A Review on Adverse Drug Reaction

Ms. Manisha Dhondising Rajput, Y. B. Rajput, L. D. Rajput

Appasaheb Birnale College of Pharmacy, Sangli.

*Corresponding Author E-mail:

ABSTRACT:

Adverse drug reactions are also known as side effects. Adverse drugs reactions (Adrs), are toxic, unintended, and undesirable impacts which occur as result of drug treatment. These reactions occur due to self-medication or due to intake of over dose of medicines without prescription. The prescribed drugs may produce undesirable effects along with main effect which leads to adverse drug reactions. Most of the adverse drug reactions are preventable. Hence, in order to avoid adverse drug reactions one should take only properly prescribed drugs.

KEYWORDS: Self-medication, Prescribed drugs, bizarre effects, chronic effects.

INTRODUCTION:^(1-5)

Any undesireable effect of a drug beyond its anticipated therapeutic effects occurring during clinical use. It is an expression that describes harm associated with use of given medications at a normal dosage during normal use. It may occur following a single dose or prolonged administration of a drug or result from combination of two or more drugs. The meaning of this expression differ from meaning of side effects as it might also imply that effect can be beneficial.

Medicinal substances are used because of their ability to affect biological processes in the body. Using such substances always carries a certain risk of unwanted or unintended effects. The readiness of the patient and healthcare provider to use a medication depends on the extent of the expected benefit of the remedy, balanced by the risk and seriousness of possible unwanted effects. The patient and their doctors also need to assess this risk in relation to how incapacitating and serious the ailment to be treated is. Accordingly, doctors and health professionals who give advice to patients, need to know as precisely as possible, the frequency and magnitude of the risks involved in medical treatment, as well as the magnitude and duration of the beneficial effects.

Every occasion when a patient is exposed to a new medicinal product is a unique situation, and they can never be certain about what might happen. However, we can learn from previous experience when patients under similar conditions have been exposed to the same or a similar medicine. During the development phase of new medicines, both beneficial and unwanted effects are recorded in clinical trials. In this way, knowledge is accumulated and allows health professionals to make a reasoned prediction of the benefits and risks to all subsequent patients taking the medicine. Observation and recording of treatment outcomes should never stop. By observing the positive as well as negative effects of medicines as they are being routinely used, and by reporting our observations to colleagues and specific monitoring centers, we can contribute to better knowledge and better medical treatment of future patients. This is part of the professional duty of every healthcare professional.

Classification of adverse drug reactions^[2]:

Adverse drug reactions are frequently classified as ‘type A’ and ‘type B’ reactions. An extended version of this classification system is shown here:

· Type A Reactions:

Type A (augmented) reactions result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose and are normally dose-dependent. Examples include respiratory depression with opioids or bleeding with warfarin. Type A reactions also include those that are not directly related to the desired pharmacological action of the drug, for example dry mouth that is associated with tricyclic antidepressants. Commonest (up to 70%) - Dose dependent, severity increases with dose. Preventable in most part by slow introduction of low dosages. Predictable by the pharmacological mechanisms, e.g., hypotension by beta-blockers, hypoglycaemia caused by insulin’s or oral hypoglycemic, or NSAID induced gastric ulcers

· Type B Reactions:

Type B (bizarre) reactions are novel responses that are not expected from the known pharmacological actions of the drug. These are less common, and so may only be discovered for the first time after a drug has already been made available for general use. Examples include anaphylaxis with penicillin or skin rashes with antibiotics. Rare, idiosyncratic, genetically determined, unpredictable, mechanisms are unknown, serious, can be fatal; unrelated to the dose, e.g., hepatitis caused by halothane, aplastic anemia caused by chloramphenicol, neuroleptic malignant syndrome caused by some anesthetics’ and antipsychotics.

· Type C Reactions (continuous drug use):

Type C, or ‘continuing’ reactions, persist for a relatively long time. An example is osteonecrosis of the jaw with bisphosphonates. Occurs as a result of continuous drug use. May be irreversible, unexpected, unpredictable, e.g. tardivedyskinesias by antipsychotics, dementia by anticholinergic medications

· Type D Reactions (Delayed):

Type D, or ‘delayed’ reactions, become apparent sometime after the use of a medicine. The timing of these may make them more difficult to detect. An example is leucopoenia, which can occur up to six weeks after a dose of lomustine. Delayed occurrence of ADRs, even after the cessation of treatment, e.g., corneal opacities after thioridazine, ophthalmopathy after chloroquine, or pulmonary/peritoneal fibrosis by methyserzide.

· Type E Reactions (End of dose):

Type E, or ‘end-of-use’ reactions, are associated with the withdrawal of a medicine. An example is insomnia, anxiety and perceptual disturbances following the withdrawal of benzodiazepines. Withdrawal reactions. Occurs typically with the depressant drugs, e.g., hypertension and restlessness in opiate abstainer, seizures on alcohol or benzodiazepines withdrawal; first dose hypotension caused by alpha-blockers (Prazosin) or ACE inhibitors.

· Type-F (Failure of therapy):

Results from the ineffective treatment (previously excluded from analysis according to WHO definition), e.g., accelerated hypertension because of inefficient control.

Adverse drug effects may be categorized into ^[6-10]:

1. Side effect:

These unwanted but often unavoidable pharmacodynamic effects

That occur at therapeutic doses. Generally, they are not serious, can be predicted from the pharmacological profile of a drug and are knowtooccur in a given percentage of drug recipients. Reduction in dose, usually ameliorates the symptoms.

2. Secondary effects:

These are indirect consequences of a primary action of the drug, e.g. suppression of bacterial flora by tetracycline’s paves the way forsuperinfections; corticosteroids weaken host defense mechanisms so that latent tuberculosis gets activated.

3. Toxic effects:

These are the results of excessive pharmacological action of the drug due to overdosage or prolonged use. Overdosage may be absolute or relative. The manifestations are predictable and dose related. They result from functional alteration or drug induced tissue damage. The CNS, CVS, kidney, liver, lung, skin and blood forming organs are most commonly involved in drug toxicity.

Poisoning – In broad sense, poisoning implies harmful effects of a chemical on a biological system. It may result from large dosage of drugs because ‘it is the dose which distinguishes a drug from a poison’.

Poison is a ‘substance which endangers life by severely affecting one or more vital functions’. Not only drugs but other household and industrial chemicals, insecticides, etc. are frequently involved in poisoning. Specific antidotes such as receptor antagonists, chelating agents or specific antibodies are available for few poisons.

4. Intolerance:

It is the appearance of characteristics toxic effects of a drug in an individualat therapeutic doses. It is a converse of tolerance and indicates a low threshold of the individual to the action of a drug. These are individuals who fall on the extreme left side of the Gaussian Frequency distribution curve for sensitivity to the drug.

5. Idiosyncrasy:

It is genetically determined abnormal reactivity to a chemical. The drugreacts with some unique feature of the individual, not found in majority of subjects, and produces the uncharacteristic reaction. e.g. Barbiturates causes excitement and mental confusion in some individual.

6. Drug allergy:

It is an immunologically medicated reactions producing stereotype Symptoms which are unrelated to the pharmacodynamics profile of the drug, generally occur even with much smaller doses and have a different time course of onset and duration. This is also called drug hypersensitivity; but does not refer to increased response which is called super sensitivity. The target organs primarily affected in drug allergy are skin, airways, blood vessels, blood and gastrointestinal tract.

Drugs frequently causing allergic actions:

Penicillin Salicylates

Cephalosporins Carbamazepine

Sulfonanudes Allopurinol

Tetracyclines ACE inhibitors

Quinolones Methyldopa

Antitubercular drugs Hydralazine

Phenothiazines Local anaesthetics

Skin tests (in trader mal, patch) or intranasal tests may forewarn in case of Type I hypersensitivity, but not in case of other types. However, these teats art not entirely reliable—false positive and false negative results are not rare.

7. Photosensitivity:

It is a cutaneous reaction resulting from drug induced sensitization of the skin to U V radiation. The reactions are of two types:

A. Phototoxic:

Drug or metabolite accumulates in the skin, absorbs light and undergoes a photochemical reaction followed by a photobiological reaction resulting in local tissue damage (sunburn-like), i.e. erythema, edema, blistering followed by hyperpigmentation and desquamation. The shorter wave lengths (290-320 nm, UV-B) are responsible. Drugs involved in acute phototoxic reactions are tetracycline; (especially demeclocycline) and tar products. Drugs causing chronic and low grade sensitization are nalidixic acid, fluoroquinolones, sulfones, sulfonamides, phenothiazines, thiazides, amiodamne. This type d reaction is more common than photoallergic reaction.

B. Photo allergic:

Drug or its metabolite induces a cell mediated immune response which on exposure to list of longer wave lengths (320-400nm, UV-A) produces a papular or eczematous one act dermatitis like picture. Rarely antibodies mediate photoallergy and the reaction takes the Item of immediate flare and wheal on exposure to seen. Dings involved are sulfonamides, sulfonylureas, griseofulvin, chloroquine, chlorpro-mazine.

8. Drug dependence:

Drugs capable of altering mood and feelings are liable to repetitive use to derive euphoria, with-drawal from reality, social adjustment etc. Drug dependence is a state in which use of drugs for personal satisfaction is accorded a higher priority than other bask needs, often in the face of known risks to health. There is a lot of confusion in terminology and definitions; the following may serve to describe different aspects of the problem.

Psychological dependence:

It is said to have developed when the individual believes that optimal state of wellbeing is achieved only through the actions of the drug. It may start as liking for the drug effects and may progress to compulsive drug use in some individuals. The intensity of psychological dependence may vary from desire to craving. Obviously, certain degree of psychological dependence accompanies all patterns of self medication.

Reinforcement is the ability of the drug to produce effects that make the user wish to take it again or to induce drug seeing behaviour. Certain drugs (opioids, cocaine) are strong reinforcers, while others (benzodiazepines) are weak reinforcers. Faster the drug acts. more reinforcing it is.

Physical dependence:

It is an altered physio-logical state produced by repeated administration of a drug which necessitates the continued presence of the drug to maintain physiological equilibrium. Discontinuation of the drug results in a characteristic withdrawal (abstinence) syndrome. Since the essence of the process is adaptation of the nervous system to function normally in the presence of the drug. it has been called 'neuroadaptation’.

Drugs producing physical dependence are—plaids, barbiturates and other depressants including alcohol and benzodiazepines. Stimulant drugs.e.g. amphetamines, cocaine produce little or no physical dependence.

Drug abuse:

Refers to use of a drug by self medication in a manner and amount that dev 'ales from the approved medical and social patterns in a given culture at a given time. The term conveys social disapproval of the manner and purpose of druguse. for regulatory agencies drug abuse refers to any use of an ilicit drug.

Drug addiction:

It is a pattern of compulsive drug use characterized by overwhelming involvement with the use of a drug. Procuring the drug and using it Likes precedence over other activities Even after withdrawal most addicts tend to relapse. Physical dependence, though a strong impetus for continued drug use, is not an essential feature addiction. Amphetamines, cocaine, cannabis, LSD are drugs which produce addiction but little/no physical dependence. On the other hand, drugs like nalorphine produce physical dependence without imparting addiction in the sense that there is little drug seeking behavior.

Drug habituation:

It denotes less intensive involvement with the drug, so that its withdrawal produces only mild discomfort. Consumption of tea, coffee. Tobacco, social drinking are regarded habituating, physical dependence is absent. Basically, habituation and addiction imply different degrees of psychological dependence and it may be difficult to draw a clear cut line of distinction between the two. Therefore, it is better to avoid using these terms in describing drug dependence and related conditions.

9. Drug withdrawal reactions:

Apart from drugs that are usually recognized as producing dependence, sudden interruption of therapy with certain other drugs also results in adverse consequences, mostly in the form of worsening of the clinical condition for which the drug was being used, e.g.

1. Acute adrenal insufficiency may be precipitated by abrupt cessation of corticosteroid therapy.

2. Severe hypertension, restlessness and sympathetic over activity may occur shortly after discontinuing clonidine.

3. Worsening of angina pectoris, precipitation of myocardial infarction may result from stoppage of IS blockers.

4. (iv) Frequency of seizures may increase on sudden withdrawal of an antiepileptic. These manifestations are also due to adaptive changes and can be minimized by gradualwithdrawal.

10. Teratogenicity:

It refers to capacity of a drug to cause fetal abnormalities when administered to the pregnant mother. The placenta does not strictly constitute a bather and any drug can cross it to a greater or lesser extent. The embryo is one of the mint dynamic biological systems and in contrast to adults, drug effects are often irreversible. The thalidomide disaster (1958-61) resulting in thousands of babies born with phocomelia (seal like limbs) and other defects focused attention to this type of adverse effect.

Drugs can affect the fetus at 3 stage:

1. Fertilization and implantation—conception to 17 days—failure of pregnancy which often goes unnoticed.

2. Onzairegmcsis-18 to 55 days of gestation—most vulnerable period, deformities are produced.

3. Growth and development -56 days onwards — developmental and functional abnormalities can occur, e.g. ACE inhibitors can cause hypoplasia of organs, specially lungs and kidneys; NSA1Ds may induce premature daunt of ductusarteriosus.

4. The type of malformation depends on the drug as well as the stage of exposure to the teratogen. Foetal exposure depends on the blood level and duration for which the drug remains in maternal circulation. The teratogenicity potential of a drug is to be considered against the background of con-genital abnormalities occurring spontaneously, which is - 2% of all pregnancies. Majority of implicated drop are low grade teratogens, i.e. increase the incidence of malformations only slightly, which may be very difficult to detect. confirm or refute. Nevertheless, some drugs have been clearly associated with causing foetal abnormalities in human beings. These are listed in the box. However, only few mothers out of those who receive these drugs during the vulnerable period will get a deformed baby, but the exact risk posed by a drug is difficult to estimate.

The US-FDA has graded the documentation of risk for causing birth defects into five categories (see- box).

It is, therefore, wise to avoid all drugs during pregnancy unless compelling reasons exist for their use regardless of the assigned pregnancy category, or presumed safety (also See-Appendix-2).

Frequency of spontaneous as well as drug induced malformations, especially neural tube defects, may be reduced by (Mate therapy during pregnancy.

11. Mutagenicity andCarcinogenicity:

It refers to capacity of a drug to cause genetic defects and cancer respectively. Usually oxidation of the drug result: in the production of reactive intermediates which affect genes and may cause structural changes in the chromosomes. Covalent interaction with DNA can modify it to induce mutations, which may manifest as heritable defects in the next generation. If the modified DNA sequences code for factors that regulate cell proliferation/growth, i.e. are proto-oncogenes, or for proteins that inhibit transcription of proto-oncogenes, a Tumour (cancer) maybe produced. Even without interacting directly with DNA, certain chemicals can promote malignant change in genetically damaged cells, resulting in carcinogenesis. Chemical carcinogenesis generally takes several (10-40) yews to develop. Drugs implicated in these adverse effects are—anticancer drugs. radioisotopes, estrogens, tobacco. Generally.drugs which show mutagenic or carcinogenic potential are not approved for marketing/are withdrawn, unless useful in life-threatening conditions.

12. Drug induced diseases:

These are also called iatrogenic (physician induced) diseases, and are functional disturbances (disease) caused by drugs which persist event the offending drug has been withdrawn and largely eliminated e.g.

· Peptic ulcer by salicylates and corticosteroids.

· Parkinsonism by phenothiazine’s and other antipsychotics.

· Hepatitis by isoniazid.

· DLE by hydralazine.

Detection and Monitoring of ADRs⁽⁹⁾:

Pre-marketing studies the safety of new medicines are rested in animal models. A great deal of risk information may be obtained from such tests, for e.g. the level of acute toxicity, which organs will be affected in case of toxicity and dose dependency of such tissue injuries. Specific animal tests for carcinogenicity, teratogenicity and mutagenicity are also available. However, animals can only serve as approximate models for humans. We do not have sufficient knowledge to extrapolate information collected from animal studies directly into risks in humans. The predictive value of the different animal tests is uncertain in all instances. If animal tests do not reveal particularly worrying results, safety tests proceed onto testing in humans in clinical trial programs.

CONCLUSION:

Monitoring of adverse drug reactions is an ongoing, ceaseless, and continuing process. Though pharmacovigilance is still in its infancy in India, this is likely to expand in the times to come. This is because, as the newer and newer drugs hit the market, the need for pharmacovigilance grows more than ever before. Therefore, monitoring of the adverse effects of newer drugs particularly of serious nature is mandatory. Physicians should report death due to drugs, life-threatening complications, hospitalization (initial or prolonged), and disability if significant, persistent, or permanent, congenital anomalies, a reaction which requires medical intervention to prevent damage, such as the administration of N-acetyl cysteine following acetaminophen overdose. It is important to remember that most adverse drug reactions would subside once the offending agent is discontinued or dosage reduced; however, many result in permanent damage. The need is to spread awareness about using minimal doses of the drugs, at least in the beginning of the treatment.

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Received on 03.03.2020 Modified on 29.03.2020

Asian J. Pharm. Res. 2020; 10(3):221-225.

DOI: 10.5958/2231-5691.2020.00038.6