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  1. Types of drug interactions Pharmacokinetic interaction Lecture 3

  2. Drug interaction • Adverse drug response produced by the administration of a drug or coexposure of the drug with another substance, which modifies the patient's response to the drug • Some drug interactions are intentional in order to provide improved therapeutic response or to decrease adverse drug effects • A precipitant drug is the drug, chemical, or food element causing the interaction • An object drug is the drug affected by the interaction

  3. Drug interactions include: a. Drug-drug interactions b. Drug-herbal interactions c. Food-drug interactions d. Pharmacogenetic interactions e. Chemical-drug interactions, such as the interaction of a drug with alcohol or tobacco f. Drug-laboratory test interactions such as chemical interactions.

  4. Classification of drug interactions • Drug interactions that occur in vivo are generally classified as: • Pharmacokinetic interactions. • Pharmacodynamic interactions

  5. Pharmacokinetic or biopharmaceutical interactions • Occur when the absorption, distribution (protein and tissue binding), or elimination (excretion and/or metabolism) of the drug is affected by another drug, chemical, or food element.

  6. Absorption • Drug interactions can affect the rate and the extent of systemic drug absorption (bioavailability) from the absorption site, resulting in increased or decreased drug bioavailability

  7. Absorption • The most common drug absorption site is in the gastrointestinal (GI) tract • However, drug bioavailability from other absorption sites, such as the skin, can be affected by drug interactions • For example, epinephrine, a vasoconstrictor, will decrease the percutaneous absorption of transdermallidocaine or transdermalfentanyl

  8. Drug -drug and drug-food interactions that affect bioavailability could be due to: a. Competition for carrier-mediated drug absorption in which the participant drug competes for the same carrier as the object i. Competition for the P-gp system (an ATP-dependent efflux pump on epithelial cells of the intestines) is involved in transport of cyclosporin and digoxin. Displacement can result in toxicity of those drugs. ii. Grapefruit juice and orange juice from Seville oranges inhibit OATP (organic anion transporting polypeptides) proteins in the epithelial cells of the small intestine, reducing the bioavailability of oral fexofenadine.

  9. Drug -drug and drug-food interactions that affect bioavailability could be due to: b. Alteration of intestinal blood flow caused by the precipitant drug. • In congestive heart disease, the blood flow to the GI tract is poor and an orally administered drug can have a slower rate of absorption. After digoxin therapy, the perfusion of the GI tract is improved along with bioavailability of the object drug.

  10. Distribution. • The distribution of the drug may be affected by : • plasma protein binding • displacement interactions • tissue and cellular interactions.

  11. Plasma protein binding and displacement • Plasma protein binding and displacement on albumin and alpha1-acid glycoprotein carrier proteins a. Valproic acid displaces phenytoin from plasma albumin protein-binding sites and reduces hepatic phenytoin clearance by inhibiting the liver's metabolism of phenytoin, resulting in higher phenytoin levels b. Aspirin is 90% to 95% protein bound and displaces warfarin from protein binding sites resulting in higher warfarin levels and increased bleeding

  12. Tissue and cellular interactions • Tissue and cellular interactions • Digoxin toxicity can be enhanced by concurrent administration of quinidine. Quinidine reduces digoxin clearance and displaces digoxin from both alpha-1 glycoproteine and albumin tissue-binding sites, leading to a higher plasma digoxin concentration

  13. Drug metabolism (hepatic clearance) • Can be affected by : • enzyme induction • enzyme inhibition • substrate competition for the same enzyme • changes in hepatic blood flow

  14. Examples • Fluconazole inhibits the hepatic metabolism of warfarin, causing increased risk of bleeding. • Carbamazepine is both a substrate and an inducer of the CYP3A4 isoenzyme, thereby inducing its own metabolism and taking 3-5 weeks to reach stable blood levels • Phenytoin is also a substrate of the CYP3A4 and induces its own metabolism. • St. John's Wort may induce CYP3A4 isoenzymes and decrease cyclosporin to subtherapeutic levels • Tobacco use (smoking) can induce the CYP1A2 isoenzyme and decrease clozapine levels, increasing the risk of therapeutic failure in treating OCD. • Grapefruit juice is a powerful inhibitor of the CYP3A4 isoenzyme, and will increase blood levels of CYP3A4 substrates

  15. Examples • Nonhepatic enzymes can be involved in drug interactions • For example, serotonin syndrome has been reported in patients receiving antidepressants such as citalopram (an SSRI inhibitor) in combination with a monamineoxidase inhibitor, such as linezolid. A considerable portion of the CYP3A4 enzymes are found not only in the liver, but also in the GI tract, where some of these substrates are metabolized. • A decrease in the hepatic blood flow can decrease the hepatic clearance for high extraction drugs, such as propranolol and morphine.

  16. Renal clearance • Renal drug clearance can be affected by changes in glomerular filtration, tubular reabsorption, active drug secretion, and renal blood flow and nephrotoxicity