Drugdrug Interactions based on Pharmacodynamic Pharmacokinetic and Pharmacodynamic Mechanisms

Pharmacodynamic-pharmacokinetic drug-drug interactions originate from situations, where a pharmacological effect of a particular drug can modify the pharmacokinetics of a second drug. For example, a compound which affects the gastrointestinal motility may influence the rate and extent of absorption of another co-administered drug by altering gastric emptying times and passage times across the small intestine. Thus the absorption of paracetamol can be delayed with concurrent administration of propantheline, a muscarinic receptor antagonist and with opiate-type analgesics. Metoclopramide and other prokinetic agents however, increase motility and transit of material in the gastrointestinal tract. The question as to whether the extent of drug absorption of a particular compound is modified by a prokinetic agent is frequently dependent on the intestinal permeability of the drug. For compounds with high permeability, the extent of drug absorption remains unchanged, since the residence times in the absorbing segments are more than sufficient to ensure complete absorption. Thus, even an increase in the gastrointestinal transit times will manifest in a change in rate but not extent of drug absorption. Another example for a pharmacodynamic-pharmacokinetic interaction is the interaction between compounds which modify the blood flow through the major clearing organs and high-clearance drugs. Propranolol, for example, by reduction of the cardiac output, diminishes the liver blood flow and reduces its own clearance and the clearance of lidocaine and bupivacaine [92, 93]. Similar interactions due to modification of blood flow in target tissues have been observed with anaesthetic agents. For example, volatile anaesthetics have been shown to delay the intramuscular absorption of ketamine in addition to diminishing the volume of distribution and clearance of a number of high-clearance compounds [94].

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