Adverse drug reactions

Question 1

What is an adverse drug reaction?

Answer 1

Preventable or unpredicted medication event, with harm to patient.

Question 2

How are adverse drug reactions classified?

Answer 2

Onset
Severity
Type

Question 3

How can the onset of an adverse drug reaction vary?

Answer 3

Acute- within 1 hour
Subacute- 1 to 24 hours
Latent- >2 days

Question 4

How can the severity of an adverse drug reaction vary?

Answer 4

Mild- requires no change in therapy
Moderate- requires change in therapy, additional treatment, hospitalisation
Severe- disabling or life-threatening

Question 5

What may be the results of a severe adverse drug reaction?

Answer 5

Results in death
Life-threatening
Requires or prolongs hospitalisation
Causes disability
Causes congenital anomalies
Requires intervention to prevent permanent injury

Question 6

What is a type A classified adverse drug reaction?

Answer 6

Extension of pharmacologic effect.

Usually predictable and dose dependent.

Question 7

What proportion of adverse drug reactions are classified as type A?

Answer 7

At least ⅔.

Question 8

Give 3 examples of type A classified adverse drug reactions.

Answer 8

Atenolol and heart block.
Anticholinergics and dry mouth.
NSAIDs and peptic ulcer.

Question 9

What is a type B classified adverse drug reaction?

Answer 9

Idiosyncratic or immunologic reaction.
Includes allergy and ‘pseudoallergy’.
Rare (even very rare) and unpredictable.

Question 10

Give 2 examples of type B classified adverse drug reactions.

Answer 10

Chloramphenicol and aplastic anaemia.

ACE inhibitors and angioedema.

Question 11

What is a type C classified adverse drug reaction?

Answer 11

Associated with long-term use.

Involves dose accumulation.

Question 12

Give 2 examples of type C classified adverse drug reactions.

Answer 12

Methotrexate and liver fibrosis.

Antimalarials and ocular toxicity.

Question 13

What is a type D classified adverse drug reaction?

Answer 13

Delayed effects (sometimes dose independent).
Carcinogenicity (e.g. immunosuppressants).
Teratogenicity (e.g. thalidomide).

Question 14

What is a type E classified adverse drug reaction?

Answer 14

Withdrawal reactions, e.g. opiates, benzodiazepines, corticosteroids.
Rebound reactions, e.g. clonidine, beta-blockers, corticosteroids.
‘Adaptive’ reactions, e.g. neuroleptics (major tranquilisers).

Question 15

What is the ABCDE classification of adverse drug reactions?

Answer 15

A: augmented pharmacological effect
B: bizarre
C: chronic
D: delayed
E: end of treatment

Question 16

How are allergies classified?

Answer 16

Type I: immediate, anaphylactic (IgE), e.g. anaphylaxis with penicillins.
Type II: cytotoxic antibody (IgG, IgM), e.g. methyldopa and haemolytic anaemia.
Type III: serum sickness (IgG, IgM), antigen-antibody complex, e.g. procainamide-induced lupus.
Type IV: delayed hypersensitivity (T cell), e.g. contact dermatitis.

Question 17

Give examples of pseudoallergies.

Answer 17

Aspirin/NSAIDs- bronchospasm.

ACE inhibitors- cough/angioedema.

Question 18

What are the common causes of adverse drug reactions?

Answer 18

Antibiotics
Antineoplastics
Anticoagulants
Cardiovascular drugs
Hypoglycaemics
Antihypertensives
NSAID/analgesics
CNS drugs

Question 19

How are adverse drug reactions detected?

Answer 19

Subjective report- patient complaint.
Objective report through direct observation of event, e.g. abnormal findings, physical examination, laboratory test, or through a diagnostic procedure.
Rare events will probably not be detected before drug is marketed.

Question 20

What is the ‘yellow card’ scheme?

Answer 20

Entirely voluntary.
Includes blood products, vaccines, contrast media.
Adverse drug reaction suspected, confirmed (high probability), frequency estimated and prescribers informed.

Question 21

Who can the ‘yellow card’ scheme be used by?

Answer 21

Can be used by doctors, dentists, nurses, coroners and pharmacists, and members of the public.

Question 22

How is the ‘yellow card’ scheme used for established drugs?

Answer 22

Only report serious adverse reactions (fatal, life-threatening, needing hospital admission, disabling).

Question 23

How is the ‘yellow card’ scheme used for ‘black triangle’ drugs (newly licensed, usually <2 years)?

Answer 23

Report any suspected adverse reaction.

Question 24

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

Answer 24

Data for drug-related hospital admissions do not separate out drug interactions, focus on ADRs.
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.
Sometimes principal cause of ADRs with specific drugs, e.g. statins.

Question 25

What is a pharmacodynamic drug interaction?

Answer 25

Related to the drug’s effects in the body. Receptor site occupancy. Additive, synergistic, or antagonistic effects from co-administration of 2 or more drugs. Synergistic actions of antibiotics. Overlapping toxicities- ethanol and benzodiazepines. Antagonistic effects- anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors).

Question 26

What is a pharmacokinetic drug interaction?

Answer 26

``` Related to the body’s effects on the drug. Alteration in absorption. Protein binding effects (distribution). Changes in drug metabolism. Alteration in elimination. ```

Question 27

What is a pharmaceutical drug interaction?

Answer 27

Drugs interacting outside the body (mostly i.v. infusions).

Question 28

What is chelation?

Answer 28

Irreversible binding of drugs in the GI tract. Alters absorption of a drug. Tetracyclines, quinolone antibiotics- ferrous sulfate (Fe2+), antacids (Al3+, Ca2+, Mg2+), dairy products (Ca2+).

Question 29

What are protein binding interactions?

Answer 29

Competition between drugs for protein or tissue binding sites. Increase in free (unbound) concentration may lead to enhanced pharmacological effect. Many interactions previously thought to be protein binding interactions were found to be primarily metabolism interactions. Protein binding interactions are not usually clinically significant but a few are (mostly with warfarin).

Question 30

What are the reactions of phase I metabolism?

Answer 30

Oxidation Reduction Hydrolysis

Question 31

What are the types of reactions in phase II metabolism?

Answer 31

Conjugation Glucuronidation Sulfation Acetylation

Question 32

List CYP450 inhibitors.

Answer 32

``` Cimetidine Erythromycin and related antibiotics Ketoconazole, etc. Ciprofloxacin and related antibiotics Ritonavir and other HIV drugs Fluoxetine and other SSRIs Grapefruit juice ```

Question 33

List CYP450 inducers.

Answer 33

``` Rifampicin Carbamazepine (Phenobarbitone) (Phenytoin) St John’s wort (hypericin) ```

Question 34

List drugs that are deliberately given together to react with each other.

Answer 34

Levodopa + carbidopa ACE inhibitors + thiazides Penicillins + gentamicin Salbutamol + ipratropium

Question 35

How may drugs be excreted from the body?

Answer 35

Excreted unchanged by kidney. Phase I reaction, then excreted by the liver or more often the kidney. Phase I reaction, then phase II reaction, then excreted by the kidney. Phase II reaction, then excreted by the kidney.

Question 36

Which CYP450 isozymes account for the largest proportion of drug metabolism?

Answer 36

CYP3A4 (36%) | CYP2D6 (19%)

Question 37

Where do drug elimination reactions usually occur? Give examples.

Answer 37

Almost always in renal tubule. Probenecid and penicillin (good)- probenecid reduces elimination of penicillin. Lithium and thiazides (bad)- thiazides reduce clearance of lithium so toxicity is more likely to occur.