or par
ticulate radiation. May accelerate drug decomposition. Mechanical (filtration):
removes but does not destroy and clarifies solutions by eliminating particulates
. Depth filter: consists of fritted glass or unglazed porcelain. Membrane (scree
n) filter: with thickness of 1-200 mm. A mesh of millions of microcapillary pore
flow rat
s filter the solution by physical sieving. Pores make up 75% of surface
e than depth filters. Particulate filters (0.5-5 mm): remove particles or glass,
rubber, plastic, etc. Used to risk of phlebitis by removing undissolved particl
es of reconstituted powders, cannot be used for blood, emulsions, suspensions,
colloids. Microbial filters (<0.22 mm): ensures microbe removal (cold sterilizat
ion). Either filter can be used as part of the tubing in drug administration (in
-line filter).
Packaging
Ampules: made entirely of glass. Single use. Disadvantages: glass fragments may
contaminate the product during opening must be filtered, not multiple use. Not c
ommonly used now. Vials: glass or plastic closed with a rubber stopper and seale
d with aluminum crimp. Advantages: can be multiple use (if bacteriostatic agent
is added), easier to remove product, no glass fragment risk, no need for filtrat
ion. Disadvantages: coring of rubber stopping can get into product, multiple use
can cause microbial contamination. Drugs that are unstable in solution are pack
aged in solid form and must be reconstituted with a diluent (sterile water or Na
Cl) before use. Lyophilization (freeze drying) can be used to dissolution rate a
nd permit rapid reconstitution. Double chamber system: one chamber with sterile
water for injection is separated from unreconstituted drug chamber by rubber clo
sure no need to enter vial twice
contamination risk. Add-vantage system: drug is
in a vial attacked to an IV bag for reconstitution. Add-vantage vial is screwed
into the top of Add-vantage IV bag and rubber diaphragm is dislodged to allow t
he mixing. Prefilled syringed: for immediate drug administration in an emergency
(epinephrine, atropine). Prefilled cartridges: ready to use parenteral packages
with accuracy and sterility. Used for narcotics. Infusion solutions: Small Volu
me Parenterals (SVP): volume < 100ml. Large VP (LVP): volume > 100ml. Packaging
materials: Glass: clarity for easy inspection, interaction with content. Plastic
polymers: durability, easy storage / disposal, weight, safety, e.g., PVC and po
lyolefin.
Routes of administration
Subcutaneous: usually in the arm or thigh. Example: insulin.
Intramuscular: e.g. mid-deltoid, gluteus medicus, < 5ml. Used for prolonged or d
elayed absorption (e.g. methylprednisolone). Intravenous: most important and com
mon, immediate therapeutic response, no recall of inadvertent overdose, e.g., an
tibiotics, cardiac drugs. Intradermal: only very limited volume, e.g., skin test
s and vaccines. Intra-arterial: deliver drug concentration into target side with
little dilution by circulation, e.g., diagnostic radiopaque materials and antin
eoplastics. Hypodermoclysis: injection of large volumes of solution into SC tiss
ue to provide continuous abundant drug supply, e.g., antibiotics for children. I
ntraspinal: e.g. local anesthetics during surgery (lidocaine, bupivacaine). Intr
a-articular: injection into joint space, e.g., corticosteroids (hydrocortisone,
methylprednisone) for arthritis. Intrathecal: injection into the spinal fluid, e
.g., antibiotics, cancer chemotherapy.
Parenteral preparations
IV admixtures: one or more sterile drug product added to an IV fluid.
IV fluids
Used in preparation of parenteral products (vehicles for IV admixtures). Dextros
e (d-glucose): 5% dextrose in water (D5W). Used for reconstitution, as hydrating
solution. Higher concentration dextrose (e.g. D10W) provide source of carbohydr
ates in parenteral nutrition. pH of D5W is 3.5-6.5
instability of acid-labile dr
ugs. Concentration > 15% give through central vein. Use cautiously in DM. Sodium
chloride: usually as 0.9% solution
isotonic (normal saline). NaCl 0.45% is half
-normal saline. Used for admixtures, fluid and electrolyte replacement. Bacterio
static NaCl for injection (0.9%): for multiple reconstitutions (bacteriostatic b
enzyl alcohol, propylparaben, methylparaben). Water: for reconstitution and dilu
tion of NaCl, dextrose. Use Sterile or Bacteriostatic Water for Injection. Ringe
rs solution: used post-surgically for fluid and electrolyte replacement. Lactated
Ringers (Hartmanns solution): contains sodium lactate, NaCl, KCl, CaCl2, may be c
ombined with D5W. Ringers injection: does not contain sodium lactate, may be comb
ined with D5W.
IV electrolytes
Cations: Sodium: main extracellular cation, important for interstitial osmotic p
ressure, tissue hydration, acid-base balance, nerve-impulse transmission, muscle
contraction. Examples: Na chloride, acetate, phosphate. Potassium: main intrace
llular cation, important for muscle (esp cardiac) contraction, neuromuscular exc
itability, protein synthesis, carbohydrate metabolism. Examples: potassium chlor
ide, phosphate, acetate. Calcium: important for nerve impulse transmission, musc
le contraction, cardiac function, bone formation, cell membrane permeability. Ex
amples: calcium chloride, gluconate, gluceptate. Magnesium: important for enzyme
activities, muscle excitability, neuromuscular transmission. Example: magnesium
sulfate. Anions: Chloride: main extracellular anion. With sodium, it controls i
nterstitial osmotic pressure, blood pH. Examples: sodium, potassium, calcium chl
oride. Phosphate: main intracellular anion. Important for enzyme activities, con
trolling calcium levels, buffer to prevent changes in acid-base balance. Example
s: sodium, potassium phosphate. Acetate: bicarbonate precursor used as alkali to
preserve plasma pH. Examples: sodium, potassium acetate.
Parenteral antibiotics
Route: direct IV, short term IV infusion, IM, intrathecal. Use: serious infectio
ns requiring concentration, GI is inaccessible.
Parenteral antineoplastics
May be toxic and hazardous during prep, administration. Safe handling: use verti
cal laminar flow hood, syringes and IV tubing with Luer-Lok fittings, closed-fro
nt cuffed surgical gowns, double layered gloves, negative pressure technique, fi
nal dosage adjustment with care, special care priming IV sets, prime before addi
ng the drug, special disposal, wash hands, monitor health of personnel. Patient
problems: Infusion phlebitis: vein inflammation, pain, swelling, heat sensation,
site redness, avoid by drug dilution and filtration. Extravasation: infiltratio
n of the drug into SC tissues surround the vein. Response: local hydrocortisone
or anti-inflammatory, antidote with cold compress, warm compress to blood flow a
nd wash vesicant away from damage tissue.
Parenteral biotechnology products
Examples: monoclonal antibodies, vaccines, colony-stimulating factors. Uses: can
cer chemotherapy, HIV, hepatitis B, infections, transplant rejection, rheumatoid
arthritis, inflammatory bowel, respiratory diseases. Characteristics: protein a
nd peptide biotechnology drugs: short t1/2, special storage (freezing, refrigera
tion), avoid vigorous shaking not to destroy protein molecules. Route: direct IV
, IV infusion, IM, SC. Require reconstitution.
Irrigating solutions
Manufactured by the same standards for IV products but not intended for injectio
n. Labeling differenced specified in USP, i.e., different acceptable particulate
matter levels, volume, container design. Topical administration: packaged in po
ur bottles into desired. For irrigating wounds, moistening dressings, cleaning s
urgical instruments. Infusion: e.g., perfuse tissues to maintain integrity of su
rgical field, remove blood, clear field of view as in urologic surgeries. Add Ne
osporin G.U. irrigant, an antibiotic, to risk of infection. Dialysis (dialysates
): e.g., in renal failure, poisoning, electrolyte disturbances. They remove wast
e matter, serum electrolytes, toxic products. Peritoneal dialysis: hypertonic di
alysate (dextrose, electrolytes) is infused in the peritoneal cavity via surgica
lly implanted catheter
remove toxins by osmosis and diffusion
finally drain. Ant
ibiotics, heparin may be added. Hemodialysis: patients blood is transfused throug
h a dialyzing membrane that removes toxins.
Needles and syringes
Hypodermic needles
Stainless steel or aluminum. Gauge: the outside diameter of the shaft. Large num
ber (27) small diameter (13). SC: 24-25. IM: 1922. Compounding: 18-20. Bevels: sl
anting edges cut into needle tips to facilitate insertion. Regular bevel: most c
ommon, for SC, IM. Short bevel: used onlyfor shallow penetration (IV). Intraderm
al bevel: most beveled. Lenghts: from to 6 inches, depending on desired penetrat
ion. IV: 1 - 2 inch. Compounding parenterals: 1. Intradermal / SC: . Intra-cardiac:
3.
Syringes
Glass or plastic barrel and tight-fitting plunger, small opening to accommodate
needle. Luer syringe: oldest, universal attachment for all needle sizes. Syringe
volumes: 0.3 60 ml. Insulin syringes have unit graduations (100 units/ml) rathe
r than volume graduations. Calibrations: may be metric or English, vary dependin
g on size. Syringe tips: Luer-Lok: threaded to ensure needle fit tightly, for an
tineoplastic drugs. Luer-Slip: unthreaded so needle does not lock into place, ma
y be dislodged. Eccentric: set off center to allow needle to remain to injection
site and minimize venous irritation. Catheter: used for wound irrigation and en
teral feedings and not for injections.
Temperature: temp
degradation. Use fridge or freezer. Degree of dilution: diluti
on ion interaction
incompatibility. Length of time in solution: time
chance of
ncompatibility Order or mixing: do not add incompatible drugs in sequence (e.g.
calcium, phosphate), mix well. Preventing incompatibilities Administer solutions
quickly after mixing, mix each drug well after addition, number of mixed drugs,
consult references.
Hazards of parenteral drug therapy
Physical Phlebitis: usually a minor problem, minimize by proper IV insertion tec
hnique, dilution of irritating drugs, infusion rate. Extravasation: caused by ve
sicant drugs Irritation: by varying injection site and applying moisturizer Pain
: common with peripheral infusion of concentration drugs, by diluting the drug o
r switching to central vein. Air embolism: can be fatal Infection: critical in c
entral IV lines, can be local or systemic (septicemia). Allergic reaction: due t
o hypersensitivity to IV solution, additive Central catheter misplacement: may c
ause air embolism or pneumothorax, verify proper placement radiologically Hypoth
ermia: due to shock or cardiac arrest, may be due to cold IV solution, injection
solution at room temp only. Neurotoxicity: serious problem in intrathecal / int
raspinal injection of drugs containing preservatives (avoid preservatives) Mecha
nical Pump/controller failure: may cause fluid overload, incorrect dose, or runa
way infusion. IV tubing: can become kinked, split, cracked, produce particles Gl
ass containers: may break
injury Rubber vial closures: may interact with drug so
lution Particulate matter Therapeutic Drug instability: may lead to therapeutic
ineffectiveness Incompatibility: may cause toxicity or effectiveness Labeling er
rors: may cause using incorrect drug or dosage Drug overdose: may be caused by r
unaway IV infusion, pump / controller failure, nursing / pharmacy errors. Preser
vative toxicity: can be serious, esp in children. Example: benzyl alcohol in pre
mature infants gasping syndrome (fatal acidotic toxic state).
Quality Control / Quality Assurance
Quality control: day-to-day assessment of all operations including analytical te
sting of raw materials and finished product. Quality assurance: oversight functi
on, involves the auditing of QC procedures and systems. Sterility testing: USP s
tandard calls for 10-test samples from large batches, minimum of 2 samples from
small batches. Test conducting using membrane sterilization method
membrane is c
ultured for microbial growth. Pyrogen testing: qualitative fever response in rab
bits or in vitro limulus lysate testing. Clarity testing: to check for particula
te matter. Swirl and look it against light source and dark background. QA progra
ms: include training, monitoring the manufacturing process, QC check, documentat
ion. Process validation: a mechanism for ensuring processes consistently result
in sterile products of acceptable quality. Includes written procedures, evaluati
on of aseptic technique by process simulation.
Elimination Kidney is the major route of elimination for water soluble drugs and
metabolites. Processes involved: glomerular filtration, tubular secretion, tubu
lar reabsorption. Filtration and secretion eilimination, reabsorption eliminatio
n. All processes are in neonates. Renal blood flow (important for glomerular fil
tration) is in neonates. Only unbound drugs undergo glomerular filtration.
Problems in drug monitoring
Therapeutic monitoring depends on correlation between serum concentration and th
erapeutic effect. The relationships are established for adults and may not work
for infants. Side effects: Most common with antibiotics (vancomycin, penicillins
, cephalosporins), anticonvulsants, narcotics, antiemetics, contrast agents. Exa
mples: red-man syndrome with vancoymcin, syndrome of inappropriate antidiuretic
hormone (SIADH) with carbamazepine. Dosing consideration: Body surface area = sq
uare root of (height x weight / 3600). Dose intervals: may be longer for neonate
s and shorter for older children.
Pregnancy
Fetal development
Withdraw all unnecessary medications 3-6 months before plans for conception. Bla
stogenesis: first 2-3 weeks after fertilization. Germ formation occurs. Embryoni
c cells are undifferentiated. Organogenesis: 2-8 weeks. Most critical period of
development as organs start to develop. Drug exposure may cause major congenital
malformations. Fetal period: 9 weeks to birth. At 9 weeks, the embryo is called
a fetus. Maturation and growth occurs. Low risk of major congenital malformatio
ns.
Placental transfer of drugs
Functions of placenta: nutrition, respiration, metabolism, excretion, endocrine
activity to maintain fetal and maternal well being. In order for a drug to cause
teratogenic or pharmacological effect, it has to pass from the maternal circula
tion to the fetal circulation through the placenta. Placenta is not a protective
barrier: most substances pass the placenta by passive diffusion due to concentr
ation gradient. Placenta acts similar to any other lipid membrane. Factors affec
ting drug transfer: Molecular weight: (< 500 dalton)
cross easily, large (hepari
n) does not cross. pH: weakly acidic and weakly basic drugs cross easily. Lipid
solubility:
cross easily. Most oral drugs are designed for optimal lipid membran
e transfer. Drug absorption: during pregnancy
gastric tone and motility
delayed
gastric emptying absorption. Drug distribution: during pregnancy
Vd with gestati
onal age, fat content, total body fluid. Plasma protein binding: only free unbou
nd drugs cross placenta. Albumin and alpha1-acid glycroprotein are during pregna
ncy free drugs. Placenta membrane becomes thinner with gestational age. Blood fl
ow with meals, exercise, drugs and may placental crossing. Embyotoxic drugs: may
terminate or shortens pregnancy, especially in early pregnancy. Examples: ACE i
nhibitors, hormones, antidepressants. st Teratogenic drugs: risk of teratogenesi
s is highest during the 1 trimester
physical malformations, mental abnormalities
. Teratogenic effect depend on the time during gestation when the drug is taken,
and organs developing at this point. FDA Classification: Category A (safety doc
umented in humans), Category B (safety documented in animals, or safe in humans
but damaging in animals), Category C (human safety unknown, may be damaging in a
nimals), Category D (damaging in humans, only use in life-threatening situations
), Category X (highly damaging in humans and may be animals, absolute contraindi
cation). Examples: vitamin A derivatives (isotretinoin), ACE inhibitors, warfari
n (use heparin instead), estrogens, androgens, thyroids (methimazole, carbimazol
e, propylthiouracil), cortisone, ethanol (Fetal Alcohol Syndrome, FAS), antibiot
ics (tetracycline (teeth), metronidazole, quinolone), anticonvulsants (phenytoin
, valproic acid, sodium valproate, trimethadione), lithium (Ebsteins anomaly), an
tineoplastics (methotrexate, cyclophosphamide, chlorambucil, busulfan), finaster
ide (avoid handling of tablets and semen of male users). Fetotoxic drugs: more l
ikely during fetal period (9 weeks to birth). CNS depression (barbiturates, tran
quilizers, antidepressants, narcotics), Neonatal bleeding (NSAIDs, anticoagulant
s, use Tylenol
Ketones
Usually absent in urine. Excreted when body has used available glucose stores an
d began to metabolize fat due to uncontrolled DM, or due to carbohydrate diet
onuria. Ketone bodies: betahydroxybutyric acid (major), acetoacetic acid, aceton
e.
Ket
Microscopy
Hematuria: presence of RBCs may indicate trauma, tumor, systemic bleeding. Squam
ous cells indicated vaginal contamination due to menstruation in women. Casts: p
rotein conglomerations may be due to renal disease. Crystals: pH-dependent, uric
acid crystals in acidic urine, phosphate crystals in alkaline urine. Bacteria:
usually absent in urine (sterile), if present may be due to UTI or urethral cont
amination.
Renal function tests
Renal function with age. Use results to adjust drug dosage if needed. renal func
tion urea / creatinine excretion
their blood levels. Azotemia/uremia: retention
of nitrogenous waste (BUN / creatinine) in blood. Renal azotemia: due to renal d
isease, e.g. glomerculonephritis. Prerenal azotemia: due to dehydration, protein
intake, hemorrhagic shock. Postrenal azotemia: tumors or stones in the uterers,
urethra, prostate. Clearance: volume of plasma from which a measured amount of
substance is eliminated (cleared) into urine per unit time. Use to measure glome
rular function
BUN (blood urea nitrogen)
Urea: end product of protein metabolism, produced in the liver. Urea is filtered
at the glomerulus, then 40% is reabsorbed at the tubules
urea clearance is 60%
of true GFR Normal BUN: 13 mg/dl. BUN: due to liver disease BUN: due to renal di
sease, renal blood flow, protein intake.
Serum creatinine
Creatinine: metabolic breakdown product of muscle creatine phosphate Normal leve
l: 1 mg/dl, but varies based on the muscle mass Creatinine excretion: by glomeru
lar filtration and tubular secretion. serum creatinine renal insufficiency. 50%
in GFR doubling of serum creatinine.
Creatinine clearance
Rate at which creatinine is removed from blood by the kidney. Normal value: 100
ml/min (100 ml of blood cleared of creatinine / min). Creatinine clearance paral
lels GFR, more sensitive than BUN. Creatinine clearance = (urine creatinine conc
entration x urine rate) / serum creatinine. Cockroft and Gault equation: used to
estimate Clcr based on body weight, age, gender, and serum Cr when urine inform
ation is N/A.
Electrolytes
Sodium
Major extracellular cation. Cellular osmosis and water balance: controlled by so
dium, potassium, chloride and water. Normal level: 140 mEq/L. Concentration is a
ratio of Na to water. Na
water balance not electrolyte balance. Na control: by
antidiuretic hormone (ADH) and aldosterone. Hypothalamus release ADH from pituit
ary gland
renal reabsorption of sodium.
Magnesium
Second most abundant intracellular and extracellular cation. Role: activates enz
ymes for carbohydrate / fat / electrolyte metabolism, protein synthesis, nerve c
onduction, muscle contraction. Normal level: 2 mEq/L. Hypomagnesemia: more commo
n, due to GI absorption, GI fluid loss, renal loss. Signs: weakness, tremor, ref
lexes, arrhythmia. Hypermagnesemia: due to Mg intake with renal insufficiency, A
ddisons disease. Signs: bradycardia, flushing, sweating, Ca.
Summary table Indicator RBC Count Hematocrit (packed cell volume) Hemoglobin Poi
kilocytosis Anisocytosis Mean corpuscular volume Normal 4.5 million/mm3 45% (~3x
Hb) 15 g/dl RBC shape RBC size 90: average RBC size, (Hct / RBC count) 35: avera
ge Hb / RBC Normal distribution 1% immature RBCs (reticulocytes) 10 mm/hr High i
n men, erythropoiesis as in hypoxemia in men, polycythemia, dehydration in men s
ickle-cell anemia folic acid, iron deficiency anemia folic acid or vitamin B12 d
eficiency anemia Low
anemia, blood loss, overhydration anemia
iron deficiency anemia hypochroma (pale RBCs), iron anemia
Mean cell Hb concentration RBC distribution width Reticulocyte count
anemia (iron, folic acid, vitamin B12 deficiency) hemolytic anemia, acute blood
loss in females, acute or chronic infection, rheumatoid arthritis, tissue necros
infection (esp. bacterial), leukemia, tissue nec
is, MI, malignancy Leukocytosis
rosis Neutrophilic leukocytosis bacteria (pneumonia), viral, fungi, stress, rheu
matism, drug hypersensitivity, tissue necrosis, leukemia Lymphocytosis viral inf
ection Basophilia
leukemia Monocytosis TB, bacterial endocarditis Eosinophilia
cute allergy, parasite infection
drug-induced aplastic anemia
Erythrocyte sedimentation rate
WBC Count
7000 / mm3
Neutrophils
Leukocytopenia bone marrow depression due to cancer, lymphoma, antineoplastic dr
ugs Neutropenia (<1000/mm3)
overwhelming infection, chemothrepay Lymphocytopenia
severe debilitating disease, immunity, AIDS
Lymphocytes
Basophils Monocytes Eosinophils
Platelet Count
225,000 / mm3
Thrombocytopenia (disease or drugs) acute MI (necrosis), skeletal muscle damage
MI injury, prognosis of unstable angina MI, liver / lung disease biliary obstruc
tion (bile duct stone), Pagets disease, osteomalacia, hyperparathyroidism Acute h
epatitis, cirrhosis, fatty liver, liver congestion (as in CHF). severe liver dam
age, less sensitive / more specific than
Creatinine kinase (CK) Cardiac troponins Troponin-T<0.1 Toponin I < 1.5 ng/ml.
Lactate dehydrogenase (LDH) Alkaline pohsphatase (ALP)
AST Liver enzymes Total serum bilirubin (Indirect / unconjugated + direct conjug
ated) Direct serum bilirubin (conjugated) Serum proteins LDH/ALP/AST/ ALT (above
) 0.5 mg/dl liver dysfunction / damage Jaundice (hemolysis, biliary obstruction,
liver cell necrosis) biliary obstruction, liver cell necrosis ( bilirubin may al
so show in urine
dark urine) (not bound to albumin, secreted to bile, filtered)
Liver disease, nephritic syndrome, cystic fibrosis) Brownish-yellow
conjugated b
ilirubin Acidic: vitamin C, ammonium chloride diabetes insipidus ( urine concentr
ation).
0.1 mg/dl 7 g/dL
Urine color pH Specific gravity Protein Glucose Ketones RBCs Squamous cells Cast
s Crystals Bacteria Blood urea nitrogen Serum creatinine Creatinine clearance So
dium
Clear yellow to deep gold Slightly acidic (6) 1.015 65 mg/24 hr. 180 mg/dl None
None None None None None 13 mg/dl. (60% of GRF) 1 mg/dl 100 ml/min 140 mEq/L
Red blood or phenolphthalein Alkaline: acetazolamide, bicaronaturia DM, glucose
or protein (nephrosis) in urine glomerular permeability, infection, disease Glyco
suria: due to DM Ketonuria: uncontrolled DM trauma, tumor, systemic bleeding vag
inal contamination due to menstruation protein conglomerations due to renal dise
ase Acidic uric acid crystals Alkaline
phosphate UTI, urethral contamination rena
l disease, renal bl. flow, protein intake renal insufficiency Na intake, hyperton
ic IV, dehydration, diabetes insipidus, Na drug (Na bicarb), mineralocorticoid).
intake, cellular breakdown (hemolysis, burns, infections), metabolic acidosis,
K sparing diuretics, ACE-I metabolic acidosis, intake, dehydration, renal failure
metabolic alkalosis, hypoventilation, bicarbonate intake, diuretics. parathyroi
d, vitamin D, thiazides, Pagets disease, intake, malignancy, metastasis, vitamin
D, parathyroid, renal insufficiency intake, renal insufficiency, Addisons disease
.
liver disease (protein is broken to urea in liver) renal insufficiency kidney di
sease, dietary intake, water intake, overhydration, mineralocorticoid, SIADH K i
ntake, vomiting, diarrhea, laxative abuse, diuretics, glucosuria, metabolic alka
losis, insulin / glucose, mineralocorticoids fasting, diarrhea, vomiting, diuret
ics metabolic acidosis, renal failure, hyperventilation, diarrhea, carbonic anhy
drase inhibitors, salicylate, methanol parathyroid, vitamin D, loop diuretics vi
tamin D, parathyroid, malnutrition / anabolism, aluminum antacids, Ca acetate, a
lcoholism GI absorption, GI fluid loss, renal loss
Potassium
140 mEq/L (only 10% extracellular)
Chloride Bicarbonate
100 mEq/L 25 mEq/L
Calcium
10 mg/dl
Phosphate
4 mg/dl
Magnesium
2 mEq/L
Mechanism: Na and also K channel blocker. SE: GI upset, diarrhea (use Al hydroxi
de), Narrow therapeutic index (target 3 ug/ml). Toxicity:
conduction SA block. C
inchonism: tinnitus, hearing loss, blurred vision, photophobia, diplobia, psycho
sis. CI: AV block, prolonged QT interval (may cause torsades, quinidine syncope
and sudden death). dose in liver dysfunction and elderly. DI: cause digitalis to
xicity, severe BP with vasodilators, alkalinizers cause
toxicity. Procainamide I
V/IM (acute) and as SR orally (long term therapy). N-acetylprocainamide: active
metabolite. SE: SLE (arthlagia, myalgia, fatigue), anticholinergic,
GI upset tha
n quinidine. Narrow therapeutic index (target 7 ug/ml). Toxicity: ventricular ar
rhythmia, conduction SA block. CI: procaine hypersensitivity, myasthenia gravis,
prolonged QT interval, torsades, AV block, SLE.
dose in CHF (due to
Vd), in kid
ney or liver damage. Disopyramide SE: ventricular dysfucntion, anticholinergic (
dry mouth, constipation, etc). Targel level: 3 ug/ml. Used orally CI: AV block,
cardiogenic shock, CHF, myasthenia gravis. Class IB Lidocaine IV/IM. For arrhyth
mia due to MI and heart surgery SE: hemodynamic compromise, CNS (dizziness, resl
tessness, tremors, convulsions), tinnitus, blurred vision. Target: 4 ug/ml. Toxi
c metabolites (glycinexylidide). DI: toxicity with phenytoin and beta blockers.
Phenytoin Orally or IV. To treat digitalis-induced arrhythmia (mostly), acute MI
, heart surgery. SE: SLE, gingival hyperplasia, nystagmus, CNS (drowsiness, atax
ia, vertigo), cardiac SE. Target: 14 ug/ml. Chronic use can cause toxicity. Mult
iple drug intractions
toxicity. Hypersensitivity reactions: blood, skin, Stevens
-Johnson, and liver. Tocainide Similar structure to lidocaine except taken orall
y (avoid in lidocaine hypersensitivity). SE: CNS (dizziness, restlessness, tremo
rs, confusion), GI upset, diarrhea, blurred vision, blood. Target: 6 ug/ml. Mexi
letine Similar structure to lidocaine but
first-pass metabolism
taken orally. SE
: dizziness, ataxia, BP,
QRS complex, blood, liver. Toxicity: tremor. Target: 1
ug/ml. Class IC Prolong QRS complex, slow of phase 0 (rapid depolarization) and
slow conduction, no effect on repolarization. May
mortality due to pro-arrhythmi
c effect use is questionable. Orally. Flecainide: Use only in refractory life-th
reatening ventricular arrhythmia. SE: -ve inotropic effect (CI in CHF), CNS (diz
ziness, headache, tremor), GI upset, blurred vision. Target: 1 ug/ml. Propafenon
e: SE: dizziness, headache, GI upset, bitter taste. Target: 0.5 ug/ml. Moricizin
e: SE: dizziness, headache, GI upset. IC: CV (arrhythmia esp in MI), eye toxicit
y (blurring, diplobia)
+
+
Class II (beta blockers)
Approved drugs for arrhythmia: propranolol, esmolol, acebutolol
Risk factors: hyperlipidemia (cholesterol > 200 mg/dl, LDL > 130 mg/dl, HDL < 35
mg/dl), hypertension, smoking, diabetes, obesity, family history, sedentary lif
e style, chronic stress type A personality, age, male gender, oral contraceptive
s, gout. Factors that O2 demand: exercise, smoking, cold temp.
Etiology
1. blood flow: atherosclerosis with or without coronary thrombosis is the most c
ommon cause. Coronary arteries are progressively narrowed by smooth muscle cell
proliferation and accumulation of lipid deposits (plaque). Coronary artery spasm
is a sustained contraction that can occur spontaneously or induced by irritatio
n (catheter, hemorrhage), cold exposure, ergot drugs. The spasm can cause Prinzm
etal angina or MI. Traumatic injury such as impact of steering wheel on the ches
t. Embolic events can also occur abruptly. 2. blood oxygenation: blood oxygen ca
rrying capacity in anemia. 3. oxygen demand: can occur with exertion or emotiona
l stress (sympathetic stimulation). Systole: two phases (contraction and ejectio
n). Contractile (inotropic) state affects oxygen requirement. ejection time
oxyg
en demand.
Angina Pectoris
Episodic reversible oxygen insufficiency. May be caused oxygen imbalance (tachyc
ardia, anemia, hyperthyroidism, hypotension, arterial hypoxemia). . Patient comp
laints: squeezing pressure, sharp pain, burning, aching, bursting, indigestion-l
ike discomfort, radiating pain to the arms / legs / neck / shoulders / back. Phy
sical examination: usually not revealing, especially between attacks. Note histo
ry, risk factors, description of attacks, precipitation patterns, intensity, dur
ation, relieving factors. Treat risk factors: Hypertension should be controlled.
Obesity should be through diet and exercise. Smoking should be stopped, but wat
ch for anxiety. Quitting results in 50% in morality. Transdermal nicotine patche
s helps quitting over 10 weeks using decreasing doses of nicotine. Nicotine gum
and bupropion can also be used. Also, clonidine. Types Stable (classic / exertio
n) angina: most common form, usually due to a fixed obstruction in a coronary ar
tery. Triggered by exertion, emotional stress or heavy meal and relieved by rest
or nitroglycerin. The pain builds a peak radiating to the jaw, neck, shoulder,
arms and then subsides. Prinzmetals angina (vasospastic or variant angina): due t
o coronary artery spasm ( blood flow). Initially occurs at rest, pain may disrupt
sleep. Calcium channel blockers are preferred over beta blockers. Nitroglycerin
may not help. Unstable angina: due to significant coronary artery vasospasm and
platelet aggregation. Characteristics: may occur at rest, response to nitroglyc
erin, pattern change / severity. Progressive unstable angina may signal imminent
MI. Immediate hospitalization required. Nocturnal angina (angina decubitus): oc
curs in the recumbent position and is not related to rest or exertion. Occurs du
e to ventricular volume ( demand). Relieved by diuretics ( left ventricular volume
). Nitrates may improve nocturnal dyspnea. Diagnostic tests ECG: normal in 60% o
f patients. May show Q-wave, T-wave inversion, ST segment. Stress / exercise ECG
: helps diagnose patients with normal ECG. ST -segment. 201 99m Stress perfusion
imaging: with thallium or technetium sestamibi. Expensive. Pharmacologic stress
test: when coronary artery disease is suspected but patient cant exercise. Use I
V dipyridamole, adenosine ( AV conduction), dobumatime to induce cardiac ischemia
in ECG. Coronary arteriography / cardiac catheterization: very specific, sensit
ive, invasive, expensive, risky (2% mortality rate). Antihyperlipidemics Bile ac
id sequestrants: Cholestyramine chloride is a basic anion-exchange resin. Colest
ipol HCl is a copolymer. Mechanism: insoluble, nonabsorbable, hydrophilic, anion
-exchange resins bind bile acids in the intestine bile acid synthesis from chole
sterol cholesterol depletion. SE: bad taste (before
Other drugs: Maximal therapy: nitrate, CCB, beta blocker combination. Morphine:
in unstable angina when nitroglycerin fails. Aspirin: use indefinitely in stable
and unstable angina. Heparin/enoxaparin/dalteparin: with aspirin in unstable an
gina.
Myocardial infarction
Severe prolonged deprivation of oxygen to part of the heart
irreversible necrosi
s. Usually due to occlusive thrombus near a ruptured atherosclerotic plaque. May
lead to ventricular fibrillation (most disorganized arrhythmia) cardiac arrest
and death (sudden death syndrome). Mortality rate: 30%. Signs and symptoms: Pers
istent severe chest pain or pressure (crushing, squeezing, elephant heavy). Pain
s beings in the chest and may radiate to the left arm, neck, leg, etc. Onset of
pain is not associated with exertion. Unlike in angina, pain persists > 30 minut
es and is not relieved by nitroglycerin. MI may be silent (no pain). Other sympt
oms: anxiety, impending doom, sweating, GI upset. Complications Lethal (ventricu
lar) arrhythmia: arrhythmias resistant to lidocaine may respond to procainamide
and bretylium. CHF: left ventricular failure pulmonary congestion
diuretics. Dig
oxin contractility, compensate for heart damage. Cardiogenic shock: due to cardi
ac output. Occurs when area of infarction > 40% and compensatory mechanisms are
ineffective. Vasopressors (alpha stimulants to BP) and inotropes may be used. Us
e vasodilators (nitropursside) to preload and afterload. Intra-aortic balloon pu
mp may be used. Diagnostic tests Because MI is life threatening emergency, diagn
osis is presumed and treatment is initiated based on complaints and immediate 12
-lead ECG. Serial 12-lead ECG: abnormalities may be absent in the first few hour
s. ST elevation. Ventricular premature beats and ventricular arrhythmia are the
most common arrhythmia. Cardiac enzymes: creatine kinase (MB-CK) is elevated wit
hin hours, peaks at 24 h and back to normal at 72 h. Cardiac troponin I and T (c
TnI, cTnT) patterns are similar to MB-CK but more sensitive. 99m Lactase dehydro
genase (LDH) use is not longer common. Cardiac imaging include tc pyrophosphate
scintigraphy, myocardial perfusion, radionucleotide ventriculography, coronary a
ngiography. Treatment: Nitrates: may chest pain anxiety and catecholamine releas
e ( coronary spasm less in oxygen demand). Morphine: causes venous pooling and pr
eload, cardiac workload, oxygen consumption (IV). Drug of choice to MI pain and
anxiety. SE: orthostatic hypotension, respiratory depression, constipation (use
docusate). Vagomimetic effect
bradyarrhythmia (if excessive
reverse using atropi
ne). Oxygen: Three liters/min via nasal cannula for chest pain, hypoxia and isch
emia Warfarin: for treatment of acute MI to mortality, prevent recurrence, compl
ications (stroke). Target INR: 2.5-3.5. Antiplatelet agents: abciximab, eptifiba
tide, tirofiban platelet glycoprotein receptors. Beta blockers: propranolol, met
oprolol, atenolol. Given in early acute MI to oxygen demand, cardiac workload, i
schemia, infarction
post MI mortality. ACE inhibitors: after MI to exercise capa
city, mortality in case of CHF, ventricular remodeling. Antihyperlipidemics: cho
lesterol MI mortality. Calcium channel blockers: avoid in acute MI or in left ve
ntricular malfunction. incidence of reinfarction. Dipyridamole: relax smooth mus
cles, coronary vascular resistance (blood flow). Also, anti -platelet action. Use
d for angina pectoris prophylaxis. SE: BP, headache, dizziness. Others: intra-ao
rtic balloon, coronary angiography, PTCA.
Thrombolytic agents Atherosclerotic plaques are made of lipids and fibrous prote
ins. Lesion rupture triggers release of serotonins, thromboxane A2 and adenosine
diphosphate alteplase
platelet aggregation
clot. The resulting fibrin traps RBC
s, platelets, plasma proteins to form thrombus. Clot dissolution is caused by co
nversion of plasminogen to plasmin mediated by plasmingoen activators. Use as ea
rly as possible (<12 h after pain starts). Absolute CI: internal / eye hemorrhag
e, intracranial / intraspinal injury, pregnancy, aneurysm, hypertension. Recombin
ant tissue plasminogen activator (t-PA): front-loaded regimen (IV bolus then inf
usion). Streptokinase (SK): SE: systemic antibody formation
chances of refractor
y response and allergy if repeated within 6 months (avoid if unknown). Monitor f
or bleeding, reperfusion arrhythmia (within 30 min), hypotension, anaphylaxis. O
ther thrombolytic agents: reteplase, tenecteplase, anisoylated plasminogen strep
tokinase activator complex (APSAC). Post thrombolysis adjunctive therapy: antipl
atelet and anticoagulant therapy after reperfusion to prevent reoccolusion, isch
emia and reinfarcation. Aspirin: during thrombolyic therapy post-infarct mortali
ty. Also: clopidrogel, ticlopidine, dipyridamole. Heparin: with thrombolytics to
prevent reocclusion after reperfusion, mortality in MI. Give bolus then infusio
n. Goal: maintain APTT (activated partial thromboplastin time) at 1.5 20 times c
ontrol. Avoid combining with streptokinase ( bleeding). Give SC, but not IM. Alte
rnatives: MWt heparins (enoxaparin, dalteparin).
39. Hypertension
Pathophysiology
Arterial pressure = cardiac output X Peripheral Resistance Cardiac output = hear
t rate X stroke volume Conditions that increase stroke volume: fever, aortic reg
urgitation, thyrotoxicosis Starling s Law: ventricular stretch
myocardial contra
ctility blood volume returning ventricular dilation Initiators of baroreceptor r
eflexes: stretch receptors located in the wall of large chest and neck arteries
Causes of hypertension: Cushing s disease, oral contraceptives, acromegaly, poly
cystic kidney disease Hypertension of unknown etiology: essential hypertension,
toxemia of pregnancy, acute intermittent porphyria Essential hypertension: unkno
wn cause (90% of cases). Chronic vasoconstriction ( tone). Endocrine hypertension
: pheochromocytoma (tumor causing in catecholamine release) Renal hypertension:
chronic pyelonephritis. Neurogenic hypertension: familial dysautonomia Other cau
ses: aortic coarctation Factors causing systolic hypertension with wide pulse pr
essure: stroke volume. aortic compliance Anesthetized patients receiving antihyp
ertensives responses to body position changes and acute blood loss, altered respo
nses to sympathomimetic drugs Perioperatively: antihypertensive drug treatment s
hould be maintained Rapid increases in BP vagal center excitation
negative iontro
pic effect ( contractility), negative chronotropic effect ( heart rate). Africans:
use Ca channel blockers and diuretic (CaD) (ACE inhibitors/beta blockers less ef
fective) Generally, avoid prescribing two drugs from the same therapeutic class.
Effectiveness of antihypertensive drugs is highly unpredictable, requires dose/
drug adjustments. Withdrawal antihypertensives gradually to reduce SE (e.g. MI w
ith b-blocker) Elderly: esp. vulnerable to CNS SE, orthostatic hypotension. Lowe
r doses may be needed.
Diuretics
Use: recommended (with beta blockers) as initial therapy for BP. Diuretics are a
lso used for CHF, edema, fluid retention. Precaution: take during the day to avo
id interruption of sleep due to frequent urination. May raise lithium level (CI)
Thiazide diuretics
Examples: Chlorthiazide, hydrochlorthiazide, cyclothiazide, polythiazide, trichl
ormethiazide, methyclothiazide, hydroflumethiazide, benzthizide, bendroflumethia
zide, chlorthalidone, metolazone, indapamide. Structure: most are related to sul
fonamides. + Mechanism: Act on Na /Cl co-transporter at the distal convoluted tu
bule. Other actions: directly dilate arterioles, total fluid (extravascular) vol
ume, cardiac output. Effects: + 1. urinary excretion of Na / water due to Na / C
l reabsorption + 2. urinary excretion of K and bicarbonate
hypokalemia potassium
dietary intake, use supplements / potassium sparing diuretics 3. blood glucose (
hyperglycermia, care with diabetics), uric acid retention (hyperuricemia, care w
ith gout), serum lipids (hyperlipidemia), calcium levels (hypercalcemia) 4. effe
ct on other antihypertensives by re-expansion of extracellular / plasma volumes.
SE: electrolyte imbalance (K, Mg, Ca dehydration, postural hypotension, dizziness, h
eadache, fatigue, hypovolemic shock, arrhythmia, palpitation), metabolic alkalos
is, K muscle cramps, light sensitivity / rash (use sunscreen), uric acid / gout,
lipoproteins, BG, sulfonamide hypersensitivity. Interactions: NSAIDs (e.g. ibup
rofen) renal perfusion
effect of thiazides. Sulfasenstivity. Hyperlipidemia
risk
of coronary artery disease. Digitoxin ( toxicity due to hypokalemia) urinary Ca
excretion use for kidney stones (calcium nephrolithiasis). Metolazone: most effe
ctive thiazide diuretic. Chronic use water reabsoprtion polyuria and polydipsia in d
iabetes insipidus (ins tead of ADH) (??)
Loop (high-ceiling) diuretics
Examples: furosemide, torsemide, bumetanide (all are sulfonamide derivatives), e
thacrynic acid. Most intense, shortest duration action. Use: patients intolerant
/ irresponsive to thiazides, or with renal imp airment ( golmerular filtration ra
te). Very strong diuretics not routinely used for hypertension. Used in edema in C
HF / liver cirrhosis / kidney disease / lungs, hypercalcemia + + Mechanism: Bloc
ks Na /K /2Cl co-transporter in the thick ascending limb of Loop of Henle (lumin
al + + 2+ 2+ side) excretion of water, Na , K , Ca , Mg , Cl
metabolic alkalosis.
BG, blood lipids, uric acid. SE: dehydration, BP, hypovolemia, K, Ca, metabolic
alkalosis, uric acid, BG, lipids, tinnitus, transient hearing loss (CI aminoglyc
osides), sulfonamide hypersensitivity, blurred vision, blood toxicity, distal tu
bular hypertrophy (with chronic use). Interactions: like thiazeds NSAIDs (e.g. ibu
profen)
effect, aminoglycosides
ototoxicity, digoxin toxicity ( K).
Potassium sparing diuretics
Examples: spironolactone, amiloride, triametrene. + Use: when if K loss and not
corrected by supplements. May combine with thiazides / loops to balance potassiu
m. Least potent diuretics. Uses: prevent hypokalemia from thiazide / loop diuret
ics, edema from CHF, liver cirrhosis, hyperaldosteronism (Spironolactone). + + +
Triamterene, amiloride mechanism: block Na channels at collecting duct
Na excha
nge with K + + and H K and H excretion
alkaline urine. Triamterene SE: hyperkale
mia, headache, dizziness, uric acid, dihyrofolate reductase
methemoglobinemia in
case of alcoholic cirrhosis. CI: history of kidney stones Spironolactone: synth
etic steroidal competitive inhibitor of aldosterone at mineralocorticoid recepto
rs at the collecting duct sodium-potassium exchange
potassium excretion
alkaline
urine use in hyperaldosteronism. SE: gynecomastia, hirsutism, menstrual disrupt
ion, lethargy, hyperkalemia. Interactions: ACE inhibitors and potassium suppleme
nts risk of hyperkalemia. Renal impairment.
Osmotic diuretics
Examples: mannitol, glycerin, urea Mechanism: highly polar, water soluble inert
chemicals, freely filtered at the glomerulus but poorly reabsorbed from renal tu
bules
osmolarity of glomerular filtrate
tubular reabsorption of water
+ diuresis
water, Na , Cl , bicarbonate excretion
alkaline urine.
Compensation
Sympathetic response: cardiac output
sympathetic activation
Ep, NEp
heart rate,
blood flow to vital organs (brain, heart). Hormonal stimulation: sympathetic blo
od flow redistribution renal perfusion
glomerular filtration rate
sodium / water
retention, activation of renin-angioensin-aldosterone system more sodium retent
ion, volume expansion. Concentric cardiac hypertrophy: ventricular remodeling. F
rank-Starling mechanism: blood volume cardiac chamber stretch to accommodate exc
ess fluid (distention) contractile force to expel fluid to the arteries.
Decompensation
Over time, compensatory mechanisms become exhausted and ineffective
viscous cycl
e of compensation compensation become self-defeating. Afterload: tension in vent
ricular muscles during contraction, amount of force needed for the ventricle to
overcome pressure in the artery, also called intravascular systolic pressure. Prel
oad: force exerted on the ventricular muscle at the end of diastole that determi
nes degree of muscle stretch, also called ventricular end diastolic pressure. As f
luid volume demand on exhausted pump fluid backup
symptoms of CHF.
Clinical evaluation
Symptoms are due to blood backing up behind the failing ventricle. Symptoms are
first related to the failing side, then to both sides. Left-sided CHF Blood cant
be pumped from the left ventricle to the peripheral circulation
left ventricle c
ant accept blood from left atrium and lung blood back up in pulmonary alveoli pul
monary edema. Symptoms: dyspnea, less effort to trigger exertional dyspnea, whee
zing cough, exertional fatigue, nocturia. Paroxysmal (sudden) nocturnal dyspnea
and orthopnea result from volume pooling in the recumbent position relieved by p
ropping with pillow or sitting upright. Physical findings: Crackles indicate air
movement through fluid-filled passages, tachycardia (early compensatory mechani
sm). Diagnostic tests: cardiomegaly (heart enlargement), left ventricular hypert
rophy, pulmonary congestion. Right-sided CHF Blood cant be pumped from the right
ventricle to the lung
right ventricle cant accept blood from right atrium and cir
culation blood back up in whole body
systemic edema.
fl
Dietary controls
Small frequent meals with calories metabolic demand sodium (3g/d) to volume. Edu
cation patient about sodium containing products (antacids, NSAIDs, sodium bicarb
onate, baking soda, water softeners).
Drug-related actions
ejection fraction can be achieved by: 1. Directly heart contractility using inot
ropic agents: dopamine, dobutamine, milrinone, amrinone. 2. resistance to ejecti
on by relaxing peripheral blood vessels: vasodilators such as hydralazine, nitro
prusside, nitrates 3. Affecting cardiac remodeling: ACE inhibitors, beta blocker
s, vasodilators (nitrates). Addressing the underlying problem is more important
than symptoms.
Digitalis glycosides (Digoxin)
Source: Plant steroidal glycosides. Digoxin: from Digitalis lanata; Digitoxin: f
rom Digitalis pupurea; Ouabain: from Strophanthus gratus. Chemistry: Sugar (glyc
one portion) + steroidal nucleus (aglycone/genin portion) bonded with glycoside
(ether) linkage. hydroxyl groups polarity protein binding / liver biotransformatio
n / renal reabsorption duration of action. Ouabin v. short duration only IV. + + +
+ Mechanism: Inhibit Na /K ATPase
intracellular Na , intracellular K , calcium e
ntry +ve inotropic effect, CO, renal blood flow (perfusion)
deactivate RAAS
diur
esis, edema, prolongs PR interval in EKG. Also: vagal tone in SA node -ve chronot
ropic effect, CNS sympathetic flow, systemic vasoconstriction. Use: CHF, left ve
ntricular systolic dysfunction, rapid atrial fibrillations / flutter, paroxysmal
atrial tachycardia. (CI in ventricular fibrillation / flutter). Dosage forms: t
ablet, capsule, injection, elixir. Dosing: Rapid digitalization: IV in acute nee
d, steady state in 1 day. Slow digitalization: orally, steady state in 1 week. S
erum levels: first sharply and then sharply as drug enters the heart. Measure af
ter 5 hr of dosing (steady state). Target: 1 ng/ml. Potassium: antagonize digita
lis effect. potassium
digitalis toxicity. DI with potassium altering drugs (diur
etics, ACE inhibitors). Magnesium: inversely related to digitalis effect ( Mg tox
icity) (similar to potassium). Calcium: digitalis inotropic effect. calcium
arrh
ythmia. Metabolism: in the kidneys. Serum creatinine affects elimination. Toxici
ty: common due to narrow therapeutic index. Can be fatal. toxicity with quinidin
e, verapamil, amiodarone. Early: GI (anorexia, diarrhea, nausea, vomiting), CNS
(headache, confusion, delirium, muscle weakness, fatigue, visual disturbance). L
ater: ventricular fibrillation / flutter, AV block, atrial tachycardia, prematur
e ventricular contraction. Treatment of toxicity: d/c digitalis and any potassiu
m depleting drug, give potassium IV if hypokalemic, treat arrhythmia with lidoca
ine IV, cholestyramine to prevent absorption (binds digitalis), purified digoxin
-specific Fab fragment antibodies.
ACE inhibitors
For long term, not acute, management of CHF. First line agents. Mechanism: enzym
e for converting angiotensin I to angiotensin II (potent vasoconstrictor)
total
peripheral resistance afterload. angiotensin II also aldosterone release
sodium
/ water retension
venous return and preload.
Vasodilators
Mechanism: afterload (artery dilation) / preload (venous dilation) pulmonary con
gestion, cardiac output. Nitroprusside: IV, dilates both veins and arteries. Pra
zosin: alpha-1 blocker, dilates both veins and arteries. Hydralazine: dilates ar
teries. Nitrates: dilates veins. Higher dose for CHF than for angina.
Beta blockers
For long term, not acute, management of CHF. Only carvedilol (Beta-1-2-Alpha-1 b
locker) is approved for CHF. Actions of norepinephrine: peripheral vasoconstrict
ion, sodium retention by the kidney, cardiac hypertrophy, arrhythmia, hypokalemi
a, cell death (apoptosis) due to stress.
Calcium channel blockers
No evidence of benefit in CHF symptoms. Do not use. Verapamil is particularly co
ntraindicated because of the significant ve inotropic effect. Nifidipines are les
s dangerous (no heart effect)
41. Thromboembolic Disease
Introduction
Defintion: venous thromboembolic disease (VTED) occurs when elements of the Virc
hows triad (vascular injury, venous stasis, hypercoaglate state ( protein C / S, a
ntirhombin III)) are present resulting in deep venous thrombosis (DVT) and pulmo
nary embolism (PE). Incidence: total is 500K, symptomatic is 250K. Risk factors:
patient specific (age>40, obesity, varicose veins, immobility, pregnancy, dose
estrogen, hypercoagulate state, lupus anticoagulant), illness / surgery (pelvic
/ hip / lower limb trauma or surgery or cancer, MI, heart failure, inflammatory
bowel, sepsis, kidney disease, polycythemia).
hypotension
desmopressin, pain amitriptyline, depression / dysphagia
liquid levo
dopa, daytime sleepiness selegiline. Definitions: Dyskinesias: reversible jerky
movements. On-off effect: oscillations in response and sudden changes in mobilit
y from no symptoms to full symptoms within minutes. End-dose (wearing-off) effec
t: may improve by shortening the dosing interval. Drug holiday: temporary d/c of
levodopa to reverse down-regulation of dopamine receptors and regain efficacy.
Individual drugs
Anticholinergic agents
Examples: benztropine, trihexyphenidyl (both structurally related to atropine),
biperidene, procyclidine, orphenadrine. Use: mild symptoms, esp. tremors (not br
adykinesia / pos. imbalance). Mechanism: block action of acetylcholine in basal
ganglia. SE: dry mouth,
sweating (
heat tolerance), urinary retention, constipati
on (use stool softener), delayed gastric emptying, intraocular tension, GI upset
, dizziness, agitation, hallucinations, hypotension. CI: obstructed GI or GU, gl
aucoma, cardiac disease. Avoid drugs with anticholinergic activity (antihistamin
es, antidepressants, phenothiazines),
digoxin level. Avoid combo with haloperido
l ( tardive dyskinesia severeity, schizophrenia,
haloperidol level).
Dopamine precursor (Levodopa/carbidopa)
Most effective. effect / SE in 4 years. Dopamine cant cross BBB (not used). Mecha
nism: Levodopa: converted by dopa decarboxylase to dopamine
dopamine in CNS (cro
sses BBB). Carbidopa: levodopa analog that does not cross BBB
peripheral decarbo
xylation of levodopa
peripheral SE,
CNS bioavailability, dose needed by 75%. SE:
due to peripheral conversion to dopamine (GI upset, arrhythmia, postural hypote
nsion). Others: hallucinations, psychosis, blood dyscriasis, GI upset, insomnia
CI: glaucoma, may activate malignant melanoma. Pyridoxine (vit B6)
peripheral de
caroxylation effect. MAOI hypertension. TCA / Food
absorption. Metoclopramide:
le
vodopa level. General dopamine agonist SE: BP, syncope, arrhythmia, insomnia, ha
llucinations, psychosis.
Direct acting dopamine agonists
Ergot alkaloids (ergolines): bromocriptine, pergolide. Others: pramipexole, ropi
nirole. All mimic dopamine effect (direct agonist). Bromocriptine SE: first-dose
cardiovascular collapse (postrual hypotension, fainting, tachycardia, dysrhythm
ias, dizziness), hallucinations, pulmonary toxicity, GI upset. V. long t1/2. res
ponse variability. Pergolide Mechanism: semisynthetic ergosine derivative. 1000x
more potent than bromocriptine. prolactin,
LH,
growth hormone. SE: dysrhythmias
, BP, hallucinations, insomnia, GI upset CI: 90% protein bound (cautious with ot
her protein bound drugs), antipscychotics contradictory effects. Non-ergot dopam
ine agonists Examples: pramipexole, ropinirole Mechanism: bind to dopamine D2/D3
receptors. Also, antioxidant/O2 free radical scavenger, moderate antidepressant
. Start dose and gradually to titrate best balance of efficacy / SE. Also d/c gr
adually. levodopa dose if used together. SE:
compared to non-selective agonists
(motor fluctuations, dyskinesia). Orthostatic hypotension, syncope, bradycardia,
hallucinations, GI upset,
met
Major Depression
Incidence: more in women (2x men). 15-20% chance in womans lifetime. Etiology: Bi
ogenic amine theory: due to depletion of serotonin and norepinephrine. Dysregula
tion theory: cyclic nature of depression is due to impaired balance of neutrotra
nsmitters not absolute or . Familial history plays a role. Clinical depression: m
ood,anhedonia, appetite , weight , sleep , psychomotor , fatigue, worthlessness,
ild, thinking / concentration, suicidal Diagnosis: using Diagnostic and Statisti
cal Manual (DSM) IV criteria. Patient must have persistent symptoms for 2 weeks.
Treatment:
Psychotherapy, pharmacotherapy, and electroconvulsive therapy. Pharmacotherapy w
ith antiderpssants is 50-60% effective. It has three phases: acute (6 wk, resolv
e symptoms), continuation (6-9 months, prevents relapse) and maintenance (3 or >
years, prevents recurrence). Drug selection: all drugs are equally effective wi
th different mechanisms and SE. Select drug with SE profile that complements the
disease process. For example, depression with psychomotor agitation sedative an
tidepressant, depression with psychomotor retardation
activating antidepressant.
Therapy initiation: start with half of the lowest dose to minimize SE to target
range in 1-2 weeks, then titrate based on response. GRADUAL. Lag time exists be
tween therapy initiation and clinical response due to changes in postsynaptic re
ceptor sensitivity. Resolution of anxiety and insomnia in 1-2 week. Full effect
in 4-6 weeks. Serotonin syndrome: tremor, seizure, hyperreflexia, hypomania, agi
tation, fever, diarrhea, confusion. May occur when two serotonin enhancing drugs
are used concomitantly or close to each other (e.g. MAOI, SSRI). Serotonin with
drawal syndrome: lethargy, myalgia, chills, dizziness, flu-like symptoms Tricycl
ic Amines (TCA) Examples: amitriptyline, nortriptyline, protriptyline, imipramin
e, trimipramine, desipramine, doexpin Serum concentrations are established for s
ome drugs. Mechanism: blocks serotonin and norepinephrine reuptake. Also bind to
cholinergic, histaminergic, alpha-adrenergic receptors (SE). SE: anticholinergi
c (blurred vision, dry mouth, constipation, urinary retention), alpha blockade (
orthostatic hypotension), antihistamine (sedation, take at bedtime), seizure thr
eshold, ECG changes, lethal if overdoes. Not first choice for depression. Other
uses: neuropathic pain, insomnia. Monoamine oxidase inhibitors (MAOI) Examples:
phenelzine, tranylcypromine, isocarboxazid. Mechanism: monoamine oxidase
block b
reak down of biogenic amines serotonin and norepinephrine in the brain Not first
choice for depression. Only for depression with agitation, hypersomnia, anxiety
. SE: orthostatic hypotension, weight gain, edema, sexual dysfunction. Isocarbox
azid liver damage. May result in accumulation of sympathomimetic amines
hyperten
sive crisis CI with decongestants, foods with tyramines (aged cheese, wine). MAO
: 2 wk washout period before start or when D/C.
Treatment
Acute, maintenance and continuation phases (like depression). Antipsychotics, an
tidepressants, and mood stabilizers may be used. Antipsychotics: short term ther
apy during acute mania to psychosis and agitation. Antidepressants: use for depr
ession with suicidal tendency. Use cautiously to avoid triggering mania. Lithium
First line therapy (except for mixed episodes or rapid cycling). Monovalent cat
ion like Na and K. Citrate salt
liquid, carbonate salt tablet. Food may delay ab
sorption. Take with food to avoid rapid rise in serum concentration and SE. High
ly distributed but takes 3 days
delayed response. Eliminated through the kidneys
with no metabolism. nd Mechanism: unknown. norepinephrine / serotonin, membrane
stabilization, cAMP / cGMP (2 messengers). Dose: narrow therapeutic index. Can
be used to acute mania ( and dose gradually, quick action for mania but slow for
deperssion) or preventative maintenance (mania, depression). Require Cp monitori
ng. If high dose psychosis, psychomotor agitation
give BZD or antipsychotics. SE
: . Monitor Cp. Categorized into early, long term, and toxicity. Polydipsia, polyur
ia, nocturia, dry mouth, weight gain, libido, tremors, CNS. Toxicity: use emesis
, gastric lavage, hemo- or peritoneal dialysis but not charcoal. st CI: renal fa
ilure, pregnancy 1 trimester. Interactions: drugs that serotonin serotonin syndr
ome. With BZD, antipsychotics
neurotoxicit y. Valproic Acid (VA) Indications: an
ticonvulsant that works as a mood stabilizer. Can be used in acute episodes or a
s a mood stabilizer. Forms: elixir sodium valproate, capsules
VPA, enteric coate
d tabs divalproex, injections
sodium valproate sodium SE: . Monitor Cp. Blood (agr
anulocytosis, thrombocytopenia), weight gain, liver / pancreas damage, GI upset
( in divalproex). CI: sensitive to enzyme inhibitors and inducers. CBZ Indication
s: anticonvulsant that works as a mood stabilizer. Use in bipolar if lithium fai
ls. nd Mechanism: modulate NEp and cAMP (G protein-linked 2 messenger system). S
E: CNS: drowsiness, dizziness, blurred vision, diplobia, nystagmus, confusion, h
eadache. Dose related: blood dyscrasias, dose gradually to avoid SE, GI upset (t
ake with food). Non dose related: skin SE. Metabolic enzyme inducer (drug intera
ctions, monitor Cp). Complete monitoring (blood count, live function, BUN, elect
rolytes, TSH). New Mood stabilizers (anticonvulsants) (gabapentin, lamotrigine)
Indications: both mood elevation during epilepsy. Not approved, though, for mood
stabilization (no systematic data). Lamotrigine: structure is similar to phenyt
oin and CBZ. Mechanism: block sodium-mediated release of glutamate and aspartate
, may also block GABA and Ach release. SE: dizziness, blurred vision / diplobia,
GI upset, rash / photosensitivity. Gabapentin: structure is similar to GABA (bu
t no effect on GABA). Mechanism: unknown. dose gradually. Short t1/2 frequent ad
ministration. SE: somnolence, dizziness, nystagmus, fatigue.
Other topics
Use of dual mood stabilizers Combination of lithium and CBZ or VPA. Watch for le
ukocytosis / leukopenia. Do not combine CBZ and VPA ( blood dyscrasias). May also
combine one of the three (older drugs) with one o f the two newer drugs (above).
Mood stabilizers in pregnancy nd rd Older drugs (lithium, VPA, CBZ) may cause bi
rth defects. If necessary, use lithium only in 2 and 3 trimester. If necessary,
give folic acid with VPA to risk.
47. Asthma and COPD
Asthma
Definition
Reversible chronic airway inflammation. It involves obstruction, airway responsi
veness, episodic asthma symptoms. Pathologic changes are not permanent. Classifi
cation: mild intermittent, and persistent (mild, moderate, severe) Incidence: 15
million Americans (one third children). 50% of children outgrow asthma by mid-t
eens, may return to asthma later in life.
Etiology
Allergens (pollen, dust mite, animal dander, mold, food), occupational exposures
(chemicals, flour, wood, textile dust), viral respiratory infections, exercise,
emotions (anxiety, laughter, stress, crying), irritant exposure (odors, chemica
ls, irritants), environmental exposure (weather change, cold air, smoke, sulfer
dioxide), drugs (hypersensitivity, aspirin, NSAID, cholinergics (bethanechol), a
nti-adrenergics (B blockers)). Allergic rhinitis is twice as common in asthmatic
s.
Pathology / pathophysiology
Postmortem examination: smooth muscle hypertrophy, airway plugs (inflammatory ce
lls, debris, proteins, mucus), vessel vasodilatation, inflammatory cellular infi
ltrate, collagen deposition. Major contributing processes Inflammatory cells: su
ch as mast cells, eosinophils, activated T cells, macrophages, epithelial cells
secrete mediators. Airway obstruction: due to bronchoconstriction, airway wall e
dema, mucus plug formation, airway remodeling, smooth muscle hypertrophy, hyperp
lasia. Obstruction ventilation
ventilation / perfusion (V/Q) imbalance
hypoxemia
and partial pressure of arterial oxygen (PaO2). Hyper-responsiveness: response
to stimuli due to inflammatory mediators and infiltration by inflammatory cells.
Airway inflammation: contributes to hyper-responsiveness, obstruction, respirat
ory symptoms, muco ciliary function, airway permeability to allergens / irritant
s. Autonomic neutral control: cholinergic sensitivity parasympathetic tone, refle
x bronchoconstriction. Airway remodeling: due to persistent inflammation in poor
ly controlled asthma collagen deposition and fibrosis
permanent airway abnormali
ties. Sequencing of events in asthma Triggering: exposure to trigger (allergen,
aspirin, virus, etc) antigen binds to IgE
attach to activated mast cells. Early
response: begins in < 30 min and resolves in < 2hr, blocked by beta agonist or c
romolyns. Late response: begins 6 hr after trigger, persistent airway obstructio
n, inflammation, hyperresponsiveness, occurs in 50% of cases, may last several d
ays, blocked by corticosteroids or cromolyns. Signaling: inflammatory cells (mas
t cells, lymphocytes, eosinophils, macrophages, epithelial cells) release chemic
al signals (cytokines, chemokines, eicosanoids, leukotrienes)
attract more infla
mmatory cells. Migration: influx of inflammatory cells (eosinophils, lymphocytes
, monocytes, granulocytes); adhesion molecules attract cells to the airways. Cel
l activation: required before cells can release inflammatory mediators. Eosinoph
ils activation inflammatory mediators
smooth muscle constriction, initiate chemo
taxis. Leukotrienes
Persistent asthma Step-down approach: aggressive. Start treatment one step above
assessed severity for rapid control, review every 3 months. Then, do gradual st
ep-wise reduction in treatment. Step-up approach: start treatment at the same st
ep as assessed severity, and adjust upward as needed. Always, control environmen
t to avoid triggers. If daily or use of inhaled albuterol
consider long-term the
rapy (e.g. anti-inflammatory). A rescue course of systemic corticosteroids may b
e used. Exercise-induced bronchospasm (EIB) Warm-up period helps prevent EIB. Pr
event EIB by using short acting beta agonist (albuterol) 15 min before exercise,
long acting beta agonist (salmeterol) 45 min before exercise, or cromolyn sodiu
m 1 hr before exercise. Keep albuterol handy. Chronic asthma (NIH guidelines) Se
vere persistent: dose inhaled steroid + dose oral steroid + long acting bronchod
ilator (inhaled or oral salmeterol, SR theophylline). Moderate persistent: inhal
ed steroid + long acting bronchodilator for nigh time symptoms (inhaled or oral
salmeterol, SR theophylline) (drop oral steroid). Mild persistent: only one of t
he following: dose inhaled steroid, inhaled cromolyn, SR theophylline, leukotrie
ne modifier. Mild intermittent: no daily medications. Albuterol for attacks.
Therapeutic agents
Beta agonists Short acting: albuterol (R- and S- isomers), levalbuterol (only ac
tive R-enantiomer), metaproterenol, pirbuterol, for acute exacerbation and EIB p
rophylaxis. Long acting: salmeterol, formoterol for asthma maintenance, EIB prop
hylaxis, nocturnal symptoms, albuterol use, COPD. Mechanism: stimulate beta 2 re
ceptors adenyl cyclase cAMP
bronchodilation, mucociliary clearance, inflammator
cell mediator release. SE: tremors (due to B2 activation in skeletal muscles),
gluconeogenesis ( glucose), activation of Na K ATPase, cardiac stimulation (due t
o partial B1 stimulation: palpitation, tachycardia), nervousness, headache. Admi
nistration: inhalation systemic SE (preferred over oral). Always use salmeterol
with in haled steroid, except for EIB prophylaxis. May combine long and short ac
ting. Tachyphylaxis: occurs due to regular use. Its due to down-regulation due to
moving of beta receptors from cell surface to inside the cell. Effect may be re
versed with steroids. Paradoxical bronchoconstriction: due to cold-Freon effect
or use of adjuvants. bronchial hyperactivity: due to irritants such as methachol
ine and histamine. May be due to albuterols S-isomer. Drug interactions: hyperten
sive crisis with MAO inhibitors, TCA and methyldopa. Beta blockers (e.g. propran
olol) bronchospasm. Combined with sympathomimetics heart effect, vasoconstrictio
n (prevent by alpha blockers, phenolamine). Corticosteroids Mechanism: Bind to g
lucocorticoid receptors in the cell cytoplasm
alter gene transcription inflammat
ory response, airway hyper-responsiveness, mucus. Use: in case of allergic compo
nent. Added only when anticholinergic / beta agonist combo is ineffective. Syste
mic steroids: used for rapid response during acute exacerbations (few hours). IV
steroids: hydrocortisone and methylprednisone. Alternative to oral steroids to
prevent respiratory arrest in hospitals. Switch to oral steroids after stabiliza
tion. Oral steroids: prednisone, prednisolone. Used in emergencies if possible w
hen there is no risk of respiratory arrest. Used in burst doses for a week. Dose
tapering may be required. Inhaled steroids: fluticasone, flunisolide, triamcino
lone, beclomethasone, budesonide. Used for chronic treatment, not for acute exac
erbations. Less SE and less efficacy. steroid penetration into bronchial tree by
giving bronchodilator several minutes prior.
Use: more effective in COPD than in asthma. Ipratropium sodium: quaternary ammon
ium compound. Used with or as an alternative to beta agonist in acute attacks. S
low onset and long duration compared to beta agonists
give regularly. SE: intrao
cular pressure if touches the eye, anticholinergic. Atropine aerosols, glycopyrr
olate (quaternary ammonium compound): rarely used due to SE and efficacy. Used i
n nebulizers Other drugs Antihistamines: if patient has allergic rhinitis. Preve
nt release of histamine mediated response that influence asthma. Antibiotics: us
ed to treat infections (change in volume, color, viscosity of sputum). Sputum cu
ltures are useless because COPD are chronically seeded. Chronic antibiotic preve
ntative used can be considered in case of frequent exacerbations. M. pneumoniae
or Legionella pneumophilia macrolide . C. nd rd pneumoniae
oral doxycycline. Pne
umonia in the hospital 2 or 3 generation cephalosporin or beta-lactam with b-lac
tamase inhibitor. Magnesium sulfate (IV): cause little bronchodilation, respirat
ory muscle strength in hypomagn esemic patients. Immunotherapy: may lung functio
n, symptoms. Non-pharmacologic Humidified O2: flow rate helps reverse hypoxemia
(use if PaO2 < 55 mmHg), esp. at night/during exercise. Goal: SaO2 > 90%. Heliox
: helium / oxygen mixture that is less dense than air
ventilation during acute a
ttack. IV fluids: and electrolytes are given if volume is depleted. Environmenta
l control: avoid allergens and triggers. Use allergen-resistant mattresses / pil
low encasements, filtration vacuum cleaners, avoid ferry pets, carpets and drape
ries. Vaccines: used to prevent infections that may trigger asthma (e.g. influen
za and polyvalent pneumococcals). Drug delivery options MDIs: accurate with good
technique and a spacer. A facemask may be needed for children. Wait 1 min betwe
en buffs. Spacers and holding chambers: drug deposition in the upper airway, ora
l absorption, local / systemic SE. Spacers are important for dose steroids or if
hand-lung coordination is poor. Nebulizers: require patient coordination. Disad
vantages: cost, time consuming, size, inconsistent drug delivery. Used in dose b
eta agonists, anticholinergics, cromolyn in children. Dry powder inhalers: more
common, avoid the use of Freon propellants, easier to use. First load the dose,
and then inhale rapidly. No spacers. Keep away from moisture.
COPD
Chronic bronchitis
Definition: excessive mucus production by the tracheo-bronchial tree edema and b
ronchial inflammation
airway obstruction. Pathophysiology: respiratory tissue in
flammation vasodilation, congestion, mucosal edema
mucus. Neutrophils infiltrati
on. Cilia impairment. Cartilage atrophy. Airways become blocked by thick, tenaci
ous mucus secretions sputum rich productive cough. Normally sterile airways beco
me colonized by Strept pneumoniae, H influenza, Mycoplasma. Recurrent viral / ba
cterial infections body defenses, mucus accumulation, ciliary activity. Airway d
egeneration
gas exchange exertional dyspnea. Hypoximia, PaCO2 (hypercapnia). Phy
sical findings: chronic productive cough after age 45 (first in winter, worse in
the morning). Progressive exertional dyspnea, obesity, wheezing, prolonged expi
ration, right ventricular failure, cyanosis (called blue bloater) Diagnostic tests
: hypoxemia
erythropoiesis polycythemia ( RBCs). WBC due to infections. Sputum: t
hick, colored (if infected), neutrophils, microorganisms. Arterial blood gas: Pa
O2 (hypoxemia), PaCO2 (hypercapnia). FEV1. Right ventricular hypertrophy and cor
pulmonale in ECG.
Emphysema
Definition: permanent alveolar enlargement and destruction of the alveolar walls
, alveolar surface area. Pathophysiology: Inflammation, mucus secretion
alveoli
air trapping. tissue damage
space into which normal lung tissue expands.. Alveol
i merge space for air trapping. Alveolar wall destruction
small airways collapse
. Hypercapnia and respiratory acidosis are uncommon because of compensatory in r
espiratory rate. Physical findings: cough is chronic but less productive than in
chronic bronchitis, starts at age 55. Exertional dyspnea is progressive, consta
nt, more severe than in bronchitis. Other findings: weight loss, tachypnea, prol
onged expiration, breath sounds. Patient usually maintain good oxygenation throu
gh tachypnea pink buffer. Diagnostic tests: small chance of AAT in blood or infect
ions in sputum. PaO2 and PaCO2 in arterial blood gas, FEV1.
Etiology
Smoking: causes pulmonary hyperactivity and persistent airway obstruction. Alpha
-1 antitrypsin (AAT) is a serine protease inhibitor
neutrophil elastase. risk of
COPD when smoking is combined with genetic ATT deficiency. Others: exposure to
irritants (sulfur dioxide, polluted air, noxious gases, dusts), family history,
social, economic factors.
Complications
Pulmonary hypertension: lung congestion pulmonary vascular bed space pulmonary h
ypertension
cor pulmonale (right ventricular hypertrophy)
right heart failure. A
cute respiratory failure: advanced emphysema brain respiratory center damage
cer
ebral oxygenation
PaCO2
hypoxia, respiratory acidosis
respiratory failure. Infec
tion: chronic bronchitis trapping of excessive air, mucus, bacteria and coughing
and deep breathing
infection. Polycythemia: in RBCs hypercoagulate state, embol
ism, stroke.
Therapy
Anticholinergics: First line treatment for COPD. Beta blockers, corticosteroids,
theophylline, O2, etc (see above) Mucolytics: such as acetylcysteine
sputum cle
arance, mucus plugs. May cause bronchospasm. Expectorants: such as guaifenesin.
Avoid potassium iodide. Chest physiotherapy: loosens secretions, re-expand lungs
, efficacy of respiratory muscle. More important in outpatient. Physical rehabil
itation: exercise tolerance and diaphragm and abdominal muscle tone. Smoking ces
sation: and avoidance of irritants. Use drugs with behavior intervention for max
imum success. Surgery: lung volume reduction therapy
48. Rheumatoid Arthritis
Introduction
Definition: chronic, systemic, autoimmune, inflammation of the synovial joint. M
ore common in women (2-3:1). 2% of the population.
Classification:
Four of the following criteria have to be met 1. Morning stiffness for 1 hour be
fore improvement 2. Three joints have fluid or soft tissue swelling 3. One joint
in the hand joints must be swollen. 4. Symmetric arthritis: involvement on both
sides of the body.
Pathophysiology
Gouty arthritis develop when monosodium urate crystals deposit in the join synov
ium
inflammatory response
gout attack
join swelling, redness, warmth, tenderness
tophi (urate deposits)
joint deformity, disability, renal impairment. Renal com
plications: Acute tubular obstruction: due to uric acid pptn in the ureters and
collecting tubes. Urolithiasis: uric acid stones due to low urine pH. Chronic ur
ate nephropathy: urate deposits in the renal interstitium.
Acute gouty arthritis
Painful arthritic attacks of sudden onset. Triggers: trauma, cold exposure. Init
ial attack is abrupt and usually occur at night or early morning very hot swolle
n, tender joints. Podagra: attack in the metatorso-phalangeal joint. Attacks las
t 1-2 weeks (longer as the disease progresses). May include fever, chills, malai
se. Diagnosis: Urate needle-shaped crystals in synovial fluid (-ve birefringence
). Serum urate, erythrocyte sedimentation rate, leukocytes. Dramatic therapeutic
response to colchicine. Acute attack pattern with remission periods.
Therapy
Immobilize affected joints. Start anti-inflammatory drugs immediately. Start ura
te-lowering drugs after attack is over. Colchicine: drug of choice for pain and
inflammation and ending the attack. Mechanism: antimitotic, chemotaxis of leukoc
yte to inflamed area, phagocytosis and urate deposition. Orally or IV (never IM
or SC due to irritation). SE: diarrhea, GI, bone marrow depression, irritation i
f given IM. NSAIDs: if first choice is colchicine is not tolerated or not starte
d immediately. Examples: indomethacin, naproxen, sulindac. SE: GI, CNS headache
and drowsiness / dizziness. Take with food. Aspirin dose uric acid secretion, do
se uric acid secretion. Corticosteroids: Methylprednisolone acetate given intraarticular with diagnostic / therapeutic aspiration. Prednisone (oral), Triamcino
lone acetonide (IM) or methylprednisolone (IV).
Intercritical gout
Symptom free period between attacks. Non-drug urate lowering: high-purine diet (
meats, legumes), obesity, alcohol. Limited effect. Prophylaxis: dose colchicine
or NSAID. Urate lowering therapy (<6 mg/dl): lifelong treatment. Allopurinol (is
opurine): production. Mechanism: xanthine oxidese ( xanthine
hypoxanthine uric ac
id). Long acting active metabolite: oxypurinol. Preferred over uricosurics in ca
se of renal impairment ( dose). SE: reversible rash ( incidence with ampicillin),
exfoliative dermatitis treat with prednisone, Stevens-Johnson syndrome. May gout
attacks if given during the attack due to mobilization of stored urate (give co
lchicine). May dissolves tophi. Uricosurics
excretion. Examples: sulfinpyrazone,
probenecid (benzoic acid derivative). Mechanism: uric acid reabsorption at the
proximal convoluted tubules. Do not initiate during acute attacks or give with c
olchicine. During the first 6-12 months may attacks. Maintain fluid intake, urin
e output and alkaline urine to risk of renal urate pptn. Build up dose gradually
. Action is antagonized by salicylates. SE: GI, blood dyscriasis (sulfinpyrazone
). CI: urinary tract stones. Chronic tophaceous gout: urate pool. Large SC tophic
. Allopurinol / probenecid combo.
50. Peptic Ulcer Disease
Introduction
Definitions
Peptic ulcer disease (PUD): circumscribed lesions of upper GI mucosa.
GERD: reflux occur via transient lower esophageal sphincter relaxation (TLESR).
People with GERD
TLESR frequency. Dyspepsia: caused by PUD, GERD, gastric cancer
, biliary tract disease.
Clinical presentation
Only 50% of patients experience classic ulcer symptoms. Pain: heartburn, aching,
burning, cramping. May be due to chemical stimulation or spasm. Duodenal ulcer
pain: more localized and often peaks between 12-2 AM. Gastric ulcer pain: less l
ocalized. Food: may duodenal ulcer pain but gastric ulcer and GERD pain. So, duo
denal ulcer patients may gain weight and gastric ulcer patients may lose weight.
Pain occurs 1.5-3 hr after meals in duodenal but only 1 hr after meals in gastr
ic ulcer. Disease course: usually chronic with remissions and exacerbations. Rel
apse may be more common in spring and autumn. Test for and eradicate H pylori an
d use maintenance drugs to recurrence.
Clinical evaluation
Blood test hypochromic anemia. Stool test
occult blood in chronic ulcers. Gastri
c secretion tests hyper-HCl secretion in duodenal ulcers, normal or subnormal HC
l secretion in gastric ulcer. Upper GI barium x-ray: reveals ulcer crater. Upper
GI endoscopy: most conclusive test. Biopsy: may be necessary to detect malignan
cy. H pylori status: using non-invasive (serology or breath test, false negative
breath test with PPI, antibiotics or bismuth compounds) or invasive (histologic
al bacterial visualization or urease activity test) tests.
Complications
Hemorrhage
Clinical picture: fresh blood vomit, bloody / tarry stool, coma, hypovolemic sho
ck (heart rate > 110, systolic BP < 100). Management: ensure airway, breathing,
circulation. IV crystalloids or colloids (e.g. hetastarch), monitor / correct el
ectrolytes, gastric lavage, vasoconstrictors, antacids, H2 antagonists, PPI, vas
opressin (GI muscle and blood vessel contraction).
Perforation
Sudden acute upper abdominal pain, rebound tenderness, and finally, peritonitis
and shock. Symptoms may with time (dangerously misleading). Emergency surgery is
needed.
Obstruction
Occurs due to inflammatory edema, spasm or scarring. Clinical picture: postprand
ial vomiting / bloating, appetite / weight loss, abdominal distension. Managemen
t: continuous gastric suction, monitor fluids and electrolyte status, perform sa
line load test to measure degree of obstruction. Liquids feeding and daily aspir
ations may be needed.
Post-surgical complications
Dumping syndrome: rapid gastric emptying in 10% of patients after partial gastre
ctomy. Clinical picture: weakness, dizziness, anxiety, tachycardia, flushing, sw
eating, abdominal cramps, nausea, vomiting, diarrhea. Occur between 15 and 120 m
inutes after the meal. Management: eat six small meals, protein and fat and carb
. Ingest fluids 1 hr before or after a meal but not with it. Give anticholinergi
cs to delay gastric emptying. Other complications: reflux gastritis, stomal ulce
ration, diarrhea, malabsorption, early satiety, iron deficiency anemia.
Refractory ulcers
Dyspeptic symptoms after 8 wk therapy. Perform gastroscopy and biopsy to exclude
: Crohns disease, TB, lymphoma, carcinoma. Treatment: only PPI offer maximum acid
. Eradicate H pylori. D/C NSAID. Perform surgery if all fails.
Maintenance regimens
70% of ulcers recur in a year (90% in 2 years) after healing and therapy d/c. Us
e long-term maintenance therapy in: concomitant disease, 4 relapses / year, many
risk factors (old, male, NSAID, alcohol, smoking, family history, history of co
mplications). H pyloric eradication need for continuous therapy.
Therapy
Antacids
As effective as H2 antagonists. Examples: magnesium, aluminum and calcium salts.
Antacids are not widely used for PUD. Continue therapy for only 7 weeks. Typica
lly given 2 hours after meals at bedtime. Effect lasts for 3-4 hours. Mechanism:
Neutralize gastric acid
gastric pH
pepsin activity and mucosal barrier
heat and
treat ulcer pain. Non-systemic antacids: such as magnesium or aluminum are pref
erred over systemic antacids (e.g. sodium bicarbonate) to avoid alkalosis. Liqui
d antacid: buffering capacity than tablets but not as convenient. Antacid mixtur
es: such as aluminum hydroxide and magnesium hydroxide each drug dose and effect
. Side effects are negated (aluminum constipation, magnesium
diarrhea). Calcium
carbonate: not preferred ( acid rebound, delayed pain relief and ulcer healing, c
onstipation, hypercalcemia). It may produce milk-alkali syndrome esp with milk (
hypercalcemia, alkalosis, kidney damage). Acid neutralizing capacity (ANC): numb
er of mEq of a 1 N solution of HCl that can be brought to a pH of 3.5 (99% neutr
alization) in 15 minutes. For duodenal ulcers, 50 mEq/hr or 125 mEq/day of antac
id is needed for neutralization. Precautions: Use calcium and magnesium carefull
y in renal disease (e.g. elderly). Sodium bicarbonate is CI in hypertension, CHF
, renal disease, edema. Use aluminum carefully in patients with dehydration, GI
obstruction. Calcium carbonate + alkali (sodium carbonate) + milk = milk-alkali
Long term aluminum hydroxide use hypo-phosphatemia, osteomalacia. Aluminum hydro
xide is used to treat hyperphosphatemia. Interactions: Generally, take other dru
gs 30-60 min before antacids. Avoid antacids (polyvalent cations) with tetracycl
ine ( absorption), cipro. May destroy enteric coating leading to premature releas
e in the stomach. Interfere with absorption of: ranitidine, cimetidine, iron, di
goxin, phenothiazines, anticholinergics. effect of sucralfate.
H2 receptor antagonists
Preferred in mild-moderate GERD due to lack of effect on GI motility. Mechanism:
competitively action of histamine at parietal cell H2 receptors
volume and H+ c
oncentration of gastric acid. General SE: nausea, dizziness, renal damage (adjus
t). Absorption is with antacids (give 1 hr befor e antacids). All available oral
or IV. Cimetidine: first drug, gastric acid by 50%. SE: liver damage, hematolog
ic (thrombocytopenia, agranulocytosis, aplastic anemia), weak androgenic (gyneco
mastia), confusion. Cytochrome P-450 inhibitor metabolism of phenytoin, theophyl
line, Phenobarbital, lidocaine, warfarin, imipramine, diazepam, propranolol, pro
cainamide. Ranitidine: more potent drug, gastric acid by 70%. Used with bismuth
citrate and clarithromycin to eradicate H pylori. Famotidine: most potent, gastr
ic acid by 94% for 10 hr. Nizatidine: newest drug, similar to ranitidine. Oral.
DI: absorption of drugs requiring acidic pH (e.g. ketoconazole).
Sucralfate
Non-absorbable disaccharide containing sucrose and aluminum.
Mechanism: adheres to the base of ulcer crater forming a mucosal protectant barr
ier against acids and bile salts (esp. in duodenal ulcers). Acidic pH is require
d for polymerization. SE: constipation. Give 1 hr before meals and at bedtime fo
r 6 weeks. Interactions: antacids sucralfate mucosal binding, give 45 min apart.
Surcralfate absorption of digoxin, iron, phenytoin, cimetidine, tetracyclines,
ciprofloxacin.
GI anticholinergics
Examples: atropine, propantheline. No proven value in ulcer healing Mechanism: b
asal and stimulated gastric acid and pepsin secretion. Most effective at night i
n large doses with antacids
delay gastric emptying. Or, take 30 min before food
( acid by 40%) SE: dry mouth, blurred vision, urinary retention, constipation, ta
chycardia CI: gastric ulcer (they prolong gastric emptying), narrow angle glauco
ma.
Prostaglandins (misoprostol)
Mechanism: PG E1 analgoue mucus
protect gastric mucosa against NSAID damage, bic
arbonate, acid. NSAID prostaglandins bicarbonate and mucus secretion
damage. Use
: QID prevention of NSAID induced gastric ulcer in risk patients. SE: diarrhea,
GI pain (take with food). CI: abortifacient, pregnancy category X.
Proton pump inhibitors
Examples (x-prazole): omeprazole, lansoprazole, esmoprazole, rabeprazole, pantop
razole. Omperazole sulfenamide is the active form. Mechanism: forms a stable dis
ulfide bond with sulfhydryl group near potassium binding site on luminal + + sid
e of gastric proton pump H K ATPase
pump shuts down. Very rapid ulcer healing an
d symptom control compared to other drugs (e.g. H 2 blockers). 90% acid reductio
n for 24 hr with no achlorhydria. Omeprazole is better than ranitidine or misopr
ostol for preventing or healing NSAID ulcers. Omperazole can be used in infants.
SE: headache, diarrhea, GI pain / upset, flatulence. Take before food. Interact
ions: absorption of drugs requiring acid pH (ketoconazole, ampicillin, iron). Om
eprazle may or cytochrome P-450 metabolism.
Bismuth compounds
Examples: bismuth subsalicylate (Pepto-Bismol), ranitidine bismuth citrate (RBC)
, colloidal bismuth subcitrate (not FDA approved). Mechanism: bismuth prevents a
dhesion of H pylori to gastric mucosa, H pylori growth, release of proteolytic e
nzymes. Use: most effective in combination with PPI or antibiotics. SE: CNS/neut
rotoxicity, dark stool / tongue, headache, diarrhea, rash, salicylism in doses (
tinnitus, hyperpyrexia, confusion, tachycardia). Antibiotics for H pylori: metro
nidazole, tetracycline, clarithromycin, amoxicillin, bismuth subsalicylate, ompe
razole / lansoprazole. Optimum regimen: bismuth subsalicylate QID + metronidazol
e QID + tetracycline QID + omperazole QD = 2 wk
90% eradication.
Prokinetic agents
Example: metoclopramide, erythromycin, cisapride (d/c due to incidence of arrhyt
hmia / torsades). Mechanism: ACh release gastric emptying (no effect on acid sec
retion). SE: diarrhea, GI upset, headache. Interactions: antifungals (ketoconazo
le, itraconazole, fluconazole, miconazole) cisapride metabolism
severe arrhythmia
. Rapid gastric emptying can affect absorption of narrow therapeutic drugs. CI:
arrhythmia, CHF, ischemic heart, renal failure, respiratory failure.
so
51. Diabetes
Introduction
Definition
1. Dysfunction in metabolism of fat, carbohydrate, protein, insulin 2. Dysfuncti
on of blood vessels and nerves function and structure 2-10% of US population (ha
lf undiagnosed)
Classification
General common symptoms: polydipsia, polyuria, dry skin, polyphagia, fatigue, fr
equent skin / vaginal infections, visual disturbances. 1. Type 1 (Insulin-Depend
ent, Juvenile-Onset, Ketosis-Prone) Insulin production/secretion is destroyed. U
sually in children and adults <30. Prone to ketoacidosis (accumulation of ketone
bodies). Dependent on exogenous insulin replacement. 10% of all diabetes. Etiol
ogy: a. Genetics: w/ family history. Linked to Human Leukocyte Antigen ( HLA) sy
stem. b. Environment: virus (e.g. rubella), toxic chemical triggers genetics / a
utoimmunity. c. Autoimmunity: anti-insulin and anti-beta-cell antibodies usually
present Clinical presentation: abrupt onset, acute presentation. Unintentional
weight loss w/ or w/o ketoacidosis. 2. Type 2 (Non-Insulin-Dependent, Adult-Onse
t) Endogenous insulin is normal, or . May or may not need exogenous insulin. 90%
of all diabetes (esp. in the elderly). Adults >30. 80% are also obese. Not prone
to ketosis except during stress (infection, surgery, trauma). Etiology: a. Gene
tics: 90% concordance between monozygotic twins. 15% chance in offspring of diab
etics. b. beta cell: insulin. c. Insulin site defect
insulin-resistant tissue (i
nsensitivity) Clinical presentation: develops gradually. Evidence of damage to r
etina, kidneys, peripheral vasculature. 3. Gestational (pregnancy) Glucose intol
erance detected during (late) pregnancy (3% of pregnants). Test tolerance 6 wk p
ostpartum. Usually returns to normal. 4. Other types (Secondary Diabetes) Due to
disease of pancreas, genetics, endocrinopathies (Cushings), drugs (thiazides, lo
ops, corticostroids, hyperglycemia) 5. Diabetes insipidus: Cause: pituitary dise
ase with production of antidiuretic hormone (ADH)
kidney cant conserve water, lit
hium ( sodium reabsorption). Symptoms: polyuria (20 L / d), severe thirst, polydi
psia, watch for dehydration. Treatment: anti-diuretic hormone (vasopressin) anal
ogs desmopressin (oral), lypressin (nasal), maintain fluids / electrolytes. (Des
mopressin is also used in Hemophilia A and von Willebrands disease).
Pathophysiology
Normal glucose regulation Insulin:
Physical findings: dehydration, serum osmolarity (> 280 mOs), no ketosis / acidos
is (hyperglycemic hyperosmolar nonketotic syndrome, HHNK), polyuria, polydipsia,
hypotension, tachycardia, palpitations, rapid respiration, nausea, vomiting, ab
dominal discomfort, CNS function (confusion, coma, seizures, myoclonic jerking).
Therapy: insulin, fluid / electrolyte replacement.
Hypoglycemia
Mild hypoglycemia symptoms: adrenergic (tachycardia, palpitations, shakiness), c
holinergic (sweating), mild CNS glucopenia ( concentration, dizziness, hunger). M
oderate hypoglycemia: CNS effect
confusion, motor impairment, no unconsciousness
. Severe hypoglycemia: coma, seizure, motor impairment. Pseudo- hypoglycemia: hy
poglycemic symptoms perceived (mostly adrenergic) but BG is normal. Hypoglycemia
unawareness: no or little symptoms but BG is low. Sweating or neurologic impair
ment is noticed. Precipitating factors: excess insulin or oral hypoglycermic, de
layed or food, exercise, alcohol, drug interaction BG, progesterone in menstruat
ion, new insulin bottle with full potency, gastroparesis (delayed stomach emptyi
ng), change in insulin injection site ( absorption if SC near exercising muscle)
. Treatment of hypoglycemia: if conscious
10-15 g fast acting simple oral carboh
ydrate (milk, juice, regular soda), 3 g glucose tablet or hard candy, honey, glu
cose gel. Repeat in 10-15 min if BG is not back to normal. If unconscious
IV glu
cose (10-15% dextrose) or glucagons injection (1 mg IM, SC, or IV).
Long-term complications
Macrovascular
Atherosclerosis: coronary, cerebrovascular, peripheral Peripheral vascular disea
se: pain, chronic cold feet, insufficient circulation to heal distal lesions gangr
ene Hypertension: with diabetes
cardiovascular disease, stroke, transient ischemi
c events. Causes acceleration of retinopathy, nephropathy, atherosclerosis. Hype
rinsulinemia / insulin resistance diabetic hypertension. Coronary artery disease
: autonomic neuropathy Silent myocardial infarction (atypical, no chest pain). M
anagement: daily dose aspirin, ACE inhibitor (for BP), cardio selective beta blo
cker (for cardiac disease).
Eye (retionopathy)
Consequence of microvascular changes, leading cause of new blindness. Treatment:
laser photocoagulation. Nonproliferative (background) retinophathy: retinal mic
roaneurysms, blot hemorrhages, retinal edema, hard exudates, macula edema Prepro
liferative retinopathy: abnormality of tiny vessels, retinal ischemia, white pat
ches of oxygenstarved retina (soft or cotton-wool spots). Proliferative retinopa
thy: lack of oxygen
weak vessel grow or proliferate (neovascularization) from re
tinal surface to vitreous cavity. Fragile vessels may bleed into vitreous cavity
hemorrhage
obscured vision
scar tissue and new vessels grow vitreous pull on th
e retina retinal detachment.
Nephropathy
Most common cause of End Stage Renal Disease (ESRD) microalbuminuria, positive d
ipstick (clinical) albuminuria, proteinuria / BP, glomerular filtration, creatin
ine. ACE inhibitors helpful, protein intake, treat UTI. For ESRD
fluid / electro
lyte restriction, dialysis.
Neuropathy
Peripheral neuropathy: esp. in sensiomotor nervous system. Symptoms first in dis
tal lower extremities then upper extremities (Stocking-glove distribution). Sign
s: impaired perception of pain / temperature
numbness / tingling, impaired balan
ce, proprioception (perception of body parts movement), motor nerve damage
muscl
e weakness / atrophy. Autonomic neuropathy: genitourinary
neurogenic bladder, se
xual dysfunction. GI gastroparesis, nocturnal diarrhea, fecal incontinence, chro
nic constipation. Cardiovascular
orthostatic hypotension, cardiac denervation.
Foot, skin and mucous membranes
Due vascular changes and peripheral neuropathy
alter nerves that control blood f
low and skin hydration Infection by staph, beta-hemolytic strept, fungus
cutaneo
us infection (furunculosis, carbuncles), Candida (genital, upper thighs, under b
reast), cellulites, lower-extremity vascular ulcers Atrophic round painless lesi
ons, diabetic dermopathy (red-brown popular spots) esp. in lower extremities. Ne
crobiosis lipoidica diabeticorum (ulcerative necrotic lesion) Peripheral neuropa
thy loss of protective sensation, inability to detect minor trauma
ulcers Infect
ion, injury, neuropathy, vascular disease
gangrene Sensory exam of feet (protect
ive sensation) 10 g monofilament Protective footwear (deep sole shoes, molded sh
oes, orthotics)
Significant interactions affecting glycemic control
Hyperglycemia (direct glucogenic effect): corticosteroids, furosemide, thiazides
, sunburns, nicotinic acid, phenytoin, pentamidine, protease inhibitors, sympath
omimetics, isoniazid, sulfinpyrazone, theophylline toxicity. Hypoglycemia: MAO-I
, fluoxetine, salicylates ( dose), alcohol, fenfluramine, pentamidine Prolonged h
ypoglycemia / masking hypoglycemic symptoms: B1 beta blockers (e.g. propranolol)
Therapy
Medical nutrition therapy (MNT)
Carbohydrate counting: 50% of total calories. DM therapy may include pre-meal sh
ort acting bolus insulin (lispro, regular, semilente). Otherwise, maintain consi
stent CHO intake. Fat: limitations on type and amount. Critical for weight loss
and treating hyperlipidemia. Target: < 30% of calorie intake and < 300 mg/day ch
olesterol. Protein: important in end stage renal disease and may delay dialysis.
Fiber: bran, beans, fruits, vegetables may help BG and lipids. Alter diet based
on stress, illness, exercise, etc. Spaced meal intervals help match hypoglycemi
c therapy effect.
Physical activity
Careful exercise cell glucose uptake
BG Careful if patient has severe retinopath
y. Patients with cardiovascular disease or over 45
cardiovascular evaluation and
stress test. Aerobic activity: e.g. swimming, walking, running, preferred due t
o positive effect on BG ( ), cardiovascular, BP, lipids, circulation, weight loss
. Anaerobic activity: e.g. weight lifting, should be avoided. Potential negative
cardiovascular, BP, retinopathy effects.
Insulin and insulin analogues
For type 1 DM and only uncontrolled type 2. Mechanism / structure: see above Fac
tors insulin requirement: infections, weight gain, puberty, inactivity, hyperthy
roidism, Cushings disease
Factors insulin requirement: renal failure, weight loss, exercise, nutrient mala
bsorption, hypopituitarism, adrenal insufficiency. Concentration: U-100 or U-500
for insulin resistance. Source: human, bovine, porcine, synthetic (Lispro insul
in, Humalog), or a mixture. Human insulins are made by enzymatic conversion of t
erminal amino acid of porcine insulin (Novolin, semisynthetic), or by recombinan
t DNA (Humulin). Human insulin
antigenicity. Short-acting: Lispro
synthetic, sho
rtest onset and duration. Regular soluble insulin with neutral pH, only clear in
sulin (IV), only insulin that can be mixed freely. Semilente (prompt insulin zin
c suspension) finely divided amorphous prep, use acetate buffer, mix only with o
ther lente, similar duration to Regular, Aspart insulin analogues. Intermediateacting: NPH (isophane insulin suspension)
similar to protamine zinc but with no
excess protamine. Lente (insulin zinc suspension)
mixture of 70% ultralente crys
tals and 30% semilente powder. Long-acting: Protamine zinc use phosphate buffer.
Ultralente (extended release zinc suspension) large crystalline. Glargine insul
in analogue (very long acting). Pre-mixed insulin: 50/50 Regular/NPH, 70/30 Regu
lar/NPH, 75/25 Lispro/Protamine Lispro regular as pre-meal bolus and NPH interme
diate for later control of hyperglycemia. Other mixtures can be prepared extempo
raneously for tailored ratios. DM Type 1 example: pre-breakfast is 2/3 of total
daily dose (TDD) 1:2 short : intermediate. Bedtime is 1/3 of TDD 1:2 like pre-br
eakfast. Or give pre-supper rapid/short and then bedtime intermediate. DM type 2
example: bedtime only or 2-3 daily injections. Subcutaneous: for routine admini
stration. Absorption of regular insulin is fastest from abdomen > arm > buttock
> thigh. Monitor variations in absorption. Randomly rotate injection site to avo
id lipohypertropy. If variations avoid random rotation of injection site. Exerci
se, hot showers, baths, massages blood flow to injection site. Abdomen is least
likely to have absorption
preferred site for preexercise insulin. Continuous Int
ravenous (insulin drip): provide Regular insulin for acute hyperglycemia, ketoac
idosis, HHNK, or during surgery. Continuous SC infusion (insulin pump): short ac
ting insulin is infused continuously during the day to deliver doses (basal insu
lin). Bolus dose (determined by algorithms) is delivered by the patient before e
ach meal. Offers tighter glycemic control. Used for diabetics with BG fluctuatio
ns, irregular work schedules, lifestyles, or meals. Require frequent SMBG (BG se
lf-monitoring) and training. SE: hypoglycemia (tachycardia, sweating, hunger, co
nvulsions and insulin shock), hypersensitivity, injection site local irritation.
Insulin secretagogues
Drugs (all acidic): Sulfonyrlureas: First gen: chlorpropamide, tolbutamide, acet
ohexamide, tolazamide, more lipid-soluble, more potent. Second gen: glyburide, g
lipizide, glimperide. Also repaglinide. Mechanism: block ATP-sensitive potassium
channels insulin pancreatic release (primary), and also as sensitizers with tim
e (secondary). Use: Type 2 (useless in type 1, require functioning beta cells).
Chlorpropamide: longest duration of action. CI in liver and kidney disease. SE s
everity and frequency, disulfiram-reaction (also with tolbutamide). Use insulin
instead during stressful conditions ( risk of hyperglycemia due to counter-regula
tory hormones release). SE: severe / prolonged hypoglycemia (esp. in the elderly
, w/ glipizide / glyburide), GI upset, sulfa sensitivity, sun sensitivity, heada
che, rash, tachycardia, hematologic problems, cholestatic jaundice. CI: allergy
to sulfa drugs, pregnancy, lactation. Altered protein binding of sulfonylureas:
alcohol, salicylates, NSAIDs, methyldopa, chloramphenicol, MAO-I, clofibrate, pro
benecid. Therapy failure: due to number of functioning beta cells. Primary: failu
re to control BG within 4 weeks. Secondary: initial control of BG, but fails to
maintain control, due to progression of DM. Repaglinide: less hypoglycemia.
Insulin sensitizers
Drugs: biguanides (metformin, basic drug), thiazolidinediones (rosiglitazone, pi
oglitazone).
TT4
hyperthyroidism, and vice versa Serum total triiodothyronine (TT3): Measures
total (free and bound) T3. TT3 rise before TT4, useful for early detection. in h
yperthyroidism (more than T4), responsible for symptoms. Pregnancy TT3. Resin tr
iiodothyronine (RT3U): Evaluates the binding capacity of TBG. Clarifies whether
abnormal T4 is due to thyroid disorder or abnormal protein binding. If abnormal
thyroid in the blood RT3U changes in same direction ( in hyperthyroid). If abnorm
al protein binding RT3U changes in opposite direction ( in hyperthyroid). Serum t
hyrotropin (TSH) assay: Serum TSH assay: most sensitive test for hypothyroid, bu
t nor reliable in hyperthyroid (TSH is suppressed). Sensitive TSH assay: uses mo
noclonal antibodies known as immuno-radiometric or immunometric (IMA) method (vs
. the older radio-immunoassay). sensitivity, cost, more commonly used to control
over treatment of replacement therapy. Free thyroxine (T4) index (FTI): Not a s
eparate test but rather an estimation of free T4 level by a calculation involvin
g serum T4 and RT3U. FTI
hyperthyroid or TBG. Strategies for testing Most common
and expensive: TT4, RT3U, FTI. Thyroid disease screening for healthy population
is not cost effective. Screen only target population (elderly, chronic disease
hospitalization, Use FTI and Sensitive TSH for disease diagnosis.
Hypothyroidism
Classification
Primary hypothyroidism: due to gland destruction or dysfunction caused by diseas
e or therapy (radiation, surgery). Secondary hypothyroidism: due to TSH secretio
n (pituitary disorder). Thyroid gland is normal but not enough TSH stimulation.
Tertiary hypothyroidism: TRH (hypothalamus) to stimulate pituitary
Causes
Hashimotos thyroiditis: chronic autoimmune thyroiditis. Treatment of hyperthyroid
ism: e.g. radioactive iodine, subtotal thyroidectoym, antithyroid drugs. Goiter:
enlargement of the thyroid gland. Endemic goiter: due to inadequate dietary iod
ine (malnutrition). Sporadic goiter: due to foods or drugs containing progoitrin
(inactive hydrolysis
active goitrin)
oxidation of iodine to iodide. Goitrogenic
drugs: propylthiouracil (PTU), iodides, cobalt, lithium, phenylbutazone. Other
causes: thyroiditis, thyroid cancer. Surgical excision
Signs and symptoms
Vague early symptoms: lethargy, fatigue, sensitivity to cold, weight gain, const
ipation. Later: features of Myxedema such as dry flaky inelastic sin, coarse hai
r, puffy face / hands / feet, eyelid droop, slow speech / thought, libido, coma
(if not controlled). Myxedema coma Life threatening condition in old patient wit
h undiagnosed hypothyroidism Precipitating factors: alcohol, sedative / narcotic
use, antithyroid overdose, d/c thyroid replacement, infection, cold exposure, r
adiation, surgery.
SE: skin rash, urticaria, pruritus, hair loss, skin piementation, drowsiness, my
algia, arthralgia. Severe SE: blood (agranulocytosis, granulocytopenia, thromboc
ytopenia), monitor blood count. Radioactive iodine (RAI) Mechanism: thyroid glan
d picks up the radioactive element iodine-131 as it would regular iodine. Radioa
ctivity destroys cells. Advantages: cure rate (100%), avoid surgical risks, cost
Disadvantages: risk of delayed hypothyroidism, delayed effect. SE: only for wom
en past childbearing years. Response is hard to gauge (too much, too little). Su
btotal thyroidectomy Partial removal of the thyroid gland. Last resort. Advantag
es: success rate, rapid cure. SE: thyroid storm, permanent hypothyroidism.
Complications
Hypothyroidism: may follow Graves disease. Thyroid storm (thyrotoxic crisis): is
a sudden exacerbation of hyperthyroidism caused by rapid release (leakage) of th
yroid hormone ( T4)
fever, tachycardia, restlessness, tremor, hyper-meabolism
dehy
dration, shock, death if not treated rapidly. Precipitating factors: thyroid tra
uma, surgery, radiation, infection, sudden d/c of antithyroid therapy. Treatment
: PTU, methimazole, proproanolol, potassium iodide ( intrathyroidal iodine intake
), supportive therapy (rehydration, cooling, AB, rest, sedation).
54. Cancer Chemotherapy
Principles of oncology
Cancel cells
Tumors arise form a single abnormal cell, which continues to divide indefinitely
. Characteristics: no growth control, can invade local tissues, can spread (meta
stasize).
Incidence
Second leading cause of death in the US. Affects 30% of all people at some point
in life. Some forms of cancer are curable if detected / treated early.
Etiology
Viruses: Epstein-Barr virus, hepatitis B, human papilloma viruses. Environmental
/ occupational exposures: ionizing / UV radiation, chemicals (benzene, asbestos
, vinyl chloride). Life-style: fat, fiber diet, ethanol, tobacco. Medications: a
lkylating agents, immunosuppressants. Genetics: inherited mutations, cancer-caus
ing genes (oncogenes).
Detection / diagnosis
Warning signs: CAUTION. Change in bowel / bladder habits, A sore that does not h
eal, Unusual bleeding / discharge, Tissue thickening or lumps (e.g. breast), Ind
igestion of difficulty swallowing, Obvious change in a wart or mole, Nagging cou
gh or hoarseness. Guidelines for screening: for asymptomatic people mammography
(breast cancer), fecal occult blood test (colon cancer), Pap smears (cervical ca
ncer). Tumor markers: biochemical indicators of the presence of neoplastic proli
feration in serum, plasma, other body fluids. Not definitive. Include: prostate
specific antigen (PSA), carcinoembryonic antigen (CEA), alpha fetoprotein (AFP).
Tumor biopsy: definitive test for cancer cells is pathology of a biopsy.
Chemotherapy
Therapy objectives
Cure: sought with aggressive therapy for long time to eradicate all disease. Exa
mple for leukemia: remission induction, attempt maximal cell kill and therapy co
nsolidation to eradicate all clinically detectable disease and get tumor cell co
unt 1000. Palliation: goal is to control symptoms when complete eradication of t
umor is unlikely or if patient refuses aggressive therapy. Adjuvant: given after
more definitive therapy (e.g. surgery) to eliminate any remaining disease. Neoa
djuvant: goal is to tumor burden before surgery or radiation.
Dosing
May be bases on body weight, BSA or AUC. BSA is preferred (correlates with cardi
ac output which determines renal / hepatic blood flow / elimination). Adjust dos
e for liver or kidney dysfunction. Dosing is usually given as short courses in c
ycles.
Combination chemotherapy
To overcome or prevent resistance, achieve cytotoxicity to resting and dividing
cells, enhance biochemical effect, rescue normal cells. Acronyms are often used
to indicate certain combinations.
Administration
IV is the most common Inrathecal: for methotrexate, hydrocortisone, cytarabine,
thiotepa.
Response to chemotherapy
Does not always correlate with survival. Complete response: disappearance of all
disease (clinical, gross, microscopic). Partial response: > 50 reduction in tum
or size for a period of time. Response rate: defined as complete response + part
ial response. Progression or no response: > 25 increase in tumor size or appeara
nce of new lesions.
Classification of chemotherapeutic agents
Alkylating agents
Prototype: mechlorethamine (nitrogen mustard) Mechanism: cross-linking and abnor
DNA replication. Nitrogen mustards: chlorambucil
mal base-pairing of DNA strands
, cyclophosphamide, ifosfamide, mechlorethamine, melphalan. Ethylenimines / meth
ylmelamines: thiotepa, altretamine. Alkyl sulfonates: bisulfan Nitrosoureas: car
mustine, lomustine, semustine, streptozocin. Triazenes: dacarbazine Platinum coo
rdination complexes: cisplatin, carboplatin Substituted ureas: hydroxyurea Other
s: procarbazine, temozolomide.
Antitumor antibiotics
Most come from Streptomyces Mechanism: alkylation (mitomycin) or intercalation.
Intercalation: drug slides between DNA base pairs and DNA synthesis. Anthracycli
nes: daunorubicin (daunomycin), doxorubicin (adriamycin, hydroxydaunorubicin), e
pirubicin, idarubicin. Anthracendiones: mitoxantrone Others: bleomycin, dactinom
ycin, mitomycin, plicamycin (mithramycin).
Antimetablites
Structural analogs of naturally occurring substrates for biochemical reactions.
Mechanism: false substitution in production of nucleic acid
DNA synthesis. Adeno
sine analogs: cladribine, fluudarabine, pentostatin (deoxycoformycin). Folic aci
d analogs (folate antagonists): methotrexate, trimetrexate, raltitrexed. Purine
analogs (purine antagonists): mercaptopurine, thioguanine Pyrimidine analogs (py
rimidine antagonists): fluorouracil, capecitabine, cytarabine, gemcitabine.
Plant alkaloids
Vinca prevent formation of the mitotic spindle arrest cell division. Examples: v
inblastine, vincristine, vindesine, vinorelbine. Camptothecins
inhibit topoisome
rase I. Examples: irinotecan, topotecan. Podophyllotoxins
inhibit topoisomerase
II. Examples: etoposide, teniposide. Taxanes microtubule assembly / stabilizatio
n cell division. Examples: taxol (paclitaxel), taxotere (docetaxel).
Hormones
Androgens: testosterone, fluoxymesterone Antiandrogens: bicalutamide, flutamide,
nilutammide. Antiestrogens: tamoxifen, toremifene. Aromatase inhibitors: letroz
ole, anastrozole, exemestane, aminoglutethimide. Corticosteroids: prednisone, de
xamthasone Estrogens: ethinyl estradiol, diethylstilbestrol. Estrogen/nitrogen m
ustard: estramustine Progestins: medroxyprogesterone, megestrol Luteinizing horm
one releasing hormone analogs: leuprolide, goserelin
Asparaginase
Mechanism: enzyme that causes the degradation of essential AA asparagine to aspa
rtic acid and ammonia. Normal cells can synthesize asparagine but tumor cells ca
n not.
Biologic response modifiers
Mechanism: alter the patients immune system to fight cancer or to SE of cancer tr
eatment. Examples: Bacillus Calmette-Guerin (BCG), Colony-stimulating factors (e
rythropoietin, filgrastim, sargramostim), interferons (alpha, beta, gamma), inte
rleukins (IL-2, IL-11), levamisole, monoclonal antibodies (rituximab, trastuzuma
b).
Toxicity of chemotherapeutic agents
Most toxic to the most rapidly proliferating cells (mucous membranes, cells, hai
r, GI tract, bone marrow).
Bone marrow depression
Most life threatening SE. Effect is dose related. WBC (especially neutrophils; n
eutropenia)
serious infections. Colony stimulating factors: used to extent of ne
utropenia. platelets (thrombocytopenia)
bleeding give platelet transfusion. Anem
ia is not as common because RBC lifespan is 120 days. Time course: onset
1 week,
lowest count point (nadir)
2 weeks, count recovery
3 weeks.
Dermatological
Alopecia: partial or complete, can not be prevented. Local necrosis: results fro
m extravasation during administration of vesicant drugs immediate pain / burning
+ possible delayed reaction tissue damage, necrosis, ulceration
require plastic
surgery. Treatment: cold for all drugs except vinca and taxanes (use heat). Ski
n changes: dryness, sun sensitivity (methotrexate, fluorouracil).
GI toxicity
Nausea and vomiting Most distressing SE from the patients viewpoint. Acute, delay
ed or anticipatory. Antiemetics are used for prophylaxis. Vomiting
dehydration,
electrolyte imbalance, esophageal tears
d/c therapy. Stomatitis Common with meth
otrexate, fluorouracil (same as skin changes) General inflammation of the oral m
ucosa or other areas of the GI with rapid turnover of cells. Symptoms: erythema,
pain, mouth dryness, lip tingling / burning, ulceration, bleeding infection, in
ability to eat. Time course: starts in 1 week, resolve in 2 weeks. Other SE: flu
orouracil
diarrhea, vincristine
constipation.
Pulmonary
Irreversible and may be fatal. Especially with bleomycin, mitomycin. Symptoms: b
reath shortness, unproductive cough.
Cardiac
Acute: transient ECG abnormalities. Not important. Chronic: irreversible CHF due
to drugs or radiation. Dexrazoxane: cardioprotective (use with doxorubicin).
Neurotoxicity
Due to intrathecal or systemic therapy. Autonomic / peripheral neuropathy: due t
o vincristine. Vincristine is fatal if given intrathecally. Peripheral neuropath
y / ototoxicity: due to cisplatin. Arachnoiditis: due to intrathecal methotrexat
e, cytarabine.
Hemorrhagic cystitis
Bladder toxicity due to cyclophosphamide and ifosfamide. Acrolein: metabolite of
these drugs chemical irritation of bladder mucosa
bleeding. Prevention: aggress
ive hydration with frequent urination, mesna (binds to acroltein
prevents it fro
m contacting bladder mucosa).
Other
Hypersensitivity: may be life threatening (anaphylaxis). Chills / fever: especia
lly with bleomycin. Hepatoxocity: liver function tests, jaundice, hepatitis. Nep
hrotoxicity: serum creatinine, BUN, electrolyte imbalance. Use amifostine to pro
tect the kidney if using cisplatin. Secondary malignancies: such as leukemia, so
lid tumors, lymphoma. Female infertility: may be temporary or permanent .
Other chemotherapeutic modalities
Surgery: can be diagnostic or therapeutic Radiation: doses of ionizing radiation
directed at the cancerous tissue. SE: stomatitis, myelosuppression, GI (nausea,
vomiting, diarrhea). Its common to combine drugs, surgery and radiation.
Use: (oxy)phenylbutazone
short term treatment of rheumatoid arthritis and gout (
not first choice). SE: SE. blood dyscrasias (agranulocytosis, thrombocytopenia,
anemias), GI uspet, ulceration, kidney damage, hyperglycemia, skin rash, CNS (dr
owsiness, headache).
Narcotic analgesics (opioids)
Chemistry Include natural opiate alkaloids and synthetic analogs Derived from op
ium (oldest drug) from poppy seed capsule. Morphine: phenolic hydroxyl group is
critical for activity. Most important alkaloid (pharmacologically and quantitati
vely). Amphoteric structure
erratic oral absorption. Agonists: morphine, codeine
, heroin, oxycodone, oxymorphone, hydromorphone, hydrocodone, dihydrocodone, mep
eridine, fentanyl (transdermal), propoxyphene, loperamide, methadone / levorphan
ol (both long t1/2), diphenoxylate, sufentanil, dezocine. Antagonists: methyl gr
oup on nitrogen atom is replaced by bulkier group. Examples: naltrexone, naloxon
e, levallorphan (?). Mixed agonists-antagonists: nalbuphine, buprenorphine, buto
rphanol, pentazocine, can ppt withdrawal symptoms if used after agonists. Mechan
ism Endogenous peptides (enkephalins, endorphins, dynorphins) provide self-pain
relief. Opioid receptors: in the brain / spinal cord (Types: , , , , ) Effct of mu
rcptor timulation (morphin-li): analgia, ation, mioi, uphoria, phy
ical pnnc, rpiratory prion, braycaria Othr action: cough uppr
ion, CTZ timulation (naua, vomiting). Opioi mimic th action of nogno
u opioi ppti at CNS opioi rcptor
pain thrhol an tolranc. Clinica
l u Morat to vr pain, acut or chronic, of vicral or omatic origin,
.g. MI, cancr, labor, tc. Pranthia an ajunct uring anthia. Antituiv (coin, xtromthorphan). Antiiarrhal (loprami, iphnoxylat).
Pur antagonit ar u a antiot to rvr SE of agonit or agonit-an
tagonit (rpiratory prion, CV prion, rowin). Naltrxon i u
for opioi aition. Do i incra graually until th apparanc of limit
ing SE Mix agonit-antagonit prfrr for acut pain rpiratory prion
ri i . Avoi with chronic opioi
withrawal. Oral: prfrr p. for chronic
tabl pain. CR morphin an oxycoon availabl for continuou pain (.g. canc
r) IM, SC: u pot-oprativly. Aborption i not prictabl. IV bolu: mot
rapi, prictabl ont for brathrough pain IV infuion: to titrat pain rl
if rapily for untabl chronic pain, p. morphin. IV PCA: for acut pot-op
rativ pain. Small o livr at frqunt intrval (10 min). Epiural / in
trathcal: for acut pot-oprativ pain an chronic cancr pain. Intrathcal o
= 0.1 piural o. Mut b prrvativ fr u to nurotoxicity of parab
n an bnzyl alcohol. Intrathcal local SE: itching, urinary rtntion. Epiura
l: brain lvl SE
giv if rpiratory prion ri i . Labor mpriin (l
nonatal rpiratory prion). Rctal: altrnativ to oral. Patint un-prf
rr, poor aborption. Tranrmal: CR fntanyl (3 ay). Altrnativ to oral fo
r chronic pain. Slow ont, rquir oral upplmnt. Avr ffct Contipatio
n: u to inttinal ton an pritali. Aftr vral ay ( with coin). P
rophylaxi: laxativ / tool oftnr combo (biacoyl / ocuat) if to b u
chronically. Rpiratory prion: mot riou. Monitor rpiratory rat if
at ri. U IV naloxon (antagonit) to rvr lif-thratning prion, bu
t may ppt withrawal if on chronic opiat.
Complianc ai
Labling / auxiliary: mut b clar, accurat an pcific Calnar / Rminr
chart: hlp th patint unrtan which mication to ta an whn to ta i
t. Spcial containr / cap: for xampl, ytm with four compartmnt for if
frnt tim prio (morning, noon, vning, btim) for ach ay of th w.
Spcial cap can iplay th tim of th ay whn th lat o wa tan. It fl
ah / bp whn it i tim for th nxt o. Complianc pacaging: fin a
pr-pacag unit that provi on tratmnt cycl of th mication. Uually
ba on blitr pacag. A goo xampl i pcial pacaging for birth contro
l pill. Anothr xampl: prnion craing o rgimn. Chil-proof cap m
ay b a problm for th lrly or patint with arthriti. Doag form: for x
ampl ER, XR an tranrmal patch.
Monitoring thrapy
Slf monitoring: by th patint of th tratmnt rgimn, rpon paramtr. P
harmacit monitoring: ba on inaquat frquncy of rfill, follow up by pho
n or mail rminr. Automatic phon call rminr ytm hav bn u. Brow
n bag program: lrly pull all mication in a bag an ta thm to a profi
onal for rviw. Dirctly obrv tratmnt: watch patint wallow rug (.g. i
n TB).
112. Pharmacoconomic
Innovativ rol for pharmacit: hom IV thrapy, rug lvl monitoring, parnt
ral nutrition managmnt, lf-car counling. Pharmacy rvic may provi p
oitiv outcom by morbiity, thraputic control, cot of tratmnt by uing
fficint thrapy, # of phyician viit, rat of rug rlat hopitalization, i
ncinc an intnity of SE. Extra yar of lif for a patint population can b
convrt to ollar for ocity. Economic mtho Tchniqu Input Output Cl
aical opration analyi Unit (.g. pharmacy hr) Unit (.g. patint monit
or) Cot ffctivn analyi Dollar Natural unit Cot bnfit analyi Do
llar Dollar Cot utility analyi Dollar Util/prfrnc Cot minimization
analyi Dollar Aum qual
Cot bnfit analyi
Mical car i an invtmnt goo (in human capital) an a conumption goo. M
aur of invtmnt bnfit: prnt valu of a pron liftim prouctivity. Bo
th input (cot) an output (bnfit) hav to b quantifi in ollar. Both
$ amount ar icount to thir prnt valu at a crtain intrt rat. Econ
omic valu = prnt valu of bnfit prnt valu of cot. Bnfit may b
ifficult to maur or to convrt to $, or both.
Bnfit
Bnfit: fin a th in cot raliz u to program implmntation. Can b
irct, inirct, or intangibl. Dirct bnfit: aving on irct cot in m
ical car. Eay to maur. Inirct bnfit: aving on inirct cot in th
mical car. Difficult to maur. It avoianc of arning an prouctivity l
o which woul hav bn incurr without th halth program. Intangibl bn
fit: ifficult, if not impoibl, to maur. Intangibl cot ar pychologic
al (pain, uffring an grif).
Dicount rat
Dicount rat i th convrion of ollar amount to prnt valu through th u
of intrt rat. icount rat: favor projct with bnfit occurring in
itant futur. icount rat: favor projct with cot occurring in itant fu
tur.
Commonly u icount rat i th yil rat on long trm gov bon. Mathmatic
al mol ar u to calculat bnfit/cot ratio. Nt Prnt Valu (NPV): a n
w mol for calculating bnfit-cot. Vry popular an currntly rcommn
by many conomit. Rat of Rturn on Invtmnt: calculat th intrt rat f
rom an initial program invtmnt ovr a potntial tram of bnfit ovr tim.
Cot ffctivn analyi
Altrnativ way ar compar for achiving rult ( BP, lif xpctancy). Simil
ar output maurmnt mut b achiv to compar program. Cot Bnfit Analy
i Cot Effctivn Analyi Output: ollar valu Output: unit not ollar D
trmin maximum bnfit or invtmnt Dtrmin lat cot combination Aum
limit rourc Aum aquat rourc Fat comparion of program Diff
rnt way to rach am objctiv L flxibl Mor flxibl
Economic prpctiv
A pharmacy rvic with poitiv bnfit/cot ratio may b goo for th ocity
a a whol but not to vry gmnt of th ocity. Exampl: rug rgimnt that
# of patint ay in acut car i goo for th ocity but may not b goo for
th hopital that pn on patint tay for rvnu. Alway conir who pay
th cot an who rciv th bnfit.
Quality of lif outcom an patint ciion
Quality of lif an atifaction with rvic ar critical. Elmnt may inclu
: probability of ucc, aociat pain, lily outcom, tc. Exampl: th qu
ality of yar within lif xtnion (halthy yar?). Exampl: untrat hyprt
nion may not critical affct aily lif, but a MI woul quality of lif. Halt
h-rlat quality of lif (HRQL) i a humanitic outcom. Uing ciion-analyi
tchniqu, a ciion tr can b ma of what happn to th patint from i
agnoi to cur. Th FDA ha bn lry of rug that quality but lif xpctanc
y. Dia ar aociat with phyical, mntal an ocial impairmnt (which c
an b ifficult to maur).
Pharmacy Managmnt (PDF fil)
Baic accounting
Accounting: proc of collcting, rcoring, ummarizing, uing financial ata
Auiting: accounting that al with vrifying that rcor ar pt an computa
tion ar ma. Booping: proc that ocumnt flow of rourc ($$, goo
) into / out of th buin, an claim of critor / ownr to tho rourc
Dual ffct of accounting: mot tranaction ar rcor twic with th ru
lt of a balanc ht. T Account: with bt on th lft an crit on th right
. Dbit = Crit. Tranaction: fical / financial vnt that ar rcor. A
ccounting prio: prio of tim ovr which tranaction ar rcor, at th n
of which incom i maur. Uually 1 yar. Not alway a calnar yar. Mtho
of rcoring tranaction: Accrual: tranaction ar rcor at th tim th
y occur. Cah: tranaction ar rcor whn cah tranfr han. Rvnu: ma
urmnt of goo ol or rvic rnr for which th buin rciv cah
or th promi of cah. Expn: rourc u up uring a prio of tim to
arn rvnu. Typ of account: ownr quity = at - liabiliti. At: r
ourc own by th buin, .g. cah, account rcivabl, builing, invnto
ry, quipmnt, furnitur, prpai inuranc.
Cycl toc: invntory pt on han to fulfill orr Buffr/afty toc: invn
tory for ca of upply/man fluctuation. Anticipatory/pculativ toc: inv
ntory for xpct in man
Stp of purchaing
Cot of goo ol (COGS): hav ramatic ffct on profit Purchaing objctiv
: right prouct / varity, quality, quantity, pric, tim 1. Mart rarch: to
trmin n/want of patint / prcribr, intify pharmacy imag an bu
in goal, pac limitation, potntial al. Dtrmining n: uag rpor
t, othr pharmaci, pharmacy mploy, qutionnair, al rp, publih
top X rug, formulari. Exampl: ara with young famili
chilrn itm, ol
lrly itm. Conir pcial ia managmnt ara, .g. athma
r famili
, iabt. 2. Effctiv purchaing polici: U opn-to-buy purcha bugt. Con
trol total $ invtmnt in invntory. U prior yar ata to forcat purcha b
ugt for ach month in th upcoming yar, ba on al an COSG. Ajut ( / )
ach month purcha ba on prviou month al an purcha. Gro margin =
al COGS. 3. Slcting upply ourc: mut b pnabl, prompt, frqunt
livry, goo rturn policy, frquncy of out-of-toc, cutomr rvic, pric,
financing arrangmnt. Option: wholal, manufactur, buying group, rac jo
bbr, tc. Wholal: avantag inclu torag of goo until n, rapi
livry, financing option, hlp with avrtiing promotion, tor layout an
ign. Rac jobbr: toc an maintain a pcifi aortmnt of goo (.g. y
gla) in a fixtur in th pharmacy. Manufacturr: not common, larg minimum
purcha. Cntral purchaing group: pool buying powr of inpnnt pharmaci
for bttr trm. 4. Ngotiating trm: pric, icount, ating, rturn poli
cy. Pharmacy margin = uggt rtail pric pharmacy cot. Quantity icount:
cumulativ (gnric rbat) or non-cumulativ ($ or % pr quantity). Cah icou
nt: for prompt paymnt (typical: 2% if pai in 10 ay, nt amount u in 30 ay
), or icount for Elctronic Fun Tranfr. Final pric i calculat aftr u
btracting tra, quantity an cah icount. Dating: tim for icount an paym
nt (prpaymnt, collct-on-livry (COD), lay). Rturn goo policy: ful
l crit within x ay, partial crit aftr y ay, non-rturnabl aftr z ay
. Chc hlv rgularly for itm not ol. Conir uing a rturn goo
rvic company (charg a f). 5. Tranfrring mrchani titl (?) 6. Rciving
, maring, tocing: count hipmnt, chc for amag, chc invoic, mar pric
(mrchani, computr), toc. Stoc pth coniration: avrag man, r
viw tim, la tim, afty toc. Invntory control inclu th following: 1
. Viual: loo at # of unit in invntory an compar with how many houl b ca
rri, orr mor if n. 2. Prioic: count toc on han at crtain intrva
l, compar to minimum targt lvl, orr mor if n. 3. Prptual: monito
r invntory all th tim (uually uing a computr). Computr ytm: al, an
alyi, trn, prptual, automatic orring, intrfac invntory an ipnin
g ytm at point of al.
Financial analyi / planning
Comparativ analyi: xpr ach financial tatmnt componnt a prcnt of
al, an compar with Digt ata. Ratio analyi: compar financial ratio wit
h ratio for th am company uring rcnt yar, an imilar group of pharmaci
in NCPA Pharmacia Digt. Solvncy: ovrall ability to pay lgal bt. Calcu
lat Currnt an Aci Tt ratio Currnt Ratio = currnt at / currnt liabil
iti. Targt > 2 Aci Tt Ratio = (Cah + account rcivabl) / currnt liabil
iti. Targt > 1 Othr olvncy ratio: currnt liabiliti / invntory, total
liabiliti / nt worth, long-trm liabiliti / nt woring capital, fix a
t / nt worth, Efficincy: how wll availabl capital i u. Invntory turnov
r ratio. Invntory turn ovr ratio = COGS / avrag invntory. Targt: 5-6. Oth
r fficincy ratio: nt al / invntory, account rcivabl an account paya
bl collction prio, nt woring capital turnovr.
Profitability: th bottom lin, important but not th only maur of ucc. R
turn on nt worth = nt profit / nt worth. Targt 25%. Nt worth = total at
total liabiliti. Nt profit / nt al: targt 5%. Nt profit / total at
. Targt 15%. Nt profit / invntory. Targt 20%. Expn: alari, wag, r
nt, utiliti, accounting / lgal f, tax, licn, inuranc, intrt, q
uipmnt, prciation. Balanc ht: inclu at an liabiliti. Currnt a
t: cah, account rcivabl, invntory. Currnt liabiliti: account payabl
, accru xpn.
Pricing
Componnt of pric = ingrint cot + rvic cot (ipning) + incom. Actu
al Acquiition Cot (AAC): pric th pharmacy pay for th prouct. Vari pn
ing on ourc, volum, incntiv an al, typ of pharmacy Avrag Wholal
Pric (AWP): NOT (?) th avrag pric th wholalr ll th prouct at. Co
t aign to prouct by manufacturr, ovrtat AAC Etimat Acquiition Cot
(EAC): tablih by thir party payr to timat AAC. Uually a prcntag
of AWP (.g. 90%). Srvic cot: avrag or pr unit cot of proviing a rvic
. Covr xpn uch a alari, rnt, utiliti, prciation. Inclu cot
to ipn. Dirct cot: rult irctly from proviing th rvic. No ir
ct cot if rvic i not provi. Dipning irct cot: labl, containr,
computr, livry cot, patint ucation matrial, pharmacy licn. Inir
ct cot: cot har by all rvic, .g. rnt, utiliti, alari, bnfit
, avrtiing, tc. Cot of proviing a rvic = all irct cot + fair har o
f inirc t cot. Cot allocation: trmining th fair har of inirct cot
. Difficult. Etimat % of mploy tim an facility pac vot to ipni
ng. Cot to ipn (COD): total ipning cot / xpct Rx volum. It i a
n timation of th avrag cot to ipn Rx. Snitiv to volum. Diffrnti
al cot; iffr among altrnativ cour of action, i.. aitional cot th
pharmacy incur for proviing a nw rvic. Non-cot factor: man, comptiti
on, imag, quality ignaling, goal, non-montary cot. Dman: quantity conum
r will b at a crtain pric. Function of pric. Elaticity of man: maur
nitivity of man to pric . Elastic demand: small in price results in big
in demand. Sellers make money by lowerin g the price. Inelastic demand is opposi
te ( price
profit) Consumers are more sensitive to price when: cost of product is
large part of total cost, differences among products, comparisons are easy, con
sumers can judge quality, switching costs are small, commodity. Image: consumers
can select based on perceptions of pharmacy image. Image is affected by: prices
, size, location, services offered, personnel, promotions, etc Price as a signal
of quality: more likely when consumers cannot judge quality, more for services
than products. Penetration pricing: price to sales volume. Loss leader pricing:
Rx prices to OTC sales. Price skimming: price for superior service.
Basic Management
Management components: self, controllable surroundings, uncontrollable surroundi
ngs, external environment. Management activities: satisfy various entities, deal
with emergencies, purchasing, recruiting, accounting, training, planning, negot
iating, sales, dealing with regulatory officials. Management actions: identify t
asks, organize resources, monitor performance / task completion, plan for future
requirements, deal with problems. Functions of management actions: target setti
ng, problem solving, leadership, team building, dealing with emergencies. Manage
ment functions: controlling, directing, organizing, planning, staffing