This document discusses factors that can modify a drug's effects in the body. It summarizes that individual responses to drugs can vary due to differences in pharmacokinetics and pharmacodynamics. Genetic and non-genetic factors like age, disease states, diet, and concurrent medications can impact drug absorption, distribution, metabolism, and excretion. Drug interactions, tolerance, and cumulative effects are also reviewed. The document emphasizes considering a patient's individual factors when determining appropriate drug dosing to achieve the desired therapeutic effects while avoiding unnecessary adverse reactions.

1. Dr. Anisha Pamarthi
JR 1
Dept. of Pharmacology
GMC, Nagpur

2. • Introduction
• Factors modifying drug action
• Summary

3. Variation in response to the same dose of a drug
between different patients & even in the same patient
on different occasions
(1) Individuals differ in pharmacokinetic handling of
drugs
(2) Variations in number or state of receptors, coupling
proteins or other components
(3) Variations in neurogenic/hormonal tone or
concentrations of specific constituents

4. Genetic NongeneticTwo categories
environmental,
circumstantial,
personal
variable

5. Quantitatively - plasma concentration and/or the
action of the drug is increased or decreased
Qualitatively-The type of response is altered
e.g. drug allergy or idiosyncrasy.

6. Factors modifying dose &
drug action
Biological Factors
Modified drug effect after repeated
administration of single drug
Modified drug effect after concurrent
administration of two different drugs

7. Age
body weight
& BSA
Gender
Genetic
Psychological
factors
Diet
Environment &
timing
Pathological
state
Route of
administration

8. Infants & Neonates
 Low gastric acidity- bioavailability of penicillins
 Prolonged gastric emptying time
 immature intestinal mucosa
 Reduced splanchnic & enteric blood flow
 Reduced PPB – higer plasma conc of free drug eg;
phenytoin, phenobarbitone
Delayed absorption of valproic acid, carbamazepine
Reduced absorption of Phenytoin , Phenobarbitone

9.  Immature BBB & relatively high cerebral
blood flow higher amounts of lipophilic drugs
enter brain
 Deficient Conjugation – Chloramphenicol
induced grey baby syndrome
 Deficient renal tubular secretion – prolongs
half life of penicillins

11. Young’s Formula
Child’s Dose =
Age in yrs
Age + 12
× Adult dose
Dilling’s Formula
Child’s Dose =
Age in yrs
20
× Adult dose

12. Cowlings formula
Dose of child = Age(years) + 1/24 x Adult dose
Fried’s formula
Dose of child= Age(months)/150 x Adult dose

13. Bastedo’s formula:
Dose of child = Age (years) + 3/30 x Adult dose
Clarks formula:
Dose of child = weight (pounds)/150 x Adult dose

15.  Cardio Vascular response to sympathomimetic
agents is reduced
 Age related decrease in renal function
renal elimination of Digoxin
 K
3/4th of the adult dose
to pt above 60 yrs

16.  The recommended dose is calculated for
medium built persons
 For obese and underweight person dose is
calculated individually
Dose =
Body weight(kg) × average adult dose
70

17.  Doses calculated may not be accurate
 In odema there is increase in BW due to fluid &
hence dose will be higher
 In severe dehydration BW is decresed & dose
will be less

18.  More precise index than body weight
Dose =
BSA (M2)
1.8
× Adult dose
For anticancer drugs eg methotrexate dose is
calculated depending on Body surface area

19.  Drug responses in men & women are not always
same
 Eg: 1. Ephedrine may produce more excitation
and tremors in women than men
2. α-methyldopa, β blockers, diuretics,
ketoconazole cause loss of libido in men

20.  In females
During menstruation : purgatives -increase
pelvic congestion -increase menstrual blood loss
 During pregnancy : Physiological changes that
alter drug disposition—
1. GI motility reduced—delayed absorption of
orally administered drug.

21. 2. Plasma and ECF volume expands—volume of drug
distribution may increase
3. Plasma albumin fall, alpha glycoprotein increases—
unbound fraction of acidic drugs increases but
basic drug decreases.
4. Hepatic microsomal enzymes undergo induction
drugs are metabolized faster.
5. Renal blood flow increased
 Uterine stimulants -risk of abortion eg ; castor oil,
ergot alkaloids

22. Drugs crossing placenta is contraindicated-
Eg - Methotrexate
ACE inhibitors
Anticholinergic drugs
Antithyroid drug
carbamazepine
lithium
phenytoin
oral hypoglycemic agent
valproic acid , warfarin

23.  There is difference in response to drugs
among different species
e.g 1) Rabbits are resistant to atropine
2) Rats & mice are resistant to digitalis
3) Rat is more sensitive to curare than
cat
These differences are important while
extrapolating results from experimental
animals to man

24.  Blacks require higher & mongols
require lower concentration of
atropine & ephedrine to dilate to
dilate their pupil
 ẞ blockers are less effective as
antihypertensive in blacks
 Indians tolerate thiacetazone
better than whites
Race

25.  At high altitudes, due to reduced rate of
biotransformation even usual doses may
produce toxicity
 Glucocorticoid taken as OD dose in morning
minimise the risk of pituitary adrenal
supression
 Diurnal variation should be considered while
determining the dose of antihypertensive drug

26.  Food interferes with absorption of
many drugs
 Eg; tetracyclines form complexes
with calcium in food & are poorly
absorbed
 Polycyclic hydrocarbons in cigarette
smoke may cause microsomal enzyme
induction
Absorption increased by
food-
Spironolactone
Lithium
Riboflavin
Absorption Reduced by
food-
Ampicillin
Rifampicin
INH

27.  Drug’s Efficacy can be affected by patient ’s
expectations and attitudes
 Some patients respond to Placebo
PLACEBO = “I SHALL PLEASE”
Placebo is inert dosage form with no specefic
biological activity but only resembles the actual
prepaation in appearance(dummy medication)
Uses
1. Clinical trials
2. Benefit a pt
psychoogically

28.  Eg : lactose, vitamins, minerals, distilled water
injection
 Injections have more pronounced effect
 Placebo can release endorphins in brain -
analgesia

29. Genetic Factor
Effects
of genetic
polymorphism
Pharmacokinetic
Pharmacodynamic
Changes in
Absorption
Distribution
Metabolism
Excretion
Variation in
Receptors,
Enzymes,
Susceptibility
to disease

30.  Production of drug metabolizing enzyme is
genetically controlled & variations are
common
 Eg:
Oxidation of Drugs : genetic polymorphism in
cyt P450 leads to variation in metabolism
eg: SSRI, Phenytoin, Warfarin

31.  Acetylation of drugs:
slow acetylators – lupus erythematous
(hydralazine)
Fast acetylators- hepatotoxicity
 Atypical Pseudocholinesterase: prolonged
apnea due to persistent action of
succinylcholine

32.  Variations in receptor, enzymes, susceptibility
to ADRs & disease
 G6PD deficiency : hemolysis (primaquine,
sulphones)
 Malignant hyperthermia: inherited abnormality
in Ca 2+release from sarcoplamic reticulum
(halothane, sevoflurane, succinylcholine)

33. 1) Gastrointestinal diseases
• Can alter absorption of orally administered drugs
• Drug absorption can be increased or decreased
e.g
In coeliac disease absorption of amoxicillin is
decreased but that of cephalexin & cotrimoxazole is
increased

34. 2) Liver disease
 Bioavailability of drugs having high first pass
metabolism is increased
 Protein binding of acidic drugs
(phenylbutazone,etc) is reduced & more drug is
present in free form

35.  Metabolism & elimination of some drugs
(morphine, lidocaine, propranolol, etc) is
decreased & dose should be reduced
 Prodrugs needing hepatic metabolism for
activation (e.g prednisone, bacampicillin) are
less effective & should be avoided

36. 3) Kidney disease
 Albumin level is altered – binding of
acidic drugs is reduced
 Permeability of blood brain barrier
is increased – opiates, barbiturates
produce more CNS depression
 Target organ sensitivity may also be
increased – antihypertensive drugs
produce more postural hypotension

37.  NSAIDs cause more fluid retention
 Thiazide diuretics which tend to reduce GFR
are ineffective in renal failure – can worsen
uremia
 Potassium sparing diuretics C/I, can cause
hyperkalemia – cardiac depression

38. 4) Congestive heart failure
 Mucosal edema & splanchnic vasoconstriction
→ decrease in drug absorption from GIT
e.g Procainamide & hydrochlorothiazide
 Expansion of extracellular fluid volume → Vd
of some drugs can increase
Loading doses of drugs like
lidocaine & procainamide should be
lowered

39.  Decreased perfusion & congestion of liver,
reduced GFR & increased tubular reabsorption
↓
decreases drug elimination
Dosing rate of drugs like lignocaine,
theophylline should be reduced

40. 5) Thyroid disease
 Hypothyroid patient → more sensitive to
digoxin, morphine & other CNS depressants
 Hyperthyroid patient → more prone to
arrhythmic action of digoxin

41. governs speed & intensity of drug responses
A drug may have entirely different uses through
different routes
e.g Magnesium sulphate
• Orally → purgation
• Applied on inflamed areas → decreases swelling
• Intravenously → produces CNS depression
& hypotension

42. Modified drug effect after repeated
administration of single drug
Drug tolerance
Drug resistance
Cumulation

43.  Need to increase the dose to produce response
of equal magnitude & duration

44.  Common with morphine, alcohol, barbiturates,
LSD
 Not uniform to all pharmacoological effects
eg: 1.tolerance developes to all pharmacological
effects of morphine except miosis &
constipation
2. to sedative action of chlorpromazine & not to
its antipsychotic effect

45. 1. Natural
2. Acquired
3. Cross tolerance
4. Tachyphylaxis

46.  Refers to genetically determined lack of
sensitivity to a drug
 e.g. Rabbits - Tolerant to atropine
Black races - Tolerant to mydriatics

47.  Occurs due to repeated use of drug
 Two types
i) Pharmacokinetic (dispositional ) tolerance
e.g. alcohol , barbiturates, amphetamine
ii) Pharmacodynamic (cellular adaptive ) tolerance
e.g. Morphine , barbiturates(barbital)

48.  Development of tolerance to pharmacologically
related drugs
 e.g. 1)Tolerance between morphine (opioid) and
heroin (opioid)
 2) Chronic alcoholics show tolerance to
barbiturates and general anaesthetics

49.  Acute development of tolerance after rapid and
repeated administration of drug over a short
interval
 Original effect can not be achieved even after
increasing dose
 e.g. Amphetamine, tyramine, ephedrine

50.  It is reduced effect or no effect of
antimicrobial agents against microorganism
Natural
• Penicillin G
is not active
against gram
positive
bacteria
Acquired
• Develops over a
period of time
• Eg:
staphylococci,
coliform
Cross
• Micro-
organisms
resistant to
one sulfa drug
exhibit
resistance to
all sulfonamides

51.  Any drug will cumulate in the body if rate of
administration is more than the rate of
elimination
 Slowly eliminated drugs can cause cumulative
toxicity
 e.g. chloroquine, digoxin

52.  To avoid cumulation-
A. One must know drug elimination- slowly or
rapidly.
B. Stop drug administration at appearance of
first warning symptom.
C. Select carefully form in which drug is to be
administered.
D. Check liver and kidney function before drug
administration.

53. Modified drug effects after concurrent
administration of two different drugs
1.Summation
2.Synergism
3.Drug
antagonism

54.  When two drugs elicit the same response, but
with different mechanisms, their combined
effect is equal to the sum of their individual
effects (1+1=2)

55.  Combined effect of two drugs is greater than
algebric sum of their individual effect
 When two drugs act at different site

56.  Synergism where one drug alters the
pharmacokinetics of other

57. • Chemical antagonism
• Physiological antagonism
• At receptor level
One drug opposing or inhibiting the action of
another drug is antagonism

58.  Two substances interact chemically to result in
inactivation of effect
eg: chelating agents form inactive soluble complexes
with heavy metals like lead
2. Physiological antagonism
 Two drugs act at different site to produce opposing
effects
eg: histamine acts on H1 receptors to produce
bronchospasm & hypotension while adrenaline
reverses the action by acting on adrenergic receptors

59. Competitive
Non-Competitive

60.  When antagonist
combines with the
same receptor on
which agonist combines
& opposes the effect
of agonist, such
antagonism is called
competitive antagonism

61.  Effect of agonist can again be obtained on
increasing the dose / concentration
Eg:1. atropine is competitive antagonist of ach at
muscarinic receptors
2. Naloxone competitive antagonist of morphine
at opioid receptor

62.  Antagonist binds tightly with same receptor
(on which agonist combines) and does not
dissociates or dissociates very slowly from
the receptor, so that the agonist cannot bind
with receptor
 Higher doses of agonist cannot overcome
effect of antagonist i.e. It is insurmountable
or irreversible

63.  The log-dose response
curve show reduced
efficacy in the presence
of irreversible
antagonist
 e.g. Irreversible
blockade of acetyl
choline esterase enzyme
by organophosphate
compounds

64.  Response of agonist is
blocked by antagonist by
acting at different site
and not on the receptor
of agonist
 e.g. verapamil
antagonises cardiac
contraction by
norepinephrine

65.  Treatment of certain conditions and poisoning
e.g. Antacids for peptic ulcer (chemical
antagonism)
Naloxone for opioid poisoning
 To overcome or reduce the adverse effect of a
drug
e.g. Use of benzhexol with trifluoperazine
reduces extrapyramidal side effects of
trifluoperazine

66.  Drug response may vary in different individuals
even when same dose is used due to altered
pharmacokinetics & pharmacodynamics
 It is very important to consider these factors
before prescribing drugs for any patient so
that desired response is achieved &
unnecessary adverse effects are avoided

67.  Basic and clinical pharmacology, Katzung :13th
edition
 H . L. Sharma, K. K. Sharma ;chapter 7
Pharmacodynamics; Principles of Pharmacology ;
2nd edition
 Padmaja Udaykumar; chapter 3
Pharmacodynamics; Medical Pharmacology; 5th
edition

68. Next PG activity by
Dr. Vinay Bajaj
Journal Reporting
27/09/17