VARIATIONS IN DRUG RESPONSIVENESS

There are 4 general mechanisms that can contribute to variation in drug responsiveness between
individuals:
1. Alteration in concentration of drug that reaches the receptor
a. may result from pharmacokinetic differences which can be affected by AGE, WEIGHT, SEX,
DISEASE STATE, GENETICS.
b. One way to deal with variability is to do repeated measures of blood plasma levels
2. Variations in concentration of an endogenous ligand
a. Propranolol - differences in effect on heart rate depends on endogenous catecholamines
b. Saralasin - effect depends on concentration of angiotensin II.
3. Alterations in number or function of receptors
a. Up/down regulation of receptors
b. Coupling to signal transduction mechanism
4. Changes in components of response distal to receptor
a. Functional integrity of biochemical processes
b. Compensatory responses
CLINICALLY DESIRABLE DRUG INTERACTIONS

Drug interactions are usually thought of as undesirable, as detrimental exaggerations or

dimunitions of the action of one drug upon another. However, drugs are also used concurrently
to enhance or improve their clinical effect.
A desirable drug interaction - may be defined as either a beneficial drug effect that is enhanced or
a detrimental effect that is mitigated by the concomitant use of another drug.
Categories of desirable drug interactions:
1. Additive: the resultant pharmacologic effect is equivalent to the combined effect of each drug
used alone.
Example: use of dopaminergic and anticholinergic drugs in treatment of parkinsonism.
2. Synergistic: the effect produced is greater than the sum of the effect of each drug used alone.
Example: the combination of sulfamethoxazole and trimethoprim to treat certain bacterial
infections.
3. Augmentative: one drug induces and prolongs an increase in the concentration of another
drug in a body fluid.
Example: Probenecid has this effect on penicillin and carbidopa prolongs and increases L-DOPA
levels.
4. Facilitative/Needful: both drugs are needed for the effect to occur, or one drug makes it
possible for the other to produce its desirable action.
Example: Use of penicillin and an aminoglycoside to treat enterococcal infections.
5. Reparative: in such drug combinations, one drug counteracts the undesirable effects of
another.
Example: Combining magnesium hydroxide (laxating) with aluminum (constipating) hydroxide.
6. Complementary: drugs are combined that act through different physiologic mechanisms to
produce a common beneficial effect.
Example: Treatment of congestive heart failure with digitalis and angiotensin converting enzyme
inhibitors.

OTHER COMMENTS
a. Interactive mechanisms may overlap. The effect of antihypertensive drugs may be both
additive and complementary; the net effect is reduction of blood pressure.

b. Another benefit of complementary drug effects may be the use of smaller doses of each drug,
which can lessen the occurrence and severity of undesirable side effects.
c. Multiple drug therapy for a disease blurs with desirable drug interactions. Drugs, acting
through different mechanisms, combine effects to produce the desired therapeutic result.
Possible Relationships Between The Therapeutic And Toxic Effects
1. Beneficial and toxic effects mediated by the same receptor - effector mechanism
a. The toxicity produced by many drugs are simply an extension of their pharmacologic actions,
i.e., insulin, thyroid hormone, anticoagulants
b. Drug is beneficial but may produce unacceptable toxicity at optimal doses
2. Beneficial and toxic effects mediated by identical receptors but in different tissues or by
different effector pathways.
a. Examples - corticosteroids, digitalis
b. Strategies to mitigate this type of toxicity include:
i) use lowest dose possible to get acceptable benefit
ii) use of adjunctive drugs to lower the dose of the first drug
iii) Employ anatomic selectivity
3. Beneficial and toxic effects are mediated by different types of receptors
a. Example - clozapine (clozaril) - antipsychotic action mediated by D2/5-HT2A/alpha1
receptors; toxic effect mediated by interaction with bone marrow stem cells.