Adverse Drug Reactions

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Adverse Drug Reactions:
Type A (Augmented)

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Predictable undesirable effects related to the normal pharmacological action of the drug.

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Adverse Drug Reactions
1- Side Effect

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- Unavoidable undesirable normal action produced by therapeutic dose of the drug
- e.g. Dry mouth induced by Atropine when used as antispasmodic

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Adverse Drug Reactions
2- Secondary Effect

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- Bad effect "consequent" to normal therapeutic action of the drug.
- e.g. Oral broad spectrum antibiotic -> decrease in intestinal flora -> decrease in Vit B & K synthesis and Superinfection

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Adverse Drug Reactions
3- Overdose

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Exaggerated normal action due to high blood level of the drug either:
- Single large dose: Insulin -> hypoglycemia
- Accumulation of repeated doses -> Digitalis

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Adverse Drug Reactions
4- Supersensitivity (Intolerance)

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- Exaggerated normal action in response to small therapeutic dose of the drug.
- Either due to decreased elimination or Up-regulation of receptors.
- e.g. Hyperthyroidism -> Supersensitivity to sympathomimetics
- Decraese the dose of the drug

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Adverse Drug Reactions
5- Cytotoxicity

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a- Cardio-toxicity: Halothane
b- Hepato-toxicity: Halothane & Paracetamol (only in toxic dose)
c- Nephro-toxicity: NSAID, Aminoglycosides (Gentamicin) & Sulfonamides.
d- Neuro-toxicity: Streptomycin (8th cranial nerve damage)
e- Bone marrow inhibition (Blood Dyscrasias): Chloramphenicol & Anti-thyroid drugs

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Type B (Bizarre or unpredictable) Adverse Effects:
1- Allergy (Hypersensitivity)

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1- unpredictable abnormal response due to antigen/antibody reaction.
2- The drug itself or its metabolite may act as an antigen or a hapten
3- NOT all patients
All drugs
Dose dependent
All drugs
First exposure
Reuse the drug again
4- Cross allergy between related drugs (Penicillin & Cephalosporins)

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Allergy Type I (Immediate, Anaphylactic or IgE mediated)

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- Ag/Ab reaction on Mast cell cause Degranulation and release of allergotoxins e.g. histamine.
- Manifestations: fever, rash, urticaria, photosensitivity, conjunctivitis, rhinitis, angio-edema, bronchial asthma, GIT disturbance & even Anaphylactic shock.
- Avoided by: history taking, intradermal test & NEVER reuse the drug again.
Treated by: Antihistaminics, SC Epinephrine, Corticosteroids & desensitization.

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Type II (Autoallergy, Cytotoxic or Cytolytic)

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Antigen + Antibody (IgG &IgM) + complement on an organ cell causes cell damage.
Example: a-Methyldopa ->Hepatotoxic, Hemolysis and bone marrow inhibition.

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Type III ( Arthus Reaction)

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Antigen + Antibody (IgG) + complement on endothelial cells -> damage of endothelium
Manifestations: Vasculitis & serum sickness

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Type IV (Delayed or Cell Mediated)

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Antigen + Sensitized T lymphocytes-> Inflammation
Manifestations: Contact Dermatitis

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Type V ( Stimulatory Reaction )

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Formation of Thyroid stimulating immunoglobulins (TSI) or Long Acting Thyroid Stimulant (LATS) similar to TSH -> Hyperthyroidism (Gravis disease)

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II) Type B (Bizarre or unpredictable adverse effects):
2) Idiosyncrasy (Pharmacogenetics)

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Unpredictable abnormal response due to genetic abnormality.
Occurs on first exposure.
Examples:
1- Hemolytic anemia: in patients with Fauvism (G6PD deficiency) induced by: Primaquine, Aspirin, Sulfonamides.
2- Succinylcholine apnea in patients with abnormal Pseudo Choline estrase.
3- Malignant Hyperthermia induced by Succinylcholine & Halothane.

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II) Type B (Bizarre or unpredictable adverse effects):
2) Idiosyncrasy (Pharmacogenetics) (2)

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4- Acute Porphyria in patients with acute intermittent porphyria induced by barbiturates due to increase in delta-amino-levulinic acid synthetase (ALA) enzyme.
5- Slow & Rapid Acetylators -> - Slow Acetylators -> accumulation of Isoniazid which competes with Vit B6 thus resulting in Peripheral Neuritis.
- Rapid Acetylators -> accumulation of Acetyl-Isoniazid which is Hepatotoxic.

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Type C (Chronic Effects):

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Effects of prolonged use of the drug:

1- Tolerance

2- Drug Dependence

3- Iatrogenic Disease

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Type C (Chronic Effects):

1) Tolerance

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- decreased or failed response to the drug

- types:

Congenital (Inborn)

Acquired

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Type C (Chronic Effects):

1) Tolerance

a- Congenital (inborn)

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1- Racial: Ephedrine doesn't produce Mydriasis in Negros

2- Species: rabbits tolerate Atropine. They have excess atropine estrase enzyme.

3- Individual (Biological) variations within any population.

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Type C (Chronic Effects):

1) Tolerance

b- Acquired (Def & Types)

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- Decreased response to drugs after repeated (long) use e.g. Morphine & Nitrates

- Types:

1- Cross Tolerance: between similar drugs e.g. Nicotine & Lobeline

2- Tachyphylaxis (Acute acquired tolerance) e.g. Ephedrine on blood pressure

3- Bacterial resistance to antimicrobials

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Mechanism of Acquired Resistance

"MAADE"

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1- decreased ABSORPTION: long use of Ethanol causes atrophic gastritis

2- incresed METABOLISM: Phenobarbital is an HME inducer which increases its own metabolism (auto-induction)

3- Down-Regulation of receptors: Salbutamol decreases beta2 receptors

4- decrease Endogenous substance: Morphine decrease Endorphins & Ephedrine

5- Antibody formation e.g. Insulin & Parathyroid hormone (of animal origin)

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Characteristics of Acquired Resistance (1/2)

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1- Reversal: if the drug is stopped for sometime, will regain normal sensetivity

2- Varies from one drug to another:

Rapid for Ephedrine & very slow with Adrenaline

NO tolerance to Digitalis & Cocaine & Diuretic effect of alcohol

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Characteristics of Acquired Resistance (2/2)

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3- Doesn't affect all actions to the same extent: Morphine: Rapid to analgesia & dec R.C. BUT NO to miosis or conistepation

4- It affects the therapeutic dose rather than the toxic dose

5- Drug dependence (Habituation & Addiction)

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Drug Dependence:

a) Habituation

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- Psychic dependence

- Sudden stop of the drug leads to psychic craving

- Example: Xanthine beverages (coffee & tea)

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Drug Dependence:

b) Addiction

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- Psychic & Physical dependence

- Sudden stop leads to Withdrawal (Abstinence) symptoms which is usually the reverse of what the addicting agent does.

- Example: Amphetamine, Morphine & Ethanol

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Type C (Chronic effects):

3- Iatrogenic disease

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Drug-induced disease

E.g. : Large dose of Resperine & Chloropromazine cause Iatrogenic Parkinsonism

Large dose of Cortisol causes Iatrogenic Cushing's disease.

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Type D (Delayed effects):

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appearing after long use of the drug:

1- Teratogenicity (Dysmorphogenesis)

2- Mutagenicity & Carcinogenicity

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Type D (Delayed effects):

1- Teratogenicity (Dysmorphogenesis)

"PATT"

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Drug induced fetal malformation especially in the first trimester.

E.g.Thalidomide: Phocomelia (absent long bones)

Phenytoin: Hare lip & Cleft lip

Aspirin: cardiac septal defect

Tetracycline: teeth & bone

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Type D (Delayed effects):

2- Mutagenicity & Carcinogenicity

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Tobacco smoking: Bronchogenic carcinoma

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Type E (End of Use Effect)

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1- Withdrawal Syndrome: of addicting drugs as morphine, cocaine & barbiturates

2- Acute Addisonian crisis: of chronic steroid therapy.

3- Worsening of existing disease: sudden stopping of beta-blocker Myocardial infarction

-Clonidine Hypertension

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Type F (Failure of therapy):

Primary:

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1) Genetic cause: idiosyncracy

2) Patho-physiological cause: failure of insulin secretagogues in treatment of Type I DM due to absolute deficiency of endogenous insulin.

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Type F (Failure of therapy):

Secondary

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Tolerance

Drug interaction