Adverse Drug Reaction

MUHAMMAD FAISAL NADEEM

IntroductionDefn: “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 requiredNot always predictable / preventable

Type AType A Type BType B

PharmacologicaPharmacologically predictablelly predictable

YesYes NoNo

Dose Dose dependentdependent

Yes Yes NoNo

IncidenceIncidence HighHigh LowLow

MorbidityMorbidity HighHigh LowLow

MortalityMortality LowLow HighHigh

ManagementManagement Dosage Dosage adjustmentadjustment

STOPSTOP

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” reactionsThese 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 factorsMultiple drug therapy

• Age1. Elderly- hypnotics, diuretics, NSAIDS, anti-

hypertensives, psychotropics, digoxin2. 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 causes1. Absorption –reduced efficacy

GI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in liver

& gut wall, concomitant drugs1. 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 motilityNarcotics, 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 causes2. Distribution

Plasma-protein and tissue bindingPlasma protein binding

Albumin – acidic drugs (warfarin)a1 acid glycoprotein – basic drugs (TCA,

lidocaine, disopyramide & propranolol)

Mechanism of dose related (Type A) reactions

• Pharmacokinetic causes3. Metabolism

Enzyme induction or inhibition – efficacy??Genetic variants – oxidation, hydrolysis,

acetylationDrugs 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

warfarinCYP2C9*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 type-severe

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 inductionCarbamazepine, barbiturates – autoinduction

Short-half life drugs (rifampicin) induce metabolism than long-half life drugs

(phenytoin)

Pharmacokinetics• Metabolism

Enzyme inductionChronic alcohol use, Cigarette smoking, St.

John’s wort (Hypericum perforatum)

Pharmacokinetics• Metabolism

Enzyme inhibitionGrapefruit juice- caution with simvastatin,

tacrolimus, vardenafilCaution when given with drugs with narrow TI –

theophylline, phenytoin, warfarin

Phamacokinetics

• Elimination1. 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

• Elimination2. Changes in active renal tubular secretion

-competition with the organic anion transporters- probenecid & penicillin

- NSAIDs, salicylates & methotrexate

Phamacokinetics

• Elimination3. 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

• EliminationDrugs 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

ameliorationOccurs 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

• DECONTAMINATION – GASTRIC LAVAGE – INDUCTION OF EMESIS – CONTRAINDICATIONS TO EMESIS – ACTIVATED CHARCOAL – OTHER 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 shockType II: Thrombocytopenia, agranulocytosis, aplastic anemia,

SLEType 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

tetracyclinesPhotoallergic: 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

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[10 ]Carcinogenicity & mutagenicity: Anticancer drugs, estrogens

[11] Drug induced deseases, Iatrogenic diseases :

Salicylates peptic ulcer; Phenothiazines parkinsonism; INH hepatitis

12. Drug withdrawal reactionPropranolol hypertensionAcute 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