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1. General Pharmacology
Abdulewhab Jemal

2. Learning Objectives
At the end of this chapter the student will be able
to:
•Define various terminologies used in Pharmacology.
•Describe about nature and sources of drugs.
•Describe the principles governing drug actions in humans
•Explain Pharmacokinetics like absorption, distribution,
metabolism and excretion (ADME) of drugs.

3. •Discusses theoretical pharmacokinetics like half-life,
steady state plasma concentration
• Elaborate pharmacodynamics like mechanism of drug
action, dose relationship
•Discuss factors affecting drug action, effectiveness and
adverse drug reactions
•Explain new drug development and evaluation

4. Definition
•Pharmacology deals with the knowledge of drugs.
•The word Pharmacology is derived from the Greek
words Pharmakon (drug) and logos (study).
•In a broad sense, it deals with interaction of exogenously
administered chemical molecules (drugs) with living
systems.
•Pharmacology is the science dealing with actions of drugs
on the body (Pharmacodynamics) and the fate of
drugs in the body (Pharmacokinetics).

5. Pharmacology as a science encompasses the following:
othe action of natural chemicals in the body;
o the origins and sources of drugs;
otheir chemical structure and physical characteristics;
o their mechanisms of action;
otheir metabolism and excretion;
ostudies of their action on whole animals, isolated organs, tissues
and cells, enzymes , DNA and other components of cells;
oultimately studies of their actions in humans and their therapeutic
uses.

6. Drugs???

7. •Drugs are chemical substances that can cause a
change in a biological system and are used by the
clinician to diagnose, prevent or cure diseases.
•The word drug has also a French origin--
'drouge' (dry herb).
•Drugs can be naturally occurring substances.

8. •WHO (1966) definition of a drug is
any substance or product that is
used or intended to be used to
modify or to explore physiological
system or pathological states for
the benefit of the recipient.

9. Subdivisions of pharmacology
Science
of Pharma
cology
PharmacokineticsPharmacokinetics
PharmacodynamicsPharmacodynamics
PharmacotherapeuticsPharmacotherapeuticsToxicologyToxicology
PharmacogeneticsPharmacogenetics
ChemotherapeuticsChemotherapeutics

10. •PharmacokineticsPharmacokinetics(Greek: Dynamis-power)
•Physiological and biochemical effects of drugs
and their mechanism of action at organ
system/ subcellular / macromolecular levels.
•Pharmacokinetics (Greek: Kinesis-
movement)
•movement of the drug in and alteration of the
drug by the body.

11. •Pharmacotherapeutics (Greek 'therapia'
means medical treatment).
• It is the application of pharmacological
information together with knowledge of the
disease for its prevention, mitigation or cure.
•Selection of the most appropriate drug, dosage
and duration of treatment taking into account
the specific features of a patient are a part of
Pharmacotherapeutics.

12. •Chemotherapy is the treatment of systemic
infection/malignancy with specific drugs
•Chemotherapeutic agents use to inhibit or
destroy invading microbes, parasites or cancer
cells with minimal effect on healthy living
tissues.

13. •Pharmacogenetics is a relatively new
field.
It deals with genetically mediated variations
in drug responses.
•Clinical Pharmacology is a branch of
pharmacology that deals with the
pharmacological effects of drugs in man.
It gives useful data about the potency,
usefulness, doses and toxicity of new drugs
for their safe clinical use.

14. •Toxicology is the branch of pharmacology
dealing with the “Undesirable" effects of drugs
on biological processes.
•It also study of poisonous effect of chemicals
(household, environmental pollutant, industrial,
agricultural, homicidal) with emphasis on
detection, prevention and treatment of
poisonings.

15. •Pharmacy is the art and science of compounding
and dispensing drugs or preparing suitable dosage
forms for administration of drugs to man or animals.
•It includes collection, identification. purification,
isolation, synthesis, standardization and quality
control of medicinal substances.
•The large scale manufacture of drugs is called
Pharmaceutics.

16. Sources & Nature Of Drugs
•Drug is a substance which is used for the
following purposes:
Diagnosis of the disease
Prevention of the disease
Treatment or palliation (relief of symptoms) of
disease
Prevention of pregnancy (i.e. contraception)
Maintenance of optimal health

17. A.Synthetic Sources 
•At present majority of drugs used in clinical
practice are prepared synthetically, such as
aspirin, oral antidiabetics, antihistamines,
amphetamine, chloroquine, chlorpromazine,
general and local anaesthetics, paracetamol,
phenytoin, synthetic corticosteroids,
sulphonamides and thiazide diuretics. 

18. •Advantages of synthetic drugs are: 
oThey are chemically pure.
oThe process of preparing them is easier and
cheaper.
oControl on the quality of the drug is excellent.
oMore effective and safer drugs can be prepared by
modifying the chemical structure of the prototype
drug.

19. B. Natural Sources
 Drugs are obtained from the following natural
sources:
•PLANTS:
Following categories of drugs are derived from
roots, leaves or barks of plants:

20. DRUG SOURCE
Atropine Atropa belladonna
Quinine Cinchona bark
Morphine Papavarum somniferum
Reserpine Rauwolfia serpentina
Nicotine Tobacco
Digoxin Digitalis lanata
Caffeine Coffee, Tea, coca

21. •ANIMALS SOURCES:
oInsulin, extracted from pork and beef pancreas, is used for
the treatment of diabetes mellitus.
oThyroid powder for treating hypothyroidism.
oHeparin is used as an anticoagulant.
oHormones and vitamins are used as replacement therapy.
oVaccines (cholera, T.B., smallpox, polio and antirabic) and
sera (antidiptheria and antitetanus) are used for
prophylaxis/treatment.

22. •MICROBIOLOGICAL SOURCES
oMany life-saving drugs are obtained from fungi, moulds
and bacteria
E.g.
o Penicillin from Penicillium notatum,
oChloramphenicol from Streptomyces venezuelae
o Grisofulvin (an anti-fungal drug) from Penicillium
griseofulvum,
oneomycin from Streptomyces fradiae
o streptomycin from Streptomyces griseus.

23. MINERAL SOURCES
oMinerals or their salts are useful pharmacotherapeutic agents.
For example:
oFerrous sulfate is used in iron deficiency anaemia.
oMagnesium sulfate is employed as purgative.
oMagnesium trisilicate, aluminium hydroxide and sodium
bicarbonate are used as antacids for hyperacidity and peptic ulcer.
oKaolin (aluminium silicate) is used as adsorbent in antidiarrheal
mixtures.
oRadioactive isotopes of iodine, phosphorus, gold are employed for
the diagnosis/ treatment of diseases particularly malignant
conditions.

24. C. SEMISYNTHETIC SOURCES
•Sometimes semi-synthetic processes are used to
prepare drugs when the synthesis of drugs
(complex molecules) may be difficult, expensive
and uneconomical or when the natural sources
may yield impure compounds.
oEg. semisynthetic human insulin and 6-
aminopenicillanic acid derivatives.

25. D. BIOSYNTHETIC SOURCES (genetically
engineered drugs)
•This is relatively a new field which is being developed by
mixing discoveries from molecular biology, recombinant DNA
technology, DNA alteration, gene splicing, immunology and
immunopharmacology.
•Eg. Some of the recent developments are
oRecombinant DNA engineered insulins (Humulin- human
insulin) for diabetes
oGenetically engineered novel vaccines (Recombinex HB - a
hepatitis-B vaccine)
oInterferon-alpha-2a and interferon-alpha-2b for hairy cell
leukaemia.

26. Drug Nomenclature
i)CHEMICAL NAME:
•This name is given according to the chemical constitution of a drug.
•It indicates the precise arrangement of atoms and atomic groups in
the molecule
E.g. 5-methoxy-2[[4-methoxy-3,5dimethyl-2pyridinyl-methyl]sulfinyl]benz-
imidazole .
•A code name, e.g. RO 15-1788 (later named flumazenil) may be
assigned by the manufacturer for convenience and simplicity before
an approved name is coined.
•However, chemical names are too complex and cumbersome to be
used in prescription.

27. ii) NON-PROPRIETARY /GENERIC NAME:
•When a drug has been found therapeutically useful, it
is given a non-proprietary name by the United States
Adopted Name (USAN) council.
•These names are used uniformly all over the world by
an international agreement through the W.H.O.
•Non-proprietary name is called official when included
in official books such as Indian, British, United States
or International pharmacopeia.
•The non-proprietary name is often referred to as
generic name. E.g Omperazol

28. iii) PROPRIETARY /TRADE/BRAND NAME:
•The pharmaceutical company, which sells the non-proprietary
drug selects the proprietary name and gets it registered.
•The trade name then becomes the sole property of the
pharmaceutical company.
•Thus a non-proprietary drug may be marketed under many
proprietary names by different firms.
•Proprietary name is usually smaller than the non-proprietary
name and it is most widely used by medical practitioners.
•eg. MEDOPRAZOLE®, OLIT®, OCID®, UFONITREN®,
LOCID®,LOSEC®.

29. Chemical Name Non-Proprietary
Name Proprietary Name
1-(4-
chlorobenzenesulphonyl-
3-propylurea)
Chlorpropamide Diabinese ®Copamide ® (Dey's)
-chlorodihydromethyl-
phenyl benzodiazepine-2-
one
Diazepam
Valium ® (Roche, India)
Calmpose ® (Ranbaxy, India)

30. •A dosage form is the physical form in which a
dose of medication is administered to the
patient. Examples include; tablets, capsule or
injection.
•The
route through which a drug is administered to t
he body
is highly dependent on the dosage form of the
drug.
Dosage Forms

31. •Drugs may be
 solid at room temperature (eg, aspirin,
atropine),
liquid (eg, nicotine, ethanol)
gaseous (eg, nitrous oxide).
•These Factors often determine the best route of
administration.

32. •various dosage forms may exist for the same
therapeutic compound, since different medical
conditions may warrant different routes of
administration.
 For example, persistent vomiting may make it
difficult to use an oral dosage form; in this case, it
may be advisable to use either an injection or a
suppository.
•specific dosage forms may be warranted for
certain medications, since there may be problems
with stability, e.g. insulin cannot be given orally
since it is digested by the gut.

33. •The following is some of dispensed
pharmaceutical preparations.
Tablets
Capsules
Aerosols
Suppositories
Nasal Drops
Ointments
Trans-dermal Patch….etc.

34. •Tablets are the most extensively used dosage
forms, have disc like shape produced by
mechanical compression of active substances,
filler and excipients. The filler provides bulk
enough to make, easy to handle and swallow.
•Tablets may be coated to:
protect perishable drugs from decomposition
 mask disagreeable taste or odour
facilitate passage on swallowing
Permit colour coding

35. •Capsules: are dosage-forms in which unit
doses of powder, semisolid, or liquid drugs are
enclosed in either a hard or a soft envelop, or
shell which is composed of gelatin.
• They may be of different sizes.

36. •Aerosol: Aerosols are suspensions of fine,
solid or liquid particles in a gas. They are
usually used to apply drugs to the respiratory
tract and skin.
•Suppositories: are solid dosage forms that are
used to administer medicine through the
rectum, vagina, or urethra. They melt, soften
or dissolve in the body cavity.
Vaginal suppositories are also called pessaries
 urethral suppositories bougies.

37. •Nasal Drops: are solutions of drugs that are instilled
in to the nose with a dropper. They are usually
aqueous because oily drops inhibit movement of cilia
in the nasal mucosa and, if used for long periods, may
reach the lungs and cause lipoidal pneumonia.
•Ointments: are semisolid preparations that are
intended to be applied externally to the skin or
mucous membranes.
•Trans-dermal Patch: medicated adhesive patch that
is placed on the skin to deliver a specific dose of
medication through the skin and into the bloodstream.

38. Brief History of Pharmacology
•Ancient Times
A series of scattered facts exists that speak of the
early history of humankind's efforts to harness the
healing properties of natural compounds.
However, what we know for certain is that ancient
peoples made extensive use of plant, animal and
mineral sources for this purpose.
Probably the earliest known natural substance used
because of its profound effects on the human body
is alcohol (ethanol).

39. •The discovery of pollen
from plants lacking both
“aromatic or decorative
potential” in the burial sites
of Homo neanderthalensis
dated to ~600,000 years ago.
•Alcohol has been used as a skin antiseptic, an appetite stimulant, a

gastric acid stimulant, an analgesic, and an anaesthetic agent.
•Today social use of alcohol dominates any therapeutic applications
•Every culture throughout history has used plant derivatives: the
leaves, fruit, bark, roots, and flowers as a means to heal.

40. Cuneiform tablets recovered from the library of
Ashurbanipal (circa 2000 BC) contain detailed
descriptions of the preparation of numerous
remedies

41. Materia Medica
The ancient discipline of
Materia Medica was devoted
to understanding the origin,
preparation and therapeutic
applications of medicinal
compounds.
It postulated that:
•Each disease has a unique
cause for which there is a
specific remedy.

42. •Pan Tsao is the great herbal "materia medica" of China.
Sken Ming probably wrote it in 2735 B.C.
It contained many vegetable and mineral
preparations as well as a few animal products.

43. Interestingly, the eastern herb
Artemisia annua L.
(wormwood), used in China
since antiquity to treat fevers,
is the source of the modern
drug qinghaosu (Artemisinin)
which shows great promise as
a modern anti-malarial
compound.
It is tolerated much better
than “traditional”
antimalarials and resistance
to its effects have not been
described.

44.  Eber's Papyrus is the
first written account of
medical experiences from
Egypt.
It contains more than
700 prescriptions including
castor-oil.

45. •Ayurveda contains the earliest Indian records
of "traditional" medicine. It dates back to 2500
BC.

"Dravyaguna" is the first Ayurvedic "materia
medica".
It includes sources, descriptions, criteria for
identification, properties, methods of preparation
and therapeutic uses of hundreds of medicinal
herbs.

46. Antiquity to the modern era
The ancients considered disease
a consequence of demonic
possession, or the wrath of god.
 Thus, in ancient times, the
treatment of illness with natural
products was invariably
accompanied by religious ritual
deemed essential to the healing
process.
 Some aspects of modern
treatment continue to involve ritual.

47. •Hippocrates (a
Greek physician of
5th century B.C.) is
known as the Father
of Modern Medicine,
because he organized
the science of
medicine on the
basis of analysis,
observations and
deductions.

48. •Theophrastus (300
BC) is called the Father
of Pharmacognosy
because of his accurate
observations of
medicinal plants.

49. •Galen, a Greek pharmacist
physician (131-201 AD),
introduced the concept of
polypharmacy.
He wrote 200 books which
included preparations of
crude vegetable drugs.
His name is retained in the
term "galanical" pharmacy.

50. Paracelsus (1493-
1541 AD) criticized
the Galenic system of
polypharmacy and
introduced the use of
simple chemicals for
treating diseases such
as mercurials in the
treatment of syphilis.

51. • Although, traditional
remedies still generally
consisted of complex
mixtures of distinct
herbs and minerals,
perhaps only one of
which possessed any
activity.

52. • For example, the purple
foxglove, Digitalis purpurea,
was one of twenty herbs used
in a folk remedy to treat
dropsy in 17
th
century
England.
• From the leaves of this plant
was isolated the cardiac
glycoside digitalis, a drug still
used today to treat heart
failure.

53. • Over time, as a more
sophisticated view of illness
evolved, an increasingly
scientific approach to the
isolation of drugs from natural
products was taken.
• In the early 19
th
century,
morphine was isolated from
the opium poppy (Papaver
somniferum) and the anti-
malarial compound quininequinine
from the bark of the cinchona
tree (Cinchona officinalis).

54. In 1897, Felix Hoffman, a
research chemist employed by
the "Farbenfabrikin vorm.
Freidr. Bayer and Co."
synthesized acetylsalicylic acid.
On February 1, 1899, Aspirin®
was registered as a trademark.
On March 6
th
of the same year,
this drug was registered with
the Imperial Patent Office in
Berlin. Aspirin quickly become
popular

55. •Pharmacology is a relatively recent branch of
medical science.
 In fact, pharmacology originated as a branch of
Physiology.
•Early half of the 19th century was the era of
heroic medicine.

56. •Samuel Haneman (10 April
1755 – 2 July 1843) stressed the
need of scientific foundation to
therapeutics.
He wrote the first edition of
his book "Pharmacologia
Sen Manuchitio ad
Materiam Medicam" which
gave birth to the discipline of
Pharmacology.

57. •The first independent
pharmacological
laboratory was set up
at Dorpat in 1849 by
Rudolf Buchhem in
the German
University.

58. •However, Oswald
Schmiedeberg (1838-
1921) is considered the
Father of Pharmacology
because he became the
first University Professor
of Pharmacology at
Strausbergin 1872.

59. •He attracted a large number of enthusiastic
workers to his laboratory and many of them
became prominent pharmacologists later on :
John Jacob Abel (1857-1938) of the U.S.A.
Arthur Robertson Cushney (1866-1926) of the U.K.
Three important pharmacologists in the U.K. were
Thomas Richard Fraser, Alfred Joseph Clark and
Henry Dale.

60. •In the United States recognition of
pharmacology as an independent science was
marked by the creation of the American
Society for Pharmacology and Experimental
Therapeutics (ASPET) in 1908.

61. Some Pharmacologists in History
•William Withering, 1741-1799 (digitalis)
•Claude Bernard 1813-1878 (d-tubo curare)
•Friedrich Sertürner 1783--1841 (morphine)
•Rudolf Buchheim 1820-1879 (1st Pharmacology
Laboratory, University of Dorpat (now Tartu, Estonia)
•Oswald Schmiedeberg 1838-1921 (Strassburg, now
Strasbourg, trained many pharmacologists)
•John Langley 1852--1926 (Receptor concept)
•Paul Ehrlich 1854-1915 (Receptor concept)
•Otto Loewi, Henry Dale (Neurotransmission)

62. PHARMACOKINETICS

63. What happens after the prescription is written?
Prescribed
Dose
Administered
Dose
Concentration
at Receptor
Physiological/therapeutic/toxic
Effect
Pharmacist errors
Patient compliance
Rate and extent of:
absorption
distribution to tissues
metabolism
Rate of excretion
P
h
a
r
m
a
c
o
k
in
e
ti
c
s
Concentration of receptors
State of receptors
Coupling of receptors to effectors
P
h
a
r
m
a
c
o
d
y
n
a
m
ic
s
Physiological
variables
Pathological
factors
Genetic
factors
Drug
interactions
Development
of tolerance

64. Time in Hours
D
r
u
g
C
o
n
c
e
n
t
r
a
t
i
o
n

Therapeutic
Range
Sub-
Therapeutic
Lethal
Dose
Peak Onset
Duration

65. •Pharmacokinetics is a term derived from the
Greek word 'kinesis' meaning a movement.
It deals with the time course of drug absorption,
distribution, metabolism and excretion.
In other words, it means "What the body does to the
drug".
It provides a rational basis for doses of a drug and helps
in dosage adjustment in altered physiological and
pathological states like aging, renal or hepatic
impairment.

66. Physicochemical Factors in Transfer of Drugs Across
Membranes
•The absorption, distribution, metabolism, and
excretion of a drug all involve its passage across cell
membranes.
•Mechanisms by which drugs cross membranes and
the physicochemical properties of molecules and
membranes that influence this transfer are critical to
understanding the disposition of drugs in the human
body.

67. •The characteristics of a drug that predict its
movement and availability at sites of action
are its
molecular size
degree of ionization,
relative lipid solubility of its ionized and
nonionized forms, and
its binding to serum and tissue proteins

68. Cell Membranes
•The plasma membrane consists of a bilayer of amphipathic
lipids
hydrocarbon chains oriented inward to the center of the
bilayer to form a continuous hydrophobic phase
hydrophilic heads oriented outward

69. •Individual lipid molecules in the bilayer vary
according to the particular membrane.
•Membrane proteins embedded in the bilayer serve
as
–receptors,
–ion channels, or
–transporters to transduce electrical or
chemical signaling pathways and
– provide selective targets for drug
actions.

70. •Drugs can pass through the membrane by:
filtration,
diffusion, or
carrier mediated transport
Endocytosis

72. Filtration

74. •Paracellular transport through intercellular gaps is
sufficiently large and allow filtration of chemicals with MW up
to 20,000-30,000.
•Therefore most drugs, if not bound to plasma proteins, whether
more water soluble or lipid soluble, will pass through capillary
gaps in to extracellular space.
allows filtration of drugs with MW up to 69,000 across
glomerular membranes in the kidney
"tight" intercellular junctions are present in specific
tissues, and paracellular transport in them is limited.
Brain
Placenta

75. Passive Membrane Transport (diffusion)
•In passive transport, the drug molecule usually
penetrates by diffusion along a concentration gradient by
virtue of its solubility in the lipid bilayer.
•Such transfer is directly proportional to the:
The magnitude of the concentration gradient across the
membrane
The lipid-water partition coefficient of the drug
The membrane surface area exposed to the drug.

76. •The greater the lipid-water partition coefficient

Higher concentration of drug in the membrane

Faster diffusion.

77. •Generally the presence of benzene ring, a
hydrocarbon chain, a steroid nucleus or halogen
groups in the molecule favors lipid solubility.
•Water solubility is favored by the possession of
alcoholic (-OH), amide (-CO.NH2) or carboxylic
(-COOH) groups and the formation of
conjugates with glucouronide or sulphate.

81. Weak Electrolytes and Influence of pH
•Most drugs are weak acids or bases that are present in solution
as both the nonionized and ionized species
•Non-ionized molecules more lipid-soluble diffuse
readily
•Ionized molecules usually are unable to penetrate the lipid
membrane because of their low lipid solubility.

83. •Therefore, the transmembrane distribution of a
weak electrolyte is determined by:
its pK
a
and
 the pH gradient across the membrane.
•The pK
a is the pH at which half (50%) the drug (weak
electrolyte) is in its ionized form.
•pH is a measure of hydrogen ion concentration – the
lower the pH, the higher the hydrogen ion
concentration and the greater the acidity of a
solution.

84. In an acidic environment, as in the stomach, acidic
drugs are unionized according to the following
simple equation:
where A− is an acidic drug and the excess hydrogen
ions (H+) drive the equation to the left.

85. In an alkaline environment, as in the small intestine
and the majority of body fluids, basic drugs are
unionized according to the following simple
equation:
where B is a basic drug and the deficit of hydrogen
ions drives the equation to the right.

86.  The ratio of non- ionized to ionized drug at each pH is
readily calculated from the Henderson-Hasselbalch
equation:

87. •This equation relates the pH of the medium
around the drug and the drug's acid
dissociation constant (pK
a) to the ratio of the
protonated (HA or BH
+
) and unprotonated (A
-

or B) forms.

90. Eg. Pka of the drug = 4.4
Plasma PH = 7.4
Gastric juice PH = 1.4

91. •Accordingly, at steady state, an acidic drug will
accumulate on the more basic side of the membrane and
a basic drug on the more acidic side.

a phenomenon termed ion trapping.
•These considerations have obvious implications for the
absorption and excretion of drugs.

93. •Keeping the PH of common media concerned
in drug transfer in view and knowing the PKa
value of the drug, one can predict
The rate and site of absorption from the GIT,
the possibility of distribution in tissues and
the rate of elimination

94. •Example:
Aspirin--------- Pka of 3.5
Stomach-------environmental PH of 1.5
Kidney(urine)-----------PH of 5.5
How is the situation of absorption and
excretion of aspirin from stomach and urine,
respectively???

95. •As a general rule, alkalinizing the urine will:
hasten the elimination of acidic drugs
( Phenobarbiton sodium, salisilates and sulphonamides)

delay excretion of basic drugs ( amphetamine sulphate
and mecamylamine).
•The opposite is true when acidifying urine.
What ????

96. •There
are some exceptions to the basic principles
mentioned
above
•Penicillin


water
soluble in both ionized and non-ionized forms
•Digoxin and chloramphinicol
incapable
of becoming ionized
•Heparin or tubocurarine

Permanently
ionized

97. Some important consequences of pH partition
Urinary acidification accelerates excretion of weak bases
and retards that of weak acids.
Urinary alkalinisation has the opposite effects: reduces
excretion of weak bases and increases excretion of weak
acids.
Increasing plasma pH (e.g. by administration of
sodium bicarbonate ) causes weakly acidic drugs to be
extracted from the CNS into the plasma.
Conversely, reducing plasma pH (e.g. by administration
of a carbonic anhydrase inhibitor such as acetazolamide

98. …Cont
Causes weakly acidic drugs to become concentrated
in the CNS, increasing their neurotoxicity
This has practical consequences in choosing a means
to alkalinise urine in treating aspirin overdose:
bicarbonate and acetazolamide each increase urine
pH and hence increase salicylate elimination,
but bicarbonate reduces whereas acetazolamide
increases distribution of salicylate to the CNS.

99. •pH partition is not the main determinant of the site of
absorption of drugs from the gastrointestinal tract.
•As the small intestine is the major region of gastrointestinal
absorption, the rate-limiting step is the delay in moving the
contents of the stomach into the duodenum.
enormous absorptive surface area of the villi and microvilli in
the small intestine
•Thus, absorption of drugs
promoted by drugs that accelerate gastric emptying (e.g.
metoclopramide) and
retarded by drugs that slow gastric emptying (e.g. propantheline)

100. Carrier-Mediated Membrane Transport
•Carrier-mediated mechanisms also play an important
role in desposition of drugs.
•Generally, such transport systems involve a carrier
molecule, i.e. a transmembrane protein which binds
one or more molecules or ions, changes conformation
and releases them on the other side of the membrane.

102. •Active transport is characterized by:
a direct requirement for energy,
movement against an electrochemical gradient,
saturability,
selectivity, and
competitive inhibition by cotransported compounds.

103. •Carrier-mediated transport, because it involves a binding step,
shows the characteristic of saturation.
•With simple diffusion, the rate of transport increases directly in
proportion to the concentration gradient
•Whereas with carrier-mediated transport the carrier sites become
saturated at high ligand concentrations and the rate of transport
does not increase beyond this point.
•Furthermore, competitive inhibition of transport can occur in the
presence of a second ligand that binds the carrier.

104. •Facilitated diffusion describes a carrier-
mediated transport process in which there is no
input of energy.
•In this case they merely facilitate the process
of transmembrane equilibration of the
transported species in the direction of its
electrochemical gradient.
and therefore, enhanced movement of the
involved substance is down an
electrochemical gradient

106. •Carrier proteins are specific and only transport
molecules that they ‘recognize’.
•Glucose enters many body cells by facilitated
diffusion and the process appears to be more
efficient than simple diffusion (insulin-
sensitive glucose transporter protein GLUT4).
•Carrier systems exist for the transport of some
amino acids and vitamins and the same carrier
can transport drugs that are structurally similar
to them.

107. •Pharmacologically important transporters may
mediate either drug uptake or efflux and often
facilitate vectorial transport across polarized cells.
Eg. P-glycoprotein encoded by the
multidrug resistance-1 (MDR1) gene.
P-glycoprotein localized in the enterocyte limits the oral
absorption of transported drugs
The P-glycoprotein also can confer resistance to some cancer
chemotherapeutic agents.

109. Endocytosis
•Endocytosis involves the cellular uptake of exogenous
molecules or complexes inside plasma membrane–
derived vesicles.
This process can be divided into two major
categories:
•(1) adsorptive or phagocytic uptake of particles that
have been bound to the membrane surface and
•(2) fluid or pinocytotic uptake, in which the particle
enters the cell as part of the fluid phase.

110. •The solute within the vesicle is released
intracellularly, possibly through lysosomal
digestion of the vesicle membrane or by
intermembrane fusion.

112. Ion Pair Transport
•Absorption of some highly ionized compounds
(e.g., sulfonic acids and quaternary ammonium
compounds) from the gastrointestinal tract
cannot be explained in terms of the transport
mechanisms discussed earlier.
•These compounds are known to penetrate the
lipid membrane despite their low lipid–water
partition coefficients.

113. •It is postulated that these highly lipophobic
drugs combine reversibly with such
endogenous compounds as mucin in the
gastrointestinal lumen, forming neutral ion
pair complexes; it is this neutral complex that
penetrates the lipid membrane by passive
diffusion.

115. DRUG DISPOSITION
•Drug disposition is divided into four stages:
absorption from the site of administration
distribution within the body
metabolism
excretion.

117. Drug Absorption, Bioavailability, and Routes of
Administration
•Absorption is the movement of a drug from its site of
administration into the central compartment and the
extent to which this occurs.
•For solid dosage forms, absorption first requires
dissolution of the tablet or capsule, thus liberating the
drug.
•The clinician is concerned primarily with
bioavailability rather than absorption.

118. •Bioavailability is a term used to indicate the fractional extent
to which a dose of drug reaches its site of action or a
biological fluid from which the drug has access to its site of
action.
•For example, a drug given orally must be absorbed first from
the stomach and intestine, but this may be limited by the
characteristics of the dosage form and the drug's
physicochemical properties.
•In addition, drug then passes through the liver, where
metabolism and biliary excretion may occur before the drug
enters the systemic circulation.
• Accordingly, a fraction of the administered and absorbed
dose of drug will be inactivated or diverted before it can
reach the general circulation and be distributed to its sites of
action.

120. •If the metabolic or excretory capacity of the liver for the drug
is large, bioavailability will be reduced substantially (the first-
pass effect).
•This decrease in availability is a function of the anatomical
site from which absorption takes place.

•Other anatomical, physiological, and pathological factors can
influence bioavailability.

Choice of the route of drug administration must be based
on an understanding of these conditions.

121. •Factors Governing choice of the route of administration, viz,
1. Physical and chemical properties of the drug (solid,
liquid, gas, solubility, stability, PH etc)
2. Site of desired action.
3. Rate and extent of absorption of the drug from different
routes.
4. Effect of digestive juices and first pass metabolism of the
drug.
5. Rapidity with which the response is desired
6. Accuracy of dosage required.
7. Condition of the patient

122. Routes of Administration
Parenteral
(IV)
Inhaled
Oral
Transdermal
Rectal
Topical
Parenteral
(SC, IM)

124. A) For systemic effect
•The drugs after absorption enter the systemic
circulation and act on tissues remote from the site of
the drug administration.
Enteral---Through GIT (oral, sublingual)
Parenteral---Injections(IM,IV, SC…)
B) For local effects
•If the desired site of drug action is specific and easily
approachable, the drug can be administered locally at the site.
 Examples: Topical administration, Inhalation, Oral
Cavities, Intra-arterial

125. A. For Systemic Effects
Oral Ingestion
•Oral ingestion has advantages
the most common method of drug administration
the safest,
most convenient,
most economical
• Oral ingestion has disadvantages
limited absorption of some drugs because of their physical
characteristics (e.g., water solubility),
emesis as a result of irritation to the GI mucosa,
destruction of some drugs by digestive enzymes or low gastric pH,
irregularities in absorption or propulsion in the presence of food or
other drugs, and
the need for cooperation on the part of the patient.
In addition, drugs in the GI tract may be metabolized.

126. •Most of the drug is absorbed from the small
intestine
The huge absorptive surface area(4500m
2
)
Long duration of contact between the drug and the
absorptive surface
•Absorption from the stomach is limited because
of small absorptive surface area and small
contact time(0.5-1hr)
•Enteric coating of a drug protects it from the
acidic environment and may prevent gastric
irritation.

127. •Factors governing absorption from the GI tract
Physico-chemical nature of the drugs
Gastrointestinal Juice
Intestinal microbial flora
First pass effect
GI motility
Splanchnic blood flow
Food
Particle size and formulation , Chemical factors

128. Sublingual Administration
• Absorption from the oral mucosa has special significance for
certain drugs despite the fact that the surface area available is
small.
• Venous drainage from the mouth is to the superior vena cava,
which protects the drug from rapid hepatic first-pass
metabolism.
• For example, nitroglycerin is effective when retained
sublingually because it is nonionic and has very high lipid
solubility.
•Thus, the drug is absorbed very rapidly.

129. •Advantages of Sublingual Administration
Quick onset of action
Avoidance of first pass effect
Can be adopted even in the presence of vomiting
•Disadvantage:
If swallowed drug may be inactive.
Drug must remain under the tongue until dissolved.

130. Transdermal Absorption
•Not all drugs readily penetrate the intact skin.
• Absorption of those that do is dependent on:
The surface area over which they are applied
Their lipid solubility because the epidermis behaves as
a lipid barrier.
Inflammation and other conditions that increase
cutaneous blood flow also enhance absorption.
•Toxic effects sometimes are produced by absorption through
the skin of highly lipid-soluble substances.
e.g., a lipid-soluble insecticide in an organic solvent.

131. •Controlled-release topical patches have
become increasingly available, including:
nicotine for tobacco-smoking withdrawal,
scopolamine for motion sickness,
nitroglycerin for angina pectoris,
testosterone and estrogen for replacement therapy,
and
various estrogens and progestins for birth
control.

132. Rectal Administration
•The drug is administered in the form of rectal suppositories.
•The rate of absorption is rather slow and bioavailability is 80-
90% of that of oral.
•Uncommon mode.
•Advantages
if the patient is unconscious
when vomiting is present
In non cooperative children
For bad taste drugs
 Potential for hepatic first-pass metabolism

133. •Disadvantages of rectal Administration
Rectal absorption is irregular and incomplete
Many drugs can cause irritation of the rectal mucosa
Difficult in application
Psychological problems

134. Parenteral Injections
•The major routes of Parenteral administration
are
intravenous,
Subcutaneous
Intramuscular
•Absorption from subcutaneous and intramuscular sites occurs
by simple diffusion along the gradient from drug depot to
plasma.
• The rate is limited by the area of the absorbing capillary
membranes and by the solubility of the substance in the
interstitial fluid.

135. •Drugs administered into the systemic circulation by any route,
excluding the intraarterial route, are subject to possible first-
pass elimination in the lung prior to distribution to the rest of
the body.
• The lungs serve as a temporary storage site for a number of
agents, especially drugs that are weak bases and are
predominantly nonionized at the blood pH, apparently by their
partition into lipid.
• The lungs also serve as a filter for particulate matter that may
be given intravenously, and they provide a route of elimination
for volatile substances.

137. Intravenous(IV)
•A drug administered by the IV route is given directly into the
blood by a needle inserted in to a vein.
• Factors relevant to absorption are circumvented by intravenous
injection of drugs in aqueous solution because bioavailability is
complete and rapid.
•Drugs can be given as aquous solutions or in very fine
suspensions.
•Drugs in an oily vehicle, those that precipitate blood
constituents or hemolyze erythrocytes, and drug combinations
that cause precipitates to form must not be given by this route.
•Most of IV administration are as bolus injection.
•Sometimes infusions are given-a continuous slow injection
Gloucose, saline, oxytocin, succinylcholine and noradrenaline.

138. •Advantages
Immediate onset of actions
100% bioavailability
Mode of administration of choice in medical emergency
To overcome first-pass effect
Use of large fluid volumes
Use of irritant drugs
•Disadvantages
High cost
Difficulty
Inconveniences
Irreversibility

139. Intramuscular (IM)
•An intramuscular injection is administration of a drug in to a
muscle(i.e. either in the arm or gluteal region).
•Onset of action is fairly rapid (10-30min.)
•Muscular activity, heat, or massage increase blood flow, so
increase the rate of drug absorption.
•Cardiovascular collapse , or shock may impede absorption.
•Aqueous solutions are more rapidly absorbed than oily
suspensions or solutions.
•To prolong duration of actions of drugs, depot preparations in
oil are given.
Eg. Medroxy progesterone acetate-given every 90 days(1 inj.)

140. •Generally the rate of absorbtion following injection of an aquos
preparation in to the deltoid is faster than that from gluteus
maximus.
•The rate is particularly slower for females after injection to the
gluteus maximus .
•Advantages
Rate of absorbtion is uniform.
Onset of action is faster than oral.
It can be given in diarhoea or vomiting
Can be used for parenteral administration of poorly water
soluble drugs.
Used to administer depot preparations
Eg. Benzathine Penicillin G.
•.

141. •Disadvantages
Pain at local site of injection
the volume of injection should not exceed 10ml.
breaks skin barrier.
Can be anxiety producing

142. Subcutaneous (SC)
•Subcutaneous injection places the drug into tissues
b/n the skin and the muscle.
•Very simple method of injection eg. Insulin inj.,
heparin
•Injection of a drug into a subcutaneous site can be
used only for drugs that are not irritating to tissue;
Severe pain, necrosis, and tissue sloughing may occur.

143. •Altering the period over which a drug is absorbed
may be varied intentionally, as is accomplished with
insulin for injection using
particle size,
protein complexation, and
pH
•The incorporation of a vasoconstrictor agent in a solution of a
drug to be injected subcutaneously also retards absorption.
The injectable local anesthetic lidocaine incorporates epinephrine
into the dosage form
•Absorption of drugs implanted under the skin in a solid pellet
form occurs slowly over a period of weeks or months;
Some hormones (e.g., contraceptives)
•Advantages and disadvantages are similar to IM injection.

144. Intraarterial
•It is the administration of drugs directly through the artery.
•Drugs are administered to artery for two reasons :
If drugs are binding to plasma proteins
To localize drugs to the site of a problem to get rapid action.
In the treatment of liver tumors and head/neck cancers.

•Intraarterial injection requires great care and should be reserved
for experts.

145. Intradermal:-administration of drugs in to the layers of
the skin.
Advantage:
absorption is slow (this advantage test for allergy).
Disadvantage:
amount of drug administered must be small.
Breaks skin barrier

146. Intrathecal
• The blood-brain barrier and the blood-cerebrospinal fluid (CSF)
barrier often preclude or slow the entrance of drugs into the CNS.
• Therefore, when local and rapid effects of drugs on the meninges
or cerebrospinal axis are desired, as in spinal anesthesia or
treatment of acute CNS infections, drugs sometimes are injected
directly into the spinal subarachnoid space.
•Examples of drugs given by this ROA
Methotrexate in the treatment of certain childhood leukaemias to
prevent relapse in the CNS.
Bupivacaine (opiate analgesics) - local anaesthetic
Baclofen (GABA analogue)- is used to treat disabling muscle
spasms
Aminoglycosides- nervous system infections with bacteria
resistant to other antibiotics

147. Intra-articular injections
•Intra-articular injections are sometimes used to
administer a drug directly into a joint, for
example with a corticosteroid in the treatment
of arthritis or a contrast agent for imaging.

148. Pulmonary Absorption (Inhalation)
•It is depositing of fine particle of drugs on the surface of a lung.
•Gaseous and volatile drugs may be inhaled and absorbed through
the pulmonary epithelium and mucous membranes of the
respiratory tract.
• Access to the circulation is rapid by this route because the lung's
surface area is large.
• In addition, solutions of drugs can be atomized and the fine
droplets in air (aerosol) inhaled.
• Advantages
The almost instantaneous absorption of a drug into the blood
 Avoidance of hepatic first-pass loss, and
 In the case of pulmonary disease, local application of the drug at the
desired site of action.
drugs can be given in this manner for the treatment of allergic
rhinitis or bronchial asthma (meter doses and fine particles).

149. Topical Application
•Drugs are applied to the mucous membranes of the conjunctiva,
nasopharynx, oropharynx, vagina, colon, urethra, and urinary
bladder primarily for their local effects.
• Occasionally, as in the application of synthetic antidiuretic
hormone to the nasal mucosa, systemic absorption is the goal.
• Absorption through mucous membranes occurs readily

150. B. For Local Effects
Topical Administration
•This method involves the application of drug to a surface up
on which it is intended to act.
Eg. Skin, eye, ears, nose, throat, vagina, rectum.
•Dosage forms include- solutions, ointments, suppositories,
and powders.

151. Inhalation
•Number of drugs can be given by inhalation to have only a
local effect on bronchiolar smooth muscles, as in bronchial
asthma.
Metered dose aerosols( salbutamol inhaler)
Oral
•Drugs which are neither absorbed nor destroyed in the GIT
may have local action in the GIT, if given orally
Antacids, purgatives, neomycin, anthelmintics
Cavities
•Drugs administered in to cavities or space have primarily local
action with little systemic effects depending up on the dose:
Joints, pleural, peritoneal, intrathecal.

152. Important Point
•The pharmacokinetic profile of a drug also depends
on its mode of administration …
•No Single method of drug administration is ideal for
all drugs in all circumstances

153. •Physico-chemical properties of drug
•Nature of dosage form
•Physiological factors
•Pharmacogenetic factors
•Disease states
Factors affecting drug absorption

154. Physicochemical properties of drug
•Physical state:-Liquids are absorbed better than solids
•Lipid or water solubility:-Drugs in aquoes solution mix more
readly than that in oily solution. However at the cell surface;
the lipid soluble drugs penetrate in to the cell more rapidly than
the water soluble drugs.
•Ionization:- Most of the drugs are organic compounds.
Unlike inorganic compounds, the organic drugs are not
completely ionized in the fluid.
Unionized component is predominantly lipid soluble and is
absorbed rapidly
Ionized component is often water soluble component which
is absorbed poorly.
•Most of the drugs are weak acids or weak bases.

155. Dosage forms
• Particle size: Small particle size is important for drug
absorbtion. Drugs given in a dispersed or emulsified state is
absorbed better
•Disintegration time and dissolution rate
Disintegration time is the rate of break up of the tablet or
capsule in to the drug granules.
Dissolution rate is the rate at which the drug goes in to
solution.
•Formulation; Usually substances like lactose, sucrose, starch
and calcium phosphate are used as inert diluents in
formulating powders or tablets.
 

156. Physiological factors
•Gastro intestinal transite time:
 Rapid absorbtion occurs when the drug is given on empty
stomach. However certain irritant drugs like salycilates and Iron
preparations are deliberately administered after food to minimize
the GI irritation.
•Presence of other agents:
Some times the presence of food in the GI tract aids the
absorption of certain drugs. eg.Grisofulvine
 Vitamin C enhances the absorbtion of Iron from the GIT.
Calcium present in milk and in antacids forms insoluble complex
with the Tetracyclines and reduce their absorption.
•Area of the absorbing surface and local circulation
• Contact time at the absorbtion surface:

157. • Pharmacogentic factors
Pharmacogenomics (Pharmacogenetics): is the study of
the genetic variations that cause individual differences in
drug response.
Individual variation occurs due to the genetically mediated
reason in drug absorption and response.
•Disease states
like malabsorbtion syndrome affects the rate and extent of
absorption

158. Distribution of Drugs
•Following absorption or systemic administration into
the bloodstream, a drug distributes into interstitial and
intracellular fluids (to reach its target site).
•Target sites may be located in various compartments:
1. Within the blood vessels. Example: blood coagulation / clot
dissolution. No problems of distribution here, drug molecules of
any size and shape can be used (when intravenously applied).
2. In the organ tissue, outside the blood vessels, but extracellular or
superficially exposed on the cell surface. Example: Most
receptors for hormones and transmitters.
3. In the organ tissue, intracellularly located. Example: Many enzyme
inhibitors.

160. •Distribution process reflects a number of
physiological factors and the particular
physicochemical properties of the individual
drug.
•The rate of delivery and potential amount of
drug distributed into tissues are determined by:
Cardiac output,
Regional blood flow,
Capillary permeability, and
Tissue volume

161. •Initially, liver, kidney, brain, and other well-perfused
organs receive most of the drug.
• Delivery to muscle, most viscera, skin, and fat is
slower.
•This second distribution phase may require minutes to
several hours before the concentration of drug in
tissue is in equilibrium with that in blood.
• The second phase accounts for most of the
extravascularly distributed drug.

162. •Drug distribution is affected by elimination
Time
S
e
r
u
m

C
o
n
c
e
n
t
r
a
t
i
o
n
0
0.5
1.0
1.5
0
Elimination Phase
Distribution Phase Drug is eliminated
Drug is not eliminated

163. •With exceptions such as the brain, diffusion of drug into
the interstitial fluid occurs rapidly.
because of the highly permeable nature of the capillary
endothelial membrane.

164. •Thus, tissue distribution is determined by the
partitioning of drug between blood and the particular
tissue.
• Lipid solubility and transmembrane pH gradients are
important determinants of such uptake for drugs that
are either weak acids or bases.
•However, in general, ion trapping associated with
transmembrane pH gradients is not large.
the pH difference between tissue and blood (approximately
7.0 versus 7.4) is small.
•The more important determinant of blood-tissue
partitioning is the relative binding of drug to plasma
proteins and tissue macromolecules

165. Plasma Proteins
• Many drugs circulate in the bloodstream bound to plasma
proteins.
Albumin is a major carrier for acidic drugs;
α
1-acid glycoprotein and b-globulin bind basic drugs.
•Nonspecific binding to other plasma proteins generally occurs
to a much smaller extent.
• The binding is usually reversible.
• Covalent binding of reactive drugs such as alkylating agents
occurs occasionally.

166. •The fraction of total drug in plasma that is bound is
determined by:
The drug concentration,
The affinity of binding sites for the drug,
The number of binding sites.
•Plasma binding is a nonlinear, saturable process.

168. •The extent of plasma protein binding also may be affected by
disease-related factors.
•For example, hypoalbuminemia secondary to severe liver
disease or the nephrotic syndrome results in reduced binding.
increase in the unbound fraction.
• Also, conditions resulting in the acute-phase reaction
response (e.g., cancer,pregnancy, arthritis, myocardial
infarction) lead to elevated levels of α
1-acid glycoprotein .
enhanced binding of basic drugs.

169. •Many drugs with similar physicochemical
characteristics can compete with each other and with
endogenous substances for the binding sites, because;
Binding of drugs to plasma proteins such as albumin is
nonselective
 The number of binding sites is relatively large (high
capacity)
•This will result in noticeable displacement of one
drug by another.
Displacement of unconjugated bilirubin from binding to
albumin by the sulfonamides and other organic anions is
known to increase the risk of bilirubin encephalopathy in
the newborn.

170. •Drug responses, both efficacious and toxic, are a
function of the concentrations of unbound drug.
•Drug toxicities based on competition between drugs for
binding sites is not of clinical concern for most
therapeutic agents.
• Steady-state unbound concentrations will change
significantly only when:
Drug input (dosing rate) is changed, or
Clearance of unbound drug is changed

171. 
Thus, steady-state unbound concentrations are
independent of the extent of protein binding.

172. •However, for narrow-therapeutic-index drugs, a transient change
in unbound concentrations occurring immediately following the
dose of a competing drug could be of concern.

Eg. the anticoagulant warfarin.
•warfarin (anticoagulant) protein bound ~98%
•Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the
body to work!
•If pt takes normal dose of aspirin at same time (normally
occupies 50% of binding sites), the aspirin displaces warfarin so
that 96% of the warfarin dose is protein-bound; thus, 0.2 mg
warfarin free; thus, doubles the ingested dose.

173. •Importantly, binding of a drug to plasma proteins limits
its concentration in tissues and at its site of action.
only unbound drug is in equilibrium across
membranes.
•Accordingly, after distribution equilibrium is achieved,
the concentration of active, unbound drug in
intracellular water is the same as that in plasma except
when carrier-mediated transport is involved.

174. •Binding of a drug to plasma protein also limits the
drug's glomerular filtration.
this process does not immediately change the
concentration of free drug in the plasma.
• However, plasma protein binding generally does not
limit renal tubular secretion or biotransformation.
these processes lower the free drug concentration,
followed rapidly by dissociation of drug from the drug-
protein complex
 thereby reestablishing equilibrium between bound and
free drug.

175. Clinical significance of plasma protein binding
As the protein binding increase, the duration of action of the drug
increase.
 In hypoproteinemia,the dose of highly protein bound drugs
should be adjusted.
When two drugs have the affinity for the same binding site, then
on simultaneous administration ,clinically important drug
interaction may occur.
Highly protein bound drugs are less effective in acute conditions.

176. 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 antimalarial
agent quinacrine, the concentration of drug in the liver may be
several thousand folds higher than that in the blood.
•Such accumulation may be a result of active transport or, more
commonly, binding.
•Tissue binding of drugs usually occurs with cellular constituents :
proteins,
phospholipids, or
 nuclear proteins

177. •Tissue binding of drugs is generally reversible.
• A large fraction of drug in the body may be bound in this
fashion and serve as a reservoir that prolongs drug action.
in that same tissue, or
at a distant site reached through the circulation.
• Such tissue binding and accumulation also can produce local
toxicity.
accumulation of Gentamicin in the kidney and vestibular
system.

178. 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 it constitutes 10% of body
weight.
•Fat may serve as a reservoir for lipid-soluble drugs.
as much as 70% of the highly lipid-soluble barbiturate
thiopental may be present in body fat 3 hours after
administration.
THC may still be detectable in the blood weeks later
marijuana uses.
•Fat is a rather stable reservoir because it has a relatively low
blood flow.

179. Bone
•The tetracycline antibiotics (and other divalent metal-ion
chelating agents) and heavy metals may accumulate in bone.
by adsorption onto the bone crystal surface and
eventually incorporated into the crystal lattice.
•Bone can become a reservoir for the slow release of toxic agents
such as lead or radium into the blood.
their effects thus can persist long after exposure has ceased.
•Local destruction of the bone medulla also may lead to reduced
blood flow and prolongation of the reservoir effect.
b/c the toxic agent becomes sealed off from the circulation.
may further enhance the direct local damage to the bone.

180. Redistribution
•Termination of drug effect after withdrawal of a drug 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.
Eg. the use of the intravenous anesthetic thiopental, 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.
• Thus, in this example, the onset of anesthesia is rapid, but so is its
termination.
• Both are related directly to the concentration of drug in the brain.

181. Central Nervous System and Cerebrospinal Fluid
• The distribution of drugs into the CNS from the blood is
unique.
•Drug penetration into the brain depends on transcellular rather
than paracellular transport.
•The unique characteristics of brain capillary endothelial cells
and pericapillary glial cells constitute the blood-brain barrier
(BBB).
• At the choroid plexus, a similar blood-CSF barrier is present
except that it is epithelial cells that are joined by tight
junctions rather than endothelial cells.
• Important determinant of drug’s uptake by the brain:
the lipid solubility of the non-ionized and unbound species
of a drug

182. • The more lipophilic a drug is, the more likely it is to cross the
BBB.
•This situation often is used in drug design to alter drug
distribution to the brain.
loratidine Vs diphenhydramine
morphine Vs heroine

183. •In general, the BBB's function is well maintained; however,
meningeal and encephalic inflammation increase local
permeability.
• Recently, BBB disruption has emerged as a treatment for
certain brain tumors such as primary CNS lymphomas.
• The goal of this treatment is to enhance delivery of
chemotherapy to the brain tumor while maintaining cognitive
function that is often damaged by conventional radiotherapy.
•Another important factor in the functional blood-brain barrier
involves membrane transporters that are efflux carriers present
in the brain capillary endothelial cell and capable of removing a
large number of chemically diverse drugs from the cell.
 P-glycoprotein (P-gp) and the organic anion-transporting polypeptide
(OATP)

184. Placental Transfer of Drugs
• The transfer of drugs across the placenta is of critical
importance because drugs may cause anomalies in the
developing fetus.
• Important general determinants in drug transfer across the
placenta:
 lipid solubility,
 extent of plasma binding,
degree of ionization of weak acids and bases
•The fetal plasma is slightly more acidic than that of the mother
(pH 7.0 to 7.2 versus 7.4), so that ion trapping of basic drugs
occurs.
•The fetus is to some extent exposed to all drugs taken by the
mother.

185. Drug Metabolism
•The lipophilic characteristics of drugs that promote their passage
through biological membranes and subsequent access to their site
of action also serve to hinder their excretion from the body
•Renal excretion of unchanged drug plays only a modest role in the
overall elimination of most therapeutic agents
lipophilic compounds filtered through the glomerulus are
largely reabsorbed into the systemic circulation

186. Drug metabolism may lead to the following
I.in-activation render less active or inactive →most
drugs.
II.Activation:-active metabolite is produced from
active drug.
Eg.Allopurinol→Alloxanthine
Diazepam→Nor diazepam
III. Activation of an inactive drug: - few drugs are inactive
as such and need conversion in the body to one or more
active metabolite. Such drug is called prodrug. eg.L-dopa
to Dopamine

187. •The metabolism of drugs and other xenobiotics into more
hydrophilic metabolites is essential for:
their elimination from the body
termination of their biological and pharmacological activity
•In general, biotransformation reactions generate more polar,
inactive metabolites that are readily excreted from the body
•However, in some cases, metabolites with potent biological activity
or toxic properties are generated

188. • Many of the enzyme systems that transform drugs to inactive
metabolites also generate biologically active metabolites of
endogenous compounds, as in steroid biosynthesis.
•Drug metabolism or biotransformation reactions are classified
in to two:
Phase I functionalization or catabolic reactions,
Phase II biosynthetic (conjugation) or anabolic reactions.

191. •A great variety of drugs undergo the sequential biotransformation
reactions, although in some instances the parent drug may already
possess a functional group that may form a conjugate directly.
•For example, the hydrazide moiety of isoniazid is known to form
an N-acetyl conjugate in a phase II reaction.
•This conjugate is then a substrate for a phase I type reaction,
namely, hydrolysis to isonicotinic acid
•Thus, phase II reactions may actually precede phase I reactions.

193. Phase I reactions
•Xenobiotic metabolizing enzymes have historically been
grouped into the phase 1 reactions, in which enzymes
carry out:
oxidation,
reduction, or
hydrolytic reactions
•The phase 1 enzymes lead to the introduction or
unmasking of what are called functional groups,
resulting in a modification of the drug, such that it
now carries an -OH, -COOH, -SH, -O- or NH
2 group.

194. N-
and O-dealkylation
N-oxidation
and
-hydroxylation
Sulfoxide
formation
Oxidative
deamination
Different types of drug modifications catalyzed by
cytochrome P450 enzymes

195. The P450 Monooxygenase System
•Cytochrome P450 enzymes are haem proteins
•Comprising a large family ('superfamily') of related but
distinct enzymes (each referred to as CYP followed by a
defining set of numbers and letter)…Eg. CYP3A
• These enzymes differ from one another in:
amino acid sequence,
regulation by inhibitors and inducing agents, and
the specificity of the reactions that they catalyse

196. oSo far, 74 CYP gene families have been described, of which
three main ones (CYP1, CYP2 and CYP3) are involved in drug
metabolism in human liver.
o Ninety percent of therapeutic and recreational drugs are
metabolized to some extent, by just five CYP450 forms in
humans.
oThese are CYP3A4 (40%) – the most abundant, CYP2D6
(20%), CYP2C9 (10%), CYP2C19 (10%) and CYP1A2 (10%).
oA further four account for most other drug metabolism:
CYP2A6, CYP2B6, CYP2C8, and CYP2E1.

197. •CYP3A4 is likely to be involved in the greatest number of
drug–drug interactions.
•CYP2C9 metabolizes several clinically important drugs with
narrow therapeutic indices. E.g. phenytoin and warfarin.
•CYP2D6 Mediate the metabolism of drugs in such diverse
therapeutic categories as antipsychotic agents, tricyclic
antidepressants, β-blocking agents, and opioid analgesics.

198. RELATIVE HEPATIC CONTENT
OF CYP ENZYMES
% DRUGS METABOLIZED BY CYP
ENZYMES
ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM

199. Isoenzyme P450 Drug
CYP1A1 Theophylline
CYP1A2 Caffeine, paracetamol, tacrine, theophylline
CYP2A6 Methoxyfluran
CYP2C8 Taxol
CYP2C9 Ibuprofen, Phenytoin, Tolbutamide, warfarin
CYP2C19 Omeprazole
CYP2D6 Clozapine, codeine, debrisoquine, metoprolol
CYP2E1 Alcohol, enflorane, halothane
CYP3A4/5 Ciclosporin, losartan, nifedipine, terfenadine
Examples of common drugs that are substrates for P450 isoenzymes

200. •Within human populations there are major sources of
interindividual variation in P450 enzymes that are of great
importance in therapeutics.
• These include genetic polymorphisms:
for example, Acetylation of INH

201. •Environmental factors are also important.
• Enzyme inhibitors and inducers are present in the diet and
environment.
For example, grapefruit juice inhibit drug metabolism
leading to potentially disastrous consequences,
including cardiac dysrhythmias
 St John's wort induces drug metabolism
Whereas cigarette smoke induce P450 enzymes.

202. Human Drug Metabolizing CYPs Located
in Extrahepatic Tissues
CYP
Enzyme
Tissue
2E1 Lung, placenta, others
2F1 Lung, placenta
2J2 Heart
3A
GI tract, lung, placenta, fetus, uterus,
kidney
4B1 Lung, placenta
4A11 Kidney

203. Other Phase I Reactions
•Not all drug oxidation reactions exclusively involve the P450
system.
ethanol is metabolised by a soluble cytoplasmic enzyme,
alcohol dehydrogenase, in addition to CYP2E1
 xanthine oxidase, which inactivates 6-
mercaptopurine
 MAO, which inactivates many biologically active
amines (e.g. noradrenaline, tyramine, 5-
hydroxytryptamine).

204. •Reductive reactions are much less common than
oxidations, but some are important
For example, warfarin is inactivated by conversion of a
ketone to a hydroxyl group by CYP2A6
•Hydrolytic reactions do not involve hepatic microsomal
enzymes but occur in plasma and in many tissues.
Both ester and (less readily) amide bonds are
susceptible to hydrolysis.

205. There are a number of drugs which may induce or
enhance production of this enzyme and it is one site of
drug interaction.
Microsomal enzyme Inducers Microsomal enzyme inhibitors

Phenobarbiton

Cimetidine
Phenytoin

isoniazid
Riphampicine chloramphenicol
Grisofulvine erytromycine
Carbamazepine
Cigarette
smoking

206. Phase II Reactions
•If a drug molecule has a suitable 'handle' (e.g. a hydroxyl, thiol or
amino group), either in the parent molecule or in a product
resulting from phase I metabolism, it is susceptible to conjugation
i.e. attachment of a substituent group
•This synthetic step is called a phase II reaction
•The resulting conjugate is almost always pharmacologically
inactive and less lipid soluble than its precursor and is excreted in
urine or bile.

208. •The groups most often involved in conjugate formation
are:
glucuronyl, sulfate, methyl, acetyl, glycyl and
glutathione.

210. oMetabolism of drugs and other foreign chemicals may not
always be an innocuous biochemical event leading to
detoxification and elimination of the compound.
oSeveral compounds have been shown to be metabolically
transformed to reactive intermediates that are toxic to
various organs.
o Such toxic reactions may not be apparent at low levels of
exposure to parent compounds since
 alternative detoxification mechanisms are not yet
overwhelmed or compromised.
 the availability of endogenous detoxifying cosubstrates
(GSH, glucuronic acid, sulfate) is not limited.
METABOLISM OF DRUGS TO TOXIC
PRODUCTS

212. First-pass (Presystemic) Metabolism
•The liver (or sometimes the gut wall) extracts and metabolises
some drugs so efficiently that the amount reaching the systemic
circulation is considerably less than the amount absorbed.
• This is known as first-pass or presystemic metabolism, which
causes low bioavailability even when a drug is well absorbed
from the gut.

214. • It is important for many clinically important drugs
•Examples of drugs that undergo substantial first-pass
elimination:
Levodopa, Lidocaine, Metoprolol, Morphine, Propranolol,
Salbutamol, Verapami, Aspirin, Glyceril trinitrate, Isosorbide
dinitrate
•a much larger dose of the drug is needed when it is given orally
than when it is given by other routes.
•marked individual variations occur in the extent of first-pass
metabolism of a given drug, resulting in unpredictability when
such drugs are taken orally.

215. •Magnitude of first pass hepatic effect is determined by
Extraction ratio (ER)
ER = CL liver / Q

where Q is hepatic blood flow (usually about 90 L per hour)

•Systemic drug bioavailability (F) may be determined from the
extent of absorption (f) and the extraction ratio (ER):
F = f x (1 -ER)

216. Excretion of Drugs
•Drugs are eliminated from the body either unchanged by
the process of excretion or converted to metabolites.

217. Renal Excretion
•Drugs differ greatly in the rate at which they are
excreted by the kidney.
Penicillin, which is cleared from the blood almost
completely on a single transit through the kidney.
Diazepam, which is cleared extremely slowly.
most drugs fall somewhere in between
metabolites are nearly always cleared more quickly
than the parent drug.

219. •Three fundamental renal processes account for
renal drug excretion:
glomerular filtration
active tubular secretion
passive diffusion across tubular epithelium.

220. Glomerular Filtration
[
•The amount of drug entering the tubular lumen by
filtration depends on:
the GFR and
 the extent of plasma binding of the drug
•Glomerular capillaries allow drug molecules of molecular weight
below about 20,000 to diffuse into the glomerular filtrate.
• Plasma albumin (68 000) is almost completely impermeable.
•Most drugs-with the exception of macromolecules such as heparin
cross the barrier freely.
• If a drug binds appreciably to plasma albumin, its concentration
in the filtrate will be less than the total plasma concentration.

221. Tubular Secretion
•Up to 20% of renal plasma flow is filtered through the
glomerulus, leaving at least 80% of delivered drug to
pass on to the peritubular capillaries of the proximal
tubule.
• Here drug molecules are transferred to the tubular
lumen by two independent and relatively non-selective
carrier systems.
one of these transports acidic drugs (as well as various
endogenous acids, such as uric acid),
while the other handles organic bases.

222. •Important drugs and related substances actively secreted
into the proximal renal tubule
Acids Bases
p-Aminohippuric acid (PAH) Amiloride
Furosemide (frusemide) Dopamine
Glucuronic acid conjugates Histamine
Glycine conjugates Mepacrine
Indometacin Morphine
Methotrexate Pethidine
Penicillin Quaternary ammonium compounds
Probenecid Quinine
 Sulphate conjugates 5-Hydroxytryptamine (serotonin)
Thiazide diuretics Triamterene
Uric acid

223. •The carriers can transport drug molecules against an
electrochemical gradient.
•Tubular secretion is potentially the most effective
mechanism of renal drug elimination.
• Unlike glomerular filtration, carrier-mediated
transport can achieve maximal drug clearance even
when most of the drug is bound to plasma protein.
•Many drugs compete for the same transport system,
leading to drug interactions.

224. Diffusion Across the Renal Tubule
•Drugs with high lipid solubility, and hence high tubular
permeability are excreted slowly.
• If the drug is highly polar, and, therefore, of low tubular
permeability, filtered drug remains in the tubule.
•its concentration rises until it is about 100 times as high in the
urine as in the plasma.
Drugs handled in this way include digoxin, and
aminoglycoside antibiotics.
Many drugs, being weak acids or weak bases, change their
ionization with pH, and this can markedly affect renal excretion.

225. •Drugs that are excreted largely unchanged in the urine.
Percentage excreted Drugs
100-75 Furosemide (frusemide), gentamicin,
methotrexate, atenolol, digoxin
75-50
Benzylpenicillin, cimetidine,
oxytetracycline, neostigmine
∼50 Propantheline, tubocurarine

226. Bilary Excretion and Enterohepatic circulation
•Liver cells transfer various substances, including drugs,
from plasma to bile by means of transport systems
similar to those of the renal tubule and which involve P-
glycoprotein.
•Various hydrophilic drug conjugates (particularly
glucuronides) are concentrated in bile and delivered to
the intestine
the glucuronide is usually hydrolyzed
releasing active drug once more
free drug can then be reabsorbed and the cycle
repeated (enterohepatic circulation)

227. Excretion by Other Routes
•Excretion of drugs into sweat, saliva, and tears is quantitatively
unimportant.
• Elimination by these routes depends mainly on:
diffusion of the nonionized lipid-soluble form of drugs
through the epithelial cells of the glands
the pH.
• Drugs excreted in the saliva enter the mouth, where they are
usually swallowed.
• The concentration of some drugs in saliva parallels that in
plasma.
•Saliva therefore may be a useful biological fluid in which to
determine drug concentrations when it is difficult or
inconvenient to obtain blood.

228. •Excretion of drugs in breast milk is important not
because of the amounts eliminated as well
• Since milk is more acidic than plasma, basic
compounds may be slightly concentrated in this fluid.
• Nonelectrolytes, such as ethanol and urea, readily enter
breast milk and reach the same concentration as in
plasma, independent of the pH of the milk
•Excretion from the lung is important mainly for the
elimination of anesthetic gases.
•Although excretion into hair and skin is quantitatively
unimportant, sensitive methods of detection of drugs in
these tissues have forensic significance

229. Theoretical pharmacokinetics
oThe goal of therapeutics is to achieve a desired beneficial effect with
minimal adverse effects.
othe clinician must determine the dose to achieves this goal.
Volume of Distribution
•The volume of distribution (V) relates the amount of drug in the body to the
concentration of drug (C) in the blood or plasma depending on the fluid
measured.
• This volume does not necessarily refer to an identifiable physiological
volume but rather to the fluid volume that would be required to contain all the
drug in the body at the same concentration measured in the blood or plasma:

230. •Vd is the volume of fluid required to contain the total dose of a
drug in the body at the same concentration as that present in
plasma
•Therefore it reflects the extent to which it is present in extra-
vascular tissues and not in the plasma.
• For a typical 70-kg man:
the plasma volume is 3 L,
 blood volume is about 5.5 L,
extracellular fluid volume outside the plasma is 12 L,
the volume of total-body water is approximately 42 L.
•Many drugs exhibit volumes of distribution far in excess of
these values.

232. •If 500 mg of the cardiac glycoside digoxin were in the
body of a 70-kg subject, a plasma concentration of
approximately 0.75 mg/ml would be observed.
•Vd???
•667 L 10 times greater than the total-body volume
of a 70-kg man.
•For drugs that are bound extensively to plasma proteins
but that are not bound to tissue components, the volume of
distribution will approach that of the plasma volume.
•Presuming that the body behaves as a single homogeneous
compartment with volume V into which drug gets
immediately and uniformly distributed.

233. •The volume of distribution may vary widely depending on:
the relative degrees of binding to high-affinity receptor sites
 the relative degrees of binding to plasma and tissue proteins,
the partition coefficient of the drug in fat,
accumulation in poorly perfused tissues.
•The volume of distribution for a given drug can differ according to
patient's:
age,
gender,
body composition,
presence of disease
•Total-body water of infants younger than 1 year of age, for example,
is 75% to 80% of body weight, whereas that of adult males is 60%
and that of females is 55%.

234. Clearance
•Clearance(Cl) is a specific pharmacokinetic term used to describe the rate
at which drug is cleared, by whatever mechanism, from a particular
volume of plasma.
•Renal clearance, CL
r, is defined as the volume of plasma containing the
amount of substance that is removed by the kidney in unit time.
•Clearance (denoted Cl) is defined as that volume of plasma completely
cleared of drug in a unit of time;
•Clearance of a drug is the factor that predicts the rate of elimination in
relation to the drug concentration.
CL=Rate of elimination
C
Total clearance is calculated by:-
Ct =Ch+Cr+Cothers
Ct=total clearance, Ch=hepatic clearance, Cr=renal clearance.


Cl= kel × V

235. First order (exponential) kinetics
•The rate of elimination is directly proportional to the drug
concentration. , CL remains constant; or a constant fraction of the
drug present in the body is eliminated in unit time
Zero order (linear) kinetics
•The rate of elimination remains constant irrespective of drug
concentration, a constant amount of the drug is eliminated in unit
time.
•The elimination of some drugs approaches saturation over the
therapeutic range, kinetics changes from first order to zero order at
higher doses.

236. •The main determinants, as explained are:
the rate of active tubular secretion and
the rate of passive reabsorption.
•For drugs that are not inactivated by metabolism, the rate of renal
elimination is the main factor that determines their duration of
action.
•These drugs have to be used with special care in individuals
whose renal function may be impaired, including the elderly and
patients with renal disease or any severe acute illness.
•For a single dose of a drug with complete bioavailability and first-
order kinetics of elimination, systemic clearance may be
determined

CL=Dose/AUC

238. Half-Life
•Half-life ( t 1/2 ) is the time required to change the amount of
drug in the body by one-half during elimination.
•Thus, nearly complete drug elimination occurs in 4-5 half
lives.
•For drugs eliminated by- First order kinetics-(t ½) remains
constant .
•Zero order kinetics-(t1/2) increases with dose

239. Steady state plasma concentration
(dosing rate =CL × C
ss)
When a drug dose is given repeatedly over a given period, a
steady state is eventually reached, at which point the amount of
drug absorbed is in equilibrium with that eliminated from the
body.
Steady state is achieved after 4 to 5 half –lives for most of the
drugs which follow first order kinetics.
o For example a drug with half life of 6 hours will be expected
to be at steady state after more than 24 hours of
administration.
The pattern of drug accumulation during repeated
administration of drug at intervals equal to its elimination half-
life.

240. Loading Dose
•It is a higher dose or a series of doses that may be given at the
onset of therapy to achieve the target concentration rapidly.
Loading= TargetCp*V
F
Maintainance Dose
the dose which is repeated at regular intervals to maintain a
steady state concentration of the drug in plasma and thus to
maintain the effect.

241. Monitoring of plasma concentration of drugs
•Cpss of a drug attained in a given patient depends on its f, V
and CL in that patient. Because each of these parameters
varies considerably among individuals

242. PHARMACODYNAMICS

243. •Pharmacodynamics deals with the study of the
biochemical and physiological effects of drugs and their
mechanisms of action.
• A thorough analysis of drug action can provide the basis
for:
the rational therapeutic use of a drug and
the design of new and superior therapeutic agents

244. Principle Of drug action
•Drugs do not impart new functions to any system, organ or
cell; they only alter the pace of ongoing activity. The basic
types of drug action can be broadly classed as:
1.Stimulation
2.Depression
3.Irritation
4.Replacement
5.Cytotoxic

245. How do drugs act????
•There are many ways in which drugs bring about their effects.
•The fundamental mechanisms of drug action can be distinguished
in to three categories.
1. Physical action:-Physical property of the drug is responsible for
its action.
Eg. Osmotic activity- magnesium sulphate.
2. Chemical action:-The drug acts according to simple chemical
equation.
Eg. Antacids neutralize gastric HCl.
3. Through receptors: - Most of the drugs act by interacting with a
cellular component called a receptor.
Receptors are protein molecules present either on the cell
surface or with in the cell.
Eg. Adrenergic receptors, cholinoceptors, insulin receptors.

246. •The effects of most drugs result from their
interaction with macromolecular components of
the organism.
•These interactions alter the function of the
pertinent component and thereby initiate the
biochemical and physiological changes that are
characteristic of the response to the drug.

247. •John Langley (1878) ----"There is
some substance or substances in
the nerve ending or gland cell
with which both atropine and
pilocarpine are capable of forming
compounds."
•He later referred to this factor as a
"receptive substance."

248. •The word receptor was introduced in 1909 by
Paul Ehrlich.
•Ehrlich postulated that a drug could have a therapeutic effect
only if it has the "right sort of affinity."
•Ehrlich said: 'A drug will not work unless it is bound'.

250. •Now receptors have been isolated
biochemically and genes encoding receptor
proteins have been cloned and sequenced.
•Receptors determine the quantitative
relationship between drug dose and
pharmacologic effect.
•Receptors are responsible for the selectivity of
drug action.
•Receptors mediate the actions of
pharmacologic agonists and antagonists.

251. Macromolecular Nature of Drug Receptors
•Most receptors are proteins
 presumably because the structures of polypeptides provide
both the necessary diversity and the necessary specificity of
shape and electrical charge
a. Regulatory proteins
The best-characterized drug receptors
Mediate the actions of endogenous chemical signals such as
neurotransmitters, autacoids, and hormones
e.g. adrenoreceptors, steroid receptors, acetylcholine
receptors.

252. b. enzymes
Almost all biological reactions are carried out under catalytic
influence of enzymes.
may be inhibited (or, less commonly, activated) by binding a
drug
eg, dihydrofolate reductase, the receptor for the antineoplastic
drug methotrexate)
Inhibition might be specific or non-specific

253. c. transport proteins
Several substrates are translocated across membranes by binding to
specific transporters.
Fluoxetine inhibit neuronal reuptake of 5-HT by interacting with
serotonin transporter (SERT).
eg, Na
+
/K
+
ATPase, the membrane receptor for cardioactive
digitalis glycosides)
d. structural proteins (Cytoskeletal proteins)
eg, tubulin, the receptor for colchicine, an anti-inflammatory
agent).

254. •Drug target sites that are not proteins include:
DNA, RNA, Membranes, Fluid compartments.

•However, most drugs act directly on receptors
that are proteins

255. Receptor Families

256. •In terms of molecular structure and the nature
of signal transduction mechanism, cell surface
receptors are classified in to three subfamilies.
1. Ion channel linked receptors
2. G-protein coupled receptors (GPCRs)
3. Receptor that are enzymes or linked enzymes

257. Ion channel linked receptors
•They are membrane receptors which are coupled to ion
channels.
•Their activation leads to opening of the channels through
which ions pass
•A fastest effect is obtained.
•Ion Channels:
Ligand-gated channels: Ion channels that open upon binding
of a mediator. Examples include: nACh receptor, GABA A
receptor etc
Voltage-gated channels: Ion channels that are not normally
controlled by ligand binding but by changes to the membrane
potential

259. G-protein coupled receptors
•Are metabolic receptors.
•They are membrane receptors which are
coupled to intracellular effectors via a G-
protein.
G-proteins are those proteins that bind
guanylate nucleotides.
 When they bind GDP they are inactive and
when they bind GTP they will be active.
 Thus they act as molecular switches.

261. •GPCRs transduce signals through different mechanisms:
by activating Adenyl Cyclase (AC)
•Ligand binding → Receptor activation→ G-protein activation→
Activation of Adenyl Cyclase→ Generation of cAMP→
Activation of protein kinase A→ Cellular effects.
•AC catalyzes formation of intracellular cAMP.
•cAMP regulates the function of various proteins such as Protein
kinase A (PKA), and PKA phosphorylated enzymes, carrier
proteins etc
•Examples include receptors for adrenaline, glucagon,
serotonine

262.  by activating Phospholipase C (PLC)
•PLC catalyzes formation of Inositol triphosphate (IP
3
)
and Diacyl glycerol (DAG)
IP
3
: increase cytosolic Ca
2+
→ Ca
2+
activate
contraction, enzyme activation etc
DAG: activates protein kinase C (PKC) → PKC
phosphorylates various proteins.

264. Receptors that are enzymes or linked enzymes

•They are cell surface receptors whose cytosolic
domain is enzyme or associate enzyme from
cytoplasm.
•Examples include insulin receptor, growth
factor receptor

265. Cytoplasmic Second Messengers
•Binding of an agonist to a receptor provides the first
message in receptor signal transduction to effector to
affect cell physiology.
•The first messenger promotes the cellular production
or mobilization of a second messenger, which
initiates cellular signalling through a specific
biochemical pathway.
•Second messengers include:
 cyclic AMP, cyclic GMP, cyclic ADP–ribose, Ca2+,
inositol phosphates, diacylglycerol, and nitric oxide (NO).

266. •For a drug to be useful as either a therapeutic or a
scientific tool, it must act selectively on particular cells
and tissues.
it must show a high degree of binding-site
specificity.
• Conversely, proteins that function as drug targets
generally show a high degree of ligand specificity;
they will recognize only ligands of a certain
precise type and ignore closely related molecules.

267. •It must be emphasized that no drug acts with complete
specificity
•In general, the lower the potency of a drug, and the higher
the dose needed, the more likely it is that sites of action other
than the primary one will assume significance.
often associated with the appearance of unwanted side-
effects, of which no drug is free.

268. Drug-receptor Interactions
•Occupation of a receptor by a drug molecule may or may not
result in activation of the receptor.
•By activation, we mean that the receptor is affected by the
bound molecule in such a way as to elicit a tissue response.
•Binding and activation represent two distinct steps in the
generation of the receptor-mediated response by an agonist.
•If a drug binds to the receptor without causing activation and
thereby prevents the agonist from binding, it is termed a
receptor antagonist.

269. • The tendency of a drug to bind to the receptors is governed
by its affinity, whereas the tendency for it, once bound, to
activate the receptor is denoted by its efficacy.
•Drugs of high potency will generally have a high affinity
for the receptors and thus occupy a significant proportion of
the receptors even at low concentrations.
• Agonists will also possess high efficacy, whereas
antagonists will, in the simplest case, have zero efficacy.
• Drugs with intermediate levels of efficacy, such that even
when 100% of the receptors are occupied the tissue
response is submaximal, are known as partial agonists.

270. •Intrinsic activity (efficacy): the ability of a drug to
activate a receptor following binding.
–It is reflected in the maximal efficacy (drugs with
high intrinsic activity have high maximal efficacy).
–Its value ranges from 0 to 1.
–Antagonists have 0 efficacy.

271. QUANTITATION OF DRUG-RECEPTOR
INTERACTIONS
•After studying quantitative aspects of drug action, Clark (1937)
propounded a theory of drug action based on occupation of receptors by
specific drugs
Hill-Langmuir Equation
•Rate of forward reaction = K
1
[D][R]
•Rate of backward reaction = K
-1
[DR]
•At equilibrium, rate of forward and backward reactions are equal.
i.e. K
1
[D][R] = K
-1
[DR]
K
-1/K
1 = [D][R]/ [DR]
K
D
= [D][R]/ [DR], where K
D
is dissociation constant

272. But [R
T
] = [R] + [DR] ═► [R] = [R
T
] – [DR]
K
D
= [D]( [R
T
] – [DR])/ [DR]
•Rearranging the above equation will give:
[DR]/[R
T
] = [D]/ ([D] + K
D
),
where [DR]/[R
T
] = P
A
, which is proportion of
receptor occupied with an agonist.
•The dissociation constant, K
D, is defined as the concentration
of drug that corresponds to 50% receptor occupancy
•K
D is related to the affinity of a drug. i.e. the smaller the
value of K
D
the higher the affinity a drug has for its receptor.

273. Which drug has the higher affinity?

274. Drug-Receptor Theories
Occupancy Theory
According to this theory, the response
generated is a function of the number of
receptors occupied by a drug.
Drug and receptor interact with each other
– Complex  effects
•Drug’s structure  “affinity”

275. a. Clark classical theory
•Response produced by a drug is proportional to the
amount of drug-receptor complex formed.
b. Stephenson modified theory of occupation
•Binding of a drug only is not sufficient; it should
have certain ability to bring a structural change to
the receptor.

276. Rate Theory
•Agonist or stimulant activity is proportional to the
rate of drug-receptor combination rather than the
number of occupied receptors.
•Agonist activity is the result of a series of rapid
association and dissociation of the drug and the
receptor.
•An antagonist has a high association rate but a low
rate of dissociation

277. The two-state receptor Model
•A very attractive alternative model for explaining the action of agonists,
antagonists, partial agonists and inverse agonists has been proposed.
•The receptor is believed to exist in two interchangeable states: Ra (active)
and Ri (inactive) which are in equilibrium.

279. Other Theories
1.Induced-fit theory of enzyme-substrate interaction
1.Substrate or drug binding to the receptor induces 3 dimensional
conformational changes in the macromolecule positioning catalytic
groups in the correct position to conduct productive chemistry or altering
membrane behavior (e.g. opens channels for calcium)
2.Macromolecular perturbation theory
1. Small molecule binding produces in a macromolecule:
1. Specific conformational perturbations (Agonist)
2. Non-specific conformational perturbations (Antagonist)
3. An equilibrum mixture of specific and non-specific changes (partial
agonist or antagonistic properties)
Reality is most likely a mixture or blend of all these theories

280. Dose-Response Relationships
•The relation between drug dose and the clinically
observed response may be quite complex.
•However, in carefully controlled in vitro systems, the
relationship between drug concentration and its effect is
often simple and may be described with mathematical
precision.

281. •These curves are Michaelis- Menten curves or
rectangular hyperbolae

282. •Effect is the effect of the
drug produced at the
given concentration of
the drug.
•Effectmax is the
maximum response of
the system to the drug.
•EC50 is that
concentration of drug
that produces a response
one-half of the maximum
response

283. Dose-Response Curves
•Dose-response curves exist for graded type of
responses.
•Dose-response curves are presented by:
a.Hyperbolic curve
b.Sigmoidal curve

284. Hyperbolic curve

A curve obtained from dose-percent response plot.

 Linear relationship exists at lower dose.

285. Sigmoidal curve

A curve obtained from Log dose-percent response plot.
 The curve has a characteristic sigmoid or S-shape
with linear portion in the middle

286. Advantages of logarithmic transformations
•Results can be plotted when doses vary even over a
1000-fold range which otherwise is not possible
• Curves become linear particularly at the middle point
•Error normally distributed independent of the dose
•Has mathematical advantage

E.g. the horizontal distance between two dose- effect
curves is a measure of the potency ratio of the two
drugs.

287. Analysis of dose-response curves

288. DRUG Potency & Efficacy
•Efficacy is the maximum effect (Effectmax) of a
drug. Potency, a comparative measure, refers to the
different doses of two drugs needed to produce the
same effect.
•Normally we plot data as effect versus log[Drug].
This makes it easier to determine EC50s and to
compare drug efficacy & potency.

289. •In
this figure, Drugs A & B have
the
same efficacy.
•Drug
A has greater potency than
B
or C because the dose of B or C
must
be larger to produce the
same
effect as A.
•Although
Drug C has lower
efficacy
than B, it is more potent
than
B at lower drug
concentrations

290. Receptor Agonism and Antagonism
•A receptor can exist in at least two conformational states,
active (R
a
), and inactive (R
i
).
•A drug that has a higher affinity for the active
conformation than for the inactive conformation will
drive the equilibrium to the active state and thereby
activate the receptor.
•Such a drug will be an agonist.

291. Full Vs Partial Agonists
•Agonists may differ in how tightly they bind to their
receptors (potency) and in the effect they produce
(efficacy).
•Some drugs may bind very tightly (are highly potent)
but produce only a modest effect (low efficacy).
•Low efficacy drugs are termed “partial agonists”
while the structurally related drugs which produce a
full effect are called “full agonists”.

293. How can an agonist be “partial”???
•A full agonist is sufficiently selective for the active
conformation that at a saturating concentration it will
drive the receptor essentially completely to the active
state.
•If a different but perhaps structurally similar
compound binds to the same site on R but with only
moderately greater affinity for R
a
than for R
i
,
its effect will be less, even at saturating concentrations.
 a drug that displays such intermediate effectiveness is
referred to as a partial agonist because it cannot promote a
full biological response at any concentration.

294. • The partial agonist may fit the receptor binding site well but is
less able to promote the receptor conformational change leading
to transduction.
• In an absolute sense, all agonists are partial;

 selectivity for R
a
over R
i
cannot be total.

296. Drug Antagonists
Molecules that
 produce their effects by preventing
receptors activation by endogenous regulatory
molecules and drugs.

 
♣ Block activation of receptors by agonists.

297. General classes of antagonists
a.Chemical Antagonists
•One drug may antagonize the action of a second by
binding to and inactivating the second drug.
Ex: Protamine (+ charge) will counteract effects of Heparin
(- charge)

298. b.

Physiological Antagonists
endogenous regulatory pathways mediated by different
receptors.
A drug affecting a physiologic effect of the other drug

Eg. glucocorticoids and insulin
c. Pharmacological Antagonists
Drugs that bind to receptors but do not act like agonists
and, therefore, do not alter receptor function.

299. •Types of antagonism at receptor site
1. Reversible antagonism
i. Competitive antagonism
ii. Non-competitive antagonism
2. Irreversible antagonism

300. Reversible antagonism
•Since weak bond is formed between a receptor
and an antagonist, the antagonism occurs
reversibly.
•Antagonists may be competitive (reversibly
displaced by agonists) or noncompetitive (not
reversibly displaced by agonists).

301. i.Competitive (surmountable or reversible) Antagonists
•Competitive antagonists interact with receptor at the same site
as the agonist.
•Competitive antagonists do not themselves produce an effect,
but they decrease in a reversible manner the apparent potency
of agonists.
•Antagonism can be overcome by increasing agonist
concentration (surmountable).

302. • A competitive antagonist, C, competes with the agonists A
for binding to the receptor, R.

303. •From the Law of Mass Action, increasing [C] will
shift the equilibrium to the left reducing the amount
of productive (effective) receptor. agonist complex.
•Increasing [A] will shift the equilibrium to the right
reducing the amount of unproductive receptor
antagonist complex.

305.  During competitive antagonism, the dose-response curve shifts
to the right causing the drug to behave as if it were less potent.

306. Implications for the clinician......
a.The extent of inhibition depends on the antagonist’s
concentration.
Eg. Propranolol Vs drug clearance
b. The extent of inhibition depends upon the concentration of
the competing Agonist
Eg. Propranolol Vs endogenous [agonist]

307. Weak partial agonists are also competitive antagonists!

308. ii. NonCompetitive (Unsurmountable) antagonists
•The antagonist binds to the receptor at a site different
from that of the agonist.
•Antagonism cannot be overcome by increasing agonist
concentration (insurmountable).
•Non-competitive antagonists decrease the maximal
response.
•An example of non-competitive inhibition is the action of
ketamine at the NMDA receptor, where the agonist is
glutamate.

312. Irreversible antagonism
•Covalent bond is formed between an antagonist and a receptor.
•Irreversibly inactivate the receptor.
•The blockage is insurmountable.
•Shifts the dose-response curve to the right and decrease the
maximal response.
•The number of remaining unoccupied receptors may be too low
for even high concentrations of agonist to elicit a maximal
response.

314. Advantages of irreversible inhibitors
Once the receptor is occupied by antagonist, the inhibitor
need no longer be present in unbound form to inhibit the
effects of an agonist.
Thus the duration of action of such an inhibitor is
relatively independent of its rate of elimination and more
dependent on the rate of turnover of receptor molecules.

315. Disadvantages of irreversible inhibitors
Phenoxybenzamine, an irreversible –adrenoreceptor
antagonist, is used to control hypertension caused by
catecholamines released by tumors of the adrenal medulla
(pheochromocytoma).
Thus blockade can be maintained even during episodic
bursts of catecholamine release.
 If overdose occurs, however, –adrenoreceptor blockade
cannot be overcome by agonist.
The effects must be antagonized physiologically by using a
pressor agent that does not act via –adrenoreceptors (e.g.
angiotensin II, vasopressin).

316. Inverse agonists
•A drug with preferential affinity for R
i actually will
produce an effect opposite to that of an agonist.
•Examples of such inverse agonists at G protein-
coupled receptors (GPCRs) do exist (e.g., 

famotidine, losartan, metoprolol, and risperidone)

317. Shape of Dose response Curves
•While many drug dose response curves approximate
to the shape of Michaelis- Menten relationships (e.g.
A), some clinical responses do not.
•Extremely steep dose-response curves (e.g. B) may
have important clinical consequences if the upper
portion of the curves represents and undesirable
extent of response (e.g. coma caused by a sedative-
hypnotic).

318. 
Steep DR curves in patients could result from cooperative
interactions of several different actions of a drug (e.g. on heart, brain
and peripheral vessels – all contributing to lower blood pressure).
 Steep DR curves may also result from receptor effector systems
which require most receptors to be occupied before a response is
observed.

319. Graded and Quantal Dose Response Curves
i.Graded response
•Dose of a drug and response are related
proportionally. i.e. the more drug is given the more
response is achieved.
•There are infinite numbers of intermediate states.
•It is used to study response of a drug in an
individual.
•In this type of relationship, the X-axis of dose-
response curve represents dose of a drug and Y-axis
percent response.
•Examples include a change in heart rate or systemic
blood pressure.

320. ii. Quantal response
•an all or none phenomena
•It is used for population
•It is commonly employed to study toxicity of a drug.
•In this type of relationship, the X-axis of dose-response
curve represents log dose of a drug and Y-axis percent
responding.
•Examples include death, pregnancy, cure, pain relief,
liver toxicity, sleep induction etc

321. •The
quantal dose effect curve is
characterized
by the median
effective
dose (ED50) - the dose at
which
50% of individuals show the
specified
quantal effect.
•The
dose required to produce a
particular
toxic effect in 50% of
animals
is called the median toxic
dose
(TD50).
•If
the toxic effect is death of the
animal,
a median lethal dose
(LD50)
may be defined.

322. Therapeutic Index
•A parameter used to predict drug safety.
•It considers the dose required for a toxic effect versus that
required for the desired beneficial effect.
•In general, a larger T.I. indicates a clinically safer
drug
•Quantal dose effect curves permit an analysis of the margin of
safety (or selectivity in response) for a specific drug.
• In animal studies, the therapeutic index is defined as the ratio
of the TD50 to ED50.
•The therapeutic index in humans is never known with great
precision.

323. if TD50 = 500 mg and ED50 = 5 mg
T.I= ?

324. Receptor-Effector Coupling and Spare Receptors
•Agonist binding to a receptor and its binding-induced
receptor conformational change are normally only the
first of many steps required to produce a
pharmacological effect.
•e.g. contrast the actions of the nicotinic receptor
agonist acetylcholine with that of beta adrenergic
receptor agonist epinephrine.

325. 
Ach
binding to the AChR results in an instantaneous
opening
of the channel pathway and cation flow through
the
pore.

327. What is coupling??
•The transduction process between receptor occupancy
and drug response is termed coupling.
•The efficiency of coupling is partly determined by the
initial conformational change in the receptor.
Thus the effects of full agonists may be more
efficiently coupled to receptor occupancy than those
of partial agonists.
•However, coupling efficiency is also determined by the
biochemical events that transduce receptor occupancy
into cellular response.

328. •High efficiency coupling may also result from spare
receptors.
Spare receptors????
•Receptors may be considered spare when the maximal
response is elicited by an agonist at a concentration that
does not produce full occupancy of the available
receptors.
•Spare receptors are not different from “nonspare”
receptors. They are not hidden.
•When they are occupied they can be coupled to response.

330. How do we account for Spare Receptors?
•In some instances, the mechanism is understood and the
“spareness” of receptors is temporal.
•In other cases where the mechanisms are not understood, we
imagine the receptors are spare in number.

332. Receptor-desensitization
•Receptor-mediated responses to drugs and hormonal agonists
often desensitize with time.
• After reaching an initial high response, the effect diminishes
over seconds or minutes even in the continued presence of the
agonist.
•This desensitization is usually reversible.
• Thus several minutes after removal of the agonist, a second
exposure to agonist results in a similar response.
•desensitization, tachyphylaxis, refractoriness, resistance, and
tolerance

333. •In most instances, the molecular basis of
desensitization is unknown.
•Could be receptor-mediated or non-receptor-
mediated.
•Receptor mediated mechanisms include loss of
receptor function, reduction of receptor number etc.
•Non-receptor mediated mechanisms include reduction
of receptor-coupled signaling components, reduction
of drug concentration, physiological adaptation.

334. •Variations in response to the same dosage of a drug between
different patients and even in the same patient in different
occasions are common due to various factors.
•Dose is the appropriate amount of a drug needed to produce a
certain degree of response in a patient.
•Different Dose strategies adopted for different types of drugs
and conditions.
Factors modifying the dosage and
action of drugs

335. 1 . Standard dose
• The same dose is appropriate for most patients.
e.g. Penicillin, Chloroquine, Mebendazole
2. Regulated dose
•The Drug modifies a finely regulated body function which can
be easily measured.
e.g Anti-hypertensives, hypo-glycemics, anticoagulants,
diuretics, general Anaesthetics.
3. Target level dose
•The response is not easily measurable but has been demonstrated
to be obtained at a certain range of drug concentration in plasma.
•An empirical dose aimed at attaining the target level is given in
the beginning and adjustments are made later by actual
monitoring of plasma concentrations.

336. 4. Titrated dose
•The dose needed to produce maximal therapeutic effect cannot
be given because of intolerable adverse effects.
•Optimal dose is arrived at by titrating it with an acceptable
level of adverse effect.
•Low initial dose and upward titration (in most non-critical
situations) or high initial dose and downward titration (in
critical situations) can be practised.
e.g. Corticosteroids

337. The various factors are discussed below
1. Body weight:
• It influences the concentration of the drug attained at the site
of action.
•The average dose is mentioned either in terms of Mg per Kg
body weight or as a total single dose for an adult weighing
between 50-100 mg.
•For exceptionally obese or lean individuals and for children
dose may be calculated on body weight (BW) basis:
Body weight (Kg)
Individual dose = -------------- × average adult dose.
70

338. •It has been argued that body surface area (BSA)provides a
more accurate basis for dose calculation.
Surface area of patient (m
2)
x adult dose
1.8
•For children, the average dose may be calculated by Clark’s
formula.
Weight of child in pound
I) Child dose = --------------------------- × Adult dose
150
II) (Young’s Rule) Age
Child dose = ---------------- × Adult dose
Age + 12

339. 2. Age:
 The pharmacokinetics of many drugs change with age.
oThe liver capacity to metabolise drugs is low and liver function is
less developed in children.
o Like children old people also present problems in dosage
adjustment.
oThe metabolism of drugs may diminish in elderly and the renal
function declines with age.
3. Sex difference
oSpecial care should be taken when drugs are administered during
menstruation, pregnancy and lactation.
oGynaecomastia is a side effect of ketoconazole, Cimitidine that
can occur only in men.
oKetoconazole causes loss of libido in men but not in women.

340. 4. Genetics: - Genetically mediated variations in drug responses
is dealt in pharmacogenetics.
Eg. The rate of acetylation of INH, Dapsone, Hydralazine,
procainamide and some sulphonamides is controlled by genes
and the dosage of these drugs depends upon the acetylator
status of the individual.
5. Route of administration
•governs the speed and intensity of drug response.
•A drug may have entirely different uses through different
routes.
e.g. magnesium sulfate given orally cause : purgation, applied
on sprained joints-decrease: swelling, while intravenously it
produces CNS depression and hypotension.

341. 6. Environmental factors and time of administration
•Several environmental factors affect drug responses
Cigarette smoking
Meal ingestion and food
Time of administration
oHypnotics
oCorticosteroids

342. 7. Placebo
•This is an inert substance which is given in the garb of a medicine.

•It works by psychological rather than pharmacological means and
often produces responses equivalent to the active drug.
• Some individuals are more suggestible and easily respond to a
placebo‘ placebo reactors'.
8. Disease states: - Several diseases can influence drug action .
Eg. Gastro intestinal diseases, Liver diseases, Kidney diseases,
congestive heart failure etc.
 

343. 9. Drug tolerance: - The phenomenon in which the individual
develops resistance to the usual effect of the drug and the original
effect can be achieved by increasing the dose of the drug. Usually
it appears after chronic administration of the drug.
•Tolerance might be
i) Pharmacokinetic/ drug disposition tolerance
ii) Pharmacodynamic/ cellular tolerance
a) Natural-due to genetic variations.
Ratial tolerance- Negroes are tolerant to mydriatics.
Species tolerance- Rabits are tolerant to Atropine.(due to
presence of atropinase).
b) Acquired- Due to repeated administration of a drug. E.g.
 Barbiturates increase the metabolism of itself.
CNS depressant drugs –due to adaptation to the tissue.

344. •Cross tolerance → development of tolerance to pharmacologically
related drugs.
Eg. Alchol/ Barbiturates , Morphine /Pethidine.
10. Cumulation
•Any drug will cumulate in the body if rate of administration is more
than the rate of elimination.
•However, slowly eliminated drugs are particularly liable to cause
cumulative toxicity
e.g. prolonged use of chloroquine causes retinal damage.
Full loading dose of digoxin should not be given if patient has
received it within the past week.
11. Other drugs
•Drugs can modify the response to each other by pharmacokinetic or
pharmacodynamic interaction between them.

345. Drug-drug interaction
•Drug-drug interaction can be defined as the modulation of the
pharmacological activity of one drug by the prior or
concomitant administration of another drug.
• In these reactions, the activity of the drug(s) may be enhanced
or diminished.
•Mechanisms of drug-drug interactions are classified into two:
1. Pharmacokinetics interaction
2. Pharmacodynamics interaction

346. 1.Pharmacokinetics interaction
•The interaction occurs at the level of the four parameters of
pharmacokinetics.
i.e. one drug decrease or increase the ADME of
another drug.
a.Absorption
Eg. Antacids containing divalent ion such as Mg2+ and
Ca2+ decrease the absorption of Tetracycline.
Caffeine increases absorption of ergotamine

347. b. Distribution
e.g. Phenyl butazone has high affinity for plasma proteins
compared with warfarine.
Thus phenyl butazone displaces warfarine and causes its toxicity
c. Metabolism (biotransformation)

A drug can be:
i. enzyme inducer e.g. Phenytoin, Phenobarbitone, Rifampicin
ii. enzyme inhibitor e.g. Cimetidine
e.g. Phenobarbitone + Warfarine → decreased effect of warfarine
Cimetidine + Warfarine → increased effect of warfarine

348. d. Excretion
e.g. Probencid + Penicillin → enhanced effect of penicillin.
2. Pharmacodynamics interaction
the interaction may occur at receptor site or non-
receptor site.
e.g. antimuscarinics and antihistamines: both types of
drugs have the ability to block muscarinic receptor

349. Types of drug-drug interactions
1.Additive…the combined effect of two drugs is equal to the
sum of the effect of each drug.
2.Synergestic…the resulting effect is more than additive).
3.Potentiation…. the increased effect of an agent by an agent
which doesn’t have an effect if given alone.
4.Antagonism…the effect of one drug is diminished by
another drug.

350. Adverse Drug Reactions (ADRs)
•An adverse drug reaction is defined as any response
to a drug that is noxious and unintended and that
occurs at doses used in man for prophylaxis,
diagnosis or therapy.
•Adverse effects may develop promptly or only after
prolonged medication or even after stop of the drug.

351. 1.Side effects
• Pharmacological effects produced with a therapeutic
dose of the drug.
2. Secondary effects
•These are indirect consequences of a primary action of the
drug, e.g. suppression of bacterial flora by tetracyclines paves
the way for superinfections; corticosteroids weaken host
defence mechanisms so that latent tuberculosis gets activated.
3. Toxic effects
•These are the result of excessive pharmacological action of the
drug due to overdosage or prolonged use.
•Overdosage may be absolute (accidental, homicidal, suicidal)
•The effects are predictable and dose related.
•hepatic necrosis from paracetamol overdosage

352. 4. Drug intolerance
•The inability of an individual to tolerate a therapeutic dose of
drug.
•Single tablet of chloroquine may cause vomiting and
abdominal pain in an occasional patient.
5. Allergic Reaction
•It is an immunologically mediated reaction producing stereotype
symptoms which are unrelated to the pharmacodynamic profile
of the drug, generally occur even with much smaller doses and
have a different time course of onset and duration.
•These reactions may be mild or severe.

353. 6. Idiosyncratic reactions: -
• indicate one’s peculiar response to drugs.
•Many idiosyncratic reactions have been found to be genetically determined.
•E.g –premaquine, Deprosone, Sulfonamides Cause haemolysis in patients
with G-6pd enzyme deficiency
7 . Mutagenicity and Carcinogenicity
•It refers to capacity of a drug to cause genetic defects and cancer
respectively.
•Usually oxidation of the drug results in the production of reactive
intermediates which affect genes and may cause structural changes in the
chromosomes.
•Covalent interaction with DNA can modify it to induce mutations, which
may manifest as heritable defects in the next generation.

354. •If the modified DNA sequences code for factors that
regulate proliferation/ growth, a tumour (cancer) may be
produced
• Without interacting directly with DNA, certain chemicals
can promote malignant change in genetically damaged
cells.
•Chemical carcinogenesis generally take several (10-40)
years to develop. Drugs implicate in these adverse effects
are-anticancer drugs radioisotopes, estrogens, tobacco.

355. 8. Teratogenic effect:
Some drugs given in during pregnancy may cause congenital
abnormalities and are said to be teratogenic.
The most sensitive period of teratogenesis during pregnancy is
3-10 weeks of pregnancy i.e the time of organogenesis.
 Teratogenecity receives a great attention after thalidamide
disaster in 1959-61 in West Germany leading to large number
of cases of phocomelia (seal limbs).

356. •Eg.
Thalidomide
Phocomelia

358. Onset
Severity
Type
Classification

359. Onset of event:
•Acute
•within 60 minutes
•Sub-acute
•1 to 24 hours
•Latent
•> 2 days
Classification

360. Severity of reaction:
•Mild
•bothersome but requires no change in therapy
•Moderate
•requires change in therapy, additional
treatment, hospitalization
•Severe
•disabling or life-threatening
Classification - Severity

361. Classification-Severity
FDA Serious ADR
–Result in death
–Life-threatening
–Require hospitalization
–Prolong hospitalization
–Cause disability
–Cause congenital anomalies
–Require intervention to prevent permanent injury

362. •Type A
•extension of pharmacologic effect
•often predictable and dose dependent
•responsible for at least two-thirds of
ADRs
•e.g., propranolol and heart block,
anticholinergics and dry mouth
Classification

363. This Type of ADR can occur
•Beneficial and Toxic Effects Mediated by the Same
Receptor-Effector Mechanism
oeg, (bleeding caused by anticoagulant therapy;
hypoglycemic coma due to insulin)
•Beneficial and Toxic Effects Mediated by Identical
Receptors but in Different Tissues or by Different
Effector Pathways
omethotrexate, which inhibits the enzyme dihydrofolate
reductase; and glucocorticoid hormones.
•Beneficial and Toxic Effects Mediated by Different
Types of Receptors
oantihistamines, nicotinic and muscarinic blocking agents

364. •Type B
•idiosyncratic or immunologic reactions
•rare and unpredictable
•e.g., Chloramphenicol and Aplastic
anemia
Classification

365. •Type C
•Associated with long-term use
•Involves dose accumulation
•e.g., phenacetin and interstitial nephritis
or antimalarials and ocular toxicity
Classification

366. •Type D
•Delayed effects (dose independent)
•Carcinogenicity (e.g.,
immunosuppressants)
•Teratogenicity (e.g., fetal hydantoin
syndrome)
Classification

367. Types of allergic reactions
•Type I - immediate, anaphylactic (IgE)
•e.g., anaphylaxis with penicillins
•Type II - cytotoxic antibody (IgG, IgM)
•e.g., methyldopa and hemolytic anemia
•Type III - serum sickness (IgG, IgM)
•antigen-antibody complex
•e.g., procainamide-induced lupus
•Type IV - delayed hypersensitivity (T cell)
•e.g., contact dermatitis
Classification

368. Drug
Classes Commonly Reported as
Causes
of Adverse Reactions
Drug Class Examples of reported adverse reactions
Antimicrobial agents Diarrhea, rash, pruritus
Antineoplastics Bone marrow suppression,
alopecia, nausea and vomiting
Anticoagulants Hemorrhage, bruising
Cardiovascular drugs Heart block, arrhythmias, edema
Antihyperglycemics Hypoglycemia, diarrhea,
gastrointestinal discomfort
368

369. Drug Class Examples of reported adverse reactions
NSAIDs Gastrointestinal ulceration and
bleeding, renal insufficiency
Opiate analgesics Sedation, dizziness, constipation
Diuretics Hypokalemia, hyperuricemia,
hyperglycemia
Diagnostic agents Hypotension, nephrotoxicity, allergic
reactions
CNS agents Dizziness, drowsiness, headache,
hallucination, neuroleptic malignant
syndrome, serotonin syndrome
Drug
Classes Commonly Reported as
Causes
of Adverse Reactions
369

370. Body Systems Commonly Affected by
Adverse Drug Reactions
•Central nervous
system
• Cardiovascular
• Endocrine
•Gastrointestinal and
hepatic
•Renal and
genitourinary
•Hematologic
•Dermatologic
•Metabolic
•Musculoskeletal
•Respiratory
• Sensory
370

371. Angioedema
371
Antibiotics-penicillins, sulfa drugs, ACE inhibitors, NSAIDs,
COXII antagonists

372. SJS
372
Sulfonamides,
lamotrigine,
procaineamide

373. TEN(toxic
epidermal necrolysis)
while using valproic acid and
lamotrigine for epilepsy
373

374. Exanthematous drug eruption: ampicillin Symmetrically arranged, brightly
erythematous macules and papules, discrete in some areas and confluent in
others on the trunk and disretely on the extremities
374

375. Drug-induced urticaria and angioedema: penicillin Large,
urticarial wheals on the face, neck, and trunk with angioedema in
the periorbital region.
375

376. Acute allergic contact dermatitis on the
lips due to lipstick
376

377. Drug-induced pigmentation: amiodarone
377

378. Warfarin (Coumadin)–induced skin
necrosis on the lower abdomen
378

379. Warfarin induced necrosis
379

380. NEW DRUG DEVELOPMENT

381. Stages in new drug development
•Synthesis/isolation of the compound: (1-2 years)
• Preclinical studies: screening, evaluation, pharmacokinetic
and short-term toxicity:· testing in animals: (2-4 years)
•Scrutiny and grant of permission for clinical trials: (3-6
months)
• Pharmaceutical formulation, standardization of chemical/
biological/ immuno-assay of the compound: (0.5-1 year)
• Clinical studies: phase I, phase II, phase III trials; long-term
animal toxicity testing: (3-10 years)
• Review and grant of marketing permission: (0.5-2 years)
• Postmarketing surveillance: (phase IV studies)

382. Synthesis/isolation of the compound
•Synthesis of drug de novo
•Purification of drugs from natural sources such as
native, folklore or herbal medicines
•Modification of structure of existing drugs –
structure – activity studies (SAR)
•Exploration of side effects of existing drugs -
awareness of potential usefulness of side effects

383. Preclinical studies
•The goals of preclinical toxicity studies
include
o identifying potential human toxicities
odesigning tests to further define the toxic
mechanisms
opredicting the most relevant toxicities to be
monitored in clinical trials.

384. Animal Studies - Preclinical Studies
Acute toxicity tests
•One administration of chemical
to each animal
•Generation of dose – response
curves
•Appropriate Pharmacological
testing to determine ED50
•Develop analytical methods for
determining absorption,
excretion, distribution and
metabolism of chemical

385. Animal Studies - Preclinical Studies
Sub-chronic toxicity tests
•usually 60 –90 days
duration
•multiple administrations
or continuous exposure
via food or water to one
dose level of a chemical
per animal

386. Animal Studies - Preclinical Studies
•Chronic toxicity tests
–2 to 5 years duration depending on species
–multiple administrations or continuous exposure
via food or water to one dose level of a chemical
per animal

388. DEFINITION OF A NEW DRUG
•Any chemical or substance not previously used in humans for the
treatment of a disease
•Combinations of approved drugs or of old drugs even though the
individual components are not new drugs
•An approved drug employed for uses other than those approved
•Anew dosage form of an approved drug; and
•Even a drug used in vitro as a diagnostic agent when its uses will
influence the diagnosis or treatment of disease in a human patient

389. INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
•The IND submitted to the FDA contains the results of all
preclinical investigations carried out in animals, including
complete toxicity data, the full pharmacologic spectrum of the
drug and any studies of absorption, distribution,
biotransformation and excretion.
•In addition, the IND must provide the following information:

390. INVESTIGATIONAL NEW DRUG
APPLICATION (IND)
•Complete composition of the drug, its source and manufacturing data
with details of all quality control measures employed to ensure exact
reproducibility of manufacture and identification of all ingredients
•Specifications of the dosage forms to be given to humans
•A description of the investigations to be undertaken, including the
doses to be administered, the route and duration of drug
administration and the specific clinical observations and laboratory
observations to be performed
•The names and the qualifications of and the facilities available to,
each investigator who will participate in the initial studies (Phase I)

391. INVESTIGATIONAL NEW DRUG APPLICATION
(IND)
–Copies of all informational material supplied to each
investigator (the data sheets supplied to the investigator
incorporate the data supplied in the IND itself)
–An agreement from the sponsor to notify FDA and all
investigators of any adverse effects that arise during either
the continuing animal studies or human tests
–Agreement to submit annual progress reports
–Certification that "informed consent" will be obtained
from the subjects or patients to whom the drug will be
given

392. PHASE I STUDIES
•Requires an FDA approved IND to commence
•Conducted in normal healthy human volunteers
•Performed under carefully controlled conditions
• Toxicological and pharmacological data obtained by a
trained clinical pharmacologist
• Drug first administered at one tenth the ultimate projected
effective dose

393. •Primary objective is to obtain a safe and tolerated dose in
humans
•Parameters of absorption, metabolism and excretion are
measured
•The pharmacokinetic study relies on measurements of
levels of the test drug in blood and urine at various times
after administration (route usually oral)

394. PHASE II STUDIES
•Randomized control trials in patients with the disease for
which the drug is intended or as a pretreatment to prevent
disease
• Numbers of patients are limited, but may be up to several
hundred
•Doses are higher than those in Phase I
• Studies may last several months to two years

395. PHASE II STUDIES
•Safety still an important concern, but efficacy is the
major emphasis
•Flexibility in the design of studies is very desirable at
this stage
•Extremely slow metabolism of drug with accumulation
of subsequent doses and toxicity might require
additional studies at this point
•Changes in the original protocol require the submission
of amendments to IND and additional review by IRB’s

396. PHASE III STUDIES
• Large-scale controlled studies
•Major objective is to develop data to permit the drug to be
marketed and used safely and effectively
•Multi-patient – multi-center study
•May involve as many as 150 clinicians, many of whom are
experienced clinical pharmacologists
• Usually involves 1500 to as many as 4000 patients

397. PHASE III STUDIES
• Study generally lasts anywhere from 2 –10 years with an
average length of 5 years
•Study examines safety and effectiveness, but emphasizes
proper dose determination
•The following studies may be conducted at this stage:
–drug biotransformation
–capacity of drug to bind to plasma proteins
–to induce or inhibit enzymes
–to interact in various ways with other drugs

398. THE NEW DRUG APPLICATION (NDA)
 

•When the sponsor is convinced that the data obtained in Phase
III studies justify approval for safety and efficacy for the
use(s) intended, the NDA is submitted

•Usually, at least 5 years has elapsed since the drug was
originally screened
•The NDA contains all of the chemical, pharmacologic,
toxicologic., clinical and manufacturing data that have been
collected in the whole process
•The NDA also contains bioequivalence and bioavailability
data

399. THE NEW DRUG APPLICATION (NDA)
 

•Samples of the drug, its labels and the package insert
that will accompany the drug in all shipments to
physicians and pharmacies.
• Submission of the NDA starts a "review clock" in
which the FDA has 180 days to respond.
•The NDA submission generally occurs essentially
when the sponsor and FDA agree that studies are
complete. Thus the NDA is approved fairly
promptly

400. THE NEW DRUG APPLICATION (NDA )
 

•If the NDA is deemed for some reason to be
incomplete, the sponsor is required to resubmit
additional
•If there is a disagreement between FDA and the
sponsor then a hearing may be held and the outcome
is appealable in Court
• Less than 25% of all new drugs for marketing are
novel or new molecular entities (NME’s). The rest
are new salts, new formulations, new indications or
duplicates of drugs previously approved for
marketing
 

401. PHASE IV – POSTMARKETING
SURVEILLANCE
•Applies to all aspects of investigation following NDA
approval and general availability of drug in widespread
clinical use.
•Claims for safety and efficacy appearing or advertising are
reviewed and approved by FDA
• Reports concerning clinical studies must be sent to FDA:
–every three months during the first year
–every six months in the second year
–annually thereafter

402. PHASE IV – POSTMARKETING
SURVEILLANCE
•Reports must include the following information
about:
–quantity of drug distributed
–copies of mailing pieces and labeling
–examples of advertising for prescription drugs
• Immediate reports on unexpected side-effects, injury,
toxic or allergic reactions and failure of the drug to
exert its expected pharmacologic reaction

403. Thanks a lot!!