Adverse Drug Reaction

MUHAMMAD FAISAL NADEEM

Introduction
Defn: an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use and suspected to be related to the drug

Trivial OR Serious Or fatal

Requires
Treatment in dosing Discontinuation Caution in future

Occurrence
immediately or after prolonged use or after termination Mild ADRs common, [incidence 10-25%] with polypharmacy

Acceptability: linked to Therap. Use; Risk Benefit Ratio

Type A: Response qualitatively normal but quantitatively abnormal Common, less serious, dose related, corrected by dose adjustment include side effect, toxic effect, withdrawal Type B: Because of patient peculiarities; Eg. Allergy, idiosyncrasy Dose related; uncommon; Serious withdrawal of drug required Not always predictable / preventable

Type A Pharmacologica lly predictable Dose dependent Incidence

Morbidity Mortality Management

Type B No No
Low Low High STOP

Yes Yes
High High Low Dosage adjustment

Type C These reactions are associated with long-term drug therapy e.g. Benzodiazepine dependence and Analgesic nephropathy. They are well known and can be anticipated. Type D reactions These reactions refer to carcinogenic and teratogenic effects. These reactions are delayed in onset

 Type E
End of dose effect for example abrupt cessation of corticosteroids produces acute adrenal insufficiency and stoppage of propranolol can produce rebound effect

Type F
Failure of therapy. OCP failure when on antitubercular therapy

Severity of ADR:
Minor: no need of therapy, antidote, or hospitalization Moderate: requires drug change , specific treatment, hospitalization Severe: Potentially life threatening; permanent damage, and prolonged hospitalization. Lethal: Directly or indirectly leads to death

Predisposing factors
Multiple drug therapy Age 1. Elderly- hypnotics, diuretics, NSAIDS, antihypertensives, psychotropics, digoxin 2. Adults- polypharmacy 3. Children- antiepileptics, cytotoxic agents, anesthetic gases, antibiotics (associated with hepatic failure), Neonates- chloramphenicol, morphine, antiarrhythmics Hepatotoxicity Na valproate

Predisposing factors
Race and genetic polymorphism - Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers) - Drug receptors - Drug transporters (P-gp or MDR1)

Mechanism of dose related (Type A) reactions

Pharmaceutical cause -pharmaceutical aspects of a dosage form Indomethacin GI bleeding

Mechanism of dose related (Type A) reactions

Pharmacokinetic causes 1. Absorption reduced efficacy GI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in liver & gut wall, concomitant drugs 1. Changes in GI pH - PPIs, H2 antagonist + weak acid, itraconazole

Pharmacokinetics
Absorption 2. Adsorption, chelation and other complexing mechanism -tetracycline and aluminum/magnesium hydroxide - kaolin/charcoal - Colestyramine, colestipol digoxin, propranolol, warfarin levothyroxine, cyclosporin

Pharmacokinetics
Absorption 3. Effects on GI motility Narcotics, atropine, antacids motility? Domperidone, metoclopramide, cisapride motility? Slow motility is dis/advantageous to penicllin & levodopa Rapid motility is dis/advantageous to enteric coated tablet & griseofulvin

Pharmacokinetics
Absorption 4. induction or inhibition of drug transport proteins Verapamil enhances digoxin bioavailability by inhibiting P-gp

Mechanism of dose related (Type A) reactions

Pharmacokinetic causes 2. Distribution Plasma-protein and tissue binding Plasma protein binding Albumin acidic drugs (warfarin) a1 acid glycoprotein basic drugs (TCA, lidocaine, disopyramide & propranolol)

Mechanism of dose related (Type A) reactions

Pharmacokinetic causes 3. Metabolism Enzyme induction or inhibition efficacy?? Genetic variants oxidation, hydrolysis, acetylation Drugs competing for glucoronidation

Microsomal oxidation
CYP2D6 or Debrisoquine hydroxylase polymorphism (5-10% Europeans) - Poor metabolizers reduced first-pass - Drugs metabolized includes psychiatric, neurological and cardiovascular - Higher incidence of extrapyramidal symptoms seen as AE of antipsychotics metabolized by CYP2D6

Microsomal oxidation
CYP2C9 -CYP2C9*1/*1 normal metabolic rate for warfarin CYP2C9*3/*3 lowest metabolic clearance rate for warfarin

Hydrolysis
Pseudocholinesterase - Decreased activity in variants leading to suxamethonium apnea

Acetylation
N-acetyltransferase rapid (Japan, Canadian, half of UK) & slow acetylators Dapsone, INH, hydralazine, phenelzine, procainamide, sulfonamides Peripheral neuropathy INH, hematologic AE- dapsone, SLE procainamide & hydralazine

Glucuronidation
Morphine, paracetamol, ethinylestradiol Glucuronyltransferases

Mechanism of dose related (Type A) reactions

4. Elimination -digoxin, ACE inhibitors, aminoglycosides antibiotics, class I anti-arrhythmic drugs (disopyramide, flecainide) and cytotoxic agents

Mechanisms of non dose-related (Type B) ADR

Pharmaceutical causes - Presence of degradation products of the active constituents - Excipients

Mechanisms of non dose-related (Type B) ADR

Pharmacokinetic causes - P-glycoprotein / MDR1 found in the cells of gut wall, surface of hepatocytes & renal tubular cells

Erythrocyte glucose-6-phosphate (G6PD) deficiency

Sex-linked inherited deficiency Weakened red cell membrane Hemolysis from primaquine, sulfonamides, sulfones and nitrofurantoin African type-mild, Mediterranean typesevere

Drugs that should be avoided with G6PD deficiency

Dapsone Niridazole Methylene blue (methylthioninium Cl) Primaquine Quinolones (ciprofloxacin, nalidixic acid, norfloxacin, ofloxacin) Sulfonamides (Cotrimoxazole)

Pharmacokinetics
Metabolism CYP3A4 in the intestinal wall grapefruit juice & felodipine & cyclosporine MAO-A in the liver & intestinal wall tranylcypromine, phenelzine & tyramine (diet) increase norepinephrine

Pharmacokinetics
Metabolism Enzyme induction Carbamazepine, barbiturates autoinduction Short-half life drugs (rifampicin) induce metabolism than long-half life drugs (phenytoin)

Pharmacokinetics
Metabolism Enzyme induction Chronic alcohol use, Cigarette smoking, St. Johns wort (Hypericum perforatum)

Pharmacokinetics
Metabolism Enzyme inhibition Grapefruit juice- caution with simvastatin, tacrolimus, vardenafil Caution when given with drugs with narrow TI theophylline, phenytoin, warfarin

Phamacokinetics
Elimination 1. Changes in urinary pH Enhance excretion of weak acids (aspirin) at alkaline pH Enhance excretion of weak base (paracetamol) at acidic pH Strong acids and bases are not affected by pH changes

Phamacokinetics
Elimination 2. Changes in active renal tubular secretion -competition with the organic anion transporters- probenecid & penicillin - NSAIDs, salicylates & methotrexate

Phamacokinetics
Elimination 3. Changes in renal blood flow - Prostaglandins produces renal blood flow - NSAIDs & lithium 4. Influence of proximal reabsorption in relation to sodium ions -Thiazide, loop diuretics & lithium decrease renal clearance of lithium

Phamacokinetics
Elimination Drugs excreted entirely by glomerular filtration is unlikely to be affected by other drugs

Malignant hyperthermia
Rapid rise in body temperature (at least 2 C per hour) Associated with anesthetics and muscle relaxants (succinylcholine) Stiffness of skeletal muscle, hyperventilation, acidosis, hyperkalemia, increased activity of sympathetic NS outcome?

Malignant hyperthermia
Associated with a sudden release of intracellular ionized Ca Antidote: D _ _ _ _ _ _ ene

Delayed adverse effects

Pigmentary retinopathy phenothiazine Vaginal carcinoma stilbestrol Malignancy immunosuppressives and chemotherapeutic agents

Adverse effects associated with drug withdrawal

Benzodiazepine withdrawal syndrome Rebound hypertension clonidine Acute adrenal insufficiency - corticosteroids

Prevention of ADR:
[1] Avoid inappropriate drugs in the context of clinical condition [2] Use right dose, route, frequency based on patient variables [3] Elicit medication history; consider untoward incidents [4] Elicit history of allergies [in patients with allergic diseases] [5] Rule out drug interactions [6] Adopt right technique: Eg slow iv injection of aminophylline [7] Carry out appropriate monitoring [Eg PT with warfarin; Li levels]

Types of ADRs
[1] Side Effects: unavoidable, predictable, dose amelioration Occurs as Extension of the same therapeutic effect: Eg.
Atropine as antisecretory in preanesthetic medication dry mouth

Occurs as a distinctly different effect: Eg.

Promethazine as antiallergic sedation Estrogen as antiovulatory nausea

Side effect exploited for a therapeutic use: Eg

Codeine [antitussive] constipating action used in diarrhoea Sulfonylureas [tested as antibacterials] were found tobl glucose

[2] Secondary effects: Indirect effect of therapy

Eg. Iintestinal microflora killed by tetracycline superinfection Corticosteroids immunity oral candidiasis

[3] Toxic effects: [Overdose or prolonged use]

Atropine delirium ; Paracetamol hepatic necrosis Barbiturates coma; Morphine respiratory failure

 EVALUATION
AIRWAY BREATHING CIRCULATION DEGREE OF CONSCIOUSNESS HISTORY OF EXPOSURE/ INGESTION PHYSICAL EXAMINATION GASTRIC LAVAGE INDUCTION OF EMESIS CONTRAINDICATIONS TO EMESIS ACTIVATED CHARCOAL OTHER DECONTAMINATION

DECONTAMINATION

SUPPORTIVE CARE
RESPIRATORY CARDIOVASCULAR CNS

 DIAGNOSTIC STUDIES
BLOOD TESTS ECG X RAYS SPECIFIC DRUG LEVELS

ENHANCING ELIMINATION
ACTIVATED CHARCOAL FORCED ALKALINE DIURESIS HAEMODIALYSIS/PERFUSION

ANTIDOTES
Organophosphates atropine, oximes Morphine naloxone Benzodiazepines flumazenil Paracetamol N- acetyl cysteine

[4] Intolerance:
Opposite of tolerance: sensitivity to low doses few doses of carbamazepine ataxia [ defective movement/gait] single dose of triflupromazine muscular dystonia

[5] Idiosyncrasy: genetically determined atypical / bizarre effect

Barbiturate excitement & mental confusion Streptomycin deafness with single dose

[6] Drug allergy: [ or hypersensitivity]

Immunologically mediated Independent of dose Occurs in a small proportion; Prior sensitization required 1-2 weeks required after first dose Drug acts as an antigen or Hapten Chemically related drugs may show cross sensitivity Same drug can cause diff allergic reactions in diff individuals

continued..
Type I: urticaria, angioedema, asthma, anaphylactic shock Type II: Thrombocytopenia, agranulocytosis, aplastic anemia, SLE Type III: Arthralgia, lymphadenopathy, Steven Johnson Synd. Type IV: contact dermatitis, fever, photosensitisation Eg: penicillin, sulfonamides, carbamazepine, methyldopa

[7]Photosensitivity:
Phototoxic: Drug accumulates in skin absorbs light photochemical reaction photobiological reaction tissue damage [Eg erythema, edema, blistering etc] Eg tetracyclines Photoallergic: drug cell mediated immune response contact dermatitis on exposure to light. Eg sulfonamides, griseofulvin etc.

[8]Drug Dependence: Psychological: Physical dependence:

[9]Teratogenicity: Drug use in pregnancy affects offspring Eg Thalidomide phocomelia; phenytoin cleft palate

[10 ]Carcinogenicity & mutagenicity: Anticancer drugs, estrogens

[11] Drug induced deseases, Iatrogenic diseases : Salicylates peptic ulcer; Phenothiazines parkinsonism; INH hepatitis

12. Drug withdrawal reaction Propranolol hypertension Acute adrenal insufficiency following withdrawal of corticosteroids

Pharmacodynamic
Antagonistic - Flumazenil and benzodiazepines (diazepam) - Salbutamol and b-blockers (propranolol) - Vit K and anticoagulants - Levodopa and dopamine antagonist

Pharmacodynamics
Additive /synergistic - antidepressants, hypnotics, antihistamines - MAOI and tyramine, amphetamines, pseudoephedrine, cough & cold medicines - TCA, antihistamines, phenothiazines anticholinergic - TCA & epinephrine

Pharmacodynamics
Additive /synergistic - Benzodiazepines and alcohol - Aspirin and warfarin - ACE inhibitor, K supplement, and K sparing diuretic hyperkalemia - Hydrocortisone & hydrochlorothiazide hyperglycemia & hypokalemia

Pharmacodynamics
Additive /synergistic - Diuretic-induced hypokalemia & hypomagnesemia increases risks of dysrhythmia caused by digoxin - Increase risk of ototoxicity and nephrotoxicity from combination of aminoglycosides and furosemide