pharmacokinetics (2).pdf ghsaaiidwdihsbdb

• Drug absorption is determined by the drug’s
physicochemical properties, formulation, and route of
administration.
• Unless given IV a drug must cross several semi-permeable
cell membranes before it reaches the systemic circulation.
• Cell membranes are biological barriers that selectively
inhibit passage of drug molecules. The membranes are
composed primarily of a bimolecular lipid matrix which
determines membrane permeability characteristics.
• Drugs may cross cell membranes by:
1. Passive diffusion
2. Facilitated Passive diffusion
3. Active Transport
4. Pinocytosis

Drugs diffuse across a cell membrane from a
region of high concentration (G.I fluid) to a low
concentration (blood).
The diffusion rate is directly proportional to the
gradient but also depends on:
1. Molecule’s lipid solubility
2. Size
3. Degree of ionization
4. Area of absorptive surface.
Because the cell membrane is lipoid, lipid-
soluble drugs diffuse most rapidly.
Small molecules tend to penetrate membranes
more rapidly than larger ones.
Passive Diffusion
• Most drugs are weak organic acids or
bases existing in unionized and ionized
forms in an aqueous environment.
• The Unionized form is usually lipid soluble
(lipophilic) and diffuses rapidly across cell
membranes.
• The ionized form has low lipid solubility
(but high-water solubility)and high
electrical resistance and thus cannot
penetrate cell membranes easily.
• The proportion of unionized form is
determined by environmental pH and
Pka(?)

• The Pka is the pH at which the concentration
of ionized and nonionized forms are equal.
• When pH is lower than Pka, the unionized
form of weak acid predominates but the
ionized form of weak base predominates.
• In plasma (pH 7.4) the ratio of unionized to
ionized form for a weak acid (e.g Pka 4.4)is
1:1000, in gastric fluid (pH 1.4) the ratio is
reversed.
• When a weak acid is given orally, most of
the drug in the stomach is unionized,
favoring diffusion through gastric mucosa.
Passive Diffusion
• For weak base with pKa of 4.4 the
outcome is reversed. Most of the drug in
stomach is ionized.
• Theoretically Weakly acidic drugs (e.g
Aspirin, Phenytoin and barbiturates) are
more readily absorbed from acidic
medium(stomach) than weakly basic drugs
(Quinidine, morphine, amphetamine and
diazepam).
• However, whether a drug is acidic or basic
most absorption occurs in small intestine
due to larger surface area and more
permeable membranes.

• The nonionized form of a weakly
acidic drug(e.g aspirin, Pka 3.5)
which crosses the gastric mucosa at
pH 2 reverts to the ionized form
within the cell (pH 7) and hence
slowly passes to the extracellular
fluid. This type of “ ion trapping”
contributes to gastric mucosal cell
damage caused by aspirin.
Passive Diffusion

• Certain molecules with low lipid
solubility e.g glucose penetrates
membranes more rapidly than
expected.
• One reason for this is facilitated
passive diffusion.
• A carrier molecule in the membrane
combines reversibly with substrate
molecule outside cell membrane and
carrier substrate complex diffuses
rapidly across the cell membrane
releasing the substrate at the interior
surface.
CARRIER MEDIATED TRANSPORT
In such cases membranes transports only the
substrate with a relatively specific molecular
configuration and the availability of carrier
limits the process.
The process does not require energy
expenditure and transport against conc.
Gradient cannot occur.
Examples:
Amino acids in brain
Anti-metabolite, anti-cancer drugs.
Anti-viral drugs
Adenosine like drugs
Riboflavin, thiamine and cyanocobalamine.
FACILITATED PASSIVE DIFFUSION:

• The process of active transport can be
blocked by inhibiting cell metabolism or by
reducing ATP levels by giving agents like
sodium cyanide and sodium fluoride.
• Drugs:
• 5-Fluorouracil by intestine
• Nitrogen mustard by lymphocytes
• Digitalis glycoside by liver
• Sympathomimetic amines by neural tissue
• Choline by cholinergic neuron.
CARRIER MEDIATED TRANSPORT
ACTIVE TRANSPORT
• It is selective, requires energy
expenditure.
• Transport against concentration
gradient.
• It is limited to drugs with similar
structure to endogenous
substances e.g ions, vitamins,
sugars and aminoacids absorbed
from specific sites in intestine.

• The particulate matter can also be
transferred by local invagination of the cell
membrane.
• Phago “ I eat”
• Poisoning by botulinum toxin
• Allergic reaction after ingestion of offending
proteins (allergens).
ENDOCYTOSIS
PINOCYTOSIS
• Pino (Greek) “ I drink”
• Cytos “ hollow vessel”
• Osis “ process”
• Pinocytosis is a process where a cell drinks or
engulf s a f luid or a drug in solution.
• Mac romolecula r solutes are f irst trapped in the
microscopic cavities f ormed on the membrane
surf ace (??)
• The membrane then fuses around and completely
encloses the f luid (containing the solute) to f orm a
vesicle.
• Later vesicle is pinched off, passing some f luid and
solute across the membrane into interior of cell.
• Insulin crosses BBB
• Anti-tumor drugs trapped in liposomes
• Receptor mediated absorption of LDL in liver
PHAGOCYTOSIS

• The absorption of drug through GI tract is
mainly by Passive diffusion through the
lipid sheath.
• Few drugs are small enough to diffuse
through the pores in the cell membrane
• Uptake of sugars and other nutrients is by
active transport.
• The gut is more permeable to nonionized
lipid soluble form of drugs
• The ability of the drug to get absorbed via
GIT and reach the systemic circulation can
be compromised as a result of drug loss
due to:
FILTRATION
• The free or unbound drug (or
metabolite) of smaller molecular size
can pass through the process of
filtration.
• It is a physical process where the
rate of filtration is proportional to
pressure gradient.
• Urea, alcohol, glucose are filtered
through glomerulus.
• Intact proteins do pass various
biological barriers such as the
capillary wall where the rate of
movement is directly proportional to
pressure gradient.
Absorption Via GI Tract

1. efflux by the P-glycoprotein
localized in the enterocytes.
2. Its metabolism in these cells
and liver
3. By vomiting
4. By disease that may affect
drug absorption
Absorption via GIT
Absorption Via Parentral Sites
• Drugs when injected IV are completely
absorbed and rapidly distributed as they
reach the blood stream without crossing any
membranes.
• Absorption following IM and SC injections
usually occur by passive diffusion from
injection site to plasma or lymph.
• Filtration is also very efficient.
• Absorption from IM is more rapid as
compared to SC because of higher
vascularity of muscles compared to
subcutaneous tissue but difference is not
large.

• Lipid soluble drugs when given
in vapourized form (anesthesia)
or as aqueous solutions
spray(salbutamol) or as spray
of suspended microfined
powder (di-sodium
cromoglycate) are absorbed by
simple diffusion from mucous
membrane of trachea and
lungs.
• Absorption is rapid because of
large surface area and high
vascularity.
Absorption via Lungs
Absorption Via Topical Sites
• Absorption of most drugs through intact skin
is ofcourse poor as keratinized epidermis
behaves as a barrier to permeability.
• Stratum basale ………. None
• Stratum spinosum
• Stratum granulosum
• Stratum corneum
However underlying dermis is quite permeable
to many lipid soluble drugs and significant
absorption can occur if skin is abraded.
Transdermal applications of (nitroglycerin,
scopolamine) and application of some drugs on
mucous membrane (oxytocin and vasopressin
nasal spray) enhances the systemic absorption
mainly because of thin and highly vascular
absorbing surface.

• Physical characteristics of some drugs might also
be changed to retard their absorption.
• E.g Insulin Zinc suspension depending on pH of
reaction insulin can form a fine amorphous zinc
suspension which is rapidly absorbed or a
crystalline zinc suspension which is slowly
absorbed.
• Each can be used separately depending upon the
effect desired and can also be mixed together to
produce an immediate but sustained effect.
• Procaine penicillin is salt to penicillin which is
only slightly water soluble. When injected as an
aqueous suspension, it is slowly absorbed and
exerts prolonged action.
Methods for delaying absorption
Using an appropriate dosage
• Slow release dosage form e.g
potassium chloride retard tablet,
diclofenac Na sustained release
tablet.
• Spansules
• Depot injections (testosterone)
• Subcutaneous Implants
are some ways to slow sustained
absorption of drug.
Changing the Physical Characteristic of Drug

• Application of tourniquet to arrest the
blood flow followed by IV injectionof local
anesthesia below the tourniquet (e.g in
whole limb) delays the systemic absorption
but prolong the local anesthetic effect.
• Increase peripheral blood flow in
conditions of shock significantly.
• Reduces the rate of absorption of injected
drugs.
Methods for delaying absorption
Adding a vasoconstrictor drug
• Addition of vasoconstrictor drug
(adrenaline or nonadrenaline) to
a solution of a local anaesthetic
e.g xylocaine, reduces the
absorption of local anesthesia
into general circulation.
• This usefully prolongs the local
anesthetic effect and reduces the
chances of systemic toxicity.
Application of Tourniquet

• Removal by local blood flow.
• Absorption from site of injection maybe
increased by increasing the local blood
flow by doing massage or applying hot
fomentation.
Methods to facilitate absorption
• Diffusion through the tissue.
• Hyaluronidase is protein enzyme.
It breaks down intracellular
matrix. Adding hyaluronidase to
injection fluid increases rate of
diffusion through interstitial
spaces and speeds up drug
absorption. E.g in urography.
Application of Tourniquet

• Dilantin Na capsules was the brand that was
being used by majority of patients. Calcium
sulphate was being used as inert diluent. It got
finished so they substituted it with lactose.
• With this replacement plasma concentration of
phenytoin reached 30 microgram/ml which was
toxic. Lactose got wetted more easily resulting in
faster dissolution and quicker
absorption................ Causing increase plasma
concentration.
• Bioavailability shows measurement of both true
rate and total amount of drug that reaches the
general circulation from administered dosage
form.
Bioavailability of Drugs
US Food and Drug administration “
The rate and extent at which the
active concentration of drug is
available at desired site of action.”
In 1968 in Australia there was
increase incidence of Phenytoin
toxicity reported in epileptic
patients.

If two or more similar dosage forms of same
drug reach the blood circulation at the same
relative rate and extent. They are called as
bio-equivalent preparation of generic drug.
Two brand preparations of phenytoin like
Dilantin ( Parke Davis) and Eptoin ( Boots)
may or may not be bioequivalent.
Equivalence
• Means comparison of one product
with another of same drug with a
set of established standards.
Bio-Equivalence
Non-Proprietary or Generic Name
• Names assigned by United States
Adopted Name (USAN) council only when
the drug has been found to be of
potential therapeutic usefulness.
• Uniformly used all over the world.
Proprietary Trade/ Brand Name
• The name given by Pharmaceutical company to
market the drug usually pref erred by medical
Practitioner.
• Copyright or registered name of the drug by which
it is sold by any drug company.

• Differences in bioavailability are primarily
seen with oral dosage forms b/c
bioavailability of any drug after I.V
administration is 100%. Some drugs e.g
phenytoin, digoxin, diazepam and
chlordiazepoxide partly get precipitated at
the site of injection and hence their
bioavailability gets reduced, if given by S.C
or I.M route.
• Differences of less than 25% in
bioavailability among several formulations of
one drug will usually have no significant
effect on clinical outcome, hence such
formulations can be called as bioequivalent.
• Measurements of bioavailability are
immaterial for drugs having higher margin of
safety e.g with water soluble vitamins,
antacids and some anti-microbial having
large therapeutic index.
• Differences in bioavailability assume a much
greater concern with drugs that show steep-
dose response relationship. E.g phenytoin,
warfarin and other oral anti-coagulants,
digoxin.
• Theophylline, anti-arrhythmics etc.
• In such cases the patients should be
stabilized with one brand formulation only.

If one structurally different drug can provide
the same therapeutic response or clinical
response as another drug these are then
called therapeutically equivalent drugs e.g
Trifluperazine ( Phenothiazine group) may be
therapeutically equivalent to Haloperidol
(butyrophenone) if both provide equivalent
therapeutic results in the treatment of
schizophrenia.
Clinical Equivalence
The two brand products of one drug
can be called clinically equivalent,
if they provide an identical invivo
pharmacological response as
measured by control of symptoms
of disease. E.g Dilantin and Eptoin
may or maynot be bioequivalent but
may be clinically equivalent if both
provide same pharmacological
response.
Therapeutic Equivalence

If two or more dosage forms of the
same drug contains the same
labelled quantities of the drug as
specified pharmacopoeia, these are
called as chemically equivalent
drugs. Example Dilantin and Eptoin
may be chemically equivalent if
they contain same quantity of
phenytoin on chemical assay.
Chemical Equivalence Factors Influencing the Absorption and
Bioavailability
Pharmaceutical Factors:
Any drug other than IV route must
dissolve before it becomes
available for absorption.
The bioavailability of drug should
decrease in the following order
Solution>suspension>capsule>table
t>coated tablet

Disintegration of solid dosage
form into fine particles depends
on the type of dosage form.
Hard tablets and coated tablets
take greater time to disintegrate
as compared to ordinary tablets
and capsules. The time required
for disintegration is saved in
powders and suspensions.
Disintegration
Dissolution
Second step is the dissolution of
the active drug from fine particles
to solution.
Factors which affect disintegration and
dissolution
1. Particle Size: a drug usually dissolves
more rapidly when its surface area is
increased by decreasing its particle
size.
Poorly soluble, slowly dissolving drugs
are often marketed in microfined or finely
particled form to facilitate absorption. E.g
microfined aspirin, spironolactone,
griseofulvin and digoxin.

Certain drugs e.g Penicillin G and
erythromycin should not be
micronized as they are unstable in
gastric fluids.
Reduction of particle size with
consequent increase in their
dissolution rate would rather result
in more extensive degradation of
drug and therefore bioavailability
would decrease.
2. Salt Form
The dissolution rate of a particular
salt is usually different from its
parent compound.
Salts of weakly acidic drugs are
highly water soluble. Free acidic
drug is precipitated from these salts
in a microcrystalline form which has
faster dissolution rate and hence
enhanced bioavailability
E.g Sodium tolbutamide and Sodium
secobarbital have better
bioavailability then tolbutamide and
secobarbital.

The absorption rate and bioavailability of a
drug depends on its crystalline form also. E.g
amorphous chloramphenicol palmitate and
amorphous novobiocin has faster dissolution
rate and bioavailability as compared to their
crystalline form.
3. Crystal Form
4. Water of Hydration
Many drugs can associate with water to
produce crystalline forms called Hydrates.
Consistent with the theophylline, caffeine, the
anhydrous form of caffeine and theophylline
have faster dissolution rate and better
bioavailability than the hydrous form.
5. Nature of Excepient and Adjuvant
These are pharmacologically inert substances
(starch, lactose, calcium sulfate, gum,
polysorbate) w/c are added to formulations as
filling material when drug contents are too
small or as binding agents to obtain proper
granular size.
These have tremendous effect on the
bioavailability of the drugs. E.g phenytoin,
digoxin, levodopa and warfarin etc.

Nonionised, lipid soluble drugs are------
Strong acids and bases are -------
Streptomycin, neostigmine, acetylcholine
and its analogs D-tubocurarine.
6. Degree of Ionisation
Pharmacological Factors
1. Gastric Emptying and GI Motility
Factors that accelerate gastric emptying, permit
drugs to reach the large absorptive surface area of
the small intestine sooner, and increase the
bioavailability unless the drug is slow to dissolve.
• Prompt gastric emptying is also important for
drugs that are unstable in gastric fluid e.g
Penicillin G.
• Gastric emptying is promoted by fasting, anxiety,
lying on right side,hyperthyroidism and drugs
like metoclopramide.
• Metoclopramide increases absorption of ethanol,
paracetamol, tetracycline and L-Dopa.

• Gastric emptying is slowed by fatty diet,
endogenous depression, lying on left side, pyloric
stenosis, hypothyroidism, drugs like atropine,
imipramine, propantheline and chlorpromazine.
• Propantheline has been found to reduce
absorption of riboflavin, sulfamethoxazole,
ethanol and paracetamol.
• The extent of absorption of drugs that are
incompletely absorbed (digoxin)may be dependent
on intestinal motility. E.g propantheline increases
while metoclopramide decreases the
bioavailability of digoxin by increasing or reducing
the transit time of the unabsorbed drug, through
small intestine.
2. Gastrointestinal Disease
• There are certain pathophysiological
factors that affect drug absorption.
• In achlorhydria gastric acid secretion is
decreased with a concomitant increase in
gastric pH.
• In Celiac disease some drugs like
amoxicillin show decreased absorption.
• Cephalexin shows increased absorption.
• Ampicillin shows no change.
• Decreased absorption of dietary folate
increases the toxicity of Clotrimoxazole.

In Crohn’s disease, there is a
disproportionate absorption of
individual components from
tablets of clotrimoxazole. The
absorption of trimethoprim is
decreased while that of
sulfamethoxazole is increased.
In gastroenteritis, there is
decreased absorption of drugs
if given orally e.g nalidixic acid,
ampicillin, and metoclopramide.
3. Food and other Substances
• GI absorption is favored by an empty stomach
while the absorption rate is reduced after the
ingestion of food.
• The rate and extent of absorption of certain
antibiotics e.g Rifampin is reduced after
meals.
• Absorption of tetracyclines is also markedly
reduced if taken with milk and milk products.
(ca ions)
• Absorption of certain antifungal drugs
(griseofulvin) is enhanced by administering
fatty diet.
• Vitamin C keeps iron in its ferrous form and
increases its bioavailability.
• Lithium is well absorbed after food, if given
empty stomach, causes diarrhea which
reduces absorption.

• All orally taken drugs first pass through
GIT wall then through Portal system
before reaching systemic circulation.
• First pass effect means the drug
degradation occurs before the drug
enters the systemic circulation.
• Net result is decreased bioavailability
and diminished therapeutic response.
• L-Dopa, Morphine, nitroglycerine,
isosorbide dinitrate and propranolol
have lower bioavailability if given by
oral route due to First pass.
4. First Pass Effect
5. Drug-Drug Interaction
• Differences in bioavailability can also be
observed due to drug-drug interaction
• Liquid paraffin decreases the
bioavailability of Vitamin A as it
emulsifies fat soluble vitamins (A,D, K
and E).
• Antacids containing aluminium, calcium
and magnesium and hematinics
containing Iron cause reduce
bioavailability of tetracycline.
• Probenecid blocks penicillin excretion
and enhances its bioavailability.

• Slow acetylators of Isoniazid and PAS show
increased bioavailability and can cause
isoniazid and PAS toxicity (American whites,
Scandinavians and Israelis).
• Fast acetylators like Japanese, Chinese and
Eskimos show reduced bioavailability.
• Fast hydroxylators of Phenytoin show
decreased bioavailability.
• Some persons have atypical Plasma
pseudocholine esterase which has very low
hydrolysing capacity for succinyl choline.
Even 1/6th of the dose can produce
therapeutic effect in such cases.
6. Pharmacogenetic Factors
7. Miscellaneous Factors
(a)Route of administration
(b)Area of absorbing surface
(c) State of circulation at site of absorption
also play a role.

Drug distribution means the
pattern of Scatter of the
specified amount of drug
among the various locations
within the body.
Part of pharmacokinetics which
deals with distribution,
metabolism and excretion is
termed as drug disposition.
DISTRIBUTION
Physiological Barriers to Drug distribution
1. Blood Brain Barrier:
Endothelial cells of brain capillaries differ
from most of the capillaries of the body as
they are tightly joined and lack
intracellular pores.
The brain capillaries are also enveloped by
less permeable cells known as glial cells.
Morphologically this constitutes the “ Blood
Brain Barrier (BBB)”
BBB places certain constraints on the
passage of drugs from the blood to the
brain and the CSF.

• CSF is secreted by the epithelial cells of
the choroid plexus and these cells are
lined by occluding zonulae.
• That means only nonionizable, lipid
soluble drugs can pass from blood to the
CSF.
• The CSF brain barrier is composed of
the epithelial cells lining the ventricles
but these are not connected by
occluding zonulae.
• Hence the CSF brain barrier is
extremely permeable to drug molecules
from CSF to brain cells.
Blood CSF Barrier
• Lipid soluble, nonionized form of drugs penetrate
more easily to brain as compared to water soluble
ionized form.
• Volatile anesthetics like ether and chloroform,
ultra short acting barbiturates like thiopental,
narcotic analgesics like morphine and heroin,
L.Dopa, sympathomimetics like amphetamine and
ephedrine and drugs like diazepam and
propranolol can cross the BBB.
• Polar compounds like dopamine, serotonin,
streptomycin and quaternary substances like d-
tubocurarine, hexamethonium, neostigmine and
acetylcholine fail to penetrate BBB.
• Inflammatory conditions as cerebral meningitis,
infections of the brain etc, alter permeability of
BBB and drugs like penicillin, ampicillin,
chloramphenicol which have poor penetration
through BBB exhibit increased permebility and
can pass.

Clinical advantage may be taken
of this fact for proper distribution
of drugs like penicillin into brain.
Penicillin being less lipid soluble
has poor penetration through
BBB but if given by intrathecal
route it can cross the CSF Brain
Barrier and reach brain in
sufficient concentration to treat
conditions like brain abscess.
Placental Barrier
The placental membrane like any other cell membrane is
lipid in nature and readily allows the transfer of non-
polar lipid soluble substances by passive diffusion.
Other transport mechanisms are active transport
(aminoacids and glucose)
Pinocytosis (maternal immunoglobulins)
Lipid soluble nonionizable drugs like hypnotics,
narcotics, general anesthesia, cardiac glycosides,
alcohol, neuroleptics and certain antibiotics can easily
cross placental barrier.
Polar and quaternary ammonium compoundse.g d-
tubocurarine and substances with high molecular weight
cannot cross placental barrier.

Certain drugs when given in first
trimester may lead to congenital
abnormalities like thalidomide,
phenytoin, streptomycin and
methotrexate.
Drugs administered during last
trimester can affect vital features
of the fetus e.g morphine can
cause fetal asphyxia while use of
antithyroid (neomercazole) can
cause neonatal goiter.
Special compartments for drug distribution
Certain drugs accumulate in tissues or
some organs of the body. Accumulation of
drugs in tissues or body compartments
can prolong drug action because the
tissues release the accumulated drug as
plasma conc. Decreases.

• Highly lipid soluble drugs like
thiopentone, DDT and
phenoxybenzamine get
selectively accumulated in fat
and adipose tissue.
• Fat is sluggish reservoir due to
lesser blood flow.
• If body fats starts depleting as
in starvation these stored
drugs can be mobilized and
cause toxicity.
Cellular Reservoir
Fat as Reservoir
• A drug may have a great affinity for
plasma protein yet be distributed in
tissues.
• This would occur if the tissue has
even an higher affinity for the drug.
This affinity would be due to several
reasons:
• Binding to tissue protein (albumins)
or to nucleoprotein. Examples are
digoxin and emetine in skeletal
muscles, heart, liver and kidney
bound to muscle protein.
• Iodine in thyroid, chloroquine in
liver, and retina. Cadmium, lead and
mercury in kidney.

• Aqueous humor (e.g
Chloramphenicol and prednisolone)
• CSF (aminosugars and sucrose)
• Joint Fluid (Ampicillin)
• Pleural (Imipramine)
• Pericardial and peritoneal sacs can
also serve as drug reservoirs.
Transcellular Reservoir
Bones and Connective Tissue as Reservoirs
• Many drugs like cisplatin, lead,
tetracycline, arsenic, fluorides form a
complex with bone salts and get
deposited in nails, bones and teeth.
• Antifungal drug griseofulvin has an
affinity for keratin precursor and is
selectively accumulated in the skin.
• Bone may become a reservoir for
slow release of toxic substances like
lead, arsenic etc into blood.

• Some drugs get bound to plasma
components such as albumin,
globulin, transferrin, ceruloplasmin,
glycoproteins and alpha and beta
lipoproteins.
• Drugs usually bind to plasma and
cellular proteins in a reversible
manner.
• It is totally the free form of the drug
that is active while the protein bound
component is inert.
• It is the free form of the drug that
can diffuse through the capillary wall
and BBB, be metabolized and be
excreted through glomerulus, saliva,
CSF or milk.
Plasma Protein Binding as Drug reservoir
Plasma Albumin
• Most of the acidic drugs e.g warfarin, penicillin,
sulfonamides, barbiturates, benzodiazepines,
NSAIDs, valproic acid, Phenytoin and salicylic
acid bind to albumin.
• There are two binding sites. Site I is specific.
Site II is not specific.
Alpha 1 acid Glycoprotein
• Mostly acidic drugs bind to albumin, while
lipophilic basic drugs like quinidine,
imipramine, lidocaine, chlorpromazine,
Prazocin, Verapamil propranolol bind to
alpha 1 AGP.
• AGP conc. Increases in Physiological
stress and pathological states.

• Highly plasma protein bound drugs remain
largely restricted to vascular compartment and
tend to have lower volume of distribution.
• Highly protein bound drugs are difficult to be
removed by dialysis.
• The binding of drugs to plasma proteins is
capacity limited and saturable process.
• In liver disease, and all diseases causing
hypoalbuminemia, even therapeutic dose can
lead to higher conc. Of free drug because of
reduced binding.
• In MI, Crohns Disease and inflammation, the
plasma conc. Of alpha 1 glycoprotein
increases. Binding of basic drugs increase.
Clinically important aspects of Plasma Protein
binding
• The normal conc. Of albumin in plasma is
0.6mmol/L. with two binding sites per
albumin molecule the binding capacity
would be 1.2mmol/L. for most drugs the
therapeutic plasma conc. Is far less than
1.2mmol/L so saturation doesn’t occur.
• Drugs like tolbutamide and sulfonamide
work at higher plasma conc. Where their
binding to albumin reaches most
saturation.Therefore increasing dose
further will increase the amount of free drug
and hence toxicity.

• More than one drug can bind to free
site on albumin. This gives rise to
displacement interactions wherein a
drug having higher affinity will displace
the one with lower affinity.
• Clinically significant displacement will
occur only with those drugs which act
at plasma conc. High enough to reach
saturation of the binding sites of
albumin. E.g salicylates, phenyl
butazone, valproic acid, naproxen and
sulfonamides.
• Warfarin, diazepam, indomethacin and
phenytoin are ruled out b/c the
therapeutic conc. Of these drugs are
much below their saturation conc. For
binding sites.
Clinically important displacement Reactions
• Phenyl butazone, salicylates and some
sulfonamides displace tolbutamide from its
binding site leading to hypoglycemia.
• Salicylates, indomethacin, phenylbutazone
and tolbutamide displace warfarin
resulting in increased risk of hemorrhage.
• Sulfonamides and vitamin k can displace
endogenous ligands like bilirubin from
protein binding sites leading to
Kernicterus in neonates.
• Salicylates displace methotrexate.

It means enzyme catalysed chemical
transformation of drugs within the
living organism.
The metabolites formed are much less
lipid soluble, not reabsorbed from
renal tubules and are finally excreted.
It mainly occurs in liver although
kidneys, intestines, adrenal cortex,
lungs, placenta and skin may be
involved to some extent.
Biotransformation
1. Formation of an inactive metabolite from
pharmacologically active drug
The biotransformation reaction of any
drug may have 4 different
consequences with respect to
Pharmacological activity of its
metabolite:
E.G Pentobarbitone (active drug) is
converted to hydroxy-pentobarbitone
(inactive metabolite).
2. Formation of active metabolite from an
inactive (pro drug) or a lesser active drug
E.G L-Dopa to Dopamine in basal
ganglia.
Prontosil to sulfanilamide etc

E.g Diazepam to oxazepam
Amitriptyline to Nortriptyline
Propranolol to 4 Hydroxypropranolol
Codeine to Morphine
3. Formation of active metabolite from
equally active drug
First Pass Metabolism
First pass metabolism or Presystemic
metabolism or First pass effect means
the drug metabolism occurring before it
enters the systemic circulation.
The end result is the decreased
bioavailability of the drug and so a
reduced therapeutic response.
First pass effect by-passed if drug is
administered parentrally (IV xylocaine
in arrthymias) or sublingually.
In liver disease it acquires greater
significance as oral bioavailability of
drug becomes higher.
3. Formation of toxic metabolite from active
drug
E.G Paracetamol to N-acetyl-p-
benzoquinoneimine (NAPQI)

These are grouped into 2 types:
1. Phase I reactions: These are degradative
reactions. The drug is diminished to a
smaller polar/ nonpolar metabolite by
introduction of a new group.
These reactions are mainly microsomal except
a few which are non-microsomal and include
oxidation, reduction and hydrolysis.
The metabolite formed may be active or
inactive.
Pathways of Drug metabolism

• Addition of oxygen and/ or removal
of hydrogen.It is the most important
and common metabolic reaction.
• Example: Aromatic hydroxylation of
phenobarbital to p-
hydroxyphenobarbital.
• Aliphatic hydroxylation of
pentobarbital to hydroxy
pentobarbital
• O-dealkylation of codeine to
Morphine
• Nonmicrosomal oxidation include
oxidation of catecholamines like
epinephrine to vinyl mendalic acid
by MAO.
Oxidation
Reduction
• Addition of hydrogen or removal of
oxygen.
• Microsomal Reduction examples
are Chloramphenicol to its
arylmetabolite
• Prontosil to sulfanilamide
• Methadone to naloxone
• Non-microsomal reduction
examples are chloralhydrate to
trichloroethanol

Breakdown of the compound by the
addition of water. This is common
among esters and amides.
Microsomal Hydrolysis are rare
except hydrolysis of pethidine to
pethidinic acid and hydrolysis of
lidocaine by hepatic bound esterase.
Non microsomal hydrolysis is
common for esters and amides.
Enzymes are esterases and
amidases. Examples procaine to
PABA by plasma choline esterase.
Hydrolysis
Phase II Reactions
These are synthetic reactions, also
known as conjugation reactions.
These maybe catalysed by
microsomal, mitochondrial or
cytoplasmic enzymes.
The metabolite formed is usually
polar, water soluble and is mostly
inactive.
There is an example of glucuronide
metabolite of morphine being more
potent than the parent compound.

This is the sole example of microsomal
conjugation.
Parent drugs or Phase I metabolites that
contain phenolic, alcoholic, carboxylic or
mercapto groups can undergo
conjugation reaction with Uridine
diphosphate glucuronic acid (UDPGA)
catalysed by microsomal UDP-glucuronic
transferase enzymes to yield drug
glucuronide conjugates which are polar
and readily excreted.
Example of drugs are: Morphine,
Paracetamol, chloramphenicol,
diazepam and sulfonamides
Glucuronide Conjugation
NonMicrosomal Conjugation
Acetylation
The reaction is catalysed by family of
enzymes called sulfotransferases found
in the cell cytoplasm of various organs.
Example: Aspirin, Methyl dopa,
Paracetamol, corticosteroids etc
Sulfate Conjugation
The reaction is catalysed by N-
acetyltransferase which utilizes acetyl co-
enzyme A as a cofactor and are found in cell
cytoplasm of various organs.
Example: Isoniazid, Dapsone, histamine etc

Acetyl coenzyme A derivatives of carboxylic
acid drugs (Aspirin, benzoic acid, nicotinic
acid etc) can couple with glycine or glutamate
in the presence of AcCoA glycine transferase
enzyme in mitochondria.
Glycine conjugation
Glutathione Conjugation
Many epoxides, No2 group containing drugs
and hydroxylamines (e.g ethacrynic acid and
sulfobromophthalein) undergo glutathione
conjugation in the presence of glutathione S
tranferase enzyme.
Drug Paracetamol too.
Methylation
Example Dopamine and Adrenaline
Drug metabolizing enzymes
Enzymes are reaction specific, protein
catalysts for chemical reaction in a biological
system.
The drug metabolizing enzymes are divided
into two types

These are the drug metabolizing enzymes
associated with the smooth surface endoplasmic
reticulum of the liver.
The principle enzyme involved are mixed function
oxidases and Cytochrome P 450(This is a
haemoprotein and is so called b/c in its reduced
form it can combine with carbon monoxide giving a
product whose peak is at 450/cm.
The microsomal enzymes are non-specific in action
and can be induced or inhibited and can metabolize
only lipid soluble drugs.
These are concerned mostly with Phase I oxidation
and reduction.
Only one microsomal enzyme carries out phase II
reaction i.e Glucuronic acid conjugation.
Microsomal Enzymes
Non-microsomal Enzymes
Enzymes of non-microsomal origin can be
prepared as soluble cell fractions and can still
retain their catalytic activity.
These are present in cytoplasm, mitochondria
of hepatic cells and in plasma.
Example MAO, esterases, amidases,
transferases and conjugages.
Reactions catalysed by them are all Phase II
reactions, certain oxidation, reduction and
hydrolytic reactions.
These are non-inducible but usually show
genetic variation e.g pseudocholine esterase
and acetyl transferase.

As a consequence of enzyme induction clinically
important drug-drug interactions may result:
1. Unwanted Pregnancy can result even when oral
contraceptive pills are used if potent enzyme
inducers like phenytoin or rifampicin are used
concomitantly.
2. Patients on enzyme inducing drugs like
barbiturates would need higher doses of anti-
coagulants like warfarin.
3. Enzyme inducers like Phenytoin accelerate the
metabolism of Vitamin D3 leading to
osteomalacia.
4. Enzyme inducers like barbiturates can also
enhance their own metabolism leading to
pharmacokinetic tolerance.
Enzyme induction can lead to drug toxicity e.g
ethanol drinkers can develop hepatotoxicity from
paracetamol overdose due to N-acetyl-P
benzoquinone
Clinical Relevance of Enzyme Induction

Potentially Adverse consequences:
1. Unexpected Nausea and vomiting due
to theophylline with concomitant
administration of chloramphenicol.
2. Enhanced bleeding tendency with
dicumarol when given with cimetidine
3. Severe respiratory depression when
morphine is given with MAOIs.
4. Severe ataxia and drowsiness with
phenytoin in combination with
dicumarol or chloramphenicol.
5. Precipitation of cardiac arrhythmias
with terfenadine when given with
chloramphenicol.
Enzyme Inhibition Clinical Relevance
Therapeutically Beneficial Consequences
1. Increased accessibility of L-
dopa in brain when given
along with Carbidopa(L-
aminoacid decarboxylase
inhibitor)
2. Aversion to alcohol after prior
administration of disulfiram
(Aldehyde dehydrogenase
inhibitor)
3. Reversal of skeletal muscle
paralysis due to d-
tubocurarine by neostigmine
(acetylcholinesterase
reversible inhibitor)

Factors affecting Drug Metabolism
1. Age: Neonates have low microsomal
enzymes and glucuronyl transferase
enzyme activity and attain full functional
capacity several weeks after birth.
• Chloramphenicol can cause grey baby
syndrome in neonates.
• Decreased Glucuronyl transferase leads to
kernicterus in neonates when free bilirubin
level in plasma rises due to displacement
of bilirubin from albumin binding sites by
sulfonamides.
• Elderly ppl above 60 have a reduced
hepatic flow.
• Metabolism of drugs like propranolol,
lidocaine, pethidine etc exhibit slow
metabolism increase chance of toxicity.

The differences in the rate of
metabolism due to sex are seldom imp
in human beings.
Male rats sleep for shorter duration
than females when given hexobarbital.
2. Sex
4. Race
3. Species
Example of specie dependent variation
in drug metabolism are few.
Rabbits metabolize atropine faster
than man as they have high atropine
esterase activity in liver.
The diet rich in protein and low in CHO enhance the
metabolism of many drugs. Rich protein diet supplies
glycine and cysteine wh ich are essential to f orm
conjugated metabolites of drugs.
Diet poor in p rotein and rich in CHO s lows metabolism(
Starvation leads to enzyme inhibition).
Def iciency of Vitamin A,C, ca and Mg a lso impairs
metabolism.
5. Nutrition and Diet
Chinese have high alcohol dehydrogenase
but a low aldehyde dehydrogenase activity.
Hence they inhibit higher plasma
concentration of aldehyde and therefore
headache, palpitation etc after consuming
alcohol.

The activity of hepatic cytochrome p-
450 linked enzyme are impaired to
varying degrees in number of
diseases like:viral hepatitis, alcoholic
hepatitis, liver cirrhosis,
hepatocellular carcinoma and heavy
metal poisoning.
Cardiac diseases limiting the blood
flow to liver may impair disposition of
drugs like propranolol etc.
Hypothyroidism decreases
metabolism of digoxin, methimazole
while hyperthyroidism enhances rate
of metabolism.
Disease

Removal of drug and its metabolite from the
body is known as drug excretion
Drug excretion
Glomerular Filtration
1. Molecular size: small molecular size drugs are
readily filtered. Drugs having molecular weight
greater than 20,000 are unable to filter. Example
heparin, dextran, insulin, and growth factors
cannot pass glomerulus.
2. Plasma Protein Binding: protein binding
decreases the renal excretion. It is the extent of
protein binding that is the rate limiting factor of
filteration. Warfarin 98% protein bound only 2%
excreted by glomerulus.
3. Renal Blood flow: The greater the glomerular
perfusion faster is drug removal from plasma

Glomerular filtration…………… removes 20%
of drug from blood…………..including kidney.
80% of
drug…………..passes…………proximal
tubule…………secreted----------tubular
lumen.
Tubular secretion………… energy requiring
carrier mediated active transport (protein
binding--------hindrance for glomerular
filtration) does not interfere with tubular
secretion b/c carrier itself is a protein
secondly resultant decreases in plasma
conc. Of free drug promotes dissociation of
protein bound drug.
2. Tubular Secretion

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