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DRUG INTERACTIONS Dr. Jorge Zimbron ST5 in General Adult Psychiatry Clinical experience Outline • Definitions • At risk groups • Types of drug interactions • Clinical tips • Example questions • References Definitions • Drug interaction • Modification of the action of one drug by another. • Can increase or decrease the effect of a drug. • Can be beneficial. • Not all clinically significant. • Pharmacodynamics • Pharmacokinetics Definitions • Pharmacokinetics may be simply defined as what the body does to the drug, as opposed to… • pharmacodynamics which may be defined as what the drug does to the body At risk groups • Elderly • Chronic illness • Prescribed more drugs • Poor kidney and liver function • People with drug and alcohol problems • People in/from developing countries • People on drugs with narrow therapeutic index. Narrow therapeutic index drugs • Lithium 1.5:1 • Phenytoin • Warfarin • Digoxin 2:1 • Gentamicin • Vancomycin • Amphotericin B Types of drug interactions • Pharmaceutical • Pharmacodynamic • Pharmacokinetic • P-Glycoprotein interactions Pharmaceutical interactions • Mixing of two incompatible drugs outside the body. • Eg. Mixing haloperidol and lorazepam im in one syringe. • No known hazardous interactions in psychotropic drugs. Pharmacodynamic interactions • Drugs competing for same target. • Commonest type of interactions. • Types: • Antagonistic • Antipsychotics vs levodopa in Parkinson’s. • Synergistic • Alcohol and TCAs – CNS depression • SSRIs & aspirin – inhibition platelet aggregation • Duration tends to depend on half-life or enzyme production. Pharmacokinetic interactions Absorption, distribution, metabolism or elimination of a drug is influenced by another. • Absorption – Phenothiazines or sulpiride with antacids. • Distribution – Protein bound drugs (>90%) • Phenytoin is displaced by diazepam – Short lived effect due to increase in metabolism. – Lysosomal trapping • Thioridazine + antidepressants Lysosomal trapping • Tissues with high lysosomal content • Lungs • Liver • Kidneys • Astrocytes • Tissues with low lysosomal content • Heart • Neurons Pharmacokinetic interactions • Metabolism (cytochrome p450 & UGTs*) – Phase 1 metabolism (oxydation, reduction, hydrolysis → conjugation → excretion). • Enzyme induction (not usually hazardous) – Carbamazepine: ↑ metabolism of TCAs and antipsychotics. • Enzyme inhibition *uridine diphosphate glucuronosyltransferases: phase 2 conjugation reactions. Covalent bond between drug and endogenous substrate (eg. glucuronide). Poorly understood. Cytochrome p450 enzymes • 11 important. 5 to remember in Ψ: – CYP1A2 – CYP2C9* – CYP2C19* – CYP2D6* – CYP3A4 *Polymorphisms = varying activity levels • Poor, extensive (normal), and ultrarapid metabolisers. – Implications for drugs and pro-drugs CYP enzyme induction • CYP3A4 – induced by carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s Wort. • Reduced efficacy of haloperidol CYP enzyme inhibition • Most likely to cause life-threatening interactions. • Usually due to competition at binding site. • Usually 1 inhibitor doesn’t affect more than 1 CYP protein. • Eg sodium valproate inhibits CYP3A4. • Leads to increased skin reactions with lamotrigine. p450 issues • Drugs usually metabolised by more than 1 CYP enzyme. • No tests for individual genetic CYP makeup. • Impossible to predict responses clinically Pharmacokinetic interactions • Absorption • Distribution • Metabolism • Excretion (kidney) – Lithium (re-absorbed proximal convoluted tubule with Na) • Thiazides ↑Na excretion → compensation by PCT ↑absorption ↑lithium P-Glycoprotein interactions • Involved in absorption, distribution, and excretion. • Member of the ATP binding cassette (ABC) transporter superfamily. – Efflux pump (intracellular to extracellular matrix) – Present throughout the body – ↓ absorption by excreting drug into intestinal lumen. – Excrete drug from liver to bile and from kidney to urine. – Present at BBB and reduces drug access to CNS Common effects of interactions • Oversedation (eg. inhibition of CYP3A4) – Elderly – RTAs – DVTs • Serotonin syndrome • Seizures – Antipsychotics – St. John’s Wort induces metabolism of carbamazepine and phenytoin. Common effects of interactions • Hypotension • Falls • Ischaemia • Hypertension • Eg MAOi + TCAs • Arrhythmias (QTc) Clinical points • Impossible to remember. – Always check! – Eg tramadol + SSRI • Impossible to predict – f/u essential • Hospital vs community prescribing • Theoretical interactions not always clinically significant – Based on animal experiments & case reports Drug interaction checkers • www.drugs.com • http://wiki.psychiatrien et.nl/index.php/Main_P age • Epocrates • Bazire • (BNF) Common interactions in clinical practice • IM olanzapine and IM benzodiazepines • Lithium and NSAIDs • Lithium and haloperidol (commonly used) • Lithium and diuretics • Thiazides • K sparing • Lithium and ACEi • SSRIs and MAOi Questions 1 A hazardous drug interaction is more likely to occur: • a if the drug in question has a wide therapeutic index • b with inhibition rather than induction of drug metabolising enzymes • c with drugs that are renally excreted • d during long-term therapy with both drugs • e in elderly people. Questions 2 Inhibitors of the cytochrome P450 enzyme system: • a affect all enzymes equally • b have a slow onset of action on the enzymes • c produce predictable effects on the metabolism of drugs that are metabolised by CYP enzymes • d include cimetidine and omeprazole • e are less likely to produce drug interactions than are inhibitors of UGTs. Questions 3 P-glycoprotein: • a is a hepatic drug-metabolising enzyme • b can be inhibited or induced by drugs • c is involved in maintenance of the blood–brain barrier • d is involved in the renal excretion of lithium • e has a well-defined role in the genesis of interactions involving psychotropic drugs. Questions 4 Elderly mentally ill people who have concomitant physical illnesses: • a can be treated safely with simvastatin while taking paroxetine • b need pose no concerns if treated with nefopam and an MAOI • c are at increased risk of hip fractures while receiving thioridazine and lorazepam • d are at greater risk of death if they are taking St John’s wort and require theophylline for a severe asthmatic attack • e have an increased chance of developing agranulocytosis if fluvoxamine is co-administered with clozapine. Questions 5 Patients in general can be: • a safely treated with a combination of penicillin and antidepressants that have epileptogenic potential • b legally prevented from driving if they are prescribed carbamazepine together with trifluoperazine • c in danger of torsade de pointes if they have alcohol dependence and are treated with sertraline • d safely co-prescribed lithium and thiazide diuretics Answers References