Adverse Drug Reactions

Question 1

What is an adverse drug event?

Answer 1

Preventable or unpredictable medication event with harm to the patient

Question 2

Describe the classification of ADRs based on onset.

Answer 2

Acute = < 1 hour Sub-acute = 1-24 hours Latent = > 2 days

Question 3

Describe the classification of ADRs based on severity of the reaction.

Answer 3

Mild – requires no change in therapy Moderate – requires change in therapy Severe – disabling or life-threatening

Question 4

Define Type A ADR.

Answer 4

Extension of pharmacological effect This is usually predictable and dose-dependent This is the most common type of ADR – 2/3

Question 5

Define Type B ADR.

Answer 5

‘Bizarre’ type of ADR Idiosynchratic or immunologic reactions includes allergy or pseudoallergy This is very rare and unpredictable

Question 6

Define Type C ADR.

Answer 6

Associated with long-term use Involves drug accumulation

Question 7

Define Type D ADR.

Answer 7

Delayed effects – sometimes dose independent

Question 8

Define Type E ADR.

Answer 8

Withdrawal reactions Rebound reactions Adaptive reactions

Question 9

Describe and explain clonidine rebound.

Answer 9

Clonidine is an alpha-2 agonist so it suppresses the release of noradrenaline Long-term use of clonidine leads to an upregulation in adrenergic receptors on the post-synaptic membrane If the dose of clonidine is missed once or twice, it will cause an increase in noradrenaline release, which then acts on an increased number of receptors so has a greater effect This causes a large increase in blood pressure

Question 10

What is the ABCDE classification of adverse drug reactions?

Answer 10

A – augmented pharmacological action B – bizarre C – chronic D – delayed E – end of treatment

Question 11

Describe the classification of allergies.

Answer 11

Type 1 – immediate, anaphylaxis (IgE) Type 2 – cytotoxic antibody (IgG + IgM) Type 3 – serum sickness (IgG + IgM) Type 4 – delayed hypersensitivity (T cell)

Question 12

Give examples of pseudoallergies.

Answer 12

1. Aspirin/NSAIDs and bronchoconstriction This occurs because aspirin and NSAIDs inhibit the production of prostanoids, which are bronchodilators This promotes the production of leukotrienes, which are bronchoconstrictors 2. ACE inhibitors and cough/angioedema ACE inhibitors prevent the breakdown of kinins Kinins accumulate in the sensory nerves in the lungs and trigger cough

Question 13

What are the most common causes of ADRs

Answer 13

Antineoplastics Cardiovascular drugs NSAIDs/analgesics CNS drugs

Question 14

What is the yellow card scheme?

Answer 14

A voluntary scheme allowing anyone to report serious adverse drug reactions New “black triangle” drugs - report any adverse reactions Older drugs - only report serious adverse reactions

Question 15

Why is it difficult to determine the incidence of drug-drug interactions?

Answer 15

There is a lack of availability of comprehensive databases Difficulty in assessing OTC and herbal drug therapy use Difficulty in determining contribution of drug interaction in complicated patients

Question 16

What are the three types of pharmacodynamic drug interaction?

Answer 16

Additive effects - 2+2 = 4 Synergistic effects - 2+2=5 each is more powerful together than alone Antagonistic effects

Question 17

What are the different types of pharmacokinetic drug interaction?

Answer 17

Alteration in drug absorption Protein binding effects Changes in drug metabolism Alteration in elimination

Question 18

What is an example of alteration of absorption?

Answer 18

Chelation - Irreversible binding of drugs in the GI tract

Question 19

Explain what is meant by protein binding effects.

Answer 19

Competition between drugs for protein or tissue binding sites It can increase free unbound concentration of a drug thus leading to enhanced pharmacological effects (e.g. warfarin)

Question 20

Which cytochrome P450 enzymes are responsible for over half of drug metabolism?

Answer 20

CYP2D6 CYP3A4

Question 21

Give a few examples of CYP450 inhibitors.

Answer 21

• Cimetidine
• Erythromycin and related antibiotics
• Ketoconazole
• Ciprofloxacin and related antibiotics
• Ritonavir and other HIV drugs
• Fluoxetine and other SSRIs
• Grapefruit juice

Question 22

Give a few examples of CYP450 inducers.

Answer 22

• Rifampicin
• Phenytoin
• Carbamazepine
• St. John’s Wort (hypericin)
• Phenobarbitone

Question 23

Describe the difference in the speed of inhibition and the speed of induction of CYP450 enzymes.

Answer 23

Inhibition is RAPID Induction takes hours/days

Question 24

Give an example of a deliberate drug interaction.

Answer 24

ACE inhibitors and thiazides

Question 25

What are the 3 features of ADR classification?

Answer 25

Onset Severity Type

Question 26

Give 3 examples of type A ADRs.

Answer 26

atenolol can slow down heart rate but if you give too much you could cause heart block anticholinergics and dry mouth, NSAIDS and peptic ulcer

Question 27

What is the ADR dose relationship for digoxin and paracetamol?

Answer 27

Type A Digoxin: ADR’s and dose positive linear relationship

Paracetamol: Low ADR to dose linear ratio until the end of the therapeutic window when the ratio shoots up

Question 28

Give 2 examples of type B ADRs

Answer 28

Example: chloramphenicol and aplastic anaemia ACE inhibitors and angioedema Common in cancer treatments

Question 29

Give 2 examples of type C ADRs

Answer 29

methotrexate and liver fibrosis, antimalarials and ocular toxicity

Question 30

Give 2 examples of type D ADRs

Answer 30

carcinogenicity (e.g. immunosuppressants) teratogenicity (e.g. thalidomide)

Question 31

Give 3 examples of type E withdrawal ADRs

Answer 31

Opiates, benzodiazepines, corticosteroids

Question 32

Give 3 examples of type E rebound ADRs

Answer 32

Clonidine, beta-blockers, corticosteroids

Question 33

Give an example of a type E adaptive ADRs

Answer 33

Neuroleptics (major tranquillisers)

Question 34

Give an example of each kind of hypersensitivity reaction

Answer 34

Type I - anaphylaxis with penicillins Type II - methyldopa and hemolytic anemia Type III - procainamide-induced lupus Type IV - contact dermatitis

Question 35

What are the 3 categories of drug interaction

Answer 35

Pharmacodynamic Related to the drug’s effects in the body Pharmacokinetic Related to the body’s effects on the drug Pharmaceutical drugs interacting outside the body

Question 36

What does inhibiting one CYP 450 not always increase the level of the drug it metabolises?

Answer 36

Other CYP 450 isoenzymes “pick up the slack” and metabolise the drug.

Question 37

Give a good and bad example of drug elimination reactions

Answer 37

probenecid and penicillin (good) lithium and thiazides (bad): thiazides increase sodium excretion and retain lithium which is very toxic at high levels.