Drug Interactions Year 2 Clinical Pharmacology

Transcription

1 1 Drug Interactions Year 2 Clinical Pharmacology Prof Mark McKeage Department of Pharmacology & Clinical Pharmacology 2 Objectives Explain the potential for interacting drugs to cause beneficial and harmful effects Recognise the main ways in which interactions occur (e.g. pharmacokinetic, pharmacodynamic) Identify the importance of liver metabolism as a point of interaction between drugs Identify sources of information about drug interactions 3 Clinical Scenario Acute chest pain Your 75 year old grandfather has recently been discharged from hospital after an acute myocardial infarct. He has been told to avoid grapefruit juice. As you are a medical student he asks you to explain why. What do you tell him?

2 4 From the Medsafe data sheet for Arrow-Simva (Simvastatin): Currently, more than 85 drugs have the possibility of interacting with grapefruit; of these drugs, 43 have interactions that can result in serious adverse effects. Older patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences. Bailey DG, Dresser G, Arnold JM Grapefruit-medication interactions: forbidden fruit or avoidable consequences? Canadian Medical Association Journal 185: What is a drug interaction? A change in one drug s effect when administered with another drug, food or other substance. 6 Interactions can be ADDITIVE/ SYNERGISTIC EFFECTS ANTAGONISTIC EFFECTS DESIRABLE EFFECTS POTENTIATION combination antibiotics ANTAGONISM antidote to overdose UNDESIRABLE EFFECTS TOXICITY LOSS OF EFFECT

3 7 Types of drug interactions Pharmacokinetic Pharmacodynamic Interacting drug alters the CONCENTRATION Interacting drug alters the EFFECT Absorption Metabolism Elimination More difficult to anticipate since they are not predictable from the clinical effects of the drugs involved. Receptor mediated Non-receptor mediated Can be anticipated based on known drug effects. 8 Unexplained loss of consciousness An 87 year old NZ European woman is brought to the Emergency Department by ambulance. Her CT scan shows a large intracerebral haemorrhage. It transpires that she is taking warfarin (a blood thinning agent). It seems likely that the haemorrhage is due to an interaction between warfarin and a medicine she has recently started. How could this happen? Dowlatshahi D et al. Stroke 2012;43: Copyright American Heart Association 9 Pharmacokinetic drug interactions Interacting drug alters the CONCENTRATION Distribution Warfarin Interacting drug Absorption Circulation - Metabolism Excretion Effect Site Blood thinning

4 10 11 Drug interactions alter absorption Change in GI ph Drug binding in GI tract disintegration/ dissolution Calcium binds thyroxine and reduces its absorption. - It is recommended that they are taken at least 4 hours apart. Malabsorption gastric emptying rate Change in gut motility intestinal transit time faeces absorption Metoclopramide increases gastric emptying and reduces absorption of digoxin from the stomach - Digoxin levels may be reduced by about one-third - Increase monitoring and dose may need adjustment Adapted from 12 Drug interactions affect hepatic metabolism Bioavailability CYP CYP Metabolism CYP Metabolism Adapted from

5 13 Core concepts Substrate: An agent that is metabolized by an enzyme into a metabolic end product and eventually excreted. Interfere with the ability of enzyme to metabolize substrate Decreased metabolism increased concentrations of substrate CYP Inducers Increase production of enzyme(s) responsible for metabolizing substrate Increased metabolism decreased concentrations of substrate 14 Time course of effect may vary Enzyme inhibitors cause rapid increases (24 hours) in the blood levels of substrates. Time to maximal drug interaction determined by: 1. Half-life and time to steady state of the inhibitor drug 2. Time required for the substrate to reach a new steady state. Enzyme inducers cause slow change (days to weeks) because it requires synthesis of the enzyme. Maximum effect may not be reached for 2-3 weeks (and take 2-3 weeks to wear off ). 15 CYP3A4 metabolises more than 50% of medicines Substrates Erythromycin Calcium channel blockers Statins Oestradiol Sildenafil HIV antivirals Cyclosporin Erythromycin Calcium channel blockers Amiodarone HIV antivirals Azoles Grapefruit juice CYP3A4 Inducers Carbamazepine Phenytoin Rifampicin St Johns Wort

6 16 Examples of clinical relevance St John s wort has caused organ rejection when added to cyclosporin therapy, by inducing CYP3A4. Sildenafil ( viagra ) can cause dangerously low blood pressure if it is taken with CYP3A4 inhibitors C9 = Warfarin NSAIDs Oral hypoglycaemics Phenytoin Amiodarone Fluoxetine Fluconazole CYP2C9 Inducers Carbamazepine Rifampicin St Johns Wort 18 Other sources of hepatic interactions Proton pump inhibitors inhibit the activation of the anti-platelet Inducers Omeprazole Fluoxetine Ketoconazole Proton pump inhibitors Anti-depressants Anti-epileptics Clopidogrel 2C19 drug, clopidogrel. CYP 2C19 Carbamazepine Phenytoin Rifampicin Beta blockers Opiates Tricyclic antidepressants Antipsychotics 2D6 If a patient taking a selective serotonin reuptake inhibitor (SSRI) antidepressant is given codeine it cannot be CYP converted to SSRI antidepressants 2D6 morphine. This results in a lack Amiodarone of pain relief. Cimetidine Anti-psychotics Theophylline Caffeine 1A2 Plasma levels of clozapine are lower in smokers so dose reduction is highly recommended CYP in patients who Inducers Amiodaroneare taking clozapine 1A2 and stop Tobacco Cimetidine smoking.

7 19 Not all hepatic drug interactions involve CYP Medsafe warning Xanthine oxidase 21 Renal elimination is an important source of drug interactions Change in renal blood flow Competition for ionic cotransport Change in urine ph Competition for use of same transporter Cimetidine competes with metformin for transport into renal cells and renal excretion - Dose may need adjustment Sodium bicarbonate alkalinises the urine and increases renal excretion of aspirin. - Used to treat salicylate poisoning More important in patients with reduced kidney function. Adapted from Shitara et al. Annual Review of Pharmacology and Toxicology. Vol. 45:

8 22 P-glycoprotein is an important efflux transporter Inhibition is site specific Bioavailability Transports drugs out of cells and into intestinal lumen, urine or bile Prevents some agents from crossing the blood-brain barrier Adapted from 23 Many drugs affect CYP3A4 and P-glycoprotein Substrates Digoxin Dabigatran Loperamide Erythromycin Calcium channel blockers HIV antivirals Cyclosporin Pglycoprotein interactions affect concentrations much less than 3A4 and only clinically significant in drugs with low DI Quinidine Erythromycin Calcium channel blockers Amiodarone HIV antivirals Azoles Grapefruit juice P-gp Inducers Carbamazepine Phenytoin Rifampicin St Johns Wort 24 Digoxin is an important P-glycoprotein substrate St John s Wort Digoxin +

9 25 Other transporters Cimetidine increases metformin concentration Cationic (e.g. OCT2) Probenecid increases penicillin concentration Anionic (e.g.oat1,3) Located in the Epithelia of intestine, liver and kidney Endothelia of blood brain barrier and blood placental barrier Müller, F and Fromm, MF. Pharmacogenomics. 2011;12(7): Clinical Scenario Major depressive episode Your friend is a keen herbal tea drinker, but is worried about a report she read in the news about someone being hospitalised after drinking Be Happy tea. She asks you if she should avoid herbal tea. What do you tell her? 27 Serotonin Syndrome Symptoms and signs include at least three of the following: agitation, ataxia, increased sweating, diarrhoea, fever, hyperreflexia, myoclonus, or shivering More likely if taking two drugs that increase serotonin levels

10 + 28 Pharmacodynamic drug interactions Interacting drug alters the EFFECT Citalopram Absorption Distribution Circulation Metabolism Excretion Interacting drug Effect Site Increase serotonin 29 Interactions can be predicted from mechanism or effect Shared receptor Shared effect Donezepil used to treat Alzheimers and anti-cholinergics (for overactive bladder) shown to have negative impact on effectiveness of donezepil. Cholinesterase inhibitors increase acetyl choline (prevent breakdown)thus have an increased cholinergic effect Donepezil (cholinesterase inhibitor) and oxybutynin (anticholinergic) Aspirin and warfarin Reduced effectiveness of donezepil. Increased bleeding 30 Receptor mediated Both drugs act through a common receptor

11 31 Non-receptor mediated Both drugs act upon the same system, but through different receptors Aspirin and warfarin Inhibit blood thinning Bleeding ACE inhibitors and NSAIDs adversely affect renal blood flow and diuretics have the potential to cause dehydration. ACE inhibitor, diuretic, NSAID Reduce renal blood flow Sildenafil and nitrate Lower blood pressure Renal failure (Severe) hypotension 32 Starting or stopping a drug is a prescribing decision that may cause a drug interaction. Knowing a few key concepts and critical medications will go a long way towards preventing a drug interaction Sources of information about drug interactions Medsafe - New Zealand Formulary - Also: Hospital medicine information service Tables are available online