PHARMACOKINETICS

Dr. Ashish Yadav

Assistant Professor
Department of Pharmacology
KIMS
 INTRODUCTION
Pharmacokinetics is the study of fate of drugs in
the body over a period of time, including the
processes of absorption, distribution,
biotransformation and excretion
• In simple terms Pharmacokinetics is “what the
body does to the drug”.
 PHARMACOKINETICS
• Absorption
• Distribution
• Metabolism (Biotransformation)
• Excretion
 ABSORPTION
• Absorption via GIT
Mainly by passive diffusion
– Mouth
• Lipophilic basic and neutral drugs are better absorbed.
• Bypass first pass metabolism.
– Stomach
• Lipophilic acidic drugs are better absorbed.
• Drugs exposed to first pass metabolism
– Intestine
• Lipophilic basic drugs are better absorbed
• Major site of drug absorption for all drugs due to large surface area
and time factor
• Drugs enter portal circulation and exposed to first pass metabolism
– Rectum
• Lipophilic basic and neutral drugs are better absorbed.
• Bypass first pass metabolism to a large extent
 ABSORPTION
• Absorption via GIT
Factors which compromise absorption
• Drug efflux by P-glycoprotein present in the
enterocytes
• First pass metabolism in enterocytes or liver
• Vomiting
• Disease affecting GIT (eg. diarrhoea)
 ABSORPTION
• Absorption via Parenteral sites
– Intravenous
• No absorption required
– Intramuscular
• Absorption by passive diffusion as well as filtration
through channels in the capillary endothelium
– Subcutaneous
• Processes same as IM route
• Bit slower than IM due to rich blood supply of the latter
 ABSORPTION
• Absorption via Lungs
– Mainly by passive diffusion
– Rapid absorption due to large surface area
• Absorption via topical sites
– By passive diffusion
– Absorption is poor through skin as keratinized
epithelium acts as barrier to permeability
– Absorption via mucous membranes is good due to
its thin and vascular absorbing surface
 Methods to delay Absorption
• Using Appropriate dosage forms
– Slow release dosage forms
• Timed release oral preparations
• Depot injections
• Subcutaneous implants
• Transdermal patches
• Changing physical characteristics of the drug
– Eg. Insulin amorphous zinc suspension is rapidly absorbed while
crystalline zinc suspension is slowly absorbed
• Adding a vasoconstrictor or applying a tourniquet
– Adding adrenaline to a local anaesthetic like lignocaine causes
vasoconstriction and prolongs the action of subcutaeously
injected lignocaine.
– Application of a tourniquet on the proximal part of limb and
then injecting the local anaesthetic IV, leads to prolonged
action of the local anaesthetic.
 Methods to facilitate Absorption
• Increasing the rate of filtration through the
tissue
– Breaking the intercellular matrix by adding
hyaluronidase to the injection
• Increasing local blood flow
– Applying hot fomentation at the site of injection
– Massaging the site of injection
 BIOAVAILABILITY
The rate at which and the extent to which the
active concentration of the drug reaches the
site of action
For practical purposes, the desired site of
action is taken to be the systemic blood
stream
 Measurement of BIOAVAILABILITY
• The drug in question is administered and
serial sampling for plasma concentration is
done.
• The data obtained is plotted on a graph as
concentration vs time curve
Measurement of BIOAVAILABILITY
(Tmax)

(Cmax)

AUC

• Parameters observed:
– Cmax: Peak plasma concentration achieved
– Tmax: Time taken to achieve peak concentration
– AUC: Area under the curve
First two parameters denote the rate while AUC denotes the
extent of absorption
 Measurement of BIOAVAILABILITY
• The quantitative
evaluation of any oral
dosage form is done
by comparing the
AUCs obtained after
administering the
same dose of the drug
via oral and IV routes

AUC (oral)
Bioavaialbility (F) (%) = x 100
AUC (IV)
 EQUIVALENCE
• Equivalence is a relative term which pertains
to comparison of two drug products for a set
of properties.
• Equivalence can be of following types:
– Bioequivalence
– Chemical Equivalence
– Clinical Equivalence
– Therapeutic Equivalence
 BIOEQUIVALENCE
• If two or more similar dosage forms of the same
drug reach the circulation at the same relative
rate and to the same relative extent, they are said
to be bioequivalent.
• Bioequivalence compares the same / similar
dosage forms of two brands of the same drug
• Differences of less than 25% in bioavailability of
two products usually have no significant effect on
clinical outcome and hence are considered
bioequivalent.
 BIOEQUIVALENCE
• Importance
– For drugs having a high margin of safety, measurements of
bioequivalence are immaterial.
– Bioequivalence assumes a greater concern for:
• Drugs having steep dose-response relationship or which obey
zero order / mixed order elimination kinetics (eg. Phenytoin,
Warfarin and other oral anticoagulants, Digoxin, Phenylbutazone,
high dose Aspirin)
• Drugs having a narrow margin of safety (eg. Antiarrythmics,
Antidiabetics, Corticosteroids, Chloramphenicol, Tetracycline,
Theophylline)
In such cases, patients stabilized on one brand should not be
switched onto another brand without confirming the
bioequivalence. Doing so can likely cause therapeutic failure
(decreased bioavailability) or drug toxicity (increased
bioavailability)
 OTHER EQUIVALENCE
• Chemical Equivalence
– If two brands of the same drug contain the same
ingredients in the same quantities, they are said to be
chemically equivalent.
• Clinical Equivalence
– If two brands of the same drug provide equivalent
biological response, they are said to be clinically
equivalent.
• Therapeutic Equivalence
– If two structurally different drugs provide the same
therapeutic response, they are said to be therapeutically
equivalent. Eg. thiazide diuretics and ACE inhibitors may
show the same control in hypertension.
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
Pharmaceutical Factors Pharmacological Factors
• Particle Size • Gastric Emptying and
• Salt form Gastric Motility
• Crystal Form • GI Disease
• Water of Hydration • Food
• Nature of Excipients • First Pass Metabolism
and Adjuvants • Drug-Drug Interactions
• Degree of Ionization • Pharmacogenetic
Factors
• Miscellaneous Factors
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
Pharmaceutical Factors
• Particle Size
– A drug having a larger surface area (smaller particle
size) is absorbed more rapidly.
• Eg. Micronized Griseofulvin and Digoxin are better absorbed
than their regular forms
• Salt form
– Weak electrolytes dissolve rapidly than their non-
electrolyte counterparts and hence are absorbed
rapidly.
• Eg. Tolbutamide sodium and Secobarbital sodium are better
absorbed than Tolbutamide and Secobarbital respectively.
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• Crystal Form
– Amorphous form of a drug is absorbed faster than
its crystalline form
• Eg. Amorphous Chloramphenicol has a faster
dissolution rate and better bioavailability than its
crystalline form
• Water of Hydration
– Salts having water of hydration exist in crystalline
form and thus have a slower rate of absorption
than anhydrous form
• Eg. Anhydrous Theophylline and Ampicillin are better
absorbed than the hydrous forms of these drugs
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• Nature of Excipients and Adjuvants
– Excipients and Adjuvants are phamacologically inert
substances (eg. starch, lactose, gum, polysorbate-80)
which are added to the formulation as filling material or as
binding agents
– Some agents act as wetting agents, ie enhance penetration
of water to accelerate dissolution and absorption (eg.
lactose, polysorbate-80)
Hence, changing of brands for drugs with narrow
therapeutic window can have adverse clinical outcomes.
• Degree of Ionization
– Non-ionized drugs are better absorbed from GIT while
highly ionized drugs are not absorbed.
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
Pharmacologic Factors
• Gastric Emptying and GI Motility
― In general, factors which increase gastric
emptying and GI motility increase absorption
• Drugs reach the large absorptive surface area of the
intestine sooner
• Increased motility is important for drugs which are
unstable in gastric acid
―However, the converse is true for drugs which are
incompletely absorbed from the GIT (eg. digoxin).
Here, decreased motility increases the extent of
absorption.
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• Gastric Emptying and GI Motility (contd.)
• Factors promoting • Factors retarding
gastric emptying gastric emptying
– Fasting – Fatty diet
– Anxiety – Depression
– Lying on right side – Lying on left side
– Hyperthyroidism – Pyloric stenosis
– Drugs like – Hypothyroidism
Metoclopramide – Drugs like Atropine,
Propantheline,
Imipramine,
Chlorpromazine
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• GI Disease
– Gastroenteritis:
• Decreased oral absorption of drugs
– Coeliac Disease:
• Absorption of some drugs (eg. amoxicillin) decreases
while that of others (eg. cephalexin) increases.
– Crohn’s Disease:
• Disproportionate absorption of individual components
of Cotrimoxazole occurs: absorption of Trimethoprim
decreases while that of Sulfamethoxazole increases.
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• Food
– In general, empty stomach favours drug absorption and food
decreases the rate (but not the extent) of absorption.
– Both rate and extent of absorption are decreased for Rifampicin
after meals.
– Similarly, milk and milk products markedly reduce the
absorption of Tetracycline (due to formation of complex with
calcium)
– Absorption of Griseofulvin is enhanced when administered with
fatty meals
– Vit. C (Citrus juices, lemonade) increases the absorption of Iron
by keeping it in its reduced (ferrous) form which is more soluble.
– Bioavailability of Phenytoin increases after meals (due to better
dissolution in bile)
– Lithium is also better absorbed with meals (on empty stomach,
it induces diarrhoea as side effect and is washed out)
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• First Pass Metabolism
– Drugs which undergo a significant first pass
metabolism show reduced oral bioavailability
• Eg. L-Dopa, Morphine, Nitroglycerine, Isosorbide dinitrate
• Drug-Drug Interactions
– Antacids containing salts of aluminium, calcium,
magnesium decrease absorption of Tetracycline
– Microsomal enzyme inducers like Barbiturates
increase hepatic metabolism of many drugs and
decrease their bioavailability
 FACTORS AFFECTING ABSORPTION
AND BIOAVAILABILITY
• Pharmacogenetic Factors
– Differences in rate of drug metabolism exist due to
differences in genetic make-up of and individual.
– Slow metabolisers show increased bioavailability and
vice versa
• Eg. Acetylation of Isoniazid is fast in Eskimos, Japanese and
Chinese while it is slow in American Whites, Mediterranean
Jews and Egyptians)
• Miscellaneous Factors
– Route of administration
– Area of absorbing surface
– Blood circulation at the site of absorption
--- To be continued ---