Pharmacotherapeutic complications 2009 Martin Štěrba, PharmD. PhD. Department of Pharmacology

1. Pharmacotherapeutic complications 2009 Martin Štěrba, PharmD. PhD. Department of Pharmacology

2. What do you know already about drug-drug interactions: The effects can • s y n e r g i s m • summation of effects • one-way : opioid analgesics + narcotics • two-way : combination of cytostatics or ATBs • potentiation of effects • one-way : Ca++ + digoxine • two-way : digoxine + thiazide diuretics

3. What do you know already about drug-drug interactions: • a n t a g o n i s m • pharmakologic:ACh + atropine • physiologic:ACh + adrenaline • chemical: heparin + protamine The effects can

4. Unintended drug-drug interactions as a pharmacotherapeutic complications • Interactions can be: • Desirable: intended and beneficial resulting into: • Increase of effect (synergism): e.g. Combination of cytostatics or ATBs • Decrease of effect (antagonism): e.g., in the treatment of overdose with antidotes • Undesirable – unintended and potentially harmful and very dangerous resulting into: • Decrease of effect (antagonism): failure of therapy (mostly one way) with potentially serious consequences • e.g., pulmonary embolia during anticoagulant treatment, transplanted organ rejection during immunosuppressive treatment, serious infections during ATB treatment • Increase of effect– induction of adverse or even toxic drug reactions

5. Unintended drug-drug interactions as a pharmacotherapeutic complications • Clinical outcomes: from trivial to life-threatening !!! • additional costs • Pay attention also onOTC drugs • Careful drug anamnesis with question on use of OTC drugs • Patient education and interdisciplinary cooperation • Increased risk: • In combination of many drugs • In combination of drugs • With narrow margins of safety • With poorly predictable dose-response • Influencing enzymes involved in drug biotransformation • Low and high age of patients • Most of interactions occur in in-patients in hospital • Higher frequency of multiple drug treatment • Setting of pharmacotherapy and introduction of new drugs • More frequent parenteral routes of drug administration

6. Mechanisms of drug interactionsI. Chemical/pharmaceutical interactions • Interaction is based on chemical or physico-chemical properties of drugs: • Before administration into the body (pharmaceutical incompatibilities, eg in syringe, infusion sol., compounded drugs). • In commercially available drugs - must be solved by pharmacists and approved and supervised by national authority • Follow tightly procedures for preparation of injectable parenterals (SPC) • Visual inspections • Compounded (individually prescribed drugs)– follow the literature (Prescriobciones magistrales, Prescribciones Pharmaceuticae) and/or consult a compounding pharmacist • At the site administration: e.g., GIT – mostly result to decreased drug absorption • E.g., Ca2+, Mg2+, či Fe3+ ions or antacids which contain them orAl3+ interact with tetracyclines or quinolones?! • Medicinal charcoal, diosmectid – adsorption of number of drugs • Cholestyramine, cholestipol – hypolipidemic resins (drug adsorption) • Sucralfate – adsorption, barrier for drugs absorbed in the stomach • Antacids –pH manipulation, adsorption, ions – chelate formation • The time-gap between these and other drugs is needed (at least 2h) !!!

7. Mechanisms of drug interactionsII. Pharmacokinetic interactions • Interactions at the A D M Elevel • Absorption(impact on total absorption or time-profile) • Chemical/physico-chemical interaction (viz previous slide) • Drugs affecting GIT motility: • Absorption is decreased by laxatives (purgatives) – increased passage through GIT (small intestine) may affect absorption and BAV of drug with slow and/or low absorption • Slowed absorption – antimuscarinics may decrease the emptying of stomach • Distribution • Competition for plasma protein binding • Displacement of one drug by another • Very high binding and narrow margins of safety to be clinically important (eg, warfarin, salicylates, oral antidiabetics, phenytoin) • Clinical relevance? Mostly another mechanism is needed • Warfarin + aspirin • Valprotate + phenytoin • Displacement from tissue proteins: quinidine may displace digoxine (in addition to decease of its renal excretion) – digoxine intoxication

8. II. Pharmacokinetic interactions • Metabolisms (biotransformation) • Impact on cytochrome P450 • There are different isoforms of CYP450 • The most important are CYP450 3A4, 2D6 (the drugs which are substrates can be found in tables) • Inducers: phenytoin, carbamazepine, barbiturates, rifampicin, griseofulvin, extract from St. Johns Worth (Hypericum perforatum) • Inhibitors: Ketoconazole, erytromycine, chloramphenicol, quinidine, cimetidine… • In some isoforms also: amiodaron, valproate, omeprazol, fluoxetine • Troublesome drugs: warfarin, cyclosporin, oral contraceptives, antiepileptics and glucocorticoids • Impact on UDP- glukuronid transferase: antiepileptics • Induction:phenytoin, carbamazepine, barbiturates • Inhibition: valproate

9. Mechanisms of drug interactionsII. Pharmacokinetic interactions Clinically important interactions at the CYP450 level

10. Mechanisms of drug interactionsII. Pharmacokinetic interactions • Excretion – mainly renal • Inhibition of tubular secretion • Uricosuric drug probenecid decrease tubular secretion of some drugs, e.g. Penicilins, • Thiazide diuretics cause relative Na+ depletion and thereby they indirectly increase Li+ reabsorbtion • Decreased renal clearence of Li+ = CNS toxicity • Inhibition of tubular reabsorbtion: • Decreased reabsorption of sulfonamides during concomitant administration of acidic drugs (e.g. Vitamin C) and aspirin in particular

11. Mechanisms of drug interactionsII. Pharmacokinetic interactions • Excretion – inhibition of tubular secretion examples:

12. Mechanisms of drug interactionsIII. Pharmacodynamic interactions • Increased or decreased pharmacological effects through effect on same receptor or same or different physiological or biochemical pathway: • Clinicallly important examples: • warfarin + aspirin – increased risk of bleeding (both PK and PD interaction, aspirin is OTC drug!) • Diuretics (eg. furosemide) + digoxine Hypokalemia during diuretic therapy increase toxicity of digoxine (competition for Na+K+-ATPase) • ACE-inhibitors + potassium sparring diuretics ACE-I increase kalemia already increased by potassium sparing diuretics (e.g. spironolacton) – risk of hyperkalemia and arrhythmias • B-blockers a verapamil (Ca2+ blockers): potentiation of negative chronotropic, dromotropic a inotropic effects:serious bradycardia and heart arrest, manifest heart failure • B-blockers and insulin:sudden hypoglyceamia without any warning

13. Prevention of drug interactions • Avoid polypragmazia • Avoid drugs with significant interaction potential • Use alternative drugs if possible • Be careful when drugs with vital indication is coadministred or when drug has a narrow safety margins • Use SPC, or specialized databases (Micromedex) or consult drug information centers