Interactions that really matter and how to manage them Dr Tana Fishman Department of General Practice and Primary Health Care, University of Auckland Linda Bryant Clinical Advisory Pharmacists Association Burning issues Real Life 1 Please note down one or two ‘burning issues’ that you came to this session with that you wanted addressed Real Life 2 Real Life 3 1 Real Life 4 Real Life 5 Real Life 6 Real Life 7 – a SINGLE patient Drug – drug interactions Interactions background When the effects of one drug are changed by the presence of another drug Reduces the effect of the ‘target drug” (the drug already there) Increases the toxicity of the target drug – often perceived as an adverse effect of one of the drugs because of increased drug concentrations Range of effects between useful, clinically trivial, increased morbidity, and fatal Variability between individuals makes prediction of absolute effect very difficult – focus on harm minimisation Incidence – up to 10% depending on classification – but severity of outcome less predictable Pharmacodynamic interactions Additive effect of similar medicines, or cancelling effect Increasing risk of hypotension with Two antihypertensives An antihypertensive + TCA Increasing renal impairment with ACE Inhibitor, diuretic and NSAID Pharmacokinetic interactions Primarily interference with: Absorption Tetracycline and food, calcium Metabolism by enzymes e.g. Cytochrome P450 P-glycoprotein 2 Cytochrome P450 enzymes In liver, intestines, kidney, lung, brain CYP 3A4 CYP 2D6 CYP 2C19 CYP 2C9 CYP 2E1 CYP 2B6 CYP 2A6 CYP 1A2 % drugs Individual metabolised variation ~ 36% 5 - 8 fold ~ 19% > 50 fold Polymorphism P-Glycoprotein (p-gp) In intestines, brain, kidney and liver Works to ‘pump out’ toxins Digoxin is a substrate and quinidine an inhibitor … so if quinidine inhibits p-gp, more digoxin is absorbed from the intestine If p-gp is inhibited in the kidney, where p-gp tries to excrete digoxin, more is retained P-g prevents drugs crossing the blood-brain barrier - so inhibition may cause drugs like loperamide to have CNS effects 5 - 10% Euro 3 - 5% Euro, 15-20% Asian 5 fold 1 - 3% Euro 12 fold 20 fold Managing interactions Work time Risk assessment What is the interaction? Is it important? How can it be managed? How common is the interaction? How severe will the interaction be if it occurs? Is it a dose-related interaction? Management An alternative, non-interacting drug Stop the target interacting drug temporarily Reduce the dosage of the target drug Monitor with Investigations – INR, blood pressure, liver enzymes Clinically – dizziness, muscle aches Scenario 1 Scenario 2 Mr A, a 76 year old man was investigated for a cough and breathlessness before an elective operation. His medicines were: A 74 year old woman had a history of hypertension and acute coronary syndrome for which she was taking: Metoprolol Aspirin Cilazapril Simvastatin Omeprazole Paracetamol Naproxen Temazepam 95 mg daily 100 mg daily 2.5 mg daily 60 mg nocte 10 mg mane 1gm tds 750mg daily 10mg nocte prn (about twice a week) The investigation found an invasive respiratory fungal infection for which itraconazole 400mg daily was required for 6 to 12 months. Simvastatin Aspirin Diltiazem Inhibace Plus® 40 mg nocte 100 mg daily 90 mg daily 5 mg / 12.5 mg daily Her osteoarthritis is severe and regular paracetamol is inadequate, even with codeine. She is started on naproxen SR 750mg daily 3 Scenario 3 Scenario 4 A 59 year old woman has severe CVD requiring: Chlorthalidone Simvastatin Enalapril Candesartan Isosorbide mononitrate Metoprolol Aspirin Omeprazole 25 mg daily 40 mg daily 20 mg daily 16 mg daily 60mg daily 47.5 mg daily 100mg daily 20 mg daily She is allergic to penicillins (rash) and felodipine (swollen ankles). She presented with likely atypical pneumonia for which one week of erythromycin 800mg twice daily was prescribed. Scenario 5 A patient with taking metformin 500mg twice daily for impaired fasting glucose developed angina and mild hypertension. When metoprolol 23.75mg was prescribed the computer beeps with a warning of an interaction A 79 year old woman had severe IDH, with two previous myocardial infarctions. Post-operatively (CABG) she developed atrial fibrillation and was initiated on warfarin. Her regular medicines became: Metoprolol Felodipine Inhibace Plus® Aspirin Warfarin Calciferol GTN spray 23.75 mg 5 mg daily 5mg / 12.5 mg daily 150 mg daily mdu (2 to 3 mg daily usually 50,000 iu monthly prn Scenario 6 An 83 year old man has IHD, heart failure and atrial fibrillation.is on: Carvedilol Quinapril Frusemide Digoxin Aspirin Isosorbide mononitrate Omeprazole Paracetamol GTN 12.5 mg twice daily 20mg daily 80 mg daily 0.125 mg daily 100mg daily 60 mg daily 20 mg daily prn prn The cardiologist has just started amiodarone, 200mg three times daily for one week, 200mg twice daily for one week and then 200mg daily Scenario 7 A 47 year old woman with Bipolar Affective Disorder is well managed on lithium 400 mg twice daily (serum concentration maintained at 0.6 to 0.8 mmol/L), and fluoxetine 20mg daily. When screened for her cardiovascular risk it was found that she had blood pressure of 152 / 98 mmHg, and a disturbed lipid profile that, in conjunction with her family history of cardiovascular disease, put her at a greater than 15% risk of a cardiac event in the next five years. Despite five months of lifestyle alteration, the cardiovascular risk remained high. Over the next three months it was determined that she could not tolerate β-blockers (extreme fatigue) or calcium channel blockers (headache, swollen ankles). Having already prescribed simvastatin 20mg at night, what are your next steps? Scenario 8 A 27 year old woman is being treated with paroxetine 20 mg daily for depression. She also experiences severe migraines that have responded only marginally to prophylactic treatment. She still gets one to two debilitating migraines every month. Having tried most other options, she now wants sumitriptan. 4 Scenario 9 A 71 year old woman with diabetes peripheral neuropathy has been using amitriptyline 50 mg at nigh to very good effect for neural pain. She now presents with depression and although CBT is to be instigated, there is a clinical need for an antidepressant. Fluoxetine 20mg daily is to be introduced. Scenario 10 A 19 year old male had difficult to control seizures. He had recently had phenytoin 450 mg daily added to his regime of valproate 1.2 gm twice daily, but had had another brief seizure. His valproate serum concentration was 280 μmol/L (350 – 700 μmol/L) and his phenytoin concentration was 82 μmol/L (40 – 80 μmol/L). His valproate dosage was increased to 1.5 gm in the morning and 1.2 gm at night. He became very lethargic, ataxic and felt ‘muddled’. His serum concentrations two weeks after the dosage increase were valproate 210 μmol/L and phenytoin 110 μmol/L. Real life - 8 Thank you 5