FAR EASTERN UNIVERSITY – NICANOR REYES MEDICAL FOUNDATION

Pharmacology A – 1.3
LECTURER: CELIA R. RAVELO, MD, FPPS
PHARMACOKINETICS MEDISINA 2019

OUTLINE  Are all drugs meant to be absorbed? No. Some drugs such as
1. PERMEATION the antacids are local drugs that are not meant to be absorbed.
2. ABSORPTION Why? Because you are only after the local effect of the drug. It
3. DISTRIBUTION is given to neutralize the acidity of the stomach. 
4. METABOLISM  During the absorption of drug, it has to go through several
5. ELIMINATION barriers.
6. SINGLE DOSE PHARMACOKINETICS
Cell Membrane
7. CONTINUOUS & MULTIPLE DOSE KINETICS
 One of the important barriers in the body 
PHARMACOKINETICS  Plasma membrane consists of a phospholipid bilayer (outer
 Refers to what the body does to a drug phosphate head = hydrophilic; inner lipid tails = hydrophobic)
 Absorption is favored when the drug is in the non-ionized &
more lipophilic form
 Lipid solubility is the most important factor that governs
absorption

KEY PHYSIOLOGIC PRINCIPLES IN ABSORPTION

1. Transport Processes
2. Blood Flow
3. Ionization
4. Protein Binding
5. Routes of Drug Administration

TRANSPORT PROCESSES
 Four pharmacokinetic properties determine the onset, intensity PASSIVE DIFFUSION
& the duration of drug action  The driving force for passive
◌ Absorption: First, absorption from the site of absorption of a drug is the
administration permits the entry of the drug (either concentration gradient across
directly or indirectly) into plasma a membrane separating two
◌ Distribution: Second, the drug may then reversibly leave body compartments
the bloodstream & distribute into the interstitial &
 In other words, the drug
intracellular fluids
moves from a region of high
◌ Metabolism: Third, the drug may be biotransformed by
concentration to one of lower
metabolism by the liver or other tissues
concentration
◌ Elimination: Finally, the drug & its metabolites are
eliminated from the body in urine, bile or feces  Does not involve a carrier, is
not saturable & shows a low
PERMEATION structural specificity
 Ability of the drug to move effectively in the body  Most common way a drug is
 Determinants of Drug Permeability: transported
◌ Solubility  Requirements:
□ Ability to diffuse through lipid bilayers (lipid solubility) ◌ Molecules have to be suspended in an aqueous solution
is important for most drugs; however, water solubility ◌ Molecules must be able to pass through a semi-permeable
can influence permeation through aqueous phases membrane
◌ Concentration Gradient  Reaches the equilibrium when the movement of molecule from
□ Diffusion down a concentration gradient – only free, one compartment to another is equal (movement never stops,
unionized drug forms contribute to the concentration it just equalizes)
gradient  Net rate of diffusion is dependent on”
◌ Surface Area & Vascularity ◌ Permeability
□ Important with regard to absorption of drugs into the ◌ Surface area of the membrane
systemic circulation ◌ Differences in the concentration from one side to the
□ The larger the surface area & the greater the other
vascularity, the better is the absorption of the drug
𝑁𝑒𝑡 𝑅𝑎𝑡𝑒 𝑜𝑓 𝑃𝑒𝑛𝑒𝑡𝑟𝑎𝑡𝑖𝑜𝑛 = 𝑃 × 𝑆𝐴 × (𝐶1 − 𝐶2 )
ABSORPTION
 Movement of a drug from its site of administration into the P = Permeability of the membrane
central compartment & the extent to which this occurs SA = surface area
 To be able to understand absorption, we must understand the C = Concentration
histology of layers through which the drugs must pass  Seen in movement of glucose into RBC or Vit. B12 across GI
epithelium

BHND | Sources: PPT + Katzung’s Basic & Clinical Pharmacology, 13th Ed. + Lippincott’s Pharmacology, 6th Ed. Page 1 of 13
 PHARMACOKINETICS Pharmacology A

Characteristics of diffusion  Acidic drugs (HA) release a proton (H+) causing a charged anion
-
1. Unsaturable (A ) to form:
2. Lacks competition 𝐻𝐴 ↔ 𝐻 + + 𝐴−
3. Does not require energy  Weak bases (BH ) can also release an H+. However, the
+

protonated form of basic drugs is usually charged & loss of a

Sources of variation in permeability of a given membrane proton produces the uncharged base:
1. Molecular Size 𝐵𝐻 + ↔ 𝐵 + 𝐻 +
 Large molecules have a hard time squeezing through small Note:
pores  Ionized = water soluble
 Cell membranes are relatively permeable to water & bulk  Nonionized = lipid soluble
flow of water can carry with it small drug molecules (<200
Da) Pronated Form Deprotonated Form
-
2. Lipophilicity Weak Uncharged (HA) Charged (A )
 Membranes in the body is a lipid bilayer so only lipophilics Acid Can easily pass through Cannot easily pass through
can easily cross the membrane the cell membrane 
3. Charge excreted renally
+
 Highly charged molecules have difficulty in permeating Weak Charged (BH ) Uncharged (B)
membranes Base Cannot easily pass Can easily pass through
4. Membrane thickness through  excreted
 Thicker membranes, slower movement renally
5. Surface Area
 Water-soluble drugs penetrate the cell membrane through
aqueous channels or pores
 Lipid-soluble drugs readily move across most biologic
membranes due to their solubility in the membrane lipid
bilayers

Permeability
 Characteristics of the different membranes or barriers of our
body 
 There are different characteristics of permeability in the body pKa
◌ Blood capillary  pH at which the ionized & nonionized concentrations are equal
□ Transport is independent of lipophilicity, charge & to 1
molecular size (except testes, placenta, CNS [BBB])  pKa is a measure of the strength of the interaction of a
□ Endothelial cells in the testes, placenta & CNS are so compound with a proton
closely associated with one another (no spaces in  The lower the pKa of a drug, the more acidic it is
between) making it hard to be penetrated
 The higher the pKa of a drug, the more basic is the drug
□ Only way to penetrate the testes, placenta & BBB is
to be lipid soluble or a transport system Henderson-Hasselbach Equation (pH
◌ Renal Glomerulus Partition Hypothesis)
□ Have large spaces compared to the regular capillary Acids
→ very permeable
 Weak acids with:
□ Larger molecules with negative charge shows slower
◌ pKa> 7.5: majority of fraction is
permeability since the glomerulus is negatively
unionized form at all pH values so
charged as well
transport is very rapid independent
◌ Nasal Mucosa, buccal mucosa, GIT, lungs
of pH
□ Transport is affected by lipophilicity, charge &
◌ pKa between 3-7.5: fraction of
molecular size
unionized portion changes for acids
◌ Hepatocytes, Renal Tubule, BBB
(only time when computation is
□ Transport is highly dependent on lipophilicity, charge
necessary)
& molecular size
◌ pKa< 2.5: fraction of unionized is so
low that transport is also slow even
IONIZATION
in the most acidic conditions
 Many drugs are weak acids or weak bases & can exist in either
nonionized or ionized forms in an equilibrium, depending on Bases
the pH of the environment & the pKa (the pH at which the  Weak bases with:
molecule is 50% ionized & 50% nonionized)
◌ pKa<5: majority of fraction is in
 Only the nonionized (uncharged) form of a drug crosses unionized form at all pH values &
biomembranes transport is independent of pH
 The ionized form is better renally excreted because it is water ◌ pKa between 5-11: fraction for
soluble unionized portion for strong bases
vary  transport is pH dependent

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 2 of 13
 PHARMACOKINETICS Pharmacology A

 The drugs transported through facilitated diffusion are larger &

less lipid soluble → need carrier proteins
 These carrier proteins undergo conformational changes
allowing the passage of drugs or endogenous molecules into
the interior of cells & moving them from an area of high to low
concentration
 Only un-ionized non-polar drugs penetrate the membrane & at
equilibrium, the concentration of the unionized species are Characteristics of facilitated diffusion
equal on both sides  Does not require energy
 Can be saturated
Acidic Medium Basic Medium
-  May be inhibited by compounds that compete for the carrier
Weak Acid Uncharged (HA) Charged (A )
+
Weak Base Charged (BH ) Uncharged (B) ACTIVE TRANSPORT
 This method of drug entry that
Sample Problem: Phenobarbital, a weak acid has a pKa of 7.2
Calculate the percent ionized in: involves specific carrier
proteins that span the
1 Blood (pH 7.4)
membrane
2 Urine (pH 7.2)
 Driven by the hydrolysis of ATP
To compute for % ionized:  Capable of moving drugs
𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 against a concentration
𝑥100
𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 + 𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 gradient, from a region of low
drug concentration to one of higher drug concentration
In blood,
𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛  Seen in renal & billary secretion of many acids & bases
= 10𝑝𝐻 −𝑝𝐾𝑎 = 107.4−7.2 = 1.58
𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛  Two limiting factors of Active Transport:
◌ Transport system
1.58
𝑥 100 = 61.24 % ◌ Energy
1.58 + 1
In Urine,
𝐼𝑜𝑛𝑖𝑧𝑒𝑑 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 Characteristics of Active Transport
= 10𝑝𝐻 −𝑝𝐾𝑎 = 107.2−7.2 = 1  Requires energy
𝑈𝑛𝑖𝑜𝑛𝑖𝑧𝑒𝑑 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
 Capable of moving against a concentration gradient
1
1+1
𝑥100 = 50%  Saturable
 Selective
2 types of passive diffusion  May be competitively inhibited by other co-transported
1 Aqueous Diffusion substance
2 Lipid Diffusion
Mechanism Direction ATP Carrier Saturable
Aqueous Diffusion
 Occurs within the larger aqueous compartments of the body Passive Down
No No No
(interstitial space, cytosol, etc) & across epithelial membrane & Diffusion gradient
endothelial lining of blood vessels Facilitated Down
No Yes Yes
◌ Permits the passage of molecules w/ MW 20,000 – 30,000 Diffusion gradient
Active Against
Yes Yes Yes
Lipid Diffusion Transport gradient
 Determined by the lipid aqueous partition coefficient of a drug ENDOCYTOSIS & EXOCYTOSIS
 Substances that are so large
Carrier-Mediated Transport  Responsible for transport of vitamin B12 complexed with a
1 Facilitated Diffusion binding protein (intrinsic factor) across the wall of the gut into
2 Active Transport the blood

Special Carriers BLOOD FLOW

 Exist for many substances that are important for cell function &  Intestine receives much more blood flow than the stomach, so
too large or too insoluble in lipid to diffuse passively through absorption from the intestine is favored over the stomach
membranes (e.g., peptides, amino acids & glucose)  Shock reduces blood flow to the cutaneous tissue, thereby
 Can be active transport or facilitated diffusion minimizing absorption from subcutaneous administration
 IM administration has a faster absorption rate than
FACILITATED DIFFUSION subcutaneous administration because the muscles are more
 Other agents can enter the vascular than the fats (found subcutaneously)
cell through specialized
transmembrane carrier
proteins that facilitate the
passage of large molecules
 Also driven by a concentration
gradient
BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 3 of 13
 PHARMACOKINETICS Pharmacology A

ROUTE OF DRUG ADMINISTRATION  Small intestine is more permeable because absorption is

 Route of administration is determined by the properties of the perfusion rate limited (more wide gaps in endothelium)
drug (e.g., water or lipid solubility, ionization) & by the  Permeability & surface area decreases progressively from
therapeutic objectives (e.g., the desirability of a rapid onset, the duodenum to the colon
the need for long-term treatment or restriction of delivery to a  Polarity of molecules also affect permeability
local site) ◌ Molecular size of lipophilic drugs does not affect
 Could be grouped according to: absorption because these drugs traverse the
◌ Intravascular vs. Extravascular membrane transcellularly
◌ Polar drugs with high MW moves paracellularly via
IntravascularDrug administration directly to the blood tight junctions & between epithelial cells 
Does not involve absorption & there is no permeability is greatly reduced if MW is > 350g/mole
loss of drugs 3. Blood Flow (Perfusion rate limited absorption)
100% bioavailability  Rate of perfusion in small intestine: 1L/min
Extravascular Includes oral, sublingual, buccal,  Rate of perfusion in stomach: 150 mL/min
subcutaneous, dermal, pulmonary, rectal 4. pH of the drug
Less than 100% of may reach the systemic  weakly acidic drugs are more rapidly absorbed in an acidic
circulation because of variable bioavailability environment
 Note that to enter the blood, drugs administered  weakly basic drugs are more rapidly absorbed in a basic
extravascularly must be absorbed environment
 No absorption step is necessary when a drug is administered pH Location
intravascularly 6.6 Duodenum
7.5 Terminal ileum
Bioavailability (BA)/(F) 6.4 Cecum
7 Colon
 Rate & extent to which an administered drug reaches the
systemic circulation
 For example, if 100- mg of a drug is administered orally & 70 5. Gastric emptying & intestinal motility
mg is absorbed unchanged, the bioavailability is 0.7 or 70%  Fats – slow gastric emptying
 Fraction of the administered dose systematically absorbed  The slower the gastric emptying time, the greater
intact: absorption because there is longer contact time
6. Dissolution rate of the drug
𝑄𝑢𝑎𝑛𝑡𝑖𝑡𝑦 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑟𝑒𝑎𝑐𝑕𝑖𝑛𝑔 𝑠𝑦𝑠𝑡𝑒𝑚𝑖𝑐 𝑐𝑖𝑟𝑐𝑢𝑙𝑎𝑡𝑖𝑜𝑛  Ability of a drug to be dissolved in the environment
𝐵𝐴 =
𝑄𝑢𝑎𝑛𝑡𝑖𝑡𝑦 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑎𝑑𝑚𝑖𝑛𝑖𝑠𝑡𝑒𝑟𝑒𝑑  Associated with the physiochemical properties of the drug
(difference of generics & branded drugs)
Sample Problem
Determine the amount of drug that is reabsorbed. Cause of Low Oral Bioavailability
Aminophylline is the ethylenediamine salt of theophylline. The preparation is
1. Insufficient time for absorption
80-85% theophylline. Given that F=100%, a patient who took 2 tablets of 200 2. Large MW or charged molecules
mg theophylline wil have absorbed mg of the drug. 3. Reaction within the GIT that competes with absorption
 Presence of enzymes also affect the absorption of drugs
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑 = 𝑆 𝐹 (𝑑𝑜𝑠𝑒) ◌ Example: Levodopa (drug for parkinson’s disease)
when taken orally undergoes decarboxylation due to
S = Salt Form or Chemical Form= 1 if no value is given
the presence of COMT (cathecol-o-methyl
F = Bioavailability
transferase) making the drug inactive
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑 = 0.8 1 400𝑚𝑔  Substances ingested with the drugs also affect absorption
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑟𝑒𝑎𝑏𝑠𝑜𝑟𝑏𝑒𝑑 = 324 𝑚𝑔 ◌ Example: Tetracycline (antibiotic) taken orally with
2+
milk or any dairy products or Ca will form complexes
Major routes of drug administration include: that cannot be absorbed
1. Enteral 4. Hepatic extraction or First Pass Effect
2. Parenteral  First pass metabolism/effect
3. Others ◌ Loss of drug as it passes for the first time through the
GI mucosa & liver during the process of absorption
Oral Route ◌ May occur both in the GIT & Liver
 Easily self-administered ◌ Note that liver is the primary metabolizing organ of
 Toxicities and/or overdose of oral drugs may be overcome with drugs
antidotes such as activated charcoal ◌ When a drug is absorbed from the GI tract, it enters
 Low gastric pH may inactivate some drugs the portal circulation before entering the systemic
circulation
Factors affecting GI absorption ◌ If the drug is rapidly metabolized in the liver during
1. Surface area of the absorbing organ the initial passage, the amount of unchanged drug
 Small intestine: 200m
2 entering the systemic circulation is 
 Stomach: 1m
2 ◌ Limits the efficacy of many oral medication such as
nitroglycerine
2. Permeability of the membranes

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 4 of 13
 PHARMACOKINETICS Pharmacology A

Representative drugs showing low oral bioavailability  The lower the extraction ratio → the higher the bioavailability
due to poor intestinal permeability ◌ Inverse Relationship between Extraction Ratio &
Amikacin Gentamicin Bioavailability 
Carbenicillin Neomycin
Cefamandazole Pyridostigmine Sublingual Route
Cefazoline Streptomycin  Higher bioavailability since it does not undergo first pass
Cefotaxime Teicloplanin metabolism. WHY?
Ceftazidime Vancomycin  Sublingual absorption provides direct access to systemic –
Representative Reactions within the not portal – veins 
GIT that Compete with Absorption
Complexation Rectal Route
 Example: Tetracycline  Rectal absorption is often erratic & incomplete
◌ Forms unabsorbed insoluble complexes with polyvalent  Drugs absorbed from suppositories in the lower rectum enter
2+ 3+ 3+
metal ions like Ca , Al , Fe vessels that drain into the inferior vena cava → bypassing the
liver
Conjugation  However, suppositories tend to move upward in the rectum
Sulfconjugation into a region where veins that lead to the liver predominate
 Example: Isoproterenol  Thus, only about 50% of the rectal dose can be assumed to
bypass the liver
◌ (+) loss of activity; inactive products
Intramuscular (IM) route
Glucoronidation  Drugs administered IM can be in aqueous solution which are
 Example: Salycylamide absorbed rapidly or in specialized depot preparations which are
◌ (+) loss of activity; inactive products absorbed slowly
 Depot preparations often consists of a suspension of the drug
Decarboxylation
in a nonaqueous vehicle such as polyethylene glycol.
 Example: Levodopa → Loss of activity ◌ As the vehicle diffuses out of the muscle, the drug
precipitates at the injection
Acid Hydrolysis ◌ The drug then dissolves slowly, providing a sustained dose
 Example: Pen G, Erythromycin → Loss of activity, inactive over an extended period of time
products
Subcutaneous (SC) route
Oxidation  Like IM injection, SC injection provides absorption via simple
 Example: Cyclosporine → Loss of activity, Products less active diffusion
 SC injection minimizes the risks of hemolysis or thrombosis
Reduction
associated with IV injection
 Example: Sulfasalazine → Active Parent drug & by-products
 May provide constant, slow & sustained effect
Adsorption  Should not be used with drugs that cause tissue irritation
because severe pain & necrosis may occur
 Example: Digitoxin → adsorption to cholestyramine which will
not be reabsorbed  Drugs commonly administered via this route: insulin & heparin

Effect of First Pass Elimination on Bioavailability Factors affecting IM & SC absorption

𝐶𝐿𝑙𝑖𝑣𝑒𝑟 1. Perfusion Rate Limited Absorption
𝐸𝑅 =  IM is more perfused than SC since there is more blood
𝑄
ER = Extraction Ratio vessels in muscles compared to SC tissues 
CLliver = Clearance in the Liver 2. Lymphatic transport
Q = hepatic blood flow (normally = 90 L/hour in a person  Not all drugs given in IM or SC are absorbed by the BV,
weighing 70 kg some will be reabsorbed via the lymphatics (e.g., peptide
 The systemic bioavailability of a drug (F) can be predicted from drugs)
the extent of absorption (f) & the extraction ratio (ER)   Lymph has larger pore so even large peptides can be
𝐹 = 𝑓 × (1 − 𝐸𝑅) absorbed
◌ Movement of drugs is by diffusion & convectional
f = usually given  flow (paracellularly)
LOW INTERMEDIATE HIGH
(< 0.3) (0.3 – 0.7) (> 0 .7) Large Polypeptide Drugs
Carbamazepine Aspirin Alprenolol  Administered IM SC or intraperitoneally
Diazepam Codeine Cocaine  Reach the systemic circulation by:
Ibuprofen Cyclosporine Meperidine ◌ Diffusion through interstitial fluids & fenestrations of the
Nitrazepam Ondansetrone Morphine capillary wall
Paroxetine Nifedipine Nicotine ◌ Connective flow through the lymphatic channels where
Salicylic Acid Nortriptyline Nitroglycerine flow is slow & absorption may continue for hours
Valproic Acid Propaxyphene
Warfarin Verapamil

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 5 of 13
 PHARMACOKINETICS Pharmacology A

3. Temperature For example,

 Temperature can alter the blood vessels
◌ If warm water is present on the site of administration,
vessels will dilate  blood flow  drug delivery
4. Degree of rubbing
 Rubbing enhances circulation in the area  absorption
All these factors affect bioavailability
 Some drugs are not given orally since they have a poor oral BA
due to their chemical structure (polar) or cannot pass through
the gaps within the vasculature
 In the liver & spleen, a significant portion of the BM is exposed due to
large, discontinuous capillaries through which large plasma proteins can
pass
 In the brain, the capillary structure is continuous & there are no slit
junctions & in order to enter the bran, drugs must pass through the
endothelial cells of the CNS capillaries or be actively transported
 Ionized or polar drugs  fail to enter the CNS because they
cannot pass through the endothelial cells that have no slit
junctions
 Lipid-soluble drugs  can penetrate the CNS because they
dissolve in the endothelial cell membrane

Bioequivalence
 Comparison of bioavailability of two drugs with the same active
ingredients (sometimes this is the difference between a generic
& branded drug)
 Two drug formulations are bioequivalent If they show
comparable bioavailability & similar times to achieve peak
blood concentrations
DISTRIBUTION
 Movement of a drug from the vascular system (systemic
circulation) to the different tissues/organs of the body
 Process by which a drug reversibly leaves the bloodstream &
enters the interstitium (extracellular fluid) & the tissues
◌ Starting point: systemic circulation
◌ End point: target organs
 Determined by the relative strength of drug binding to tissue
components versus plasma proteins (force that attracts the
drugs to stay in the blood vessel)
◌ As long as the drug stays in the circulation, the distribution
of the drug has not taken place yet
◌ Distribution has occurred once the drug has moved out of
the circulation
Types of movement from intravascular to extravascular space
1. Transcellular
 Lipid soluble drug molecules can easily pass through the
cell membrane
2. Paracellular or Convective Flow
 Slightly polar drugs cannot move transcellularly so they
move in between cells in capillaries with significant gaps
Phases of Distribution
st
1 1 Phase: Well perfused organs (heart, liver, kidney, brain)
receive most of the drug during the first few minutes after
absorption
nd
2 2 Phase: Delivery to muscle, most viscera, skin & fat which is
slower & limited by blood flow
Factors affecting Drug Distribution
1. Blood flow or perfusion
 Rate of blood flow to the tissue capillaries varies widely
 For instance, blood flow to the “vessel-rich organs” (brain,
liver & kidney) is greater than that of the skeletal muscles
2. Membrane & Capillary Permeability
 Determined by capillary structure & by the chemical
nature of the drug
 Capillary structure varies in terms of the fraction of the
basement membrane (BM) exposed by slit junctions
between endothelial cells
3. Binding of drugs to plasma proteins & tissues
 Albumin is the major drug-binding protein & may act as a
drug reservoir (as the concentration of free drug ecreases
due to elimination, the bound drug dissociates from the
protein) maintaining the free-drug concentration as a
constant fraction of the total drug in the plasma
 Protein bound drugs have limited movement
 Only free drugs are active because they can readily pass
through membranes & bind to their receptors
◌  fraction of unbound/free drug =  apparent volume
of distribution
 Degree of binding is expressed as the bound:total
concentration ratio (Values > 0.9 = Highly bound
 Acidic drugs bind to albumin
 Basic drugs bind to 1-glycoprotein
 Only highly protein bound drugs with small volume of
distribution are affected by changes in protein binding
◌ Vd of drugs that are normally bound to plasma
proteins can be altered by liver disease (through 
CHON synthesis) & kidney disease (through urinary
protein loss)
◌ For example, warfarin, an anticoagulant, is more than
90% protein bound in circulation  inactive
□ However, if warfarin is given to patient with
nephrotic syndrome (a disease wherein an
individual excretes proteins in urine), it will have
no protein to bind to, it becomes active &
patient will suffer from bleeding
 Only unbound drugs cross the membrane
 Protein binding can only affect the rate of distribution IF
the rate limiting step is the permeability & not the
perfusion 
4. Partitioning to Fat
 Lipid solubility
Factors affecting Rate of Drug Distribution to the Tissues
1 Perfusion Rate
2 Permeability Rate
3 Ionization
4 Protein Binding
Permeability rate limited
 Drug distribution is limited by membrane permeability
 Especially true for polar drug diffusing across tightly knit
membranes
 Lipophilicity & degree of ionization affect distribution
Permeability Rate Limited Transportation
 Limiting factor is dependent on permeability of capillary wall
 Example: Blood brain barrier wherein drugs should be lipophilic
to pass through

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 6 of 13
 PHARMACOKINETICS Pharmacology A

Perfusion rate limited  If a drug is protein bound, it has a low volume of distribution
 When tissue membranes present no barrier with distribution ◌ Degree of binding is determined bind the ratio of bound to
 Well perfused tissues receive drug faster than poorly perfused unbound drugs
tissues ◌ Values more than 0.9 = Highly bound 

Perfusion Rate Limited Transportation Apparent Volume of Distribution (Vd)

 Movement of drug wherein the only limiting factor from
intravascular space to the tissues is PERFUSION because
capillaries are perforated (MW or other factor does not matter)
 If there is increased blood flow, there will be more drugs
transported
 When membranes offer no resistance to movement of
molecules, the rate limiting step is perfusion
 Example: Drugs transport to capillaries in small intestine &
glomeruli
 Relates the amount of drug in the body to the plasma
concentration according to the following equation:
𝐴𝑚𝑜𝑢𝑛𝑡 𝑜𝑓 𝑑𝑟𝑢𝑔 𝑖𝑛 𝑡𝑕𝑒 𝑏𝑜𝑑𝑦 𝑎𝑡 𝑒𝑞𝑢𝑖𝑙𝑖𝑏𝑟𝑖𝑢𝑚 (𝐷𝑂𝑆𝐸 × 𝐹)
𝑉𝑑 =
𝑃𝑙𝑎𝑠𝑚𝑎 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
 Calculated parameter for Vd has no direct physical equivalent
(not a real volume)
 “The amount of drug in the body at equilibrium is equal to the
plasma drug concentration”

Ionization
 When a drug is ionized, it is water soluble & polar
 When a drug is nonionized, it is lipid soluble & non polar 
 Only affects rate of permeation if it has to cross a very strict
membrane like a blood brain barrier

Weak acids with

 pKa > 7.5:
◌ most are in nonionized form at all pH values
◌ transport is very rapid independent of pH
 pKa < 2.5 (strong acids)
◌ nonionized form is low “Memorize niyo dapat ito.”
◌ transport is slow even in most acidic environments
 nonionized portion only changes for acids with pKa values  The larger the volume of distribution, the smaller the fraction
between 3 to 7.5 of drug in the plasma
 Low Vd (approximates plasma volume or ECF) → drug is
Weak bases with:
restricted to a particular compartment
 pKa < 5
 If Vd = TBW → drug is concentrated within intracellular
◌ mostly nonionized at all pH values
compartment or may be sequestered in fat tissues
◌ transport is independent of pH
 Vd is useful in predicting plasma drug concentration
 pKa between 5 to 11 (strong bases)
◌ transport is pH dependent 𝐷𝑂𝑆𝐸 × 𝐹
𝑃𝑙𝑎𝑠𝑚𝑎 𝑑𝑟𝑢𝑔 𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 =
𝑉𝑑
PROTEIN BINDING
 When drug reaches the system, it binds to plasma & tissue 𝑉𝑑 × 𝑃𝐷𝐶
proteins 𝑃𝐷𝐶 =
𝐹
◌ Acidic drugs bind to albumin
◌ Basic drugs bind to 1-glycoprotein What is the usefulness of knowing the volume of distribution?
 Binding is reversible because fraction of unbound & bound  It is useful in predicting the plasma drug concentration
proteins should be equal  After all, as doctors, you need to know whether the plasma
◌ When equilibrium is disturbed, fraction bound drugs will drug concentration is within the therapeutic level
released to become free so equilibrium will be restored
◌ Unbound drugs: can freely move & cross membranes Sample Problem: A 50-kg took 2 tablets of 500 mg/tablet of
◌ Bound Drugs: Inactive & cannot be distributed nor paracetamol. What is the estimated PDC if bioavailability is 80% & Vd
excreted = 0.90 L/kg?
 Binding sites are nonselective → drugs can displace one
another 𝐷𝑂𝑆𝐸 × 𝐹 1000 𝑚𝑔 × 0.8 800
𝑃𝐷𝐶 = = = = 17.77 𝑚𝑔/𝐿
𝑉𝑑 0.90 𝐿/𝑘𝑔 × 50𝑘𝑔 45
 Only unbound drugs can cross the membrane

 Protein binding & Ionization can only affect the rate of diffusion
or penetration if the rate limiting step is the permeability & not
the perfusion

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 7 of 13
 PHARMACOKINETICS Pharmacology A

ELIMINATION Biotransformation Classification

 Includes 2 pharmacokinetic properties: Phase I (functionalization/redox reactions)
◌ Metabolism  Results in the loss of pharmacological activity although there
 Kidney cannot efficiently eliminate lipophilic drugs are examples of retention or enhancement of activity
that readily cross cell membranes & are reabsorbed in  Makes the drug more polar/ionized (water soluble) by
the DCT unmasking a functional group
st
 Therefore, lipid-soluble agents are 1 metabolized  Modification of the drug molecule via
into more polar (hydrophilic) substances in the liver ◌ Oxidation ◌ Hydrolysis
◌ Excretion ◌ Reduction ◌ Hydration
 Once a drug enters the body, the process of elimination begins  Enzyme Involved:
(elimination = metabolism + excretion) ◌ NADPH-CYTOCHROME P450 REDUCTASE
 Concerns the processes involved in the elimination of drugs ◌ CYTOCHROME P450 (CYP450)
from the body (and/or plasma) & their kinetic characteristics □ Found in the smooth endoplasmic reticulum of the
 Major modes of drug elimination are: liver
◌ Biotransformation to inactive metabolites (metabolism) □ CYP3A4 accounts for the metabolism of over 50% of
◌ Excretion via the kidney the prescription drugs metabolized in the liver
◌ Excretion via other modes including the bile duct, lungs,  End Product:
sweat, etc ◌ Water soluble, polar drugs  not reabsorbed  easily
excreted
METABOLISM ◌ Lipid soluble, nonpolar drugs  reabsorbed  may still be
 Sum of all chemical reactions for biotransformation of active  need to undergo phase II reaction
endogenous & exogenous substances which takes place in the
living cell
 Elimination has three major routes which include:
◌ Hepatic metabolism (biotransformation) → highest
capacity for metabolism 
◌ Biliary metabolism
◌ Urinary metabolism
 Together, these elimination processes decrease the plasma
concentration exponentially (that is, a constant fraction of the
drug present is eliminated in a given unit of time)

Biotransformation
 Biotransformation is an important mechanism by which the
body terminates the action of many drugs. HOW?
◌ By metabolic conversion of drug molecules to more water-
soluble metabolites that are more readily excreted
◌ By transforming drugs from hydrophobic to hydrophilic
CYTOCHROME P450 ENZYMES
molecules to facilitate elimination
CYP1A2 Caffeine, Ciprofloxacin, Theophylline, R-Warfarin
 Main Goal: make drugs more water soluble for easy excretion
CYP2C9 Ibuprofen, Naproxen, Phenytoin, S-Warfarin
𝐷𝑟𝑢𝑔 → 𝐼𝑛𝑎𝑐𝑖𝑣𝑒 𝑚𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑡𝑒(𝑠) CYP2C19 Diazepam, Omeprazole
CYP2D6 Codeine, Dextromethorphan, Fluoxetine, Haloperidol,
 In many cases, metabolism of a drugs results in its conversion
Loratadine, Metoprolol, Paroxetine, Risperidone,
to compounds that have little or no pharmacologic activity
Thioridazine, Venlafaxine
𝐷𝑟𝑢𝑔 → 𝐴𝑐𝑡𝑖𝑣𝑒 𝑚𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑡𝑒(𝑠)
 In some cases, metabolism of a drug may lead to the formation Phase II (biosynthetic/conjugation reactions)
of metabolites that also have pharmacologic actions  May follow phase I or occur directly
 Leads to formation of covalent linkage between a functional
𝑃𝑟𝑜𝑑𝑟𝑢𝑔 → 𝐷𝑟𝑢𝑔 group on the parent compound with glucuronic acid, sulfate,
 A few compounds (prodrug) have no activity until they undergo glutathione, amino acids or acetate
metabolic activation  Makes a drug more polar by conjugating with an endogenous
compounds via the activity of transferases
 Type of conjugation:
◌ Glucuronidation
◌ Sulfation
◌ Glutathione (GSH) conjugation
◌ Acetylation
 Enzyme involved: TRANSFERASES

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 8 of 13
 PHARMACOKINETICS Pharmacology A

Factors that modify Drug Metabolism  Acutely, depending on the residual drug levels at the active site
Age → they may competitively inhibit metabolism of a
 Increased susceptibility to the pharmacologic or toxic activity of simultaneously administered drug
drug has been reported in very young (infant, neonates, 1-2
years old) & very old patients (80s) compared with young adults Exposure to environmental pollutants & industrial chemicals
 Due to reduced activity of metabolic enzyme OR reduced  Diet & environmental factors contribute to individual variations
availability of essential endogenous cofactors in drug metabolism
 Certain enzymes are not yet present in the very young & there ◌ Charcoal-broiled foods & vegetables → induce CYP1A
are some enzymes that decline as you grow old ◌ Grapefruit juice → inhibit CYP3A
 Some enzymes may be present in young individuals but are still ◌ Cigarette smokers metabolize some drugs more rapidly
in inactive form than nonsmokers because of enzyme induction

Genetic Polymorphism Disease States

 Not all individuals have the same rate of activity of enzymes  Acute or chronic diseases that affect liver architecture or
(some are rapid & slow metabolizers) function → may affect hepatic metabolism of some drugs
 Alcohol dehydrogenase  Example: alcoholic hepatitis, alcoholic cirrhosis,
◌ Lesser in amount in females than males in novice drinkers hemochromatosis, chronic active hepatitis, biliary cirrhosis &
acute viral or drug-induced hepatitis
 NAT (N-acetyltransferase) enzyme which metabolizes INH
(Isoniazid)  Depending on their severity, they may significantly impair
◌ Caucasians: slow acetylators → slow metabolism of INH → hepatic drug-metabolizing enzymes particularly microsomal
have higher incidence of isoniazid-induced peripheral oxidases → affecting drug elimination
neuritis, drug-induced autoimmune disorders &
bicyclicaromatic amine-induced bladder CA Toxic Metabolism
◌ Asians: rapid acetylators → good metabolism of INH  Drug metabolism is not synonymous with drug inactivation
 Some drugs are converted to active products by metabolism
Enzyme Induction or Inhibition  If these products are toxic, severe injury may result under some
CYP450 INDUCERS CYP450 ENZYME INHIBITOR circumstances
Phenobarbital Erythromycin
Nicotine Ketoconazole Example: Acetaminophen Poisioning
Rifampin Ciprofloxacin  Acetaminophen is conjugated to harmless glucuronide &
Phenytoin Quinidine sulfate metabolites when it is taken in recommended doses by
Carbamazepine Cimetidine patients with a normal life function
St. John’s Worts (Supplement) Grapefruit Juice  If a large overdose is taken, the phase II metabolic pathways
Chronic Ethanol Consumption Acute Ethanol Intoxication are overwhelmed & a phase I P450-dependent system converts
Omeprazole some of the drug to a reactive intermediate (N-acetyl-p-
Ritonavir benzoquinoneimine)
Chloramphenicol  The intermediate is conjugated with glutathione to a third
harmless product if glutathione stores are adequate.
Enzyme Induction (Increased rate & extent of metabolism)
 However, if glutathione stores are exhausted, the reactive
 Usually results from increased synthesis of cytochrome P450 intermediate combines with sulfhydryl groups on essential
drug-oxidizing enzymes in the liver as well as the cofactor, hepatic cell proteins resulting in cell death
heme

CYP450 Inducers
 Increases the activity of metabolic enzymes → drugs will be
metabolized much faster → drugs will be easily excretable →
cannot sustain plasma drug concentration → not as effective

CYP450 Enzyme Inhibitors

 May inhibit the metabolic enzymes → leading to slow
metabolisms of the drug → it’ll stay much longer in the body →
may lead to toxicity

Concomitant use of other drugs

 Many substrates (due to their relatively high lipophilicity) are
retained at the:
◌ Active site of the enzyme
◌ Non-specifically bound to the lipid endoplasmic reticulum
membrane
 In this state, they may induce microsomal enzymes particularly
after repeated use

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 9 of 13
 PHARMACOKINETICS Pharmacology A

EXCRETION CLINICAL PHARMACOKINETICS

 Most important organ for excretion → Kidney
 Other routes of excretion include fecal, respiratory,
cerebrospinal fluid, milk, sweat & saliva

Factors that modify excretion of drugs

1 Age
2 Disease States
 In patients with renal failure → decreased urine output →
unable to excrete drugs → risk for drug accumulation &
adverse effects
 In patients with liver failure, there may be impairment of
drug-metabolizing enzymes (particularly microsomal
oxidases) → affecting drug elimination
◌ For example, the half lives of chlordiazepoxide &
Half-Life
diazepam in patients with liver cirrhosis or acute viral
hepatitis are greatly increased → leading to  Determines how often we should give a drug 
prolonged action of drugs → may cause coma in  Can be determined through the volume of distribution &
patients with liver disease when given in ordinary clearance of a drug
doses
3 Rate of Excretion Systemic Exposure
 Increased urine flow → less contact time → less  Can be determined through the clearance & bioavailability of a
reabsorption drug
 Decreased urine flow → more contact time → more  “How long should you give a drug to your patient?”
reabsorption
4 Enterohepatic Recirculation Physiologic Variables Affecting the
Primary Pharmacokinetic Parameters
 When a certain drug is rendered inactive by the liver →
PRIMARY PHYSIOLOGIC
conversion to metabolite which is then secreted into the
PHARMACOKINETIC VARIABLES
bile toward the intestine where it should be excreted → PARAMETERS
acted upon by enzymes (glucoronidase enzyme) produced Blood flow at the site of absorption, Gastric
by microbial flora → conversion of water-soluble drug to Absorption Rate
Emptying (Oral), Intestinal Motility (Oral)
lipid soluble again → leading to reabsorption → goes back Gastric Emptying, Secretion of acid in stomach
to circulation Bioavailability & hydrolytic enzymes in the bile, Intestinal
Drugs/Substances that undergo Enterohepatic Circulation Motility
Aspirin Phenobarbital
Hepatic Hepatic Blood Flow, Binding in the Blood,
Carbamazepine Phenytoin
Dapsone Quinine Clearance Hepatocellular Activity
Digoxin Rifampicin Renal Blood Flow, Binding in the Blood, Active
Methamphetamine Salicylate Renal Clearance Secretion, Active Reabsorption, Urine pH, Urine
Paracetamol TCAs Flow, GFR
Phencyclidine Anticoagulants Binding in the blood, Binding in tissues,
Phenothiazine Napthalene Volume of
Partitioning in Fat, Body Composition, Body
5 Ion Trapping Distribution
Size

Ionization Increases Renal Clearance of Drugs Primary Pharmokinetic Parameters

 Includes:
◌ Clearance – reflects the drug eliminating capacity of the
body
◌ Volume of Distribution – distribution of drug within the
body
◌ Bioavailability – extent of drug uptake into the systemic
circulation

Clearance
 Volume of plasma cleared of drug per unit time (NOT the
 Only free, unbound drug is filtered amount of drug that is eliminated)
 Both ionized & nonionized forms of a drug are filtered  Relates to the rate of elimination with the drug concentration
 Only nonionized forms undergo active secretion & active or
passive reabsorption 𝑅𝑎𝑡𝑒 𝑜𝑓 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐷𝑟𝑢𝑔
𝐶𝐿 =
 Ionized forms of drugs are “trapped” in the filitrate 𝑃𝑙𝑎𝑠𝑚𝑎 𝐷𝑟𝑢𝑔 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛
 Acidification of urine → increases ionization of weak bases →
increases renal elimination Units = Volume per unit time
 Alkalinization of urine → increases ionization of weak acids →
increases renal elimination 𝐶𝐿 = 𝐵𝑙𝑜𝑜𝑑 𝐹𝑙𝑜𝑤 𝑄 × 𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑖𝑜

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 10 of 13
 PHARMACOKINETICS Pharmacology A

How quickly does a drug decline in the body? Factors that Influence Renal Clearance
 Determine by the fractional rate of elimination (k) 1 Plasma Drug Concentration
 The higher the PDC, the higher is the possibility of
𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 (𝐶𝐿) excretion provided that the drug is not protein bound 
𝑘=
𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐷𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡𝑖𝑜𝑛 (𝑉𝑑 ) 2 Plasma Protein Binding
 Proteins with MW ≥ 20,000 Da are not easily filtered
 Albumin has a MW of 69,000 Da
Hepatic Clearance 3 Urine Flow
 Includes biliary excretory clearance & hepatic metabolic  Urine flow can be enhanced by diuretics
clearance 4 Urine pH

𝐻𝑒𝑝𝑎𝑡𝑖𝑐 𝐵𝑙𝑜𝑜𝑑 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 = 𝑄 𝐻 × 𝐸𝐻 Factors Affecting the Reabsorption of Drugs in the Kidneys
1 Polarity; Lipid Solubility
QH = Hepatic Blood Flow
EH = Hepatic Extraction Ratio 2 Urine Flow
3 Urine pH
𝑅𝑎𝑡𝑒 𝑜𝑓 𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛  Altered by diet, drugs & clinical state of the patient
𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑖𝑜 =  Extremes of urine pH: 4.5 – 7.5
𝑅𝑎𝑡𝑒 𝑜𝑓 𝑃𝑟𝑒𝑠𝑒𝑛𝑡𝑎𝑡𝑖𝑜𝑛

HEPATIC EXTRACTION RATIO OF Effect of Urine pH on the Reabsorption of Basic Drugs

REPRESENTATIVE DRUGS & METABOLITES 1 A basic drug that is polar in its nonionized form is never
LOW INTERMEDIATE HIGH reabsorbed regardless of its degree of ionization in urine unless
(< 0.3) (0.3 – 0.7) (> 0 .7) it is actively transported
Carbamazepine Aspirin Alprenolol  Example: Gentamycin
Diazepam Codeine Cocaine 2 A very weakly basic nonpolar drug whose pKa is around 6 or
Ibuprofen Cyclosporine Meperidine below is extensively reabsorbed at all values of urine pH
Nitrazepam Ondansetrone Morphine  Its renal clearance is low especially when it is bound to
Paroxetine Nifedipine Nicotine plasma proteins
Salicylic Acid Nortriptyline Nitroglycerine  Example: Propoxyphene
Valproic Acid Propaxyphene 3 For strong bases with pKa value approaching 12 or greater, little
Warfarin Verapamil or no reabsorption is expected throughout the range of urine
pH because of ionization
First Pass Consideration  Renal clearance is independent of urine pH
 Fraction of drug that escapes elimination by the liver is the  Example: Guanethidine
upper limit of ORAL BIOAVAILABILITY 4 For basic nonpolar drugs with pKa values between 6 & 12, the
extent of reabsorption varies from negligible to almost
 𝑀𝑎𝑥𝑖𝑚𝑢𝑚 𝑂𝑟𝑎𝑙 𝐵𝐴 = 1 − 𝐻𝑒𝑝𝑎𝑡𝑖𝑐 𝐸𝑥𝑡𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑖𝑜 complete depending on the urine pH
 Example: Amphetamine
Renal Clearance
𝑅𝑎𝑡𝑒 𝑜𝑓 𝑈𝑟𝑖𝑛𝑎𝑟𝑦 𝐸𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 Effect of urine pH on Reabsorption of Acidic Drugs
𝐶𝐿𝑅 =
𝑃𝑙𝑎𝑠𝑚𝑎 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛  Acids are reabsorbed less & have larger renal clearance at
higher urine pH
Mechanisms by which drugs are cleared from the Kidneys
1 An acid with pKa of 2 or less is completely ionized at all urine pH
1 Glomerular Filtration
& is not reabsorbed
 Amount of blood flow to the kidney = 1.1 L/minute
 Renal clearance is high & not affected by urine pH
 Average GFR = 120 mL/min
 Example: Chromoglycic acid
 Only unbound drug is filtered
 Drug must be lipid soluble 
2 Very weak acid with pKa > 8 is mostly un-ionized throughout the
range of urine pH
2 Active Secretion
 Renal clearance is low & insensitive to pH
 Active transport of drug from blood to the lumen of the
 Example: Phenytoin
nephron
 Occurs in the PCT
3 For nonpolar acids whose pKa lies between 3 to 7.5, the renal
clearance is sensitive to pH
 Some drugs cannot be filtered so they are actively
secreted which requires active transport (ATP)
 Secretion of drug is inferred IF the rate of excretion
 Weak acids & bases showing pH-sensitive reabsorption are
exceeds the rate of filtration  generally flow-rate dependent\
3 Reabsorption
Forced dieresis & urine pH control
 Occurs if nonionization is enhanced 
◌ Active Reabsorption  Forced dieresis must be made only in drugs whose major route
◌ Passive Reabsorption of drug elimination is the kidney
 The compound must be extensively reabsorbed in the renal
tubule
 If reabsorption is pH sensitive, forced dieresis alone, pH contol
alone or combination of both may be of value

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 11 of 13
 PHARMACOKINETICS Pharmacology A

Total Clearance Elimination Rate Constant

𝐷𝑜𝑠𝑒 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒
𝑆 𝐹
𝑇𝑖𝑚𝑒
 𝐸𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑜𝑛 𝑅𝑎𝑡𝑒 𝐶𝑜𝑛𝑠𝑡𝑎𝑛𝑡 𝐾 = 𝑉𝑜𝑙𝑢𝑚𝑒 𝑜𝑓 𝐷𝑖𝑠𝑡𝑟𝑖𝑏𝑢𝑡 𝑖𝑜𝑛
𝐶𝐿 =
𝐶𝑃𝑠𝑠 𝐴𝑣𝑒
0.693×𝑉𝑑
S = Salt Form (usually 1 unless there is a given value)  𝑡1/2 = 𝐶𝐿
F = Bioavailability
Dose/time = Given Example: Compute for t1/2 of Phenobarbital if CL is 0.24 L/hour, Vd=
CPss Average = Average PDC 0.5 L/kg
Sample Problem: 0.693 × 0.5𝐿/𝑘𝑔 × 60𝑘𝑔
A 60-kg patient was given Phenobarbital Gr I (65mg/tablet) 𝑡1/2 = = 86.6 𝑕𝑜𝑢𝑟𝑠
0.24 𝐿/𝑕𝑜𝑢𝑟
twice/day. Compute for clearance if average PDC is 20 μg/mL. F=
90%. Therapeutic Half-Life = 99 ± 16 hours
130𝑚𝑔
1 0.90 ( )
24 𝑕𝑜𝑢𝑟𝑠
𝐶𝐿 = Fraction of Dose Remaiing
20 𝑚𝑔/𝑚𝐿
 Fraction of the dose remaining in the reservoir per unit time
𝐿 𝑚𝐿 relative to the number of half lives
𝐿 0.005 0.008
𝑘𝑔 𝑘𝑔
𝐶𝐿 = 0.24 = =
𝑕𝑜𝑢𝑟 𝑕𝑜𝑢𝑟 𝑚𝑖𝑛𝑢𝑒 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝑜𝑓 𝐷𝑜𝑠𝑒 𝑅𝑒𝑚𝑎𝑖𝑛𝑖𝑛𝑔 = 𝐻𝑎𝑙𝑓 𝐿𝑖𝑓𝑒
Fraction Excreted Unchanged Zero-Order Kinetics
 “How much of the drug is being excreted without being  Constant amount of drug is eliminated per unit time
metabolized?”

𝑅𝑒𝑚𝑎𝑙 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒  Constant Rate process – rate of process cannot be increased

 𝐹𝑟𝑎𝑐𝑡𝑖𝑜𝑛 𝐸𝑥𝑐𝑟𝑒𝑡𝑒𝑑 𝑈𝑛𝑐𝑕𝑎𝑛𝑔𝑒𝑑 = 𝑇𝑜𝑡𝑎𝑙 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 even when the drug concentration is increased

SINGLE DOSE PHARMACOKINETICS  Half-life decreases as the amount in the body decreases;
Half-Life dependent on initial drug concentration
 Time it takes for plasma drug concentration to go down by 50%
 For example, if 80 mg is administered & 10 mg is eliminated
0.693 every 4 hours, the time course of drug elimination is:
𝑡1/2 =
𝑘

First-Order Kinetics
 Linear on a semilogarithmic paper
 (+) Constant proportion of the drug in the body is eliminated Example: A patient was given
per unit time drug Y with initial PDC of 0.20
 A constant fraction of the drug is eliminated per unit time mmol/L. After approximately
(half-life is constant) 33 seconds, 0.10 mmol/L is
 Half life is concentration INDEPENDENT & is a constant Value eliminated & 0.10 mmol/L
 For example, if 80 mg of a drug is administered & its remained.
elimination half-life = 4 hours, the time course of its elimination  Following zero-order
is: elimination, this drug has
elimination rate of 0.003
mmol/L/sec
 To reduce the remaining
Example: A patient was given 0.10 mmol/L to half, it
drug X with a half life of 7 will only take another 17
minutes. seconds
 If the drug follows first-  This drug will be totally eliminated at approximately 67 seconds
order kinetics, 50% of the
drug is eliminated every 7 FEATURES FIRST-ORDER ZERO-ORDER
minutes Elimination Rate Variable Constant
 From an initial PDC of Half-Life Constant Variable
0.20 mg/mL, only 0.10 Michaelis-Menten Kinetics
mg/mL would remain  Follows linear kinetics until enzymes become saturated
after 7 minutes  Enzymes responsible for metabolism/elimination become
 After another 7 minutes saturated resulting in non-proportional increase in drug levels
nd
(2 Half-life), 50% of the remaining drug will be eliminated so  Decline in the levels of the chemical in the body is exponential
that the remaining amount will be 0.05 mg/mL
 Half-life increases with increased dose
 After the third half-life, only 0.025 mg/mL will remain & so on
 Composition of the excretory products may change
 Competitive inhibition can occur
 Dose-response curves may show unusually large increase in
response to increasing dose

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 12 of 13
 PHARMACOKINETICS Pharmacology A

CONTINUOUS DOSE & MULTIPLE DOSE KINETICS Maintenance Dose

 To initiate drug therapy, the clinician must select the
appropriate route of administration, dosage, dosing interval
 Selection of a regimen depends on various patients & drug
factors including how rapidly therapeutic levels of a drug must
be achieved
Steady State Concentration
 Reached when the rate of drug elimination is equal to the rate
of drug administration such that the plasma & tissue levels
remain relatively constant
 Fluctuate (oscillate) between a maximum & a minimum steady
state concentration within each dosing interval
◌ With repeated administration at regular intervals, the
plasma concentration of a drug oscillates about a mean
◌ Using smaller doses at shorter intervals reduces the
amplitude of fluctuations in drug concentration
 Takes about 4-5 half lives to reach steady state concentration
 Drugs are generally administered to maintain a steady state
concentration within the therapeutic window
 It takes 4 to 5 half-lives for a drug to achieve a steady state
concentration
 To achieve a given concentration, the rate of administration &
the rate of elimination of the drug are important
 The dosing rate can be determined by knowing the:
◌ Target concentration in plasma (CPss)
◌ Clearance (CL) of the drug from the systemic circulation
◌ Fraction (F) absorbed (bioavailability)
◌ Salt or Chemical Form (S) of a drug = usually 1
𝐶𝐿 × 𝐶𝑃𝑠𝑠 × 𝑇𝑖𝑚𝑒
𝑀𝑎𝑖𝑛𝑡𝑒𝑛𝑎𝑛𝑐𝑒 𝐷𝑜𝑠𝑒 =
𝑆×𝐹
Example: What will be the concentration dose of Phenobarbital to
produce a steady concentration of 10 μg/mL?

0.09𝑚𝐿 𝑚𝑖𝑛 𝑢𝑔
Example of achievement of steady state using different dosage / min × 60 × 40 𝑘𝑔 × 10 × 24 𝑕𝑜𝑢𝑟𝑠
𝑘𝑔 𝑕𝑟 𝑚𝐿
regimens: 𝑀𝐷 =
0.9
 Curve B of the figure on the 𝑀𝐷 = 57,600 𝜇𝑔 = 57.6 𝑚𝑔
right shows the amount of 1
= 65 𝑔 (1 𝑡𝑎𝑏𝑙𝑒𝑡 𝑎 𝑑𝑎𝑦 𝑜𝑟 𝑡𝑎𝑏𝑙𝑒𝑡 2𝑥 𝑎 𝑑𝑎𝑦
drug in the body when 1 unit 2
of a drug is administered IV &
repeated at a dosing interval
that corresponds to the half-
life of the drug
 At the end of the first dosing
interval, 0.50 units of drug
remain from the first dose
when the second dose is
administered
 At the end of the second
dosing interval, 0.75 units are
present when the third dose
is given
 The minimal amount of drug remaining during the dosing
interval progressively approaches a value of 1.00 unit, whereas
the maximal value immediately following drug administration is
progressively approaches 2.00n units
 Therefore, at the steady state, 1.00 unit of drug is lost during
the dosing interval, which is exactly matched by the rate of
administration. That is, the “rate in” equals the “rate out”

Loading Dose
 Sometimes rapid obtainment of desired plasma levels is needed
(for example, in serious infections or arrhythmias)
 Therefore, a “loading dose” of drug is administered to achieve
the desired plasma level rapidly followed by a maintenance
dose to maintain the stead state
 In general, the loading dose can be calculated as:
𝑉𝑑 × 𝐶𝑃𝑠𝑠
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 =
𝑆×𝐹

Sample Problem: A 15-year old, 40 kg, female was diagnosed to have

seizure disorder for which Phenobarbital was prescribed. What is
the loading dose to produce a plasma concentration of 10 μg/mL?
𝐿
0.7 × 40 𝑘𝑔 × 10 𝑚𝑔/𝐿
𝑘𝑔
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 =
1 × 0.9
𝑚𝑔
𝐿𝑜𝑎𝑑𝑖𝑛𝑔 𝐷𝑜𝑠𝑒 = 311 𝑚𝑔 = 325 𝑚𝑔 (5 𝑡𝑎𝑏𝑙𝑒𝑡 𝑜𝑓 65 )
𝑡𝑎𝑏𝑙𝑒𝑡

BHND | Sources: Lecture notes + PPT + Katzung, 13th Ed + Lippincott , 6th Ed + First Aid (2015) Page 13 of 13