This document provides an overview of principles of pharmacokinetics, pharmacodynamics, and pharmacogenetics. It discusses key topics including absorption, distribution, metabolism, and excretion of drugs. Absorption involves drugs being taken up into systemic circulation and is influenced by route of administration, drug properties, and gastrointestinal factors. Distribution of drugs to tissues depends on blood flow, permeability, protein binding, lipophilicity, and tissue storage. Metabolism transforms drugs via phase I and phase II reactions, mainly in the liver, and can activate or inactivate compounds.

1. PRINCIPLES OF PHARMACOKINETICS,PHARMACODYNAMICS AND
PHARMACOGENETICS
Prepared by:
KRISHNA PRASAD DAHAL
PHARM D. (PU)
RPh. (Pb); RPh. (NEPAL)
CLINICAL PHARMACIST at G.N.S. SAGARMATHA ZONAL HOSPITAL
FACULTY MEMBER OF PHARMACOLOGY AND TOXICOLOGY
SAPTARISHI HEALTH SCIENCE COLLEGE
RAJBIRAJ, NEPAL

2. PHARMACOKINETICS
• Pharmacokinetics is derived from Greek word “pharmacon” and “kinetics” where
it means “drug” and “movement” respectively.
• Pharmacokinetics can be defined as the changes that occur in drugs that happens
when the drug is in body.
• Simply it can be defined as what body does to the body.
• Parameters that are extensively studied under pharmacokinetics are
• Absorption
• Distribution
• Metabolism
• Excretion

3. Absorption
• Absorption is the process by which a drug is taken up to the systemic circulation.
The rate and amount of absorption depends on the environment where the drug
is absorbed (i.e. oral, topical, inhalation) and the physical and chemical properties
of the drug (i.e. lipid and water solubility)
• In some cases drugs may exhibit their effect without getting absorbed and are
usually for local action for e.g.
• Inhalation directly to bronchioles or lungs in case of asthma.
• For direct effect on GIT such as antacids.
• For local effect in rectum via suppositories.
• For local application on skin.

4. • However in most cases drug has to be absorbed through the physiological
barriers. For the drug given orally, barriers includes are wall of intestine and
capillaries pores present in capillaries also to pass to CNS the drug has to pass
through Blood Brain Barrier (BBB).
MECHANISM OF ABSORTION FROM GI TRACT
Depending on their chemical properties drug may absorb from gut wall by
following process.
I) Diffusion
II) Active transport
III) Endocytosis
IV) Ion pair formation

5. I) Diffusion
The movement of drug molecules across the concentration gradient i.e.
from its higher concentration to its lower concentration through the
membrane separating two compartment is known as diffusion.
This movement does not require any carrier molecules as well as energy.
Majority of drugs are absorbed by this mechanism.
II) Active transport
The movement of drug molecules across the membrane by the carrier
molecules along with utilization of the Energy (hydrolysis of ATP molecules)
is known as active transport.
This type of movement capable of moving drugs against a concentration
gradient i.e. from its lower concentration to its higher concentration.

6. III) Endocytosis (phagocytosis or pinocytosis)
This type of absorption is used to transport drugs of exceptionally large
molecules across the cell membrane. Endocytosis involves engulfment of a
drug molecules by the cell membrane and transport into the cell by
pinching off the drug filled vesicles.
Then the vesicles inside the cell dissolve or break down to release the drug
molecule in the matrix of cell.
IV) Ion pair formation
Drugs which are highly ionized or charged molecules penetrates the
membrane poorly. When these ions or charged molecules liked with the
oppositely charged ions, ion pairs are formed which behaves as the neutral.
This neutral complex diffuses across the membrane. E.g. the formation of
an ion pair of propranolol (basic drugs) with oleic acid.

7. FACTORS AFFECTING ABOSRPTIONOF DRUGS
Different factors affecting the absorption of drugs are
Route of administration:
Route of administration has got the major information in the absorption of
the drugs. IV administration does not require any absorption process
whereas Inhalation of drugs has rapid onset of action than the oral route of
administration.
Ph of drugs and stomach
Most drugs are Either acidic or Basic. Acidic drugs are rapidly absorbed in
the acidic environment whereas basic drugs are absorbed in the basic
environment.
Basic drugs are ionized in the acidic environment of stomach so tablets are
coated in order to remain intact.

8. Particle size of drug molecules
smaller the size of the drug there is rapid absorption and produce rapid
action and vice versa.
Area of absorbing surface
larger the surface area of site of absorption, greater is the rate of
absorption and smaller the surface area lesser is the absorption.
Microvilli present in intestine helps in increasing surface area of absorption
of food as well as drug molecules.
Solubility of drugs
Greater the solubility of drugs in the stomach and intestinal juice greater is
the absorption and vice versa.
Blood flow to the site of absorption
More the blood to the site of absorption more is the absorption of drugs
and vice versa.
So, the absorption of drug from intestine is greater the absorption from
stomach.

9. Time of contact at the absorption site
Time of contact of drugs in the absorption site depends upon the motility of
intestine (peristalsis). If any drugs is administered along with gastric motility
increasing drugs concomitantly the absorption of the first drug is lesser due
to faster peristalsis.
Expression of P-glycoprotein
P-glycoprotein is a transmembrane transporter protein responsible for
transporting various molecules including drugs across the membrane.
The cell where there is high expression of P-glycoprotein molecule there is
efflux of drugs from the cell decreasing the absorption of the drugs.
Metabolism of drugs
Some drugs such as propranolol and Levodopa are rapidly Metabolized in
the gut wall or resulting in decreasing of absorption of drugs.

10. DISTRIBUTION
After the drug is absorbed in the systemic circulation then the drug is distributed to
the different organ and system and return back to blood stream from the organ,
extracellular fluid. This reversible transformation of drug from and to the systemic
circulation is known as distribution of drug.
This transformation of drug is affected by various factors such as:
a) Blood flow
b) Capillary permeability
c) Protein binding
d) Lipophilicity
e) Tissue storage

11. A) Blood flow
The rate of blood flow to various organs varies according to the cardiac
output which in turn affect the distribution of drugs. The organ which are
highly perfused to the blood such as heart, brain, kidney, lungs receive the
high amount of drugs than the low perfused organs such as skin, skeletal
muscle, bone marrow.
B) Capillary permeability
Capillary structure and chemical nature of drug determine its permeability.
Capillary structure varies according to the slit junctions between the
endothelial cells. In liver and spleen the capillary permeability is greater
through which plasma protein can pass but in brain the slit junctions in
capillaries are closed so to enter the drugs in CNS the dugs must pass
through the endothelial cells of capillaries or undergo active transportation
of drugs.

12. C) Protein binding
Binding of the drug to the plasma protein results in poor distribution to
the tissue compartment. The major drug binding protein is Albumin and
act as drug reservoir. The drug binding to the protein are not available for
therapeutic activity as well as metabolism. As the concentration of
the free drug reduces by the process of elimination, the bound drugs
dissociates and available for activity as well as elimination. Protein
binding maintains free drug concentration.
D) Lipophilicity
crossing of the cell membranes depends on the chemical property of the
drug. Highly lipophilic drugs cross the membrane easily than the hydrophilic
drug because hydrophilic drugs do not readily penetrate the cell membrane
and must pass through the slit junctions.

13. E) Tissue storage
Some drugs has property of affinity to the specific tissue as follows:
i) Digoxin: Muscle and Heart
ii) Iodine: Thyroid
iii) Chloroquine: Brain
iv) Atropine: Iris
v) Tetracycline: Bone/Teeth

14. Metabolism/Biotransformation
• The process by which a drug gets transformed from its original form to the other
form is known as metabolism. It is also referred as chemical alteration of the drug
in the body.
• Most of the drugs administered are metabolized in the liver, which contains
metabolizing enzymes. Metabolism also takes place in kidney, spleen, skin, lungs
and tissues.
• As the result of metabolism either the drug is changed into active form or most of
time drug transformed into inactive metabolite.
Factors affecting metabolism
The main factors that affects drug metabolism are age, sex, body temperature,
enzyme modulators, presence of disease and diet.

15. Reaction of drug metabolism
Kidney cannot efficiently excrete lipophilic drugs that readily cross cell membranes
and are reabsorbed in the distal convoluted tubules. Therefore, lipid soluble agents
are first metabolized into more polar (hydrophilic) substances in the liver via two
general sets of reaction called
1. Phase I reactions
2. Phase II reactions
1. Phase I reactions/non-synthetic reactions
Phase I reaction most frequently involved in drug metabolism and are
catalyzed by microsomal enzymes in liver.
This reaction leads to activation or de-activation pf compounds.
Phase I reaction undergoes following reactions such as:

16. a) Oxidation
b) Reduction
c) Hydrolysis
d) Cyclization
e) De-cyclization
A) Oxidation
Reaction occurring by addition of oxygen or removal of hydrogen.
It is the most common type of phase I reaction.
B) Reduction
Reaction occurring by removal of oxygen or addition of hydrogen.
This reaction is the converse of oxidation reaction and working in opposite
direction.
It is less common than oxidation reaction.

17. C) Hydrolysis
enzymatic cleavage of the drug molecule in presence of water is known as
hydrolysis.
Ester hydrolysis and Amide hydrolysis are common reactions taking place
for metabolism.
D) Cyclization
Formation of ring structures from a straight chain compound.
E.g. Proguanil
E) De-cyclization
Formation of straight chain from cyclic compounds or opening up of the ring
of the molecule is known as De-cyclization.
E.g. Phenytoin

18. 2. Phase II reaction/synthetic reaction
These reactions involves conjugation of the drug itself or the
molecules generated from phase I reaction with an endogenous
substrate/molecules which are generally carbohydrates or amino
acids. The resulted conjugated molecules are easily excreted in
urine or bile.
Conjugation reactions have high energy requirement.
Following reactions occurs in phase II reactions.
a) Glucoronide conjugation
b) Methylation conjugation
c) Acetylation
d) Sulfate conjugation
e) Glutathione conjugation

19. Excretion
Excretion is defined as the complete removal of drug from the body in its
unchanged form while Elimination is defined as the complete removal of drug from
body after metabolism.
Excretion of the drug helps in optimizing drug therapy and minimizing toxicity.
Excretion of most drug takes place from
a) Kidney
b) Liver
c) Sweat
d) Saliva
e) Exhalation
f) Breast milk

20. PHARMACODYNAMICS
Pharmacodynamics is derived from the Greek word “pharmacon” and “dynamics”
which means “drug” and ”power” respectively.
It simply can be defined as the power of drug or what drug does to the body.
It is also the study of the biological and therapeutic effect and mechanism of action
of a drug.
Mechanism of drug action
Mechanism of drug action can be categorized into five parts:
a) Receptor mechanism
b) Anti-metabolite
c) Enzyme inhibition
d) Action on cell membrane
e) chelation

21. A) Receptor mechanism
Here the drugs binds to their respective receptors and perform their function as
either agonist or antagonist to produce desired therapeutic effect.
For examples acetylcholine activates the cholinergic receptors and perform
parasympathomimetic action whereas Atropine deactivates the cholinergic
receptors and shows parasympatholytics action.
B) Antimetabolites
Antimetabolites are the compound that are structurally similar to the
endogenous molecules but perform the opposite function to the
metabolite.
Antimetabolites competitively binds in place of the actual molecule
involved in metabolic process but the end result is not produced as desired.
Examples are Methotrexate (anticancer drug) and sulfonamide (anti-
bacterial drugs).

22. C) Enzyme inhibition
Certain drugs acts by inhibiting the enzymes that are involved I
metabolic process.
Inhibition of enzymes result in the greater activity of the
endogenous because the molecules are not metabolized as a
result of inactivation of their metabolizing enzymes.
D) Cell membrane
Some drugs produces their effect by acting on the cell
membrane itself.
e.g. of this type drug is Amlodipine which produces its action by
blocking the calcium channels present in the myocardial cells and
smooth muscles of blood vessels resulting in dilating of the blood
vessels.

23. E) Chelation
Chelating agents like Desferroxamine, Dimercaprol binds to the
iron and toxic metals (heavy metals) in the body to form drug-
metal complex which are non toxic and area readily eliminated.
PRINCIPLE (TYPES) OF DRUG ACTION
Drugs perform their action by following ways.
a) Stimulation
b) Depression
c) Irritation
d) Cytotoxic effect
e) Replacement
f) Modification of immune status

24. A) Stimulation
A drug may produce a desired effect by stimulation of a receptor of the certain
endogenous chemical. For e.g. Salbutamol stimulates β-2 receptors of
adrenaline to produce bronchodilation.
B) Depression
A drug may produce a desired effect by depressing the activity of certain
endogenous chemicals. Barbiturates/Alcohol act as an CNS depressant.
C) Irritation
Certain drugs may produce a desired act by causing irritation. E.g. castor
and Senna shoe their laxative action by irritating the nerve terminals on the
GIT.
D) Cytotoxic effect
A drug produce cytotoxic effects by causing toxicity to the undesired cells of
the body. E.g. Cancer cells are treated with selective cytotoxic action
without affecting the host/normal cells.

25. E) Replacement
Replacement therapy means the use of certain drugs in
deficiency states. E.g. use of insulin in diabetes patient.
F) Modification of immune status
Vaccines or antigens induce production of specific antibody
against particular causative microorganisms. Thus they act by
altering the immune status of the body.

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