Factors Modifying Drug Action

Question 1

Drug Factors

Answer 1

1. Route of administration:
   When a drug is administered through different routes it commonly exhibits qualitative variations and sometimes quantitive variations.

• Qualitative variations :
The drug may produce entirely different response when administered through different routes
I.e;
~ magnesium sulphate orally-> purgative effect
~ magnesium sulphate parenterally->
CNS depression
~magnesium sulphate locally-> reduce oedema in inflamed area

• Quantitative variation :
Oral dose of drug is usually larger than I.V dose since in I.V there is 100% bioavailability of drug
I.e morphine I.V -> 5–10 mg
Morphine oral -> 30-60 mg

2. Presence of other drugs :
   May be in the form of;-
   • Potentiation
   • synergism
   • antagonism
3. Cumulation :
   When the elimination of the drug is slower than the rate of administration; the drug mag accumulate and cause cumulative toxcity
   I.e digoxin, emetin

Question 2

Patient factors

Answer 2

1. Age :
   • In neonates metabolising function of liver and excretory function of kidney is not fully developed
   I.e, chloramphenicol can cause gray baby syndrome

• in elderly the renal and hepatic functions progressively decline
I.e, dose of amino-glycosides is less than normal adult dose

2. Body weight :
   • Rather than calculating dose on the basis of body weight which is inappropriate, a more accurate method for calculating dose is on the basis of body surface area (BSA)

• Nomograms are used to calculate BSA

• Dose of anti cancer drugs and few others drugs are calculated on the basis of BSA

3. Gender :
   • Diuretics and clonidine decrease libido in men
   • Torsades de pointes is a adverse drug reaction which effects women more than men
4. Diet and environmental factors
   • milk reduces absorption of tetracyclines
   • fatty meal increase the absorption of griseofulvin
5. Genetic Factor :
   • G6PD deficiency and haemolytic anaemia
   • succinyl choline apnoea
   • slow and fast acetylators
6. Psychological factors
   • Doctor’s behaviour and as well as patients can affect response to the drug
   • some patients even response to inert dosage forms ( placebo effect )
   I.e sugar tablets and distilled water is used as injections
7. Pathological states :
   a. GI disorders
   Achlorhydria reduces the absorption of acidic drugs in the
   stomach by causing its ionization.
   In malabsorption syndrome  the absorption of some drugs is reduced.

b. Liver disease:
In chronic liver diseases, the metabolism of drugs is greatly reduced which will increase bioavailability of drugs having high first-pass metabolism, e.g. propranolol.

c. Renal failure:
Clearance of drugs that are excreted through kidney is impaired.
For example, the incidence of nephrotoxicity and ototoxicity is more with aminoglycosides in the presence of renal failure

Question 3

Tolerance

Answer 3

•repeated administrations of drugs can result in decrease of their pharmacological effect, hence larger amount of dose is required to produce effect
I.e, ephedrine, opioids
• tolerance is commonly seen with drugs like morphine, alcohol, amphetamine

MOA of tolerance:
1. Pharmacokinetic tolerance:-
Reduced concentration of the drug at the site of action is due decreased absorption and increased metabolism and excretion. I.e Barbiturates

2. Pharmacodynamic tolerance :-
   • The drug effect is reduced, which may be due to decreased number of receptors and neurotransmitters. (Down regulation)
   I.e opioids, barbiturates
3. Cross tolerance;-
   • Tolerance exhibited by two closely related drugs is called cross tolerance
   I.e between opioids & nitrates or ether and alcohol.
4. Tachyphylaxis:
   • when the drug is administered repeatedly at short intervals, the response diminishes rapidly.
   • this is commonly seen with noncatecholamines; ephedrine, amphetamine