Mechanisms of Pharmacokinetic Drug Interactions

Mechanisms of Drug Interactions

The three mechanisms by which an interaction can develop are —

1. Pharmaceutical Interaction – Also called as incompatibility, it is a physicochemical interaction that occurs when drugs are mixed in i.v. infusions causing precipitation or inactivation of active principles, for example, ampicillin, chlorpromazine and barbiturates interact with dextran in solutions and are broken down or form chemical complexes.

2. Pharmacokinetic Interactions – These interactions are those in which the absorption, distribution, metabolism and/or excretion of the object drug are altered by the precipitant and hence such interactions are also called as ADME interactions. The resultant effect is altered plasma concentration of the object drug. Pharmacokinetic interactions can thus be classified as –

(i) Absorption interactions – are those where the absorption of the object drug is altered. The net effect of such an interaction is –

·           Faster or slower drug absorption

·           More, or, less complete drug absorption.

Major mechanisms of absorption interactions are –

·           Complexation and

·           adsorption. Alteration in GI

·           pH. Alteration in gut motility.

·           Inhibition of GI enzymes.

·           Alteration of GI microflora.

·           Malabsorption syndrome.

(ii) Distribution interactions – are those where the distribution pattern of the object drug is altered. The major mechanism for distribution interaction is alteration in protein-drug binding.

(iii)Metabolism interactions – are those where the metabolism of the object drug is altered. Mechanisms of metabolism interactions include –

·           Enzyme induction – increased rate of metabolism

·           Enzyme inhibition – decreased rate of metabolism. It is the most significant interaction in comparison to other interactions and can be fatal.

(iv) Excretion interactions – are those where the excretion pattern of the object drug is altered. Major mechanisms of excretion interactions are –

·           Alteration in renal flood flow – e.g. NSAIDs (reduce renal blood flow) with lithium.

·           Alteration of urine pH – e.g. antacids with amphetamine.

·           Competition for active secretion – e.g. probenicid and penicillin.

·           Forced diuresis.

3. Pharmacodynamic Interactions – are those in which the activity of the object drug at its site of action is altered by the precipitant. Such interactions may be direct or indirect.

(i) Direct pharmacodynamic interaction is the one in which drugs having similar or opposing pharmacological effects are used concurrently. The three consequences of direct interactions are –

(a) Antagonism: The interacting drugs have opposing actions, e.g. acetylcholine and noradrenaline have opposing effects on heart rate.

(b) Addition or Summation: The interacting drugs have similar actions and the resultant effect is the sum of individual drug responses, e.g. CNS depressants like sedatives, hypnotics, etc.

(c) Synergism or Potentiation: It is enhancement of action of one drug by another, e.g. alcohol enhances the analgesic activity of aspirin.

(ii) Indirect pharmacodynamic interactions are situations in which both the object and the precipitant drugs have unrelated effects but the latter in some way alters the effects of the former, for example, salicylates decrease the ability of the platelets to aggregate thus impairing the haemostasis if warfarin induced bleeding occurs.

The resultant effect of all pharmacodynamic interactions is thus altered drug action without a change in plasma concentration.

Of the various types of interactions, the pharmacokinetic interactions are most common and often result in differences in pharmacological effects. Several examples of such interactions are known but few are clinically significant. Clinically important effects are precipitated by drugs having low therapeutic indices, e.g. digoxin or those having poorly defined therapeutic end-points, e.g. antipsychotics.

The net effect of all pharmacokinetic interactions is reflected in the altered duration and intensity of pharmacological action of the drug due to variation in the plasma concentration precipitated by altered ADME. All factors which influence the ADME of a drug affect its pharmacokinetics. The same has already been dealt with in sufficient details in the respective chapters. A summary of some of the important pharmacokinetic interactions is given in Table 7.1.

Fig. 7.1. Major sites of pharmacokinetic interactions