W7 32 systemic adverse drug reactions

Question 1

Are drugs safe?

Answer 1

Have to weigh up the harm vs the benefit

Question 2

Why might there be variation in drug responses - pharmacokinetics?

Answer 2

Individual factors - age, gender, ethnic background, weight, diseases, family history, genome, circadian rhythm, epigenome, microbiome, placebo effect.
Environment - nutrition, drug-drug interactions, chemical exposures, lifestyle, circadian rhythm, epigenome, compliance

Question 3

What is an adverse drug reaction?

Answer 3

‘Any response to a drug that is noxious and unintended and that occurs at doses used in man for prophylaxis, diagnosis or therapy’

Question 4

What is an adverse event?

Answer 4

‘An adverse event is any abnormal sign, symptom, lab test, syndromes combination of such abnormalities, untoward or unplanned occurrence (eg an accident or unplanned pregnancy), or any unexpected deterioration in a concurrent illness’

Question 5

What are the different types of adverse effects and give an example for each?

Answer 5

1. Adverse events that are not reactions to medicines, eg fainting at the sight of a needle prior to immunisation
2. ADRs (not from errors), eg developing idiosyncratic skin reaction to antibiotic
3. ADRs from medication errors, eg anaphylaxis to penicillin in known hypersensitivity
4. Medication errors that cause harm that are not ADRs - a cannula penetrates a blood vessel and a haematoma results
5. Medication errors that don’t cause adverse events, eg omitted dose of chronic medication with no adverse event

Question 6

Are ADRs preventable and common?

Answer 6

They are not uncommon. Nearly 75% could have been prevented.

Question 7

What medications can be given by process of error to produce what adverse outcome?

Answer 7

Penicillin, macrolides - drugs given despite history of allergy or poor documentation of allergy - can result in allergic reaction
Insulin - patient nil by mouth but insulin not adjusted - can cause hypoglycaemia
ACE inhibitors - lack of laboratory monitoring - can cause impaired renal function
Warfarin - lack of therapeutic monitoring - eg haemorrhage, elevated INR

Question 8

Examples of important ADRs

Answer 8

Erythema multiforme, drug-induced lupus, Torsades de Pointes, gingival hyperplasia

Question 9

What are the 7 different ways to classify ADRs?

Answer 9

1. Seriousness
2. Type of drug
3. Labelled or unlabelled
4. Type of reaction (A-F, Rawlings and Grahame-Smith et al)
5. Likelihood (causality)
6. Time course
7. Combine (dose, time course, susceptibility DoTs)

Question 10

What is a serious reaction?

Answer 10

Any reaction which results in or prolongs hospitalisation (42%)
Serious reactions can include those that are:
- fatal
- life threatening
- disabling/incapacitating
- cause congenital abnormalities
- medically significant

Question 11

What is the A,B Rawlings Thompson?

Answer 11

Proposed 2 types of reaction, A as dose related and B as non-dose related

Question 12

What are Type A Rawlins Thompson reactions?

Answer 12

Dose related, common, predictable, related to pharmacology, low mortality
Eg digitoxin toxicity, bradycardia from a beta blocker, or sedation from a hypnotic. On target effect but more of an effected than is wanted, augmented.

Question 13

What are type B Rawlins Thompson reactions?

Answer 13

Not dose related, uncommon, unpredictable, not related to pharmacology, high mortality
Eg penicillin hypersensitivity, malignant hyperthermia, hepatitis
Eg ACE inhibitor induced angioedema: life threatening, rare

Question 14

What is angioedema?

Answer 14

Swelling because of vasodilatation of blood vessels

Question 15

What are type C reactions?

Answer 15

Dose related and time related
Uncommon
Related to cumulative dose
Eg chronic use of corticosteroids can lead to muscle hypertrophy, can lead to Cushing’s syndrome

Question 16

What are type D reactions?

Answer 16

Time related, uncommon
Usually dose related
Occurs some time after the use of the drug
Eg renal cancer with Aristolochia, skin cancer, lymphomas and other cancers following topical pimecrolimus and tacrolimus. Usually affect the motor system eg from schizophrenic drugs
Oxytetracycline - pleasing to young palate but can cause dental dysplasia and colour changes

Question 17

What are type E reactions?

Answer 17

End of use
Withdrawal reactions, uncommon, occur soon after withdrawal
Eg myocardial infarction after beta blocker withdrawal, BZD withdrawal

Question 18

What are type F reactions?

Answer 18

Failure
Common, dose related
Often caused by drug reactions
Eg oral contraceptives

Question 19

How might myocardial infarction occur after beta blocker withdrawal?

Answer 19

(Beta blockers slow the heart rate down)
Using beta blockers for a long time means there is probably some receptor downregulation of the beta receptors, tolerance. When taking away beta blockers, there’s fewer receptors but the endogenous adrenaline in the body causes a reflex tachycardia that sometimes causes MI.

Question 20

What are the important factors in ADRs - DoTS?

Answer 20

Dose, time, susceptibility

Question 21

When can the ADR occur in relation to dose?

Answer 21

Can occur at:
Doses below therapeutic dose - eg anaphylaxis with penicillin
In the therapeutic dose range - eg nausea with morphine
At high doses - eg liver failure with paracetamol

Question 22

How is dose considered in ADRs?

Answer 22

All effects can be considered - toxic effects, collateral effects, hypersusceptibility

Question 23

Describe the dose-response curve (PG337 CURVE)

Answer 23

As dose increases, therapeutic response changes from: hypersusceptibility, collateral effects, toxic effects

Question 24

What are hypersusceptible, collateral and toxic effects?

Answer 24

Hypersusceptible - low doses will make someone very ill
Collateral effects - normal side effects - occur in the normal dose that we use to produce the intended effect
Toxic effects - occur in too high doses and will produce too high toxic metabolites and negative effects

Question 25

How can the time course affect and characterise ADRs?

Answer 25

With the first dose
Early, or after a time, or with long-term treatment
On stopping treatment (withdrawal)
Delayed

Question 26

How does susceptibility differ with ADRs?

Answer 26

Not everyone is at equal risk

Question 27

How can susceptibility of patients be defined, give examples?

Answer 27

Genetics - haemolysis with chloroquine in G6PD deficiency
Age - parkinsonism with prochlorperazine in the elderly
Sex - ACE inhibitor induced cough in women
Physiological state - phenytoin in pregnancy
Exogenous drugs or foods - warfarin cranberry juice and increased INR
Disease - gentamicin and deafness in renal failure

Question 28

What are the simplified questions for if an ADR occurs definitely due to a drug? (Actual questions read pg338)

Answer 28

Challenge - did side effect happen at or after treatment started
De-challenge - stopped when treatment stopped?
Re-challenge - began again on re-starting/re-exposure of drug
No alternative causes for the reaction (ie the drug not the disease)

Question 29

What symptom should you ask men about?

Answer 29

Ask men about ED

Question 30

How do you treat ADRs?

Answer 30

STOP the suscept drug(s) or
PAUSE the suspect drug(s) or
REDUCE the suspect drug(s) ? - consider why drug therapy is prescribed, and whether alternative treatment is available
+ TREAT the symptoms

Question 31

What is the yellow card scheme/pharmacovigilance?

Answer 31

Process of identifying and then responding to, safety issues about marketed drugs, i.e., reporting side effects or drugs

Question 32

What runs the yellow card scheme?

Answer 32

MHRA and CHM

Question 33

What are black triangle drugs?

Answer 33

Means ‘intensive monitoring’
Contains a new active substance, is a biological medicine with new indications, has conditional approval, company been asked for more data