Lecture 13- ADRs

Adverse Drug Reactions (ADRs)

• Adverse drug reaction (ADR): An unwanted or harmful reaction following medication administration, suspected to be related to the drug.
• Pharmacovigilance: The science and activities related to detecting, assessing, understanding, and preventing ADRs.
• Adverse drug event (ADE): An unwanted medical occurrence during treatment with a medication, but not necessarily caused by the medicine.
• Toxic effect: Adverse effects at high dosages, usually an exaggeration of the desired therapeutic effects.
• Side effect: Dose-related or not, includes both desirable and undesirable effects with different mechanisms from the primary pharmacological action.
• Adverse reaction/effect: All undesired effects, regardless of their mechanism or dosage.

Importance of ADRs

• Reduced adherence to medication regimens.
• Reduced drug efficacy (preventing the use of a fully effective dosage).
• Reduced quality of life.
• Increased morbidity and mortality.
• Reduced drug choices.
• Diagnostic confusion.
• Reduced patient confidence.

Factors Influencing ADRs

• Drug factors: Non-selective, narrow therapeutic window, teratogenic, etc.
• Patient factors: Age, sex, genetics, etc.
• Clinical factors: Duration of treatment, dose adjustments (up- and down-titration), drug interactions, drug choices (especially during pregnancy), and comorbidities.

Classification of ADRs

• Type A (Augmented): Related to the drug's pharmacological action, common, usually not severe, and predictable. Dose-dependent (can be alleviated by dose reduction). Examples: Sedation with barbiturates, bleeding with anticoagulants, bronchoconstriction with propranolol, sedation with diphenhydramine. Can have beneficial side effects (e.g., weight loss in some cases).
• Type B (Bizarre): Not related to the drug's pharmacological action; related to patient susceptibility (e.g., genetic), rare, unpredictable, and may be severe or fatal. Examples: Idiosyncratic reactions (Stevens-Johnson syndrome following lamotrigine or carbamazepine), immunologic reactions (anaphylaxis with penicillin), allergic reactions (mild erythema/rash with penicillin, sulfonamides, and some antiepileptic drugs). Immediately stop the medication and avoid similar medications.

Type C (Chronic Treatment Effects)

• Related to prolonged treatment duration and cumulative dosage.
• Examples: Dyskinesia with levodopa, weight gain and osteoporosis with steroids.

Type D (Delayed Effects)

• Irreversible.
• Examples: Teratogenic (thalidomide) or carcinogenic (azathioprine).

Type E (End of Treatment Effects)

• Withdrawal syndrome, especially when treatment is abruptly stopped.
• Examples: Headache, anxiety, dizziness, sleep disturbances, gastrointestinal disturbances, benzodiazepine withdrawal syndrome, adrenocortical insufficiency after steroid treatment.

Type F (Failure of Therapy)

• Unexpected treatment failure due to drug interactions (pharmacokinetic or pharmacodynamic).
• Examples: Enzyme inducer drugs decrease warfarin effect.

High-Risk Patient Groups

• Elderly
• Neonates
• Renal or hepatic impairment
• Polypharmacy
• Multiple disease states
• Asian origin
• Female
• Atopic

Types of ADRs (Severity)

• Mild: Does not require treatment or hospitalization.
• Moderate: Requires treatment and prolongs hospitalization for at least one day.
• Severe: Potentially life-threatening, permanently disabling, requiring intensive medical care, or results in cancer.

Frequency of ADRs

• Categorization of ADR frequency. (Table presented)

Assessing Causality

• Nature of the reaction
• Timing of the reaction
• Relationship to drug dose
• Other possible causes of the symptoms
• Improvement when the drug(s) is stopped
• Whether the reaction has been reported before

ADR Avoidance

• Up to 70% of ADRs are avoidable.
• Incorrect dosing or administration.
• Obvious interactions
• Use of contraindicated drugs.
• Use in inappropriate clinical indications.

Minimizing ADRs

• Avoid unnecessary drug use.
• Check drug history before prescribing.
• Identify patients with co-existing diseases.
• Avoid drug interactions with drugs and foods.
• Provide patient counseling.
• Identify drugs known to cause dose-related side effects.

Case Study Example (Page 24)

• A 67-year-old woman with a widespread rash (erythema multiforme) resulting from gliclazide.
• The treatment for such reactions is to stop the problematic drug (gliclazide).
• Other medication causes are also considered for the subsequent occurrence of pancreatitis.

Case Study Example (Page 32)

• A patient was administered sitagliptin.
• The possibility of pancreatitis due to sitagliptin.
• The frequency of pancreatitis with sitagliptin is presently unknown.

Case Study Example (Page 30-33)

• The patient developed acute pancreatitis. This is followed by resolution of this reaction when gliclazide was stopped.
• Another drug (sitagliptin) was introduced, leading to readmission for developing pancreatitis.
• The drug most likely causing the acute pancreatitis is sitagliptin.