Post on 07-Apr-2018
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Safety margin and drug
toxicity
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Safety Margin or Therapeutic Index
TD50 (median toxic dose)
Therapeutic index= -------------------------------ED50 (median effective dose)
Larger the therapeutic index safer the drug
LD1
Certain safety factor = --------------------
ED99
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Adverse Drug Effects Any undesirable or unintended
consequence of drug administration Any response to a drug that is noxious
and unintended and that occurs at doses
used in man for the prophylaxis, diagnosis,or therapy of disease or for modificationof physiological function WHO
Adverse event: Any untoward event thatoccurs during treatment not necessarilywith causal relationship to treatment
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Adverse drug reactions (ADR) Predictable: Type A :(Augmented),
mechanism basedAugmented pharmacological propertiesSide effects, toxic effects, Drug withdrawal
effects
Common, dose related, Reversible
Unpredictable: Type B: (Bizarre)Not known action of drugIdiosyncracy, AllergyLess common, Non dose relatedSerious; may require withdrawal
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ADR.
Type C (Chronic effects): After prolonged useEg: Analgesic nephropathy
Type D (Delayed effects): Occurring years
after treatment.Eg: Second malignancy, teratogenicity
Type E (End of treatment effects):Occurs
when drug is suddenly discontinued.Eg: Rebound hypertension after stoppingpropranolol
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ADR: Severity
Minor: No treatment required Moderate: Requires change in treatment, change
of drug Severe: Potentially life threatening,
permanent damage Lethal: Directly or indirectly contributes to
death
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ADR1. Side effects:
Unwanted ,unavoidable pharmacodynamic effectsat therapeutic dosesEg. Antihistaminics cause sedation
2. Secondary effects:Indirect consequence of primary action of a drug
Eg. Tetracyclines cause superinfection
3. Toxic effects:Due to overdose or prolonged useEg. Respiratory failure by morphine
Absolute (accidental, suicidal or homicidal)
Relative (usual dose of gentamicin in renal
failure)
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ADR4. Intolerance:
Low threshold to the action of drug Eg. EPS with single dose of
Metoclopromide
5. Idiosyncrasy: Genetically determined abnormal
responses to drug or food
Eg. Barbiturates cause excitement andmental confusionChloramphenicol causes aplastic
anemia
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6. ADR: Drug allergy (drug hypersensitivity)
Immunologically mediated reaction Unpredictable Occur in previously sensitized individualsTypes of drug allergy:Humoral: Anaphylactic:Type I- within minutes Cytolytic: Type II- within 72 hours Immune complex mediated[Arthus]:Type III-
after 72 hours, but within 1-2 weeks
Cell mediated: Delayed hypersensitivity -Type IV:Develops
after 12 hours
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Drug allergy-Type I [Anaphylaxis]
Exposure todrugEg.Penicillin
IgE ABFixed tomast cells
Reexposure AG+AB
Release of mediators:
Histamine, 5-HT, PGs,LTs, PAF
Anaphylactic shock:Hypotension,
Bronchospasm,
Urticaria Etc.
Treatment:Medical emergency
Inj.Adrenaline[1:1000] 0.3 to 0.5 ml i.m.
Inj.Hydrocortisone 100 mgi.v.
Inj.Diphenhydramine 25mg i.v.
Oxygen
i.v. fluids
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Type II hypersensitivity (cytolytic)
Drug + component of a specific tissue cell act as AG.
The resulting antibodies (IgG,IgM) bind to the target cells
On re-exposure AG: AB reaction takes place on the surface of
these cells
Activation of complement and cytolysis
Eg: Thrombocytopenia, agranulocytosis, aplastic anaemia,
haemolysis, organ damage, SLE
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Type III: Immune Complex Mediated Reaction
When antibodies (Ig G or Ig M) and antigen coexist immunecomplexes are formed
Immune complexes are removed by reticuloendothelial system
Some immune complexes escape phagocytosis
Immune complexes deposited on vascular endothelium and
leading to inflammatory response causing tissue injury
Eg: Rashes, serum sickness, polyarteritis nodosa, Stevens-
Johnson syndrome
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Type-lV (delayed hypersensitivity) reactions
Mediated through production of sensitized T lymphocytescarrying receptors for the AG.
On contact with the AG these T cells produce lymphokines
Lymphokines attract granulocyte and generate an inflammatory
response
The reaction generally takes> 12 hours to develop.
Eg: Rashes, serum sickness, polyarteritis nodosa, Stevens-
Johruon syndrome
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Drug allergy-Type IV [Delayed]
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7. Carcinogenicity & mutagenicity:
Ability of the drug to cause cancer andgenetic defects respectively
Eg. Tobacco, anticancer drugs
8. Iatrogenic diseases: physician inducediatros= physician
Parkinsonism PhenothiazinesPeptic ulcer Aspirin,corticosteroidsHepatitis - Isoniazid
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9.Teratogenicity: terataos= monster
Capacity of the drug to cause fetalabnormalities when given in pregnancy
I. Preimplantation: conception to 17 days-Abortionii.Organogenesis:18-55 days-Deformitiesiii. Growth & development:56 days onwards-
Developmental & functional abnormalitiesEg:Thalidomide Phocomelia
Corticosteroids Cleft lip
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Cleft Palate HydrocephalusAnticancer drugs
Phocomelia
Thalidomide
Neural tube
DefectsValproate
Hand defects
Warfarin
Fetal alcoholsyndrome
AlcoholHydantoin syndrome
Phenytoin
Human teratogenic drugs
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Tetracycline
Staining
After Tt
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10. PhotosensitivityDrug induced sensitization of skin to UVradiation
Photoallergic:
Drug/its metabolite induce cell mediated immune
response which on exposure to light of longer wavelengths produces a papular/eczematous contact dermatitis
like picture. Eg: sulfonamides, chlorpromazine
Phototoxic:
Drug/its metabolite accumulates in the skin, absorbs light
and undergoes a photochemical reaction followed by a
photobiological reaction resulting in local tissue damage.
Eg: Tetracyclines, sulfonamides
http://images.google.co.in/imgres?imgurl=http://i47.photobucket.com/albums/f195/LupusWebsite/cutaneouslupus.jpg&imgrefurl=http://www.lupusmctd.com/index.php?topic=474.msg1511&h=260&w=384&sz=14&hl=en&start=8&um=1&usg=__KhR8qLox4AfDFohBIlREv12A5kc=&tbnid=raSHFxvV2vrqnM:&tbnh=83&tbnw=123&prev=/images?q=photosensitivity&um=1&hl=en&sa=N8/3/2019 Saftey Margin & Drug Toxicity[1]
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11.Organ toxicityHepatotoxicity: INH, Rifampicin
Nephrotoxicity: Aminoglycosides
Ototoxicity: Aminoglycosides,Frusemide
Ocular toxicity: Ethambutol,Chloroquine
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12. Drug dependence A state of use of drug for personal
satisfaction with known risk to health Due to interaction - living organism + Drug Always includes a compulsion to take the drug
continuously or periodically Psychological dependence: Intense desire to
take drug and immense satisfaction later Physical dependence: Altered physiological state
produced by repeated administration of a drugwhich necessitates the continued presence of thedrug to maintain physiological equilibrium
Discontinuation leads to withdrawal syndrome
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Poisoning
Poisons in small doses are the bestmedicines; and useful medicines in too
large doses are poisonousWilliam Withering 1789
Poison is substance which endangers life by
severely affecting one or more vital functions
Accidental/suicidal/homicidal
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Treatment of Poisoning1. Resuscitation and maintainance of vital
functionsAirway, BP, Body temp., Blood sugar
2. Termination of exposure
Fresh air, remove wet clothes, wash,3. Prevention of absorption
Gastric lavage, Activated charcoal,
4. Hastening eliminationDiuresis, Altering urine pH, Hemodialysis
5. Antidote: Eg: Atropine in OP poisoning
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Prevention of adverse effects Right dose, route, frequency
Previous history drug allergy andallergic diseases
Rule out drug interactions Correct technique of administration
Therapeutic drug monitoring (TDM) ifappropriate
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Pharmacovigilance Actively look for adverse drug effects Activities relating to detection, assessment,
understanding and prevention of adverse effects orany other drug related problem
Information collected byRegional centers to
Zonal centers toNational centers toUppsala monitoring center(Sweden)
Uses Educating doctors about ADE Assessing safety of drugs
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ADR Effects (Erythema Multiforme)
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ADR Effects (Gingival Enlargement due to
Ca2+-Channel Blockers)