Pharmacology 14b - Adverse Drug Reactions

Anil Chopra

  1. To appreciate the clinical significance of adverse drug reactions (ADRs)
  2. To understand the ways in which ADRs can be categorised and why this is of practical relevance in prescribing
  3. To understand nature of drug interactions, especially if these lead to important ADRs

Adverse drug reactions are defined as preventable or unpredicted medication events that cause harm to a patient. They cause substantial morbidity and mortality and is around the 4th-6th cause of death among hospitalised patients. It is a great health burden and 60% is preventable.

The onset of an adverse drug reaction can be:

Acute: within 1 hour

Subacute: between 1 and 24hrs

Latent: more than 2 days

The severity of an adverse drug reaction can be:

Mild: requiring no change in therapy

Moderate: requires a change or addition to the therapy. Patients are hospitalised.

Severe: disabling or life threatening. It can prolong hospitalisation, result in congenital abnormalities and requires serious intervention to prevent injury.

The new DoTS scheme is being used to classify adverse drug reactions. This is “Dose, Time, Susceptibility”.

There are 5 different types of adverse drug reaction:

Type A: Augmented Pharmacological Effects

Causes an extension of pharmacological effect

Usually only occurs in an overdose

Responsible for at least two-thirds of ADRs

e.g., atenolol and heart block, anticholinergics and dry mouth, NSAIDS and peptic ulcer

Type B:Bizarre Effects

Idiosyncratic or immunogenic response

Cause immune response

Normally unpredictable

includes allergy and “pseudoallergy”

e.g., chloramphenicol and aplastic anaemia, ACE inhibitors and angioedema

Type C: Chronic Effects

Associated with long-term use

Involves dose accumulation

e.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity

Type D: Delayed Effects

Delayed effects (sometimes dose independent)

Carcinogenicity (e.g. immunosuppressants)

Teratogenicity (e.g. thalidomide)

Type E: End of Treatment Effects

Withdrawal reactions

  • Opiates, benzodiazepines, corticosteroids

Rebound reactions

  • Clonidine, beta-blockers, corticosteroids

“Adaptive” reactions

  • Neuroleptics (major tranquillisers)

There is also a new proposed type F for (Failure of therapy).

Allergic Reactions

There are 4 main types of allergic reaction:

Type I - immediate, anaphylactic (IgE)

  • e.g., anaphylaxis with penicillins

Type II - cytotoxic antibody (IgG, IgM)

  • e.g., methyldopa and haemolyticanaemia

Type III - serum sickness (IgG, IgM)

  • antigen-antibody complex
  • e.g., procainamide-induced lupus

Type IV - delayed hypersensitivity (T cell)

  • e.g., contact dermatitis

A pseudoallergy is a bodily reaction with symptoms similar to that of an allergy but it lacks immunological specificity.

Causes of Adverse Drugs Reactions

•Antibiotics

•Antineoplastics

•Anticoagulants

•Cardiovascular drugs

•Hypoglyceamics

•Antihypertensives

•NSAID/Analgesics

•CNS drugs

Detecting Adverse Drug Reactions

•Subjective report

–patient complaint

•Objective report:

–direct observation of event

–abnormal findings

•physical examination

•laboratory test

•diagnostic procedure

Rare events are usually not detected before the drug is marketed.

Yellow Card Scheme

This is a scheme by which doctors, nurses, coroners and pharmacist can send information about suspected adverse drug reactions to the Committee on Safety of Medicines (part of the Medicines Control Agency).

-if the drug is established then only serious adverse effects are recorded

-if the drug is newly licensed (under 2 years old) then it has a black triangle on it ▼ and ANY adverse effects should be sent in immediately.

If an ADR is susptected, then the frequency is calculated and prescribers are informed as needs be.

Mechanisms of Drug Interaction

Pharmacodynamic Drug Interactions

Pharmacodynamic drug interactions relate to drugs effects on the body.

They can occur due to additive, synergistic or antagonistic effects of 2 drugs for receptor site occupancy. E.g.

-Synergistic actions of antibiotics

-Overlapping toxicities - ethanol & benzodiazepines

-Antagonistic effects - anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)

Pharmacokinetic Drug Interactions

These relate to the body’s effect on the drug e.g.

Alteration in absorption

  • Chelation of toxic metals via irreversible binding in the GI tract.

Protein binding effects

  • Competition between drugs for protein or tissue binding sites
  • Increase in free (unbound) concentration may lead to enhanced pharmacological effect
  • Protein binding interactions are not usually clinically significant but a few are (mostly with warfarin)

Changes in drug metabolism

  • Drug metabolism can be inhibited or enhanced by other drugs.
  • Interaction with CYP 450 (primary metabolism) isoenzymes
  • Most drugs are metabolised by a number of different isoenzymes.
  • Secondary metabolism i.e. Glucuronidation, sulphation & acetylation can also be affected.
  • Inhibitors of CYP 450 include
  • Cimetidine
  • Erythromycin and related antibiotics
  • Ketoconazole etc
  • Ciprofloxacin and related antibiotics
  • Ritonavir and other HIV drugs
  • Fluoxetine and other SSRIs
  • Grapefruit juice
  • Inducers of CYP 450 include
  • Rifampicin
  • Carbamazepine
  • Phenobarbitone
  • Phenytoin

Alteration in elimination

  • These generally affect the renal tubule e.g. lithium and thiazides

Deliberate interactions:

  • Levodopa and carbidopa
  • ACE inhibitors and thiazides
  • Penicillins and gentamicin
  • Salbutamol and ipratropium