Pharmacologic Principles:

Pharmacokinetics
Clinical Pharmacokinetics

 Is the process of using drug

concentrations pharmacokinetics
principles and pharmacodynamic
criteria to OPTIMIZE drug therapy in
individual patients.
 Absorption

 Definition : …The process by which a drug moves

from its site of administration to the systemic
circulation
 Most common route of administration is oral
 Also, Intramuscular, intradermal, subcutaneous,
rectal, inhalation, topical etc.
 Barriers to Oral Absorption
Intestine
Liver
D D D
D D D Por
tal
Ve
D D D in D
D D MDD M
Solubility D M MD
DD D D
D D D D
D D
Stability
D D
D D Metabolism Body
D D D Permeability
D D
D D
 Oral Absorption

 GI epithelium is the main barrier.

 Adapted for absorption due to a large
surface area.
 Most important mechanism is
Passive diffusion
 Compound travels across the gut wall cell
TRANSCELLULAR absorption
 Passive Diffusion

 To be absorbed, the drug needs to

be….

In solution (pH effect)

In an unionised state (pKa)
Cross membranes (lipophilicity)
 Pharmacokinetics: Absorption
Factors That Affect Absorption
 Route of Administration of the drug
 Dosage formulation

 Status of the absorptive surface

 Rate of blood flow to site of administration

 pH at site of administration

 Status of GI motility

 Food or fluids administered with the drug

Drug Absorption of Various
Oral Preparations
Liquids, elixirs, syrups Fastest
Suspension solutions 
Powders 
Capsules 
Tablets 
Coated tablets 
Enteric-coated tablets Slowest
Gastric Emptying and Motility
 Factors Affecting Gastric
Emptying

Fatty food 
Carbohydrate 
Temperature of Food 
Body Position Upright faster than lying

Drugs  or 
 Distribution

 The REVERSIBLE transfer of a drug

between the systemic circulation and the
tissues

Refers to movement of drug into tissues

(Usually a passive process)
The transport of a drug in the body by
the bloodstream to its site of action.
 Volume of Distribution

 Smallest Vd  31.2 ml/kg (Plasma Volume) *

 Vd  374.2 ml/kg (Intracellular Fluid) *
 Vd  297.0 ml/kg (Extracellular Fluid) *
 Vd  668.0 ml/kg (Total Body Water) *
 No upper limit due to tissue binding
*: These results are reported in rat
 Distribution Depends on:
 Areas of rapid distribution: heart, liver,
kidneys, brain
 Areas of slow distribution: muscle, skin, fat
 Protein-binding
 Water soluble vs. fat soluble
 Blood-brain barrier
Distribution
 Plasma Protein Binding
D + P ↔ DP
 Albumin (acidic drugs)
 Glycoprotein (basic drugs)
 Fibrinogen, lipoproteins (both, minor)
VARIATION IN PLASMA PROTEIN
CONCENTRATION

A. High levels of plasma

proteins.
B. Reduced levels of
plasma proteins.
 Pharmacokinetics: Metabolism
(Also Known As Biotransformation)

The biologic transformation of a drug into

an inactive metabolite, a more soluble
compound, or a more potent metabolite.
 Liver (main organ).
 Kidneys.

 Lungs.

 Plasma.

 Intestinal mucosa.
Metabolic reactions
 Biotransformation is divided into two stages:
 Phase I biotransformation usually results in
only a small increase in hydrophilicity.
Typically introduces functional groups for
subsequent conjugation in Phase II.
 Phase II biotransformation usually results in
a large increase hydrophilicity, frequently
follows phase I biotransformation.
Metabolic reactions
There are four main patterns of drug
metabolism. These are:
Phase I
 oxidation

 reduction

 Hydrolysis

Phase II
 conjugation
 Cytochrome P450 (CYP)
Biotransformations

 Chemically diverse small molecules are

converted, generally to more polar compounds
 Reactions include:
 Aliphatic hydroxylation, aromatic hydroxylation
 Dealkylation (N-,O-, S-)
 N-oxidation, S-oxidation
 Deamination
 Dehalogenation
Cytochrome P450 Isoforms
 CYP1A2
 CYP3A4

 CYP2C9

 CYP2C19

 CYP2D6
Cytochrome P450 Nomenclature,
e.g. for CYP2D6
 CYP = cytochrome P450
 2 = genetic family

 D = genetic sub-family

 6 = specific gene

 NOTE that this nomenclature is

genetically based: it has NO functional

implication
 CYP450
Relative Importance of Relative Quantities
P450s in Drug Metabolism of P450s in Liver
CYP2E1 CYP1A2

CYP1A2
?
CYP2C

CYP3A CYP2C
CYP2D6 CYP2E1

CYP3A
CYP2D6

Shimada T et al. J Pharmacol Exp Ther 1994;270(1):414.

Conjugation (Phase 2 Reactions)
 Major Conjugation Reactions
 Glucuronidation (high capacity)

 Sulfation (low capacity)

 Acetylation (variable capacity)

 Examples: Procainamide, Isoniazid

 Other Conjugation Reactions: O-Methylation,
S-Methylation, Amino Acid Conjugation
(glycine, taurine, glutathione)
 Many conjugation enzymes exhibit
polymorphism
 Metabolism
Factors that decrease metabolism:
 Cardiovascular dysfunction

 Renal insufficiency

 Starvation

 Obstructive jaundice

 Slow metabolizers: CYP or acetylators

 Pharmacokinetics: Metabolism
Delayed drug metabolism results in:
 Accumulation of drugs
 Prolonged action of the drugs

Stimulating drug metabolism causes:

 Diminished pharmacologic effects
Pharmacokinetics: Excretion
The elimination of drugs from the body
 Kidneys (main organ)
 Liver
 Bowel
 Biliary excretion

 Enterohepatic circulation

 Exhalation
 sweat, milk, semen…..
Summary –
ADME Determined By:
 Drug characteristics

 Physicochemical properties
 Structure

 Suitability as substrates for receptors and

enzymes
Pharmacokinetics
Half-life.
 The time it takes for one half of the original
amount of a drug in the body to be removed.
 A measure of the rate at which drugs are

removed from the body.

 Nonlinear Pharmacokinetics
Linear pharmacokinetics

Absorption, distribution, and
elimination are first-order

Area Under the Curve (AUC)

processes

AUC proportional to dose

Pharmacokinetic parameters
are INDEPENDENT of dose.
Dose
Nonlinear PK

At least one process is NOT first-

Area Under the Curve (AUC)

order

AUC is not proportional to the
dose

One pharmacokinetic parameter
is DEPENDENT on dose
Dose
and the frequency of dosing relative to its half life
 Question 1:
How many
Steady State half life we
need to
reach
Conc.
steady
state?

Question 2:
What is the
relation
between
the input
and out put
rate at
steady
state?

Time
 Time
Conc.
 Reasons for Pharmacokinetic Variability


Body weight (body fat vs. lean muscle)

Age

Gender (ex. pregnancy)

Genetic disposition

Disease states

Drug interactions

Food interactions
If the reason for the pharmacokinetic variability is
known, it can be accounted for in dose optimization
 Drug Delivery
Biopharmaceutics

Pharmacokinetics
PK/PD-modeling

Pharmacodynamics
Pharmacodynamics

Maher khdour
Msc. Clinical Pharmacy
Al-Quds University
 Drug Receptors and Pharmacodynamics
(how drugs work on the body)

The action of a drug on the body,

including receptor interactions,
dose-response phenomena, and
mechanisms of therapeutic and
toxic action.
 Drug Receptor
 A macromolecular component of a
cell with which a drug interacts to
produce a response
 Usually a protein
Types of Receptors
 Ligand-gated ion channels
 G protien-coupled receptors
 Enzyme-linked receptors
 Second messengers
 Intracellular receptors
 Discussion………..see figure below
Drug receptor interactions
Drug - Receptor Binding

D+R DR Complex
Affinity

Affinity – measure of propensity of a drug to bind

receptor; the attractiveness of drug and
receptor
 Covalent bonds are stable and essentially

irreversible
 Electrostatic bonds may be strong or weak,

but are usually reversible

 Drug Receptor Interaction
DR Complex Effect

Efficacy (or Intrinsic Activity) – ability of a

bound drug to change the receptor in
a way that produces an effect; some
drugs possess affinity but NOT efficacy
dose response curves
k 1 
[D] + [R] [DR] effect

k -1

at equilibrium: k1/k-1 = affinity const.

[D] x [R] x k1 = [DR] x k-1 k-1/k1 = dissociation const.

(kd)
so that: [DR] = k1
[D] [R] k-1

the lower the kd the more potent

the drug

2004-2005
 Pharmacodynamics:-
 Agonist:-
drugs bind to and activate the receptor in some
fashion, which directly or indirectly brings about
effect.
 Affinity:
this is a measure of how avidly a drug binds to
its receptor. It is characterised by the
equilibrium dissociation constant (KD) which is
the ratio of rate constants K+1, K-1.
 Pharmacodynamics:-

 Partial Agonist:
An agonist that cannot elicit the same maximum
response as a full agonist, which depends on
affinity to the receptor.

 Intrinsic efficacy:-
which is the ability to elicit a response when it
binds to receptor .
Example : opening of an channel or activation .
Pharmacodynamics:-
Pharmacodynamics:-
 Pharmacodynamics:-
 Antagonist:-
this is a drugs that bind to the receptors but do
not activate it i.e has no intrinsic efficacy. It
may be Competitive or irreversible.

 Competitive antagonist:-
bind reversibly with receptor and the tissue
response can be returned to normal by
increasing the dose of agonist example of
acetylcholine and atropine.
Pharmacodynamics:-
 Irreversible antagonist:
binds irreversibly to receptor site they from covalent
bond, with very high affinity no matter how much
agonist is given because the receptor are unavailable .

 Chemical antagonist:-
it dose not need receptor at all thus one drug antagonize
the action of second drug by binding, and inactivating
the second drug. [ Protamine (+) charge and heparin
(-) protein .
Pharmacodynamics:-

 Physiologic antagonist:
between endogenous regulatory pathways. Catabolic
actions of glucocorticoids hormones ↑ed blood sugar.
Physiologically opposed by insulin. Other example
acetylcholine caused bradycardia , physiologically
opposed by isoprotrerenol .
Pharmacodynamics:-
 Potency
refers to the concentration (EC50) or dose
(ED50) required to produce 50% of the drug's
maximal effect.
 Efficacy:
references the response to the drug. Therefore
clinical effectiveness will depend not on
potency but on maximal efficacy
 Relative Potency

hydromorphone

morphine

codeine
Analgesia

aspirin

Dose
Pharmacodynamics:-
Pharmacodynamics:-
 Drugs A and B are more potent than drugs C and
D because of the relative positions of their dose-
response curves along the dose axis (log
concentration)
 Drugs, A and B, are more potent than drugs C and
D, even though the maximal response for drug A
is less than the maximal response for drugs C or
D.
 Note that drugs B, C and D are equally
efficacious (similar maximal efficacies), more
effective then the more potent drug A.
Pharmacotherapeutics:
Monitoring
Tolerance
 A decreasing response to repetitive drug
doses
Dependence
 A physiologic or psychological need for

a drug

Copyright © 2002 by Mosby, Inc.

All rights reserved.
Effectiveness, toxicity,
lethality
 ED50 - Median Effective Dose 50; the
dose at which 50 percent of the
population or sample manifests a given
effect
 TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect
 LD50 - Median Toxic Dose 50 - dose
which kills 50 percent of the subjects
 Theraputic index ( Margin of safety )
Ratio of TD50 to ED50
Quantification of drug safety

TD50 or LD50
Therapeutic Index =
ED50
 Drug A
100 sleep
death

Percent 50
Responding

0
ED50 LD50

dose
2004-2005
 Drug B
100 sleep
death

Percent 50
Responding

0
ED50 LD50
dose
Quantification of drug safety

TOLERENCE
Physical dependence
Addiction
Dynamics
 Drug receptor interaction
 Tolerance
decrease response to a drug as a result of repeated
drug administration
 Physical dependence
 A state in which the body has adapted to drug
exposure in such a way that an abstinence syndrome
will result if a drug D/C