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Introduction of adverse effects

Adverse effects are defined as any undesirable or unintended effect due to drug administration. It is a broad term and includes all kinds of noxious effects such as trivial, serious, or even fatal.

Adverse drug reaction (ADR): According to WHO,  Adverse drug reaction can be defined as “any response which is noxious, unintended and which occurs at doses normally used in humans for prophylaxis, diagnosis or therapy of disease conditions, or for modification of physiological function”.

Adverse effects may develop promptly or only after prolonged medication or even after the stoppage of the drug. Adverse effects have been classified in many ways. One may divide them into:

1) Predictable (Type A or Augmented) reactions.

2) Unpredictable (Type B or Bizarre) reactions.

3) Severity of adverse drug reactions.

Adverse drug event: Any untoward medical occurrence that may present during treatment with medicine, but which does not necessarily have a causal relationship with the treatment.

Pharmacovigilance: Pharmacovigilance has been explained by the WHO (2002) as the “science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problems”. Activities involved in Pharmacovigilance are:

  • ADR monitoring
  • Dissemination of ADR data
  • Changes in the labeling of medicines

Prevention of adverse effects to drugs:

  1. Avoid all inappropriate use of drugs in the context of the patient’s clinical condition.
  2. Use appropriate dose, route, & frequency of drug administration which are based on patient’s specific variables.
  3. Elicit and take into consideration the previous or preceding history of drug reactions.
  4. Elicit history of allergic diseases and exercise caution
  5. Rule out the possibility of drug interactions when more than one drug is prescribed.
  6. Adopt correct drug administration technique (e.g. intravenous injection of vancomycin must be slow).
  7. Carry out appropriate laboratory monitoring (e.g. prothrombin time with warfarin, and serum drug levels with lithium).

Classification Of Adverse Effects:

  1. Type A (augmented ) reaction
  2. Type B (bizarre ) reactions
  3. Type C (chronic)reaction
  4. Type D(delayed) reaction
  5. Type E (end) reaction
  6. Type F (failure)
  7. Type G (genotoxicity)
  8. Type H(hypersensitivity)
  9. Type U(unclassified)

Type A (augmented ) reaction/Predictable reactions:

These are predictable reactions to a drug that are related to its pharmacological actions. It is a dose-dependent reaction. The incidence of mortality may be high or low depends on the dose. They include such as side effects, secondary effects, and toxic effects. The treatment method is dose reduction is required.

e.g. Warfarin that causes bleeding, hypoglycemia caused by anti-hyperglycemic drugs such as sulfonylureas.

Type B (bizarre ) reactions:

These are non-dose related to unpredictable reactions to drugs. They are not related or associated with the pharmacological actions of the drug. Allergic reactions and idiosyncrasy are unpredictable reactions. The incidence of mortality is low or high. Treatment is drug discontinuation.

e.g. allergic reactions caused by penicillins.

Type C reaction (Chronic effects):

Chronic effects of the reaction i.e prolonged when the use of drugs. e.g. peptic ulcer caused by chronic use of NSAIDs

Type D reaction:

It is a delayed type of reaction. E.g. teratogenicity caused by thalidomide.

Type E reaction:

It is an end of treatment effects. E.g. withdrawal response to morphine.

Type F reaction: It is a failure of treatment.

Type G reaction: It is also called genotoxicity.

Type H reaction: It is also called hypersensitivity.

Type U reaction: It is also called unclassified.

 

The severity of adverse drug reactions:

Minor adverse drug reaction:

  • There is no therapy, the antidote for the reaction or prolongation of hospitalization is required.

Moderate adverse drug reaction:

  • Requires a change in drug therapy, specific treatment, or prolongs hospital stay by at least one day.

Severe adverse drug reaction:

  • Potentially life-threatening conditions cause permanent damage or require intensive medical treatment.

Lethal adverse drug reaction:

  • Directly or indirectly contributes o role to the death of the patient.

 

Adverse effects may be categorized into:

  • Side effects
  • Secondary effects
  • Toxic effects
  • Intolerance
  • Idiosyncrasy
  • Drug allergy
  • Photosensitivity
  • Drug dependence
  • Drug withdrawal reactions
  • Teratogenicity
  • Mutagenicity & carcinogenicity
  • Drug-induced diseases

 

Side effects:

The side effects are unwanted but often unavoidable pharmacodynamic effects that occur at therapeutic doses. Usually, they are not serious conditions, can be predicted from the pharmacological profile of a drug, & are known to occur in a given percentage of drug recipients. Reduction in dose usually ameliorates the symptoms.

Example;

  • Atropine is used in pre-anesthetic medication for its antisecretory action and the side effect is dryness of the mouth.
  • Glyceryl trinitrate(GTN) relieves angina pectoris by dilating peripheral vasculatur which is also responsible for postural hypotension and a throbbing headache.

Secondary effects:

The indirect consequences of a primary action of the drug.

For example;

  • Superinfection in patients treated with antimicrobials.
  • Diuretic-induced hypokalemia causing digoxin toxicity.
  • Latent tuberculosis activation in corticosteroid receiving patient.

Toxic effects:

The toxic effects are the result of the excessive or desirable pharmacological action of the drug due to overdosage or prolonged use. Overdosage may be absolute (such as accidental, homicidal, suicidal conditions) or relative (i.e. usual dose of gentamicin antibiotics in presence of renal failure).

Example,

  • Hepatic necrosis from paracetamol overdose.
  • High dose of atropine causing delirium.
  • Morphine overdose causing respiratory failure.
  • Prolonged use of streptomycin (antitubercular) causing vestibular damage.
  • Imipramine (antidepressant) overdose causes cardiac arrhythmia.

 

Poisoning:

It implies the harmful effects of a chemical on a biological system. It may result from large or huge doses of drugs due to the fact that “it is the dose which distinguishes a drug from a poisonous substance”.

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

 

General detoxification and supportive measures are:

  • Resuscitation and maintenance of vital functions:
    • Ensure patent airway, adequate ventilation, give artificial respiration/ 100% oxygen inhalation as needed.
    • Maintain blood pressure and heartbeat by fluid and crystalloid infusion, pressor agents, cardiac stimulants, pacing, defibrillation, etc. as needed.
    • Maintain body temperature.
    • Maintain blood sugar level by infusion of dextrose, especially in patients with altered sensorium.
  • Termination of exposure (decontamination):
    • By removing the patient to fresh air for inhaled poisons, washing your skin and eyes (for poisons entering from the surface), induction of emesis with syrup ipecac or gastric lavage (for ingested poisons).
  • Prevention of absorption of ingested poisons:
    • A suspension of 20–40 g (1g/kg) of activated charcoal, which has a large surface area and can adsorb different chemicals, should be administered in 200 ml of water.
  • Hastening elimination:
    • Inducing diuresis (by furosemide, mannitol drugs) or altering urinary pH (alkalinization for acidic drugs such as barbiturates, aspirin). Haemodialysis and haemoperfusion may be done.

 

Intolerance:

The appearance of characteristic features of toxic effects of a drug in an individual at therapeutic doses. It is the converse or inverse of tolerance & indicates a low threshold of the individual to the action of a drug.

For example;

  • One tablet of chloroquine -vomiting and abdominal pain ( occasionally inpatient).
  • Only a few doses of carbamazepine in some people may cause ataxia
  • A single dose of triflupromazine drug induces muscular dystonias in some individuals people, especially children.

Idiosyncrasy:

It is genetically determined or identified abnormal reactivity to a chemical. The drug interacts with some unique features of the individual, not found in the majority of subjects, and produces an uncharacteristic reaction.

For example;

  • Barbiturates cause excitement and mental confusion
  • Quinine agent causes cramps, diarrhea, purpura, asthma, and vascular collapse.
  • Chloramphenicol: non-dose-related serious aplastic anemia (in rare individuals). 

 

Drug allergy:

It is an immunologically mediated or arbitrate reaction producing stereotype symptoms that are unrelated to the pharmacodynamic profile of the drug. Generally, occur even with much narrower doses and have a different time course of onset and duration. It is also called drug hypersensitivity but does not refer to increased response which is called supersensitivity. Types of drug hypersensitivity:

  • Type-I reactions
  • Type-II reactions
  • Type-III reactions
  • Type-IV reactions

Those associated with humoral antibodies: Types I, II & III. Those associated with cell-mediated immunity: Type IV(delayed hypersensitivity).

Type I hypersensitivity (Immediate type, anaphylactic) reactions:

It is a rapidly occurring reaction, hence known as an immediate hypersensitivity reaction. The manifestations such as itching, urticaria, hay fever, asthma, or even anaphylactic shock. Anaphylactic shock is a medical emergency condition and should be treated promptly or immediately with

  1. Injection adrenaline (1:1000) 0.3-0.5 mL intramuscularly.
  2. Inj. Hydrocortisone 100-200 mg intravenously.
  3. Inj. Pheniramine 45 mg IM/IV. 4)Intravenous fluids.
Adverse effects

Type II Hypersensitivity(Cytotoxic) reactions:

The antibodies such as Ig G and Ig M react with cell-bound antigens in the body & which causes the activation of complement, which destroys the cells.

Some examples are;

  • Blood transfusion reactions, Hemolytic anemias produced by quinine, quinidine, cephalosporins, etc.
Adverse Effects

 

Type III hypersensitivity  (Arthus, serum sickness) reactions:

In this reaction, Mainly Ig G antibodies involved. Some examples are Serum sickness (fever, urticaria, joint pain, lymphadenopathy) with penicillins and sulphonamides; acute interstitial nephritis with non-steroidal anti-inflammatory drugs (NSAIDs), and Stevens-Johnson syndrome with sulphonamides.

Adverse Effects

 

Type IV hypersensitivity/ Cell-mediated or delayed ) Reactions:

It is mediated by sensitized T lymphocytes. Re-exposure to the antigen leads to a local inflammatory response. The manifestations generally occur 1-2 days after exposure to the sensitizing antigen, e.g. Contact dermatitis due to local anesthetic creams, topical antibiotics drugs, and antifungal agents.

 

Management of the drug hypersensitivity:

  • Stop the offending drug immediately.
  • Antihistamines , glucocorticoids administration.
  • In case of anaphylactic shock.
  • Measures for resuscitation:
    • The positioning of the patient: reclined position, oxygen, CPR if required.
    • Adrenaline: 0.5mg IM(1:1000) repeat q 5-10min if required, if IV required to dilute 1:10000 or 1:100000 and to be injected slowly.
    • Glucocorticoids are intravenous for severe/recurrent cases.

 

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