CPTP 3.8 Adverse Drug Reactions

Question 1

Why do adverse effects of drugs occur?

Answer 1

Can be any of:
• Non-specifity of drug, or metabolite of drug
• Exaggerated pharmaceutical effects when concentration too high at target
• Therapeutic target hit, but in wrong tissue (gastroenteritis can be treated by antimuscarinics, which also cause dry mouth)

Question 2

What is assessed when prescribing a drug, with regard to its adverse effects? How is this maximised?

Answer 2

The risk to benefit ratio

• Choose the appropriate class of drug, and then the right individual agent
• Choose the right dose for the patient
• Optimise duration of treatment

Question 3

What is the difference between an adverse drug reaction and a side effect?

Answer 3

Side effects can include unexpected benefits of a treatment (e.g. hypnotic effects of antidepressants helping sleep)

An adverse drug reaction is harmful or unpleasant and warrants:
• Treatment
• Alteration of dosage
• Withdrawal of the product
An adverse drug reaction can also occur with the product the drug is contained within, not just the drug itself

Question 4

What is an adverse drug event?

Answer 4

An adverse outcome (e.g. falling) that occurs after the use of a drug, but may or may not be linked to the use of that drug

Question 5

How are adverse drug events assessed for causal links?

Answer 5

Prescription event monitoring - observational cohort study where prescribers report all of the adverse events, and this information is gathered to find associations

Question 6

What are the severities of ADRs?

Answer 6

Mild
  •  No change in therapy necessary
Moderate
  •  Requires changes in therapy
Severe
  •  Life threatening or disabling requiring hospitalisation

Question 7

What is angioedema?

Answer 7

Swelling of dermis, epidermis, mucosal and submucosal tissues, usually occurring at site of contact (e.g. lips)

Question 8

At which phase of clinical trials are adverse drug reactions usually detected? Why?

Answer 8

Phase 4 -pharmacovigilance (after drug goes to market)

They are not seen during clinical trials because:
• Stages 1-3 don’t have the statistical power to detect ADRs (e.g. adverse effects could happen in only 1 in 5000 people)
• May not last long enough for them to manifest
• Trials only use uncomplicated patients so drug interactions may be less likely to be encountered

Question 9

What type of ADRs are detected before the drug goes to market?

Answer 9

Pharmacologically predictable and short time onsets –> detection in phases 1-3

Question 10

What frequency of hospital admissions are due to adverse drug reactions?

Answer 10

6.5% (costing £2bn)

Question 11

What effects can ADRs have on patients

Answer 11

• Reduce patient confidence and compliance
  
  • Reduce QoL
  • Create diagnostic confusion

Question 12

What proportion of ADRs are avoidable?

Answer 12

70%

Question 13

How are ADRs minimised in practice?

Answer 13

• Starting with small doses and titrating up
  
  • Reducing interactions by taking good drug histories
  • Avoiding unnecessary drug use
  • Prophylactic therapy for ADRs (e.g. PPIs with aspirin)
  • Be wary of contraindications

Question 14

What are the classification systems of ADRs?

Answer 14

• Rawlins-Thompson classification

Question 15

Outline the Rawlins-Thompson classification system

Answer 15

Type A: Augmented (C)
• A result of the normal pharmacodynamics, but quantitatively exaggerated (e.g. anticholinergic effects of TCAs)

Type B: Bizzare (U)
• Unrelated to the drugs normal pharmacology (e.g. anaphylaxis)

Type C: Chronic (U)
• Dose-related and time-related due to CUMULATIVE dose (e.g. HPA suppression by corticosteroids)

Type D: Delayed (U)
• Time-related (tardive dyskinesia after use of antipsychotics, or carcinogenesis)

Type E: End of use (U)
• Withdrawal syndromes

Type F: Failure (C)
• Unexpected failure of therapy

Question 16

Describe how type A and B of Rawlins-Thompson differ.

Answer 16

Type A
  •  Common (C)
  •  Dose-dependant
  •  Predictable
  •  Low morbidity and mortality
Type B:
  •  Uncommon (U)
  •  Not dose-dependant 
  •  Unpredictable 
  •  High morbidity and mortality

Question 17

What is Stevens-Johnson syndrome and what causes it?

Answer 17

A form of toxic epidermal necrosis (cell death causes epidermis to separate from dermis) where 3-30% of the body is blistered (if it is more, it is called something else)

Can occur as a hypersensitivity allergic reaction ADR to the anti-epileptic therapy lamotrigine, NSAIDs or penicillin

Question 18

What pharmacological errors may cause drug failure?

Answer 18

• Incorrect dose

* Drug interactions

Question 19

What is the alternative to Rawlins-Thompson?

Answer 19

DoTS classification:
• Dose
• Timing
• Susceptibility

Question 20

Describe the ‘Dose’ branch of the DoTS classification

Answer 20

Dose
• ‘Toxic effects’ are when an ADR occurs at higher than the usual dose
• ‘Collateral effects’ occur at standard doses due to different tissues or different mechanisms
• ‘Hypersusceptibility reactions’ are ADRs that occur at sub-therapeutic doses in susceptible people.

Question 21

Describe the ‘Time’ branch of the DoTS classification

Answer 21

Timing
  •  'Time independent reactions' occur at any time during treatment
  •  'Time dependent reactions':
        > 'Rapid Reactions'
        > 'Early Reactions'
        > 'Intermediate Reactions'
        > 'Later Reactions'
        > 'Delayed Reactions'

Question 22

Describe what is meant by:

1) ‘Rapid Reactions’
2) ‘Early Reactions’
3) ‘Intermediate Reactions’
4) ‘Later Reactions’
5) ‘Delayed Reactions’

Answer 22

1) ADR that occurs when drug is administered too rapidly
2) ADR that occurs early in treatment but then abates with continued treatment (e.g. anxiety on antidepressants)
3) Occur after some delay. If it hasn’t occurred after a set time, it wont at all.
4) ADR risk increases with continued exposure, includes withdrawal symptoms (Tardive dyskinesia with antipsychotics)
5) Occur after exposure, even if drug is withdrawn (e.g. carcinogenesis)

Question 23

What is ‘red man syndrome’?

Answer 23

When the antibiotic vancomycin is administered too quickly (Rapid Reaction)

Question 24

Describe the ‘Susceptibility’ branch of the DoTS classification

Answer 24

Raised susceptibility present in some but not others (allergies), or may follow a distribution (e.g. by level of renal function)

Question 25

What is susceptibility affected by? What are the implications of these on how the drug should be used?

Answer 25

Age
• Adjust doses based on age

Gender
• Adjust doses based on gender

Disease (e.g. renal or hepatic)
• Screen for diseases and reduce doses accordingly
• Watch out for contraindications

Exogenous factors (interactions with drugs and food)
  •  Avoid co-administration 

Genetics
• Same as with diseases

Question 26

Which four main drug classes account for the majority of preventable drug related hospital admissions?

Answer 26

In order:
  •  NSAIDs
  •  Antiplatelets 
  •  Anticoagulants 
  •  Diuretics

Question 27

Are the amounts of ADRs increasing or decreasing? Why?

Answer 27

Increasing
• Ageing population
• More polypharmacy
• More OTC, internet or alternative medicines