بسم الله الرحمن الرحيم

ADVERSE DRUG REACTIONS

definition: Adverse dug event: is “an injury resulting from the use of a drug. includes harm caused by the drug (adverse drug reactions and overdoses) and harm from the use of the drug (medication error) What is an adverse drug reaction (ADR)? An adverse drug reaction is a “response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for the modification of physiologic function.

What is a medication error? Medication errors are mishaps that occur during prescribing, transcribing, dispensing, administering, adherence, or monitoring a drug.

Why learn about ADRs? Over 2 million serious ADRs occur yearly! 100,000 deaths occur yearly. Is the 4 th leading cause of death ahead of pulmonary disease, DM,AIDS and automobile accidents deaths. 136 billion dollars is the yearly economic burden. Greater than total cost of cardiovascular or diabetic care. Causes 1 out of 5 injuries or deaths per year to hospitalized patients. Mean length of stay, cost and mortality for ADRs patients are double that for control patients.

Classifications: Type a: augmented reaction Type B: bizarre reaction dose independent & un predictable 1- idiosyncratic (genetic) 2- drug allergy & anaphylaxis Type C: continues reaction Type D: delayed drug reaction carcinogenesis - teratogenesis Type E: end of treatment reaction (sudden withdrawal) Type F: failure of therapy

Type A Occur in all patients Predictable and dose dependant 1- due to exaggerated normal pharmacological effect: B-blocker  hypotension diazepam  sedation diuretic  hypokalemia 2- due to effect in undesired location: chlorpromazine  galactorrhea, parkinsonism cytotoxic drug  bone marrow depression

Type B- bizarre reactions Occur in some patients only Un related to known actions of the drug Unpredictable and not dose dependent Low incidences but fatal reactions glucocorticoid eye drops  glaucoma oral contraceptives  jaundice can affect any organ, but the most common organs involved are liver, skin, and bone marrow life-threatening type B adverse reactions include: hepatotoxicity, aplastic anemia, and blood dyscrasias.

Type B- bizarre reactions 1- Idiosyncrasy (genetic) abnormality: Slow acetylators G6P deficiency Cholinesterase deficiency 2-Drug allergy and anaphylaxis: Penicillin- insulin- heparin Management: adrenaline- anti histamine and oxygen.

Type C- continueous drug interaction Due to prolonged use Antipsychotic  parkinsonism NSAI and analgesics  nephropathy

Type D- delayed reaction Carcinogenesis: Takes a long time > 3 years Estrogens causes  endometrial cancer Cyclophosphamide  mutation. Staff handling cytotoxic drugs  protective measures

Teratogenesis: Stilbosterol  abortion & vaginal adenocarcinoma Tetracycline  discoloration of teeth & altered bone growth Phenytoin  cleft lip Valproate  spina bifida Misoprestol  abortion

Type E- end of treatment reactions: Sudden withdrawal of drugs  rebound effects Clonidine, B blockers  rebound hypertention Corticosteroids  adrenocortical insufficiency. Antiepileptic  seizures.

Causes of ADRs: 1-Patient factors: Age- pharmacokinetic variable- drugs- breast feeding- disease state. Older and younger patients are more susceptible due to their insufficient detoxification mechanisms. And their lower liver and renal functions. Chloramphenicol  Gray baby syndrome The elderly are more likely to multiple Drugs so they are more prone to drug interaction

2-Drug factors: 1-Narrow therapeutic index drugs Digoxin  cardiac arrythmias Theophylline  heart & CNS stimulant Phenytoin  confusion, nystagmus Anticoagulants  haemorrhage Lithium  nephrotoxicity, tremors

2- allergic drugs : antibiotics 3- cytotoxic drugs: anti cancers 4-Dose of the drug: require regular therapeutic drug monitoring 5-duration of treatment: prolonged treatment by diazepam may lead to  addiction Corticosteroids  adrenal suppression 6-route of administration.

3-Predisposing factors. digitalis + low k  arrhythmia atracurium + low Ca  paralysis(skeletal muscle relaxant used during surgery for endotracheal tubing and mechanical ventilation) 4-Environmental factors DDT  enzyme inducer smokers  require higher doses of drug halothane in theatre air  pregnant staff abortion & hepatotoxicity.

ADRs can occur as a result of: - drug- drug interaction - drug- disease interaction - drug- food interaction

Drug- drug interaction Interactions can occur before or after administration: A-Interactions before administration: Phenytoin precipitate in dextrose solution Amphotrecine precipitates in saline Gentamycine is incompatible with most beta- lactams, resulting in loss of antibiotic effect.

B-after administrations: 1-Pharmacokinetic interactions: -GI: Omeprazole Lansoprazole H 2 - antagonist - kidney: Aminoglycosides: tubular toxicity Sulfonamides: crystallurea Thiazide: interstitial nefritis Reduced absorption of ketoconazole and delavirdine

- liver: Nearly always due to interaction at phase 1 (oxidation, reduction and hydrolysis) rather than phase 2 (conjugation) hepatitis  (a) Viral hepatitis: halothane &Phenytoin (b) focal hepatitis: aspirin (c) Chronic hepatitis : methyledopa, diclofenac cholestasis  camoxiclave, carbamazepine, chloropromazine, flucloxacilline steatosis  tetracycline (especially if expired), ketoprofen, methotrexate, amiodarone, acetaminophen hepatic necrosis : Paracetamol is a major cause of drug- related morbidity and mortality in humans, capable of producing hepatic necrosis after a single toxic overdose.

Pulmonary: Many drugs are known for their adverse effects on the lungs: nitrofurantoin, amiodarone chemotherapy, cyclophosphamide, and methotrexate Examples of their effects on the lung: drug induced SLE granulomatus lung disease allergies (asthma, bronchitis, pneumonitis) pleural effusion and oedema interstitial fibrosis pulmonary vaculities.

- blood: Phenytoin: megaloplastic anaemia Chloramphenicol: aplasti canaemia Aspirin- nitrofurantoin: haemolytic anaemia.

Consequences of drug metabolism: drug Toxic metabolite Active metabolite Inactive metabolite Reversible metabolite toxicity Enhance activity Altered activity Prolong activity Loss of activity

ADRs as a consequence of drug metabolism: Enalapril (inactive) Enalapril (inactive) hydrolysis Enalaprate (active) Enalaprate (active) activation Codeine (inactive) Codeine (inactive) Morphine (active) Morphine (active) activation

ADR as a result of product similar to parent drug Terfenadine toxic Terfenadine toxic fexofenadine. Less toxic fexofenadine. Less toxic metabolism accumulation Obliterated metabolism by enzyme inhibitors (erythromycin) Death, cardiac arrest and ventricular arrhythmias

drug disease interaction Liver disease Kidney disease Cardiac disease (low hepatic blood flow) Hypo or hyper thyroidsm drug food interaction: Warfarin and vitamin K containing food Grapefruit juice

Management and prevention of ADRs: Continues education of health team Education of patient and family Special consideration of patients of high risk Drug monitoring Adjustment of dosages Detection of drug interaction.

  rational therapy: Cimitidine with NSAIDs K therapy with diuretics Anti emetics and iron with cytotoxic drugs Pyridoxine with isoniazide Sodium bicarbonate with allopurinol and sulphonamides

Shields of protection!

How can we manage drug interactions? Avoid concurrent use in case of harmful outcome Changne the dose, sequence and time of administration Use safe alternatives (ranitidine instead of cemetidine) Treat any developed symptoms Monitor drugs levels in the serum Monitor vital signs. Separate the drugs 2H in between.