passive reabsorption Occurs by simple diffusion. Drugs should be in their non-ionized form to undergo passive reabsorption. Hence, polar drugs are more readily excreted through the kidneys. When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption decreases. When the urine is more alkaline, the degree of ionization of acidic drug increases and the reabsorption decreases.

1. 3. Passive reabsorption
• Occurs by simple diffusion.
• Drugs should be in their non-ionized form to
undergo passive reabsorption.
• Hence, polar drugs are more readily excreted
through the kidneys.
− When the urine is acidic, the degree of
ionization of basic drug increase and their
reabsorption decreases.
− When the urine is more alkaline, the degree of
ionization of acidic drug increases and the
reabsorption decreases.
15
1

2. Factors affecting excretion
of drugs
• Renal state
• Drug volume of distribution
• Degree of protein binding
• pH of the urine
• Competition for active tubular transport
• Age of the patient (elderly and neonates or
infants)
152

3. 3
Biliary Excretion
• The liver secretes about 1 L of bile daily.
• Drugs pass into bile through selective systems
with only few drugs crossing by diffusion.
• Most drugs secreted by the liver into the bile
are not reabsorbed.
• Once in the intestine, most are usually
passively reabsorbed that the drugs will
reenter the blood that perfuse the intestine and
again be carried to the liver (enterohepatic
recirculation).

4. 4
Ctnd…
• Mainly conjugated drugs are excreted.
• Conjugation (especially glucuronidation)
generally enhances biliary excretion since it
both:
 Introduces a strong polar (i.e., anionic)
center
 Increases its molecular weight
• Conjugated drugs are hydrolyzed by gut
enzymes such as -glucuronidase for
reabsorption.

5. 5
Ctnd…
• Hepatobiliary excretion is affected by
factors such as:
– Hepatic blood flow
– Rate of biotransformation
– Transport into bile
– Rate of bile formation
– Intestinal flora

6. 6
Pulmonary excretion
• Mainly for drugs that are volatile and gas
• The rate depends on blood solubility of the
drug, cardiac out put and respiratory rate.
– Eg; ethanol and NO

7. 7
Sweat and Saliva
 Excretion depends on the diffusion of un-ionized
lipid-soluble form across the epithelial cells of the
glands.
 Quantity excreted is determined by the pKa of the drug
and the pH of the secretions formed in the glands.
 Excretion into sweat may be responsible for the
skin reactions caused by some therapeutic agents
 Substances excreted into saliva are usually
swallowed.
 Excretion of drugs into saliva accounts for the drug
taste of certain compounds given by IV.

8. Excretion in Milk
• Concentration of drugs in milk depends on
many factors, including:
 amount of drug in the maternal blood
 lipid solubility of the drug
 the drug‘s degree of ionization
 the extent of its active excretion
• Milk is more acidic (pH 6.5) than plasma,
hence basic drugs are more concentrated
in this fluid.
15
8

9. Clearance
• The drug's rate of elimination (by all routes)
normalized to the concentration of drug C in
some biological fluid OR
• Volume per unit time freed of drug (volume of
fluid i.e. blood or plasma that would be
completely freed of drug to account for the
elimination)
9

10. 10
Ctnd…
• Clearance of a drug is the factor that
predicts the rate of elimination in relation to
the drug concentration.
• It is important to note the additive character
of clearance.
• Elimination of drug from the body may
involve processes occurring in the kidney,
liver, lung, and other organs.

11. Ctnd…
• Clearance is additive; a function of
elimination by all participating organs.
"Other" sites may include the lungs and
other sites of drug metabolism.
• The two most important sites for drug
elimination: kidneys and liver
11

12. Ctnd…
• It is not possible to measure and sum
these individual clearances.
• How-ever, total clearance can be derived
from the steady-state equation:
12

13. 13
Factors affecting clearance
– Renalfunction
– Hepaticfunction
– Cardiacoutput
– Blood flow rate: in heartfailure-clearance
declines
– Plasma proteinbinding

14. 14
Drug Half-Life
• Drug half-life is defined as the time required
for the amount of drug in the body to
decrease by 50%.
• The elimination of a drug usually follows
first-order kinetics.
– Concentration of drug in plasma drops
exponentially with time.
• This can be used to determine the half-life,
t½, of the drug.
t1/2 = ln 0.5/ke =0.693Vd/CL

15. 15
Drug Half-Life…
• Drug Half-Life is increased by:
1. Diminished renal plasma flow or hepatic blood
flow (HF)
2. Decreased ability to extract drug from plasma
(in renal disease)
3. Decreased metabolism (drug inhibits or in
hepatic insufficiency, as with cirrhosis)
• On the other hand, the half-life of a drug may
be decrease by:
1. Increased hepatic blood flow
2. Decreased protein binding, and
3. Increased metabolism

16. 16
Drug Half-Life…
• Drug half-life is important clinically in
indicating:
– Dosing interval or frequency of administration
– The time required to reach the steady state
concentration (4 or 5 t1/2)
– Estimate the time needed for complete
elimination of a drug from the body

17. TIME COURSE OF DRUG
RESPONSES
• To achieve the therapeutic objective, we must
control the time course of drug responses.
• We need to regulate the time:
– at which drug responses start
– they are most intense
– they cease
• The four pharmacokinetic processes are the
major determinants of the time course over
which drug responses take place.
167

18. Figure: Relation between pharmacokinetics and pharmacodynamics.
18

19. 19
Plasma Drug Levels
• In most cases, the time course of drug action
bears a direct relationship to the
concentration of a drug in the blood.
• Clinical Significance of Plasma Drug
Levels:
– For most drugs, there is usually direct correlation
between therapeutic and toxic responses and
plasma drug levels.

20. 20
Ctnd…
• Two Plasma Drug Levels Defined:
–Two plasma drug levels are of special
importance:
1. The minimum effective concentration
(MEC): plasma drug level below which
therapeutic effects will not occur
2. The toxic concentration: the plasma
level at which toxic effects begin

21. Ctnd…
• Therapeutic Range
– Is a range of plasma drug levels, falling between
the MEC and the toxic concentration.
– The objective of drug dosing is to maintain
plasma drug levels within the therapeutic range.
– The width of the therapeutic range is a major
determinant of the ease with which a drug can
be used safely.
• Drugs that have a narrow therapeutic range are
difficult to administer safely.
• Conversely, drugs that have a wide therapeutic
range can be administered safely with relative
ease. 17
1

22. a. Single-Dose Time Course
• Plasma drug levels change over time after a
single dose of an oral medication.
– Drug levels rise as the medicine undergoes
absorption.
– Drug levels then decline as metabolism and
excretion eliminate the drug from the body.
– There is a period of latency between drug
administration and onset of effects.
– The extent of this delay is determined by the rate
of absorption.
172

23. Single-Dose…
– The duration of effects is determined largely by
the combination of metabolism and excretion.
– When levels fall below the MEC, responses will
cease.
– Metabolism and excretion are the primary
determinants of how long drug effects will
persist.
17
3

24. 17
4
Figure: Single-dose time course

25. 25
b. Drug Levels Produced with
Repeated Doses
– Multiple dosing leads to drugaccumulation.
• The Process by Which Plateau Drug
Levels Are Achieved
– Administering repeated doses will cause a drug to
build up in the body until a plateau (steady level)
has been achieved.
– When the amount of drug eliminated between
doses equals the dose administered, average
drug levels will remain constant and plateau will
have been reached.

26. Figure: Drug accumulation with repeated administration.
26

27. Repeated Doses…
• Time to Plateau
– When a drug is administered repeatedly in the
same dose, plateau will be reached in
approximately four half-lives.
– As long as dosage remains constant, the time
required to reach plateau is independent of
dosage size.
17

28. 28
Repeated Doses…
• Techniques for Reducing
Fluctuations in Drug Levels
–When a drug is administered repeatedly,
its level will fluctuate between doses.
• The peaks must be kept below the toxic
concentration.
• The troughs must be kept above the
MEC.

29. 29
Repeated Doses…
–Three techniques can be employed to
reduce fluctuations in drug levels.
• Administer drugs by continuous infusion.
• Administer a depot preparation, which
releases the drug slowly and steadily.
• Reduce the size of each dose and the
dosing interval (keeping the total daily
dose constant).

30. Repeated Doses…
• Loading Dose
– When plateau must be achieved quickly, a
large initial dose called loading dose can be
administered.
• Maintenance Doses
– Plateau level can be maintained by giving
smaller doses.
– These smaller doses are referred to as
maintenance doses.
30

31. Repeated Doses…
• Decline from Plateau
– When drug administration is discontinued,
most (94%) of the drug in the body will be
eliminated over an interval equal to about four
half-lives.
– The time required for drugs to leave the body
is important when toxicity develops.
– NB: The concept of half-life does not apply to
the elimination of all drugs.
• A few agents, most notably ethanol (alcohol),
leave the body at a constant rate, regardless of
how much is present.
18

32. Kinetics of fixed-dose/fixed-time-
interval regimens
• Multiple IV injections:
– When a drug is given repeatedly at regular
intervals, the Cp increases until a Css is
reached.
– Some drug from the first dose remains in
the body at the time that the second dose is
administered, and some from the second
dose remains at the time that the third dose
is given, and so forth.
182

33. Ctnd…
− Therefore, the drug
accumulates until the rate
of drug loss exactly
balances the rate of drug
administration, i.e., until a
steady state is achieved.
18
3
Figure: Predicted plasma concentrations of a drug given by infusion
(A), twice-daily injection (B), or once-daily injection (C).

34. Orally administered drugs:
• Orally administered drugs
may be absorbed slowly, and
Cp of the drug is influenced
by both the rate of:
– absorption
– elimination
Figure: Predicted plasma concentrations of a
drug given by repeated oral administrations.
18

35. Ctnd…
• This relationship can be expressed as:
F = the fraction absorbed (bioavailability)
T = dosage interval
35

36. 36
Kinetics of Continuous
Administration
• Assume that the administered drug
distributes into a single body compartment.
Kinetics of IV infusion
• With continuous IV infusion, the rate of drug
entry into the body is constant.
• In the majority of cases, the elimination of a
drug is first order.

37. 37
Steady-state drug levels in blood
• The plasma concentration of drug rises
until the rate of drug eliminated from the
body precisely balances the input rate.
• Thus, a steady-state is achieved in which
the plasma concentration of drug remains
constant.
• Note: The rate of drug elimination from the
body = (CLt)(C), where CLt = total body
clearance and C = the plasma
concentration of drug.

38. Influence of the rate of drug infusion
on the steady state:
Where, Css = the steady-state concentration
Ro = the infusion rate
ke = the first-order elimination rate constant
Vd = the volume of distribution
• Because ke, CLt, and Vd are constant for
most drugs showing first-order kinetics, Css
is directly proportional to Ro.
38

39. Time required to reach the steady-
state drug concentration:
• The concentration of drug rises from zero
at the start of the infusion to its ultimate
steady-state level, Css.
• The fractional rate of approach to a steady
state is achieved by a first-order process.
– Exponential approach to steady state: The
rate constant for attainment of steady state is
the rate constant for total body elimination of
the drug, ke.
18

40. 40
Ctnd…
– Thus, 50% of the final Css is observed after the
time elapsed since the infusion, t, is equal to t1/2.
– Waiting another half-life allows the drug
concentration to approach 75% of Css.
– The drug concentration is ninety percent of the
final steady-state concentration in 3.3 times t1/2.
– For convenience, therefore, one can assume that
a drug will reach steady-state in about four half-
lives.

41. Ctnd…
• The time required to reach a specific
fraction of the steady-state is described by:
where, f = the fractional shift and t = the time
elapsed since the start of the infusion.
41

42. 42
Effect of the rate of drug infusion on
the time to achieve Css
• The sole determinant of the rate that a drug
approaches steady state is the t1/2 or ke.
– The rate of approach to steady state is not
affected by the rate of drug infusion.
• The rate of infusion does not influence the
time required to reach the ultimate steady-
state concentration.
• This is because the steady-state
concentration of drug rises directly with the
infusion rate.

43. Rate of drug decline when the
infusion is stopped
• When the infusion is stopped, the plasma
concentration of a drug declines to zero with
the same time course required steady state.
• This relationship is expressed as:
Where, Ct = the plasma concentration at any time
Co = the starting plasma concentration
ke = the first-order elimination rate constant
t = the time elapsed
43

44. 44
Routes of Drug Administration
• Are path ways (routes) through which a drug
is administered into the body.
• Drugs are administered for either their action
in the locality of their administration or for
general systemic purpose.
• Many factors dictate the route the drug should
be administered.

45. 19
5
Factors to be considered in selecting
the route of drug administration
• Drug related factors (nature of the drug/
physicochemical properties of the drug)
• Patient related factors (patient condition)
• Onset of action we need
Quick response (for sever problems)
Delayed (slow) response (for mild problems)
• The desired effect: Local effect or systemic
effect (usually oral or intravenous routes are
used for systemic effect)
• The route of administration determines onset
and duration of action of drugs.

46. a. Oral route (PO)
• Drug is swallowed with adequate water (pure
water) through the mouth.
• It is the most common route of drug
administration.
• It is the simplest, safest and most
economical route of administration for
systemic effect.
• Reversal of overdose is possible by using
emesis, gastric lavage and adsorption by
activated charcoal.
46

47. 47
Advantages
• Administration is easy, convenient and
inexpensive
• Does not require maximal sterility
• Large volume may be given
• Relatively safe
• Limit the number of systemic infections
that could complicate treatment

48. 48
Disadvantages
• The onset of drug action is relatively slow.
• High variability of absorption (irregular absorption)
• Drugs can be destroyed (inactivated) by enzymes,
gastric acid (penicillin G) and micro-flora.
– e.g., insulin degraded by enzymes
• Requires compliance
• Not suitable for vomiting or unconscious
patients and uncooperative patients
• Local irritation
• First pass effect: in GI and liver first-pass
metabolism leading to decrease in
bioavailability

49. 49
First-pass Metabolism
• Drugs taken orally are first taken to liver
(via portal circulation) where they are
metabolized before reaching to rest of the
body.
– The amount reaching systemic circulation is
less than the amount absorbed.
• Results?
– Low bioavailability → low serum level of active
drug that can produce action

50. 20

51. b. Sublingual route
• Place the pill or direct spray between the
underside of the tongue and the floor of the
oral cavity.
– Allows a drug to diffuse into the capillary
network & enter the systemic circulation
directly
• Administration of an agent, sublingually, has
several advantages.
– rapid absorption
– convenience of administration
– low incidence of infection
– avoidance of the harsh GI environment
– avoidance of first-pass metabolism 51

52. 52
Advantages Disadvantages
 Rapid effect: can be used in
emergency
 High bioavailability
 No first pass effect
 No GIT irritation
 No food-drug interaction
Not for
- Irritant drugs
- Frequent use
Sublingual…
Dosage form: friable tablet

53. c. Buccal route
• Place the medication between the
patient‘s cheek and gum.
53

54. d. Parenteral route
 P a r = beyond and enteral = intestine
 D r u g directly introduced into tissue fluids
or blood without having to cross the
intestinal mucosa.
 S u i t a b l e :
– Drugs poorly absorbed from the GI tract, eg,
heparin.
– Agents that are unstable in the GI tract, eg,
insulin
– Treatment of unconscious patients
– Under circumstances that require a rapid
onset of action
20

55. 55
Parenteral…
• Not subjected to first-pass metabolism or
harsh GI environments
• Provides the most control over the actual
dose of drug delivered to the body
• These administrations are irreversible an
may cause:
–Pain
–Fear
–Local tissue damage
–Infections

56. • The parenteral route includes:
– Intravenous (I.V.) (into veins)
– Subcutaneous (S.C.) (under skin)
– Intramuscular (I.M.) (into muscles)
– Intradermal (I.D.) (into skin)
– Intra-arterial (I.A.) (into arteries)
– Intrathecal (I.T.) (cerebrospinal fluids )
– Intraperitoneal (I.P.) (peritoneal cavity)
– Intra-articular (Synovial fluids)
56
Parenteral…

57. Intravenous (IV) route
• Drug is administered through superficial veins.
• The most common parenteral route
• Only aqueous solutions can be injected
• Dose required is smallest as bioavailability is 100%.
57

58. 58
Advantages
• Rapid onset of action (for emergency conditions)
• Absorption is instantaneous and complete; 100%
bioavailability and rapid onset
• Avoids first-pass metabolism
• Precise control over plasma drug levels is
possible.
• Used for irritating & bad taste drugs
• Administration of large volume of drug (infusion)
• Suitable for vomiting & unconscious patients
• No food-drug interaction
• No gastric irritation

59. • only for water soluble drugs
59
Disadvantages
• high cost
• needs skill
• sterilization
• we cannot reverse injection
• could cause fluid overload
• increased risk of infection and embolism and
chance of error
• pain during injection
• hemolysis or cause other adverse reactions
• self medication is not possible
• needs accurate dose calculation

60. Intramuscular (IM) route
• Drug is injected in one of the large skeletal
muscles: deltoid, triceps, gluteus maximus,
rectus femoris etc…
• Drugs can be:
– in aqueous solutions which are absorbed rapidly
OR
– in specialized depot preparations which are
absorbed slowly
• Often consist of a suspension of the drug in a
nonaqueous vehicle such as polyethylene
glycol.
21

61. 61
Intramuscular...
• vehicle diffuses out of the muscle
• the drug precipitates at the site of injection
• then dissolves slowly, providing a sustained
dose over an extended period of time
–Examples of sustained-release drugs are
haloperidol and depot
medroxyprogesterone.
• These drugs produce extended neuroleptic
and contraceptive effects, respectively.

62. Advantages
• Only barrier is capillary
wall.
• Used for:
– poorly soluble drugs
– depot preparations to
decrease number of
injections
Disadvantage
• Inconvenience;
discomfort with
administration
62

63. Subcutaneous (SC) route
• Drug is injected under the skin in the subcutaneous
tissue.
• Almost identical to IM for advantages and
disadvantages
• Requires absorption via simple diffusion and is
somewhat slower than the IV route.
• Minimizes the risks of hemolysis or thrombosis
associated with IV injection
• May provide constant, slow, and sustained effects
• Should not be used with drugs that cause tissue
irritation, because severe pain and necrosis may
occur
21

64. Subcutaneous…
 S e l f injection is simple
 O i l y solution or a
q
u
e
o
u
s
suspensions can be
injected for prolonged
action.
Epinephrine is sometimes
combined with a drug
administered
subcutaneously (eg, with
lidocaine) to restrict its
area of action.
64

65. 65
Intrathecal
• BBB typically delays or prevents the
absorption of drugs into the central nervous
system (CNS)
– When local, rapid effects are needed, it is
necessary to introduce drugs directly into the
cerebrospinal fluid.
– For example, intrathecal amphotericin B is used
in treating cryptococcal meningitis.

66. 66
e. Rectal route
• Application or insertion of a drug into the
rectum.
− Commonly used to administer antiemetic agents
• Fifty percent of the drainage bypasses the
portal circulation.
• Biotransformation of drugs by the liver is
minimized.
• Used for both local and systemic effect

67. 67
Advantages
• Suitable for vomiting patients, unconscious
patients and uncooperative patients for the
oral route
• Prevent the destruction of the drug by intestinal
enzymes or by low pH in the stomach
• Reduces first pass effect (at least by 50%)
Disadvantage
• Unreliable absorption (absorption is often erratic
and incomplete)
• Many drugs irritate the rectal mucosa
• Less convenient than the oral route

68. 68
f. Vaginal route
• Drugs are applied (inserted) into the
vagina.
• Used for local or systemic effect.
– Usually used for the treatment of local
ailments
• Some drugs are absorbed well; can be
used for systemic application.

69. 69
Problems associated with vaginal
route of drug administration
Inconstant hormonal influence in the
epithelium (vaginal fluid may be thick or thin)
Problem of personal hygiene
Influence of sexual inter course
• Male semen is alkaline and may increase the pH
of the vagina and hence affecting drug
absorption.

70. 70
g. Topical routes
• Drugs are applied to skin, ear, eye, nose,
vagina, respiratory tract
• Usually used to provide local action
• No first pass metabolism

71. 71
Skin (dermal, transdermal)
• Dermal:
– Cream, ointment (local action)
• Transdermal:
– Absorption of drug through skin (i.e. systemic
action)
– Achieves systemic effects by application of drugs
to the skin, usually via a transdermal patch
Stable blood levels(controlled drug delivery system)
No first-pass metabolism
Drug must be potent or patch becomes too large

72. Ctnd
…
• The rate of absorption can
vary markedly depending on:
– the physical characteristics of
the skin at the site of application
– the lipid solubility of the drug
• Often used for the sustained
delivery of drugs.
– nitroglycerin
– scopolamine
– nicotine transdermal patches
72

73. Eye drop administration
• Use a medication dropper to place the
prescribed dosage on the conjunctival sac.
73

74. Nasal medication administration
74

75. Aural medication administration
• Manually open the ear canal and administer
the appropriate dose.
75

76. 76
h. Inhalational route
• Drug is inhaled through the mouth or nose
for local effect in respiratory tract or for
systemic effect.
• It is used usually for local effect.
• Oral inhalation:
– Provides rapid delivery of a drug across the
large surface area of the mucous
membranes of the respiratory tract and
pulmonary epithelium
– Produces an effect almost as rapidly as
does IV injection

77. 77
Inhalational…
– Used for drugs that are gases for example,
some anesthetics and those that can be
dispersed in an aerosol
– Effective and convenient for patients with
respiratory complaints such as asthma or
chronic obstructive pulmonary disease
– The drug is delivered directly to the site of
action, thereby minimizing systemic side
effects
– Examples: bronchodilators, such as albuterol,
and corticosteroids, such as fluticasone

78. 78
Inhalational…
• Nasal inhalation:
–Involves administration of drugs directly
into the nose
• Nasal decongestants, such as oxymetazoline
• Anti-inflammatory corticosteroids such as
mometasone furoate
• Desmopressin in the treatment of diabetes
insipidus
• Salmon calcitonin, a peptide hormone used
in the treatment of osteoporosis

79. 79
Advantages Disadvantages
Rapid absorption (large surface
area)
Provide local action in
limited systemic effect
 less side effects
 no first pass effect
Not suitable for
irritant drugs
Only for some
drugs as inhalation
anesthetics &
bronchodilators
Inhalational…
Dosage form: aerosol, nebulizer

80. 80
3. Pharmacodynamics
Objectives
• At the end of this chapter the students will be
able to:
– define terminologies
– explain mechanism of drug interaction with its action
site
– define receptors and ligands
– explain the important practical consequences of the
receptor concept
– describe macromolecular nature of receptors
– explain mechanisms of drug action
– classify antagonists
– describe the dose response curves

81. 81
Pharmacodynamics…
• Pharmacodynamics is the study of the
biochemical and physiological effects of
drugs and the molecular mechanisms by
which these effects are produced.
– It is the study of what drugs do to the body and
how they do it.
• Drugs interact with receptors to produce
their characteristic effects.
– Receptors are functional macromolecular
components of the organism.

82. Pharmacodynamics…
• Drugs potentially are capable of altering
both the extent and rate at which any
bodily function proceeds.
• Drugs do not create effects but instead
modulate intrinsic physiological functions.
23
2

83. Receptors
• What are receptors?
– Are mainly macromolecules whose function is
to recognize and respond to endogenous
chemicals and xenobiotics.
– Are sites where drugs interact to produce their
effect
– Therapeutic and toxic effects of drugs result
from their interactions with molecules in the
patient.
– A molecule which binds (attaches) to a
receptor is called a ligand.
– There are drugs which don‘t need receptors to
produce an action, eg, antacids.
23

84. 84
Receptors…
• Receptors have become the central focus
of investigation of drug effects and their
mechanisms of action.
– Many drug receptors have been isolated and
characterized in detail.
– This open the way to precise understanding of
the molecular basis of drug action.

85. 85
Receptors…
• The receptor concept has important
practical consequences for:
→the development of drugs and
→arriving at therapeutic decisions in
clinical practice
• These consequences form the basis for
understanding the actions and clinical uses
of drugs.
• They may be briefly summarized as
follows.

86. 86
Receptors…
1. Receptors largely determine the
quantitative relations between dose or
concentration of drug and pharmacologic
effects.
2. Receptors are responsible for selectivity
of drug action.
3. Receptors mediate the actions of both
pharmacologic agonists and antagonists.

87. 23
7
Macromolecular Nature of Drug
Receptors
• Most receptors are proteins.
• The best-characterized drug receptors are
regulatory proteins
– This class of receptors mediates the effects of
many of the most useful therapeutic agents.
• Other classes of proteins that have been
clearly identified as drug receptors include:
enzymes (eg, Cholinesterase, DNA polynmerase)
transport proteins (eg, Na+/K+-ATPase)
structural proteins (eg, tubulin)

88. Table: Drug Receptors
88

89. 89
Mechanism of drug actions
• Refers to the specific biochemical
interaction through which a drug substance
produces its pharmacological effect.
• Usually includes mention of the specific
molecular targets to which the drug binds.
• A drug can produce action in the following
ways.

90. Mechanism of drug actions...
1. By physical means
– Osmotic action, eg, osmotic diuretics
– Adsorption, eg, kaolin and activated charcoal act
as antidiarrheal as they adsorb toxins
2. Through chemical reaction, eg, Antacids,
Protamine
3. By targeting specific cellular
macromolecules
– Transport systems (Ion channels, Carrier
molecules)
– Enzymes: By acting as a false substrate for the
enzyme/By inhibiting enzyme activity
– Receptors: Act by combining with their receptors.
240

91. Drug-Receptor Interactions
• Receptors are any functional
macromolecules in a cell to which
a drug binds.
− Drug + receptor
complex
Drug-receptor
response
• Under normal conditions, receptor activity is
regulated by endogenous compounds (NTs,
hormones)
• Drugs can mimic or block the actions of
EDCs
91

92. 92
Theories of drug-receptor
interactions
• There are three main theories:
I. Occupancy theory
II. Rate theory
III. Allosteric theory

93. I. Occupancy theory
a. Simple Occupancy Theory
• States that:
– The intensity of response to a drug is
proportional to the number of receptors
occupied.
– Maximum response will occur when all
available receptors have been occupied.
• Limitations:
– Does not explain:
• why one drug be more potent than another
• how one drug can have higher maximal
efficacy than another
24
3

94. 94
Occupancy theory…
a. Modified Occupancy Theory
– Ascribes two qualities to drugs:
1. Affinity: the strength of attraction between a
drug and its receptor
– High affinity stronglyattracted
– Low affinity weaklyattracted
– Drugs with high affinity are verypotent

95. 95
Occupancy theory…
2. Intrinsic activity: the ability of a drug
to activate a receptor
– Drugs with high intrinsic activity cause
intense receptor activation.
– Reflected in its maximal efficacy
– Two drugs may occupy the same
number of receptors but produce effects
of different intensity.

96. 96
II. Rate Theory
• Postulated that the biological response is
proportional to the rate at which the drug combines
with the receptor.
– This implies that an agonist must dissociate rapidly
from the receptor to enable other successful
associations and subsequent generation of quanta of
excitation.
• An antagonist is assumed to dissociate slowly to
prevent the generation of other quanta of excitation.
• Dissociation rate constant is the factor which
determines whether a drug is an agonist, antagonist
or partial agonist (according to the rate theory).

97. 97
III. Allosteric theory
• Receptors can exist in a variety of discrete
conformational states differing in the ability of that
state to produce a response.
• MWC model, 1965, assumes that conformational
states exist independently of the drug and that the
drug simply controls in which conformational state
the receptor exists.
– A drug acts as an agonist, antagonist, or partial agonist
depending upon its affinity for active or inactive states.
• KNF model, 1966, ―thedrug can induce new
conformational states in the receptor‖.
– A drug acts as an agonist, antagonist, or partial agonist
based on its ability to induce conformational states that
are active or inactive.‖

98. 98
TYPES OF RECEPTORS
• Generally, receptors are classified into 4
classes (based on structure & signal
transduction mechanism).
a. Ligand-gated ion channels
b. G-protein coupled receptors (GPCRs)
c. Kinase linked receptors
d. Intracellular receptors

99. Figure: Transmembrane signaling
mechanisms.
99

100. 100
a. Ligand-and voltage gated ion
channels
• Drugs that bind to ligand-gated ion channels
alter the conductance of ions through the
channel protein.
• Mediate the actions of fast neurotransmitters,
eg, nAChR, GABAAreceptor
• They are involved mainly in fast synaptic
transmission.
• Ligand binding and channel opening occur on a
millisecond time scale.
• Many important drugs act by either mimicking
or blocking the actions of endogenous ligands
that regulate ion channels.

101. 101

102. 102
Ctnd…
• Voltage-gated ion channels do not bind
ligands directly but are controlled by
membrane potential; such channels
are also important drug targets.
– For example, verapamil inhibits voltage-gated
calcium channels that are present in the heart
and in vascular smooth muscle.

103. 103
b. G-protein coupled receptors
• GPCRs traverse plasma membrane 7
times (serpentine receptors)
• Are cell surface receptors
• Receptors for >50% of clinically used
drugs
• Intracellularly, they are coupled to G-
proteins
• G-proteins have 3 subunits α, β and 
subunits.
– G-proteins regulate down stream proteins.

104. 104

105. 105
G-protein coupled…
• Agonist binding to the GPCR leads to
conformational change in the receptor.
– Results in the interaction of receptors with G-
proteins
• When GPCRs bind with their agonists
– Conformational change in the GPCRs
– Binding of G-protein with the GPCRs
– Dissociation of the α subunit from the β complex

106. 106
G-protein coupled…
– α subunit diffuses & activates/inhibits effector
systems
– Effector systems of the GPCRs could be:
• Adenylate cyclase: the enzyme responsible
for cAMP formation
• Phospholipase C: the enzyme responsible
for inositol triphosphate and diacylglycerol
formation
• Ion channels: particularly calcium and
potassium channels.

107. 107
G-protein coupled…
• The adenylate cyclase/cAMP system
– cAMP is synthesized within cells from ATP by the
action of adenylate cyclase.
– cAMP regulates the activity of protein kinases
which in turn regulate many aspects of cellular
function including, for example, enzymes
involved in:
• energy metabolism
• cell division and cell differentiation
• ion transport; ion channels
• the contractile proteins in smooth muscle.

108. AC
108
Drug
outside
GPCR plasma
membrane
ATP cAMP + PPi
cytosol
 
GDP 
GTP GDP
  
 GTP

109. 109

110. G-protein coupled…
• The Phospholipase C/Inositol Phosphate
System
– PIP2 is the substrate for enzyme PLC, which splits
it into diacylglycerol (DAG) and inositol 1,4,5-
trisphosphate (IP3).
– IP3 binds to the IP3 receptor on ligand-gated
calcium channel present on the membrane of the
endoplasmic reticulum and cause release of Ca2+
to the cytosol.
– The main effect of DAG is to activate a membrane-
bound protein kinase, protein kinase C (PKC),
which catalyses the phosphorylation of a variety of
intracellular proteins. 26
0

111. 111

112. 112

113. 113
G-protein coupled…
• Ion Channels as Targets for G-proteins
– GPCRs can control ion channel function
directly by mechanisms that do not involve
second messengers such as cAMP or IP3.
– These actions are produced by direct
interaction between the G-protein subunit (βγ
subunit) and the channel, without the
involvement of second messengers.

114. 114
c. Kinase-linked receptors
• Responds to protein mediators.
• Comprise an extracellular ligand-binding
domain linked to an enzymatic intracellular
domain by a single transmembrane helix.
• Activation involves dimerization of receptors,
followed by autophosphorylation of tyrosine
residues.
• The phosphotyrosine residues act as acceptors
for a variety of intracellular proteins, thereby
allowing control of many cell functions.

115. 115
Kinase-linked…
• The enzymatic activity could be protein
kinase or guanylate cyclase.
• Includes receptors for insulin and various
cytokines and growth factors (protein
kinase), atrial natriuretic factor (guanylate
cyclase).

116. 116

117. 117
d. Nuclear Receptors
• Ligands include steroid hormones, thyroid
hormones, vitamin D and retinoic acid.
• Receptors are intracellular proteins, so ligands
must first enter cells.
• Receptors consist of a conserved DNA-binding
domain attached to variable ligand-binding and
transcriptional control domains.
• DNA-binding domain recognizes specific base
sequences, thus promoting or repressing
particular gene expression.

118. 118
• Effects are produced as a result of altered protein
synthesis and, therefore, are slow in onset.
• The time course of activation and response of
these receptors is much longer than that
of the other mechanisms.
Nuclear Receptors…

119. 26
9
Intra cellular

120. 120
Terms in drug receptor
interaction
• Affinity: the ability of drug to bind with receptor
• Agonists: are drugs that bind to and activate
the receptor, which will bring about the
pharmacological effect
– Affinity with intrinsic activity
• Intrinsic activity: is the natural ability of the
drug to produce an effect

121. 121
Ctnd
…
• Full Agonists: are drugs that can activate the
receptor-effector system to the maximum
extent
– Produces the maximal pharmacologic effect at
its receptor-effector system.
• Partial Agonists: are drugs that bind and activate
the receptor; however, the evoked response is not
as high as a ‗full‘ agonist.
– May act as either an ‗agonist‘ or as an
‗antagonist‘???
– Have affinity but less intrinsic activity

122. 122
Ctnd
…
• Inverse Agonists: are drugs that bind to the
receptor and stabilize it in its inactive
(nonfunctional) conformation
– Generates effects that are the opposite of the
effects produced by conventional agonists at
the receptor.
• Antagonist: drugs bind with receptor, but
don‘t have an effect by itself
– So, they have affinity but not intrinsic
activity
– Zero intrinsic activity

123. 123
Receptor Regulation
• Receptors are dynamic components of the
cell.
• In response to continuous activation or
continuous inhibition, the number of
receptors on the cell surface can be
changed.
• They exist in a dynamic equilibrium.
– Being synthesized inside the cell, inserted into
the cell membranes, sequestered out of the
membranes, and degraded at various rates.

124. 124
Receptor regulation…
• Receptors are dynamically regulated in
number, location and sensitivity.
• These changes are usually referred to as
‗up-regulation‘ or ‗down-regulation‘ of the
receptor.
• Regulatory changes can occur over short
times (minutes) and longer periods
(days).

125. Receptor regulation…
1. Desensitization
• Occurs following frequent or continuous
exposure of the receptor to the agonist over a
short period of time.
• It is a rapid and reversible process that
desensitizes the tissue to further receptor-
agonist interaction for only a few minutes.
• Following desensitization, the conformational
equilibrium of the receptor molecule is restored
and the cells recover full responsiveness to the
agonist.
• Mechanism of desensitization for many receptors
– Not known……….??? 27
5

126. 126
Receptor regulation…
2. Internalization
• Occurs following frequent or continuous
exposure of the receptor to the agonist
over a relatively short period of time
(minutes to hours).
• In this particular process, receptor
molecules are recycled intact to the
plasma membrane via endocytic vesicles.

127. 127
Receptor regulation…
3. Down-Regulation
• Is another important process that regulates
receptor-mediated responses.
• It occurs only after prolonged or repeated
exposure of cells to the agonist over a long
period of time (hours to days).
• Down-regulation decreases the number of
receptor molecules present in the cell or tissue.
• It is a much slower process than rapid
desensitization and is less readily reversible.

128. 128
Receptor regulation…
• Down-regulation may cause relative tolerance
to the effects of an agonist drug in some patients
• Tolerance refers to a decrease in the intensity
of the response to a given dose of a
drug????????
4. Up-Regulation
• Occurs when receptor activation is blocked
for prolonged periods of time (usually
several days)
– By pharmacologic antagonists or by
denervation

129. 129
Agonists, Antagonists, Partial
Agonists, Inverse Agonists
1. Agonists
• They are drugs that can mimic the body's
own regulatory molecules
• They have both affinity and intrinsic activity
2. Antagonists
• Prevent receptor activation by endogenous
regulatory molecules or drugs
• Are drugs with affinity for a receptor but with
no intrinsic activity

130. Figure: Antagonist
classification.
130

131. a. Competitive antagonists
• Compete with agonists in a reversible fashion for the
same receptor site
• When the antagonist is present, the log-dose
response curve is shifted to the right.
– Results in a parallel shift of the dose-response curve.
b. Non-competitive receptorantagonists
• Can bind to either the active site or an allosteric
site of a receptor.
• A noncompetitive antagonist that binds to the
active site of a receptor can bind either
covalently or with very high affinity;
– In either case, the binding is effectively
irreversible 281

132. 132
Ctnd…
– Because an irreversibly bound active site
antagonist cannot be ―out-competed,‖even at high
agonist concentrations, such an antagonist
exhibits noncompetitive antagonism.
• A noncompetitive allosteric antagonist acts by
preventing the receptor from being activated,
even when the agonist is bound to the active site.
• A characteristic difference between competitive
and noncompetitive antagonists is that
competitive antagonists reduce agonist potency,
whereas noncompetitive antagonists reduce
agonist efficacy.

133. 133

134. 284
c. Nonreceptor Antagonists
• A chemical antagonist inactivates the agonist of
interest by modifying or sequestering it.
− Protamine (+vely charged) is an example of a
chemical antagonist; to the heparin (-vely
charged) class of anticoagulants and thereby
inactivates these agents.
• A physiologic antagonist most commonly
activates or blocks a receptor that mediates a
response physiologically opposite to that of the
receptor for agonist.
– For example, in the treatment of hyperthyroidism,
ß-adrenergic antagonists are used as
physiologic antagonists.

135. 3. Partial Agonists
• Have only moderate intrinsic activity;
maximum response is lower than a full
agonist.
• They can act as agonist as well as antagonist
– When administered alone it produces low to
moderate receptor activation, however blocks the
action of a full agonist.
– Because partial agonists and full agonists bind to
the same site on a receptor, a partial agonist can
reduce the response produced by a full agonist.
285

136. 136
4. Inverse Agonists
• In some cases, there is intrinsic activity
(―tone‖)of the receptor system, even in the
absence of an endogenous ligand or an
exogenously administered agonist.
• An inverse agonist acts by abrogating this
intrinsic (constitutive) activity of the free
(unoccupied) receptor.
• Both inverse agonists and competitive
antagonists act to reduce the activity of a
receptor.

137. 137
Ctnd…
• In the presence of a full agonist, both
competitive antagonists and inverse
agonists act to reduce agonist potency.
• However, that a competitive antagonist has
no effect in the absence of agonist,
whereas an inverse agonist deactivates
receptors that are constitutively active in
the absence of agonist.

138. A ‘Model’ for Drug-Receptor
Interactions
• Modern concepts of drug-receptor interactions
consider the receptor to have at least two
conformations:
– Ri (inactive) and Ra (active)
• In the Ri conformation, the receptor is
inactive/nonfunctional and produces no effect
• In the Ra conformation, the receptor can
activate its effectors and produce an effect,
even in the absence of a ligand.
– The effect produced in the absence of agonist
(which is a small observable effect) is referred to
as ‗Constitutive Activity‘. 28
8

139. A ‘Model’ forDrug-Receptor…
• In the absence of ligand, a receptor exists in a state
of equilibrium (Ri = Ra) between the two
conformations.
• Full Agonists have a much higher affinity for
binding to the Ra and are able to fully stabilize it
– i.e., they have high intrinsic efficacy
• Binding of full agonists favors the formation of the
Ra-D complex with a much larger observed effect.
• Partial Agonists have an intermediate affinity for
binding to both Ri and Ra forms (Ra-D = Ri-D),
– Better affinity for the Ra form. 28
9

140. A ‘Model’ for Drug-Receptor…
• They do not stabilize the Ra form as fully as full
agonists, (i.e., partial agonists exhibit low
intrinsic efficacy).
• Pharmacologic Antagonists have equal
affinity for binding to both the Ra and Ri forms
of the receptor molecule.
– So how do they produce their effect??????
• Inverse Agonists have a much higher affinity
for binding to the inactive form of the receptor
molecule
– May produce effects that are the opposite of
the effects produced by conventional
agonists at that receptor 29
0

141. 29
1
Figure: Model of drug–receptor

142. 142
DOSE–RESPONSE RELATIONSHIP
• Is the relationship between the amount of
dose and the intensity of response produced
• Determines:
o the minimum amount that we can use
o the maximum response
o how much the dose can be increased to
produce the desired increase in response

143. 143
Dose–response…
• The degree of effect produced by a drug is
generally a function of the amount of drug
at the site of action (receptor).
– Response ~ concentration of drug in receptor
– Concentration of drug in receptor ~ conc. of
drug in plasma
– Concentration of drug in plasma ~ drug
administered
– So, response ~ drug administered
– Expressed in dose—response curves

144. 144
Dose–response…
• Quantification of drug level at the site of
action is difficult and hence either the dose
administered or its plasma concentration are
considered during quantification.
• Two types of dose response curves
a. Graded dose response curve
b. Quantal dose response curve

145. a. Graded dose-response curve
• Graded response: the response continuously
increase as the administered dose continuously
increase.
• The graph is done by giving different doses of a
drug to single individual & recording response.
• More common than quantal dose-response,
since involve single patient/animal.
145

146. 146
Graded dose-response…
• The relationship between the dose of a drug
and its therapeutic effect in a patient is
considerably complex.
• However, in an in vitro system (e.g., cell
culture), the relationship between drug
concentration and effect is simple and can be
described by Graded Dose-Response
Curve (hyperbolic or sigmoid) based on the
following equation:

147. Graded dose-response…
– E = Effect observed at concentration C.
– Emax = Maximal response that can be
produced by the drug.
– EC50 = Concentration of the drug that
produces 50% of the maximal effect.
147

148. 148
Graded dose-response…
• During a drug-receptor interaction, drug
agonists bind to or occupy receptor molecules
with a characteristic affinity for the receptor.
• The relationship between drug bound to
receptor molecules (B) and the concentration
of free (unbound) drug (C) can also be
described by Graded Dose-Binding Curve.
• Dose-response data is usually presented as a
sigmoid curve of the drug effect as a function
of the logarithm of the dose

149. Graded dose-response…
• Graded Dose-Binding Curve (hyperbolic or
sigmoid) based on the following equation:
– B = Drug bound to receptor molecules at conc. C.
– Bmax = Total concentration of receptor sites that
are bound to the drug at infinitely high
concentrations of free drug.
– Kd = ‗Equilibrium Dissociation Constant, is the
concentration of free drug at which 50% of
maximal binding is observed.
149

150. Figure: Relations between drug concentration and drug
effect (A ) or receptor-bound drug (B).
150

151. Figure: Graded dose-response and dose-binding
graphs.
151

152. 152
Graded dose-response…
• Emax characterizes drugefficacy.
– If Emax is low, drug efficacy is low; if Emax is high,
drug efficacy is high.
• EC50 characterizes drug potency.
– If EC50 is low, drug potency is high; if EC50 is
high, drug potency is low.
• Kd characterizes the drug‘s affinity for binding
to the receptor.
– If Kd is low, binding affinity is high; if Kd is high,
binding affinity is low.

153. 153
Graded dose-response…
• The drug effect is changing rapidly at
lower doses (as compared to a very slow
change in the effect at high
concentrations).
• Finally, doses may be reached at which no
further increase in response can be
achieved.

154. 154
b. Quantal Dose-Response Curves
• Represents the percentage of individuals (or
laboratory animals) under study who exhibit a
specified drug effect
─ Therapeutic effect
─ An undesirable drug effect
─ A lethal effect or
─ Any other drug effect plotted as a function of log
drug dose.
• A quantal dose-response curve illustrates the
potential variability of responsiveness to the
drug among individuals in a given human
population.

155. 155
Quantal Dose-Response…
• Relationship between dose and some
specified quantum of response among all
individuals taking the drug
• Its construction requires that data be
obtained from many individuals.
• Effect is either present or absent (all or none)
– Eg, protection of convulsion by anti-epileptic
agents.

156. ED50: the dose that
produces response in
50% of the individuals
156
LD50: the dose that
cause death in 50% of
the animals

157. 157
Quantal Dose-Response…
• Median Effective Dose (ED50): is the drug
dose at which 50% of individuals exhibit
the specified quantal effect
• Median Toxic Dose (TD50): is the drug
dose required to produce a particular toxic
effect in 50% of individuals or laboratory
animals
• If the toxic effect is death of the
laboratory animal, a Median Lethal Dose
(LD50) can be experimentally defined.

158. 158
Maximal efficacy and relative potency
• Dose-response curve can reveal two
characteristic properties of drugs:
 maximum efficacy
 relative potency

159. Maximum efficacy
• Is indicated by the height of the dose
response curve
• A drug with a maximum efficacy is not always
desirable than a drug with lower efficacy.
Relative potency
• Refers to the amount of drug that must be
given to elicit an effect.
• Rarely important characteristic of a drug
• The potency of a drug implies nothing about
its maximal efficacy.
30

160. 31
0
Dose-response curves demonstrating efficacy and
potency

161. 311

162. • Most potent: B; A & Bmore
potent than C and D
• Least potent: D
• Highest efficacy: A, C, D
• Lowest efficacy: B
• Full agonist: A, C, D (high
Emax)
• Partial agonist: B (low
Emax)
− None are pure antagonist
because pharmacologic
effect is produced (pure
antagonist = no effect)
− B can be used as
antagonist – competitive
antagonist
31
2

163. 163
The therapeutic Index (TI)
• Relates the dose of the drug required to
produce a desired effect to the dose of the
drug which produces an undesirable effect.
• Represents an estimate of the safety of a
drug
• In animal studies, the therapeutic index is
defined as the ‘TD50/ED50’ ratio for a
particularly relevant therapeutic effect.
• Clinically acceptable risk of toxicity from a
drug depends on the severity of the disease
being treated.

164. 164
Ctnd…
• The Therapeutic Window (or Therapeutic
Range) of a drug is a more clinically useful
index of safety
• It describes the dosage range (i.e., the
difference) between the minimum effective
therapeutic concentration/dose (MEC) and
the minimum toxic concentration/dose
(MTC) of a drug in humans
• Both the Therapeutic Index and the
Therapeutic Window depend on the specific
toxic effect used in the determination

165. 165

166. 31

167. 4. Adverse Drug Reactions (ADR)
Risk-benefit Ratio
• When prescribing drugs a physician must
assess risk to benefit ratio in the individual
patient by choosing an appropriate class of
drug then an appropriate individual agent.
• Is it effective?
• What are the chances of adverse effect ?
• Are there features in this patient which affect
choice, eg, other drugs, organ failure, aged
• Tailoring the dose
• Considering duration of treatment
317

168. Adverse Drug Reactions…
• ADR: defined as any response to a drug that
is noxious and unintended and that occurs at
doses used for prophylaxis, diagnosis or
therapy.
• Adverse drug reactions can range in intensity
from annoying to life threatening effects.
• ADR can be predictable or nonpredictable:
– Predictable: arise from known
pharmacological property of the drug, e.g.,
side effect & toxic effect
– Nonpredictable: allergy & idiosyncrasy
(adverse drug reaction that occurs in a small
number of persons and no correlation to
dosage) 31
8

169. Adverse Drug Reactions…
Definitions
1. Side effects: are pharmacological effects
produced with therapeutic dose of the
drug.
– E.g., dryness of mouth with atropine and
useful when used as pre-anesthetic
medication
2. Toxic effect: excessive pharmacological
action of the drug due to over dosage or
prolonged use.
319

170. Adverse Drug Reactions…
3. Untoward/Secondary effects: indirect
consequences of primary action of drug
– e.g., suppression of bacterial flora by
tetracycline paves the way for
superinfection; corticosteroids weaken host
defense mechanisms and latent tuberculosis
gets activated.
4. Idiosyncratic reaction: genetically
determined ADR, which could be:
− dose related [neuropathy by INH] or
− dose unrelated [hemolytic anemia by
primaquine, sulphonamides, dapsone]
32
0

171. 171
Adverse Drug Reactions…
5. Hypersensivity reaction/allergy:
– Type I (anaphylactic reaction): antigen +
IgE on basophil/mast cell
• Anaphylaxis, asthma
– Type II (cytotoxic reaction): antigen +
IgM/IgG
• Penicillin binds RBC, evokes production
of antibody and lysis
– Type III (immune complex mediated
reaction): skin rashes due to NVP.

172. Adverse Drug Reactions…
6. Teratogenic effect: the
effect of drug to cause fetal
abnormalities when
administered to the pregnant
mother.
– E.g., thalidomide cause
phocomelia [absent or
grossly abnormal limbs]
7. Carcinogenicity and
mutagenicity: a drug to
cause cancer and genetic
defects respectively.
172

173. 173

174. 174
Types of ADR
• Type A (Augmented)
– Related to the principal action of the drug
• PD effects (eg, bronchospasm by β-blockers)
– Dose related & occur in everyone
– Treated by reducing the dose/withholding the dose
• Type B reactions (bizarre)
– Not related to the principal action of the drug
• Not part of the normal pharmacology of the drug
– Occur in some people
– Not dose related and is unpredictable
– Include idiosyncrasy and drug allergy

175. 175
Types of ADR…
– Account for most drug fatalities
• Eg, Anaphylactic reaction in penicillin administration
and Aplastic anemia by chloramphenicol
• Type C reactions (continuous)
– Dose and time related
– Related to cumulative effect
– Treated by reducing the dose/withholding the
dose
• Eg, osteoporosis with oral steroids, hypothalamic-
pituitary-adrenal axis suppression by corticosteroids

176. Types of ADR…
• Type D reactions (delayed)
– Are delayed (have a lag time) after use of the drug
– Uncommon
– Treatment is often intractable
• Eg, Teratogenic effects, carcinogenicity, tardive
dyskenesia
• Type E reactions (end of use)
– Occur soon after the end of use (withdrawal
syndrome)
– Are uncommon
– Treated by reintroducing the medicine and then
withdrawing slowly
• Eg, opiate withdrawal syndrome, withdrawal
syndrome with benzodiazepines, myocardial
ischemia with β-blocker withdrawal 32
6

177. 177
Types of ADR…
• Type F reactions (failure of therapy)
– May be dose related & is common
– Often caused by drug interaction
– Treated by increasing dose and considering
the effects of concomitant therapy
• Eg, oral contraceptives + enzyme inducers,
resistance to antimicrobials, tetracyclines +
calcium

178. Table: Some examples of predictable drug
reactions
178

179. Table: Some examples of unpredictable drug reactions (with
incidences where known)
179

180. Predisposing factors for ADR
33
0
1. Age (increased risk in very young & very old
(especially over 70) ages)
– Gray baby syndrome in neonates with
chloramphenicol
2. Sex: increased incidence in women
3. Genetics: inter-individual & inter-ethnic
4. End-organ failure, e.g. liver & renal
impairment
5. Polypharmacy: taking multiple drugs at the
same time (drug interactions)
6. Multiple disease states
7. Allergy: history of allergy to one drug may
predispose to further allergy

181. 181
5. Drug Interactions
• Drug could have an interaction with other agents
that are administered to body concomitantly
– Other drugs
– Foods taken
– Beverages
– Herbs
• Drug interaction could be significantly important
or harmful

182. Type of interaction: based on type of
agents that interact
• Drug –drug interaction
Eg, Antacids Vs Ketoconazole: Ketoconazole
needs an acidic environment for better
absorption; antacid alkalinize the media, so
↓absorption
• Drug-food interaction
Eg, Grape fruit juice Vs phenytoin: grape
fruit juice is CYP3A4 enzyme inhibitor →
decrease the metabolism of drug by this
enzyme → increased risk of toxicity
182

183. • Drug – beverage interaction
Eg, Benzodiazepine Vs Alcohol: both are CNS
depressants, sedation effect → additive sedative
effect
MAOIs Vs wine: since wine have tyramine which
have sympathetic effect and increase the synthesis
of NE + MAOI inhibit the metabolism of NE →
excess NE → hypertensive crises
• Drug-herbal interaction
E.g, Saint John's Vs warfarin: Saint John's is
liver microsomal enzyme inducer → increases
metabolism of warfarin → decreased
therapeutic outcome
183

184. 184
• Drug- interaction can be classified as:
A. Pharmacokinetics level interaction
B.Pharmacodynamics level interaction
Type of interaction: Based on level of
interaction

185. 185
A. Pharmacokinetic level interaction
Absorption level interaction
 Ergotamine + caffeine: ergotamine better
absorbed from small intestine and caffeine
↑motility, thus ↓emptying time → facilitate
absorption of ergotamine from small intestine
(high surface area and alkaline media favor
absorption)
 Cholestyramine + FeSO4: Cholestyramine is
large macromolecule which have potential to
adsorb other agents, so FeSO4 adsorbed to
Cholestyramine → absorption

186. 186
Pharmacokinetic level interaction…
• Tetracycline + antacid: interaction in 3
ways
– TTC needs an acidic environment for better
absorption & since antacid creates alkaline
media → absorption ↓ (neutralization)
– Antacid contains heavy metals like Ca2+, Mg2+;
since TTC is chelating agent, form chelates → ↓
absorption (complexetion)
– Since most antacids are gely and massy
adsorption may take place between antacid and
TTC → ↓ absorption (adsorption)

187. Pharmacokinetic level interaction…
Distribution level interaction
• Main factor for this interaction is high plasma
protein binding capacity & low excretion rate
• So displacement of these drugs by other
highly plasma protein binding drug → ↑free
drug level in plasma → toxicity
Eg, Warfarin + phenylbutazone: both are with
highly plasma protein binding capacity, so taking of
phenylbutazone while in warfarin therapy, warfarin
displaced from albumin by phenylbutazone
↑free warfarin in plasma bleeding
187

188. Pharmacokinetic level interaction…
Biotransformation level interaction
• A drug administered may induce or inhibit the liver
microsomal enzyme; as a result there may be drug
interaction in concomitant use of 2 or more than 2 drugs
• Common:
33
8
Enzyme inducers
− Phenobarbital
− Carbamazepine
− Phenytoin
− Rifampin
− NVP & EFV
− Gresofulvin
Enzyme inhibitors
− Cimetidine
− Ketoconazole
− Erythromycin
− Isoniazid
− CAF
− Omeprazole
− Grape fruit juice
Eg, Cimetidine + Warfarin → bleeding …??
Phenobarbital + OCT → pregnancy…??

189. Pharmacokinetic level interaction…
Excretion level interaction
• Mostly occur at two levels
– Tubular secretion: since there is carrier case
• Eg, probencid + penicillin: normally penicillin
has short duration of action → ↑duration by
↓excretion
– Tubular reabsorption: since there is pH based
ionization of drug and further degree of
reabsorption
• Eg, weak acid drug + bicarbonate → ↑ excretion
339

190. 190
B. Pharmacodynamic interaction
I. Agonizing interaction
• It occurs by modification of
pharmacological response of one drug by
another
1. Additive: Occurs when the
combined effect of two drugs is
equal to the sum of the effects of
each agent given alone; 2 + 2 = 4
• e.g, H1 antagonist + CNS depressant

191. 191
Pharmacodynamic interaction…
1. Potentiation: A situation where by one
drug enhance the action of another drug
without having an effect by itself; 0 + 1 > 1
– e.g, Caffeine + ergotamine
2. Synergism: When the combined effects of
two drugs are much greater than the sum
of the effects of each agent given alone; 1
+ 1 >>> 2
– e.g, penicillin + amino glycosides, NE + Digoxin

192. 192
Pharmacodynamic interaction…
II. Antagonizing interaction
1. Chemical antagonism: Involve direct
chemical interaction between agonist and
antagonist
– Eg, chelating agent (dimercaprol) + heavy
metals (Hg, Au…)
2. Functional (physiologic) antagonism:
Involve interaction of two drugs that act
independently of each other but happen to
cause opposite effect
– Eg, acetylcholine + epinephrine, NE + histamine

193. 193
Pharmacodynamic interaction…
3. Receptor/pharmacologic
antagonism
– Competitive
– Noncompetitive

194. 194
Pharmacodynamic interaction…
Competitive
• Is most frequently encountered type of drug
antagonism in clinical practice
• Is competition of agonist and antagonist for
same site in receptor
– If bond is loose
– Antagonism↑ as concentration of antagonist ↑
and inversely if ↑agonist concentration →
antagonism ↓
– Characterized by a parallel shift to right in dose
response curve
– Emax is equal
– ED50 increased

195. Competitive antagonism
Antagonist
Receptor
Antagonist-Receptor
Complex
DENIED!
Competitive
Inhibition
34

196. 34
6

197. Pharmacodynamic interaction…
Non-competitive antagonism
–Involve 2 binding site in receptor for
antagonist and agonist
• Active site noncompetitive antagonist
(irreversible active site binding)
• Noncompetitive allosteric antagonist
34
7

198. 198
Pharmacodynamic interaction…
• Irreversible (not equilibrium) antagonism
–If bond is covalent
–As the concentration of antagonist
increase
oThe slope of the agonist curve ↓
oThe maximum response ↓
oNo change of ED50
–When the amount of antagonist is
adequate no amount of agonist can
produce any response.

199. 199

200. 200
Pharmacodynamic interaction…
• Noncompetitive allosteric antagonist
–The binding is reversible or irreversible.
–It influence transduction pathway of the
agonist.
–Similar dose response curve for agonist
with irreversible antagonist, the only
difference is specificity

201. Receptor
Agonist
‘Inhibited’-Receptor
DENIED!
Non-competitive antagonism
Antagonist
Non-competitive
Inhibition
35

202. 202
Consequences of drug-drug
interactions
–Intensification of effects
Increased therapeutic or adverse
effects
–Reduction of effects
Inhibited drug effects; either beneficial
or detrimental

203. 203
6. Individual Variation in Drug
Responses
• Because of individual variation, we must
tailor drug therapy to each patient.
• The following are major factors that can
cause one patient to respond to drugs
differently than another.

204. 204
Factors Altering Drug Responses
Body weight
Age
 Infants
• Small volume of body fluid compartment
• Incomplete development of the BBB
• Undeveloped renal system
• Undeveloped enzyme system
 Old people: deteriorated body functions
Sex: Women respond faster due to their
relative small body size

205. – altered electrolyte status
205
Factors Altering…
 Route of administration
 Time of administration
 Physiological variables: fluid and electrolyte balance,
acid-base status, blood flow and body temperature.
 Tolerance to drugs
 Pathological factors that alter pharmacokinetics and
pharmacodynamic parameters; special attention is
given to renal and hepatic problems
– kidney disease
– liver disease
– acid-base imbalance

206. drug effect. 206
Factors Altering…
Genetic factors
Emotional factors
Environmental
 More of a hypnotic drug is required to induce
hypnosis during day time than during night
 More dose of antihypertensive drug is required
to lower blood pressure in cold weather than in
hot one.
Nutritional state
 Starvation causes decreased protein synthesis
(drug metabolizing enzymes), hence enhanced