Adverse Effects of Drugs
Content
ADVERSE EFFECTS OF DRUGS
Prof. Solomon Sunder Raj M.Pharm, PhD Head of the Department of Pharmacology Bharath Institute of Technology, Hyderabad, India
INTRODUCTION
• When a drug is administered to a patient, essentially two types of reactions can occur, desired effects and the undesired effects. • The desired drug effects are those clinically beneficial actions for which the drug has been prescribed. • The undesirable drug effects are those which do not have those any pharmacological actions.
ADVERSE EFFECT: Adverse effect is any undesirable unintended consequence of drug administration. It includes all kinds of noxious effects ADVERSE DRUG REACTION(ADR): An adverse drug reaction is any response to a drug which is noxious (injurious) and unintended and which occurs at doses used in man for prophylaxis, diagnosis or therapy of disease.
Some antihistamines cause drowsiness and also control symptoms of allergies.
When antihistamines are taken during day time, drowsiness is an unwanted effect
Major adverse drug reactions
• • • • • Allergic reactions Anaphylactic shock Coma Cardiac arrhythmias Congestive heart failure • • • • • Convulsions Hypertension Diabetes mellitus Paralysis Kidney or liver dysfunction
PHARMACODYNAMIC EFFECTS
DESIRABLE OR BENEFICIAL EFFECTS
UNDESIRABLE OR ADR
EXPECTED UNDESIRABLE EFFECTS (TYPE A - ADR)
UNEXPECTED UNDESIRABLE EFFECTS (TYPE B - ADR)
UNDESIRABLE EFFECTS
EXPECTED UNDESIRABLE EFFECTS UNEXPECTED UNDESIRABLE EFFECTS
Side effects
Hypersensitivity or allergy
Genetically determined ADR Idiosyncratic responses
Secondary effects
Toxicity
SIDE EFFECTS:
These are observed even with the therapeutic doses of the drug These are usually mild and manageable Eg: DICYCLOMINE (anti cholinergic drug) – dryness of mouth PROMETHAZINE (antihistaminic drug) - sedation
Secondary effects:
These are indirect consequences of the main pharmacodynamic action of the drug Eg: Development of super infection after suppression of bacterial flora by ANTIBIOTICS Weakening of host defenses after use of CORTICOSTEROIDS
Toxicity:
These are exaggerated form of side effects which occur due to over doses or after prolonged use of the drug.
Eg: morphine - respiratory failure in overdose Imipramine – vestibular damage on prolonged use
HYPERSENSITIVITY
Hapten
+ Body protein
Antigen
Mechanism of the allergic Response: After first exposure to the drug
Stimulus for formation Of antibodies
antibody
Hapten
+
Body protein
Antigen
Antibody
After re-exposure to the same drug
Antigenantibody complex
allergy
Release of chemical mediators
Tissue Or mast cells
Drugs may cause following types of allergy: Type 1 (immediate type):
Allergy develops within minutes and lasts for 2-3 hrs. Antibodies IgE get fixed to the mast cells. On exposure to drug AG:AB reaction takes place on the mast cell surface releasing mediators like 5-HT, histamines, leukotrienes, prostaglandins etc Ex: Bronchospasm
TYPE 2 (AUTO OR ACCELERATED ALLERGY)
It occurs within 72 hrs of drug administration. Drug and component of specific tissue cell act as AG.
The resulting antibodies (IgG,IgM) bind to target cells, on reexposure AG:AB reaction takes place on the surface of these cells, cytolysis occurs. Eg: Thrombocytopenia Haemolysis Organ damage
Type 3(Delayed allergy)
• It occurs after 72 hrs but within 1-2 weeks of drug administration. • These are mediated by circulating antibodies. • AG:AB complexes bind and precipitate on vascular endothelium giving rise to destructive inflammatory response. Eg: Stevens Johnson Syndrome (arthritis, nephritis, mental symptoms)
TYPE 4 (CELL MEDIATED ALLERGY)
• These are mediated through production of sensitized T-lymphocytes carrying receptors for the AG.
• On contact with antigen these T-cells produce lymphokines which attract granulocytes and generate an Inflammatory response. Eg: contact dermatitis rashes fever
IDIOSYNCRACY
It is genetically determined abnormal reactivity to a chemical. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces uncharacteristic reaction. Eg: Barbiturates cause excitement and mental confusion Chloramphenicol produces serious aplastic anaemia.
MISCELLANEOUS ADRS
Photosensitivity:
It is a cutaneous reaction resulting from drug induced sensitization of skin to UV radiation. The reactions are of two types :
phototoxic : Drug or it’s metabolite accumulates in skin,
absorbs light and undergoes a photochemical reaction followed by a photo biological reaction resulting in local tissue damage.
photo allergic: Drug or it’s metabolites induces a cell
mediated immune response which on exposure to light of longer wavelengths produces dermatitis.
TERATOGENICITY
• An agent that causes toxic effects on foetus is called as teratogen. • Teratogenecity is defined as foetal abnormalities caused by administration of drugs during pregnancy. Eg: Thalidomide disaster resulted in thousands of babies born with phocomelia. (seal like limbs)
MUTAGENICITY AND CARCINOGENICITY
• It refers to capacity of drug to cause genetic defects. • Usually oxidation of the drug results in production of reactive intermediates which affect genes and may cause structural changes in the chromosomes.
• Covalent interaction with DNA can modifyit to induce mutations, which may be seen as heritable defects in the next generation. If the modified DNA sequences code for factors that regulate cell proliferation or growth i.e. are protooncogenes, or for proteins that inhibit transcription of protooncogenes, a tumour (cancer) may be produced.
MULTIPLE DRUG REACTIONS
• The presence of a second drug may modify the actions of a simultaneously administered drug. • Sometimes drugs are used together (drug combinations) to obtain a better clinical response than either drug could achieve alone.
• In contrast, indiscriminate multiple drug use can be hazardous as the chances of ADRS increase with each drug
FACTORS
• AGE: Infants are at high risk of ADRS because their
capacity to metabolise drugs is not fully developed.
Eg: chloramphenicol - gray baby syndrome tetracyclines - improper growth of bones discoloration of teeth
• GENDER: some ADRS are more common in women than
in men. Woman are reputed to be more susceptible to the toxic effects of digoxin, heparin and captopril. Eg: chloramphenicol induced aplastic anaemia is twice as common in women than in men.
PREGNANCY AND BREAST FEEDING
Antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACE) and angiotensin II receptor blockers pose a risk to the health and normal development of a foetus. During pregnancy requires a doctor’s supervision. Drugs like alcohols, warfarin, lithium, phenytoin shows some ADRS during pregnancy.
Some adverse drug reactions
Drug
Paracetamol Anticancer drugs
ADR
Liver damage Hair loss & anaemia
Chloramphenicol
Tetracyclines
Gray baby syndrome
Discolouration of teeth Drowsiness Hypertension
Antihistamines
Ephedra extracts
Aspirin and other NSAIDS
These exist their anti inflammatory effect by inhibition of the enzyme COX. This enzyme involves in the formation of prostaglandins. These drugs inhibits Prostaglandins. Prostaglandins inhibit the acid secretions. Due to the inhibition Of prostaglandins acid secretions are increased. It leads to peptic ulcer (gastrointestinal bleeding)
PREVENTION
Use appropriate dose, route and frequency of drug administration based on patient’s specific variables. Elicit and take into consideration previous history of drug reactions. Elicit history of allergic diseases and exercise caution. Adopt correct drug administration technique. Avoid all inappropriate use of drugs in the context of patient’s clinical condition.
REFERENCES
• • • • • • Tripathi Rang & Dale Goodmann & Gilman Lippincott Williams & Wilkins P.N.Bennett M.J.Brown
Prof. Solomon Sunder Raj M.Pharm, PhD Head of the Department of Pharmacology Bharath Institute of Technology, Hyderabad, India
INTRODUCTION
• When a drug is administered to a patient, essentially two types of reactions can occur, desired effects and the undesired effects. • The desired drug effects are those clinically beneficial actions for which the drug has been prescribed. • The undesirable drug effects are those which do not have those any pharmacological actions.
ADVERSE EFFECT: Adverse effect is any undesirable unintended consequence of drug administration. It includes all kinds of noxious effects ADVERSE DRUG REACTION(ADR): An adverse drug reaction is any response to a drug which is noxious (injurious) and unintended and which occurs at doses used in man for prophylaxis, diagnosis or therapy of disease.
Some antihistamines cause drowsiness and also control symptoms of allergies.
When antihistamines are taken during day time, drowsiness is an unwanted effect
Major adverse drug reactions
• • • • • Allergic reactions Anaphylactic shock Coma Cardiac arrhythmias Congestive heart failure • • • • • Convulsions Hypertension Diabetes mellitus Paralysis Kidney or liver dysfunction
PHARMACODYNAMIC EFFECTS
DESIRABLE OR BENEFICIAL EFFECTS
UNDESIRABLE OR ADR
EXPECTED UNDESIRABLE EFFECTS (TYPE A - ADR)
UNEXPECTED UNDESIRABLE EFFECTS (TYPE B - ADR)
UNDESIRABLE EFFECTS
EXPECTED UNDESIRABLE EFFECTS UNEXPECTED UNDESIRABLE EFFECTS
Side effects
Hypersensitivity or allergy
Genetically determined ADR Idiosyncratic responses
Secondary effects
Toxicity
SIDE EFFECTS:
These are observed even with the therapeutic doses of the drug These are usually mild and manageable Eg: DICYCLOMINE (anti cholinergic drug) – dryness of mouth PROMETHAZINE (antihistaminic drug) - sedation
Secondary effects:
These are indirect consequences of the main pharmacodynamic action of the drug Eg: Development of super infection after suppression of bacterial flora by ANTIBIOTICS Weakening of host defenses after use of CORTICOSTEROIDS
Toxicity:
These are exaggerated form of side effects which occur due to over doses or after prolonged use of the drug.
Eg: morphine - respiratory failure in overdose Imipramine – vestibular damage on prolonged use
HYPERSENSITIVITY
Hapten
+ Body protein
Antigen
Mechanism of the allergic Response: After first exposure to the drug
Stimulus for formation Of antibodies
antibody
Hapten
+
Body protein
Antigen
Antibody
After re-exposure to the same drug
Antigenantibody complex
allergy
Release of chemical mediators
Tissue Or mast cells
Drugs may cause following types of allergy: Type 1 (immediate type):
Allergy develops within minutes and lasts for 2-3 hrs. Antibodies IgE get fixed to the mast cells. On exposure to drug AG:AB reaction takes place on the mast cell surface releasing mediators like 5-HT, histamines, leukotrienes, prostaglandins etc Ex: Bronchospasm
TYPE 2 (AUTO OR ACCELERATED ALLERGY)
It occurs within 72 hrs of drug administration. Drug and component of specific tissue cell act as AG.
The resulting antibodies (IgG,IgM) bind to target cells, on reexposure AG:AB reaction takes place on the surface of these cells, cytolysis occurs. Eg: Thrombocytopenia Haemolysis Organ damage
Type 3(Delayed allergy)
• It occurs after 72 hrs but within 1-2 weeks of drug administration. • These are mediated by circulating antibodies. • AG:AB complexes bind and precipitate on vascular endothelium giving rise to destructive inflammatory response. Eg: Stevens Johnson Syndrome (arthritis, nephritis, mental symptoms)
TYPE 4 (CELL MEDIATED ALLERGY)
• These are mediated through production of sensitized T-lymphocytes carrying receptors for the AG.
• On contact with antigen these T-cells produce lymphokines which attract granulocytes and generate an Inflammatory response. Eg: contact dermatitis rashes fever
IDIOSYNCRACY
It is genetically determined abnormal reactivity to a chemical. The drug interacts with some unique feature of the individual, not found in majority of subjects, and produces uncharacteristic reaction. Eg: Barbiturates cause excitement and mental confusion Chloramphenicol produces serious aplastic anaemia.
MISCELLANEOUS ADRS
Photosensitivity:
It is a cutaneous reaction resulting from drug induced sensitization of skin to UV radiation. The reactions are of two types :
phototoxic : Drug or it’s metabolite accumulates in skin,
absorbs light and undergoes a photochemical reaction followed by a photo biological reaction resulting in local tissue damage.
photo allergic: Drug or it’s metabolites induces a cell
mediated immune response which on exposure to light of longer wavelengths produces dermatitis.
TERATOGENICITY
• An agent that causes toxic effects on foetus is called as teratogen. • Teratogenecity is defined as foetal abnormalities caused by administration of drugs during pregnancy. Eg: Thalidomide disaster resulted in thousands of babies born with phocomelia. (seal like limbs)
MUTAGENICITY AND CARCINOGENICITY
• It refers to capacity of drug to cause genetic defects. • Usually oxidation of the drug results in production of reactive intermediates which affect genes and may cause structural changes in the chromosomes.
• Covalent interaction with DNA can modifyit to induce mutations, which may be seen as heritable defects in the next generation. If the modified DNA sequences code for factors that regulate cell proliferation or growth i.e. are protooncogenes, or for proteins that inhibit transcription of protooncogenes, a tumour (cancer) may be produced.
MULTIPLE DRUG REACTIONS
• The presence of a second drug may modify the actions of a simultaneously administered drug. • Sometimes drugs are used together (drug combinations) to obtain a better clinical response than either drug could achieve alone.
• In contrast, indiscriminate multiple drug use can be hazardous as the chances of ADRS increase with each drug
FACTORS
• AGE: Infants are at high risk of ADRS because their
capacity to metabolise drugs is not fully developed.
Eg: chloramphenicol - gray baby syndrome tetracyclines - improper growth of bones discoloration of teeth
• GENDER: some ADRS are more common in women than
in men. Woman are reputed to be more susceptible to the toxic effects of digoxin, heparin and captopril. Eg: chloramphenicol induced aplastic anaemia is twice as common in women than in men.
PREGNANCY AND BREAST FEEDING
Antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACE) and angiotensin II receptor blockers pose a risk to the health and normal development of a foetus. During pregnancy requires a doctor’s supervision. Drugs like alcohols, warfarin, lithium, phenytoin shows some ADRS during pregnancy.
Some adverse drug reactions
Drug
Paracetamol Anticancer drugs
ADR
Liver damage Hair loss & anaemia
Chloramphenicol
Tetracyclines
Gray baby syndrome
Discolouration of teeth Drowsiness Hypertension
Antihistamines
Ephedra extracts
Aspirin and other NSAIDS
These exist their anti inflammatory effect by inhibition of the enzyme COX. This enzyme involves in the formation of prostaglandins. These drugs inhibits Prostaglandins. Prostaglandins inhibit the acid secretions. Due to the inhibition Of prostaglandins acid secretions are increased. It leads to peptic ulcer (gastrointestinal bleeding)
PREVENTION
Use appropriate dose, route and frequency of drug administration based on patient’s specific variables. Elicit and take into consideration previous history of drug reactions. Elicit history of allergic diseases and exercise caution. Adopt correct drug administration technique. Avoid all inappropriate use of drugs in the context of patient’s clinical condition.
REFERENCES
• • • • • • Tripathi Rang & Dale Goodmann & Gilman Lippincott Williams & Wilkins P.N.Bennett M.J.Brown
