Clinical Pharmacokinetics University of Nizwa College of Pharmacy and Nursing School of Pharmacy Clinical Pharmacokinetics PHCY 350 Lecture-12 Drug Dosing in Special Populations- Drug-Drug Interactions Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

Course Outline Upon completion of this lecture the students will be able to explain the outcomes of drug-drug interactions, analyze the pharmacokinetic drug interactions in clinical conditions, manage the drug interactions.

Drug interaction can be defined as “a measurable modification (in magnitude and/or duration) of the action of one drug by the prior or concomitant administration of another substance, including prescription, non-prescription drugs, food, alcohol, cigarette smoking or diagnostic tests Outcomes of drug interactions: Loss of therapeutic effect Toxicity Unexpected increase in pharmacological activity Beneficial effects (e.g. additive & potentiation or antagonism (unintended). Chemical or physical interaction e.g. I.V incompatibility in fluid or syringes mixture

High Risk Drugs Narrow therapeutic index – Aminoglycosides – Digoxin – Phenytoin – Lithium – Warfarin Steep dose-response curve – Carbamazepine – Quinidine – Oral Contraceptives

High Risk Patients Multiple drug therapy Severely ill patients CV disease Epilepsy GI disease Psychiatric disease Clinical Significance Most interactions result in little clinical significance Only a small number have major consequences such as being life threatening Consequences can usually be averted by awareness

MECHANISM OF DRUG INTERACTION Pharmacokinetic interactions Absorption Distribution Biotransformation Excretion Pharmacodynamic interactions Receptor interaction Receptor sensitivity Neurotransmitter release/Drug transportation Electrolyte balance Physiological interactions Pharmaceutical interactions

Pharmacokinetic Interactions Altered GIT absorption due to Altered pH Altered bacterial flora Formation of drug chelates or complexes Drug induced mucosal damage Altered GIT motility Altered pH: The non-ionized form of a drug is more lipid soluble and more readily absorbed from GIT than the ionized form does E.g. Antacids, H2 blockers delay the absorption of Ciprofloxacin and Ketaconazole

Altered intestinal bacterial flora: Antibiotics kill a large number of the normal flora of the intestine that influences the absorption of other drugs. E.g. In 10% of patients receive Digoxin…..40% or more of the administered dose is metabolized by the intestinal flora that increases the concentration and toxicity of the drug Complexation or chelation: E.g. Tetracycline interacts with iron preparations Milk (Ca2+ ) forms insoluble complexes of drugs Antacid (aluminum, magnesium, ferrous) hydroxide Decrease absorption of ciprofloxacin by 85% due to chelation

Drug-induced mucosal damage: Antineoplastic agents (Cyclophosphamide, Vincristine, Procarbazine) Inhibit absorption of several drugs (E.g. Digoxin) Altered motility: Metoclopramide (antiemetic) increase absorption of cyclosporine due to the increase of stomach emptying time and increase the toxicity of Cyclosporine, Digoxin

Altered Distribution: Displaced protein binding: It depends on the affinity of the drug to plasma protein The most likely bound drugs is capable to displace others The free drug is increased by displacement by another drug with higher affinity E.g. Phenytoin (90%), Tolbutamide (96%) and warfarin (99%) are highly bound to plasma protein and displaces drugs like Aspirin, Sulfonamides, Phenylbutazone Effect is transient as clearance returns free levels to pre-interaction levels Hence, clinically not much important

Altered Metabolism: The effect of one drug on the metabolism of the other is well documented The liver is the major site of drug metabolism but other organs can also do e.g., WBC, skin, lung, and GIT CYP450 family is the major metabolizing enzyme in phase I (oxidation) % drugs metabolized by CYP enzymes 3A4 60% 2D6 25% 1A2 15% 2C9 Small no. but significant interactions 2C19 Small no. but significant interactions

Enzyme induction: A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself Most CYPs are inducible but not CYP2D6 Time course of interaction depends on half-life of inducer Rifampicin has short half-life and induction apparent with 24 hours Phenobarbitone has longer half life so time to complete induction takes longer

Known induction by Rifampicin Phenobarbitone Carbamazepine Cigarette smoke e.g., Carbamazepine (antiepileptic drug) increases its own metabolism Phenytoin increases metabolism of Theophylline and decreases its level leading to poor therapy outcome Phenobarbital increases the metabolism of Warfarin, resulting in reduced anticoagulation Enzyme induction involves protein synthesis, therefore, it needs time up to 3 weeks to reach a maximal effect

It is the decrease of the rate of metabolism of a drug by another one. This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity. Inhibition of the enzyme may be due to the competition on its binding sites, so the onset of action is short may be within 24h. When an enzyme inducer (e.g. Carbamazepine) is administered with an inhibitor (Verapamil) The effect of the inhibitor will be predominant. E.g. Erythromycin inhibit metabolism of Astemazole (anti – histaminic) and Terfenadine Increase the serum concentration of the antihistaminic leading to increasing the life threatening cardio toxicity.

Cimetidine reduces the clearance of Theophylline Cimetidine reduces the clearance of Theophylline causing an increase in adverse effects Omeprazole Inhibits oxidative metabolism of diazepam First-pass metabolism: Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor. E.g. Rifampin lowers serum concentration of Verapamil level by increase its first pass metabolism.

Renal excretion Active tubular secretion It occurs in the proximal tubules. The drug combines with a specific protein to pass through the proximal tubules. When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug, this will reduce such a drug excretion increasing its con. and hence its toxicity. E.g. Probenecid Decreases tubular secretion of Methotrexate

Passive Tubular Reabsorption Excretion and reabsorption of drugs occur in the tubules by passive diffusion which is regulated by concentration and lipid solubility. Ionized drugs are reabsorbed lower than non-ionized ones E.g. Sodium bicarbonate increases lithium clearance and decreases its action Antacids Increases Salicylates clearance and decreases its action.

Managing drug interaction Monitoring therapy and making adjustments Monitoring blood level of some drugs with narrow therapeutic index e.g. Digoxin, anticancer agents…etc Monitoring some parameters that may help to characterize the early events of interaction or toxicity e.g., with warfarin administration, it is recommended to monitor the prothrombin time / INR to detect any change in the drug activity Increase the interest of case report studies to report different possibilities of drug interaction