I.

Mechanisms of Drug Action

- Primary target: transcription factors in the

nucleus
Activation of receptor through dissociation from
binding proteins Ligand-receptor complex
moves to nucleus Dimerization of ligandreceptor complex Bind to transcription
factors regulating gene expression
- Hours to days
E.g. Steroid receptors
Tubulin target of antineoplastic agents e.g.
paclitaxel
Dihydrofolate reductase target of
antimicrobials e.g. trimethoprim
50s subunit of bacterial ribosome target of
macrolide antibiotics e.g. erythromycin

A. Drug-Receptor Interaction
Drug (Signal) Bind to receptors (Signal detector)
Initiate series of reactions Specific intracellular
response
Second messenger or effector molecules part of
series of events that translates agonist binding into
a cellular response
Drug-receptor complex, magnitude of
response
B. Major Families of Receptors
1. Ligand-gated ion channels Changes in
membrane potential or ionic concentration in
the cell
- Mediate neurotransmission, cardiac or muscle
contraction
E.g. Cholinergic nicotinic receptors Na+ influx,
K+ outflux
GABA receptors increase Cl- influx and
hyperpolarization of neurons
Local anesthetics bind to voltage-gated sodium
channel; inhibits Na+ influx and decreases
neuronal conduction
2.

G protein-coupled receptors Protein

phosphorylation
- Extracellular: Receptor domain
Intracellular: Interacts with G protein or
effector molecule
3 Protein Subunits of G Protein
a. subunit binds GTP
b. and subunits anchor G protein in the
cell membrane

Agonist + receptor and GTP binding

dissociation of -GTP complex from complex
Complexes interact with cellular effectors e.g. enzyme,
protein, ion channel (sometimes effectors produce
second messengers to create cascade effect)
E.g. and adrenoceptors
3.

4.

Enzyme-linked receptors Protein and

receptor phosphorylation (activates a kinase
enzyme)
- Conformational changes cytosolic
enzyme activity (depends on structure and
function)
- Possess tyrosine kinase activity as part of
receptor structure
Activated receptor autophosphorylation of
tyrosine phosphorylation of other proteins
E.g. Insulin receptors
Intracellular receptors Protein
phosphorylation and altered gene expression
(interact with intracellular receptor)
- Ligand diffuse into cell to interact with
receptor (ligand must have sufficient lipid
solubility)

Hydrophilic ligand binds to extracellular receptors

Hydrophobic ligand binds to intracellular receptors
cAMP mobilization of stored energy, conservation of
water by the kidney (vasopressin), Ca2+ homeostasis
(PTH), and, rate and contractile force of heart muscle
(b-adrenomimetic catecholamines)
-

Regulate adrenal and sex steroids production,

smooth muscle relaxation

cGMP intestinal mucosa and vascular smooth muscle

II.

cGMP, relaxation of vascular smooth muscle

Classification of Drug Action

Competitive agonist reduce agonist potency (

EC50)
Noncompetitive antagonist reduce agonist
efficacy ( Emax)
1.

a.

b.
c.

2.

Agonist binds to receptor and produces a

biologic response based on:

Agonist concentration

Fraction of activated receptors

Full agonist binds to receptor and produces
maximal biologic response that mimics the
response of endogenous ligand
Full agonist + receptor Stabilize receptor at
active state
Should produce the same Emax for a
receptor population
Partial agonist act as an antagonist of the full
agonist
act as both an agonist and antagonist
Inverse agonist Stabilize the inactive receptor
and cause active receptors to convert to
inactive
Antagonist bind to a receptor with high
affinity but possess zero intrinsic activity
Decrease the effect of agonist when
present
Occur either by:

Block drugs ability to bind to

receptor

Block ability to activate receptor

a.

Competitive antagonist antagonist and

agonist bind to the same receptor in a
reversible manner
Prevents agonist to bind to its receptor and
maintain receptor at inactive state
Inhibition can be overcome by increasing
number of agonist
Shift agonist dose-response curve to the
right (EC50*) without affecting Emax

EC50* - concentration of drug that gives halfmaximal response

b.

c.

Irreversible antagonist bind covalently to the

active site of receptor, reducing the number of
sites available for the agonist
Downward shift of Emax, no shift of EC50
values
Cannot be overcome by increasing number
of agonist
Noncompetitive
Allosteric antagonist downward shift of Emax,
no change in EC50 value of agonist
Binds to site other than agonist-binding
site, prevents receptor from being
activated by agonist
E.g. picrotoxin + inside of GABA-controlled Clchannel no Cl- can pass through even when
the receptor is fully activated by GABA

d.

Functional antagonism antagonist act at a

completely different receptor functionally
opposite effect to agonist
E.g. Epinephrine
Histamine + H1 histamine receptor (bronchial
smooth muscle) bronchoconstriction
(bronchial tree) Epinephrine + 2adrenoceptors (bronchial smooth muscle)
muscle relaxation (Physiologic antagonism)

III.

Emax assumes all receptors are occupied by the

drug and no increase in response is observed if
higher concentration of drug is obtained
IV.

Quantal Dose-Response Relationships

Useful for determining doses to which most of the

population responds
Quantal response dose-response relationship
between dose of the drug and proportion of a
population that responds to it
ED50 drug dose that causes a therapeutic
response in half of the population
Therapeutic Index ratio of the dose that
produces toxicity in half of the population (TD50) to
the dose that produces clinically desired or
effective response (ED50) in half of the population
-

V.

Reaction Kinetics

Michaelis-Menten Equation
-

Graded Dose-Response Curves

Drug concentration, pharmacologic effect

(gradually until all receptors are occupied
(maximum effect))
Potency measure of the amount of drug
necessary to produce an effect of a given
magnitude
-

Determined by the concentration of drug

producing 50% of the maximum effect
(EC50)

Efficacy magnitude of response a drug causes

when it interacts with a receptor
-

Dependent on:

number of drug-receptor
complexes formed

intrinsic activity of drug

Efficacy, therapeutic benefits

Measure of drugs safety

value, wideness of margin between
doses that are effective and doses that are
toxic
Determined by drug trials and accumulated
clinical experience

E + S (reversible) ES complex product

+ free enzyme regeneration
Assumptions:

[S] > [E] so that the percentage of

total substrate bound by the
enzyme at any one time is small

[ES complex] does not change with

time (steady-state assumption
intermediates)
Rate of formation of ES = Rate of
breakdown of ES

Rate of reaction is measured as

soon as enzyme and substrate are
mixed forming product with very
small concentration

Michaelis constant (Km) characteristic of

enzyme and its particular substrate
-

Reflects affinity of enzyme for the

substrate
Numerically equal to substrate
concentration at which reaction velocity =
Vmax
Does not vary with enzyme concentration
Km, affinity of enzyme for substrate
(because low concentration of substrate is
needed to half-saturate the enzyme)
Km, affinity of enzyme for substrate
(because a high concentration of substrate
is needed to half-saturate the enzyme)

Rate of reaction is directly proportional to [E] at all

[S]

E.g. Anticancer drugs, diagnosis of

peripheral vascular diseases

[S] < Km velocity of reaction is proportional to

substrate concentration (First-order with respect to
substrate)

B. Extravascular routes
1. Oral easily self-administered
Toxicities or overdose may be overcome
with antidotes E.g. activated charcoal
a. Enteric-coated coating protects drug
from stomach acid
Delivers drug to the intestine (less
acidic)
For drugs that are acid unstable
b. Extended-release has special
coatings/ingredients that control drug
release
Slower absorption, prolonged duration of
action
Maintain concentration in the therapeutic
range over a longer period of time
For drugs with short half-lives
2. Rectal Bypasses the portal circulation
Prevent destruction of drug in the GI
environment
Useful if the drug induces vomiting when
given orally
3. Topical used when a local effect of the drug is
desired
4. Intramuscular can be in aqueous solutions
(absorbed rapidly) or in specialized depot
solutions (absorbed slowly)

[S] > Km velocity is constant and equal to Vmax;

rate of reaction is independent of substrate
concentration (Zero-order with respect to
substrate)
Zero-order kinetics enzyme is saturated by a
high free drug concentration and the metabolism
rate remains constant over time
-

Constant amount of drug is metabolized

per unit of time
Rate of elimination is constant and does
not depend on drug concentration

First-order kinetics obey Michaelis-Menten

kinetics
-

Concentration of drug < Km

Rate of drug metabolism and elimination is
directly proportional to the concentration of
free drug

Half-life time required to change the amount of

drug in the body by 50% during elimination or
during a constant infusion
a.
b.

Zero-order half-life half-life decreases with

decreasing concentration
First-order half-life length of half-life is
constant

VI.
Absorption
A. Intravascular routes
1. Intravenous (IV) most common parenteral
route
Useful for drugs not absorbed orally e.g.
rocuronium (neuromuscular blocker)
Permits rapid effect and maximum degree
of control over the amount of drug
delivered
Bolus: full amount of drug is delivered to
systemic circulation almost immediately
IV infusion: drug is infused over a longer
period of time peak plasma
concentrations, duration of circulating
drug levels
Advantageous for drugs that cause
irritation when administered via other
routes because the substance is rapidly
diluted by the blood
2. Intra-arterial method of delivering a drug
directly into artery or arteries to localize its
effect to a particular organ/body region
First-pass and cleansing effects of the lungs
are not available when the agent is given
by this route

Depot preparations often consists of a suspension

of the drug in a nonaqueous vehicle e.g.
polyethylene glycol
Vehicle diffuses out of the muscle Drug
precipitates at site of injection Drug dissolves
slowly Sustained dose over an extended period
of time
E.g. haloperidol, medroxyprogesterone
5.

6.

Intradermal administered into the corium of

the skin
Common sites of injection are the arm and
the back
Performed as diagnostic measures E.g.
tuberculin, allergy testing
Subcutaneous absorption via simple diffusion
Slower than IV route
Minimizes risk of hemolysis and thrombosis
associated with IV injection
Constant, slow, and sustained effects
E.g. insulin, heparin

VII.
Mechanisms of Drug Absorption
1. Passive diffusion Driving force: concentration
gradient across a membrane separating two
body compartments (drug moves from high to
low)
No carrier involved
Not saturable
Low structural specificity
2. Active transport involves carrier proteins

3.

4.

5.

Drugs that closely resemble the structure

of naturally occurring metabolites are
actively transported across cell membranes
using carrier proteins
Energy-dependent (through ATP hydrolysis)
Moves drug from high to low concentration
Saturable
Selective
Competitively inhibited by other
cotransported substances
Facilitated diffusion Large molecules enter
cell through specialized transmembrane carrier
proteins
Carrier proteins undergo conformational
changes
Move drugs from high concentration to low
concentration
Does not require energy
Saturated
Inhibited by compounds that compete for
the carrier
Endocytosis Engulfment of exceptionally large
drug by the cell membrane and transport into
the cell by pinching off the drug-filled vesicle
E.g. Vitamin B12
Exocytosis Secrete substance out of the cell
through vesicle formation
E.g. Norepinephrine (neurotransmitter)

VIII.
Factors Affecting Drug Absorption
1. pH
Weakly acidic drugs: release proton, form
charged anion
Weakly basic drugs: protonated form is
charged, loss of proton produces
uncharged
Drug passes through membranes more
readily if it is uncharged
pKa, acidity
pKa, basicity
Distribution equilibrium is achieved when
the permeable form of a drug achieves an
equal concentration in all body water
spaces
2. Blood flow to the absorption site - blood flow,
absorption
E.g. intestine
- Shock reduces blood flow severely to
cutaneous tissues, SC absorption
3. Total surface area available for absorption -
surface area, efficient absorption
E.g. intestinal brush borders with microvilli
4. Contact time at the absorption surface if
drugs moves very quickly in the GI tract, it is
not well absorbed
Presence of food in the stomach both
dilutes the drug and slows gastric
emptying drug taken with a meal is
generally absorbed more slowly
5. Expression of P-glycoprotein
Expressed in liver, kidneys, placenta,
intestines, brain capillaries

expression, P-glycoprotein reduces drug

absorption
P-glycoprotein Transmembrane transporter
protein responsible for transporting various
molecules (e.g. drugs), across cell membranes
Involved in transportation of drugs from
tissues to blood
Associated with multidrug resistance
IX.
Phases of Metabolism
A. Phase I
Lipophilic drugs Introduction or
unmasking of polar functional group e.g.
OH or NH2 Polar molecule
Catalyzed by cytochrome P450 system
important for metabolism of endogenous
(e.g. steroids, lipids) and exogenous
(xenobiotics) substances
Cytochrome P450 is a superfamily of hemecontaining isozymes that are located in
most cells primarily in the liver and GI tract
Not involving the P450 system: amine
oxidation, alcohol dehydrogenation,
esterases, and hydrolysis
B. Phase II conjugation reaction with an
endogenous substrate e.g. glucuronic acid,
sulfuric acid, acetic acid, or amino acid results
in polar, usually more water-soluble
compounds that are therapeutically inactive.
If the metabolite from phase I metabolism
is sufficiently polar, it can be excreted by
the kidneys or in bile (many phase I
metabolites are still too lipophilic to be
excreted)
Glucuronidation most common and most
important conjugation reaction
X.
Renal Process
A. Glomerular filtration
Drug (through renal arteries) Kidneys
formation of glomerular capillary plexus
drug not bound to album flows through
capillary slits Bowman space
Lipid solubility and pH DO NOT influence
passage of drugs into glomerular filtrate
GFR variations and protein binding drugs
AFFECT passage of drugs into glomerular
filtrate
B. Proximal tubular secretion
Drug not transferred into glomerular filtrate
Leave glomeruli through efferent
arterioles Form capillary plexus
surrounding nephric lumen in the proximal
tubule
Secretion occurs in the proximal tubules by
two energy-requiring active transport
systems:
a. Anions E.g. deprotonated forms of
weak acids
b. Cations E.g. protonated forms of weak
bases
C. Distal tubular reabsorption

Drug moves toward distal convoluted

tubule, concentration of drug, exceeds
perivascular space Uncharged drug
Diffuse out of the nephric lumen
Systemic circulation
Urine pH manipulation can be done to
increase fraction of ionized drug in the
lumen to:
a. Minimize amount of back diffusion
b. Increase clearance of an undesirable
drug

Ion trapping
XI.
-

Weak acids: eliminated by alkalinization of

urine
Weak bases: increased acidification of
urine
Drug Clearance
May occur via intestines, bile, lungs, and
breast milk
Drugs not absorbed after oral
administration or not excreted directly into

the intestine or into bile are eliminated

through feces
Lungs eliminate anesthetic gases

Total Body Clearance sum of all clearances

from the drug-metabolizing and drugeliminating organs
-

Kidney often the major organ of

elimination
Liver contribute through metabolism
and/or excretion into the bile