U1L4 2022 ADRs and Poisoning PDF

Unit 1 Lecture 4: Drug Harms (ADRs and poisoning) Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; NUI Galway University ofGalway.ie Overview At the end of this lecture you will be able: • to ide...

Unit 1 Lecture 4: Drug Harms (ADRs and poisoning) Dr Louise Rabbitt MRCPI Email: [email protected] Specialist Registrar, Clinical Pharmacology and Therapeutics, Galway University Hospitals; NUI Galway University ofGalway.ie Overview At the end of this lecture you will be able: • to identify a number of important adverse drug reactions • To provide examples of drugs that produce such ADRs • to be aware of how our knowledge of ADRs has a bearing on treatment Unit 1, Part 2: Drug Action and clinical effects Clinical Evaluation Specific drug examples Therapeutic effects Mechanism of action Harmful effects Dose response Clinical Trials Systematic reviews ADRs Phase IV Phases 1-III Meta analyses Poisoning Types University Treatment ofGalway.ie Risk:Benefit “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy” (Paracelsus. 14931541). University ofGalway.ie Post-marketing Surveillance University ofGalway.ie The need for post-marketing data • “Information about a drug is never complete” (Lasagna, 1980). • Pre-marketing trials with stringent inclusion/exclusion criteria may not be representative (females often under-represented). • Post-marketing, the drug is introduced into the general patient population. • As larger numbers are exposed for longer, increasingly comprehensive safety data is gathered. • Drug-drug interactions Pharmacovigilance: Methods • Encompasses a number of pharmaco-epidemiological techniques. • MEDWatch (USA), spontaneous adverse event reporting cards (“Yellow” cards, UK), WHO adverse drug experience database. • Doctors and patients can contact drug companies directly via dedicated hotlines. • Post-marketing studies, e.g. randomized controlled trials, Phase IV intervention studies, Case-control studies, data bank comparisons. Adverse drug reactions (ADRs) • An ADR (adverse drug reaction) is a harmful or unwanted effect of a drug. • Often display dose response relationship • Many (but not all) ADRs are produced at doses much higher than the therapeutic dose Adverse Drug Reactions Related to the known pharmacological action of the drug • • • • “Type A” (“Augmented”) Generally predictable Dose related Eg: postural hypotension with antihypertensives, bleeding with anticoagulants Unrelated to known pharmacological action • May be dose-related – eg paracetamol • Unpredictable/idiosyncratic – may occur at therapeutic doses • “Type B” (“bizarre”) • often immunological, often related to an active metabolite • Eg anaphylaxis to penicillin, aplastic anaemia from chloramphenicol, agranulocytosis from clozapine Measures of risk and benefit Therapeutic Index LD50 /ED50 • Lethal Dose in 50% of population • ‘Effective’ Dose in 50% of population • Based on toxicity data (animal models) • Individual variation and idiosyncratic reactions not included? More measures of risk and benefit Number Needed to Treat (NNT) The number of patients who need to be treated in order to show the given effect Number Needed to Harm (NNH) Statins and muscle pain • Statins have been very successful in reducing risk of cardiovascular problems. • Most common adverse effect is muscle pain. • A rare side effect is rhabdomyolysis. • Cerustatin (Baycol) was voluntarily withdrawn from the market in 2001 following implication in severe adverse muscle reactions and death. Drugs in pregnancy 3rd and 11th weeks (critical stages). Increased free drug in plasma. Dangers to foetus before birth. Teratogenic effects, e.g. isotretinoin, antiepileptic drugs. Drugs should not be administered to a woman during pregnancy unless the potential benefit to the mother outweighs the risk to the foetus. Category Interpretation A Controlled studies in Humans show no risk B No evidence of risk in humans (human data reassuring) (Animals positive) C Risk cannot be ruled out (Human data lacking; animal studies positive OR not done) D Positive risk of evidence (Human data show risk; benefit may outweigh risk X Contraindicated in pregnancy (Animal or human data positive) FDA Classification Prescribing in pregnancy – remember the effect of the drug and the effect of Potential adverse the illness effect of the drug on the foetus Benefit of treating the disease in the mother Teratogenesis: Timing How do we minimise teratogenic risk? Developmental and reproductive toxicology studies as part of drug development. Multiple species. Post-marketing observational studies Epidemiological studies – must bear in mind the high background risk of congenital malformations and reporting bias. Pregnancy Planning Appropriate counselling Up to 50% of pregnancies are unplanned – all patients of childbearing potential should be considered antenatal and counselled appropriately If starting a teratogenic medicine, counsel on appropriate and reliable contraception and start during menstrual period. Thalidomide • Introduced in late 1950s as a “safe” alternative sedative to barbiturates • Administered to pregnant women during first trimester (critical period) for morning sickness • Produces phocomelia (deletion of long bones of limbs) • Withdrawn in early 1960s • FDA category “X” • Currently used for the treatment of leprosy and multiple myeloma Sodium valproate in pregnancy Sodium Valproate during pregnancy can result in foetal valproate syndrome (FVS), which can include cognitive difficulties, learning disabilities and autism, as well as some physical abnormalities. In the UK, in 2018 a report revealed that only 1 in 4 women taking the medication were informed of the risks The UK Medicines and Healthcare Products Regulatory Agency (MHRA) introduced the following measures: 1. fully informed of the risks 2. advised on the importance of using effective contraception 3. invited for a yearly review of their treatment Clinical management principles • Use medicines if the expected benefits are greater than the expected risks • Try to avoid first trimester use • Use drugs that have been extensively used in pregnancy (not new drugs) • Use monotherapy where possible • Use the minimum dose required to achieve the desired therapeutic target • Absence of data does not imply safety Drug therapy in the young • GIT absorption (pH and emptying times). • Plasma binding is reduced in neonates. • Conjugation deficient in some neonates (chloramphenicol). • All aspects of renal function are reduced at birth. • Drugs in breast milk: a number of drugs are absolutely contraindicated while the mother is breast-feeding. Drug-induced hypersensitivity Pruritus: may be the first sign of drug hypersensitivity. Erythematous eruptions: skin rash, most common type of drug-induced skin reaction. Urticaria: “hives”, “nettle rash”. Anaphylactic shock: Life-threatening reaction. Release of various substances, among which is histamine causing vasodilatation, increased capillary permeability, tissue oedema. Hypotension, urticaria and erythema of face and neck. Treat with adrenaline, chlorpheniramine, corticosteroids. Drug Allergy: Hypersensitivity Immune Reaction Timing Clinical Presentation Type I: IgE mediated <1-2 hours Urticaria, angioedema, respiratory distress, gi symptoms, hypotension, anaphylaxis Type II: Cytotoxic 10 hours-weeks Anaemia, thrombocytopenia Type III (immune complex) 1-3 weeks Serum sickness-like reaction, fever, urticaria, vasculitis, arthritis/arthralgia Type IV: T-cell mediated 2-14 days Maculopapular rash, Stevens Johnson Syndrome, DRESS syndrome Stephens-Johnson Syndrome due to Carbamazepine Khoo ABS, Ali FR, Yiu ZZN, et al Carbamazepine induced Stevens-Johnson syndrome. Case Reports 2016;2016:bcr2016214926. Penicillin Allergy Reported in up to 10% of population 93% found to not have allergy on formal testing https://www.dropthelabel.ca/ Cardiovascular and blood systems • Bleeding (excess antiplatelet/anticoagulant effects) • Alterations in heart function (e.g. dysrhythmias) • Aplastic anaemia (suppression of all bone marrow function, most serious type), agranulocytosis (complete absence of neutrophils in the blood), thrombocytopenia (reduction in platelet count) Clozapine and agranulocytosis • The National Institute for Health and Clinical Excellence (NICE) guidelines for schizophrenia specify that “in individuals with evidence of treatment resistant schizophrenia, clozapine should be introduced at the earliest opportunity” • Agranulocytosis occurs in about 1% of patients taking clozapine (highest between 6-18 weeks after commencement). It is potentially fatal • Full blood counts (FBC) need to be monitored regularly • Agranulocytosis is an idiosyncratic reaction so difficult to predict Aspirin and serious bleeds From Derry, S and Loke, YK (2000): Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. British Medical Journal 1170-1171 Thioridazine and QT prolongation 30 20 10 H al op er id ol O la nz ap in R e is pe rid on e Q ue tia pi ne Zi pr as id on Th e io rid az in e 0 2.0 Total deaths SGAs Chlorpromazine Thioridazine 1.5 1.0 0.5 0.0 University ofGalway.ie 19 94 19 96 19 98 20 00 20 02 20 04 20 06 20 08 20 10 20 12 Death rate per million population • Prolongs QT interval by blockade of the delayed rectifier cardiac potassium channel (Ik) coded for by HERG • QT prolongation leads to serious ventricular arrhythmias • Withdrawn from the market in 2005 QTc prolongation (ms) 40 Year Handley, S., Patel, M.X. & Flanagan, R.J. (2016): Antipsychotic-related fatal poisoning, England and Wales, 1993–2013: impact of the withdrawal of thioridazine, Clinical Toxicology, 54: 471-480 Central Nervous System • Nausea and vomiting: activation of vomiting centre. • Headache: vasodilators, e.g. nitrates. • Dizziness (most centrally acting drugs), tinnitus (aminoglycosides), drowsiness, Parkinsonism (antipsychotics). • Drug-induced anxiety/depression • Addiction concerns Codeine addiction • Codeine is an opioid originally derived from the opium poppy. • Converted in the body to morphine • Present in a range of OTC medicines that used to be freely available on shelves. • In August 2010, the Pharmaceutical Society of Ireland (PSI) introduced new guidelines: “codeine medicines must not be directly accessible to the public on shelves and most be stored in an area of the pharmacy under the pharmacist's direct management and supervision and out of sight to the public.” • “Patients should be facilitated and encouraged in obtaining medical assistance for any health problems related to codeine misuse.” Rimonabant and psychiatric effects • Cannabinoid (CB1) receptor antagonist developed for the treatment of obesity • Marketed as Accomplia in 2006 in Europe and Brazil but not in USA • Postmarketing surveillance in Europe showed a doubling of the risk of psychiatric disorders in obese patients • Removed from the market in 2008 Moreira, F.A. and Crippa, J.A.S. (2009): The psychiatric side-effects of Rimonbant. Rev. Bras. Psiquietra 31: 145-153 Theralizumab – lessons learned from a phase 1 trial • Theralizumab (TGN1412) – a potential treatment for B cell lymphoma • 2006: 6 participants injected with active drug (at 1/500 the toxic dose identified in mice) rapidly became unwell and developed a life-threatening cytokine storm with multiorgan failure requiring ICU admission. • Huge impact on conduct of future trials (dosing interval between subjects, choice of starting dose, pre-clinical data, preparation for adverse events). • Did a highly selective monoclonal designed for humans fail to show this side-effect in pre-clinical animal studies? 2016 - BIA 10-2472 BIA 10-2474 was proposed for treating anxiety and motor disorders associated with Parkinson’s disease, and chronic pain in people with cancer and other conditions. Phase I conducted at Biotrial, 90 subjects received different doses of the drug, and the remainder a placebo. Single doses has no serious effects But on receiving repeated higher doses, the first participant fell ill on 10 January and died on 17 January. Biotrial halted the trial on 11 January; the other five affected people were hospitalized in the days that followed. http://www.nature.com/news/scientists-in-the-dark-after-frenchclinical-trial-proves-fatal-1.19189#/graphic Summary • A number of adverse reactions can occur to drugs at pharmacological doses, but the more severe ones usually manifest at higher doses • Such ADRs can be demonstrated to affect the different systems of the body • Awareness of the effects often only become known following a period of post-marketing surveillance • Knowledge of such drug-induced effects helps in making risk:benefit decisions Poisoning University ofGalway.ie University ofGalway.ie Posioning Data for USA, 2018 Many groups of drugs feature in the top 25 substance categories involved in human poisoning exposures in 2018 Many are centrally-acting Gummin, DD et al (2019): 2018 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS) Annual Report. Clinical Toxicology Antidepressant Deaths 600 500 Deaths In the UK, deaths were a concern, particularly with TCAs TCAs Dosulepin SSRIs Others Total 400 300 200 Handley and Flanagan, 2014 600 10 20 08 20 06 20 04 20 02 20 00 20 98 19 96 19 19 94 0 Year 400 Handley and Flanagan, 2014 200 9 20 8 0 20 0 0 20 2 0 20 4 0 20 6 0 20 8 1 20 0 1 20 2 1 20 4 1 20 6 18 19 96 19 94 0 19 However, in recent years, deaths have increased, due to perhaps to increased prescribing of these drugs 100 Deaths Reductions in TCA prescribing have seen a marked reduction in deaths with increased prescribing of SSRIs and other newer antidepressants Year Michael Jackson case Died at home in June, 2009 Los Angeles coroner ruled Jackson's death was caused mainly by two drugs propofol and lorazepam Propofol found in Jackson's system was equivalent to that used during anaesthesia for major surgery Other drugs: Diazepam, midazolam lidocaine, ephedrine Dr. Conrad Murray found guilty of involuntary manslaughter Opioid epidemic in USA The misuse of and addiction to opioids (including prescription pain relievers, heroin, and synthetic opioids such as fentanyl) has become a serious national crisis in the USA. Welfare rates and costs of heroin and prescription opioid overdose related admissions in the U.S. increased substantially from 2001 to 2012. In 2018, 128 people died each day after overdosing on opioids Response to the opioid epidemic U.S. Department of Health and Human Services (HHS) is focusing its efforts on five major priorities: 1. improving access to treatment and recovery services 2. promoting use of overdose-reversing drugs 3. strengthening our understanding of the epidemic through better public health surveillance 4. providing support for cutting-edge research on pain and addiction 5. advancing better practices for pain management The National Institutes of Health (NIH), a component of HHS, in the summer of 2017, met with pharmaceutical companies and academic research centres to discuss: 1. safe, effective, non-addictive strategies to manage chronic pain 2. new, innovative medications and technologies to treat opioid use disorders 3. improved overdose prevention and reversal interventions to save lives and support recovery Novichok • Organophosphate nerve agents • Irreversibly bind acetylcholinesterase • preventing degradation of acetylcholine and producing the cholinergic or muscarinic toxidrome. • Coma, mydriasis, hypersalivation, diaphoresis, respiratory failure, seizures… • Also target neurons in peripheral nervous system • Highly potent • Treatment: atropine (competitive muscarinic receptor antagonist) Steindl, et al. Novichok nerve agent poisoning, The Lancet, Volume 397, Issue 10270, 2021, Pages 249-252, ISSN 0140-6736, https://doi.org/10.1016/S0140-6736(20)32644-1. (https://www.sciencedirect.com/science/article/pii/S0140673620326441) Treatment of posioning Strategies • Decontamination (irrigation, charcoal, emetics) • Therapeutic intervention (fluids, intubation, oxygen, ventilation) • Drugs (antiemetics, antihistamines, benzodiazepines, antibiotics) • Antidotes A case… • Susan, a 60 year old woman, is undergoing a colonoscopy, she is given Midazolam to sedate her for the procedure • At the end of the procedure, the endoscopy team notice that Susan is unrouseable, has a very slow breathing rate, and her blood oxygen saturation levels have dropped to 90% • They administer Flumazenil and Susan wakes up. Flumazenil: competitively inhibits the activity of benzodiazepine that interact with benzodiazepine receptors site on the GABA/benzodiazepine receptor complex Naloxone • Antagonist of the µ , δ and κ receptors. • On its own, Naloxone does not affect pain threshold normally but blocks stress-induced analgesia and can exacerbate clinical pain. • Naloxone rapidly reverses opioid-induced analgesia and respiratory depression, and is used mainly to treat opioid overdose or to improve breathing in newborn babies affected by opioids given to the mother. • Naloxone precipitates withdrawal symptoms in morphine dependent patients or animals. Source: Rang and Dale p.549 Antidotes Drug Antidote Mechanism Paracetamol N-acetylcysteine (NAC) Neutralises the NAPQI metabolite Insulin Glucagon Increases plasma glucose levels Opioids Naloxone Antagonist of the mu opioid receptor Benzodiazepines Flumazenil Antagonist of the benzodiazepine receptor Heparin Protamine Forms an neutralising inactive complex Anticholinesterases Pralidoxime Prevents “ageing” of cholinesterase Summary • Certain drug groups are amongst the most frequently encountered poisonings • Introducing safer drugs in a class can reduce serious poisoning events (such as with antidepressants) • Reducing availability can have an impact on deaths associated with drugs (such as paracetamol) • US Opioid-related deaths are a major public health concern • Treatment of poisoning can be generic or related to a specific drug class