Drug–drug interactions
There are two main types of drug interactions, pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions arise when one drug increases or decreases the pharmacological effect caused by a second drug that may be given concurrently. Pharmacokinetic interactions occur when one drug alters a pharmacokinetic component of another drug thereby causing a change in its effective concentration at its site of action. The relationship between the pharmacodynamic and pharmacokinetic characteristics and the subsequent therapeutic response can be summarized by the following equations:
Magnitude of therapeutic response ¼ drug pharmacodynamics + drug
pharmacokinetics + individual biological variation
Magnitude of clinical response ¼ potency at site of action + drug
concentration at site of action + biological status of the patient With regard to the differences between the pharmacodynamic and pharmacokinetic drug interactions, it would appear that pharmacokinetic interaction produces the same result as a change in the dose of the drug. For example, combining the SSRI antidepressant fluoxetine with a sub-therapeutic dose of a tricyclic antidepressant could result in a two- to threefold elevation in the blood concentration of the tricyclic as fluoxetine inhibits its metabolism via the 2D6/3A4 isozymes. However this change in the pharmacodynamic response to the tricyclic antidepressant could (a) result in unexpected cardiotoxicity due to the abrupt increase in the concentration of the drug in the cardiac tissue resulting in the block of the fast sodium channels and (b) prolong the elimination half-life of the tricyclic antidepressant thereby resulting in a cumulative toxicity of the drug. Thus the SSRI, by inhibiting the metabolism of the tricyclic, has changed the clearan ce of the drug as illustrated by the equation:
Rate of dosing-Clearance!Steady-state concentration-Therapeutic response
By decreasing the clearance due to cytochrome P450 inhibition, but maintaining the same dose and rate of dosing, the steady-state concentration of the tricyclic antidepressant increases thereby enhancing the therapeutic or toxicological response. In clinical practice, pharmacokinetic drug interactions may be dismissed as an idiosyncrasy of the patient rather than a potential drug hazard.
Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. In addition to the above examples, toxicity problems can also arise when one drug induces the metabolism of the second drug. Toxic metabolites, which are not normally present in a sufficiently high concentration to be noticeable, may increase due to the increase in their concentration as a consequence of enzyme induction. For example, carbamazepine induces P450 3A3/4 which enhances the metabolism of valproate. This leads to the increased production of the 4-ene metabolite of valproate which is hepatotoxic.
There are two main types of drug interactions, pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions arise when one drug increases or decreases the pharmacological effect caused by a second drug that may be given concurrently. Pharmacokinetic interactions occur when one drug alters a pharmacokinetic component of another drug thereby causing a change in its effective concentration at its site of action. The relationship between the pharmacodynamic and pharmacokinetic characteristics and the subsequent therapeutic response can be summarized by the following equations:
Magnitude of therapeutic response ¼ drug pharmacodynamics + drug
pharmacokinetics + individual biological variation
Magnitude of clinical response ¼ potency at site of action + drug
concentration at site of action + biological status of the patient With regard to the differences between the pharmacodynamic and pharmacokinetic drug interactions, it would appear that pharmacokinetic interaction produces the same result as a change in the dose of the drug. For example, combining the SSRI antidepressant fluoxetine with a sub-therapeutic dose of a tricyclic antidepressant could result in a two- to threefold elevation in the blood concentration of the tricyclic as fluoxetine inhibits its metabolism via the 2D6/3A4 isozymes. However this change in the pharmacodynamic response to the tricyclic antidepressant could (a) result in unexpected cardiotoxicity due to the abrupt increase in the concentration of the drug in the cardiac tissue resulting in the block of the fast sodium channels and (b) prolong the elimination half-life of the tricyclic antidepressant thereby resulting in a cumulative toxicity of the drug. Thus the SSRI, by inhibiting the metabolism of the tricyclic, has changed the clearan ce of the drug as illustrated by the equation:
Rate of dosing-Clearance!Steady-state concentration-Therapeutic response
By decreasing the clearance due to cytochrome P450 inhibition, but maintaining the same dose and rate of dosing, the steady-state concentration of the tricyclic antidepressant increases thereby enhancing the therapeutic or toxicological response. In clinical practice, pharmacokinetic drug interactions may be dismissed as an idiosyncrasy of the patient rather than a potential drug hazard.
Another practical example of a pharmacokinetic drug interaction concerns the incidence of seizures in patients given a standard (300mg/ day) dose of clozapine. Should the patient be given an SSRI antidepressant (such as fluoxetine, fluvoxamine, sertraline or paroxetine) concurrently then the clearance of clozapine could be reduced by up to 50%, an effect which would be comparable with a doubling of the dose. This could lead to a threefold increase in the risk of the patient suffering a seizure. In addition to the above examples, toxicity problems can also arise when one drug induces the metabolism of the second drug. Toxic metabolites, which are not normally present in a sufficiently high concentration to be noticeable, may increase due to the increase in their concentration as a consequence of enzyme induction. For example, carbamazepine induces P450 3A3/4 which enhances the metabolism of valproate. This leads to the increased production of the 4-ene metabolite of valproate which is hepatotoxic.
No comments:
Post a Comment