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What is Pharmacology?

study of substances that react with


living systems through chemical
processes
BINDING to regulatory molecules
ACTIVATING or INHIBITING normal
body responses

Pharmacology: Areas of
Study
Medical Pharmacology
science of substances used to
prevent, diagnose & treat disease
Toxicology
deals with undesirable effects of
chemicals on living systems
(cells to ecosystems)
- Poisons & Organ toxicity

Pharmacology: Areas of
Study

2 MAIN SUBDIVISIONS:

Pharmacokinetics processes that


determine the concentration of drugs
in body fluids & tissues over time
- what the body does to the drug

Pharmacodynamics actions of drugs


on target organs
- what the drug does to the body

Pharmacology: Areas of
Study
Pharmacotherapeutics use of drugs
in the treatment of disease
Pharmacogenomics study of genetic
variations that cause differences in
drug response

Nature of Drugs
DRUG
- natural product, chemical
substance, or pharmaceutical
preparation for administration to
diagnose or treat a disease
- any substance that brings about a
change in biologic functions
through its chemical actions

Nature of Drugs
Synthetic
1. Aspirin
2. Barbiturates
3. Local anesthetics
Xenobiotics:
chemicals not synthesized in the
body

Nature of Drugs

isolated from
natural sources
or synthesized in
the laboratory
drugs intended
for
administration to

Nature of Drugs
Pharmaceutical Preparations
1.
2.
3.
4.
5.

TABLETS AND CAPSULES


SOLUTIONS AND SUSPENSIONS
SKIN PATCHES
AEROSOL
OINTMENTS, CREAMS, LOTIONS, AND
SUPPOSITORIES

Nature of Drugs
Routes of Administration
1. Topical Administration
2. Systemic Administration
A. Enteral
Administration
3. Oral
4. Rectal
5. Sublingual
6. Buccal
C. Transdermal
Administration
D. Inhalation
Administration

B. Parenteral
Administration
1.
Intravenous
2.
Intramuscular
3.
Subcutaneous
4.
Intrathecal
5.
Intra-articular
6.
Intra-dermal
7.
Epidural

Nature of Drugs
Drug Size
MW: 7 (Lithium)
59,050 (altepase)

Intravenous
or Intraarterial

MW 100-1000
drugs must be able to move from site
of administration to site of action

Nature of Drugs
Drug Reactivity & Drug-Receptor Bonds
1. Covalent very strong
e.g. ASA + cyclooxygenase
2. Electrostatic more common; relatively
strong (ionic bonds), weak (hydrogen
bonds), very weak (van der Waals forces)
3. Hydrophobic weak; interaction of lipidsoluble drugs with cell membrane

Nature of Drugs
Drug Reactivity & DrugReceptor Bonds
Drugs that form weak bonds with
receptors are more selective.

Nature of Drugs
Drug Shape
Complementary to its receptor as a
key to a lock
Stereoisomerism
*one enantiomer may be more potent than
the other
* one enantiomer more susceptible to drugmetabolizing enzymes (duration of action)

Me-too drug
structurally very similar to already known
drugs, with only minor differences.
genericdrugwith an identical formulation
and stated indications as adrugpreviously
approved by the FDA
chemically related to the prototype, or other
chemical compounds which have an identical
mechanism of action

Nature of Drugs
Side Effects
nuisance; tolerated to gain benefit of therapeutic effect
e.g. dry mouth & sedation of antihistamine

Adverse Effects
undesired and may be harmful
e.g. persistent diarrhea

Toxic Effects
Poisoning, extremely harmful & may be life-threatening

PHARMACOKINETIC
PRINCIPLES
Processes:
Absorption entrance of a drug
into the bloodstream
Distribution various tissues &
organs
Metabolism biotransformation
Elimination excretion of drug
(renal, intestinal, respiratory)

PHARMACOKINETIC
PRINCIPLES
Absorption
Permeation
-Movement through barriers separating
compartments
-Oral drug intestinal wall capillary wall
BBB walls of capillaries perfusing the
brain

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
1. Aqueous diffusion drugs diffuse through
aqueous channels
large aqueous compartments (interstitial
space, cytosol)
epithelial membrane tight junctions &
endothelial pores
(MW 20,000-30,000)

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
2. Lipid diffusion most important limiting factor in
permeation
- lipid:aqueous partition coefficient determines how
readily drug moves between aqueous & lipid media
- Ability of weak acid & weak base to move from
aqueous to lipid media or vice versa varies with the
pH of the medium

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
Electrostatic charge of ionized molecule attracts water
dipoles polar, water-soluble & lipid-insoluble complex
Weak acid neutral molecule that can reversibly
dissociate into an anion & proton
C8H7O2COOH C8H7O2COO- + H+
Neutral ASA

ASA anion

Weak base neutral molecule that forms cation by


combination with a proton
C12H11O2CIN3NH3+ C12H11O2CIN3NH2 + H+
Pyrimethanine cation

Neutral Pyrimethanine

PHARMACOKINETIC
PRINCIPLES

Mechanisms of Permeation

Law of Mass Action = these reactions move to the


left in acidic environment (low pH, excess protons)
& to the right in alkaline environment
C8H7O2COOH

ACID
Neutral ASA

BASE

ASA anion

C12H11O2CIN3NH3+
Pyrimethanine cation

C8H7O2COO- + H+

C12H11O2CIN3NH2 + H+
Neutral Pyrimethanine

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers for molecules that are
too large or too insoluble to lipid
(peptides, AA, glucose)
- facilitated diffusion & active transport
- selective, saturable , inhibitable

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
ABC ATP- binding cassette family
- Less selective & expel foreign
molecules
1. P-glycoprotein or MDR1 (multi-

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
2. MDRP (MDR protein) transporters
- for excretion of drugs & metabolites in
urine & bile
- plays a role in resistance of tumors to
chemotherapeutic drugs

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
3. Special Carriers
SLC (Solute carrier) family
- important in uptake of Neurotransmitters
NET (Norepinephrine transporter)
SERT (Serotonin transporter)
VMAT (Vesicular monoamine transporter)

PHARMACOKINETIC
PRINCIPLES
Mechanisms of Permeation
4. Endocytosis/Exocytosis for molecules
that are too large & impermeant
e.g. B12 (intrinsic factor)
Fe (transferrin)
Neurotransmitters

PHARMACOKINETIC
PRINCIPLES
Absorption
Bioavailability fraction of unchanged
drug reaching systemic circulation following
administration
IV 100%
IM, SC, Transdermal - < 100%
Oral, Rectal - < 100%

PHARMACOKINETIC
PRINCIPLES
Factors affecting Bioavailability
A. Extent of Absorption
Incomplete Low Bioavailability
Oral administration incompletely absorbed in the
gut
Hydrophilic drug cannot cross CM
Hydrophobic drug cant cross water layer adjacent
to cell
Reverse transporter P-glycoprotein
pumps drug out of gut wall back into

PHARMACOKINETIC
PRINCIPLES
Factors affecting
Bioavailability
B. First-Pass Effect
- portal blood delivers drug to the
liver prior to entry in systemic
circulation
Direct access to systemic veins

Alternative Routes
Sublingual
Transdermal

PHARMACOKINETIC
PRINCIPLES
Summary
Factors controlling Rate of
absorption:
1.Degree of ionization
2.Surface Area
3.Blood flow
4.Gastric emptying time & GI
motility

PHARMACOKINETIC
PRINCIPLES
Distribution
Volume of Distribution (V)
- Defined with respect to blood, plasma, or water
- An apparent volume necessary to contain the
amount of drug homogenously found in blood,
plasma, or water
- Can vastly exceed physical volume of the body

0.4 L/kg

0.04 L/kg

0.6 L/kg

0.2L/kg

PHARMACOKINETIC
PRINCIPLES
Distribution
Volume of Distribution
V = Amount of drug (dose)
C plasma conc.

= 500 mg
0.01 mg/ml

= 50000 ml or 50L
e.g. A 500 mg New drug was administered . The
plasma concentration is 0.01mg/ml. What is the V?

PHARMACOKINETIC
PRINCIPLES
Distribution
COMPARTMENT
Total body water
Extracellular
water
Blood

Fat
Bone

EXAMPLE OF DRUGS
Ethanol: Small water
soluble
Gentamicin: Large water
soluble
Heparin: Strongly plasma
protein-bound large
molecules
DDT : highly lipid soluble
Lead, Fluoride: ions

PHARMACOKINETIC
PRINCIPLES

Distribution

Binding to Plasma Proteins


- Use to achieve ideal therapeutic regimen:
1. sufficient amount of drug reach site of action to bring
desired effect
2. drug should not disappear too rapidly in site of action

PHARMACOKINETIC
PRINCIPLES
Distribution
Binding to Plasma Proteins
1. Albumin most important; high affinity to drugs
2. Glycoproteins
3. Lipoprotein
4. Globulins

PHARMACOKINETIC
PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
1. Extent of binding free drug (unbound) able to distribute
2. Ability to diffuse through CM lipophilic
3. Degree of perfusion higher perfusion, faster equilibrium
Lung - 10 Kidney - 4
Heart
- 0.6 Brain - 0.5
Muscle 0.025 Fat - 0.003

PHARMACOKINETIC
PRINCIPLES
Distribution
Factors Affecting Rate of Distribution:
4. Properties of tissue membrane
Blood Brain Barrier tightly joined capillaries covered by
foot-like processes of astrocytes
Placental Barrier
separates fetal & maternal blood
- lipid-soluble drugs diffuse easily; water-soluble
drugs diffuse poorly

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation
Why is this necessary?

1. Active organic drugs tend to be lipophilic &


remain unionized or partially ionized in
physiologic pH; readily reabsorbed in
nephron
2. Lipophilic compounds are strongly bound to
albumin & not readily filtered
3. Prolonged duration of action if termination
is through renal excretion

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Site:
Kidneys
Brain
Skin
GI tract
Gastric acid - penicillin
Digestive enzymes insulin
Enzymes in intestinal wall

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Site:
Plasma
hydrolyzed by
e.g. succinylcholine
pseudocholinesterase
lidocaine
Lungs
e.g. converts Angiotensin I to
Angiotensin II

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation
Major Categories

Phase I Reactions
- convert parent drug to a more polar metabolite by
introducing or unmasking a functional group
(-OH, -NH2, -SH) to be readily excreted
Oxidations Deamination
Desulfuration Reductions
Hydrolyses
e.g. Isoniazid N-acetyl conjugate hydrolyzed to
isonicotinic acid

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation
Major Categories
Phase II Reactions

- those not readily eliminated undergo


subsequent reaction in which endogenous
substrate
combine with newly incorporated functional
group to form highly polar conjugate
Glucuronic acid Acetic acid
Sulfuric acid
Amino acid

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Phase II Reactions
- relatively faster
- previously terminal inactivation events or true
detoxification
- May precede Phase I reaction
Conjugates
- Polar molecules readily excreted & often
inactive
- Involves high-energy intermediates & specific
transfer enzymes

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation
Subcellular Site:

Endoplasmic reticulum
Mitochondria
Cytosol
Lysosomes
Plasma membrane
Microsomes lamellar membranes of
ER reform into vesicles after

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Transferases located in microsomes or


cytosol
1. UDP (uridine 5diphosphate)glucoronosyl transferase most dominant
e.g. coupling of UDP derivative of glucuronic
acid with bilirubin (Glucuronidation)
2. Sulfotransferase
- sulfation of PAPS (3phosphoadenosine 5phosphosulfate)

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Transferases
3.GSH (glutathione) transferase
- GSH conjugation
4. N-acetyl transferase
e.g. Isoniazid N-acetyl conjugate
- acetylation
5. Methyltransferase
- transmethylases methylation
Epoxide Hydrolases water conjugation

Absorptio
n

Metabolism
Phase I

Drug

Drug

Elimination

Phase II
Conjugate

Drug
metabolite
with modified
activity
Inactive drug
metabolite

Conjugate

Conjugate

Drug

Lipophilic

Hydrophilic

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation

Metabolism to Toxic Products


- Compounds metabolically
transformed to reactive
intermediates that are toxic to
various organs

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation
Acetaminophen
Glucuronidation

CYP1 CYP3A4
Sulfation

Non-toxic Reactive Non-toxic


Glucuronide
Intermediates

Sulfate

(N-acetylbenzoiminoquinone)

+
GSH
Neucleophillic
conjugation
cellular proteins
Mercapturic Acid
conjugate

Liver Cell Death

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation: Variables


in Differences
1. Genetics
Genetic polymorphissm
- genetic factors influence enzyme
levels
- occurrence of variant allele at
population
frequency 1%

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation: Variables in Differences


1. Genetics
Autosomal Recessive Traits
e.g. Succinylcholine
metabolized half rapidly in persons with
deficiency
of pseudocholinesterase or
butyrylcholinesterase
(BCHE)
INH slow acetylators phenotype
- 50% Caucasians, less common in

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation: Variables in


Differences
2. Age increase toxicity in extreme ages

Neonate deficiency in UGT


Glucoronide formation - adult value at 3-4yo

Elderly decline of liver to recover from injury


3. Sex
Male faster metabolism

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation: Variables in Differences


4. Diseases

Liver diseases impaired hepatic drugmetabolizing enzymes


Cardiac diseases impaired hepatic blood flow
Pulmonary diseases reduced hepatic
metabolism
Endocrine diseases
Hypothyroidism - reduced hepatic metabolism
Hyperthyroidism increased hepatic metabolism

PHARMACOKINETIC
PRINCIPLES

Drug Biotransformation: Variables in


Differences
5. Nutritional & environmental
charcoal-broiled food
cruciferous vegetables
grapefruit - inhibitor
cigarette smoke
pesticides

inducers

inducers

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Common Pathways:
Sweat
Saliva
Milk
Respiratory - role not significant in excretion
- when drugs are metabolized into
products that can be exchanged
from blood into respiratory system
- excreted by lungs

PHARMACOKINETIC
PRINCIPLES

Drug Excretion
Common Pathways:

GI - after oral administration, portion of


drug is unabsorbed & is excreted in the
feces
Enterohepatic pathway
lipid soluble drug liver bile
intestine blood liver

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Common Pathways:
Renal

- blood filtered & reabsorbed


- urinary waste products & nonabsorbable form are
excreted
- excretion of drug & metabolite: water soluble
Acidic drug basic urine
Basic drug acidic urine

Fruits
Protein rich
Vegetables
food
Na2HCO3
Probiotics

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Clearance: measure of the body to eliminate the drugs


: factor that predicts rate of elimination in relation to
drug concentration
: defined in respect to blood, plasma or unbound in
water
CL = Rate of Elimination (mg/min)
C (mg/ml)
e.g. A 1 liter of water contains 1000mg drug. After
an hour 100mg of drug has been removed. What is
the clearance of this drug?
100 ml/hr

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Clearance : dividing rate of elimination at each organ by conc. of drug


yields respective clearance, together equal total systemic
clearance
CL

kidney

= Rate of Elimination kidney


C

CL liver = Rate of Elimination liver


C
CL other = Rate of Elimination other
C
CL systemic = CL

kidney

+ CL liver + CL other

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

First-order elimination
: constant over concentration
range
: elimination is not saturable
: rate of drug elimination is directly
proportional to concentration

Drug Concentration
(%max)

100
80
-

60
-

40

Time

20
0

Drug Concentration
(%max)

100 .0

10.0

1.0 -

Time

0.1

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Zero-order elimination
Capacity-limited elimination
Mixed-order, saturable, dose or
concentration dependent
Nonlinear or Michealis-Menten
elimination

Drug Concentration
(%max)

60

40

20

Time

Drug Concentration
(%max)

100
-

80

100

10
Time

PHARMACOKINETIC
PRINCIPLES

Steady state concentration (Css)


In multiple dosing or constant infusion, drug will
accumulate until amount administered per unit
time is equal to amount eliminated per unit time

100
75

50

Plasma Concentration
(%of steady state)

Drug Excretion

25

1
7

2 3 4
8Time

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Flow Dependent Elimination


Drugs are cleared readily
Elimination depend primarily on
rate of drug delivery to organs of
elimination
Blood flow is main determinant of
drug delivery

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

Half life
Time required to change the amount
of drug in the body by during
elimination or constant infusion
Time course will depend on V & CL
t1/2 = 0.7 x V
CL

Elimination can be
described by exponential
process, time taken for 2fold decrease is
proportional to log 2 (0.7)

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

100
75

50

Drug
accumulation
in constant rate
of infusion

Plasma Concentration
(%of steady state)

Half life
Indicates time required to attain 50% steady state
or to decay 50% from steady state

25

1
7

2 3 4 5 6
8Time (half lives)

Drug elimination
after constant
rate of infusion
reached steady
state

PHARMACOKINETIC
PRINCIPLES

Drug Accumulation

Whenever drug doses are repeated, drug will


accumulate in the body until dosing stops
Detectable if dosing is shorter than 4 half-lives
Inversely proportional to fraction of a dose lost
in each dosing interval

PHARMACOKINETIC
PRINCIPLES

Drug Excretion

100
75

50

Peak

Css

Trough

Plasma Concentration
(%of steady state)

Average concentration (Cav)


In repeated doses, concentration fluctuates
around a mean (Css) with peak & trough values

25

1
7

2 3 4
8Time

PHARMACODYNAMIC PRINICPLES:
Objectives:
1. Identify the different target proteins and discuss their
mechanisms of drug-receptor interactions
2. Discuss the concepts of affinity, intrinsic activity,
selectivity and specificity
3. Describe signal transduction mechanisms, the
different types of G-proteins, and second messenger
system
4. State the occupancy theory and receptor inactivation
theories
5. Describe the different dose-response curves and the