Adverse Drug Reactions and Drug Interactions

7/28/2019 Adverse Drug Reactions and Drug Interactions

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Adverse Drug Reactions and Drug Interactions

Adverse Drug Reaction:

Response to a drug which is noxious, unintended and occurs at doses used in man forprophylaxis, diagnosis and therapy (WHO)

Unwanted or harmful reaction experienced after the administration of a drug or combinationof drugs under normal conditions of use and suspected to be related to drug

Type of adverse reactions:

Type A (Augmented) Type B (Bizarre) Type C (Chronic) Type D (Delayed) Type E (End of use) Type F (Therapeutic failure) Type G (Genetic/genomic)Classification is based on

Dose relatedness Time course SusceptibilityType A ADRsintrinsic to the drug effects

Type B ADRs - idiosyncratic

Predisposing factors:

Multiple drug therapy Age1. Elderly- hypnotics, diuretics, NSAIDS, anti-hypertensives, psychotropics, digoxin2. Adults- polypharmacy


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3. Children- antiepileptics, cytotoxic agents, anesthetic gases, antibiotics (associated withhepatic failure), Na valproate

4. Neonates- chloramphenicol, morphine, antiarrhythmicsReyes syndrome - ?

HepatotoxicityNa valproate

Gender- Females have 1.5-1.7 folds of developing ADR than males- Women are prone to develop blood dyscrasias with phenylbutazone & chloramphenicol- Histaminoid reactions with neuromuscular blocking drugs Intercurrent disease- Hepatic/renal disease- HIVskin reactions with co-trimoxazole- Critical illness- Trauma Race and genetic polymorphism- Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers)- Drug receptors- Drug transporters (P-gp or MDR1)Mechani sm of dose related (Type A) reactions

Different doses to produce the pharmacologic effect Different responses to a defined dosePharmaceutical cause

-pharmaceutical aspects of a dosage form

IndomethacinGI bleeding


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Pharmacokinetic causes

1. Absorptionreduced efficacyGI motility, gastric contents, disease, absorption in the GI tract, first-pass metabolism in

liver & gut wall, concomitant drugs

2. DistributionPlasma-protein and tissue binding

3. MetabolismEnzyme induction or inhibitionefficacy??

Genetic variantsoxidation, hydrolysis, acetylation

Drugs competing for glucoronidation

Microsomal oxidation CYP2D6 or Debrisoquine hydroxylase polymorphism (5-10% Europeans)

- Poor metabolizersreduced first-pass- Drugs metabolized includes psychiatric, neurological and cardiovascular- Higher incidence of extrapyramidal symptoms seen as AE of antipsychotics

metabolized by CYP2D6

CYP2C9-CYP2C9*1/*1normal metabolic rate for warfarin

CYP2C9*3/*3lowest metabolic clearance rate for warfarin

Hydrolysis Pseudocholinesterase

- Decreased activity in variants leading to suxamethonium apnea

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

hydralazine


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Glucuronidation Morphine, paracetamol, ethinylestradiol Glucuronyltransferases

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

Pharmacokinetic causes- P-glycoprotein / MDR1found in the cells of gut wall, surface of hepatocytes & renal

tubular cells

Pharmacodynamic causes-target organsgenetic, immunologic, neoplastic or teratogenic

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)


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Sulfonamides (Cotrimoxazole)Hereditary methemoglobinemias

Methemoglobin reductase - cyanosisPorphyrias

Inherited disorder in heme biosynthesis Abdominal and neuropsychiatric disturbances Excretion of excessive amounts of porphyrin precursors 5-ALA (aminolaevulinic) or

porphobilinogen

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?

Associated with a sudden release of intracellular ionized Ca Antidote: D _ _ _ _ _ _ eneGlucocorticoid glaucoma

Cholestatic jaundice induced by oral contracepitves

Immunologic reasons for abnormal response

Features:- No relation to the unusual pharmacologic effects of the drug- Delay between the 1st exposure to the drug and subsequent occurrence of the ADR- Small doses may elicit the reaction once the allergy is established- Reaction disappears on withdrawal- Illness is often recognizable as a form of immunologic reactionDelayed adverse effects

Pigmentary retinopathyphenothiazine


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Vaginal carcinomastilbestrol Malignancyimmunosuppressives and chemotherapeutic agentsAdverse effects associated with drug withdrawal

Benzodiazepine withdrawal syndrome Rebound hypertensionclonidine Acute adrenal insufficiency - corticosteroids

DRUG INTERACTIONS:

Occurs when the effects of one drug are changed by the presence of another drug, herbalmedicine, or some environmental chemical agent

Outcome

Good or bad or fatal

Mechanism of drug interactions

Pharmacokinetic pharmacodynamic Who are susceptible? Polypharmacy Hepatic or renal disease Long-term therapy for chronic illness Critically ill ICU patients Patients who have more than one prescribing MD Drugs with high risk of interaction- Concentration dependent toxicity

1. Digoxin2. Lithium3. Aminoglycosides4. Cytotoxic agents


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5. Warfarin- Steep dose response curve

1. Verapamil2. Sulfonylureas3. Levodopa

- Patient dependent on therapeutic effect1. Immunosuppresives (e.g. cyclosporin, tacrolimus)2. Glucocorticoids3. Oral contraceptives4.

Anti-epileptics

5. Anti-arrhythmics6. Anti-psychotics7. Antiretrovirals

- Saturable hepatic metabolism1. Phenytoin2. Theophylline

Pharmacokinetic:

Absorption1. Changes in GI pH

- PPIs, H2 antagonist + weak acid, itraconazole

2. Adsorption, chelation and other complexing mechanism

-tetracycline and aluminum/magnesium hydroxide

- kaolin/charcoal

- Colestyramine, colestipoldigoxin, propranolol, warfarin levothyroxine, cyclosporin

3. Effects on GI motility

Narcotics, atropine, antacids motility?


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Domperidone, metoclopramide, cisapride motility?

Slow motility is dis/advantageous to penicllin & levodopa

Rapid motility is dis/advantageous to enteric coated tablet & griseofulvin

4. Induction or inhibition of drug transport proteins

Verapamil enhances digoxin bioavailability by inhibiting P-gp

Distribution- Dependent on ionic composition, lipid solubility, and protein-binding characteristics

- Plasma protein binding

Albuminacidic drugs (warfarin)

1 acid glycoproteinbasic drugs (TCA, lidocaine, disopyramide & propranolol)

MetabolismCYP3A4 in the intestinal wallgrapefruit juice & felodipine & cyclosporine

MAO-A in the liver & intestinal wall tranylcypromine, phenelzine & tyramine (diet)

increase norepinephrine

DexamethasoneR-warfarin CiprofloxacinImipramine Disulfiramhalothane VerapamilMidazolam Tobacco smoketheophylline Cimetidinetheophylline OmeprazoleDiazepam Phenytoin - Nifedipine

Enzyme induction

Carbamazepine, barbituratesautoinduction

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

(phenytoin)


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Chronic alcohol use, Cigarette smoking, St. Johns wort (Hypericum perforatum)

Enzyme inhibition

Grapefruit juice- caution with simvastatin, tacrolimus, vardenafil

Caution when given with drugs with narrow TItheophylline, phenytoin, warfarin

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

2. Changes in active renal tubular secretion

- Competition with the organic anion transporters- probenecid & penicillin

- NSAIDs, salicylates & methotrexate

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

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

drugs

5. Biliary excretion and enterohepatic shunt

Ethinylestradiol conjugates & antibiotics

6. Drug transporter proteins

P-glycoprotein present in renal proximal tubule, hepatocytes, intestinal mucosa,

and blood brain barrier

Inhibitors- verapamil, atorvastatin


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Inducers- rifampicin

Pharmacodynamic

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

Additive /synergistic-

Antidepressants, hypnotics, antihistamines

- MAOI and tyramine, amphetamines, pseudoephedrine, cough & cold medicines- TCA, antihistamines, phenothiazines anticholinergic- TCA & epinephrine- Benzodiazepines and alcohol- Aspirin and warfarin- ACE inhibitor, K supplement, and K sparing diuretic hyperkalemia- Hydrocortisone & hydrochlorothiazide hyperglycemia & hypokalemia- Diuretic-induced hypokalemia & hypomagnesemia increases risks of dysrhythmia

caused by digoxin

- Increase risk of ototoxicity and nephrotoxicity from combination of aminoglycosidesand furosemide

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Adverse Drug Reactions and Drug Interactions