1. Adverse Reactions, Pharmacovigilance and Interactions

2. Adverse Reactions Any substance introduced into the body can pose a risk at normal doses, and all are potentially toxic if given in overdose However, we should keep in mind that the great majority of treatments are safe and effective if the principles of pharmacology and pharmacokinetics are carefully applied We will discuss risk in terms of side-effects, adverse drug reactions, and toxicity

3. Side-effects A consequence of the pharmacological mechanism of action of the drug – usually due to presence of receptors in a number of tissues or lack of receptor specificity Examples include drowsiness with the older antihistamines, constipation with opioids etc. In some situations, a ‘side-effect’ can be a therapeutic effect e.g. antihistamines for sedation, opioids for diarrhoea

4. Adverse Drug Reactions (ADRs) An ADR is any response to a drug that is undesirable and unintended and that occurs at doses used in humans, for prophylaxis, diagnosis or therapy, excluding therapeutic failure WHO definition

5. Types of ADRs Type A ‘Predictable’ ADRs: Predicted from pharmacological reaction and are usually dose-related (eg bradycardia from beta-blocker) Type A by far the majority of ADRs encountered in clinical practice With careful selection of drug, dose etc. many Type A ADRs can be avoided

6. Types of ADRs cont. Type B: ‘Unpredictable’ ADRs: Unpredictable from pharmacology of drug and are not dose-dependent; can be very serious May not be picked up in clinical trials if low incidence Often involve hypersensitivity reactions (eg penicillin anaphylaxis, malignant hyperthermia of anaesthesia, agranulocytosis with clozapine) Sometimes reclassified as Type A after a period of clinical use if mechanism is elucidated

7. Incidence of ADRs Many surveillance studies have been performed both in hospital and community In addition meta-analyses and systematic reviews ADRs responsible for hospital admissions average about 5% (range 2-12%); in the community the range is far greater (2-40%) reflecting the complexity of data gathering and the criteria used

8. Incidence of ADRs cont. In both cases, the great majority of ADRs were deemed preventable The economic costs of ADRs are very high

9. Patient Risk Factors for ADRs Age (young, elderly, renal/hepatic function) Disease State e.g. CHF, HIV Gender: females approx. 1.5 x greater risk

10. Patient Risk Factors for ADRs cont. Genetics: different phenotypes for handling drugs Immunological factors: some patients hypersensitive Number of drugs patient is taking: an obvious risk factor, especially in the elderly

11. Drug Risk Factors for ADRs Narrow therapeutic index e.g. digoxin, lithium Route of administration e.g. iv drugs can produce immediate effects Formulation/bioavailability: as discussed previously

12. Drug Risk Factors for ADRs cont. Additives/excipients: patients may be hypersensitive to these rather than the active drug In general, patients may not receive sufficient information about side-effects, ADRs etc. in advance

13. Identification of ADRs Establishing causal relationships difficult Accurate drug history required (including non- prescription and complementary products Temporal relationship needs to be established (many ADRs can be ‘delayed’ reactions)

14. Identification of ADRs cont. Detailed medical history required ‘Dechallenge’ and ‘rechallenge’ may or may not be possible (or ethical!)

15. ADR examples Iron containing preparations given orally – GI irritation and pain – Nausea appears to be dose related – Altered bowel habit, either diarrhoea or constipation These side effects can occur at common therapeutic doses Choice of which Iron preparation prescribed should be guided by that individual’s response to that particular preparation (try a fully funded type first)

16. ADR examples Vitamin A containing preparations – Rough skin – Dry hair – Enlarged liver – Teratogenic These adverse reactions only occur at very large doses (e.g. several times usual therapeutic dose)

17. Pharmacovigilance ADR reporting systems Followed from thalidomide tragedy in 1960s Data on safety gathered by pharmaceutical companies from pre-clinical testing, clinical trials and postmarketing surveillance studies (case studies, cohort studies, case-control studies etc.) Also several national reporting systems

18. Voluntary Reporting Scheme in NZ Reporting form in MIMS etc Sent to Centre for Adverse Reaction Monitoring (CARM) - based at University of Otago Reports assessed by Medical Assessor, with reference to prescribers, to produce a database of ADRs

19. Voluntary Reporting Scheme in NZ Reports to Medicines Adverse Reactions Committee at MoH Annual report by Medsafe A good scheme but main problem with all voluntary schemes is ‘under-reporting’

20. Intensive Reporting Intensive Medicines Monitoring Programme (IMMP); also based at Otago A small number (about six – see MIMS) of newly marketed medicines on the scheme at any one time

21. Intensive Reporting cont. All prescriptions for patients on these agents are followed – pharmacist records kept Successful in early identification of new ADRs (e.g. ACE inhibitor cough) Only a handful of such schemes worldwide, NZ reputation very high

22. Poisoning (Toxicology) Due to toxic effects (overdosage) of drugs and other agents Both accidental and deliberate causes Children at special risk – especially of Iron or Paracetamol overdose Drugs often in combinations, making treatment difficult High number of acute medical admissions

23. Treatment: non-specific measures Maintenance of ventilation/blood pressure Reducing absorption - emptying stomach by emesis or washouts - substances to bind poison Increasing elimination - renal elimination by altering pH of urine - haemoperfusion Ensure hydration, electrolyte balance

24. Individual Agents contd. Paracetamol - causes liver damage which may be fatal, due to production of toxic metabolite when normal liver enzyme system is saturated (at about 10g of paracetamol). Methionine (orally) or n-acetylcysteine (infusion) may be effective antidotes if administered early Iron - iron chelating agent desferrioxamine IV as antidote

25. Drug Interactions Mostly drug-drug interactions (DDIs), but Also drug-food, drug-alcohol interactions Don’t forget complementary therapies and non- prescription medicines Not all DDI’s are ‘bad’ – e.g. sometimes we use a DDI to enhance effects of one of the agents Estimated approx. 20% of ADRs due to DDIs

26. Drug Interactions cont. Many theoretical interactions but really we want to know those of therapeutic significance Many clinically important drug interactions involve the effect of one drug on the metabolism of another

27. Drug-nutrient interactions Specific drug-nutrient interactions listed in ‘Dietitians New Zealand Inc. Clinical Handbook’ Interaction explained briefly, including a mechanism and a practical recommendation Several other interaction texts exist including ‘Stockley’s Drug Interactions’

28. Object or Precipitant Drug whose effect or action is altered by introduction of another agent is the object drug Drug which alters or precipitates a change in the effect of the other drug is the precipitant drug

29. Any Particular Drugs? Special care must be taken with patient on low therapeutic index/steep dose-response curve medicines (consider how these medicines will ‘mix’ with what you are prescribing): Digoxin Lithium Warfarin Aminoglycosides Cytotoxics Levodopa Verapamil Sulphonylureas

30. More Drugs of Concern Patient dependent on therapeutic effect: Immunosuppressants (e.g. cyclosporin) Glucocorticoids Oral contraceptives Antiepileptics Antipsychotics Antiarrhythmics Antiretrovirals Enzyme inducers or inhibitors: Inhibitors e.g. cimetidine, erythromycin Inducers e.g. barbiturates, antiepileptics, rifampicin

31. Mechanisms 1.Pharmaceutical incompatabilities 2.Pharmacodynamic interactions 3.Pharmacokinetic interactions (ADME)

32. 1. Pharmaceutical Incompatibilities Occur before drugs introduced to the body e.g. absorption of benzodiazepines onto rubber, or absorption of carbamazepine to an enteral feed tube Often involves precipitation of additives to intravenous fluids and other formulations e.g. precipitation of certain antibiotics in IV fluids, neomycin in aqueous cream etc. Exposure time and number of drugs mixed important Usually picked up by pharmacist or checking BNF etc.

33. 2. Pharmacodynamic Interactions Direct competition at receptor sites - salbutamol/metoprolol - morphine/naloxone Additive effects at receptor sites - e.g. use of two NSAIDs concurrently

34. 2. Pharmacodynamic Interactions cont. Indirect effects at site of action - amiloride plus potassium supplements (hyperkalaemia) - NSAIDs and warfarin (increased risk of bleeding)

35. 3. Pharmacokinetic Interactions Absorption – Chelation describes the process where two separate parts of a mixture will bind strongly to each other – Many metal ions (as supplements or antacids ) will bind drugs, thereby preventing them from being absorbed. E.g. antacids, Ca or Fe containing products given at the same time as doxycycline will prevent absorption of the antibiotic.

36. 3. Pharmacokinetic Interactions cont. Absorption - Gastric emptying and motility Drugs with anticholinergic effects (e.g, tricyclic antidepressants) reduce gastric emptying and decrease bioavailability of levodopa Metoclopramide increases gastric emptying and speeds absorption of paracetamol

37. Pharmacokinetic Interactions cont. Distribution Generally not clinically significant

38. Pharmacokinetic Interactions cont. Metabolism The great majority of drug interactions of clinical significance involve the effect of one drug on the metabolism of another Phase I metabolosm in the liver is mediated through the Cytochrome P450 mixed oxidase system In fact Cytochrome P450 is comprised of nearly 60 isoenzymes, each expressed from an individual gene We are just starting to elucidate the importance of genetic determination of each individual’s CYP profile

39. CYP Profiling Four main families of CYP450 enzymes Divided into sub-families; Sub-family enzymes numbered For example CYP1A2 etc. It is beyond this course to give further detail but CYP2D6 is well studied and shows inter-individual variability and CYP3A4 is involved in the metabolism of many drugs (it is found both in liver and intestinal epithelium)

40. Enzyme Inhibitors Well known enzyme inhibitors include cimetidine; erythromycin, clarithromycin; ciprofloxacin; azoles e.g. fluconazole; allopurinol, antivirals By inhibiting CYP enzymes, they will reduce the metabolism of object drugs using the same metabolic pathway

41. Enzyme Inhibitors cont. If the object drug has a low therapeutic index then adverse effects may occur For example, if warfarin is the object drug, the risk of bleeding is markedly increased due to rise in blood levels of warfarin (not being metabolised) Similar concerns apply to theophylline, cyclosporin, phenytoin, oc’s etc. as object drugs

42. Enzyme Inducers Well known enzyme inducers include rifampicin, barbiturates, carbamazepine, phenytoin, St John’s Wort; also alcohol and cigarette smoking Involves production of additional enzyme so takes place gradually over several days or weeks

43. Enzyme Inducers cont. Enzyme induction increases metabolism of the object drug and decreases its pharmacological effects For therapeutically important object drugs (e.g. cyclosporin, oral contraceptives, corticocosteroids, warfarin) there is a risk of therapeutic failure

44. Pharmacokinetic Interactions cont. Excretion Changes in urinary pH - At alkaline pH weak acids are not reabsorbed and therefore excreted (eg salicylates) - At acid pH weak bases are not reabsorbed and therefore excreted (eg amphetamines) - Urine acidification or alkalinisation used to treat poisoning – or to try to mask drugs used in sports or for illicit drug screening!

45. Pharmacokinetic Interactions cont. Excretion Changes in active excretion - some drugs compete for the same active transport system in the kidney tubule - examples include probenecid (excreted preferentially) and penicillins or antiretrovirals; methotrexate and NSAIDs (excreted preferentially)

46. Drug-Food, Drug-Alcohol Interactions Grapefruit contains flavonoids (CYP3A4 inhibitor in intestine) – increases bioavailability of felodipine, statins Alcohol and CNS drugs (additive or synergistic effects with tricyclics, sedatives, opioids etc.) Complementary medicines (eg St John’s Wort) – enzyme inhibitor: care with cyclosporin etc.

47. Drug-Food, Drug-Alcohol Interactions cont. Vit K – Warfarin (antagonism of warfarin effects) MAOIs and certain foods containing tyramine (cheese etc.) – increase blood pressure Disulfiram, metronidazole and alcohol (build up of acetaldehyde due to alcohol dehydrogenase inhibition)