The principle of drug kinetics.

1. Pharmacokinetics
Basic and applied Pharmacology
Dr. Rupendra K Bharti
MD Pharmacology

2. • Pharmacokinetics: - (What the body does to
the drug)
• It is a branch of pharmacology, which deals
with the journey or movement of the drug ‘in,
through and out from the body’.
• In other words, its deals with the scientific
study of the absorption, distribution,
biotransformation (metabolism), and
excretion (ADME) of drugs.

3. • The transfer of drug from its sites of administration
to the blood is called absorption.
• Its transfer from blood to tissues is called
distribution.
• The drug attains its effective concentration at the
site of action and produces its effects.
• Then the drug is metabolized, which is called
biotransformation.
• After the drug has done its work, it is to be thrown
out of the body. This process is called excretion.

6. Transport mechanism across the
cell membrane

8. Passive diffusion
• The drug diffuses across the membrane in the
direction of its concentration gradient.
• This is the most important mechanism for
majority of drugs; drugs are foreign substances
(xenobiotics), and specialized mechanisms are
developed by the body primarily for normal
metabolites.
• Factors led to increase diffusion:
– Lipid soluble
– Particle size
– Polarity
– Ionized/unionized status

9. Weak Electrolytes and the Influence of
pH
• Many drugs are weak acids or bases that are
present in solution as both the non-ionized and
ionized species.
• The non-ionized molecules usually are more lipid
soluble and can diffuse readily across the cell
membrane.
• The ionized molecules usually are less able to
penetrate the lipid membrane because of their
low lipid solubility, and passage will depend on
the leakiness of the membrane related to the
membrane’s electrical resistance.

10. • The transmembrane distribution of a weak
electrolyte is influenced by its pKa and the pH
gradient across the Ka membrane.
The pKa is the pH at which half the drug a
(weak acid or base electrolyte) is in its ionized
form.

11. Ion trapping
• The unionized form of acidic drugs which
crosses the surface membrane of gastric
mucosal cell, reverts to the ionized form
within the cell (pH 7.0) and then only slowly
passes to the extracellular fluid.
• A weak electrolyte crossing a membrane to
encounter a pH from which it is not able to
escape easily.
• This may contribute to gastric mucosal cell
damage caused by aspirin.

12. Filtration
• Filtration is passage of drugs through aqueous
pores in the membrane or through
paracellular spaces.
• Lipid-insoluble drugs cross biological
membranes by filtration if their molecular size
is smaller than the diameter of the pores.
• Majority of cells (intestinal mucosa, RBC, etc.)
have very small pores (4 Å) and drugs with
MW > 100 or 200 are not able to penetrate.

13. Specialized transport
Carrier-Mediated Membrane Transport

14. Active transport
• It requires energy.
• Movement against an electrochemical gradient,
saturability, selectivity, and competitive inhibition by
co-transported compounds.
• It uses the electrochemical energy stored in a gradient
to move another molecule against a concentration
gradient;
– e.g., the Na+–Ca2+ exchange protein uses the energy stored
in the Na+ gradient established by the Na+, K+-ATPase
mechanism to export cytosolic Ca2+.

15. Cont…
– The Na+-dependent glucose transporters SGLT1 and SGLT2
move glucose across membranes of gastrointestinal (GI)
epithelium and renal tubules by coupling glucose transport
to downhill Na+ flux.
• It is inhibited by metabolic poisons, and transports
the solute against its electrochemical gradient (low
to high), resulting in selective accumulation of the
substance on one side of the membrane.

16. Facilitated diffusion
• No ATP required.
• Work in the direction of its electrochemical
gradient, i.e. from higher to lower
concentration .
• It mearly facilitates permeation of a poorly
diffusible substrate,
– e.g. the entry of glucose into muscle and fat cells
by the glucose transporter GLUT 4.

18. Absorption
• Absorption is the process by which a drug
passes from its site of administration into
the blood stream or circulation of the
body.
• From here, the drug moves to its site(s) of
action.
• When given by oral route, absorption is the
first step in the passage of a drug through
the body.

19. • Whereas, it is introduced directly into the
bloodstream when given by intravenous
administration.
• Absorption of the drug is 100% when
given by
–intravenous route and
–always less than 100% when given by
intramuscular, subcutaneous or oral route.

20. Factor affecting absorption
Drug factors:
• Aqueous solubility: The drugs are absorbed in
liquid form only.
– So the oral drug needs to be converted in to liquid form
before absorption.
– Drugs in liquid form are absorbed better.
– The dissolution and disintegration of a drug are the two
important factors, which decide the rate and extent of
absorption.
Example: dispersible tablets are absorbed and act
faster.

21. Dose of drug
• The higher the dose, faster will be the
absorption due to the concentration gradient
and diffusion thereby.

22. Presence of food
• The presence of food may interfere with
the dissolution and absorption of certain
drugs, as well as delay the transit time of a
drug from the stomach to the small
intestine.
• Some food constituents may form
absorbable complexes with the drugs which
decrease absorption process.
• So most of the drugs are absorbed better if
taken empty stomach, until or unless
contraindicated.

23. • Tetracyclines with calcium present in milk.
• Food delays gastric emptying.
• Most drugs are absorbed better if taken in empty
stomach.
• But:
– fatty food greatly enhances lumefantrine absorption.
– Highly ionized drugs, e.g. gentamicin, neostigmine are
poorly absorbed when given orally.
• Certain drugs are degraded in the GIT:
– penicillin G by acid,
– insulin by peptidases.

24. Body factors
• Area of absorbing surface:
– Absorption of the drug is faster, if area of the
absorbing surface is more.
• Vascularity of the absorbing surface:
– increased blood flow at the site of absorption
increases the rate of absorption, similarly as
the wet clothes dry faster on exposure to the
fast wind.

25. Route of administration
Oral:
• The barrier in absorption from this route is the
epithelial lining (biological membrane) of GIT.
• The drugs have to cross the biological membrane,
which is a lipid bilayer and allows the more lipid
soluble drugs to be absorbed faster.

26. Advantages Disadvantages
• Easier acceptance • Slow absorption compared to IV, IM, SC.
• Commonly used • Unable to use in children and elderly
• Most common method of
administration
• Physical factors are play pivotal role for
orally absorption
• Economical • Can’t achieve spontaneous action
• Increase patients compliance • Unpalatable drugs (chloramphenicol) are
difficult to administer.
• Safest methods in adult & mentally
fit patients
• May cause nausea and vomiting
(emetine).

27. Other
• Controlled-Release Preparations
• Sublingual Administration
• Transdermal Absorption
• Rectal Administration

28. Subcutaneous
• The drugs are deposited in the vicinity of
capillaries and absorption occurs through the
large paracellular spaces around the
capillaries.
• The large molecules of drugs, which cannot
be absorbed through capillaries, are
absorbed via lymphatics.
• The absorption is slightly slower than the
intramuscular route.

29. • Intramuscular:
–The absorption is faster than subcutaneous
and more consistent.
–The muscular exercise and application of
heat at the site increases the rate of
absorption.
• Intravenous:
–Here the drug is directly put in to the
circulation and within no time the drug
circulates throughout the body.

30. Other
• Intra-arterial.
• Intrathecal
• Pulmonary Absorption
• Topical Application
– Mucous Membranes
– Eye.

32. BIOAVAILABILITY
• It is a measure or fraction of
administered dose of a drug that reaches
the systemic circulation in the
unchanged or active form.
• Bioavailability of the drug injected
intravenously is 100%.

33. • It is generally lower after oral ingestion
because the drug may be incompletely
absorbed or undergo first pass metabolism
in the intestinal wall and liver.
• Bioavailability after subcutaneous or
intramuscular injection is also less than
100% due to the local binding of drugs.
• It is also responsible for success or failure of
an antimicrobial regimen.

35. Extent of Absorption
• Blood concentration-time curves illustrating how changes in the rate of absorption and extent of
bioavailability can influence both the duration of action and the effectiveness of the same total
dose of a drug administered in three different formulations.
• The dashed line indicates the target concentration (TC) of the drug in the blood.

36. First pass metabolism
• The first-pass metabolism (first pass
effect also known as or presystemic
metabolism) is a phenomenon of drug
metabolism whereby the concentration of
a drug is greatly reduced before it reaches the
systemic circulation.
• It is the fraction of drug lost during the process
of absorption which is generally related to
the liver and gut wall.

37. • First pass metabolism may occur in the liver
(for propranolol, lidocaine, GTN) or in the gut
(for benzylpenicillin and insulin).
• After a drug is swallowed, it is absorbed by
the digestive enzyme and enters the hepatic
portal circulation.
• It is carried through the portal vein into
the liver before it reaches the rest of the body.

38. Cont…
• The liver metabolized many drugs, sometimes
to such an extent that only a small amount
of active drug emerges from the liver to the
rest of the circulatory system.
This first pass through the liver thus greatly
reduces the bioavailability of the drug.

39. Drug with high first pass metabolism
(NIL By HMT)
• N- Nitrate
• I- Imipramine, Isoprenaline
• L- Lignocaine
• By- propranolol
• H- Hydrocortisone
• M- Morphine
• T- Testosterone

40. Bioequivalence
• Drug products are considered to be
pharmaceutical equivalents if they contain the
same active ingredients and are identical in
strength or concentration, dosage form, and
route of administration.
• Two pharmaceutically equivalent drug products
are considered to be bioequivalent when the
rates and extents of bioavailability of the active
ingredient in the two products are not
significantly different under suitable test
conditions.

41. Distribution

42. • Drug distribution is the process by which a drug
is carried from its site of absorption to its site
of action.
• When a drug enters the bloodstream, it is
carried most rapidly to the organs having rich
blood supply, such as the :
– Heart
– Liver
– Kidneys
– Brain

43. Cont…
• Areas with less blood supply receive the
drug slowly.
–Example: muscle, skin, and adipose tissue.
• The drug remains in the body in bound and
unbound (Free) form.
• There is always equilibrium between bound
and unbound form of the drug.

44. Cont…
• The unbound form is the active form of the
drug and while in the bound state, the drug
is incapable of eliciting a pharmacological
effect.
• When a plasma concentration of the
unbound drug diminishes, the bound drug
is released from its binding sites.

45. Cont…
• The acidic drugs preferably bind to albumin
and the basic drugs to Alfa acid
glycoprotein.
• This protein-binding act as a temporary
store house for drugs and also prolongs the
drug action and acts like sustained release
technology.

46. Apparent volume of distribution (Ad)
• Presuming that the body behaves as a single
homogeneous compartment with volume V
into which the drug gets immediately and
uniformly distributed.
• Ad: The volume that would accommodate all
the drug in the body, if the concentration
throughout was the same as in plasma.

47. example

48. The distribution of drug depends
upon following factors
• Lipid solubility and lipid water partition
coefficient.
• Ionization at physiological pH
• Extent of binding to plasma and tissue
proteins
• Differences in regional blood flow
• Diseases like renal failure, liver failure,
heart failure and cirrhosis of liver.

49. Plasma Proteins
• Many drugs circulate in the bloodstream
bound to plasma proteins.
• Albumin is a major carrier for acidic drugs; α1-
acid glycoprotein binds basic drugs.
• The binding is usually reversible; except
alkylating agents, which bound to plasma
protein covalently.

50. Cont…
• Some drugs bind to proteins that function as
specific hormone carrier proteins, such as:
– The binding of oestrogen or testosterone to sex
hormone–binding globulin or
– The binding of thyroid hormone to thyroxin-
binding globulin.
• The extent of binding and the unbound
fraction are relatively constant.

51. Cont…
• Highly plasma protein bound drugs does not
cross membranes.
• They tend to have smaller volumes of
distribution.
• The bound fraction is not available for action.
• Plasma protein binding is a temporary storage of
the drug.
• High degree of protein binding generally makes
the drug long acting, because bound fraction is
not available for metabolism or excretion

52. Cont…
• One drug can bind to many sites on the
albumin molecule. Conversely, more than one
drug can bind to the same site. This can give
rise to displacement interactions among
drugs bound to the same site(s).
– Aspirin displaces sulfonylureas.
– Sulfonamides and vit K displace bilirubin
(kernicterus in neonates).
– Aspirin displaces methotrexate.
– Indomethacin, phenytoin displace warfarin

53. PPB & Disease state
• The extent of plasma protein binding also
may be affected by disease-related factors.
– Hypoalbuminemia secondary to severe liver
disease or nephrotic syndrome results in reduced
binding and increase in the unbound fraction.
– In the acute-phase reaction response (e.g., cancer,
arthritis, myocardial infarction, Crohn’s disease)
lead to elevated levels of α1-acid glycoprotein and
enhanced binding of basic drugs.
• It is important if the drug follows saturation
kinetics.

55. Tissue Binding
• Many drugs accumulate in tissues at higher
concentrations than those in the extracellular
fluids and blood.
– For example, during long-term administration of the
anti-malarial agent quinacrine, the concentration of
drug in the liver may be several thousand times that in
the blood.
• Tissue binding of drugs usually occurs with
cellular constituents such as proteins,
phospholipids, or nuclear proteins and generally is
reversible.

56. Cont..
• It may serve as a reservoir that prolongs drug
action in that same tissue.
• Such tissue binding and accumulation also can
produce local toxicity.
– Accumulation of the aminoglycoside antibiotic
gentamicin in the kidney and vestibular system.

57. Some drugs have selective preference for the
deposition in the various body tissues, which are
important for the clinical as well as toxicological point
of view:
Body organs Distributed Drugs
Retina Chloroquine (bound to nucleoproteins)
Liver Chloroquine, tetracyclines, emetine, digoxin.
Thyroid Iodine.
Kidney Digoxin, chloroquine, emetine
Skeletal
muscle, heart
Digoxin, emetine (bound to muscle proteins).
Bone and
teeth
Tetracycline, heavy metals (bound to
mucopolysaccharides of connective tissue

58. Fat as a Reservoir
• Many lipid-soluble drugs are stored by physical
solution in the neutral fat.
• In obese persons, the fat content of the body may
be as high as 50%, and even in lean individuals fat
constitutes 10% of body weight; hence fat may
serve as a reservoir for lipid-soluble drugs.
– For example, as much as 70% of the highly lipid-
soluble barbiturate thiopental may be present in body
fat 3 hours after administration, when plasma
concentrations are negligible and no anesthetic
effects are measurable.

59. Bone
• The tetracycline antibiotics and heavy metals may
accumulate in bone by adsorption onto the bone
crystal surface and eventual incorporation into the
crystal lattice.
• Bone can become a reservoir for the slow release of
toxic agents such as lead or radium into the blood.
• The adsorption of drug onto the bone crystal surface
and incorporation into the crystal lattice have
therapeutic advantages for the treatment of
osteoporosis.
– Phosphonates such as sodium etidronate bind tightly to
hydroxyapatite crystals in mineralized bone matrix.

60. Redistribution
• Termination of drug effect after withdrawal of a
drug usually is by metabolism and excretion but
also may result from redistribution of the drug
from its site of action into other tissues or sites.
• Redistribution is a factor in terminating drug
effect primarily when a highly lipid-soluble drug
that acts on the brain or cardiovascular system is
administered rapidly by intravenous injection or
by inhalation.

61. Intravenous anesthetic thiopental
• Is a highly lipid-soluble drug.
• Because blood flow to the brain is so high, the drug
reaches its maximal concentration in brain within a
minute of its intravenous injection.
• After injection is concluded, the plasma concentration
falls as thiopental diffuses into other tissues, such as
muscle.
• The concentration of the drug in brain follows that of
the plasma because there is little binding of the drug
to brain constituents.
The onset of anesthesia is rapid, but so is its termination.
Both are related directly to the concentration of drug in
the brain.

62. CNS and Cerebrospinal Fluid
• The capillary endothelial cells in brain have
tight junctions and lack large paracellular
spaces.
• Only lipid-soluble drugs are able to penetrate
and have action on the central nervous
system.
• P-gp and anion transporter (OATP) present in
brain and choroidal vessels extrude many
drugs that enter brain.

63. • Capillary constituting blood brain or blood-CSF barrier.
• Tight junctions between capillary endothelial cells and
investment of glial processes or choroidal epithelium do
not allow passage of non lipid-soluble molecules/ions

64. Cont…
• Inflammation of meninges or brain increases
permeability of these barriers allows many
drugs.
• In parkinsonism: Dopamine doesn’t cross BBB.
– Levodopa has been used which is a prodrug easier
crosses BBB and converted to dopamine.
• Unable to penetrate:
– Catecholamines, 5-HT, acetylcholine

65. Cont…
• In medulla oblongata; the CTZ center where
BBB is not present.
• This also called vomiting center.
• Even at certain periventricular sites (anterior
hypothalamus) BBB is deficient.
• The drug act on CTZ easier cross the BBB like
5HT-3 inhibitors.

66. Placental Transfer of Drugs
• Placental membranes allow free passage of
lipophilic drugs, while restricting hydrophilic
drugs.
• Placenta have some efflux P-gp and other
transporters like BCRP, MRP3 also serve to limit
foetal exposure to maternally administered
drugs.
• The drug metabolism also take place in placenta
which may lead to increase or decrease the
exposure of drug to the foetus.
• By the action of influx transporters, drugs like
morphine easier crosses the placenta and affect
foetus.

67. Metabolism (Biotransformation)

68. • It is also called the biotransformation of
the drug.
• It is necessary for the elimination of a
drug from the body through various
excretory routes.
• To be eliminated from the body by way of
the kidneys, a compound must be fairly
soluble in water.

69. Cont…
• Because many drugs are not very water
soluble, they must first undergo drug
metabolism or biotransformation to convert
them to a more water-soluble form.
• In other words, it converts the drug in
another form which is excretable.
• Metabolism also permits the body to
inactivate a potent drug before it
accumulates and produces toxic effects.

70. Cont…
• Metabolism also permits the body to activate
the prodrug into its active form.
• Most biotransformation reactions occur in the
liver, but they also can occur in the
– gastrointestinal tract,
– lungs,
– kidneys, and
– skin.
Sites of metabolism:
– The primary site is liver.
– The other sites are kidney, intestine, lungs and
blood circulation.

72. Effects of metabolism
• Metabolism leads to:
– Inactivation of the active drugs:
• Drugs are made inactive or less active.
– Eg: paracetamol, ibuprofen, propranolol etc.
– Activation of the inactive drug:
• Some drugs need conversion in the body to active
form and are inactive as such.
• Such a drug is called prodrug.
– Active metabolites formation from an active drug:
• Some drugs are active even after their conversion
to their metabolites.

73. Metabolism reactions are of two types
• Non-synthetic/Phase I reactions:
–A functional group is generated or
exposed—metabolite may be active or
inactive.
–The non-synthetic reactions involve:
• Oxidation
• Reduction,
• Hydrolysis,
• Cyclization and
• Decyclization processes.

74. Oxidation
• This reaction involves addition of oxygen/negatively
charged radical or removal of hydrogen/positively
charged radical.
• Oxidations are the most important drug
metabolizing reactions.
• Oxidative reactions are mostly carried out by a
group of monooxygenases in the liver, which in the
final step involve a cytochrome P-450
haemoprotein, NADPH, cytochrome P-450
reductase and molecular O2.

75. Metabolizers Drugs
CYP3A4/5 • Carryout biotransformation of largest number (nearly 50%)
of drugs.
• Losartan, nifedipine hydrocortisone, mifepristone,
simvastatin, ritonavir, carbamazepine and cyclosporine are
also metabolized by CYP3A4/5.
• Inhibitors: erythromycin, clarithromycin, ketoconazole,
itraconazole, verapamil, diltiazem, ritonavir and grape fruit
juice.
CYP2D6 • Metabolizes nearly 20% drugs such as TCA, SSRI,
neuroleptics, antiarrhythmics, β-blockers and opiates
• Inhibitors: quinidine results in failure of conversion of
codeine to morphine → analgesic effect of codeine is lost.
CYP2C8/9 • >15 % drugs metabolised including phenytoin,
carbamazepine, warfarin, ibuprofen, tolbutamide,
repaglinide, celecoxib and losartan.

76. Metabolizers Drugs
CYP2C19 • Metabolizes > 12% drugs including omeprazole, lansoprazole,
phenytoin, diazepam, propranolol.
• Rifampicin and carbamazepine are potent inducers and
omeprazole is an inhibitor.
CYP1A1/2 • Metabolism theophylline, caffeine, paracetamol,
carbamazepine.
• It is more important for activation of procarcinogens.
• Inducer: Apart from rifampicin, carbamazepine, polycyclic
hydrocarbons, cigarette smoke and charbroiled meat
CYP2E1 • It catalyses oxidation of alcohol, holothane, and formation of
minor metabolites of few drugs, notably the hepatotoxic N-
acetyl benzoquinoneimine from paracetamol.
• chronic alcoholism induces this isoenzyme.

77. Some prodrugs
Prodrug Active form
Acyclovir Acyclovir triphosphate
Fluorouracil Fluorouridine monophosphate
Bacampicillin Ampicillin
Prednisone Prednisolone
Sulindac Sulfide metabolite
Enalapril Enalaprilat
Alfa-Methyldopa a-methyl norepinephrine
Fosphenytoin Phenytoin

78. Reduction
• This reaction is the converse of oxidation and
involves cytochrome P-450 enzymes working
in the opposite direction.
• Alcohols, aldehydes, quinones are reduced.
• Primarily reduced are chloralhydrate,
chloramphenicol, halothane, warfarin.

79. Hydrolysis
• This is cleavage of drug molecule by taking up
a molecule of water.
• Hydrolysis occurs in liver, intestines, plasma
and other tissues.
– Examples of hydrolysed drugs are choline esters,
procaine, lidocaine, procainamide, aspirin,
carbamazepine-epoxide, pethidine, oxytocin.

80. • Cyclization:
– This is formation of ring structure from a straight
chain compound, e.g. proguanil.
• Decyclization:
– This is opening up of ring structure of the cyclic
drug molecule, e.g. barbiturates, phenytoin.

81. Synthetic/ Phase II reactions
• Here the drug or its phase I metabolites are
conjugated with an endogenously derived
substrate to form an easily excretable
substance.
– This reaction requires energy.
– The synthetic reactions involve:
• Glucoronide conjugation,
• Acetylation,
• Methylation,
• Sulphate/ glycine/glutathione conjugation etc.

82. Glucuronide conjugation
• This is the most important synthetic reaction
carried out by a group of UDP-glucuronosyl
transferases (UGTs).
• Compounds with a hydroxyl or carboxylic acid
group are easily conjugated with glucuronic acid
which is derived from glucose.
– Examples are— chloramphenicol, aspirin,
paracetamol, diazepam, lorazepam, morphine,
metronidazole.
• Glucuronidation increases the molecular weight
of the drug which favours its excretion in bile.

83. Acetylation
• C: clonazepam
• S: sulfonamides, dapsone
• H: hydralazine
• I: isoniazid
• P: PAS, procainamide
• N-acetyltransferases (NATs), and rate of
acetylation shows genetic polymorphism (slow
and fast acetylators). Mostly seen with INH.

84. Methylation
• The amines and phenols can be methylated by
methyl transferases (MT);
• Drugs:
– adrenaline, histamine, nicotinic acid, methyldopa,
captopril, mercaptopurine

85. • Sulfate conjugation:
– chloramphenicol, methyldopa, adrenal and sex
steroids.
• Glycine conjugation:
– Salicylates, nicotinic acid and other drugs having
carboxylic acid group are conjugated with glycine.

86. Simultaneous and/or sequential
metabolism of a drug by phase I and phase
II reactions

89. Phase 1 and phase 2 reactions
Phase I reaction Phase II reaction
• It changes functional group of
drug molecule and uses
cytochrome P450
monooxygenase.
• It attach a conjugate to the
drug molecule.
• Reaction are:
• Oxidation (most common)
• Reduction
• Hydrolysis
• Decyclization
• Reactions are:
• Glucuronide conjugation
(most common)
• Acetylation
• Methylation
• Sulfate conjugation

90. Microsomal and Non-Microsomal Enzymes
Microsomal Enzymes:
– These are located on smooth endoplasmic
reticulum.
– Present primarily in liver, kidney, intestinal mucosa
and lungs.
– They catalyzes the oxidation, reduction, hydrolysis
and glucuronide conjugation.
– These are inducible by drugs, diet and other
chemicals.
• Example: monooxygenase, cytochrome P450
etc.

91. Non-Microsomal Enzymes:
• These are located in cytoplasm and
mitochondria.
• Present primarily in liver and plasma.
• They catalyzes some oxidation, reduction,
many hydrolysis and all conjugations except
glucuronide conjugation.
• These are not inducible by drugs, diet and
other chemicals.
– Example: esterases, amidases, flavoprotein
oxidases and conjugases.

92. Microsomal enzymes properties
• All anti-fungal are microsomal enzyme inhibitor
except Griseofulvin.
• All anti Epileptics are microsomal enzyme inducer
except Valproate.
• Acute alcoholism is a microsomal enzyme inhibitor,
while Chronic alcoholism is microsomal enzyme
inducer.

93. Microsomal Enzyme Inducer
(GARIMAS)
Microsomal Enzyme Inhibitor
G—Griseofulvin
A— Anti Epileptics (Phenobarbitone,
Phenytoin and carbamazepine)
R— Rifampin
I— Isoniazid
M— Meat
A— Alcohol
S— Smoking
Ketoconazole
Valproate
protease Inhibitor (M/C Ritonavir)
Selective Serotonin Reuptake Inhibitor
C— Ciprofloxacin
O- Oral contraceptive pills
C- Cimetidine
A— Allopurinol
E— Erythromycin

94. Consequences of microsomal
enzyme induction
• Decreased intensity and/or duration of action of
drugs that are inactivated by metabolism, e.g.
failure of contraception with oral contraceptives.
• Increased intensity of action of drugs that are
activated by metabolism.
• Tolerance— due autoinduction, e.g.
carbamazepine, rifampin.
• Precipitation of acute intermittent porphyria
• Intermittent use of an inducer may interfere with
adjustment of dose of another drug.
• Interference with chronic toxicity testing in
animals.

95. Uses of enzyme induction
• Congenital non-haemolytic jaundice:
– It is due to deficient glucuronidation of bilirubin;
phenobarbitone hastens clearance of jaundice.
• Cushing’s syndrome:
– phenytoin may reduce the manifestations by
enhancing degradation of adrenal steroids which are
produced in excess.
• Chronic poisonings:
– by faster metabolism of the accumulated poisonous
substance.
• Liver disease.

96. Hofmann Elimination
• This is the inactivation of drug in the body,
where no enzyme is involved in the
inactivation of the drug, but spontaneous
molecular rearrangement occurs.
– Eg: atracurium, cistracurium.

97. First pass metabolism
• It is the metabolism of a drug at the site of
absorption during its passage from the site
of absorption into the systemic circulation.
• All orally administered drugs are exposed to
drug metabolizing enzymes in the intestinal
wall and liver.
• This is called presystemic metabolism as it
occurs before the drug reaches the systemic
circulation.

98. Cont…
• It can be avoided by administering the drug
through sublingual, transdermal or
parenteral routes because the portal
circulation is bypassed.
• The extent of first pass metabolism differs
for different drugs and is an important
determinant of oral bioavailability.
• The first pass metabolism is highest, when
the drug is given by oral route.

99. Due to this fact:
• Oral dose is always higher than sublingual
or parenteral dose.
• Due to differences in the extent of first pass
metabolism, the oral dose differs for
individual patients.
• In patients with severe liver disease, the
oral bioavailability is slightly increased.

100. DRUG INTERACTIONS
• When two drugs are given together, a drug
interaction occurs.
• The pharmacological effects of one drug are
potentiated or diminished by another drug.
• This is due to the interaction at
pharmacokinetic or pharmacodynamic level.

101. Cont…
• If the administration of two or more drugs
produces a pharmacological response that
is greater than that which would be
expected by the individual effects of each
drug together, the drugs are said to be
acting synergistically.
• If one drug diminishes the action of
another, it is said to act antagonistically.

102. Cont…
• Drug interaction may be synergistic or
antagonistic (explained earlier along with
synergism/antagonism).
• Drug interactions may occur at any step in
the passage of a drug through the body
during its administration, absorption,
distribution, metabolism, or excretion.

103. Cont…
• Interactions may also take place at the
receptor site of a drug.
• Drugs may interact with foods, laboratory
test substances and environmental
pollutants.
• Drug interactions may be beneficial or
harmful.

104. EXCRETION

105. • Excretion is the process of removing a drug or its
metabolites from the body.
• Drugs and their metabolites may be eliminated
from the body in several different ways. Such as
in
– Urine
– Faces
– Exhaled air
– Saliva
– Sweat
– Tears
– Breast Milk

106. Urine or renal excretion
• The substances which are made water
soluble after biotransformation can be
easily excreted through this route.
• The nephron is a basic renal unit.
• Three mechanisms of renal excretion
operate simultaneously at the nephron
level.
– These mechanisms are
– Glomerular Filtration
– Tubular Reabsorption (Selective)
– Tubular Secretion

107. Glomerular filtration
• The drug/ metabolites/ substances, which
are smaller in size than the glomerular
capillary pores are easily filtered through
the glomerulus and reach the proximal
tubules.
• The protein bound drug and bigger
molecules cannot be filtered through the
glomerulus. Hence, excretion depends
upon glomerular filtration rate.

108. Tubular reabsorption (Selective)
• The highly lipid soluble drugs are
reabsorbed from the proximal tubules.
• The ionization of a drug also affects
this process.

109. Tubular secretion
• Certain drugs and natural metabolites
are actively secreted in the tubule for
the purpose of excretion.
We can say that:
• Net Renal excretion = (glomerular filtration+
tubular secretion) - tubular reabsorption

110. b) Faeces:
–Both the unabsorbed fraction of a drug and
the drugs excreted through bile, are
excreted in Faeces.
• Eg: erythromycin, OCPs, ampicillin etc.
c) Exhaled air:
–The volatile liquids and gases are excreted
through this route.
• Eg: alcohol and anesthetic gases.

111. d) Saliva, Sweat and Tears:
–Lithium and some heavy metals are
excreted through this route.
e) Breast Milk:
–More lipid soluble and less protein bound
drug are excreted through this route.
• E.g.: tetracycline, methotrexate, indomethacin
etc.

112. KINETICS OF ELIMINATION
• Drug elimination is the sumtotal of metabolic
inactivation and excretion
• Depending upon the ability of the body to
eliminate a drug, a certain fraction of the
central compartment may be considered to be
totally ‘cleared’ of that drug in a given period
of time to account for elimination over that
period.

113. Clearance (CL)
• The clearance of a drug is the theoretical
volume of plasma from which the drug is
completely removed in unit time.
• CL = Rate of elimination/C
– where C is the plasma concentration

115. First order kinetics
• The rate of elimination is directly proportional
to the drug concentration, CL remains
constant.
• Means a constant fraction of the drug present
in the body is eliminated in unit time.
• This applies to majority of drugs which do not
saturate the elimination processes
(transporters, enzymes, blood flow, etc.) over
the therapeutic concentration range.

116. Zero order kinetics
• The rate of elimination remains constant
irrespective of drug concentration, CL
decreases with increase in concentration; or a
constant amount of the drug is eliminated in
unit time, e.g. ethyl alcohol.
• This is also called capacity limited elimination
or Michaelis-Menten elimination.

117. First order kinetics Zero order kinetics
Rate of elimination of a drug is
directly proportional to its plasma
concentration.
Rate of elimination is constant
irrespective of its plasma
concentration.
Accumulation of drug does not
occur
Accumulation of drug occurs
Level of drug remains constant,
inspite of increase in dose
Toxicity can occur if dose of the
drug is increased
Drug follows first order kinetics till
the saturation of various
elimination mechanisms
Drug follows zero order kinetics
after the saturation of various
elimination mechanisms
Example: most of the drugs Eg: phenytoin, warfarin,
theophylline, tolbutamide

118. Plasma half Life
• The Plasma half-life (t½) of a drug is the
time taken for its plasma concentration to
be reduced to half of its original value.
• The t ½ reflects the decline of systemic drug
concentrations during a dosing interval at
steady-state.
• For a one-compartment model, t ½ may be
determined readily by inspection and used to
make decisions about drug dosage.

121. Cont…
• After 1st t½–50% drug is eliminated.
• After 2nd t½–75% (50 + 25) drug is
eliminated.
• After 3rdt½ – 87.5% (50 + 25 + 12.5) drug is
eliminated.
• After 4tht½–93.75% (50 + 25 + 12.5 + 6.25)
drug is eliminated.
• Thus, nearly complete drug elimination
occurs in 4–5 half lives.

122. • Solid line:
– Plasma concentrations reflecting drug accumulation during a constant-rate infusion of a
drug.
– Fifty percent of the steady-state concentration is reached after one half-life, 75% after
two half-lives, and over 90% after four half-lives
• Dashed line:
– Plasma concentrations reflecting drug elimination after a constant-rate infusion of a
drug had reached steady state.
– Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc.
– The “rule of thumb” that four half-lives must elapse after starting a drug-dosing
regimen before full effects will be seen is based on the approach of the accumulation
curve to over 90% of the final steady-state concentration.

124. Half-life of some drugs
Drugs T ½
Aspirin 4 hr
Digoxin 40 hr
Azithromycin >50 hr
Digitoxin 7 days
Doxycycline 20 hr
Phenobarbitone 90 hr

125. Clinically implication of Plasma half-life
• Knowledge about the plasma half-life is an
important factor which guides us to:
– Determine the frequency of drug
administration.
– Duration of drug action.
– Time of excretion.

126. Semilog plasma concentration-time plot of a drug
eliminated by first order kinetics after intravenous
injection

127. Dosage Regimens

128. Temporal characteristics of drug effect and relationship to the therapeutic
window (e.g., single dose, oral administration)

129. Target concentration
• It is the minimum level of plasma
concentration of drug which is necessary to
get the desired therapeutic effect.
• To achieve this target concentration, we
need to administer the drug in loading or
maintenance dose at right interval of time
depending upon the type of drugs and
disease the patient is suffering from.

130. Loading Dose
• To attain the target concentration rapidly,
sometimes a large single dose or few
quickly repeated doses need to be given in
the beginning, this is called the loading
dose of a drug.
– Eg: digoxin, chloroquine, doxycycline etc.

131. Maintenance Dose
• To maintain the target concentration, the
dose which is required to be given at
specified intervals is called maintenance
dose.
• This is always on the lower side than the
loading dose.
– Eg: digoxin, chloroquine, doxycycline etc.

132. Calculations
• A target plasma theophylline concentration of
10 mg/L is desired to relieve acute bronchial
asthma in a patient. If the patient is a non-
smoker and otherwise normal except for
asthma, the mean clearance id 2.8 L/h/70 kg.
Since the drug will be given as an intravenous
infusion

133. TARGET DOSE
• Dosing rate = CL X TC
= 2.8 L/h/70 kg X10 mg/L
= 28 mg/h/70 kg
• Therefore, in this patient, the infusion rate
would be 28 mg/h/ 70 kg.

134. Maintenance dose
• If the asthma attack is relieved, the clinician
might want to maintain this plasma level using
oral theophylline, which might be given every
12 hours using an extended-release
formulation to approximate a continuous
intravenous infusion.

135. Cont…
• Bioavailability (Foral) is 0.96.
• When the dosing interval is 12 hours, the size
of each maintenance dose would be:
• Maintenance dose = Dosing Rate/F X Dosing
interval
= 28 mg/h/0.96 X 12 h
= 350 mg

136. Cont…
• A tablet or capsule size close to the ideal dose
of 350 mg would then be prescribed at 12-
hour intervals.
– If an 8-hour dosing interval was used, the ideal
dose would be 233 mg; and
– if the drug was given once a day, the dose would
be 700 mg.

137. • Relationship between frequency of dosing and maximum and minimum plasma
concentrations when a steady-state theophylline plasma level of 10 mg/L is desired.
• The smoothly rising black line shows the plasma concentration achieved with an
intravenous infusion of 28 mg/h.
• The doses for 8-hour administration (orange line) are 224 mg; for 24-hour
administration (blue line), 672 mg. In each of the three cases, the mean steady-state
plasma concentration is 10 mg/L.

139. Special drug delivery system

140. Dermojet
• In this method no needle is used.
• A high velocity jet of drug solution is projected
through a micro-fine orifice using a gun like
device.
• The solution gets deposited in the
subcutaneous tissue.
• It is pain less method.

141. Pellet implantation
• The drug is presented in the form of solid
pellet.
• It is introduced surgically with the help of
trochar and cannula.
• The drug keeps on releasing for weeks and
month.
– Eg. DOCA, testosterone

142. Implants
• Crystalline drug packed in tube and capsule
made of suitable material are implanted
under the skin.
• Uniform and slow a release of a drug occurs
for months together.

143. Liposomes
• This are minute vesicles made of
phospholipids into which the drug is
incorporated.
• Used for targeted drug delivery.
– Eg. Some anticancer drug and amphotericin B.

144. Monoclonal antibodies
• These are antibodies which selectively react
with specific antigen.
• These are produced using bio technology and
cell culture methods.
• Used for targeted drug delivery.
– E.g. Rituximab. Cetuximab etc.