adverse drugs reactions & drug-drug interaction (ADRs & DDIs)

Question 1

define adverse drug event

Answer 1

preventable or unpredicted medication event with harm to the patient

Question 2

how are adverse drug reactions classified

Answer 2

onset, severity, type

Question 3

3 classifications of onset of adverse drug reactions

Answer 3

acute: within 1 hour (e.g. anaphylaxis); sub-acute: 1-24 hours; latent: over 2 days

Question 4

3 classifications of severity of adverse drug reactions

Answer 4

mild: requires no change in therapy; moderate: requires change in therapy, additional treatment, hospitalisation; severe: disabling or life-threatening

Question 5

6 possible features of a severe adverse drug reaction

Answer 5

results in death, life-threatening, requires/prolongs hospitalisation, causes disability, causes congenital anomalies, requires intervention to prevent permanent injury

Question 6

what is a type A adverse drug reaction (responsible for >2/3 of adverse drug reactions)

Answer 6

extension of pharmacologic effect which is usually predictable and dose dependent

Question 7

3 examples of a type A adverse drug reaction

Answer 7

atenolol and heart block, anticholinergics and dry mouth, NAIDs and peptic ulcers

Question 8

2 types of type A adverse reactions

Answer 8

linear increase in toxicity compared to dose e.g. digoxin; at wide dose range relatively harmless, but beyond certain dose is sharp increase in toxicity (e.g. liver damage) e.g. paracetamol

Question 9

what is a type B adverse drug reaction (rare and unpredictable)

Answer 9

idiosyncratic (happen in some patients but not others) or immunological reaction, including allergy and pseudoallergy

Question 10

2 examples of a type B adverse drug reaction

Answer 10

chloramphenicol and aplastic anaemia (total bone marrow failure), ACE inhibitors and angioedema

Question 11

example of a serious type B adverse drug reaction which is totally unexpected (don’t know enough to predict toxicity)

Answer 11

herceptin for breast cancer which causes cardiac toxicity (routine now is to test pre-clinical drug for cardiac toxicity)

Question 12

what is a type C adverse drug reaction

Answer 12

associated with chronic use, involving dose accumulation

Question 13

2 examples of type C adverse drug reactions

Answer 13

methotrexate and liver fibrosis, antimalarials and ocular toxicity

Question 14

what is a type D adverse drug reaction

Answer 14

delayed effects (sometimes dose independent), including carcinogenecity (e.g. immunosuppressants) and teratogenicity (e.g. thalidomide)

Question 15

3 classes of type E adverse drug reactions (end-of-dose reactions)

Answer 15

withdrawal (lose ability to compensate when drug removed), rebound (stop drug and end up worse than at start), adaptive (non-beneficial)

Question 16

examples of withdrawal type E adverse drug reactions

Answer 16

opiates, benzodiazepines, corticosteroids

Question 17

examples of rebound type E adverse drug reactions

Answer 17

clonidine, B-blockers, corticosteroids

Question 18

examples of adaptive type E adverse drug reactions

Answer 18

neuroleptics (major tranquilisers)

Question 19

clonidine withdrawal as an example of a rebound type E adverse drug reaction

Answer 19

treat for hypertension: after stopping drug (e.g. run out of clonidine), BP increases beyond that which it started (rebound in SNS outflow)

Question 20

ABCDE classification of adverse drug reactions

Answer 20

Augmented pharmacological effect, Bizzare, Chronic, Delayed, End-of-treatment

Question 21

type 1 allergic reaction: features, antibody and examples

Answer 21

immediate, anaphylactic; IgE; anaphylaxis with penicillins

Question 22

type 2 allergic reaction: features, antibodies and examples

Answer 22

cytotoxic antibody; IgG, IgM; methyldopa and haemolytic anaemia

Question 23

type 3 allergic reaction: features, antibody and examples

Answer 23

serum sickness; IgG, IgM; antigen-antibody complex e.g. procainamide-induced lupus

Question 24

type 4 allergic reaction: features, cell and examples

Answer 24

delayed hypersensitivity; T cell; contact dermatitis

Question 25

define pseudoallergies

Answer 25

similar presentation to a true allergy, though due to different causes (pharmacological not immune reaction)

Question 26

2 examples of pseudoallergies

Answer 26

aspirin/NSAIDs causing bronchospasm (don’t give to asthmatics as these prevent dilator prostaglandin production while still producing leukotrienes); ACE inhibitors causing cough/angioedema

Question 27

8 common causes of adverse drug reactions

Answer 27

antibiotics, antineoplastics, anticoagulants, cardiovascular drugs, hypoglycemics, antihypertensives, NSAID/analgesics, CNS drugs

Question 28

frequency of adverse drug reaction compared to number of medications

Answer 28

as number of medications increases, frequency of adverse drug reaction increases

Question 29

2 reports used to detect adverse drug reaction

Answer 29

subjective (patient complaint), objective

Question 30

2 features of objective report used to detect adverse drug reaction

Answer 30

direct observation of event, abnormal findings (physical examination, laboratory test, diagnostic procedure)

Question 31

in drug development, when will adverse drug reactions be detected

Answer 31

if rare, probably not before drug is marketed

Question 32

describe the yellow card scheme

Answer 32

includes blood products, drugs, vaccines and contrast media: for well established drugs, report serious adverse reactions, and for newly licensed (black triangle) drugs, report any suspected adverse reaction

Question 33

what happens following yellow card adverse drug reaction

Answer 33

adverse drug reaction suspected -> adverse drug reaction confirmed -> frequnecy estimated -> prescribers informed

Question 34

difficulties of estimating incidence of drug-drug interactions

Answer 34

data only focuses on adverse drug reactions, difficult in assessing over-the-counter and herbal drug therapy use, difficult to determine contribution of drug interaction in complicated patients

Question 35

importance of drug-drug interactions relating to adverse drug reactions

Answer 35

sometimes drug-drug interactions are prinicpal cause of adverse drug reactions with specific drugs e.g. statins

Question 36

define pharmacodynamic drug interactions

Answer 36

drug effect on body (receptor site occupancy)

Question 37

define pharmacokinetic drug interactions

Answer 37

effect of body on drug (ADME)

Question 38

define pharmaceutical drug interactions

Answer 38

drugs interacting outside body (mostly i.v. infusions)

Question 39

3 pharmacodynamic drug interactions effects from co-administration of 2 or more drugs and examples

Answer 39

additive (drugs have same effect), synergistic (one drug potentiates another drug more than if both administered separately e.g. antibiotics, overlapping toxicities of ethanol and benzodiazepines), antagonistic (anticholinergic medications)

Question 40

4 pharmacokinetic drug interactions

Answer 40

alteration in absorption, protein binding effects, changes in drug metabolism, alteration in elimination

Question 41

chelation as example of alteration in absorption, with examples of drugs

Answer 41

irreversible binding of drugs in GI tract; e.g. tetracyclines or quinolone antibiotics with ferrous sulfate, antacids or dairy products

Question 42

effect of competition between drugs for protein or tissue binding sites

Answer 42

displace other drug from binding protein, increasing free unbound concentration and leading to enhanced pharmacological effect

Question 43

drug example of when protein binding interactions are clinically significant (most are not)

Answer 43

warfarin

Question 44

3 options for drug metabolism and elimination

Answer 44

excreted unchanged by kidney, phase 1 then phsae 2 metabolism in liver then kidney, just phase 2 metabolism in kidney

Question 45

S35

Answer 45

S35

Question 46

3 reactions in phase 1 metabolism

Answer 46

oxidation (most common), reduction, hydrolysis

Question 47

4 reactions in phase 2 metabolism to produce polar water-soluble excretable molecule

Answer 47

conjugation: glucuronidation, sulfation, acetylation

Question 48

most extensively studied system of drug metabolism that is inhibited or enhanced by co-administration of other drugs

Answer 48

CYP 450

Question 49

what can CYP 450 substrates be metabolised by

Answer 49

single isozyme (predominantly) or multiple isozymes (most drugs)

Question 50

what may happen if drug is co-administered with CYP 450 inhibitor

Answer 50

some isozymes may compensate for inhibited isozyme

Question 51

2 most common CYP 450 isozymes metabolising drugs

Answer 51

CYP 3A4, CYP 2D6

Question 52

4 usual CYP 450 inhibitors

Answer 52

cimetidine, erythromycin and related antibiotics, ketoconazole, ciprofloxacin and related antibiotics

Question 53

3 other CYP 450 inhibitors

Answer 53

rotonavir and other HIV drugs, fluoxetine and other SSRIs, grapefruit juice

Question 54

5 usual CYP 450 inducers

Answer 54

rifampicin, carbamazepine, phenobarbitone, phenytoin, St John’s wort (hypericin)

Question 55

speed of CYP 450 inhibition vs induction

Answer 55

inhibition is very rapid, induction takes hours/days

Question 56

major location of drug elimination interactions

Answer 56

renal tubule

Question 57

example of a good drug elimination interaction

Answer 57

probenecid and penicllin

Question 58

example of a bad drug elimination interaction

Answer 58

lithium and thiazides (cause increased excretion of Na+ and retention of lithium to toxic levels)

Question 59

why are some drug interactions deliberate

Answer 59

increase effect (different mechanisms of action but same therapeutic effect)