PL 309

General
Pharmacology
Pharmacokinetics
 Intended learning outcomes (ILOs)

By the end of this lecture, students will be able to:

Explain drug absorption, distribution, metabolism &
excretion concepts.
Define volume of distribution, clearance, elimination,
half-life, first-order, zero order.
Describe the concept of plasma steady state.
 Pharmacokinetics
• Pharmacokinetics is the study of drug disposition in
the body and focuses on the changes in drug
plasma concentration.
• includes the processes of ADME
o Absorption
o Distribution
o Metabolism (Biotransformation)
o Excretion Elimination
 Absorption
• It refers to the passage of drug molecules
from the site of administration into the
circulation.
• The process of drug absorption applies to all
routes of administration, except ???
 Processes of Absorption

A,B: Passive Diffusion: Fick’s law; Lipid diffusion; Aqueous diffusion

C: Carriers ; facilitated diffusion (cephalexin; with conc. gradient) and
Active transport (5-fluorouracil; ATP and against conc. gradient)
Outside the cells (ABC (ATP-binding cassette) includes permeability (P)-
glycoprotein or multidrug resistance type 1 transporter (MDR1),
multidrug resistance-associated protein (MRP): resistance to neoplastic
drugs. Inhibition of Pgp by amiodarone, erythromycin and propranolol
increase tissue levels of these drugs and augment pharmacologic effects
D: Endocytosis and Exocytosis (too large; vitamin B12)
 Processes of Absorption

A,B: Passive Diffusion: Fick’s law; Lipid diffusion; Aqueous diffusion

C: Carriers ; facilitated diffusion (cephalexin; with conc. gradient) and
Active transport (5-fluorouracil; ATP and against conc. gradient)
Outside the cells (ABC (ATP-binding cassette) includes permeability (P)-
glycoprotein or multidrug resistance type 1 transporter (MDR1),
multidrug resistance-associated protein (MRP): resistance to neoplastic
drugs. Inhibition of Pgp by amiodarone, erythromycin and propranolol
increase tissue levels of these drugs and augment pharmacologic effects
D: Endocytosis and Exocytosis (too large; vitamin B12)
 Fick’s Law of Diffusion

C1 is the higher concentration

C2 is the lower concentration
Permeability coefficient is a measure of the mobility of
the drug molecules in the medium of the diffusion
path.
 Absorption

The rate of absorption depends on the:

1. Route of administration
2. Chemical characteristics and the solubility of the
drug in the tissue in which it is placed
3. Environment where the drug is absorbed:
• pH
• Blood flow to the absorption site
• Total surface area available for absorption
• Contact time at the absorption surface
 B- Effect of pH on drug absorption

• A drug passes through membranes more

readily if it is uncharged
 Bioavailability

Routes of administration other than IV may

result in partial absorption and lower
bioavailability, which is the fraction of an
administered dose of unchanged drug that
reaches the systemic circulation
For IV delivery, absorption is complete; that
is, the total dose of drug reaches the
systemic circulation. Drug delivery by other
routes may result in only partial absorption
and, thus, lower bioavailability.
Factors Affecting
Bioavailability
 Factors Affecting Bioavailability

1. First-pass hepatic metabolism

2. Solubility of the drug: For a drug to be
readily absorbed, it must be largely
hydrophobic, yet have some solubility in
aqueous solutions.
3. Chemical instability or enzymatic
destruction of some drugs in GIT, such as
penicillin G and insulin
 Factors Affecting Bioavailability

4. Formulation of the drug

(Pharmaceutical Form):
Particle size, salt form, crystal polymorphism,
enteric coatings and the presence of excipients
(such as fillers, binders and dispersing agents) can
influence the ease of dissolution and, therefore,
alter the rate of absorption.
This is critical with some drugs eg.
anticoagulants, antidiabetics, adrenal steroids
& some antibiotics….
 2.Distribution & Binding Of Drugs

• Drug distribution is the process by which a drug

reversibly leaves the bloodstream and enters the
interstitium (extracellular fluid) and/or the cells of
the tissues.
• The delivery of a drug from the plasma to the
interstitium primarily depends on blood flow,
capillary permeability, the degree of binding
of the drug to plasma and tissue proteins,
and the relative hydrophobicity of the drug.
 2.Distribution & Binding Of Drugs

• Once a drug has entered the circulation, it is

distributed to different compartments in the
body.
• Dissolved in plasma water, Bound to plasma
protein or to tissue proteins.
• Distribution of drugs influences its site of action
eg. crosses the BBB to enter the brain or not.
• The strength of this binding would affect the time
of its stay in the body & there for duration of
action.
 Volume of Distribution (Vd)

 Volume of Distribution (Vd):

Definition:
Is the volume in which the amount of drug would
need to be uniformly distributed to produce the
observed blood concentration.

Vd =
Total amount of the drug in the body
Plasma drug concentration
 Apparent Volume of
Distribution
• Vd, is defined as the fluid volume that is required to
contain the entire dose of drug in the body at the
same concentration measured in the plasma.
 Interpretation of the
Volume of Distribution
• Plasma compartment: If a drug has a high
molecular weight or is extensively protein bound, it
is too large to pass through the slit junctions of the
capillaries (heparin and warfarin)
• Extracellular fluid: If a drug has a low molecular
weight but is hydrophilic, it can pass through the
endothelial slit junctions of the capillaries into the
interstitial fluid (aminoglycosides)
• Total body water: If a drug has a low molecular
weight and is lipophilic (Ethanol)
 Interpretation of the
Volume of Distribution
Some drugs have a Vd that is much larger than total
body water; indicating that the drug is concentrated
intracellularly, with a resulting low concentration in the
plasma.
Many weak bases, such as the antidepressant
fluoxetine (Prozac), have a large Vd (40–55 L)
because of intracellular ion trapping.

A large Vd may also result from sequestration into fat

tissue, such as occurs with the antimalarial agent
chloroquine.
 Binding of drugs to plasma proteins

1. Binding to plasma proteins is reversible and

constitutes a reservoir for drugs in plasma.
2. A part of the drug will be Free which is the
Active part.
3. Diseases modify protein bindings of drugs eg
renal, liver diseases & hypoalbuminemia.
4. Drugs can displace each other from plasma
proteins
 Passage of drugs across

1.The Blood Brain Barrier( BBB ):

o This barrier is a unique example of unequal
distribution of drugs From Blood to Brain
& CSF
o Lipid Insoluble drugs do not cross it readily eg.
atenolol compared to propranolol( lipid soluble).
2.Placental Barrier:
o The fetal &maternal blood streams are
separated by a lipid barrier that readily allows
the passage of lipid soluble substances but
excludes water soluble compounds
 Drug Elimination

A- Drug Metabolism
Before being excreted in the urine, most drugs
undergo Metabolic Alteration which occurs
predominantly in the liver.

Metabolic alteration of drug molecules involves two

kinds of biochemical reactions which often occur
Sequentially
( PHASE I & PHASE II reactions).
These Phase reactions MOSTLY takes place in
the LIVER.
 Phases of Drug
Biotransformation
 Phase I Reactions

There is change in the drug molecule by

oxidation, reduction or hydrolysis
Cytochrome P450

More active metabolites & sometimes more

Toxic
Eg Propranolol, phenytoin ( Oxidation)
Eg. Clonazepam, chloramphenicol (Reduction)
Eg. Aspirin (Hydrolysis)
Procaine
Phase I reactions utilizing the
P450 system
The microsomal cytochrome P450 (CYP)
monooxygenase system
(Microsomal mixed-function
oxidases)
 Specificity
 Genetic variability and
polymorphism
 Inducers
family name; subfamily, and specific
 Inhibitors isozyme
 Phase I reactions not
involving the P450 system
A few drugs are oxidized by cytoplasmic
enzymes. For example, ethanol is oxidized to
aldehyde by alcohol dehydrogenase, and
caffeine and the bronchodilator theophylline
are metabolized by xanthine oxidase.
Other cytoplasmic oxidases include
monoamine oxidase, for oxidation of
catecholamines or histamine and a site of
action for some psychotropic medications.
 CYP inducers
Certain drugs (phenobarbital, rifampin, and
carbamazepine) are capable of increasing the
synthesis of one or more CYP isozymes →
increased biotransformation of drugs → ↓ plasma
concentrations of drugs metabolized by these CYP
isozymes, with concurrent loss of pharmacologic
effect.
For example, rifampin, an antituberculosis drug
significantly decreases the plasma concentrations of
human immunodeficiency virus (HIV) protease
inhibitors, thereby diminishing their ability to
suppress HIV replication.
 CYP inhibitors
Some drugs, however, are capable of inhibiting
reactions for which they are not substrates (for
example, ketoconazole), leading to drug interactions.
Omeprazole is a potent inhibitor of three of the CYP
isozymes responsible for warfarin metabolism. If the
two drugs are taken together → ↑ warfarin’s plasma
concentrations → ↑ anticoagulant effect and
increased risk of bleeding.
Grapefruit juice inhibits CYP3A4 → ↑ levels and/or
greater potential for toxic effects with drugs, such as
nifedipine, clarithromycin, and simvastatin, that are
metabolized by this system.
 Consequences of Drug Metabolism

Enzyme inducers:
Enzyme Inhibitors:
e.g. Phenobarbital,
e.g.Chloramphenicol,
Phenylbutazone, Rifampicin
Cimetidine, MAO
diphenyhydantoin,
Inhibitors, ketoconazole,
Carbamazepine
Erythromycin
•Are drugs that
•Those drugs
stimulate the
inhibit the metabolism
metabolism Of other
Of certain drugs
drugs that are acted
Metabolized in the liver
upon by P450,and so
By P450,leading to an
will decrease their
increase in their blood
concentration in the
Level.
blood.
 Phase II Reactions

Involves Conjugation to form

Glucoronates, Sulphates or Acetylated compd.

Highly polar compds to be rapidly eliminated.

Eg. Morphine, paracetamol, salicylates
( glucoronic acid )
Eg. Oral contraceptives steroids ( sulphuric
acid)
Eg. Isoniazid, Dapsone ( acetic acid )
 Factors Responsible for Variation in
Drug Metabolism

• Genetic Factors: e.g. succinyl choline apnea

• Age: eg. Grey baby syndrome in neonate using
chloramphenicol.
• Fever: Sometimes increase in body temperature
increases the T½ of some drugs.
• Thyroid Hormones: T½ of some drugs is
increased in hypothyroidism.
• Liver Disease: T½ of drugs like diazepam is
increased in hepatic cirrhosis.
• Induction or Inhibition of drug metabolism .
 Metabolism

It is important to determine:

• The order of reaction ( zero or first order ).

• Plasma half life ( T ½ ).
• Correlation between T½ & order of kinetics
 Kinetics of Metabolism
1. First-order kinetics (linear
kinetics): The metabolic
transformation of drugs is
catalyzed by enzymes, and
most of the reactions obey
Michaelis- Menten kinetics.

Each half-life, the concentration

decreases by 50%
 Kinetics of Metabolism
2. Zero-order kinetics (non-linear): With a few
drugs, such as aspirin, ethanol, and phenytoin, the
doses are very large. Therefore, [C] is much greater
than Km, and the velocity equation becomes

The enzyme is saturated by a high free drug

concentration, and the rate of metabolism remains
constant over time.
A constant amount of drug is metabolized per unit of
time. The rate of elimination is constant and does not
depend on the drug concentration.
Elimination t1/2
 Correlation Between t½ & Order of
Kinetics

• In 1st order kinetics, t½ is a constant

character.
• In zero order kinetics no single value
for its t½ can be quoted.
 Importance of t1/2
1- determine dosing frequency
2- to estimate time to reach steady state
3- estimate time required for drug removal
after stopping it
 Steady State
When the drug is first administered, the rate of
administration is much greater than the rate of
elimination, because the plasma concentration is so
low.
As the drug continues to be administered, the rate of
drug elimination gradually increases, whereas the
rate of administration remains constant.
Eventually, as the plasma concentration rises
sufficiently, the rate of drug elimination equals the
rate of drug administration. At this point, the steady-
state equilibrium is achieved.
 Steady State
The time to reach the steady
state is a function of the
elimination half-life of the
drug. Any first-order process
requires about 4-5 half-lives
to be completed.
The time required to reach
the steady state is
independent on the rate or
frequency of drug
administration.
 Steady State

Once steady state is reached, using a

certain dose, this will produce:
A constant drug action and therefore
NO Toxicity
NO Decreased therapeutic effect.
 Factors affecting the steady state

• Dose or Rate of administration

• Rate of elimination
e.g.: Change in liver function or
kidney function .
 Css
The steady-state drug concentration
depends on the drug dose administered per
unit of time and on the half-life of the drug.
Steady State
 Indications of drug monitoring of
plasma concentration:

1- When a drug affects infrequent events

such as:
Epileptic seizures
or Attacks of cardiac arrhythmia.
2- When there is no rapid and reliable
determination of an effect such as:
mood changes in cases of depression.
 Indications of drug monitoring of
plasma concentration:

3- To reduce Side Effects e.g.:

Renal or Auditory damage by
aminoglycosides.
 Indications of drug monitoring of
plasma concentration:

4- To diagnose and treat overdose for

some drugs.
5- To check patient compliance.
6- When metabolic or elimination
mechanisms are impaired.
7- To define dose schedule of new drugs.
 Indications of drug monitoring of
plasma concentration:

When there is difficulty to distinguish

between:
Therapeutic and Toxic effects e.g.
Digoxin therapy
(low therapeutic index).
 N.B. Therapeutic Index

• Is the ratio of LD50 (the dose which is

lethal to 50% of experimental animals)
to ED50 ( the dose that gives the
desired response in 50% of
experimental animals).
Therapeutic index = LD50 / ED50
Therapeutic index is a measure of drug
safety, thus the higher the index the
safer is the drug.
 Drug Excretion
• Excretion is the removal of drug from body fluids
and occurs primarily in the urine.
• Other routes include in bile, sweat, saliva, tears,
feces, breast milk, and exhaled air.
 Drug Excretion
1. Glomerular filtration:
The glomerular filtration rate (GFR) is
normally about 125 mL/min but may
diminish significantly in renal disease.
Lipid solubility and pH do not
influence the passage of drugs into
the glomerular filtrate. However,
variations in GFR and protein binding
of drugs do affect this process.
• Warfarin?????
 Drug Excretion
2. Proximal tubular secretion:
Secretion primarily occurs in
the proximal tubules by two
energy-requiring active
transport systems: one for
anions and one for cations.
 Drug Excretion
2. Proximal tubular secretion:
Each of these transport
systems shows low specificity
and can transport many
compounds. Thus, competition
between drugs for these
carriers can occur within each
transport system.
For example, the secretion of
penicillins and other weak
acids is inhibited by
probenecid, an agent used to
treat gout.
 Drug Excretion
3. Distal tubular reabsorption:
As a drug moves toward the distal convoluted tubule,
its concentration increases and exceeds that of the
perivascular space. The drug, if uncharged, may
diffuse out of the nephric lumen, back into the
systemic circulation.
Most nonelectrolytes, including ethanol, are passively
reabsorbed across tubular cells.
 Ion trapping
 Excretion of Drugs

1- Renal Excretion:
• The Urine is the principal
medium in which drugs &
metabolites leave the body.
• The More water soluble is the
drug the Greater the fraction
that remains in the urine.

2- Biliary Excretion:
• Some drug metabolites like
glucuronides into the
deudenom in the bile (
enterohepatic circulation)
• eg,.Stilbesterol.
 Excretion of Drugs

3-Excretion in the Expired air:

• Eg Volatile anesthetics

4-Excretion in Breast Milk

• eg. Tetracycline,
thiouracil are secreted in
high concentration which
is dangerous on the baby.
 Contraindication of Thionamides

Pregnancy: Crosses the

placental barrier
(propylthiouracil is the
safest)
Lactation : Excreted in the
milk
 Hemodialysis

• Used in renal failure to

remove toxic waste
substances normally
removed by the kidneys,
from the pt’s blood.
• Hemodialysis is important
with drugs which:
o Have good water solubility.
o Are not tightly bound to plasma
proteins.
o Small molecular weights
(< 500).
o Small vol. distribution
o Not extensively stored or
distributed into tissues.
 Questions

• ……………….. is the amount of unchanged drug

that reaches the plasma and it is complete with
…… route.
• One advantage of sublingual route is
…………………………, however one of the
disadvantages is ……………………….