Transcript Free Radicals in Biology and Medicine

Adverse Drug Reaction
Unnikrishnan M K
Additional Prof in Pharmacology,
Manipal College of Pharmaceutical Sciences,
Manipal 576 104
Introduction
• Defn: Undesirable effect at normal dose:
– trivial OR serious Or fatal
• Requires
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Treatment
 in dosing
Discontinuation
Caution in future
• Occurrence
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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: Predictable & Type B Unpredictable
• 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
Severity of ADR: Minor/ moderate/
severe/ lethal
• Minor: no need of therapy, antidote, or
hospitalization
• Moderate: requires drug change , specific
treatment, hospitalization
• Severe: Potentially life threatening; permanent
damage, and prolonged hospitalisation.
• Lethal: Directly or indirectly leads to death
Prevention of ADR: [cannot be totally
avoided; only minimized]
[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 viz Side effect;
Secondary effect; Toxic effect
[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 tobl glucose
Secondary Effects & Toxic Effects
• [2] Secondary effects: Indirect effect of therapy
– Eg. Iintestinal microflora killed by tetracycline
superinfection
– Corticosteroids  immunity  activation of latent
tuberculosis
• [3] Toxic effects: [Overdose or prolonged use]
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Atropine  delirium ;
Paracetamol  hepatic necrosis
Barbiturates  coma;
Morphine  respiratory failure
Intolerance and
Idiosyncrasy
• [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
– Quinine  cramps , diarrhoea, purpura, asthma, vascular
collapse
Drug allergy: [ or hypersensitivity]
• [6] Drug allergy: [ or hypersensitivity]
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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
Drug allergy: continued..
• Variable time course: Sensitive people may later tolerate drug
• 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 &
photoallergic]
• 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.
ADRs continued..
• [8]Drug Dependence: Psychological: (Habituation) &
Physical dependence: with withdrawal symptoms
• [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