following presentation covers the topic pharmacodynamics, factors affecting drug response and mechanism of drug action in detail.

1. Pharmacodynamics,
mechanism of drug
action and factors
modifying drug response
Presented by: Aishwarya sinha

2. CONTENTS
 Pharmacodynamics
 Principles of drug action
 Mechanism of drug action
 Receptor subtypes
 Action effect sequence
 Transducer mechanism
 Dose response relationship
 Factors affecting drug response
 Conclusion
 References

3. PHARMACODYNAMICS
 Pharmacodynamics is the study of drug effects
 it elucidates the complete action-effect sequence and the
dose-effect relationship.
 Modification of the action of one drug by another drug
is also an aspect of pharmacodynamics.

4. PRICIPLES OF DRUG ACTION
 Drugs ( except those gene based) do not impart new
functions to any system, organ or cell; they only alter
the pace of ongoing activity.
 The basic type of drug action can be classified as:
STIMULATION DEPRESSION IRRITATION REPLACEMENT
CYTOTOXIC
ACTION

5. STIMULATION
 It refers to selective enhancement of the level of activity
of specialized cells, e,g.
 adrenaline stimulates heart
 However, excessive stimulation depression of that
function. Eg- high dose of picrotoxin (CNS stimulant)
produces convulsions followed by coma and respiratory
depression.

6. DEPRESSION
 It means selective diminution of activity of specialized
cells, eg-
 barbiturates depresses CNS
 Certain drugs stimulate one type of cells but depress the
other, e.g. acetylcholine stimulates intestinal smooth
muscle but depresses SA node in heart.

7. IRRITATION
 This connotes a nonselective, often noxious effect and is
particularly applied to less specialized cells (epithelium,
connective tissue).
 May result in loss of function.

8. REPLACEMENT
 This refers to the use of natural metabolites, hormones
or their congeners in deficiency states.
 levodopa in parkinsonism,
 insulin in diabetes mellitus,
 iron in anaemia.

9. CYTOTOXIC ACTION
 Selective cytotoxic action on invading parasites or
cancer cells, attenuating them without significantly
affecting the host cells is utilized for cure/ palliation of
infections and neoplasms, e.g.
 penicillin, chloroquine, zidovudine, cyclophosphamide,
etc.

10. MECHANISM OF DRUG ACTION
 Majority of drugs produce their effects by interacting
with discrete target biomolecules which are usually
proteins, which can be grouped into:-
ENZYMES ION CHANNELS
TRANSPOTERS RECEPTORS

11. ENZYMES
 Almost all biological reactions are carried out under catalytic
influence of enzymes; hence, enzymes are a very important target
of drug action.
 Drugs can either increase or decrease the rate of enzymatically
mediated reactions.
 in physiological systems enzyme activities are often optimally set.
 Drugs foreign substance, hence; stimulation of enzymes by
drugs is unusual.

12.  Several enzymes are stimulated through receptors and second
messengers, e.g.
 adrenaline stimulates hepatic glycogen phosphorylase through β
receptors and cyclic AMP.
Stimulation of an
enzyme
Increases affinity
for substrate
Rate of reaction
(kM)

14.  ENZYME INDUCTION (synthesis of more enzyme protein)
causes apparent increase in enzyme activity. Enzyme induction is
different from stimulation as kM does not change.
 ENZYME INHIBITION is a common mode of drug action.
ENZYME
INHIBITION
SPECIFIC
INHIBITION
COMPETITIVE
NON
COMPETITIVE
NON SPECIFIC
INHIBITION

15. NON SPECIFIC INHIBITION
 Heavy metals, strong acids, alkalies, alcohol, formaldehyde
inhibit enzyme non specifically.
 These inhibitors are too damaging to be used systemically.
Chemical or
drugs
Alter tertiary
structure of
enzyme
Inhibition of
enzyme

16. SPECIFIC INHIBITION
 Many drugs inhibit a particular enzyme without affecting others,
it is called as specific inhibition.
SPECIFIC
NHIBITION
COMPETITIVE
EQUIIBRIUM
TYPE
NON
EQUILIBRIUM
TYPE
NON
COMPETITIVE

17. COMEPTITIVE (EQUILIBRIUM TYPE)
 The drug being structurally similar competes with the normal
substrate for the catalytic binding site of the enzyme so that the
product is not formed or a nonfunctional product is formed, and a
new equilibrium is achieved in the presence of the drug.

18.  It binds only to enzyme and not to enzyme-substrate complex
(ES).
 This type of inhibition is mostly surmountable, i.e. inhibition can
be overcome by increasing the dose of the substrate.
 It results in increase in Km(Michaelis menton’s constant) but
does not affect the Vmax.
Km: amount of
substrate required to
produce half of the
maximal velocity
Vmax: maximum
reaction velocity.

19.  If the drug binds very strongly to the active site, so that it cannot
be displaced even by large concentration of substrate, it can result
in irreversible competitive inhibition. In this type of inhibition,
Km rises and Vmax decreases. Organophosphates are irreversible
competitive inhibitors.

20. COMPETITIVE (NON EQUILIBRIUM
TYPE)
 drugs which react with the same catalytic site of the enzyme but
either form strong covalent bonds or have such high affinity for
the enzyme that the normal substrate is not able to displace the
inhibitor. Eg:-
 Organophosphates react covalently with the esteretic site of the
enzyme cholinesterase.
 kM is increased and Vmax is reduced in these type of inhibition

21. NON COMPETITIVE INHIBITION
 The inhibitor reacts with an adjacent site and not with the
catalytic site, but alters the enzyme in such a way that it loses its
catalytic property.
 Thus, kM is unchanged but Vmax is reduced.
 It binds to both enzyme as well as ES with equal affinity
 This type of inhibition is insurmountable, i.e. inhibition cannot be
overcome by increasing the dose of the substrate.

22.  Mostly non-competitive inhibitors are irreversible but carbonic
anhydrase inhibitors are reversible non-competitive inhibitors.

24. ION CHANNELS
 Proteins which act as ion selective channels participate in
transmembrane signaling and regulate intracellular ionic
composition. This makes them a common target of drug action.
Drugs Ion channels Ligand gated
G- protein
Voltage
operated and
stretch sensitive
channels

25. TRANSPORTERS
substrates
Translocated across
membrane
Using specific
transporter
(carrier)
Diffusion against
concentration
gradient
Diffusion in
direction of
concentration
gradient

26.  Many drugs produce their action by directly interacting with the
solute carrier (SLC) class of transporter proteins to inhibit the
ongoing physiological transport of the metabolite/ion. Eg:-
 Desipramine and cocaine block neuronal reuptake of
noradrenaline by interacting with norepinephrine transporter
(NET)
 Amphetamines selectively block dopamine reuptake in brain
neurons by dopamine transporter (DAT).

27. RECEPTORS
 The largest number of drugs do not bind directly to the effectors,
but act through specific regulatory macromolecules called as
receptors.
 Receptor: It is defined as a macromolecule or binding site located
on the surface or inside the effector cell that serves to recognize
the signal molecule/drug and initiate the response to it, but itself
has no other function.
 Two important terms related to the receptors are affinity and
intrinsic activity (IA).

28.  If a drug has no affinity, it will not bind to the receptor. So, all
type of drugs acting via receptors (agonist, antagonist, inverse
agonist and partial agonist) possess some affinity for the
receptors.
 Drugs may be divided into four types based on their intrinsic
activities.
AFFINITY: the
ability of a drug
to combine with
the receptor.
INTRINSIC
ACTIVITY: the
ability to activate
the receptor. It
varies from –1
through zero to +1.

29. BASED ON INTRINSIC ACTIVITY:-
AGONIST
INVERSE AGONIST
ANTAGONIST
PARTIAL AGONIST

30.  AGONIST: It will bind to the receptor and activate it maximally.
i.e. IA is +1.
 ANTAGONIST: Binds to the receptor but produces no effect (IA
is 0). But now agonist is not able to bind to the receptor because
these are already occupied by the antagonist. Thus, it decreases
the action of the agonist but itself has no effect.

31. TYPES OF ANTAGONISM
• Binds to the drug and prevents absorption
• Eg- charcoal binds to alkaloids
PHYSICAL
ANTAGONIST
• Combines chemically
• Eg- chelating agents binds to metal
CHEMICAL
ANTAGONIST
• Binds to different receptor to produce opposite
action
PHYSIOLOGICAL
ANTAGONIST
• Produces opposite actions by binding to the same
receptor
PHARAMCOLOGICAL
ANTAGONIST

32.  PARTIAL AGONIST: It activates the receptor submaximally (IA
between 0 and +1). It will produce the similar effect in the
absence of agonist but it will decrease the effect of a pure agonist.
 INVERSE AGONIST: These type of drugs bind to the receptor
and produce opposite effect (IA is negative).

33. RECEPTOR SUBTYPES
 The delineation of multiple types and subtypes of receptors for
signal molecules has played an important role in the development
of a number of targeted and more selective drugs.
 The following criteria have been utilized in classifying receptors:
1. Pharmacological
criteria
2. Tissue distribution
3. Ligand binding
4. Transducer pathway
5. Molecular cloning

34. Pharmacological criteria
 Classification is based on relative potencies of selective agonists
and antagonists. This is the classical and oldest approach with
direct clinical bearing.
 It was used in:-
Cholinergic
receptors
M
type
N
type
Adrenergic
receptor
α
β

35. TISSUE DISTRIBUTION
 The relative organ/tissue distribution is the basis for designating
the subtype e.g. the cardiac β adrenergic receptors as β1 , while
bronchial as β2 .
 This division was confirmed by selective agonists and antagonists
as well as by molecular cloning.

36. LIGAND BINDING
 Measurement of specific binding of high affinity radio-labelled
ligand to cellular fragments (usually membranes) in vitro, and its
displacement by various selective agonists/antagonists is used to
delineate receptor subtypes.
 Multiple 5-HT receptors were distinguished by this approach.

37. TRANSDUCER PATHWAY
 Receptor subtypes may be distinguished by the mechanism
through which their activation is linked to the response,. e.g. M
cholinergic receptor acts through G-proteins, while N cholinergic
receptor gates influx of Na+ ions.

38. MOLECULAR CLONING
 The receptor protein is cloned and its detailed amino acid
sequence as well as three dimensional structure is worked out.
 Subtypes are designated on the basis of sequence homology.

39. ACTION-EFFECT SEQUENCE
 ‘Drug action’ and ‘drug effect’ are often loosely used
interchangeably, but are not synonymous.
 Drug action is the initial combination of the drug with its receptor
resulting in a conformational change in the latter (in case of
agonists), or prevention of conformational change through
exclusion of the agonist (in case of antagonists).
 Drug effect is the ultimate change in biological function brought
about as a consequence of drug action, through a series of
intermediate steps (transducer).

40. RECEPTOR
RECOGNITION
OF SPECIFIC
LIGAND
MOLECULE
TRANSDUCTION
OF SIGNAL
INTO A
RESPONSE

41. TRANSDUCER MECHANISMS
 A handful of transducer pathways are shared by a large number of
receptors, the cell is able to generate an integrated response
reflecting the sum total of diverse signal inputs.
 The transducer mechanisms can be grouped into 5 major
categories
G-protein
coupled
receptor
ION channel
receptors
Enzyme
linked
receptor
JAT-SKAT
binding
receptor
Nuclear
receptors

42. G-PROTEIN COUPLED RECEPTOR (GPCRs)
 These are a large family of cell membrane receptors which are
linked to the effector (enzyme/channel/transporter) through one or
more GTP-activated proteins (G-proteins) for response
effectuation.
 STRUCTURE OF GPCRs: The molecule has 7 α-helical
membrane spanning hydrophobic amino acid (AA) segments
which run into 3 extracellular and 3 intracellular loops.
 Agonist binding site between helices on extracellular face.

43. Inactive
state GDP
is bound
to α
subunit
Activatio
n of GDP
GTP
causes
displacem
ent of α
subunit
activation/i
nhibition

44.  A number of G proteins distinguished by their α subunits have
been described. The important ones with their action on the
effector are:
Gs: Adenylyl
cyclase activation,
Ca2+ channel
opening
Gi: adenylyl
cyclase inhibition,
K+ channel opening
Go: Ca2+ channel
inhibition
Gq: Phospholipase
C activation

45.  A limited number of G-proteins are shared between different
receptors and one receptor can utilize more than one G-protein
(agonist pleotropy), e.g. the following couplers have been
associated with different receptors

46.  The rate of GTP hydrolysis by the α subunit and thus the period
for which it remains activated is regulated by another protein
called ‘regulator of G protein signaling’ (RGS). The onset time of
response through GPCRs is in seconds.
 There are three major effector pathways through which GPCRs
function.
cAMP
Pathway
Phospholipase
IP3/DAG
Pathway
Channel
regulation

47. A. ADENYLYL CYCLASE: cAMP
PATHWAY
Activation of
AC
Intracellular
accumulation
of cAMP
cAMP
dependent
protein
kinase
cAMP
activates
Ca2+ channel
cycle cyclic
nucleotide
gated
channel

48. Cyclic GMP (cGMP) as a second messenger
 the cGMP serves as an intracellular second messenger only in a
limited number of tissues Vascular
smooth
muscle
Intestinal
mucosal
cell
kidney
Mediates
relaxation
Inhibition of salt
and water
absorption
Anion secretion
and natriuresis

49. B. Phospholipase C: IP3-DAG pathway
Activation of
phospholipase Cβ (PLcβ)
by the activated GTP
carrying α subunit of Gq
hydrolyses the
membrane
phospholipid
phosphatidyl inositol
4,5-bisphosphate
(PIP2 )
generates the second
messengers inositol
1,4,5-trisphosphate
(IP3 ) and
diacylglycerol (DAG).
IP3 being water
soluble diffuses to
the cytosol and
mobilizes Ca2+
from endoplasmic
reticular depots
The lipophilic DAG
remains within the
membrane, but
recruits protein
kinase C (PKc) and
activates it with
the help of Ca2+.

50. C. CHANNEL REGULATION
 The activated Gproteins (Gs, Gi, Go) can also open or inhibit
ionic channels specific for Ca2+ and K+ , without the
intervention of any second messenger like cAMP or IP3, and
bring about hyperpolarization/depolarization/changes in
intracellular Ca2+ concentration.
Gs
Opens Ca2+
channels in
heart and
skeletal muscle
Gi/Go
Opens K+
channels in
heart and
skeletal muscle

51. ION CHANNEL RECEPTORS
 Also called as ligand gated ion channels.
 AGONIST binding channel opens depolarization/
hyperpolarization/
changes in cytosolic ionic composition
These are the fastest acting receptors.
It includes GABAA and 5-HT3 receptors.

52.  The receptor is usually a pentameric protein. The subunits are
mostly arranged round the channel like a rosette and the α
subunits agonist binding sites.
 The onset and offset of responses through this class of receptors
is the fastest (in milliseconds).

53. TRANSMEMBRANE ENZYME LINKED
RECEPTOR
 This class of receptors are utilized primarily by peptide
hormones, [(insulin, epidermal growth factor (EGF), nerve
growth factor (NGF) and many other growth factor receptors.]
 The commonest protein kinases are the ones which phosphorylate
tyrosine residues on the substrate proteins and are called ‘receptor
tyrosine kinases’ (RTKs)
 These are made up of a large extracellular ligand binding domain
connected through a single transmembrane helical peptide chain
to an intracellular subunit having enzymatic property.

54. unliganded monomeric state Kinase remains inactive
Binding of hormones
Dimerization of receptor
Conformational changes
activate the kinase to
autophosphorylate tyrosine
residues on each other
increases their affinity for
binding substrate proteins.
response

55. TRANSMEMBRANE JAK-STAT BINDING
RECEPTOR
 This type of receptor has two sites
Extracellular
site
Drug
binds
Intracellular
site
Enzymatic
activity

56. Agonist induced
dimerization
alters the
intracellular domain
configuration
increase its affinity
for a cytosolic
tyrosine protein
kinase JAK (Janus
Kinase).
JAK gets activated
and phosphorylates
tyrosine residues of
the receptor
Binds to STAT (signal
transducer and
activator of
transcription).
phosphorylated STAT
dimerize and
translocate to the
nucleus
regulates gene
transcription resulting
in a biological
response

58. RECEPTORS REGULATING GENE
EXPRESSION
 Synonyms: transcription factors, nuclear receptors
 these are intracellular (cytoplasmic or nuclear) soluble proteins
which respond to lipid soluble chemical messengers that penetrate
the cell.
 These may be present in the cytoplasm (glucocorticoids,
mineralocorticoids, and vitamin D) or in the nucleus (T3 , T4 ,
Retinoic acid, PPAR, estrogen, progesterone and
testosterone).

59.  Both type of receptors finally act by nuclear mechanisms (i.e. by
affecting transcription).
 All the intracellular receptors are considered a part of ‘Nuclear
Receptor Superfamily.

60. Hormone binds to
receptor
Restricting proteins
are released
Receptor dimerizes
DNA binding regulatory
segment folds in active
configuration
The liganded receptor
dimer moves to the
nucleus
The whole complex
attaches to specific DNA
sequences of the target
genes and facilitates their
expression so that specific
mRNA is synthesized on the
template of the gene.
This mRNA moves to
the ribosomes and
directs synthesis of
specific proteins
which regulate
activity of the target
cells.

61. REGULATION OF RECEPTORS
 Receptors exist in a dynamic state; their density and efficacy to
elicit the response is subject to regulation by the level of on-going
activity, feedback from their own signal output and other
physiopathological influences.
 This has clinical relevance in clonidine/CNS depressant/ opioid
withdrawal syndromes, sudden discontinuation of propranolol in
angina pectoris.
Prolonged
deprivation of
agonist
supersensitivity of
the receptor and
effector system

62. Mechanism unmasking of
receptors or their
proliferation (up
regulation) or
accentuation of
signal
amplification by
the transducer.
Continued
receptor
stimulation
desensitization or
refractoriness

63.  The changes may be brought by:
 Masking or internalization of the receptor (it becomes
inaccessible to the agonist) or impaired coupling of the transducer
to the receptor. In this case refractoriness develops as well as
fades quickly.
 Decreased synthesis/increased destruction of the receptor (down
regulation): refractoriness develops over weeks or months and
recedes slowly.

64. FUNCTIONS OF RECEPTORS
 To propagate regulatory signals from outside to inside the effector
cell when the molecular species carrying the signal cannot itself
penetrate the cell membrane.
 To amplify the signal.
 To integrate various extracellular and intracellular regulatory
signals.
 To adapt to short term and long term changes in the regulatory
mechanism and maintain homeostasis

65. NON RECEPTOR MEDIATED DRUG ACTION
 This refers to drugs which do not act by binding to specific
regulatory macromolecules.
 Drug action Physical/chemical
means
Small molecules/ions
enzymes

66. DOSE RESPONSE RELATIONSHIP
 When a drug is administered systemically, the dose-response
relationship has two components:
 the intensity of response increases with increase in dose (or more
precisely concentration at the receptor), but at higher doses, the
increase in response progressively becomes less marked.
dose-plasma
concentration
relationship
plasma
concentration-
response
relationship.

67. DOSE RESPONSE CURVE
 It is a graph between the dose of a drug administered (on X-axis)
and the effect produced by the drug (on Y-axis).
 As plasma concentration is more closely related to response, the
graph between plasma concentration and response is usually
called DRC.
 Two types
Dose plasma
concentration curve
plasma
concentration-
response curve.
Quantal
Graded

68. QUANTAL DRUG RESPONSE CURVE
 Variation in sensitivity of response to increasing doses of the drug
in different individuals can be obtained from quantal DRC.
 When the response is an ‘all or none’ phenomenon (e.g.
antiemetic drug stopping the vomiting or not), the y-axis
(response axis) shows the number of person responding and X-
axis shows the plasma concentration.
 It is used to calculate ED50 and LD50 .

69.  MEDIAN EFFECTIVE DOSE : It is the dose that will produce
the desired response in half of the (50%) recipients.
 MEDIAN LETHAL DOSE: : It is the dose that will result in
death of 50% of the animals receiving the drug.
ED50 potency
LD50 safer the drug

70.  THERAPEUTIC INDEX (T.I.): It is a measure of the safety of
a drug. It is calculated as a ratio of LD50 to ED50 .
 Drugs having high T.I. are safer whereas those having low T.I. are
more likely to be toxic.
 T.I = LD50 / ED50

71.  When the response can be graded (e.g. reduction in BP), the y-
axis shows the magnitude of response.
 DRC is usually hyperbola in shape.
 As curved lines cannot give good mathematical comparisons, so
usually the dose is converted to log dose to form log DRC, which
gives a sigmoid shaped curve.
 Three important parameters (potency, efficacy and slope of curve)
can be determined from DRC.

72. POTENCY
 It is the measure of the amount of a drug needed to produce the
response.
 Drugs producing the same response at lower dose are more potent
whereas those requiring large dose are less potent.
 In DRC, more a drug is on left side of the graph, higher is its
potency and vice a versa.

73. EFFICACY
 It is the maximum effect produced by a drug.
 More the peak of the curve greater is the efficacy.
 It is clinically more important than potency.

74. SLOPE
 If the DRC is steeper, that means the response will increase
dramatically with slight increase in dose.
 drugs having steeper DRC have narrow therapeutic index (like
barbiturates) than those having less steep curves (e.g.
benzodiazepines).
 DRC can also be utilized to know whether a drug is competitive
or non competitive inhibitor.

75. Competitive
inhibitor
Non
competitive
inhibitor
Curve will
shift to right
Flattening of
DRC
efficacy
decreases
same agonist will
have less potency
in the presence of
antagonist.

76. PHARMACOGENETIC CONDITION
 Due to different genetic make up, some drugs have different
effects in different individuals, so these drugs may show either
toxicity or lack of effect in certain individuals, if used in
conventional dosage.
 ACETYLATOR POLYMORPHISM: Some individuals are slow
acetylators and some are fast acetylators. The drugs metabolized
by this route may be ineffective in fast acetylators and may show
toxicity in slow acetylators. Drugs are: Sulfonamide, Hydralazine,
Isoniazid, Procainamide.

77.  Glucose-6-phosphate Dehydrogenase (G-6-PD) Deficiency:
Oxidant drugs may produce hemolysis in the patient with
deficiency of this enzyme.
 Atypical Pseudocholinesterase and Succinylcholine:
Succinylcholine is a very short acting drug due to metabolism by
pseudocholinesterase. In such individuals this drug may produce
prolonged apnea.

78.  Inability to Hydroxylate Phenytoin.
 Resistance to Coumarin Anticoagulants.
 Malignant Hyperthermia by Halothane.

79. FACTORS MODIFYING DRUG RESPONSE
 The same dose of a drug can produce different degrees of
response in different patients and even in the same patient under
different situations. Various factors modify the response to a drug.
BODY WEIGHT
AGE
SEX
SPECIES AND RACE
DIET AND ENVIRONMENT
ROUTE OF ADMINISTRATION

80. GENETIC FACTOR
DOSE
DISEASES
REPEATED DOSING
PSYCHOLOGICAL FACTORS
PRESENCE OF OTHER
DRUGS

81. BODY WEIGHT
 The recommended dose is calculated for medium built persons.
For the obese and underweight persons, the dose has to be
calculated individually.
 Body surface area is a better parameter for more accurate
calculation of the dose, it is inconvenient and hence not generally
used.

82. AGE
 The pharmacokinetics of many drugs change with age resulting in
altered response in extremes of age.
 In newborn due to lack of fully mature organs, various drugs can
have different effect than adults. The blood-brain barrier is not
well-formed and drugs can easily reach the brain. The gastric
acidity is low, intestinal motility is slow, skin is delicate and
permeable to drugs applied topically.
CHLORAMPHENICOL
GREY BABY
SYNDROME

83.  Hence calculation of the appropriate dose based on the body
weight is important to avoid toxicity.
 Also pharmacodynamic differences could exist,
BARBITURATES
EXCITATION
SEDATION

84.  In the elderly, the capacity of the liver and kidney to handle the
drug is reduced and they are more susceptible to adverse effects.
Hence lower doses are recommended, e.g. elderly are at a higher
risk of ototoxicity and nephrotoxicity by streptomycin.

85. SEX
 The hormonal effects and smaller body size may influence drug
response in women. Special care is necessary while prescribing
for pregnant and lactating women and during menstruation.

86. SPECIES AND RACE
 Response to drugs may vary with species and race. For example,
rabbits are resistant to atropine. Such variation makes it difficult
to extrapolate the results of animal experiments.
 Blacks need higher doses of atropine to produce mydriasis.

87. DIET AND ENVIRONMENT
 Food interferes with the absorption of many drugs. For example,
tetracycline form complexes with calcium present in the food and
are poorly absorbed.
 Polycyclic hydrocarbons present in the cigarette smoke may
induce microsomal enzymes resulting in enhanced metabolism of
some drug.

88. ROUTE OF ADMINISTRATION
 Occasionally route of administration may modify the
pharmacodynamic response, E.g.:-
MAGNESIUM
SULPHATE
PURGATIVE
INTRACRANIAL
TENSION
LOCAL EDEMA
ANTICONVULSANT

89. GENETIC FACTORS
 Variations in an individual’s response to drugs could be
genetically mediated.
 Pharmacogenetics is concerned with the genetically mediated
variations in drug responses.
 The differences in response is most commonly due to variations
in the amount of drug metabolizing enzymes since the production
of these enzymes is genetically controlled.
 EXAMPLES-

90. A. ACETYLATION OF DRUGS
 The rate of drug acetylation differs among individuals who may
be fast or slow acetylators, e.g. INH, sulfonamides and
hydralazine are acetylated.
 Slow acetylators treated with hydralazine are more likely to
develop lupus erythematosus

91. B. ATYPICAL
PSEUDOCHOLINESTERASE
 Succinylcholine is metabolised by the enzyme
pseudocholinesterase.
 Some people inherit an atypical pseudocholinesterase which
cannot quickly metabolise succinylcholine.
 When succinylcholine is given to such people they develop a
prolonged apnea due to persistent action of succinylcholine.

92. DOSE
 The response to a drug may be modified by the dose
administered. Generally as the dose is increased, the magnitude of
the response also increases proportionately till the ‘maximum’ is
reached.
 Further increase in doses may with some drugs produce effects
opposite to their lower-dose effect, e.g.
MYASTHENIA
GRAVIS
NEOSTIGMINE
MUSCLE
POWER
MUSCLE
PARALYSIS

93. DISEASES
 Presence of certain diseases can influence drug responses, e.g.
 Malabsorption Drugs are poorly absorbed.
 Liver diseases Rate of drug metabolism is reduced due to
dysfunction of hepatocytes. Also protein binding is reduced due
to low serum albumin.
 Cardiac diseases In CCF, there is edema of the gut mucosa and
decreased perfusion of liver and kidneys. These may result in
accumulation and toxicity of drugs like propranolol and
lignocaine.

94. REPEATED DOSING
 Repeated dosing can result in -
 CUMULATION : Drugs like digoxin which are slowly eliminated
may cumulate resulting in toxicity.
 TOLERANCE: Tolerance is the requirement of higher doses of a
drug to produce a given response.
TOLERANCE
ACQUIRED
NATURAL

95.  Natural tolerance The species/race shows less sensitivity to the
drug, e.g. rabbits show tolerance to atropine; Black race are
tolerant to mydriatics.
 Acquired tolerance develops on repeated administration of a
drug. The patient who was initially responsive becomes tolerant,
e.g. barbiturates, opioids and nitrites produce tolerance.
 Tolerance may develop to some actions of the drug and not to
others, e.g. morphine— tolerance develops to analgesic and
euphoric effects of morphine but not to its constipating and miotic
effects.

96. MECHANISM OF TOLERANCE
DEVELOPMENT
 Pharmacokinetic Changes in absorption, distribution, metabolism
and excretion of drugs may result in reduced concentration of the
drug at the site of action and is also known as dispositional
tolerance, e.g. barbiturates induce microsomal enzymes and
enhance their own metabolism.
 Pharmacodynamic Changes in the target tissue, may make it less
responsive to the drug. It is also called functional tolerance. It
could be due to down regulation of receptors as in opioids or due
to compensatory mechanisms of the body, e.g. blunting of
response to some antihypertensives due to salt and water
retension.

97.  Cross tolerance is the development of tolerance to
pharmacologically related drugs, i.e. to drugs belonging to a
particular group. Thus chronic alcoholics also show tolerance to
barbiturates and general anesthetics.
 Tachyphylaxis is the rapid development of tolerance. When some
drugs are administered repeatedly at short intervals, tolerance
develops rapidly and is known as tachyphylaxis or acute
tolerance, e.g. ephedrine, amphetamine, tyramine.

98. PSYCOLOGICAL FACTORS
 The doctor-patient relationship influences the response to a drug
often to a large extent by acting on the patient’s psychology.
 The patients confidence in the doctor may itself be sufficient to
relieve a suffering, particularly the psychosomatic disorders. This
can be substantiated by the fact that large number of patients
respond to placebo.
 Placebo is the inert dosage form with no specific biological
activity but only resembles the actual preparation in appearance
(dummy medication).

99.  Placebo medicines are used in –
 1. clinical trials as a control to compare and assess whether the
new compound is significantly better than the placebo.
 2. to benefit or please a patient psychologically when he does not
actually require an active drug as in mild psychosomatic disorders
and in chronic incurable diseases.
 Substances used as placebo include lactose, some vitamins,
minerals and distilled water injections.

100. PRESENCE OF OTHER DRUGS
 The concurrent use of two or more drugs can influence the
response of each other.
 The two drugs that interact does not necessarily mean that their
concurrent use is contraindicated, many can be used together with
dose adjustments. Eg-
 Additive prolongation of prothrombin time and bleeding by
administration of ceftriaxone or cefoperazone to a patient on oral
anticoagulant.

102. CONCLUSION
 Pharmacokinetics and pharmacodynamics models help in
understanding the various parameters involved with controlled
release systems.
 They also help in designing specific requirements required for
drug molecules to be formulated as controlled release system,
there by enhancing better opportunities for the development of
controlled release systems in future.

103. REFERENCES
 Essentials of medical pharmacology 8th edition : Dr. K D Tripathi
 Review of pharmacology 14th edition : Sparsh Gupta
 Basic and clinical pharmacology : Bertram G. Katzung
 Textbook of pharmacology for dental and allied health sciences-
Padmaja Udaykumar