adrs and interactions
TRANSCRIPT
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Adverse Drug Reaction
MUHAMMAD FAISAL NADEEM
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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
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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
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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
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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
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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
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• 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
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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
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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
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Predisposing factors
• Race and genetic polymorphism- Drug-metabolizing enzymes (poor, extensive & ultra-rapid metabolizers)
- Drug receptors- Drug transporters (P-gp or MDR1)
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Mechanism of dose related (Type A) reactions
• Pharmaceutical cause-pharmaceutical aspects of a dosage form
Indomethacin – GI bleeding
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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
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Pharmacokinetics• Absorption
2. Adsorption, chelation and other complexing mechanism
-tetracycline and aluminum/magnesium hydroxide- kaolin/charcoal
- Colestyramine, colestipol – digoxin, propranolol, warfarin levothyroxine, cyclosporin
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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
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Pharmacokinetics• Absorption
4. induction or inhibition of drug transport proteins
Verapamil enhances digoxin bioavailability by inhibiting P-gp
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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)
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Mechanism of dose related (Type A) reactions
• Pharmacokinetic causes3. Metabolism
Enzyme induction or inhibition – efficacy??Genetic variants – oxidation, hydrolysis,
acetylationDrugs competing for glucoronidation
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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
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Microsomal oxidation
• CYP2C9-CYP2C9*1/*1 – normal metabolic rate for
warfarinCYP2C9*3/*3 – lowest metabolic clearance
rate for warfarin
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Hydrolysis
• Pseudocholinesterase- Decreased activity in variants leading to
suxamethonium apnea
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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
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Glucuronidation
• Morphine, paracetamol, ethinylestradiol• Glucuronyltransferases
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Mechanism of dose related (Type A) reactions
4. Elimination-digoxin, ACE inhibitors, aminoglycosides
antibiotics, class I anti-arrhythmic drugs (disopyramide, flecainide) and cytotoxic
agents
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Mechanisms of non dose-related (Type B) ADR
• Pharmaceutical causes- Presence of degradation products of the
active constituents- Excipients
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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
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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
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Drugs that should be avoided with G6PD deficiency• Dapsone
• Niridazole• Methylene blue (methylthioninium Cl)
• Primaquine• Quinolones (ciprofloxacin, nalidixic acid,
norfloxacin, ofloxacin)• Sulfonamides (Cotrimoxazole)
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Pharmacokinetics• Metabolism
CYP3A4 in the intestinal wall– grapefruit juice & felodipine & cyclosporine
MAO-A in the liver & intestinal wall – tranylcypromine, phenelzine & tyramine (diet)
increase norepinephrine
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Pharmacokinetics• Metabolism
Enzyme inductionCarbamazepine, barbiturates – autoinduction
Short-half life drugs (rifampicin) induce metabolism than long-half life drugs
(phenytoin)
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Pharmacokinetics• Metabolism
Enzyme inductionChronic alcohol use, Cigarette smoking, St.
John’s wort (Hypericum perforatum)
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Pharmacokinetics• Metabolism
Enzyme inhibitionGrapefruit juice- caution with simvastatin,
tacrolimus, vardenafilCaution when given with drugs with narrow TI –
theophylline, phenytoin, warfarin
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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
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Phamacokinetics
• Elimination2. Changes in active renal tubular secretion
-competition with the organic anion transporters- probenecid & penicillin
- NSAIDs, salicylates & methotrexate
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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
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Phamacokinetics
• EliminationDrugs excreted entirely by glomerular
filtration is unlikely to be affected by other drugs
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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?
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Malignant hyperthermia
• Associated with a sudden release of intracellular ionized Ca
• Antidote: D _ _ _ _ _ _ ene
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Delayed adverse effects
• Pigmentary retinopathy – phenothiazine• Vaginal carcinoma – stilbestrol
• Malignancy – immunosuppressives and chemotherapeutic agents
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Adverse effects associated with drug withdrawal
• Benzodiazepine withdrawal syndrome• Rebound hypertension – clonidine
• Acute adrenal insufficiency - corticosteroids
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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]
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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
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[2] Secondary effects: Indirect effect of therapy
– Eg. Iintestinal microflora killed by tetracycline superinfection
– Corticosteroids immunity oral candidiasis
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[3] Toxic effects: [Overdose or prolonged use]– Atropine delirium ; – Paracetamol hepatic necrosis– Barbiturates coma; – Morphine respiratory failure
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• 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
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• 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
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[4] Intolerance: – Opposite of tolerance: sensitivity to low doses– few doses of carbamazepine ataxia [ defective
movement/gait]– single dose of triflupromazine muscular
dystonia
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[5] Idiosyncrasy: genetically determined atypical / bizarre effect– Barbiturate excitement & mental confusion – Streptomycin deafness with single dose
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[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
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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
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[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.
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[8]Drug Dependence: Psychological: Physical dependence:
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[9]Teratogenicity: Drug use in pregnancy affects offspring
Eg Thalidomide phocomelia; phenytoin cleft palate
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[10 ]Carcinogenicity & mutagenicity: Anticancer drugs, estrogens
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[11] Drug induced deseases, Iatrogenic diseases :
Salicylates peptic ulcer; Phenothiazines parkinsonism; INH hepatitis
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12. Drug withdrawal reactionPropranolol hypertensionAcute adrenal insufficiency following
withdrawal of corticosteroids
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Pharmacodynamic
• Antagonistic- Flumazenil and benzodiazepines
(diazepam)- Salbutamol and b-blockers (propranolol)
- Vit K and anticoagulants- Levodopa and dopamine antagonist
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Pharmacodynamics
• Additive /synergistic- antidepressants, hypnotics, antihistamines
- MAOI and tyramine, amphetamines, pseudoephedrine, cough & cold medicines
- TCA, antihistamines, phenothiazines anticholinergic
- TCA & epinephrine
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Pharmacodynamics
• Additive /synergistic- Benzodiazepines and alcohol
- Aspirin and warfarin- ACE inhibitor, K supplement, and K
sparing diuretic hyperkalemia- Hydrocortisone & hydrochlorothiazide
hyperglycemia & hypokalemia
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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