Pharmacology:

Pharmacokinetics : what the body does to

the drug (absorption, distribution,
biotransformation, and excretion)
Pharmacodynamics : what the drug does to
the body

Physicochemical factors in transfer of

drugs across membranes
1. Drug factors: size and shape, degree of
ionization, lipid solubility, protein binding.
2. Membrane factors: a bilayer amphipatic
lipids; proteins serve as receptors, channels,
or transporters.
3. Types of transport: a) cellulars (passive
diffusion, active transport, facilitated
diffusion); b) paracellular (filtration).

Passive membrane transport is directly

proportional to:

Drug concentration gradient across the

membrane.
Lipid: water partition coefficient.
Cell surface area
Differences in pH

[1]

[1000]

A- + H+

HA

Total
[HA]+[A]

pH = 7.4

Plasma

[1001]

Lipid Mucosal Barrier

pH = 1.4

Gastric Juice

[1]

HA
Weak acid HA
nonionized

[1000]

[1001]

A- + H+
A- + H+

pKa = 4.4

ionized

Active membrane transport:

Requirement for energy.

Against electro-concentration gradient.
Saturability.
Selectivity.
Inhibited by cotransported compounds.

Transporter proteins:

Mediate drug uptake or efflux.

P-glycoprotein is an important efflux
transporter in hepatocyte, brain capillaries,
and enterocyte.

Transporter proteins (TP):

There are two major TP superfamilies: 1) ABC (ATP

binding cassete); 2) SLC (Solute carriers).
The SLC type of transporter mediate either uptake or
efflux, whereas ABC transporters mediate only
unidirectional efflux.
Most ABC proteins are primary active transporters,
which rely on ATP hydrolysis to actively pump their
substrates across. Among the best known transporter in
the ABC superfamily is P glycoprotein (P-gp, also termed
by MDR1, encoded by ABCC7).It is an important efflux
transporter in hepatocyte, brain capillaries, and
enterocyte.
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Transporter Proteins (TP):

SLC superfamily includes genes that encode

facilitated transporters and ion-coupled secondary
active transporters that reside in various cell
membrane.
Many serve as drug targets or in drug absorption
and disposition. Widely recognized transporters
include the serotonin and dopamine transporters.
Drug transporters operate in pharmacokinetic and
pharmacodynamic pathways, including pathways
involved in both therapeutic and adverse effects.

Absorption

The rate and the amount of a drug leaves

its side of administration
Different sites of administration have
different rate & extend of absorption
GI motility, malabsorptive states, and food
may alter the oral absorption
Physicochemical properties of the drug
affect its absorption
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Administration

A knowledge of the advantages and

disadvantages of the different routes is of
primary importance in deciding the choice of
administration: oral, sublingual, suppository,
inhalation, local, topical, intravenous,
intramuscular, subcutan, etc.

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Bio-availability (1)

The rate & the amount of administered

drug reaches the systemic circulation intact
The rate depends on pharmaceutical
factors and GI absorption, the extent
depends on the extent of absorption and
the extent of pre-systemic metabolism

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Bio-availability (2)

Dosage form of a drug from different

manufacturers sometimes differed in their
bioavailability
Rectal solution, but not suppository
formulation, is absorbed better than oral
formulation, and the potential for first passmetabolism is less potential

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Distribution (1)

Unbound drug is distributed into interstitial and

cellular fluids
The rate and the extent of a drug distributed
into extra vascular fluids depend on
physiological factors, physiochemical properties,
and the extend of its binding to plasma proteins
Two phases of distribution: faster and slower
Lipid solubility is an important determinant of
tissue uptake

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Distribution (2)

Highly bound drug will yield an increase in

unbound fraction in cases or renal
impairment, the last trimester of
pregnancy, displacement by other drugs
and saturability of protein binding
BBB restricts the entry of drugs into CFS
and CNS extra cellular space
Termination drug effect may also result
from redistribution
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Distribution of drugs into and out of CNS

It is unique because functional barriers are present

Brain capillary endothelial cells have continuous tight
junction
The unique precapillary cells also contribute to BBB
At the choroid plexus a similar barrier is also present.
The lipid solubility and the unbound of the drug is
determinant of its uptake by the brain
Efflux carrier is another important factor in functional
BBB
Drugs also exit CNS along the flow of CFS through villi

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Placental Transfer

Drug may cause congenital anomalies

Lipid solubility, extend of plasma binding, and
degree of ionization are determinant of the transfer
Fetal plasma is slightly more acidic (pH 7.0-7.2), so
that ion trapping of basic drugs occur
P-glycoprotein is present in placenta
The view that placenta is an absolute barrier is
inaccurate

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Plasma Proteins (1)

Acidic drugs are bound to albumin

Basic drugs are bound to acid glycoprotein
The binding is usually reversible
Drugs bound to plasma is determined by conc.,
affinity, and number of binding sites
Plasma binding is saturable process
Within the therapeutic ranges the unbound fraction
is relatively constant.
Hypoalbuminemia results in reduced binding

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Plasma Protein (2)

Elevated levels of acid glycoprotein enhance binding

of basic drugs
Drugs with similar physicochemical properties can
compete each other
Only unbound drug is in equilibrium across
membranes
Unbound drug in intracellular water is the same as
that in plasma.
Binding also limits glomerular filtration of the drug.

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Fat as Reservoir

Lipid soluble drugs are stored in the neutral fat

In obese the fat content may be as high as 50% of
body weight
Fat serves as an important reservoir for lipid soluble
drugs. For example, 70% thiopental may be present
in body fat 3 hours after administration.
Muscles, bones, and plasma proteins can serve as
drug reservoirs

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Redistribution

From its site of action into other tissues

May terminate drug effect
Thiopental is a good example

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Biotransformation (1)

To generate more polar, inactive metabolites that are

readily excreted from the body
Classified as phase I and Phase II reactions. Phase I
results in the loss of pharmacological activity; phase
II lead to conjugate with endogenous compounds.
Conjugates are highly polar, inactive, and rapidly
excreted. Phase I is in ER: phase II is cytosolic.
There are three major types of biotransformation
reactions: oxidative, hydrolysis, and conjugation.
Cytochrome P450 1,2, and 3 families (GYP1, CYP2,
and CYP3) are responsible for the oxidative
metabolism of numerous drugs

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Biotransformation (2)

Cyp3A4 is involved in biotransformation of a

majority of all drugs and it is expressed in
significant amount in GI tract.
The first-pass metabolism limits the oral
availability of highly metabolized drugs.
Drugs that are metabolized by or bind to the
same CYP have a high potential for
pharmacokinetic interactions.
Epoxide hydrolase is detoxification enzyme,
hydrolyzing highly oxides generated from
CYP450 oxidation reactions to inactive, water
soluble metabolites.
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Biotransformation (3)

Glucoronidation is quantitatively the most important

conjugation reation.
UDP-glucoronyl transferases catalyze the tranfer of an
activated glucoronic acid molecule to form glucoronide
conjugates.
The increased water solubility of the glucoronide
conjugates promotes their renal elimination.
Most phase II reactions are cytosolic, but UDPglucoronyl tranferases are microsomal enzymes.
Acetylated metabolites often are less water soluble, that
prolongs their elimination from the body.

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Factors affecting drug biotransformation

(1)

A hallmark of drug metabolism is large variability.

A combination of genetic, environmental, and
physiological factors are involved in regulation of
drug biotransformation.
The most important factors are genetically
determined polymorphism in drug oxidations and
conjugations, concomitant use of other drugs,
pollutants and chemicals, disease, and age. These
factors can decrease efficacy, prolong effects, or
increase toxicity.

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Factors affecting drug biotransformation

(2)

A number of genetic polymorphisms are exist: poor,

intermediate, extensive, or ultrarapid metabolizer.
A polymorphism also occurs in N-acetyl transferase
Greater likelihood of type side effects in poor
metabolizer.
Drugs and pollutants can induce the synthesis or inhibit
the action of CYP450 protein. Many CYP450 inducers
can also induce phase II biotransformation. Inhibition
drug biotransformation enzymes results in elevated drug
blood levels, prolonged pharmacological effects, and an
increased incidence of drug toxicity.

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Factors affecting drug biotransformation

(3)

Impairment of liver function can alter hepatic drug

biotransformation.
Decreases in hepatic blood flow can decrease the
biotransformation of drugs with high extraction ratio.
In the elderly, metabolic capacity is reduced.
Drug metabolizing enzymes develop early in fetal life, but the
level even lower following 2-4 weeks postpartum.
Induction of certain metabolizing enzymes occurs in the second
and third semester.
Oral contraceptives are potent inhibitor of CYP450

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Renal excretion

Lipid soluble drugs are not readily eliminated until they are
metabolized to be more polar compounds.
Excretion of drugs and their metabolites involves three processes:
glomerular filtration, active tubular excretion, and passive tubular
reabsorption.
Renal function is low in neonatus
Only unbound drug is filtrated; organic anions and cations are
transported by carrier-mediated secretion into proximal tubuli;
weak acid and bases undergo net passive reabsorption; passive
reabsorption of weak acids and bases is pH dependent

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Biliary, Fecal, and Other

Excretion

Organic anions including glucoronides, and

organic cations are actively transported by Pglycoprotein into bile. These metabolites may be
excreted in the feces; but more commonly they
are reabsorbed into the blood and ultimately
excreted in the urine.
Drugs in breast milk are sources of unwanted
effects in nursing infant. Milk is more acidic,
basic compounds may be slightly concentrated.

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Pharmacodynamics
Is the study of the mechanism of action, the
biochemical and physiological effects of
drugs, and the relationship between
concentration and effect

30

Mechanism of Action

The effect of most drugs results from

interaction with macromolecules which
initiates the biochemical and physiological
changes.
A drug is potentially capable of altering the
rate of which any bodily function proceeds.
Drugs do not create effects, but instead
modulate physiological function.

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32

Drug Receptors

Proteins form the most important class of receptors. They serve

as receptor for endogenous regulatory ligands.
Many drugs act selectively on such physiological factors
Drugs that bind to physiological receptor and mimic the effect of
the endogenous regulatory compounds are termed agonist.
Drugs that bind to receptors but do not mimic the effect of
endogenous agonist are termed antagonist.
Drugs that are partly as effective as agonist are termed partial
agonist.
Drugs that stabilize the receptor from conformational changes
are termed negative antagonist or inverse agonist.

33

SAR and Drug Design

Affinity of a drug for its receptor and its intrinsic activity are
determined by its chemical structure.
Minor modification in the drug molecule may result in major
changes in pharmacological properties.
Exploitation of SAR often lead to the synthesis of a congener
with a more favorable ratio of therapeutic to toxic effects,
enhanced selectivity, or better pharmacokinetic properties.
Chemical modulation of a physiological agonist may yield
therapeutical useful antagonists of hormones or neurotransmitter.

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Physiological Function of Receptors

The function of physiological receptors consist of binding

appropriate ligand and, in response, propagating its regulatory
signals in the target cell.
The regulatory actions of a receptor may be exerted directly on
its cellular target, effector protein, or may be conveyed by
intermediary cellular molecules, tranducers.
The receptor, its cellular target, and any intermediary cellular
molecules are referred as receptor-effector system or signal
transduction pathway.
The receptor act catalytically and hence are biochemical signal
amplifiers.

35

Structural and Functional Families of

Physiological Receptors

Members of various classes of receptors and many

of the associated transducer and effector protein
have been purified, and their mechanism of action
are understood in considerable biochemical detail.
Receptors, transducers, and effectors can be
expressed via molecular genetic strategies and
studied in cultured cells. Alternatively, they can be
expressed in large amounts in cell of bacteria or
yeast to facilitate their purification.

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Structural and Functional Families of

Physiological Receptors (2)
1.

2.
3.

4.

5.

Receptor protein kinases (tyrosine phosphatase,

adenyl cyclase).
Ion channels (nicotinic cholinergic, GABA)
G-protein coupled receptors (for biologic amines,
eicosanoids, peptide hormones)
Transcription factors (for steroid, thyroid, vit D,
retinoids) that regulate the the transcription of
specific genes.
Cytoplasmic messengers (cyclic AMP, Ca++).

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Quantitative Pharmacodynamics

The dose-response curve (DRC) depicts the

observed effect as a function of drug concentration
in the receptor. A dose-response curve is typified by
a maximal asymptote value when all receptor sites
were occupied.
A DRC is plotted with the log concentration.
A DRC has three basic properties: threshold, slope,
and maximal asymptote.
A drug does two things to receptor: bind and change
their behavior. Binding is governed by affinity;
changing is governed by efficacy.

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41

Receptor Occupancy Theory (1)

Ka
A + R AR Stimulus Response
Response = receptor x efficacy x receptor
occupancy
number
(binding)
Efficacy=intrinsic activity= the power of the drug to
induce response.

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Receptor Occupancy Theory (2)

Stimulus is the initial effect of drug upon the

receptor itself.
Stimulus is then transduced by the system to
yield observed response.
Affinity is increased by the increase of Ka.
The fraction of receptors occupied by the
drug is determined by the concentration the
drug and Ka.

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% maximal responsese

100

100

50

50
EC50

0
[A]

Log [A]

44

Quantifying Agonism

Drugs have two observed properties in biological

systems, i.e. potency and magnitude of effects,
when a biological response is produced.
Potency is controlled by four factors: two relate to
the receptors (density and efficacy of the stimulus
response), and the other two relate to the drugreceptor interaction (affinity and efficacy).

45

Quantifying Antagonism

Antagonism is associated with blockade of

receptors.
Competitive antagonist: a drug lacks intrinsic
efficacy but retains affinity and competes with the
agonist shift to the right of agonist dose-response
curve, and no change in maximal asymptotic
response.
Partial agonist: increasing concentration of a partial
agonist will inhibit response.
Non competitive antagonist: an antagonist that
dissociate too slowly from the receptor.

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% Maximal Effect

Relative potency

100

100

80

80

60

60

40

40

20

EC50x

EC50y

Relative efficacy
x

20
0

0
Log [Agonist]

Log [Agonist]

47

Full agonist

Level of Response (arbitrary units)

200

Ri

DRa

150

Partial agonist

DRi

DRa

100
Inactive compound

DRi

Inverse agonist

DRi

DRa

50
D
Ra

0
Log [Drug]

48

49

50

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