Adverse Effects of Drugs PDF FFP1 RCSI 2024

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Title Adverse Effects of Drugs Course FFP1 Code FFP1-72 Lecturer Prof Will Ford 337 wford...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Title Adverse Effects of Drugs Course FFP1 Code FFP1-72 Lecturer Prof Will Ford 337 [email protected] Date November 2024 Dermot Cox  Learning objectives Describe the nature of predictable/pharmacological adverse effects Describe the nature of unpredictable/non-pharmacological adverse effects Describe the nature of idiosyncratic/dose-independent adverse effects Describe the role of medication errors in adverse drug events Describe the role of contaminants and generic bioequivalence in ADEs Describe the risk management strategies for drugs with serious ADEs  Adverse drug events (ADE) ADE – event – includes medication errors, adverse drug reactions, allergic reactions, and overdoses 82% of American adults take at least one medication and 29% take five or more In 2016, the age-adjusted rate for drug-poisoning deaths for males (26.2 per 100,000) was almost double that of females (13.4) In 2020, 91,799 drug overdose deaths occurred in the United States (28.3 per 100,000 people) 75% of these involved opioids  Other causes of ADE Incidence of 4 per 1000 Antibiotics (16%) 1 in 1000 risk of an ADE (allergy most common) – 1 in 4000 chance of preventing a serious complication of upper respiratory tract infection Anticoagulants (32% of patients >65 years of age) – Warfarin, rivaroxaban, and dabigatran are in top 10 causes of ADEs Phenytoin (anti-seizure medication) – zero-order kinetics Opioid analgesia – Greater than the death rate from heroin Insulin  Unwanted effects of drugs Side effects – relatively minor – reversible when treatment ceases or after a short while Adverse effects – More serious – May be life threatening Drug interactions – Unwanted effects that occur in presence of other drugs Contraindications – Conditions that may precipitate an unwanted effect  Unwanted vs desirable effects Opiates – When treating pain, constipation is an unwanted effect – When treating diarrhoea, constipation is a desirable effect Anti-histamine (H1 antagonists / inverse agonists) – When treating allergy drowsiness is unwanted – When used to prevent travel sickness drowsiness may be desirable  Types of toxicity - mechanisms Pharmacodynamic toxicity (predictable) – Excessive pharmacological action – Alternative pharmacological action Aspirin (bleeding vs. anti-inflammatory action) Anti-histamines (multiple receptors) – Overdose toxicity Pharmacokinetic (unpredictable?) – Induction / inhibition / competition of P450 enzymes Idiosyncratic – Allergic response – Hyperthermia with general anaesthetics Withdrawal – Steroid, beta blocker, anti epileptic, PPI withdrawal  Thalidomide Marketed by Chemie Grünenthal, Germany Introduced as a sedative (1957) – Safe, as it did not cause respiratory depression Found to be a good antiemetic (off-label use for morning sickness) Withdrawn in 1961 due to teratogenic effects – Prevents angiogenesis Not tested on pregnant animals – Species dependent: mice less sensitive than humans  Thalidomide today Acts as an immunomodulator used to treat – Hansen’s disease / leprosy* – Cancer – graft versus host disease in children – HIV mouth ulcers & wasting Prescribed under a Risk Evaluation & Mitigation Strategy (REMS, FDA) STEPS Lenalidomide is a new derivative – also a teratogen  Diethylstilboestrol Non-steroidal oestrogen – Decrease menopause symptoms Approved* by FDA in 1947 – To prevent miscarriage – For oestrogen deficient states – Post-coital contraceptive – Banned in chickens 1959/66 Shown to be a teratogen in 1971  DES teratogenicity DES Daughters – increased risk of the development of clear cell adenocarcinoma (CCA) of the vagina and cervix, breast cancer – Pregnancy-related problems Miscarriage, stillbirth, ectopic pregnancy, premature labour, preeclampsia DES sons, grandsons – Urogenital abnormalities, e.g., hypospadia DES grandchildren – Infertility – Cerebral palsy  Drug regulation 1950’s Very little formal regulation Most at the discretion of the pharmaceutical company No teratogenicity studies required Thalidomide was not approved by FDA – Not used in the USA Changed the global regulatory environment  Source of ADEs Active Pharmaceutical Ingredient (API) Contaminants – Due to synthesis – Due to degradation of API Excipients – Used to, e.g., bulk up, stabilise, surface coat, colour, flavour Propellants – e.g., CFCs - chlorofluorocarbons – Montreal Protocol 1987 – Replaced with HFCs - hydrofluorocarbons  Why are toxic drugs allowed? API is usually well tested in vitro and in vivo before approval API-mediated toxicity is due to – A species-specific effect – A metabolite, possibly species-specific Toxicity may only occur in a small number of patients – Only detected after many patients are treated – Pharmacogenetics Fate of drugs in the body  Cytochrome P450 CYP enzymes metabolise the medications With chronic administration (greater than 1-3 weeks), some drugs stimulate hepatocytes to produce larger amounts of drug-metabolising enzymes (inducers) Enzyme induction accelerates drug metabolism. Larger doses of the drug may now be needed Or lead to a drug overdose?* Apparent inhibition may occur with concurrent administration of two or more drugs that compete for the same metabolising enzymes Drug metabolism by CYP450 enzymes Drug metabolism by CYP450 enzymes Paracetamol – substrate Beta-blockers – substrate Theophylline - substrate Codeine – substrate* Tobacco – inducer Tricyclic antidepressants – substrate Warfarin – substrate Fluoxetine (SSRI) – inhibitor Cabbage – inducer St John’s wort, grapefruit juice, turmeric - inhibitors Drug metabolism by CYP450 enzymes Phenytoin – substrate Erythromycin – inhibitor Omeprazole – inducer Oestrogens – substrates St John’s wort – inducer NSAIDS- substrate Warfarin-substrate Fluconazole- inhibitor  Case study: paracetamol N-acetyl-p-benzoquinone imine  Paracetamol overdose treatment Requires replenishing glutathione (GSH) GSH is not orally active N-Acetylcysteine is orally active and converted to GSH 𝜓GSH is orally active form of GSH  Idiosyncratic toxicity Dose-independent Often due to genetic polymorphisms – CYP polymorphisms Can be immunological Very difficult to identify e.g., coumarin, used for its smell of “vanilla” – Vanilla grass, tonka bean, cinnamon, strawberries… – Bitter taste  Coumarin hepatotoxicity High level of hepatotoxicity in rats – Toxicity is dose dependent Low level of toxicity in humans (0.37%) Banned as a foodstuff by FDA in 1954 – Considered a carcinogen – Re-analysis of rat data suggests that the hepatic lesion was cholangiofibrosis (bile duct proliferation, not a neoplasm) not cholangiocarcinoma  Coumarin metabolism Human metabolite Mouse & human Rat metabolite metabolite & probable hepatotoxin  Contaminants While a very pure form of the API is used there may still be by-products from synthesis – May be batch specific – May be due to some conditions changing during manufacture – These may cause ADE especially cancer API degrades over time influenced by storage conditions – Heat – Light – Humidity  Contaminants Degradation of API has two major effects – Reduced dose of API – Presence of potentially toxic by-products Ranitidine (H2 antagonist) and valsartan, losartan and irbesartan (Angiotensin II Receptor Blockers) recalled due to presence of N-Nitrosodimethylamine (NDMA) – a known carcinogen – Contaminant  Ranbaxy Indian generic pharmaceutical company Major supplier of generic medicines Multiple violations of regulations with product recalls In 2013 pleaded guilty to felony charges for selling adulterated drugs and fined $500 million In 2014 banned by FDA from selling APIs to US Dr Reddy Ranatidine (2019) Valsartan, losartan and irbesartan (2019)  Generics After a drug’s patent lapses (20 years) Are generics the same as branded product? Does it matter?  Bioequivalence “The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study” (FDA)  Bioequivalence Usually measured by comparing Cmax and AUC between two products Bioequivalence defined as confidence interval (CI) of test within 0.8 and 1.25 of reference Generic drugs only need to show bioequivalence with approved product in a small number of healthy volunteers Bioequivalence  Problems with bioequivalence Drug A: Brand product (AUC: 1) Drug B: Generic product (AUC: 0.8) bioequivalent Drug C: Generic product (AUC: 1.25) bioequivalent Thus 10 mg tablet – A=10 mg API – C=12.5 mg API – B= 8 mg API Patient optimised on Drug C and switched to B – 37% reduction in dose of API – Drug B, switch to C – 56% increase Is that acceptable for this drug?  Adverse effects A large phase III study may involve up to 10,000 patients on drug Identifies adverse effects with incidence of 0.1% Adverse effects with