PHARMACOKINETICS

DR MUHAMMAD AMJAD
LEARNING OBJECTIVES
 Define pharmacokinetics and pharmacodynamics and explain their
importance in drug therapy.
 Understand the fundamental pathways of drug movement and
modification in the body, including absorption, distribution, metabolism,
and excretion.
 Discuss the routes of drug administration and factors affecting drug
absorption, distribution, and clearance.
 Explain drug-receptor interactions and the concept of drug-receptor
complexes.
 Describe drug-receptor binding, affinity, efficacy, and the differences
between agonists and antagonists.
 Discuss receptor properties, desensitization, and signaling mechanisms
involved in drug action.
 Explore the role of pharmacodynamics in determining the action of a
drug on the body and the influence of drug concentrations on the
response magnitude.
 Summarize the various types of drug-responsive signaling mechanisms,
including enzyme-linked, ion channel-linked, G protein-linked, and
nuclear-linked pathways.
 PHARMACOKINETICS

 Definition:
- refers on how the body acts on the drug

- involves the study of absorption, distribution, metabolism

(biotransformation) and drug excretion
 AIM OF DRUG THERAPY

- To prevent, cure or control various disease states

adequate drug doses must be delivered to the

target tissues

so that therapeutic yet NON – toxic levels are

obtained
Overview

 Too much of a drug will result into toxic effects & too little will
not result into the desired therapeutic effects.
4 Fundamental Pathways of Drug
Movement & Modification in the
Drug at the site of Administration
Body 1.
ABSORPTION
(INPUT)
Drug in 2.

plasma drug in tissues
DISTRIBUTION

metabolites in tissues
3. METABOLISM

4. ELIMINATION
(OUTPUT)
Drug & metabolites in urine, feces, or bile
 Routes of Drug
- Determined
Administration
primarily by the
properties of
the drug
MAJOR ROUTES
OF DRUG
ADMINISTRATIO
N
1. Enteral
2. Parenteral
3. Others
ENTERAL routes
A. ORAL
B. SUBLINGUAL
C. RECTAL
A. ORAL
- most common route of
administration
- Most variable
- most complicated pathway
- Cheapest
- Non - invasive
[NOTE: most drugs are absorbed in
the GIT & encounter the liver
before they are distributed into the
B. SUBLINGUAL
Placement under the tongue
- Allows the drug to diffuse into
the capillaries & therefore to
enter the systemic circulation
Advantage: the drug bypasses
the intestine & liver & thus
avoids 1st pass metabolism
c. Rectal
- Useful if the drug induces vomiting if
given orally or if the patient is already
vomiting
- Drainage of the rectal region bypasses
the portal circulation
- Similar to the sublingual route, it prevents
the destruction of the drug by intestinal
enzymes or by the low pH in the stomach
[note: commonly used to administer anti –
emetic agents]
 PARENTERAL routes

IM /
IV / SC / intramuscu
intravascular subcutaneous lar
2. Parenteral
a. IV / intravascular
- IV injection is the most
common parenteral route
- For drugs which are not absorbed orally
- Bypasses the liver
- Permits a rapid effect and a maximal degree of control over the
circulating levels of the drug
- Can introduce bacterial contamination at the site
- Can cause hemolysis
  Disadvantages

parenteral  more risk of addiction when it

comes to injecting drugs of
abuse
 Advantages  Belonephobia, the fear of
needles and injection.
 Fast: 15–30 seconds for  If needles are shared, there is
IV, 3–5 minutes for IM risk of HIV and other
and subcutaneous (SC) infectious diseases
 It is the most dangerous route
 100% bioavailability
of administration
 suitable for drugs not  If not done properly,
absorbed by the gut or potentially fatal air boluses
those that are too (bubbles) can occur.

irritant (anti-cancer)
 IV can deliver
continuous medication,
e.g., morphine for
patients in continuous
pain, or saline drip for
Parenteral
 Used for drugs which are
poorly absorbed in the GIT
 Unstable drugs
 For unconscious patients
 Circumstances that require a
rapid onset of action
 Provides the most control over
the actual dose delivered to
the body
b. IM / intramuscular

Drugs administered

aqueous sol’n
specialized depot
preparations
c. SC /
subcutaneou
s
- This route of
administration
like IM requires
absorption &
somewhat
slower than
the IV route
other

Intrathecal/intraventicular
Topical
Transdermal
Oralinhalation
Nasal inhalation
3. Others
a. Inhalation
- Provides a rapid delivery of a drug
across a large surface area of the
mucus membranes of the
respiratory and the pulmonary
epithelium
- Effect is as rapid as IV injection
- For gaseous drugs
- No systemic side effects
 Advantages
 Fastest method, 7–10
seconds for the drug to
reach the brain

 Disadvantages
 Typically a more addictive
route of administration
because it is the fastest,
leading to
instant gratification.
 Difficulties in regulating
the exact amount of
dosage
 Patient having difficulties
administering a drug via
inhaler
3. Others
b. Intranasal
- Through the nose

eg. : desmopressin,
salmon calcitonin,
cocaine,nasal
decongestants
anti inflammatory
corticosteriods
c. Intrathecal,
intraventricular
- Introducing drugs
directly into the
cerebrospinal fluid /
CSF
Eg., amphotericin B
bypasses the
bloodbrain barrier,
which prevents or
delays the absorption
e. Transdermal
- This route of administration achieves
systemic effects by application of drugs
to the skin, usually by using a
transdermal patch.
- Rate of absorption varies markedly,
depending on the physical characteristics
of the skin as well as the lipid solubility
of the drug.
- Eg., nitroglycerin
d. Topical
- Is used when a
local effect of a
drug is required

- Eg., clotrimazole,
atropine
 ABSORPTION OF DRUGS

 Is the transfer of a drug from

its site of administration to the
bloodstream

 IV delivery – absorption is
complete.
 100% BIOAVAILIBILITY
Bioavailability

Refers to the fraction of an

administered drug that reaches the
systemic circulation
- Important to calculate drug dosages
for non intravenous routes of drugs.
- Drug 100mg
- Systemic circulation -70mg
- Bioavailability -0.7-----70%
Drug Distribution
- Affected by the following
factors:
- Is the process by
which a drug
reversibly leaves the - [Link] output and Blood Flow
bloodstream & - 2. Capillary permeability
enters the  capillary structure
interstitium  Chemical nature of the drug
(extracellular fluid)  blood brain barrier
and / or the cells of - 3. Binding of Drugs to proteins
the tissues. - [Link]
DRUG CLEARANCE
THROUGH METABOLISM
 Drugs are often eliminated by
biotransformation and or
excretion into the URINE OR
BILE.

 LIVER – the MAJOR SITE FOR

DRUG METABOLISM
[Link] ELIMINATION

 Removal of a drug from the  Drugs that have been made

body may occur via a number water soluble in the liver are
of routes, the most important often readily excreted in the
being the kidney or urine kidneys.
 Other routes:  Kidney dysfunction can lead to
toxic levels of the drug in the
- bile, intestine, lung, milk,
body because the drug cannot
be excreted.
[Link]
 TWO DRUGS FORMULATIONS ARE
BIOEQUIVALENT IF THEY SHOW

 1-COMPARABLE BIOAVAILABILITY
AND

 2-SIMILAR TIMES TO ACHIEVE PEAK

BLOOD CONCENTRATIONS.
[Link] EQUIVALENCE

 TWO DRUG FORMULATIONS ARE

THERAPEUTICALLY EQUIVALENT IF THEY
ARE
 PHARMACEUTICALLY EQUIVALENT THAT IS
SAME
( DOSAGE,ACTIVE INGREDIENT,ROUTE OF
ADMINSTRATION)
 WITH SIMILAR CLINICAL AND SAFETY
PROFILES.
 Therefore two drugs that are bioequivalent
may not be therapeutically equivalent.
Pharmacodynamics

DRUG-RECEPTOR INTERACTION
• Pharmacodynamics describes the
action of a drug on the body and the
influence of drug concentrations on the
magnitude of the response.

• Drug exert their effects ,by interacting

with the receptors present on the cell
surface or within the cell.

• The drug-receptor complex initiates

alterations in biochemical and/or
molecular activity of a cell by a process
 Pharmacodynamics
(how drugs work on the body)
 many drugs inhibit enzymes
Enzymes control a number of metabolic processes
A very common mode of action of many drugs
 in the patient (ACE inhibitors)
 in microbes ( penicillins)

 some drugs bind to:

 proteins (in patient, or microbes)
 the genome (cyclophosphamide)
 microtubules (vincristine)
Pharmacodynamics
 most drugs act (bind) on receptors
 in or on cells
 form tight bonds with the ligand
 exacting requirements (size, shape)
 can be agonists (salbutamol), or
antagonists (propranolol)
 receptors have signal transduction
methods
Drug Receptor
A macromolecular component
of a cell with which a drug
interacts to produce a
response
Usually a protein
Drug receptor
A protein macromolecule
produced by the body that was
designed by nature to interact
with an endogenous molecule
(ligand), but which will also
interact with a drug molecule, if
it has the correct chemical
structure
Types of Protein Receptors

1. Regulatory – change the

activity of cellular enzymes
2. Enzymes – may be inhibited
or activated
3. Transport – e.g. Na+ /K+
ATP’ase
4. Structural – these form cell
parts
 SIGNAL TRANSDUCTION

 DRUGS ACT AS SIGNALS

 RECEPTORS ACT AS SIGNAL DETECTORS.

 Signal transduction in drugs is how a cell

converts a drug's signal (from binding a
receptor) into a functional response
 Cells have many different types of receptors, each of
which is specific for a particular agonist and produces
a unique response.

 The magnitude of response is proportional to the

number of drug receptor complexes

 Most receptors are named for the type of agonist

that interacts best with it .(histamine receptor)
• Receptors exist in atleast two states
1-INACTIVE( R)
2-ACTIVE (R*)

• These are in reversible equilibrium with one

another, usually favouring the inactive state.

• Binding of agonist
• R -------- R* ---- PRODUCE
BIOLOGICAL EFFECT .

• Binding of an antagonist
• Occupy the receptor but do not increase the
fraction of R*,and may stabilize the receptor in
the inactive state.
 Drug – receptor binding
D+R DR Complex

Affinity

Affinity – measure of tendency 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

2004-
2005
 AGONIST
A drug having high affinity for receptor and
has high intrinsic activity is called
“AGONIST”
OR
A drug that initiates a pharmacological
action by binding to a receptor, that mimic
the action of endogenous compounds is
called
“ AGONIST”
2004-2005
Agonist Drugs
drugs that interact with and
activate receptors; they possess
both affinity and efficacy
two types
Full – an agonist with maximal
efficacy
Partial – an agonist with less
then maximal efficacy
PARTIAL AGONIST

A drug having same affinity for receptor as

an agonist but less intrinsic activity than
full agonist is called “PARTIAL AGONIST”.
A partial agonist in presence of full agonist
acts as antagonist, as it occupies the
receptor and does not allow the full
agonist to bind with receptor.
 REVERSE OR INVERSE AGONIST

 Some drugs produce pharmacological responses by binding

to the receptors that are specifically opposite to those of an
agonist, such drugs are called “REVERSE OR INVERSE
AGONIST.”
 For example agonist action of benzodiazepines on
benzodiazepine receptor in C.N.S produces sedation, muscle
relaxation, anxiolysis and controls convulsions. -carolines
also bind to these receptors and cause stimulation, anxiety,
increased muscle tone and convulsions.
 Both benzodiazepines and -carolines act as agonist and
produce opposing effects, in this example benzodiazepines
act as reverse agonist.
 Antagonist Drug
Antagonists interact with the
receptor but do NOT change
the receptor
they have affinity but NO
efficacy
two types
Competitive
Noncompetitive
 Antagonist
•High affinity
•Low intrinsic activity

Antagonist
Competitive Antagonist

competes with agonist for

receptor
surmountable with increasing
agonist concentration
displaces agonist dose
response curve to the right
(dextral shift)
reduces the apparent affinity of
the agonist .
 Reversible Antagonist
•High affinity
•Low intrinsic activity

Antagonist
Noncompetitive Antagonist
 drug
binds to receptor and stays
bound
 irreversible – does not let go of
receptor

 this
looks like competitive
antagonist
 but,as more and more receptors
are bound (and essentially
destroyed), the agonist drug
 Irreversible Antagonist
•High affinity
•Low intrinsic activity

Irreversible Antagonist
Agonists and antagonists
 agonist has affinity plus intrinsic activity

 antagonist has affinity but no intrinsic activity

 partial agonist has affinity and less intrinsic activity

 competitive antagonists can be overcome

 Receptor properties

A drug may act on more than one type

of receptors differing both in function
and binding characteristics.

 Number of receptors is not fixed but is

constantly being changed.
 When number of receptors is increased
it is called “Up Regulation” and when
number of receptors is decreased it is
called “Down Regulation.”
Receptor properties
 Change in the number of receptors
depends upon
 Disease State
 Quantity
 Frequency and duration of the drug
used
 Persistent use of antagonist causes
up regulation of receptors and that
of agonist causes down regulation
of receptors
 Receptor Regulation

 Sensitization or Up-regulation
1. Prolonged/continuous use of receptor blocker
2. Inhibition of synthesis or release of
hormone/neurotransmitter - Denervation
 Desensitization or Down-regulation
1. Prolonged/continuous use of agonist
2. Inhibition of degradation or uptake of agonist

Homologous vs. Heterologous

Uncoupling vs. Decreased Numbers
 Desensitization
 Agonists tend to desensitize receptors
 Homologous (decreased receptor
number)
 Heterologous (decreased signal

 Antagonists tend to up regulate

transduction)
receptors
 Drugs/hormones talk to the cell through these ears (receptors).
 1. Up-regulation (Sensitization) = Ears increase
 When does it happen?
 When you use a blocker for a long time
 Or when nerve is cut / chemical not coming
 I am not hearing anything… let me make more ears
 Result:
 More receptors
 Cell becomes more sensitive
 Example:
 If blocker is stopped → strong response happens
2. Down-regulation (Desensitization) = Ears decrease

When does it happen

•When you use an agonist again and again
•Or when chemical stays too long

What does the body say

“Too much noise! Let me remove some ears!”
Result:
•Less receptors
•Drug effect becomes less (tolerance)
3. Homologous vs. Heterologous (Very simple)

Homologous:
Only one ear type gets tired
(Only that same receptor)
Heterologous:
Many ear types get tired
(Many receptors affected)
Uncoupling vs Decreased numbers

Uncoupling:
Ear is there, but wire is cut
Drug binds, but no effect

Decreased numbers:
Ears are removed ❌
So less effect

Blocker long time → Receptors increase (Up)

Agonist long time → Receptors decrease (Down)
Signaling Mechanisms

 Binding of an agonist drug to its receptor activates an

effector or signaling mechanism.

 Several
different types of drug responsive signaling
mechanisms are known.
Signal transduction

1. ion channel linked

(speedy)
2. G protein linked
(amplifier)
3. enzyme linked
(multiple actions)

4. nuclear (gene) linked

(long lasting)
1. Ion channel
receptors
Structure:
•Protein pores in the
plasma membrane

2004-
2005
2. G protein linked (amplifier)

2004-
2005
 enzyme linked
(multiple actions)

 Receptors that are enzymes themselves (or directly activate

enzymes) when a drug or hormone binds, causing multiple actions
•A inside the cell.
ligand (like insulin or growth factor) binds to the outside part of the receptor on the cell membrane.
•The receptor has an extracellular domain (outside cell) and intracellular domain (inside cell).

•The intracellular part of the receptor acts as an enzyme (usually tyrosine kinase).
•Binding of ligand causes receptor dimerization (two receptor units come together).
•This activates the enzyme activity inside the receptor.

•Activated enzyme (tyrosine kinase) adds phosphate groups (phosphorylates) to certain proteins inside the cell.
•This switches proteins “on” → starts a chain of chemical reactions.
2004-
2005
nuclear (gene) linked
(long lasting)

 Some drugs, like steroids and thyroxine,

enter the cell and bind to receptors in the
cytoplasm or nucleus. This complex
moves to the DNA and changes gene
activity, leading to the production of new
proteins. The effect is slow (hours to
days) but long-lasting.
Summary
 most drugs act through receptors
 there are 4 common signal transduction methods
 the interaction between drug and receptor can be described
mathematically and graphically
 agonists have both affinity and intrinsic activity .
 antagonists have affinity only
 antagonists can be competitive .
 non-competitive when mixed with agonists
 agonists desensitize receptors.
 antagonists sensitize receptors.