Adverse Drug Reactions Part 1 PDF

ADVERSE DRUG REACTIONS PART 1 R E B E K A H R AY M O N D LEARNING OUTCOMES Define the term adverse drug reaction (ADR) Understand the difference between an ADR and an adverse event Understand the impact of ADRs on the healthcare system Identify the key risk factors for ADRs Descri...

ADVERSE DRUG REACTIONS PART 1 R E B E K A H R AY M O N D LEARNING OUTCOMES Define the term adverse drug reaction (ADR) Understand the difference between an ADR and an adverse event Understand the impact of ADRs on the healthcare system Identify the key risk factors for ADRs Describe the common ADR classification, principles of the alternative classification DoTS ADVERSE DRUG REACTIONS IN PRACTICE  DEFINITION OF TERMINOLOGY  ADVERSE EVENT WHO 2017 Any negative or harmful occurrence that takes place during treatment, that may or may not be associated with a medicine.  ADVERSE DRUG REACTION WHO 1972 'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function'  ADVERSE DRUG REACTION The National Reporting and Learning Scheme uses the definition from EU directive 2010/84/EU; ‘A response to a medicinal product that is noxious and unintended, resulting not only from the authorized use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorization, including the misuse, off-label use and abuse of the medicinal product.’  SIDE EFFECT WHO ‘Any unintended outcome that seems to be associated with treatment, including negative or positive effects.’ ADVERSE DRUG REACTIONS All events Adverse drug events Adverse drug reactions All ADRs are AEs but not all AEs are ARDs WHY ARE ADRS A PROBLEM?  PUBLIC HEALTH BURDEN Over a period of six months in two large hospitals in Merseyside the following was found: – 1,225 admissions judged to be related to an ADR – This is equal to a prevalence of 6.5% of total admissions – 72% were avoidable – Projected annual cost of such admissions to the NHS was £466 million!!  HOW COMMON ARE ADRS? Up to 40% patients in the community experience ADRs In the UK Non Steroidal Anti-Inflammatory Drug (NSAID) use alone accounts for1 65,000 emergency admissions/year 12,000 ulcer bleeding episodes/year 2,000 deaths/year 1Blower et al. Emergency admissions for upper gastrointestinal disease and their relation to NSAID use. Aliment Pharmacol Ther 1997; 11: 283-291 ARE ADRS AVOIDABLE? 30-50% are preventable Obvious interactions – many drugs interact with warfarin Use of contra-indicated drugs – use of a non-selective beta-blocker in an asthmatic → bronchospasm Drug use in an inappropriate clinical indication or medically unnecessary – antibiotics for a viral infection CL ASSIFICATION OF ADR  ADR CLASSIFICATION Onset of event: Acute (2 days) Type of reaction (Rawlins and Thompson, 1977; Aronson, 2002) : Type A (Augmented), B (Bizarre), C (Cumulative/Chronic), D (Delayed), E (Exit/End of therapy), F (Failure), G (Genotoxicity), H (Hypersensitivity), U (Unclassified). Severity: Minor, Moderate, Severe or Lethal DoTS System (Aronson &Ferner, 2003) : Dose related, time-related, susceptibility. Classification of ADR Features Examples Type A (Augmented) Relatively common, Pharmacological, predictable Dose related, Improves if medicine is withdrawn. Type B (Bizarre) Dose independent, Idiosyncratic, Unpredictable, immunological, Rare but may be serious Type C (Cumulative/ Related to drug concentration chronic) Type D (Delayed) Becomes apparent sometime after use of a medicine Type E (Exit/ end of Begins only when the medicine use) is stopped or dose is reduced Type F (Failure) Unexpected failure of therapy Type G (Genotoxicity) Causes irreversible genetic damage Type U (Unclassified) Mechanism not understood Classification of ADR Features Examples Type A (Augmented) Relatively common, Hypoglycemia with sulfonylureas Pharmacological, predictable Dose related, Improves if medicine is withdrawn. Type B (Bizarre) Dose independent, Idiosyncratic, Anaphylaxis with pencillins Unpredictable, immunological, Rare but may be serious Type C (Cumulative/ Related to drug concentration Pituitary axis suppression with chronic) corticosteroids Type D (Delayed) Becomes apparent sometime Leucopoenia occurring up to six after use of a medicine weeks after a dose of lomustine. Type E (Exit/ end of Begins only when the medicine Withdrawal reactions due to use) is stopped or dose is reduced opioids, benzodiazepines, Type F (Failure) Unexpected failure of therapy Taking an antibiotic (enzyme inducer) while on OC Type G (Genotoxicity) Causes irreversible genetic Teratogenic agents like damage thalidomide Type U (Unclassified) Mechanism not understood Taste disturbances with simvastatin DOTS ADR CATEGORIES New categorisation to allow a more precise description of an ADR but it may be complex for practitioners and limited to researchers and pharmacovigilance officers. Dose – Toxic: ADR result of drug levels too high – Collateral: ADR result at normal drug level – Hypersusceptibility: ADR results at drug levels too low Time – Independent: ADR that occurs at any time during treatment – Dependent: Rapid administration, first dose, early, intermediate, late, withdrawal Susceptibility – Age, Gender, Ethnicity, Genetic, Pregnancy, Breastfeeding & Disease DOTS EXAMPLES Osteoporosis due to Corticosteroids Dose: Collateral – ADR occur at normal doses Time: independent/late – ADR months after treatment Susceptibility: Age & Gender – Older female patients Anaphylaxis due to Penicillin Dose: Hypersusceptibility – ADR occur at very low doses Time: Dependent/first dose – ADR STAT at first dose Susceptibility: Requires previous sensitisations MECHANISMS OF ADR Mechanisms of many ADRs is unknown or incompletely understood. Some may relate to pharmacokinetics (e.g. hepatic/renal impairments) or linked to genetics Four broad mechanisms for ADRs: 1. Exaggerated therapeutic response at the target site (e.g. bleeding with Warfarin) 2. Desired pharmacological effect at another site (e.g. headache with GTN) 3. Additional (secondary) pharmacological actions (e.g. prolongation of the QT interval of the electrocardiogram … many drugs!) 4. Triggering an immunological response (e.g. anaphylaxis due to ….. many drugs!) WHO IS AT RISK OF AN ADR?  PREDISPOSING FACTORS FOR ADRS Age: the elderly and neonates are at greater risk Gender: Women are generally at greater risk Ethnic origin: may effect drug metabolism (e.g. Glucose-6-phosphate dehydrogenase deficiency) Impaired hepatic and/or renal functions Specific diseases e.g. asthma & beta-blockers Polypharmacy: increases risk of interactions, (pharmacodynamics, absorption, distribution, metabolism & excretion), herbal medicines and dietary products Any previous history of an ADR  RISK FACTOR: CHILDREN At birth, a neonate's metabolic function is not yet fully developed: – Neonates and young children cannot metabolise systemic chloramphenicol resulting in toxic levels causing severe hypotension and grey baby/grey toddler syndrome. – Neonates cannot metabolise and detoxify benzyl alcohol preservative present in some injections (clindamycin, etanercept) resulting in metabolic acidosis and respiratory problems (gasping syndrome). – Neonates' livers do not metabolise alcohol efficiently so ethanol present in e.g. phenytoin oral liquid can cause CNS and respiratory depression. Children respond differently to some medicines: – Children and adolescents are more prone to acute dystonic reactions to metoclopramide than fully mature adults – Under 16s are more at risk of Reye’s syndrome when exposed to aspirin for fever.  RISK FACTORS - ELDERLY Tendency to renal impairment so increased risk of toxicity with renally excreted medicines such as digoxin, morphine, lithium and methotrexate. Impaired homoeostasis so they are more prone to: – Dehydration e.g. with diuretics. – Postural hypotension and falls e.g. with tricyclic antidepressants and levodopa based antiparkinson medicines. – Poor temperature regulation e.g. with antipsychotics. Elderly have a proportionately lower lean body mass, less total body water and a relative increase in total body fat. This results in: – Decreased volume of distribution for water-soluble medicines such as digoxin and lithium causing increased plasma concentration. – Increased volume of distribution for fat-soluble medicines such as benzodiazepines and antipsychotics resulting in accumulation with continued use  RISK FACTOR: FEMALE Females have a higher risk of developing an ADR compared with males. Females generally have a lower body weight and a lower lean body mass than males. Females have about double the risk of developing a drug allergy compared with males including photosensitivity and systemic lupus erythematosis. Females metabolise medicines differently and tend to have a reduced hepatic clearance. Females are more at risk of QT prolongation with certain antiarrhythmic medicines than men at the same plasma concentration – being female is a recognised risk factor for QT prolongation. Females are at greater risk of electrolyte disturbances with diuretics and toxicity with digoxin.  RISK FACTOR: ETHNICITY Certain ethnic groups are more likely to carry a specific gene which could predispose them to risk of a specific adverse drug reaction: – Greater risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with carbamazepine and to a lesser extent phenytoin if patients carry the HLA-B*1502 allele. People of Han Chinese, Hong Kong and Thai origin are more likely to carry this gene. Allopurinol triggers the syndrome in Chinese people with the HLA B1508 gene. – Rosuvastatin is more likely to cause myopathies and rhabdomyolysis in those of Asian origin. – Abacavir can cause a potentially fatal hypersensitivity reaction in those carrying the HLA-B*5701 allele – more prevalent in Caucasians. – People from the Indian subcontinent, are at greater risk of developing diabetes, coronary heart disease and partly due to diet and lifestyle factors. They are at greater risk of developing diabetes and hyperlipidaemia when on glucocorticosteroids such as prednisolone. – People of Afro-Carribean origin are at greater risk of developing angioedema with ACE inhibitors and Angiotensin II receptor blocking medicines.  Stevens–Johnson syndrome A rare but serious disorder that affects the skin, mucous membrane, genitals and eyes. Unpredictable, often begins with flu-like symptoms, followed by a red or purple rash that spreads and forms blisters. The affected skin eventually dies and peels off. A medical emergency that requires treatment in hospital, often in intensive care or a burns unit. Skin pain is the most common symptom. Flu-like symptoms are also usually present during the initial stages, and may include: generally unwell, a high temperature, headache, joint pain & cough. Facial swelling and swollen lips covered in crusty sores After a few days a rash appears, which may look like a target – darker in the middle and lighter around the outside. The rash isn't usually itchy, and spreads over a number of hours or days. Large blisters then develop on the skin, which after bursting leave painful sores. Medications associated with a high risk of Stevens-Johnson syndrome are: allopurinol, carbamazepine, cotrimoxazole and other anti-infective sulfonamides, lamotrigine, nevirapine, certain types of non-steroidal anti-inflammatory drugs (NSAIDs) – including meloxicam, piroxicam and tenoxicam, phenobarbital, phenytoin, sertraline Toxic epidermal necrolysis (Lyell's syndrome) is when >30% of the body surface area is involved. It is called SJS when 4 medicines are at greater risk of ADRs especially if also elderly: – 58% ADR risk with 5 medicines. – 82% ADR risk with 7 or more medicines. There is a higher prevalence of polypharmacy and co-morbidities in older people: – >40% of ambulatory patients over 65 years old use at least 5 different medicines per week and 12% use at least 10 medicines per week. – About 1 in 3 older patients taking more than 5 medicines will experience an ADR each year, and the majority of these will require medical attention. WHICH DRUGS ARE OFTEN RESPONSIBLE? Davies et al (2009) found the following drugs to be the most common causes of ADR in hospital in- patients; Opiates Warfarin Diuretics Cephalosporins Systemic corticosteroids Compound analgesia Inhaled β-agonists Macrolides Penicillins LMW heparins  ADR CAUSATION The most important question – was the drug responsible? Judgement of risk-benefit balance Assessing causality Probable: information available to support causation Possible: some supportive information available Unassessable: information missing to support or against causation Unlikely: Information available against causation Strength: the stronger an association is, the higher the causation Consistency: repeated cases/observations of the association of drug and the ADR Specificity: a few ADRs are completely unique  ADR IDENTIFICATION Identify ADR and associating causation is difficult: Why? 1. The reaction may be so unusual that causation by a common and familiar medicine is not considered. 2. The ADR closely mimics a common and familiar disease. 3. There is a long delay between initiation of drug therapy and the appearance of the ADR. 4. The medicine evokes a relapse of a disease that is already established or may provoke a disease in a naturally susceptible subject. 5. A specific clinical situation may be so complex (i.e. multiple diseases and drug treatments) that its medicine-related components escape notice.  DIAGNOSING ADR Few ADRs are unique – Be more suspicious when medicines with a low therapeutic index (e.g. digoxin, theophylline, warfarin) are prescribed. – Also be vigilant with NSAIDs which are frequently associated with ADRs. The timing of the onset of the symptoms relative to the start of medication therapy is one of the most important pieces of evidence that raises suspicion of an ADR. It is important to check authoritative sources for previous evidence of similar associations reported by others. Finding other reports does not prove that the presentation is caused by an ADR, but it adds further plausibility to this explanation. The time course to resolution after stopping the medicine (de-challenge) may also be of help. Consider laboratory investigations (e.g. East Asians who have the gene marker HLA-B*1502 likely to suffer from Stevens-Johnson Syndrome when given phenytoin or carbamazepine ADR MANAGEMENT Continue medication Regular review of prescribed medications (and the ADR actively treated (STOPP/START) by other means) If an antihistamine is required, avoid older ones like chlorphenamine which are highly anticholinergic and can cause falls and cognitive impairment. Choose a non-sedating variety Reduce dose such as loratadine or cetirizine. When treating anxiety try to avoid benzodiazepines which can cause confusion, sedation, memory impairment and falls. Withdraw medicine Consider alternatives such as CBT, or (temporarily or permanently) relaxation therapy if appropriate. If using any CNS drugs in elderly patients the general advice is to start low and titrate up slowly while monitoring for effect and any ADRs.  ADR REPORTING All prescribers and other healthcare professionals allied to medicine have a professional obligation to report suspected ADRs. In the UK, suspected ADRs are reported to the MHRA via the Yellow Card Scheme.Yellow Card reports are now usually completed electronically using the MHRA website although paper yellow cards are available in the back of the BNF. Healthcare professionals should report all: – suspected ADRs for new medicines – identified by the inverted black triangle ▼ symbol as being under more intensive surveillance. – suspected black triangle ▼ or serious ADRs occurring in children, even if a medicine has been used off-label. – serious suspected ADRs for established vaccines and medicines, including unlicensed medicines, herbal remedies, and medicines used off-label. ADVERSE DRUG REACTIONS PART 2 R E B E K A H R AY M O N D LEARNING OUTCOMES To able to define various adverse drug reactions (ADR) Identify ADRs and which drugs can cause them Provide appropriate management advice, and have knowledge of resources available. BODY SYSTEMS AND ADRS Consider ADRs related to: Renal system Cardiovascular Cutaneous Endocrine Gastrointestinal Haematological Musculoskeletal Respiratory GI ADR ORAL CAVITY  ORAL CAVITY Dry mouth (Xerostomia): It is reported that over 400 medications that can create dry mouth. Most of these medications have an antiadrenergic / anticholinergic effect. Antihypertensives Urinary incontinence drugs Antipsychotics Antidepressants Diuretics Antihistamines Antiulcer/antidiarrheal drugs Opiates/narcotics  ORAL CAVITY Tooth staining and dental hypoplasia such as tetracycline. Candidiasis: Inhaled corticosteroids Oral lesions known as erythema multiforme e.g. sulphonamides, tetracycline, phenytoin, NSAIDs  ORAL CAVITY Gingival enlargement: overgrowth of the periodontal tissue. If severe- may cover the whole tooth. Surgical removal of gingival tissue may be the only treatment if drug cannot be discontinued e.g. phenytoin, ciclosporin and CCBs.  MANAGEMENT OF ORAL CAVITY ADRS Smoking, alcohol, and suboptimal oral hygiene might also contribute to oral cavity changes and should be addressed through patient education and support. If it is not possible to discontinue or switch an offending medication, scheduling doses to avoid taste disturbances at mealtimes overnight can be considered. Drinking plenty of water or chewing sugarless gum may help relieve dry mouth symptoms. Patients using corticosteroid inhalers are counselled to rinse their mouth with water after inhalation and use a spacer device. Antifungal oral suspension or gel may be used without discontinuing corticosteroid therapy Gingival enlargement- Mild case = better oral hygiene together with professional dental cleaning. More severe cases- surgery.  OESOPHAGEAL ADRS Several medicines can induce direct oesophageal injury (oesophagitis/ulcerations or erosions), while others promote gastroesophageal reflux (GERD) Chemical property of the drug plays a role as well as duration of medication contact with oesophagus. Most common medications causing oesophageal irritations/inflammation by directly irritating the oesophageal lining include: bisphosphates, NSAIDs, tetracycline, quinidine, potassium chloride, vitamin C, and iron tablets. Effect ranges from mild to severe ulceration or stricture.  MANAGEMENT OF OESOPHAGEAL ADRS Counselling for direction of administration for drugs like alendronic acid: Tablet to be swollen whole with plenty of water while sitting or standing on an empty stomach at least 30 mins before breakfast. Patient should stand or sit upright for at least 30 mins after administration. If ADR symptoms occur seek medical attention and discontinue the medication. Change route of administration if an option or switch to a suitable alternative. Supportive additional treatment e.g. PPI in some cases may help.  STOMACH ADRS Nausea and Vomiting: common side effects of many drugs. Mostly associated with chemotherapy treatment and opioids. May be controlled with antiemetic if needed to prevent dehydration and electrolyte imbalance.  STOMACH ADRS Delayed gastric emptying: anticholinergic drugs leading to symptoms of nausea, bloating, and abdominal pain. Ulcers (gastroduodenal) and bleeding: NSAIDs- either by: direct damage to the mucosa suppression of PG (which maintains an intact gastric mucosal barrier by mucus and bicarbonate, maintaining mucosal blood flow and acid secretion).  STOMACH ADRS Identify high risk patients for ulceration/bleeding. Counsel patients about signs and symptoms of bleeding and ulceration. High risk patients who need to continue treatment with NSAIDs should be offered PPI. Taking it with food or milk and using enteric-coated formulations (no strong evidence though) may partially help. Consider discontinuing NSAID or switching to COX-2 selective inhibitors if possible.  LARGE INTESTINE ADRS CHASSANY O, ET AL, 2000 Diarrhoea: May be due to drugs interfering with electrolyte balance in the GI tract OR due to reduction of normal colonic flora- most common example is antibiotic induced C.diff.  LARGE INTESTINE ADRS Drug-induced diarrhoea may resolve spontaneously with or without withdrawal of the causative agent. Antimicrobials are responsible for 25% of drug-induced diarrhoea. If pseudomembranous colitis is suspected, the antibacterial should be withdrawn, symptomatic treatment of diarrhoea started and specific antibacterial therapy initiated. Symptomatic treatment consists of diet and oral rehydration therapy. In cases of severe diarrhoea, hospitalisation can be necessary for parenteral rehydration therapy. Antiperistaltic agents such as loperamide, diphenoxy-late, and codeine can be useful in patients with profuse diarrhoea to slow intestinal transit and thus alleviate discomfort. However, these agents should be avoided in patients with severe diarrhoea, as possible colonic retention of bacteria and toxins could lead to the development of toxic megacolon, especially if the diarrhoea is related to a change in the microflora. LARGE INTESTINE ADRS  LARGE INTESTINE ADRS Constipation: Common side effect-either due to decrease colon motility or disturbed fluid secretion and absorption. Drugs include: aluminium antacids, antidepressants, antiepileptic, antipsychotics, calcium supplements, opiate painkillers, diuretics and iron supplements. Management includes: Adjusting any constipating medication, if possible. Advise the person about increasing dietary fibre, drinking an adequate fluid intake, and exercise. Offer oral laxatives if dietary measures are ineffective, or while waiting for them to take effect. Opioid-induced constipation: Avoid bulk-forming laxatives. Use an osmotic laxative (or docusate sodium to soften the stools) and stimulant laxative (e.g. bisacodyl).  HEPATIC ADRS Jaundice Cholestasis – co-amoxiclav Steatosis Fibrosis and cirrhosis - methotrexate PRINCIPLE MUSCULOSKELETAL ADRS LEON ET AL 2005 Musculoskeletal ADRs Drugs (> 30 Reports) Drugs (3-30 Reports) Drugs Myalgia Fluoroquinolones ACE inhibitors , Angiotensin-II receptor antagonists Statins Antipsychotic drugs, Beta-adrenoceptor blocking drugs, Bisphosphonates, Calcium- channel blockers Donepezil, Fibrates, Interferon beta, Leukotriene receptor antagonists, Macrolides, NSAIDs Oral antidiabetic drugs, Proton pump inhibitors Selective serotonin reuptake inhibitors, Trivalent oral iron Myopathy/Rhabdomyolysis Statins Antipsychotic drugs, Corticosteroids Fibrates, Fluoroquinolones, Macrolides Arthralgia/arthritis/ Fluoroquinolones ACE inhibitors, Antiepileptic drugs, Antipsychotic drugs, Bisphosphonates arthropathy Statins Cephalosporins, Fibrates, Immunosuppressive agents, Iron chelating agents, NSAIDs, Nucleoside reverse transcriptase inhibitors Penicillins, Proton pump inhibitors, Trivalent oral iron Tendinitis/tendon rupture Fluoroquinolones Corticosteroids, Statins Osteonecrosis Bisphosphonates Antipsychotic drugs  MUSCULOSKELETAL ADRS: STATINS Myopathy, myositis and rhabdomyolysis are rare Although myalgia commonly reported- actual muscle toxicity is rare. Discontinue if statin suspected to be cause of myopathy with CK >5 times the normal upper limit or if symptoms are severe. Reintroduce lower dose and monitor if symptoms resolve and CK back to normal.  MUSCULOSKELETAL ADRS: FLUOROQUINOLONES Tendon damage May occur within 48 hours or even several months after stopping quinolones. (time-independent) Risk increases by concomitant use of corticosteroids If tendonitis suspected- stop immediately. Fluoroquinolones contraindicated in children & adolescents = destruction cartilage weight bearing joints in immature animals Of fluoroquinolones, levofloxacin 1st for tendon rupture. Rhabdomyolosis reported with moxifloxacin but fortunately very rare.  MUSCULOSKELETAL ADRS: CORTICOSTEROIDS Tendinopathies, osteoporosis & myopathy Tendinopathies associated with oral & parenteral routes, rarely topical Correlates with increased CK level Inhibition of protein synthesis – enhancement of muscle apoptosis ↓ bone density, regardless of disease being treated – more than 5mg oral tx = rapid ↑ risk of fracture (with oral and inhaled corticosteroids) Long term tx = ↓ intestinal Ca absorption, suppresses osteoblastic formation, stimulates osteocyte apoptosis. Overall pathophysiology is complex and still unclear  MUSCULOSKELETAL ADRS: BISPHOSPHONATES Very prolonged half-life incorporated into the skeleton, without being degraded Osteonecrosis of the jaw – image shows bisphosphonate-related osteonecrosis of the jaw at extraction site of tooth. Necrotic, non- healing exposed bone extends up the ramus and to the buccal aspect of tooth Develops spontaneously or after dental treatment Zoledronic acid 10% patients – onset average of 18 months Mechanism still unclear Priority screening & early intervention needed – no effective procedure MUSCULOSKELETAL ADRS: BISPHOSPHONATES MHRA/CHM advice June 2011: Atypical femoral fractures have been reported rarely with bisphosphonate treatment mainly in patients receiving long-term treatment for osteoporosis. Treatment should be evaluated periodically based on assessment of benefits and risks, particularly after 5 or more years of use. Patients should be advised to report any thigh, hip or groin pain during treatment.  MUSCULOSKELETAL ADRS: PROTON PUMP INHIBITORS Very commonly taken drug worldwide……….. one to watch Several large studies linked PPI use to fractures, so in 2010 the FDA issued a warning about potential fracture risk although several other studies showed conflicting results and inconsistency. Recommendation: PPI should be prescribed for appropriate indication at the lowest effective dose for the shortest period. Patients at risk for osteoporosis should maintain an adequate intake of Ca and vit D and if necessary receive preventative therapy. MUSCULOSKELETAL ADRS: PROTON PUMP INHIBITORS Less than 1% patients may suffer from muscle cramps, myalgia, joint and leg pain. Some growing anecdotal evidence, unclear whether drug interactions involved. Mechanism unclear  RESPIRATORY ADRS Bronchospasm/Cough Fibrosis Pleural effusion Pulmonary hypertension Respiratory Failure NASAL CONGESTION AIRWAY OBSTRUCTION Management: Stop agent and introduce an alternative PARENCHYMAL LUNG DISORDERS Delayed reactions but dramatic clinical presentation requiring prompt diagnosis and withdrawal of the suspect drug. CARDIOVASCULAR ADRS Hypertension Hypotension Bradycardia Tachycardia Prolonged QT intervals Arrhythmias Heart Failure  HYPERTENSION Optimal blood pressure of 120/80 mmHg Hypertension = persistent systolic over diastolic pressure of > 140/90 mmHg  HYPOTENSION No standard definition Symptoms are usually transient and may occur on standing: – Headache – Blurred vision – Dizziness – Syncope Risk of first dose hypotension minimised by initiating treatment at bedtime and/or gradually titrating dose up towards an optimal therapeutic dose  BRADYCARDIA Bradycardia = resting heart rate 100 bpm. Examples: – Pseudoephedrine – Anticholinergic Drugs Benzatropine Trihexyphenidyl Tricyclic Antidepressants (TCA) Phenothiazine Antipsychotics Antimuscarinic Bronchodilators – Dihydropyridine calcium channel blockers (e.g. Nifedipine) – Diuretics – Minoxidil – Initial treatment with Alpha-blockers (e.g. Doxazosin) – Withdrawal of Clonidine – Thyroxine – overtreatment – Nicotine replacement therapy – Beta-2 adrenoreceptor agonists (salbutamol) – Theophylline  PROLONGED QT INTERVAL & TORSADES DE POINTES Torsades de pointes = ‘twisting of the points’ in reference to the characteristics of cardiac axis seen on an ECG. A specific type of abnormal heart rhythm that can lead to sudden cardiac death. Prolongation of the QT interval can increase a person's risk of developing this abnormal heart rhythm. Upper limit for men 440ms and women 470ms. Anything above 500ms refer to cardiology and stop agent. Above 440ms and less than 500ms, repeat ECG and consider reduce dose/refer to cardiology/switch drug. PROLONGED QT INTERVAL & TORSADES DE POINTES  HEART FAILURE Inability of the heart to supply sufficient blood to meet the metabolic demands of the body ADR of heart failure by either reducing cardiac output or by causing excess fluid retention and circulating volume overload. OVERVIEW Use drugs appropriately noting their indication of use Ask about allergies and idiosyncrasies Other medications- OTC Age, renal and hepatic functions, genetics and sex Avoid inappropriate polypharmacy Monitor and follow up Consider excipients Counsel patient Report through the Yellow Card Scheme RESOURCES FOR MANAGEMENT GUIDANCE Summary of product characteristics (SmPC): https://www.medicines.org.uk/emc or https://www.gov.uk/pil-spc Local hospital protocols British National Formulary, MedicinesComplete (Martindale/Martindale’s ADR Checker and Stockleys) Literature Consider that these resources may not always have the answers, and so clinical judgement and utilisation of your peers i.e. doctors, nurses and other pharmacists is essential! CONCLUSION Define ADR Recognise the different types and classifications of ADR Able to manage ADR Understand the importance of reporting ADRs  CAN YOU IDENTIFY THE LIKELY CAUSE? EXAMPLE SHORT ANSWER QUESTION What is an adverse drug reaction (ADR) and how are they classified? Mr AS has been admitted with an asthma exacerbation. Whilst taking a drug history the patient complains of a fever and painful rash on their hand. Consider the potential ADR and management, discussing risk factors that could pre-dispose the patient to ADRs using the SPC provided. https://www.medicines.org.uk/emc/product/15032/smpc Summary Care Record Date: 07/03/2021 Patient: AS Age: 65 Allergies: None DHx: MHx Salbutamol 100mcg 2 puffs PRN Asthma (Diagnosed March 2013) Clenil modulite 100mcg 2 puffs BD Gout (Diagnosed February 2021) Paracetamol 500mg-1g QDS PRN Allopurinol 100mg OD  RISK FACTOR: ETHNICITY Certain ethnic groups are more likely to carry a specific gene which could predispose them to risk of a specific adverse drug reaction: – Greater risk of developing Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with carbamazepine and to a lesser extent phenytoin if patients carry the HLA-B*1502 allele. People of Han Chinese, Hong Kong and Thai origin are more likely to carry this gene. Allopurinol triggers the syndrome in Chinese people with the HLA B1508 gene. – Abacavir can cause a potentially fatal hypersensitivity reaction in those carrying the HLA-B*5701 allele – more prevalent in Caucasians. – Rosuvastatin is more likely to cause myopathies and rhabdomyolysis in those of Asian origin. – People from the Indian subcontinent, are at greater risk of developing diabetes, coronary heart disease and partly due to diet and lifestyle factors. They are at greater risk of developing diabetes and hyperlipidaemia when on glucocorticosteroids such as prednisolone. – People of Afro-Carribean origin are at greater risk of developing angioedema with ACE inhibitors and Angiotensin II receptor blocking medicines. THANK YOU Acknowledgments: Tadeh Tamasi Dr Nada Shebl Dr Ahmed Ameer REFERENCES AND RESOURCES References Lee, A. Adverse Drug Reactions 2nd Edition. Pharmaceutical Press 2006 NICE CKS Adverse drug reactions | Health topics A to Z | CKS | NICE Varallo, FR. Et al. (2017) Imputation of adverse drug reactions: Causality assessment in hospitals. PLoS ONE 12(2): e0171470. accessed 30/11/2022 available at: http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0171470&type=printable Aronson JK, Ferner RE. Joining the DoTS: new approach to classifying adverse drug reactions. BMJ. 2003 Nov 22;327(7425):1222-5. accessed on 30/11/2022 available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC274067/ Resources MHRA free CPD resource, accessed 30/11/2022 available at: https://www.gov.uk/drug-safety-update/new-cpd-e-learning-module-on- reporting-suspected-adverse-drug-reactions CPPE WHO-UMC system for standardized case causality assessment. World Health Organization accessed on 30/11/2022 available at: Clinical assessment | UMC (who-umc.org)