adverse drugs reactions & drug-drug interaction (ADRs & DDIs) Flashcards
adverse drug reactions: classify the different types of ADRs, explain how genetic differences influence individual response to drugs, and explain how factors such as polypharmacy, age, diet and renal function can effect drug reactions; enzyme inducers and inhibitors: list the drugs that are known to be enzyme inducers and inhibitors and explain how they may cause ADRs
define adverse drug event
preventable or unpredicted medication event with harm to the patient
how are adverse drug reactions classified
onset, severity, type
3 classifications of onset of adverse drug reactions
acute: within 1 hour (e.g. anaphylaxis); sub-acute: 1-24 hours; latent: over 2 days
3 classifications of severity of adverse drug reactions
mild: requires no change in therapy; moderate: requires change in therapy, additional treatment, hospitalisation; severe: disabling or life-threatening
6 possible features of a severe adverse drug reaction
results in death, life-threatening, requires/prolongs hospitalisation, causes disability, causes congenital anomalies, requires intervention to prevent permanent injury
what is a type A adverse drug reaction (responsible for >2/3 of adverse drug reactions)
extension of pharmacologic effect which is usually predictable and dose dependent
3 examples of a type A adverse drug reaction
atenolol and heart block, anticholinergics and dry mouth, NAIDs and peptic ulcers
2 types of type A adverse reactions
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
what is a type B adverse drug reaction (rare and unpredictable)
idiosyncratic (happen in some patients but not others) or immunological reaction, including allergy and pseudoallergy
2 examples of a type B adverse drug reaction
chloramphenicol and aplastic anaemia (total bone marrow failure), ACE inhibitors and angioedema
example of a serious type B adverse drug reaction which is totally unexpected (don’t know enough to predict toxicity)
herceptin for breast cancer which causes cardiac toxicity (routine now is to test pre-clinical drug for cardiac toxicity)
what is a type C adverse drug reaction
associated with chronic use, involving dose accumulation
2 examples of type C adverse drug reactions
methotrexate and liver fibrosis, antimalarials and ocular toxicity
what is a type D adverse drug reaction
delayed effects (sometimes dose independent), including carcinogenecity (e.g. immunosuppressants) and teratogenicity (e.g. thalidomide)
3 classes of type E adverse drug reactions (end-of-dose reactions)
withdrawal (lose ability to compensate when drug removed), rebound (stop drug and end up worse than at start), adaptive (non-beneficial)
examples of withdrawal type E adverse drug reactions
opiates, benzodiazepines, corticosteroids
examples of rebound type E adverse drug reactions
clonidine, B-blockers, corticosteroids
examples of adaptive type E adverse drug reactions
neuroleptics (major tranquilisers)
clonidine withdrawal as an example of a rebound type E adverse drug reaction
treat for hypertension: after stopping drug (e.g. run out of clonidine), BP increases beyond that which it started (rebound in SNS outflow)
ABCDE classification of adverse drug reactions
Augmented pharmacological effect, Bizzare, Chronic, Delayed, End-of-treatment
type 1 allergic reaction: features, antibody and examples
immediate, anaphylactic; IgE; anaphylaxis with penicillins
type 2 allergic reaction: features, antibodies and examples
cytotoxic antibody; IgG, IgM; methyldopa and haemolytic anaemia
type 3 allergic reaction: features, antibody and examples
serum sickness; IgG, IgM; antigen-antibody complex e.g. procainamide-induced lupus
type 4 allergic reaction: features, cell and examples
delayed hypersensitivity; T cell; contact dermatitis
define pseudoallergies
similar presentation to a true allergy, though due to different causes (pharmacological not immune reaction)
2 examples of pseudoallergies
aspirin/NSAIDs causing bronchospasm (don’t give to asthmatics as these prevent dilator prostaglandin production while still producing leukotrienes); ACE inhibitors causing cough/angioedema
8 common causes of adverse drug reactions
antibiotics, antineoplastics, anticoagulants, cardiovascular drugs, hypoglycemics, antihypertensives, NSAID/analgesics, CNS drugs
frequency of adverse drug reaction compared to number of medications
as number of medications increases, frequency of adverse drug reaction increases
2 reports used to detect adverse drug reaction
subjective (patient complaint), objective
2 features of objective report used to detect adverse drug reaction
direct observation of event, abnormal findings (physical examination, laboratory test, diagnostic procedure)
in drug development, when will adverse drug reactions be detected
if rare, probably not before drug is marketed
describe the yellow card scheme
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
what happens following yellow card adverse drug reaction
adverse drug reaction suspected -> adverse drug reaction confirmed -> frequnecy estimated -> prescribers informed
difficulties of estimating incidence of drug-drug interactions
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
importance of drug-drug interactions relating to adverse drug reactions
sometimes drug-drug interactions are prinicpal cause of adverse drug reactions with specific drugs e.g. statins
define pharmacodynamic drug interactions
drug effect on body (receptor site occupancy)
define pharmacokinetic drug interactions
effect of body on drug (ADME)
define pharmaceutical drug interactions
drugs interacting outside body (mostly i.v. infusions)
3 pharmacodynamic drug interactions effects from co-administration of 2 or more drugs and examples
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)
4 pharmacokinetic drug interactions
alteration in absorption, protein binding effects, changes in drug metabolism, alteration in elimination
chelation as example of alteration in absorption, with examples of drugs
irreversible binding of drugs in GI tract; e.g. tetracyclines or quinolone antibiotics with ferrous sulfate, antacids or dairy products
effect of competition between drugs for protein or tissue binding sites
displace other drug from binding protein, increasing free unbound concentration and leading to enhanced pharmacological effect
drug example of when protein binding interactions are clinically significant (most are not)
warfarin
3 options for drug metabolism and elimination
excreted unchanged by kidney, phase 1 then phsae 2 metabolism in liver then kidney, just phase 2 metabolism in kidney
S35
S35
3 reactions in phase 1 metabolism
oxidation (most common), reduction, hydrolysis
4 reactions in phase 2 metabolism to produce polar water-soluble excretable molecule
conjugation: glucuronidation, sulfation, acetylation
most extensively studied system of drug metabolism that is inhibited or enhanced by co-administration of other drugs
CYP 450
what can CYP 450 substrates be metabolised by
single isozyme (predominantly) or multiple isozymes (most drugs)
what may happen if drug is co-administered with CYP 450 inhibitor
some isozymes may compensate for inhibited isozyme
2 most common CYP 450 isozymes metabolising drugs
CYP 3A4, CYP 2D6
4 usual CYP 450 inhibitors
cimetidine, erythromycin and related antibiotics, ketoconazole, ciprofloxacin and related antibiotics
3 other CYP 450 inhibitors
rotonavir and other HIV drugs, fluoxetine and other SSRIs, grapefruit juice
5 usual CYP 450 inducers
rifampicin, carbamazepine, phenobarbitone, phenytoin, St John’s wort (hypericin)
speed of CYP 450 inhibition vs induction
inhibition is very rapid, induction takes hours/days
major location of drug elimination interactions
renal tubule
example of a good drug elimination interaction
probenecid and penicllin
example of a bad drug elimination interaction
lithium and thiazides (cause increased excretion of Na+ and retention of lithium to toxic levels)
why are some drug interactions deliberate
increase effect (different mechanisms of action but same therapeutic effect)
