F7 Drug interactions and adverse drug reactions Flashcards
1
Q
when is an interaction said to occur?
A
when the effects of one drug are changed by the presence of another drug, food, drink or an environmental chemical agent
2
Q
what are the possible effects of drug interactions?
A
- decreased action of drug
- increased action of drug
- adverse effects
3
Q
state some factors contributing to drug interactions
A
- multiple drug therapy
- multiple prescribers
- multiple pharmacological effects of drug
- multiple disease / predisposing illness
- increased by conditions such as renal impairment
- poor patient compliance
- advancing age of patient
- drug related factors
4
Q
why can multiple pharmacological effects of a drug increase its potential for interactions?
A
more chance of multiple receptors being affected
5
Q
why does renal impairment increase the potential for drug interactions?
A
results in accumulation of drug and increased chance of toxicity and interactions
6
Q
describe when pharmaceutical drug interactions occur
A
occur when drugs interact secondary to their physical properties or structure of the drug
7
Q
describe when pharmacokinetic drug interactions occur
A
occur when concurrent use of 2 or more drugs affects the ADME of at least 1 drug
8
Q
describe what pharmacodynamic drug interactions involve
A
involve either an additive, synergistic or antagonistic interaction that may favour or harm the patient
9
Q
describe how drug interactions may affect absorption of drugs. give an example
A
- 2 drugs may interact to alter rate of uptake
- eg. tetracycline and Fe2+ salts or Ca2+ (milk)
10
Q
where are interactions influencing absorption most likely to occur and why?
A
- most likely to occur within GIT
- this is because oral route is most frequently used for drug administration
11
Q
what could a drug interactions affecting absorption cause?
A
- faster or slower drug absorption
- more or less complete absorption
12
Q
state 4 possible influencing factors of drug interactions affecting absorption
A
- changes in GI pH
- changes induced by chelation (developing complex compounds from the drug)
- changes in GI motility
- transporter based interactions
13
Q
explain how changes in GI pH can influence drug interactions affecting absorption
A
- passive absorption of drugs best in uncharged form
- rises in pH may influence absorption of other drugs
14
Q
explain how changes in GI pH can affect absorption of ketoconazole
A
- ketoconazole insoluble in water and ionised at low pH
- must be in acidic environment to be absorbed
- acidic suppression can reduce AUC by 80%
15
Q
state a drug that ketoconazole cannot be prescribed with
A
- omeprazole
- different antifungal must be prescribed if patient is on omeprazole
16
Q
state drugs that can cause rises in pH
A
antacids
H2 antagonists
PPIs
17
Q
what kind of drug is ketoconazole?
A
antifungal
18
Q
explain how changes by chelation can influence drug interactions affecting absorption using an example
A
eg. tetracyclines or ciprofloxacin form insoluble chelates with Ca, Al, Bi and Fe
- resulting in reduced antibacterial effect
19
Q
what must be advised when giving out ciprofloxacin to reduce interactions from changes by chelation?
A
- don’t have any metal ion containing things within 3 hours of taking
- eg. supplements containing calcium / aluminium, tea with milk etc.
20
Q
use an example to explain how changes in GI motility can influence drug interactions affecting absorption
A
eg. metoclopramide accelerates absorption of other drugs (use in antimigraine drugs)
21
Q
describe P-glycoprotein interactions as an example of transporter based interactions
A
- encoded by MDR1 gene
- efflux pump so pumps drugs out into lumen
- structural diversity of its substrates
- both inhibitors / inducers produce significant interactions
22
Q
describe the quinidine-digoxin interaction as an example of transporter based interactions
A
- both have cardiovascular benefits
- digoxin is a P-glycoprotein substrate
- quinidine is a P-glycoprotein inhibitor
- quinidine increase the bioavailability of digoxin by inhibiting P-glycoprotein efflux in the intestine and the liver during the first-pass effect
23
Q
explain what is meant by alteration in protein-drug binding that causes interactions with the distribution of drugs
A
- reduction in the extent of plasma protein binding of one drug caused by the presence of another drug
- results in an increased unbound fraction of the displaced drug
- drug-protein / drug-albumin complexes can be affected by other compounds (may be displaced to make more drug free in the blood which causes toxicity)
24
Q
when are drug-protein / drug-albumin complexes formed?
A
when drugs are carried through the body to transport from organ to organ
25
state some drugs that can displace anti-coagulants (eg. warfarin) from drug-protein complexes
- phenylbutazone
- chloral hydrate
- salicylates
26
state some drugs that can displace tolbutamide from drug-protein complexes
sulphonamides
27
state some drugs that can displace methotrexate from drug-protein complexes
- sulphonamides
- salicylates
28
state a drug that can displace phenytoin from drug-protein complexes
valproic acid
29
state some effects of anti-coagulant displacement from protein-drug complexes
increased clotting time
risk of bleeding
30
state an effect of tolbutamide displacement from protein-drug complexes
increased hypoglycaemic effect
31
state an effect of methotrexate displacement from protein-drug complexes
methotrexate toxicity
32
state an effect of phenytoin displacement from protein-drug complexes
phenytoin toxicity
33
what are most metabolic drug interactions due to?
competition for the CYP$%) enzyme which is expressed in the liver and catalyses the phase I oxidation of more than half of all medical drugs
34
what are CYP450 enzymes responsible for?
inactivating drugs (or activating prodrugs)
35
what can metabolism by CYP450 enzymes be affected by?
- other drugs and molecules
- metabolism can be inhibited or accelerated
36
what is meant by enzyme induction?
- increase in the expression of the enzyme (especially increasing transcription)
37
state 4 major CYP enzymes
1A2
2C9
2D6
3A4
38
inducers, substrates and inhibitors of CYP1A2 enzyme
inducers:
- barbecued meat
- tobacco smoke
- omeprazole
substrates:
- clozapine
- estradiol
- haloperidol
- theophylline
inhibitors:
- fluoroquinolone
39
inducers, substrates and inhibitors of CYP2C9 enzyme
inducers:
- phenobarbital
- rifampicin
substrates:
- ibuprofen
- losartan
inhibitors:
- isoniazid
- verapamil
40
inducers, substrates and inhibitors of CYP2D6 enzyme
inducers:
- phenobarbital
- rifampicin
substrates:
- carvedilol
- metoprolol
- tricyclic antidepressants
- neuroleptics
- SSRIs
- codeine
inhibitors:
- quinidine
- fluoxetine
41
inducers, substrates and inhibitors of CYP3A4 enzyme
inducers:
- rifampicin
- carbamazepine
- dexamethasone
- phenytoin
- St John's wort
substrates:
- cyclosporine
- tacrolimus
- nifedipine
- verapamil
- statins
- estradiol
- progesterone
- testosterone
- haloperidol
inhibitors:
- HIV protease inhibitors
- amiodarone
- macrolides
- azole antimycotics
- grapefruit juice
42
explain the interaction between antidepressants and drugs such as rifampicin or fluoxetine
- if an individual takes antidepressants they will be metabolised by CYP2D6 enzymes but if they also take rifampicin or fluoxetine (for example) an interaction will occur
- this is because rifampicin and fluoxetine are inducers of CYP2D6 so they accelerate the metabolism of the antidepressant taken
- this reduces the level of the tricyclic antidepressant in the blood
- results in therapeutic failure
43
what is St John's wort effective for?
mild to moderate depression
44
what is St John's wort and how can it affect certain medicines?
- enzyme inducer
- can increase metabolism of some medicines (eg. oral contraceptives)
45
what can the simultaneous use of oral contraceptives and St John's wort result in?
- pregnancy
- metabolism of contraceptives is increased by St John's wort
- levels in the blood decline and tablets don't have the full therapeutic effect
46
describe enzyme induction
- increase activity of metabolising enzymes
- may take a week or 2 for effect
- effect may persist on stopping inducer
47
describe enzyme inhibition
- rapid onset of 1-2 days
- often reverse quickly on stopping
48
what is the most common type of polymorphism?
- SNP (single nucleotide polymorphism)
- mutations leading to amino acid substitutions
49
describe and explain the metabolism interactions between PPIs and clopidogrel
- PPIs (particularly omeprazole) inhibit cytochrome P450 2C19
- clopidogrel is a prodrug that is metabolised to its active metabolites in 2 steps
- CYP2C19 plays an essential part in this
50
which PPI should be used to replace omeprazole in the presence of clopidogrel and why?
- pantoprazole
- doesn't affect cytochrome P450
- evidence suggests that it does not interact
51
give an example of a direct pharmacodynamic interaction involving antagonism
naloxone inhibits effects of opioids and is used as a rapid antidote to opioid overdose
52
give an example of direct pharmacodynamic interactions involving addition or summation
metoclopramide and other drugs are used in combination to prevent nausea and vomiting in patients undergoing chemotherapy
53
what are the 3 types of direct pharmacodynamic interaction?
- antagonism
- addition / summation
- synergism / potentation
54
describe indirect pharmacodynamic interactions and give an example
- unrelated effects but alters the effect of the former
- eg. salicylates decrease the ability of the platelets to aggregate thus impairing the homeostasis if warfarin induced bleeding occurs
55
what is meant by an adverse event, adverse drug event and adverse drug reaction?
adverse event
- harm occurs during treatment with a drug
adverse drug event
- harm caused by drug application but not necessarily causally related
adverse drug reaction
- unwanted reaction or harm caused by the drug itself at normal dosage
56
what is an on-target adverse effect?
drug binds its intended receptor but at an inappropriate concentration or in the incorrect tissue
57
what is an off-target adverse effect?
drug binds a receptor it was not intended for
58
what are toxic metabolites?
metabolism leads to compounds that are equally active or toxic as drug
59
what is an idiosyncratic response?
rare reaction which reflects individual genetic differences in the response to the drug
60
what are the 5 main classifications of adverse drug reactions?
A augmented
B bizarre
C chronic
D delayed
E end of use
61
what are the 3 sub classifications of augmented adverse drug reactions?
pharmacological
pathological
genotoxic
62
describe type A adverse drug reactions: augmented
- most common
- largely predictable from drug's pharmacology
- preventable
- dose-dependent
- reversible on reducing / withdrawing drug
63
what are type A adverse drug reactions generally associated with?
low mortality but high morbidity
64
what may type A adverse drug reactions be caused by?
- exaggeration of therapeutic effect due to an overdose (pharmacological)
- disease condition like hepatic or renal failure (pathological)
- injury to DNA by therapeutic agent (genotoxic)
65
describe type B adverse drug reactions: bizarre
- idiosyncratic (genetic influences)
- immunological reaction
- unpredictable and difficult to detect in clinical trials
- often involve a chemically reactive metabolite rather than parent drug
- less common but usually severe
66
what are type B adverse drug reactions usually associated with? give 2 examples
- associated with higher mortality
- eg. anaphylaxis with beta-lactam antibiotics such as penicillins
- eg. Stevens-Johnson syndrome
67
what can Stevens-Johnson syndrome be and what can it be caused by?
- type B adverse drug reaction
caused by:
- sulphonamides
- trimethoprim
- NSAIDs
- penicillin
- some anticonvulsants
- others too
68
describe type C adverse drug reactions
- continuing / chronic
- those persisting for a relatively long time
69
give an example of a type C adverse drug reaction
osteonecrosis of the jaw with bisphosphonates such as alendrotnic acid, benzodiazepine dependence, analgesic nephropathy
70
describe type D adverse drug reactions
- delayed
- become apparent some time after the use of a medicine making them difficult to detect
- common in cancer patients with anti-cancer meds so monitoring is essential
71
give an example of a type D adverse drug reaction
leucopenia can occur up to 6 weeks after a dose of lomustine, carcinogenic and teratogenic effects
72
describe type E adverse drug reactions
- end of use
- associated with withdrawal of a medicine
73
give an example of a type E adverse drug reaction
insomnia, anxiety and perceptual disturbances following withdrawal of benzodiazepine such as midazolam, antidepressants, corticosteroids
74
how are adverse drug reactions reported?
Yellow Cards in BNF submitted to CSM (Commission on Human Medicines)
