Drug–Drug interaction

1. Drug–Drug interaction Faculty of Pharmacy Department of Pharmacology 5th year Pharmacy Students Dr. Hany El-Bassossy http://www.staff.zu.edu.eg/helbassossy

2. Introduction Definition: A drug interaction is a situation in which a substance affects the activity of a drug:

3. Introduction Drug interactions should be avoided, due to the possibility of poor or unexpected outcomes. However, some drug interactions are useful, such as co-administering probenecid with penicillin (delayed excretion of penicillin, less dose is needed). • Co-administration of carbidopa with levodopa (Parkinson’s disease), levodopa is metabolized in the peripheral tissues outside the brain, which decreases the effectiveness of the drug. • Carbidopa inhibits the peripheral metabolism of levodopa, more levodopa reach the brain, reduces the risk of side effects.

4. Types of interaction Pharmacodynamic interaction Modification of the pharmacological effect without altering concentration (e.g. the co-administration of a receptor antagonist and an agonist) Pharmacokinetic interaction Alteration of the concentration that reaches its site of action.

5. Pharmacodynamic interaction Examples: • Many diuretics lower plasma K+ conc, and thereby predispose to digoxin toxicity. • Sildenafil inhibits the isoform of phosphodiesterase (type V) that inactivates cGMP; consequently, it potentiates organic nitrates, which activate guanylate cyclase, and can cause severe hypotension in patients taking these drugs. • MAOI increase the amount of noradrenaline (norepinephrine) stored in noradrenergic nerve terminals and interact dangerously with drugs, such as ephedrine or tyramine, that release stored noradrenaline.

6. Pharmacodynamic interaction Examples: • Warfarin competes with vitamin K, preventing hepatic synthesis of various coagulation factors. If vitamin K production in the intestine is inhibited (e.g. by antibiotics), the anticoagulant action of warfarin is increased. • The risk of bleeding, especially from the stomach, caused by warfarin is increased by drugs that cause bleeding by different mechanisms (e.g. aspirin , which inhibits platelet thromboxane A2 biosynthesis and which can damage the stomach.

7. Pharmacodynamic interaction Examples: • Sulfonamides prevent the synthesis of folic acid by bacteria and other micro-organisms; trimethoprim inhibits its reduction to tetrahydrofolate. Given together, the drugs have a synergistic action of value. • Histamine H1 receptor antagonists, such as promethazine, commonly cause drowsiness as an unwanted effect. This is more troublesome if such drugs are taken with alcohol.

8. Pharmacodynamic interaction Examples: • Non-steroidal anti-inflammatory drugs (NSAIDs, ibuprofen or indometacin, inhibit biosynthesis of PGs, including renal vasodilator PGE2, PGI2). If administered to patients receiving: • treatment for hypertension, they cause increase in blood pressure. • diuretics for chronic heart failure, they can cause salt and water retention and hence cardiac decompensation

9. Pharmacokinetic interaction Absorption: • Gastrointestinal absorption is slowed by drugs that inhibit gastric emptying, (atropine or opiates). • Addition of adrenaline to local anaesthetic injections; the resulting vasoconstriction slows the absorption of the anaesthetic, thus prolonging its local effect. • Colestyramine, a bile acid-binding resin, binds several drugs (e.g. warfarin, digoxin), preventing their absorption if administered simultaneously.

10. Pharmacokinetic interaction Distribution: • One drug may alter the distribution of another. • Displacement of a drug from binding sites in plasma or tissues transiently increases the concentration of free (unbound) drug, but this is followed by increased elimination. • Protein-bound drugs that are given in large enough dosage to act as displacing agents include various sulfonamides and chloral hydrate; trichloracetic acid, a metabolite of chloral hydrate, binds very strongly to plasma albumin.

11. Pharmacokinetic interaction Distribution: • Displacement of bilirubin from albumin by such drugs in jaundiced neonates, the undeveloped bilirubin metabolism premature liver, allows unbound bilirubin to cross the immature BBB and cause kernicterus. • Phenylbutazone displaces warfarin and inhibits metabolism of the pharmacologically active (S) isomer, prolonging prothrombin time and resulting in increased bleeding. • Quinidine, verapamil and amiodarone displace digoxin from tissue-binding sites and reduce its renal excretion; they consequently can cause severe dysrhythmias through digoxin toxicity.

12. Pharmacokinetic interaction Metabolism: • Phase 1 (oxidation, reduction, or hydrolytic reactions) leading to drug inactivation. • Phase 2, in which enzymes form a conjugate of the phase 1 product to produce a metabolite with improved water solubility and increased molecular weight, thereby facilitating drug elimination

13. Pharmacokinetic interaction Metabolism: • Enzyme induction • e.g. by barbiturates, ethanol or rifampicin. • The inducing agent is normally itself a substrate for the induced enzymes, resulting in tolerance. • It is clinically important in starting treatment with carbamazepine. low initial dose to avoid toxicity (because liver enzymes are not induced initially) and gradually increased (as it induces its own metabolism)

14. Pharmacokinetic interaction Metabolism: • Enzyme induction • Enzyme induction is exploited therapeutically by administering phenobarbital to premature babies to induce glucuronyltransferase, thereby increasing bilirubin conjugation and reducing the risk of kernicterus

15. Pharmacokinetic interaction Metabolism: • Enzyme inhibition • P450 system, slows the metabolism and increases the action of other drugs metabolised by the enzyme • non-sedating antihistamine terfenadine and imidazole antifungal (ketoconazole) and other drugs that inhibit the CYP3A subfamily of P450 enzymes • This can result in prolongation of the QT interval on the electrocardiogram and a form of ventricular tachycardia in susceptible individuals • Grapefruit juice reduces the metabolism of terfenadine and other drugs, including ciclosporin and several calcium channel antagonists

16. Pharmacokinetic interaction Metabolism: • Enzyme inhibition • The therapeutic effects of some drugs are a direct consequence of enzyme inhibition (e.g. the xanthine oxidase inhibitor allopurinol, used to prevent gout) • Xanthine oxidase metabolises several cytotoxic and immunosuppressant drugs, as mercaptopurine, the action of which is thus potentiated and prolonged by allopurinol • Disulfiram, an inhibitor of aldehyde dehydrogenase used to produce an aversive reaction to ethanol, also inhibits metabolism of other drugs, including warfarin

17. Pharmacokinetic interaction Haemodynamic effects: • Variations in hepatic blood flow influence the rate of inactivation of drugs that are subject to extensive presystemic hepatic metabolism (e.g. lidocaine , propranolol) • A reduced cardiac output reduces hepatic blood flow, so negative inotropes (e.g. propranolol) reduce the rate of metabolism of lidocaine by this mechanism

18. Pharmacokinetic interaction Drug excretion: • Inhibition of tubular secretion • Probenecid was developed to inhibit penicillin secretion and thus prolong its action. It also inhibits the excretion of other drugs, including zidovudine. • Other drugs have an incidental probenecid-like effect and can enhance the actions of substances that rely on tubular secretion for their elimination.

19. Pharmacokinetic interaction Drug excretion: • Alteration of urine flow and pH • Diuretics tend to increase the urinary excretion of other drugs, but this is seldom clinically important. . • Conversely, loop and thiazide diuretics indirectly increase the proximal tubular reabsorption of lithium (which is handled in a similar way as Na+), and this can cause lithium toxicity in patients treated with lithium carbonate for mood disorders. • The effect of urinary pH on the excretion of weak acids and bases is put to use in the treatment of poisoning with salicylate but is not a cause of accidental interactions.

20. Sites of interaction • Interaction at GIT • Change in gastric pH • Chelation in GIT • GIT motility • Membrane alteration, ex antineoplastic drugs • Pharmacokinetic interaction • Induction ex barbiturates and coumarins/steroid H/ nicotine • Inhibition ex MAOI or tricyclic antidepressants

21. Sites of interaction • Interaction at the plasma proteins • ex. Warfarin and phenylbutazone • bilirubin and sulphonamides/aspirin

22. Sites of interaction • Interaction at receptors • Enhancement • Additive • Summation, ex aspirin and codeine • Membrane alteration, ex antineoplastic drugs • Potentiation ex salicylates and pentobarbitone • Synergism ex alcohol and barbiturates • Antagonism • Pharmacological (competitive or non-competitive), (reversible or irriversible) • Physiological ex histamine and adrenaline on broncheal muscles • Chemical ex Heparin and protamine sulphate

23. Sites of interaction • Drug interactions at the kidney • Competition for active renal tubular secretion • ex Penicillin and pronecid • Salicylate and uric acid • Change in urine pH • ex acidic pH more exretion of basic drugs