Adverse Drug Reactions (ADRs) are the detrimental or seriously unwanted effects of the drug which results at therapeutic, prophylactic, or diagnostic dose level. Adverse Drug Reactions results call for a decrease in the dose or withdrawal of the drug from future use. The incidences of ADRs are due to the availability of many potent drugs.
Adverse Drug Reactions (ADRs) can be defined as follows:
- Adverse Drug Reactions is a damaged state which can result from medical involvement related to a drug.
- As per WHO, adverse drug reactions are defined as any noxious and unwanted effect of a drug that occurs at doses given to a human being for prophylaxis, diagnosis, or treatment.
Toxicity indicates a direct effect of the drug at a high dose result in damaging cells. Following are some examples of toxicity reactions. Overdose of Paracetamol produced liver damage, Gentamicin produced eight cranial nerve damage, an overdose of Ethambutol and Chloroquine produced oculotoxicity. Other examples of toxicity reactions are Mutagenicity, Carcinogenicity, and Teratogenicity.
Reasons for Increasing Adverse Drug Reactions (ADRs):
Following are the reasons leading to an increase in the chances of adverse drug reactions:
- Increase the availability of potent drugs.
- The availability of drugs without prescription.
- The exposure of man to drugs and chemicals via a polluted environment.
- Polypharmacy i.e. irrational use of many drugs together needlessly.
- Use of self-medication for minor ailments.
The number of Adverse Drug Reactions occurring are minor but around 70% of the reported ADRs include; rash, itching, headache, drowsiness, convulsion, insomnia, double vision, extra-sensitivity to light, ringing in ears, and GI disturbances, etc.
Classification of Adverse Drug Reactions (ADRs)
Predictable or Type 1 or Non-immunologic Reactions
In this type of reaction, the qualitative responses are normal but quantitative responses are abnormal. The responses in predictable reactions are less serious, commonly occurring; dose-dependent reactions and the responses can be corrected by adjusting a dose of the drug. The reactions include; side effects, toxic effects, withdrawal symptoms, etc. The majority of Adverse Drug Reactions are caused by predictable, non-immunologic effects (75 to 80%).
Following are the types of predictable reactions:
- Excessive pharmacological effect.
- Side effects.
- Toxic effects.
- Secondary pharmacological effect.
- Rebound response after discontinuation.
Excessive Pharmacological Effect:
It develops in all patients if the excessive dosage is given result in excessive pharmacological effects. It is seen in cardioactive agents, CNS depressants, hypoglycemic agents, and hypotensive agents.
It is common in neonates, infants, and elderly patients also in patients with kidney diseases, who have lost more than 70% of their kidney function with normal doses. It is also common for an inpatient with lower albumin levels due to liver or kidney damage. Example: At an excessive dosage of Digoxin produces bradycardia; Morphine and bradycardia produce respiratory depression in bronchitis patients.
Side effects are some extension of pharmacological effects produced at therapeutic doses. It is dose-related and minor.
Side effects result as an extension of the same therapeutic effects. For example: atropine produces dry mouth which is used as an anti-secretory in preanesthetic medication. A side effect is a markedly different effect. For example: promethazine, as antiallergic produces sedation and estrogen, is anti-ovulatory, and produces nausea.
A side effect of most of the drugs is exploited for therapeutic use. The examples of such side effects of a drug that is used as an indication are as follows:
- Codeine (antitussive) has constipating side effects which are used in the treatment of diarrhea.
- Sulfonylureas (tested as anti-bacterial) are found to decrease blood glucose levels.
- Prazosin produces postural hypotension.
- Hypokalemia produced by Furosemide.
- Nitrates produce headaches.
The effects produce at overdose or prolonged use of the drug. Following are some examples of toxic effects:
- Atropine causes delirium.
- Paracetamol causes hepatic necrosis.
- Barbiturates cause coma.
- Morphine causes respiratory failure.
Secondary Pharmacological Effect:
Some of the drugs have other many pharmacological actions at commonly administered dosage. The effect produced by the drug is different than the drug administered initially for prevention or treatment means it is an indirect consequence of primary drug action.
Following are some examples of secondary pharmacological effects:
- Patients receiving the antihistaminic drug for the prevention of motion sickness or in the allergic skin reaction may become drowsy.
- Vitamin deficiency or opportunistic infections occur in patients whose normal bowel flora has been altered by antibiotics like tetracyclines.
- Diuretic-induced hypokalaemia causes digoxin intolerance.
Rebound Response after Discontinuation/Drug Withdrawal Reactions:
The use of long-term of many medications produces tolerance at the cellular level. Sudden withdrawal of such medication may give rise to severe adverse effects. These reactions occur in absence of a drug causing it. These types of reactions are common with drugs that act on CNS. For example: narcotics, analgesics, hypnotics, ethanol, etc. It can also result in some antihypertensive drugs and corticosteroids. The withdrawal effects can be minimized by the gradual withdrawal of drugs.
Following are the examples of drug withdrawal response:
- Clonidine is an antihypertensive agent which causes severe rebound hypertension if its use discontinues suddenly.
- The long-term use of CNS depressants like; benzodiazepines, barbiturates, and alcohol after sudden withdrawal result in confusion, delirium, tachycardia, and convulsion.
- Anti-epileptic drug withdrawal may increase seizures.
Unpredictable or Type B or Immunologic Reactions
The reaction generally results due to the presence of some patient peculiarities. For example: Allergy, Idiosyncrasy. The reaction is based on the patient and not on drug action. It is less common and dose-independent. If the reactions are more serious then immediate withdrawal of that drug is required. Following are the types of unpredictable reactions:
- Idiosyncrasy or Pharmacogenetics.
- Genetically determined toxicity.
- Allergic drug reaction (hypersensitivity reaction).
- Super sensitivity.
(a) Idiosyncrasy or Pharmacogenetics:
Idiosyncrasy refers to an inherent peculiarity of an individual and it is described as an unusual response/abnormal response to a drug or highly exaggerated usual response produced by some drugs with usual doses in a few individuals.
It is a genetically determined atypical/ bizarre effect.
Following are the examples of idiosyncrasy reactions:
- Administration of an analgesic drug to a patient with renal disease may induce tumors of the kidney pelvis.
- High doses of stilbesterol during pregnancy produce vaginal adenocarcinoma.
- Long-term uses of estrogens produce uterine cancer.
- Long-term uses of Azathioprine, Cyclophosphamide may induce lymphoid tumors.
- Barbiturate produces excitement and mental confusion.
- Quinine produces cramps, diarrhea, purpura, asthma, vascular collapse.
- Prolonged apnoea is caused by pseudocholinesterase deficiency.
- Aspirin produces bronchial asthma.
(b) Genetically Determined Toxicity:
The reactions occur in patients with special genotype or genetic make-up. In some literature, this reaction is included in idiosyncrasy reaction.
Following are examples of genetically determined toxicity:
- Hemolytic anemia caused exposure with primaquine, sulphonamide, nitrofurantoin, quinine, chloroquine in deficiency of Glucose-6-Phosphate Dehydrogenase (G-6-PD) in RBCs.
- Hereditary deficiencies of plasma cholinesterase are unable to hydrolyze the succinylcholine thus it causes prolonged apnoea for a few hours in case of plasma pseudocholinesterase deficient people.
- Some of the drugs are metabolized by acetylation in the liver by enzyme N-acetyl transferase for example: Procainamide, Isoniazid, and hydralazine. In slow acetylators, there is a slow response with enzyme N-acetyl transferase for metabolization which results in the development of systemic lupus erythematosus with hydralazine and polyneuritis with isoniazid. While the fast acetylators may show drug resistance or failure of response.
(c) Allergic Drug Reaction (Hypersensitivity Reaction):
It includes all the reactions mediated by antigen-antibody reactions involving sensitized lymphocytes. Drugs act as a foreign antigen that reacts with antibodies in the human body to cause undesirable effects like; skin rashes, bronchospasm, angioedema, anaphylactic shock, vasculitis, etc. These reactions require previous exposure to the drug itself or a closely related chemical drug. An allergic reaction is not dose-related and it does not correlate with the action of a drug.
Protein and peptides can act as complete antigens but most drugs are small molecules and do not stimulate antibody production. But they may combine with other carrier macromolecule and function as haptens or partial antigens which stimulate the biosynthesis of antibodies. These are then attached to body tissue and when this drug sensitized person is re-exposed to the drug, a reaction occurs between the hapten and preformed antibodies result in tissue damage leading to signs and symptoms of drug allergy.
It is the most serious type of drug allergic reaction. This involves the formation of specific types of antibodies that belong to the IgE class. These antibodies are present on the surface of tissue cells. Upon re-exposure of antigen, it combines with antibodies on the target tissue and results in the liberation of inflammatory mediators like; histamine, 5-hydroxy tryptamine (5-HT), and prostaglandin which are responsible for reaction and symptoms. Anaphylaxis may be localized or generalized, in the gut, it produced diarrhea and abdominal pain, it produces asthma when it occurs in bronchi, and produce edema when the reactions occur on the surface of the skin. Generalized anaphylaxis is characterized by bronchospasm, circulatory collapse with hypotension, and sometimes skin rashes. The most serious type of anaphylaxis is known as Anaphylactic shock in which there is obstruction of respiratory passage and lowering of blood pressure. If there is a complete obstruction for a few minutes then it results in death.
Following are examples of drugs that produce allergic reactions:
- Penicillin, dextran, anesthetics, and iodine-containing compounds produce anaphylaxis reactions.
- Sulphonamide, phenylbutazone, thiouracil produces leucopenia.
- Quinidine, thiazide, digoxin produces thrombocytopenia.
(d) Super sensitivity:
It demonstrated the increase in the responsiveness to a drug that produced either from denervation or following administration of a drug (a receptor antagonist) for a prolonged period. For example, the blocking of dopamine receptors by chlorpromazine may cause supersensitivity by up-regulating dopamine receptors.
It consists of phototoxic and photoallergic reactions.
- Phototoxic reaction: In which the reaction occurs due to drug accumulation in the skin which absorbs light upon exposure to light results in a photochemical reaction.
- Photobiological or Photoallergic reaction: In this reaction causes tissue damage e.g. erythema, edema. It is a cell-mediated immunological response that produces contact dermatitis on coverage to light e.g. sulfonamides, griseofulvin, etc.
It is the opposite of tolerance and there is the appearance of adverse drug reactions at the therapeutic dose level. Following are some examples of intolerance:
- Chloroquine causes vomiting and abdominal pain.
- Few doses of carbamazepine cause ataxia [defective movement/gait].
- Phenobarbitone may cause excitement and mental confusion.
- Single exposure of triflupromazine causes muscular dystonia.
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