Factors modifying

drug response
 Variation in response to same
dose of a drug between different
patients and in the same patient
on different occasions is rule
rather than exception
• Difference in Pk handling-
Propranolol> atenolol
• Variation in number or state of
receptors
 Factors modifying drug response:

 Physiological factors (age, sex, pregnancy, lactation, body

wt., food)

 Pathological state (kidney or liver disease)

 Environmental factors

 Psychological /emotional state

 Interaction with other drugs/ food.

1.Body size-
• It influences the drug conc. attained at
the site of action.
• Average adult dose refers to
individuals of medium built.
• Obese, lean7 and children dose is
calculated1.0on B.W basis.
7
• Dose = BW(in Kg) X Average
adult dose.
• Dose = BSA(m2) X A. adult
2.Age-
Children dose(C.D) is often
calculated from adult dose.
 C.D=Age
age X adult dose (Young's
+12
Formula)
2
0
 C.D = age X adult dose (Dilling’s
Formula)
Can be calculated on BW or BSA.
 Newborns/infants-
• Absorption may be altered due to low
gastric acidity & slow intestinal
transient.
• Transdermal absorption is faster.
• BBB is more permeable& drugs attain
higher conc. in CNS
e.g., accumulation of uncojugated
bilirubin causes kernicterus.
• Inadequate metabolism-
• 1st yr-drug metabolism is faster than
adults-
e.g., Theophylline, Phenytoin- has a t1/2
is shorter.
• High dose is required than adults
which are excreted as unchanged-
Digoxin.
• Solid dosage forms & aerosols are
difficult-in young children.
• More susceptible to special adverse
Elders-
• Slower absorption due to low motility,
blood flow & lesser Ptn binding, and
Vd of lipophilic & hydrophilic drugs.
• Renal function progressively declines-
Drug dose has to .
e.g., Streptomycin is 0.75g after 50yrs
& 0.5g after 75yrs of age when
compared to 1g for adults.
• Drug metabolising activity & liver
• Aged are relatively intolerant to
digitalis.
• Responsiveness to agonists &
antagonists are in elders.
• Incidence of ADR are more in elders.
3) Sex-
• Females have smaller body size &
requires less dose.
• mortality with Digoxin for CCF is more
in women > men.
• Drugs adm during pregnancy can
affect the foetus due to-
• Physiological changes occur in
pregnancy are-
Lipophilic drugs cross placental
barrier
changes in plasma ptn binding,
GIT motility
 CO
GFR & renal elimination
Metabolism of some drugs .
E.g., pregnant uterus becomes more
sensitive to oxytocin.
Lactation-
• Avoid drugs during lactation due to
harm to baby
• Drugs easily appear in milk but <
therapeutic dose
• E.g., tetracycline, sedatives,
hypnotics, opioids
4.Specices & Race-
• Rabbits-atropine, rats/mice- digitalis.
• Rats are sensitive to curare than cats.
• Blacks require high & Mongols
requires low doses of atropine &
ephedrine.
• β-Blockers are less effective as Anti-

HTN agents in caribbeans.

• Apalstic anaemia with
Chloramphenicol is less in Indians
6) Genetics-
• Dug dose producing same effect may
vary among different individuals.
• All key determinants of drug response
are controlled by genetically.
• P.genetics -deals with genetic
influences on drug action as well as
drug handling by body.
• P.genomics -use of genetic
information to guide the choice of the
•Atypical pseudocholine esterase Succinylcholine apnoea

•G-6PD deficiency Haemolysis- primaquine, dapsone,

sulphonamides

•Low activity of CYP2C9 variants Risk of bleeding-Warfarin

•TMPT deficiency Risk of bone marrow toxicity - 6MP

•UGT1A1*28 allele- glucuronyl Neutropenia-Irinotecan

transferase

•DPD deficiency Toxicity-5FU

•Over expression P-gp Tumour resistance-anticancer drugs

•Poly morphisim of NAT-2 Neuropathy-INH

SLE-hyralazine, procanamide
Abnormal CYP2D6 Poor metabolism of Metoprolol,
debrisoquine, codeine fails to
produce analgesia.

Raynodine receptor- abnormal Malignant hyperthermia-halothane

Poor hydroxylation Phenytoin toxicity

Narrow iridicorneal angle Attack of angle closure glaucoma -

mydratics

Genotyping of the individual -but

application is limited
E.g. simple spot test for G-6-PD
6.Route of administration-
• Governs the speed & intensity of
response.
• Parental adm –more rapid response &
predictable drug actions.
• Drug may diff. uses through different
routes of adm-
MgSO4
 Orally- purgation
 Topical-Sprained joints- reduces
 Oxytocin – IV infusion – induction of
labour
IM – PPH
intranasal spray – milk
ejection
7.Environmental factors and time of
administration-
• Several environmental factors affects
drug response like-
passive smoking, charcoal broiled meat,
insecticides
Time of Food & drug intake also
interferes with response- Ampicillin &
Griseofulvin.
Hypnotics effective in night times.
8. Psychological factor-
• Efficacy of drug can be affected by
pt’s beliefs , attitude & expectations –
CNS acting drugs.
• Placebo- I shall please.
• Its a pharmacological inert substance
given in the name of medicine to pt.
• It works by pharma, physio,
psychological means & often
produced equivalent response to the
9.pathological states-
GIT:
 Coeliac disease- Cephalexin↑, amoxicillin↓
 Gastric statis in migraine ↓
 Achlorhydria ↓aspirin
 NSAIDs aggravate PUD.
Liver :
 BA ↑ for high first metabolism drugs
 Albumin ↓.. So PPB of acidic drugs
 Metabolism & elimination of lidocaine,
morphine is decreased
No simple test like creatinine
clearance to guide the extent of
alteration in drug disposition, kinetics
of diff drugs is affected by diff.
extents.
Drug action also altered;
 Sensitivity of brain.. Morphine,
barbiturates.
 Oral anticoagulants ↑PT as clotting
factors low.
Congestive cardiac failure:
 ↓ absorption from g.i.t (mucosal
edema) e.g. procainamide
 ↓ elimination as result of ↓ perfusion
& congestion of liver, ↓ GFR,
 Loading & maintenance doses of
lidocaine should be lowered.
 More sensitive to digitalis.
kidney disease
 Clearance ↓ for drugs excreted
unchanged ..
Aminoglycosides, digoxin.
 Dose should be reduced or interval
prolonged
 Albumin is low/altered in structure.
 BBB permeability ↑ so CNS
depresants.
 Pethidine (X)---- norpethidine.
 NSAIDs cause fluid retention.
 X nephrotoxic drugs amino
glycosides, AMP-B, Vancomycin,
cyclosporine, Tetracyclines (except
Doxycycline).
 Urinary antiseptics- Nalidixic acid,
nitrofurantoin fail to act.
Thyroid disease
 Hypothyroid.. Sensitive to morphine,
Digoxin
11.other drugs:
Pharmacokinetic / pharmacodynamic
eg: diabetics receiving OHA / insulin
furosemide & aminoglycoside –
enhanced ototoxicity
12. Cumulation
Rate of administration>>>
elimination
Chloroquine -Retinal damage
13.Tolerance
• Requirement of higher dose to
produce same response.
• Loss of therapeutic use (sulfonylurea's
in type 2 DM).
• Tolerance is widely a adaptive
biological phenomenon.
• Tolerance may be a Natural and
Acquired.
a) Natural – inherently less sensitive to
b) Acquired-
Repeated use of a drug in an
individual who is in initially
responsive.
 Uninterrupted presence favours to T.
 T doesn’t develop to atropine,
cocaine, digitalis, Sodium
Nitroprusside.
 T may not develop to all actions of a
same drug.
constipating & miotic actions.
 Sedative action of phenobarbitone
but not to antiepileptic action.
c) Cross tolerance
 Developed only to Pharmacologically
related drugs.
 Alcoholics- tolerant to barbiturates
and GA
 Closer drugs …. More complete is
cross Tolerance.
Mechanisms
 PK/ Drug disposition–
Effective conc. of the drug at the site of
action is due to drug metabolism.
e.g., Barbiturates, carbamazepine &
amphetamine.
 PD/ cellular– drug action lessened due
to down regulation of receptors or ↓
in response effectuation.
e.g., morphine, barbiturates & nitrates.
14.Idiosyncrasy—
• Persons responds to certain drugs in a
completely abnormal from the usual
actions of that drug.
• Thus morphine may produce
excitation instead of sedation.
• Some of these actions have been
found to be due to genetic
abnormality.
Eg: barbiturates – excitement, confusion
15.Tachyphylaxis ( tachy-fast, phylaxis -
protection)
• Rapid development of tolerance when
doses of a drug repeated in a quick
succession –reduction in response.
• Mostly with indirectly acting drugs-
Ephedrine, Tyramine, Nicotine.
• They act by releasing CA >>>>>
synthesis- due to depletion of stores.
• May be also due slow dissociation of
16.Drug resistance– tolerance of
microbes to AMAs.
a) Drug tolerant: -Loss of affinity of
target biomolecule
E.g.: trimethoprim
b) Drug destroying: - Elaborates
enzyme
E.g.: staphylococci, haemophilus
,gonococci -β lactamases.
c) Drug impermeable: Lack transport
Prevention of drug resistance :
• No indiscriminate, inadequate or
unduly prolonged use of AMA
• Prefer narrow spectrum AMAs
• Use combination of AMAs. Eg:
TB
• Intensive treatment
17.Potentiation:
• Enhancement of effect of one agent
by another; so that the combined
effect is more than the sum of their
individual effects is called
“Potentiation.”
• In case of potentiation one agent has no effect
when give alone but increases the effects of
other co-administered drug. 0 + 1 =  2.
Example:
• Levodopa + Carbidopa => Parkinsonism.
18. Synergism – Additive &
supraadditive
a) Additive:
Effect of drugs A +B = effect of drug A
+ effect of drug B
Eg: aspirin + paracetamol
b) Supraadditive:
Effect of drug A+B > effective of drug
A+ effect of drug B
Eg: acetylcholine + physostigmine
19. Antagonism: physical, chemical,
physiological & receptor.
a) Physical: -Charcoal – alkaloids
b) Chemical:
KMnO4 – alkaloids
Chelating agents – complex metals
c) Physiological :
Histamine, adrenaline – bronchial
muscle, BP
d) Receptor-competitive , non
equilibrium & non competitive .
i) Competitive:
Agonist, antagonist – same receptor
Reversed by increasing concentration
E.g.: Ach, d-tubocurarine at NMJ
ii) Non equilibrium :
E.g.: OP compounds – cholinesterase
iii) Non competitive :
+2
iv) Negative antagonism-
• Produces actions that are opposite
to those of agonists.
E.g. β-carbolins-BZD receptors.
Importance:
 Correcting the adverse effects of a
drug
E.g. H2 blockers - NSAIDs
 Treatment of drug poisoning
E.g. morphine – naloxone
20.Drug interactions- It may result in
• Alteration in effectiveness / toxicity of
one drug by another drug
simultaneously adm.
• Biological interference with lab tests-
mislead the diagnosis.
D. D. interactions can occur –
In vitro- Penicillin's + AMG’s given in a
same syringe.
I) In vivo- due to P.K reasons-
b) Alteration in distribution-
• Salicylates, sulphonamides displaces
the tolbutamide &
Warfarin- hypoglycaemia & bleeding.
c) Alteration in metabolism-
• Barbiturates- anticoagulant effect of
Warfarin.(E.induction)
• MAOI’s- Resp. Depression of
morphine.(E.inhibition).
d) Alteration in excretion-
ii) In vivo- due to P.D reasons-
a) Different antagonism
b) Interfere with neuronal uptake/N.T
release-
TCA blunts Anti-HTN effect of
clonidine.
c) additive/summation-Discussed
earlier.
d) Changes in ionic balance-
Loop diuretics the digitalis toxicity due
• Extra matter of ur interest
Temperature-
• Addition of mild to moderate
hypothermia decreases the systemic
clearance of CY450 metabolizes drugs
between 7-22% per degree Celsius
below 37c during cooling. The
addition of hypothermia decreases
the potency and efficacy of certain
drugs .
• The therapeutic index of certain drugs
• Food-Drug Interaction
• 􀂾 Grapefruit juice may inhibit metabolism of
certain drugs, raise the blood levels
(coadministration of grapefruit juice produce a
40% increase in blood levels of felodipine- drug
for hypertension), and lead to toxicity level.
• 􀂾 Grapefruit juice may inhibits
• cytochrome P450 enzymes and decrease
metabolism of certain drugs: One glass (200 ml)
is sufficient