Adverse Drug Reactions (ADRs) Lecture 13 - PDF

Adverse drug reactions (ADRs) of different medications Lecture 13 1446 H Psychopharmacology (CPY 490) Definitions Adverse drug reaction (ADR)-Unwanted or harmful reaction following administration of a medication or a combination of medications, and suspecte...

Adverse drug reactions (ADRs) of different medications Lecture 13 1446 H Psychopharmacology (CPY 490) Definitions Adverse drug reaction (ADR)-Unwanted or harmful reaction following administration of a medication or a combination of medications, and suspected to be related to the drug. Pharmacovigilance-Science and activities related to detection, assessment and understanding and prevention of ADRs. Adverse drug event-Unwanted medical occurrence that may present during treatment with a medicine, but not necessarily have a causal relationship with medicine. Terms Toxic effect >> limited to adverse effects at high dosage, ususlay in form of exaggeration of therapeutic desired effects. Side effect >> may be dose related or not, but includes both desirable and undesirable effects of different mechanism from primary pharmacological action. Adverse reaction or adverse effect >> precise, all unwanted effects, regardless of their mechanism or dosage. Importance of ADRs Reduced adherence Reduced drug efficacy (prevent usage of fully effective dosage) Reduced quality of life Increased morbidity and mortality Reduced drug choice Diagnostic confusion Reduced patient confidence Factors influence ADRs Drug factors-non-selective, narrow therapeutic window, teratogenic,.. Patient factors- age, sex, genetics,... Clinical factors- duration of treatment, dose (up- and down-titration of dose), drug interaction, drug choice such as in pregnancy, comorbidity. Classification of ADRs Type A (Augmented) reactions Type B (Bizarre) reactions Type C (Chronic) reactions Type D (Delayed) effects Type E (End of treatment) effects Type F (Failure of therapy) effects Type A (Augmented) reactions Related to a pharmacological action of the drug Common ADRs (high incidence) Usually not severe (low mortality) Predictable Dose dependent (can be alleviated by dose reduction) Examples: sedation with barbiturates, bleeding with anticoagulants >> primary mechanism of action. Bronchoconstriction with propranolol (non-cardio-selective beta blocker), sedation with diphenhydramine (non-selective antihistamine, blocks H1- receptor) >> other sites of action. May be beneficial side effects in some cases >> weight loss. Sildenafil (Viagra®) First oral treatment for erectile (sexual) dysfunction. Discovered based on side effects. "Originally, we were testing sildenafil, the active drug in Viagra, as a cardiovascular drug and for its ability to lower blood pressure''. "But one thing that was found during those trials is that people didn't want to give the medication back because of the side effect of having erections that were harder, firmer and lasted longer.'’ >> Pfizer. Type B (Bizarre) reactions Not related to pharmacological reaction, related to patient’s susceptibility (such as genetic) Rare May be very severe / fatal (high mortality) Unpredictable, not dose related Often well recognised ADRs but new drugs ADRs not well recognised (post- marketing surveillance) Idiosyncratic reactions >> Stevens-Johnson syndrome following lamotrigine or carbamazepine. Immunological reactions >> anaphylaxis with penicillin. Immediately stop medication, avoid medication with similar profile. Allergic reactions Mild erythema, 90% (rash) >> >> anaphylaxis, 0.05% Penicillin, sulfonamide. Maculopapular rash with some antiepileptic drugs, 5-17% (lamotrigine, carbamazepine, phenobarbital, phenytoin). Skin rash 11 Stevens-Johnson syndrome Type C (Chronic treatment effects) Related to prolonged treatment duration and cumulative dosage. Common Examples: dyskinesia with levodopa, weight gain and osteoporosis with steroids Type D (Delayed effects) Irreversible Examples: teratogenic (thalidomide) or carcinogenic (azathioprine) Thalidomide 1958- thalidomide marketed for morning sickness in pregnancy. At least 8000 children (like this baby) in 46 countries were born without arms, legs, ears, partially sighted or completely blind. Many others died at birth. This led to develop drug regulatory authorities. Type E (End of treatment effects) Withdrawal syndrome especially when treatment is stopped abruptly. Examples: headache, anxiety, dizziness sleep disturbances, gastro- intestinal disturbances after stopping paroxetine. Benzodiazepine withdrawal syndrome, adrenocortical insufficiency after steroid treatment. Type F (Failure of therapy) Unexpected failure of therapy due to drug interaction Pharmacokinetic or pharmacodynamic drug –drug interactions. Examples: enzyme inducer drugs decrease warfarin effect. High Risk Patient Groups Elderly Neonates Renal or Hepatic impairment Polypharmacy Multiple Disease States Asian Origin Female Atopic Types of ADRs Mild: A reaction that does not required treatment or hospital stay. Moderate: A reaction that requires treatment and or prolongs hospitalization by at least one day. Severe: A reaction that is potentially life threatening or contributes to the death of patient is permanently disabling requires intensive medical care or results in a cancer. Frequency of ADRs 23 Assessing causality Nature of the reaction Timing Relationship to dose Other possible causes for the symptoms Improvement when drug(s) stopped Has reaction been reported before ADRs are avoidable Up to 70% are preventable Incorrect dosing or administration Obvious interactions Use of contra-indicated drug Use in an inappropriate clinical indication How to Minimise ADRs Avoid unnecessary drug use Check Drug History before prescribing Identify patients with co-existing disease Avoid drug interactions with drugs and foods Patient counselling Identify drugs known to produce dose-related side effects Case study A 67 year old woman with an extensive rash is referred urgently to hospital. The rash started on the backs of her hands and spread very quickly to the arms, trunk, neck, and face. The lesions consist of concentric rings with frank blistering in some areas. Lesions have also started to appear on her lips and inside her mouth. Her medications include: ramipril 10mg once daily, simvastatin 40mg at night, aspirin 75mg once daily, metformin 1g twice daily, gliclazide 40mg each morning. She was started on aspirin 5 years ago following a stroke. At about the same time, she was diagnosed with type 2 diabetes and has been taking metformin, ramipril, and simvastatin for over 4 years. She was prescribed gliclazide during her annual diabetes review 2 months ago. The patient denies taking any over-the-counter medicines or herbal remedies. She has not made any significant changes to her diet and there is no history of recent infection. On admission: Blood pressure = 127/75 mmHg Body Mass Index = 26kg/m2 HbA1c = 8.0% (64mmol/mol) Her U + Es, renal and liver function are normal. Case study Which drug is most likely to be causing erythema multiforme? Case study Which drug is most likely to be causing erythema multiforme? According to the side-effects under the prescribing notes for sulphonylureas (BNF), hypersensitivity reactions can occur, usually in the first 6–8 weeks of therapy. They consist mainly of allergic skin reactions which progress rarely to erythema multiforme. The monograph for ramipril, also includes erythema multiforme as a side- effect. The time at which erythema mutiforme occurred in this patient is closely related to the time from when gliclazide was started and characteristic of hypersensitivity reactions with sulphonylureas. Case study Type of reaction, erythema multiforme, (A, B, …) Case study How should this adverse drug reaction (ADR) be managed? Case study How should this adverse drug reaction (ADR) be managed? This patient has suffered a major manifestation of erythema multiforme accompanied by mucosal involvement after starting gliclazide. Gliclazide should be stopped and the reaction should be clearly documented in the patient’s medical record and allergy history to prevent recurrence. If the reaction does not subside after stopping gliclazide, other causes for the reaction should be considered. Treatment to ameliorate the symptoms of erythema multiforme can be provided as necessary. Case study The patient’s gliclazide therapy is stopped and the erythema mutiforme resolves. She is started on sitagliptin 100mg once daily. She is readmitted 3 weeks later with nausea, vomiting, and severe, persistent abdominal pain which radiates to the back. Symptoms started 6 hours ago. Serum amylase = 610iu/litre (0–140)Serum lipase = 530iu/litre (0–160)Urea = 7.4mmol/litre (2.5–6.5)Calcium = 2.4mmol/litre (2.2–2.6)Blood glucose = 11mmol/litre (3.5–10)White blood cell count = 12 x 109/litre (4–11 x 109)Bilirubin = 10micromol/litre (5–17)Serum aspartate aminotransferase = 45iu/litre (0– 35)eGFR = 105mL/minute/1.73m2Blood pressure = 120/70mmHg X-ray of the abdomen shows no evidence of gallstones or pancreatic calcification. Abdominal ultrasound shows no evidence of pancreatic necrosis or dilatation of intrahepatic ducts. A diagnosis of acute pancreatitis is made but causality is not known. The patient is nil by mouth and placed on supportive therapy including parenteral analgesia, intravenous fluids, and intravenous insulin. Case study Which drug is most likely to be causing acute pancreatitis? Case study Which drug is most likely to be causing acute pancreatitis? According to the prescribing notes for statins, pancreatitis can occur very rarely. ACE inhibitors can also cause pancreatitis. The monograph for sitagliptin, includes pancreatitis as a side-effect that is also reported (BNF). This episode of pancreatitis seems to have coincided with initiation of treatment with sitagliptin. Case study How frequently has pancreatitis been reported with sitagliptin? The frequency of pancreatitis with sitagliptin is not known. Pancreatitis was identified as a side-effect with sitagliptin from spontaneous reports received post-marketing. It is not possible to calculate the frequency of side-effects from spontaneous reporting rates alone as neither the number of patients using the drug nor the extent of under-reporting is known. The ADR should be reported to National Pharmacovigilance Center (NPC) in Saudi Arabia and BNF (British National Formulary). Case study Type of reaction acute pancreatitis? Questions 38 Thank you 39