Saftey Margin & Drug Toxicity[1]

8/3/2019 Saftey Margin & Drug Toxicity[1]

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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
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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)
http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=/websites/emedicine/derm/images/Large/103Cam65016.jpg&template=izoom2


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ADR Effects (Gingival Enlargement due to

Ca2+-Channel Blockers)

Documents

Saftey Margin & Drug Toxicity[1]