Drug interactions ELMS learning event 30 th November

Drug interactions ELMS learning event 30 th November 2017 Omar Seedat

Introduction • Understanding risk-benefit • “One of the first duties of the physician is to educate the masses not to take medicine. ” – William Osler, Canadian physician (12 July 1849 – 1919) • Medicine is a collection of uncertain prescriptions the results of which, taken collectively, are more fatal than useful to mankind. – Napoleon Bonaparte, French general & politician (1769 - 1821) • Pressure to prescribe? • Age of the internet

Outline • Brief overview of key areas • Case studies • Putting it together

Overview • What is an enzyme inducer? • What is an enzyme inhibitor? • What is a pro-drug? • Additive toxicity

Overview 1 Enzyme inducers LOWER the concentration of the substrate drug Enzyme inhibitors RAISE the concentration of the substrate drug Pro-drugs have the opposite effect

Overview 2 Additive risks • • Bleeding risk Hyperkalaemia Hyponatraemia CNS depression QT prolongation Serotonergic toxicity Renal toxicity Liver toxicity

Case study 1 • 66 year old woman, h/o hypothyroidism presents with increasing fatigue and bradycardia. TSH risen markedly • Meds: Levothyroxine 75 mcgod, simvastatin 40 mgon , verapamil 40 mgtds , warfarin, citalopram 40 mgod, OTC calcium and iron supplements

Case study 1 Which drug interactions are the likely cause of her increased TSH? Other concerns?

Absorption- Levothyroxine/Quinolones • Easily bound by cations and binders • Acid stomach important for absorption – PPIs will affect • When a patient has had a stable TSH on thyroid replacement, now increased TSH – look for an absorption problem – Drug compliance is normally good in patients

Other concerns • Citalopram indication and dose • Statin dose with CCB • OTC supplement use – Further investigation

Citalopram and long QT • MHRA Drug Safety Update 2011; 5: 5. • Current recommendations on maximum doses Maximum doses Adults <65 y >65 y Hepatic impairment Citalopram 40 mg 20 mg Escitalopram 20 mg 10 mg • Concomitant use with other drugs that prolong the QT interval not recommended • Medication review- citalopram still indicated?

Case study 2 • 45 yrs old female • PC: palpitations • Recent anaphylaxis, being investigated for allergies • Meds: Epipen, antihistamines, steroids • Exam: temp: 37. 4, pulse 98 BP 120/80 ABC fine • PX: Propranolol 10 mg 1 -2 TDS prn

Case study 2 Prescription for symptoms necessary ooh? Is Indication anaphylaxis or angio-oedema? Cautions/contra-indications? Properties of Propranolol and Adrenaline – predictable interaction • Severity of interaction: Severe- potentially life threatening. Evidence for interaction: Study • Query the propranolol dose given for this indication? • •

Case Study 3 • PMH : Familial hypercholesterolaemia, Hypertension and Type 2 Diabetes • Meds: Ramipril, Amlodipine, Metformin, Simvastatin and Bezafibrate • Antibiotic choices – Co-amoxiclav – Clarithromycin – Levofloxacin – Cefuroxime – Trimethoprim

Case study 3 • Simvastatin-bezafibrate (rhabdomyolysis) • Simvastatin-clarithromycin (rhabdomyolysis) • Amlodipine-clarithromycin (Hypotension? )

Statin toxicity • • Fibrates (gemfibrozil greatest, contra-indicated combination) Azole antifungals Amiodarone (4 -5 fold increase) Erythromycin/clarithromycin HIV protease inhibitors (process to add specialist/otc drugs? ) CCBs (Verapamil/Diltiazem/Amlodipine/felodipine) Least Drug interactions with Pravastatin (different pharmacokinetics) • Non concurrent dosing Risk factors - age, renal imp, hepatic imp, hypothyroidism, genetic polymorphisms, other muscle disorders Onset 1 week to four years ! (Hansen et al. Archives of Internal Medicine 2005; 165: 2671– 6).

• Rhabdomyolysis is a dreaded and life threatening statin associated side effect • Rare with statin alone but drug interactions increase risk • Managing statin-induced myopathy • Myalgia, myositis – Art rather than true science - Under prescribing of statins in high-risk patients (Finniken S et al, BJGP 17 X 693485) - Adverse media reports affecting statin compliance (BMJ 2016; 353: i 3283)

MHRA advice • Drug Safety Update 2014; 7(10): H 1 – Considerations when prescribing statins • Drug Safety Update 6(1) 2012 -Advice on drug interactions - Dose limitations

Case study 4 72 yrs old female, PMH AF hypertension Meds: losartan warfarin and bisoprolol Widespread bruising on back, legs and back of both hands • Was prescribed a new drug 7 days ago, still taking it, completes course today • •

What medication was prescribed? • • • Amoxicillin Codeine Prednisolone Azithromycin Metronidazole Co-Trimoxazole

Warfarin interactions Decrease metabolism (increase PT) Severe Possible* Co-trimoxazole Erythromycin Amiodarone Ketoconazole/miconazole/ Fluconazole/Itraconazole Metronidazole Carbamazepine Quinolones Trimethoprim Omeprazole Clarithromycin Azithromycin Oral corticosteroids *Especially important in frail elderly pts

Warfarin and Antibacterials • Altered (usually enhanced) response reported with virtually every class • Some are clear and established , others unclear and unpredictable • Drug interaction advice to patients – See NICE CKS

Important warfarin interactions • Co-trimoxazole • Paracetamol (almost never suspected) • Prednisolone – How to act is important – Not to overreact • Miconazole oral gel Drug Safety Update volume 11 issue 2, September 2017: 1.

Case study 5 • 61 yr old male admitted with chest pain after recent ablation, ECG showed fast AF. INR was subtherapeutic. • Was prescribed a GTN spray. Warfarin was changed to Rivaroxaban • PMH: AF, hyperlipidaemia, osteoarthritis, hypertension • GP meds list: Bisoprolol, Ibuprofen, omeprazole, DHC, paracetamol, Ramipril, Ezetemibe, GTN, Rivaroxaban, Tadalafil

Putting it together 2 D 6 3 A 4 1 A 2 2 B 6 2 C 9 3 A 5 3 A 7 2 C 19 X Drug vs Prodrug Additive Opposing Strong Moderate Weak X

Clinically significant interactions 1. The interaction is STRONG 2. The outcomes are BAD bleeding, stroke risk, unwanted pregnancy 3. The effect is noticeable Cancer risk, BP changes

Computerised alert systems Beware of alert fatigue! BNF: www. evidence. nhs. uk Other sources: https: //www. sps. nhs. uk/ Stockleys (online available) SPC https: //reference. medscape. com/drug-interactionchecker (On adastra as a web link) • https: //www. crediblemeds. org (good for QT drugs and also has a clinically important drug interactions list) • • •

Thank you Any questions omar. seedat@nhs. net