This document discusses many factors that can affect how drugs act in the body. It identifies genetic and non-genetic factors like body size, gender, age, nutrition, race, route of administration, environmental conditions, and diseases. These factors can impact drug absorption, distribution, metabolism, and excretion in ways that influence drug concentrations over time. It also covers concepts like tolerance, drug interactions, drug accumulation, and how psychological factors may modify a drug's effects. A thorough understanding of factors that can influence drug action is important for safe and effective use of medications.

1. FACTORS
EFFECTING DRUG
ACTION
SUBJECT- PATHOPHYSIOLOGY (PC511), UNIT- 1
PRIYANSHA SINGH (MS PHARM- PHARMACOLOGY & TOXICOLOGY, NIPER GUWAHATI)

2. Introduction
THERE ARE VARIATIONS IN RESPONSE TO THE SAME DOSE OF DRUG AMONG VARIOUS PATIENTS
OR IN THE SAME PATIENT ON DIFFERENT OCCASIONS.
1. VARIATIONS IN PHARMACOKINETIC HANDLING OF DRUG DUE TO VARIATIONS IN PLASMA/
TARGET SITE CONCENTRATION WHICH IS MORE COMMONLY SEEN IN DRUGS WHICH ARE
METABOLIZED (PROPRANOLOL) RATHER THAN THE DRUGS WHICH ARE EXCRETED UNCHANGED
(ATENOLOL).
2. VARIATIONS IN No./ STATE OF RECEPTORS, COUPLING PROTEINS OR OTHER COMPONENTS IN
RESPONSE EFFECTUATION.
3. VARIATIONS IN NEUROGENIC/ HORMONAL CONCENTRATIONS LIKE ATROPINE INDUCED
TACHYCARDIA IS DUE TO DIFFERENCES IN VAGAL TONE, PROPRANOLOL CAUSES BRADYCARDIA
DEPENDING UPON SYMPATHETIC TONE etc.
Categories of factors: Genetic and Non-genetic including environmental, circumstantial and
personal variables
• Factors modify drug action
– Quantitatively – action increased or decreased
– Qualitatively: Altered response – allergic reaction or idiosyncrasy

3. Factorsaffectingdrugaction
1. BODY SIZE
2. GENDER BASED
3. AGE BASED
4. NUTRITION
5. GENETIC FACTORS
6. RACE & SPECIES
7. ROUTE OF ADMINISTRATION
8. ENVIRONMENTAL FACTORS
9. PSYCHOLOGICAL FACTORS
10. PATHOLOGICAL CONDITIONS
11. DRUG INTERACTIONS
12. CUMULATION
13. TOLERANCE

4. BODY SIZE
1. Influences the conc. of the drug attained at the site of action obese/lean/children. It is
actually more related to Volume of Distribution (Vd) and its pattern.
Individual dose = {BW(kg)/70} x average adult dose
2. BSA is a more accurate measure of dose calculation as total water, extracellular fluid
volume & metabolic activity are better related with BSA.
Individual dose = [BSA(sq. m.)/1.7] x average adult dose
3. BSA can be calculated by Dubois Formula
BSA (m2) = BW (kg)0.425 x Height (cm)0.725 X 0.007184
4. Dose recommendations in terms of BSA is available for only Anticancer drugs and other
handful of drugs. Otherwise BW is taken as an index to measure the dose.

5. GENDER BASED FACTORS
1. Females have smaller body size – required doses are lower
2. Digoxin in Maintenance therapy of heart failure has a higher mortality rates among women than men
3. Beta blockers, methyldopa, diuretics – sexual function interference in males.
4. Gynecomastia – Metoclopramide, chlorpromazine, ketoconazole etc.
5. In females, special consideration must be given to menstruation, lactation and pregnancy.
6. Pregnancy – particularly in 3rd trimester there are marked & progressive physiological changes during
pregnancy which alters drug disposition.
Eg.- GIT motility is reduced causing delayed absorption of orally administered drug
Eg.- Plasma & ECF expands Vd may increase.

6. FACTORS EFFECTING DUE TO AGE
 Infants & children are not small adults – physiological differences
 Low g.f.r and tubular transport therefore T1/2 of Gentamicin and Penicillin (drugs excreted by G.F.R.) is prolonged by 3-5 times.
 Low hepatic drug metabolizing systems in new-borns – grey baby syndrome due to chloramphenicol
 Blood brain barrier (BBB) is more permeable- drugs attain a higher concentration in CNS (accumulation of unconjugated bilirubin
causes Kernicterus)
 Absorption of drugs altered – lower gastric acidity and slow intestinal transit
 Faster transdermal absorption and faster rectal absorption – Diazepam for febrile seizures in children <5 Y.O.
 After 1 year faster metabolism than adults – phenytoin, carbamazepine T1/2 is shorter in children

7.  Aged population are relatively intolerant to digitalis. The responsiveness of beta adrenergic receptors to
both agonists and antagonists is reduced in the elderly & sensitivity to other drugs may also be altered.
 Due to prostatism in elderly males, even mild anticholinergic activity of the drug can accentuate bladder
voiding difficulty.
 Elderly are also likely to be on multiple drug therapy for various CVS disorders which increases the
chances for drug interactions.

8. INFLUENCE OF NUTRITION ON DRUG
ACTION
Dietary intake influences the drug pharmacokinetic parameters and disposition.
1. Absorption- presence of food either increases or decreases the absorption of drugs.
2. Distribution- a previously bound drug is displaced and it increases the plasma conc. Of the
drug leading to an increased effect.
3. Metabolism- high protein diets are linked with increased drug metabolism & drug
carbohydrate diets are linked with decreased drug metabolism. Malnourishment decreases
metabolism.
4. Excretion- High protein diet increases kidney function/ GFR.

9. GENETIC FACTORS
1. Determinants of drug responses – transporter, enzymes, ion channels, receptors and
couplers – controlled genetically -Individual variation of responses
2. Pharmaco-genetics: Use of genetic information to guide the choice of drug and dose on an
individual basis – to identify individuals who are either more likely or less likely respond to a
drug.
3. Pharmaco-genomics: the use of genetic info to guide the choice of drug and dose on an
individual basis. It tends to identify individuals who are either more likely or less likely to
respond to a drug, as well as those who require altered dose of certain drugs.
so far genetic abnormalities have been identified
Personalized medicine goal yet to achieve
G-6PD deficiency – Primaquine, chloroquin, quinine, dapsone, aspirin
Malignant hypothermia with halothane etc.
Low variants of CYP2C9 – Warfarin bleeding; Isoniazid - acetylators

11. RACE & SPECIES
 Species variation in drugs responses do exist
 Some strains of rabbits – resistant to atropine
 Rat and mice are resistant to digitalis
 Race – racial differences have been observed
Eg.1 Blacks require higher doses of atropine and
ephedrine, while Mongols require lower doses
Eg.2 Africans – beta blockers are less effective
Eg.3 SMON – Japan but not among Indian

12. ROUTE OF ADMINISTRATION

13. ENVIRONMENTAL FACTORS
Drug metabolism may get induced –
exposure to insecticides, carcinogens,
tobacco smoke and charcoal broiled meat
etc.
Food interferes absorption of some drugs
while enhances some drugs – ampicillin
gets reduced griseofulvin gets enhanced

14. PSYCHOLOGICAL FACTORS
 Efficacy of a drug can be affected by patient`s beliefs, attitudes and expectations –
particularly CNS drugs – more GA in nervous and anxious patients – alcohol and
performance
 Placebo: An inert substance which is given in the garb of medicine. Works by
psychodynamic effects (not pharmacodynamics) – sometimes responses equivalent to
active drugs
 Placebo reactors
 Induce psychological responses – release of endorphins in brain
 Uses – Control device in clinical trials and to treat a patient
 Lactose tablet/capsules or water injections etc.
 Nocebo: Negative psychodynamic effects evoked by the pessimistic attitude of the
patients. Can oppose the effect of the active medication prescribed.

16. PATHOLOGICAL CONDITIONS
 Diseases can influence drug disposition – GIT diseases, Liver diseases, Kidney
diseases, Congestive heart failure and Thyroid etc.
 GIT: Coeliac diseases – amoxicillin absorption decreased while Cephalexin
and cotrimoxazole increased; Achlorohydria – Reduced aspirin absorption –
NSAIDs aggravate peptic ulcer

17.  Liver diseases: Liver disease (cirrhosis) influence drug action
Increased bioavailability of drugs with high first pass metabolism
Serum albumin reduced – protein bound drugs like Warfarin – more free
Metabolism and elimination of drugs may be reduced – Doses should be
reduced – Morphine, Propranolol, lignocaine etc.
Prodrugs are less effective (becampicillin)

18.  Kidney diseases: Pharmacokinetics of many drugs are affected
Clearance of drugs in unchanged form (aminoglycosides, digoxin,
phenobarbitone) reduced – parallel to CLcr - loading dose not altered –
should be reduced
Plasma protein, albumin reduced – binding of acidic drugs affected
Permeability of BBB increased – Opiates etc. more CNS depression
Drugs acting via kidney mechanism – become ineffective – Thiazides and
urinary antiseptics

19.  CVS disorders- Alter drug kinetics by decreased absorption
(Thiazide), (2)
 modifying Volume of distribution Lignocaine), (3) retarding
the elimination (lignocaine)- decreased perfusion and
congestion of liver; reduced g.f.r, increased tubular
reabsorption – doses need reduction

20.  Thyroid diseases:
 Hypothyroid states – sensitive to digoxin, morphine and CNS
depressants;
 Hyperthyroid states – resistant to inotropic action – prone to cause
arrhythmia by digoxin
 OTHER MISCALLANEOUS CONDITIONS

21. DRUG INTERACTIONS
Presence of other drugs:
Drug interactions –
Pharmacokinetic and
Pharmacodynamic

22. CUMULATION
 If Rate of administration > Rate of elimination – cumulation. Slowly
eliminating drugs are prone – Prolonged use of Chloroquine can cause
retinal damage

23. TOLERANCE
 Requirement of higher dose of a drug to produce a given response – refractoriness –
sulfonylureas in type 2 diabetes and beta-2 agonists in bronchial asthma - adaptive
biological phenomena
 Natural: Species/individual inherently less sensitive – Rabbits to atropine and Blacks to
beta – blockers
 Acquired: Repeated use of a drug in an individual who was initially responsive become
non-responsive (tolerant) – CNS depressants
 Due to uninterrupted presence of drug in the body it favors occurrence of tolerance in
the body.
 Tolerance may develop to one action of the drug – but not to other action –
Chlorpromazine, phenobarbitone, Morphine
 Cross tolerance: Tolerance to pharmacologically related drugs – alcoholics to barbiturates
and GA; Morphine and Pethidine

24. SUMMARY
Remember the different factors modifying drug actions
Remember: Young’s formula, Placebo, Cumulation, Tolerance,
cross tolerance and Tachyphylaxis
Drug use in children, elderly, pregnancy and different
pathological states will be discussed individually