Dr.

RAGHU PRASADA M S
MBBS, MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.

1
PHARMACOKINETICS:
Pharmacokinetics is the science of the kinetics of drug absorption,
distribution, and elimination (i.e, excretion and metabolism).
PHARMACODYNAMICS:
Pharmacodynamics refers to the relationship between the drug
concentration at the site of action (receptor) and pharmacologic
response.

ABSORPTION:
“The process of movement of unchanged drug from the site of
administration to systemic circulation is called as absorption”.
It can also be defined as the process of movement of unchanged
drug from the site of administration to the site of measurement i.e
plasma.
The process whereby drug moves from the muscle,
digestive tract or other site of entry into the body
towards the circulatory system

Drugs are administered away from their site of action .

To reach their site of action they are permeate from
one compartment to another by crossing the different
barriers.
So the drugs have to cross the cell membranes.
Fluid bi-layer of phospholipids.
Scattered membrane protein molecules embedded in
bi-layer serve as
Receptors--- selective targets for drug action
Ion channels
Transporters
Lipid molecules are capable of lateral movement.
It is flexible
Has high electrical resistance
Relatively impermeable to highly polar molecules
Highly permeable to lipid soluble drug molecules
1. Passive diffusion
Lipid diffusion
Aqueous diffusion
2. Carrier mediated transport
Active transport
Facilitated diffusion
3. Pinocytosis
Endocytosis
Exocytosis
Pores of about 10 nm and 50 to 70 nm were inferred to
be present in membranes based on capillary membrane
transport studies. These small pores provide a channel
through which water, ions, and dissolved solutes such as
urea may move across the membrane.
Passive Diffusion: Passive diffusion is the
process by which molecules spontaneously
diffuse from a region of higher concentration
to a region of lower concentration. This process is
passive because no external energy is
expended
Important for drug molecules too large or too insoluble
in lipid to diffuse passively through membranes.
Carriers are trans-membrane proteins.
The drug molecules chemically related to naturally
occurring peptides, amino-acids, or sugars can use
these carriers.
Carrier binds one or more molecules or ions, changes
conformation & releases them on the other site of
membrane.
Main sites:
Renal tubule.
Biliary tract.
Blood brain barrier. (BBB)
Gastrointestinal tract. (GIT)

Types:
Active Transport
Facilitated Diffusion:
Active transport: The characteristics are:
Against the concentration gradient
Energy dependent , obtained from hydrolysis of ATP
Carrier is required
Selective
Saturable
Competitive inhibition by another drug binding to same
carrier.
 Reverse transporters: Carriers specialized in expelling
foreign molecules as the enter the cells.
One large family is ABC (ATP binding cassette ) family
It includes P-glycoprotein or multidrug resistance type
1 (MDR1) transporter, found in the brain, testis &
other tissues and in some drug resistant neoplastic
cells
It can be inhibited by grape fruit juice & certain
drugs i.e VERAPAMIL.
2. Multidrug resistance –associated protein (MRP)
transporters play important role in excretion of drug or
its metabolites into urine or bile.
Facilitated Diffusion: A mechanism to enhance
diffusion of drugs with low lipid solubility.
Along a concentration gradient
Carrier mediated: Carrier increases lipid solubility of
drug →↑rate of diffusion
Not energy dependent
Saturable
Competitive inhibition
e.g. Glucose entry into the cell by Glucose transporters-
GLUT1-GLUT5
Specific receptors for transport proteins must be
present for this process to work.
Endocytosis: Drugs which have very large molecules
(macromolecules) can be engulfed by the cell
membrane in a vesicle & carried into the cell &
released within the cell by pinching off the vesicle &
breakdown of its membrane.
Examples:
Transport of vitamin B12 with a binding protein (
intrinsic factor) across gut wall.
Iron is transported into hemoglobin synthesizing RBCs
precursors with transferrin.
Exocytosis is the reverse of endocytosis.It is
responsible for secretion of many substances from
cells. e.g. Expulsion of neurotransmitters into the
synaptic cleft.
The neurotransmitter substances are stored in
membrane bound vesicles in nerve endings to
protect them from metabolic destruction .
Appropriate activation of nerve ending causes
expulsion of its contents in to the synaptic cleft.
 GI Lumen GI Barrier Blood
Solid dosage form

1 Non-ionic drug Non-ionic drug

3

3
Granules or Drug in solution
aggregates At absorption site 4

2
3

Ionic drug Ionic drug

Fine particles

Sequence of events in the absorption of drugs from orally administered

solid dosage forms
Physicochemical/ Pharmaceutical factors:
Drug solubility & dissolution rate
Particle size & effective surface area
Polymorphism & amorphism
Pseudoploymorphism (hydrates/solvates)
Salt form of the drug
Lipophilicity of the drug pH- Partition-hypothesis
pKa of drug & gastrointestinal pH
Drug stability
Physicochemical/ Pharmaceutical factors :
Disintegration time (tablets/capsules)
Dissolution time
Manufacturing variables
Pharmaceutical ingredients (excipients/adjuvants)
Nature & type of dosage form
Product age & storage condition
 Pharmacokinetic factors :
Route of administration
Membrane physiology
a) Nature of cell membrane
b) Transport processes
Age
Gastric emptying time and Intestinal transit time
Gastrointestinal pH
Disease states
Blood flow through the GIT
Gastrointestinal contents: a) Food- drug interactions
b) Fluids c) Other normal GI contents
Presystemic metabolism by: (first pass metabolism)
a) Luminal enzymes b) Gut wall enzymes
PHYSICOCHEMICAL/PHARMACEUT-
ICAL FACTORS
1) Drug solubility & dissolution rate :
The rate determining steps in absorption of orally
administered drugs are:
1. Rate of dissolution
2. Rate of drug permeation through the biomembrane.
Dissolution is rate determining step for hydrophobic &
poorly aqueous soluble drugs.
E.g. Griseofulvin & Spironolactone.
Permeation is the rate determining step for hydrophilic
& high aqueous soluble drugs.
E.g. cromolyn sodium OR Neomycin.
2) Particle size and effective surface area:
Particle size may play a major role in drug absorption.
Dissolution rate of solid particles is proportional to
surface area
Smaller particle size, greater surface area then higher
will be dissolution rate, because dissolution is thought to
take place at the surface area of the solute( Drug).
Particle size reduction has been used to increase the
absorption of a large number of poorly soluble drugs
E.g. Bishydroxycoumarin, digoxin, griseofulvin
We have to reduce the size of particles up to 0.1 micron
to increase surface area of absorption. So these can be
achieved by “micronisation process’’.
a) HYDROPHILIC OR b) HYDROPHOBIC
a) HYDROPHILIC DRUGS:
In hydrophilic drugs the small particles have higher
energy than the bulk of the solid resulting in an
increased interaction with the solvent. Examples,
1.Griesiofulvin – Dose reduced to half due to
micronisation.
2.Spironolactone – the dose was decreased to 20 times
3.Digoxin – the bioavailability was found to be 100% in
micronized tablets.
After micronisation it was found that the absorption
efficiency was highly increased
b) HYDROPHOBIC DRUGS:
In this micronisation techniquies results in decreased
effective surface area & thus fall in dissolution rate.
The hydrophobic surface of the drugs adsorbs air
on to their surface which inhibits their wettability.
Ex Cyclosporin
Drug stability:
A drug for oral use may destabilize either during its shelf
life or in the GIT.
Two major reasons for poor bioavailability

-Degradation of the drug into inactive form and

-Interaction with one or more different component(s)
either of the dosage form or those present in the GIT to
form a complex that is poorly soluble or is not absorbable
Many drugs are weak acids/bases
Can be ionized, unionized
Varies with pH of environment
Acids release H+
Strong: All H+ released
Weak: Some H+ released
Ka quantitates strength of acid
Oral – 5<100% bioavailability
First pass effect is significant
Absorption in small intestine is primarily dependent on
physico-chemical properties
Non ionised compounds –ethyl alcohol and Low molecular
weight substances –urea readily cross cell membrane
Rectal -30<100% bioavailability
Only about 50% of the rectal dose may pass through liver
(external haemorrhoidal veins).
Barriers here are colonial mucosa, anaerobic organisms
and enzymatic activity E.g. Metoclopramide, ergotamine,
lidocaine
Bioavailability characteristics with
different routes

Absorption of Drugs Lung – gases, liquid droplets

5<100% bioavailability
The drug can have local effects - Epinephrine for asthma.
The drug can have systemic effects - general anesthetics.
Large surface area, limited thickness of pulmonary
membrane and high blood flow allow for almost instant
absorption by diffusion Avoid first pass effect

Lungs are also site of first pass excretion

Intra-arterial: nearly 100% bioavailable
Intra-arterial injection is used to deliver drugs directly to organs, for
example, in cancer chemotherapy, and in the use of vasopressin for GI
bleeding.
Intrathecal: nearly 100% bioavailable
Injection directly into the cerebrospinal fluid (CFS) ensures complete
CNS bioavailability for drugs that can not cross the blood-brain barrier.
E.g. Mepivacaine and prilocaine for spinal anesthesia.
Intravenous (IV): nearly 100% bioavailabe
IV administration introduces drug directly into the venous circulation.
IV bolus is used for immediate therapeutic effect, typically for general
anesthesia and for treatment of cardiac arrhythmia.
Intramuscular (IM): nearly 100% bioavailable
For drugs and vaccines that are not absorbed orally, for
example, aminoglycosides, insulin and hepatitis vaccine.
The IM route is often used for sustained medication and
specialized vehicles, such as aqueous suspensions, oily
vehicles
Topical route:
Transdermal: 80<100 % bioavailable
Continuous release of drug over a specified period, low
presystemic clearance, and easy drug withdrawal by simply
removing the device, and good patient convenience and
compliance.
Intranasal:
Intranasal administration may be used for local or systemic
effects. Local effects include treatment of nasal allergies,
rhinitis, and nasal congestion. Nasal delivery for systemic
effects is established for a small number of drugs
E.g. Vasopressin analogues and oxytocin are commercially
available for intranasal dosage.
Vaginal: vaginal absorption can give rise to rapid and
efficient systemic delivery.
E.g. vaginal rings and biodegradable microspheres
Sublingual/Buccal:
Drugs can be absorbed from the oral cavity itself or
sublingually. Absorption from either route is rapid,
sublingual more so apparently because of greater
permeability of sublingual membranes and rich blood
supply.
E.g. organic nitrates, barbiturates, papaverine,
prochlorperazine, benzodiazepines.
Bioavailability is defined as the fraction of
unchanged drug reaching the systemic
circulation following administration by
any route
Factors influencing bioavailability

First pass metabolism

Solubility of drug
Chemical instability
Drug formulation
Enzyme induction
Individual variation
The tmax is independent of dose and is dependent on the rate
constants for absorption (ka) and elimination (k)
At Cmax, sometimes called peak concentration, the rate of drug
absorbed is equal to the rate of drug eliminated. Therefore, the
net rate of concentration change is equal to zero
AUC is a measure of the body’s exposure to a drug

32
The AUC-Area Under Curve is expressed in the units of
mg-hr/ml
Planimeter –an instrument for measurement of area of
plane figures
Cut and weigh method- that means to cut out the area
under the entire curve on rectilinear graph paper and
weigh it on analytical balance
Mathematical –using trapezhoid rule
When drug is absorbed across the GI tract, it enters the
portal circulation before entering the systemic circulation.
Here some part of drug gets metabolized and amount of
unchanged drug that gains access to the systemic circulation
is decreased. Ex- lidocaine, morphine, nitroglycerine,
propranolol
 THANK YOU
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