DRUG INTERACTIONA Flashcards
the coagulation cascade
- complex series of enzyme reactions which ultimately leads to the formation of insoluble fibrin from soluble fibrinogen.
- the system consists of proteolytic enzymes and cofactors
intrinsic and extrinsic pathways of the coagulation cascade
intrinsic pathway start within the blood vessels.
extrinsic pathway- fewer enzymes, requires tissue factor released from damaged cells outside the blood flow.
both pathways meet at factor 10.
warfarin
- has a similar has a similar structure to vitamin K and competitively competes with it.
- warfarin inhibits the enzymatic reduction of vitamin K to its active hydroquinone form.
- vitamin K-dependent glutamate carboxylation of precursor clotting factors II, VII, IX and X
- action takes several days to develop because of T1/2 of clotting factors in plasma
- action is reversed by vitamin K
heparin
- measure in units and biologically assayed as from animal sources such as pigs/cows
- 2 types standard ‘unfractionated heparin’ with a short duration of action and LMWH low molecular weight heparins are fragments of heparin and have a longer duration of action.
- thrombin lla converts fibrinogen to fibrin and activates factor XIII which stabilises fibrin links
- enzyme inhibitor antithrombin III neutralises all serine proteases in the cascade
mechanism of action of unfractionated heparin
antithrombin III (AT III) inactivates thrombin (lla). heparin interacts with AT III and IIa by binding to them and increasing the inactivation of IIa. heparin also speeds up anticoagulatory effects of (AT III) on factor Xa by binding to AT III.
mechanism of action of low molecular weight heparin (LMWH)
LMHW speeds up the anticoagulatory effects of (AT III) on factor Xa by binding to AT III
- examples are dalteparin, enoxaparin and tinzaparin
- londer duration of action measure can be given subcutaneously once daily post-surgery
- no need for monitoring
- more predictable pharmacokinetics
used in DVT/PE treatment
- dose based on weight
interactions
an interaction is said to occur when the effects of one drug are changed by the presence of another drug, food, drink or an environmental chemical agent. result of interaction there is either increased toxicity or therapeutic failure.
may be harmful or benefitial
resources of drug interactions
BNF.
Stockley’s Drug Interactions- indicates significance.
computer alerts- variable, a recent study indicated that the different systems were inconsistent.
strategies to address interactions
- narrow therapeutic index NTI drugs are defined as those drugs where small differences in dose or blood concentration dependent, serious therapeutic failures or adverse drug reactions e.g. digoxin, methotrexane, lithium, gentamicin, warfarin.
- avoid concomitant prescription of the high-risk drugs
- choose non-interacting alternatives
- reduce dose
- monitor the patient
pharmacokinetic mechanisms of interaction
absorption:
2 drugs may interact to alter rate uptake e.g. tetracycline (Doxycycline) and iron/calcium.
Fe2+, Ca2+ decreases the absorption of doxycycline, levothyroxine Tannins and iron
-> pH:
passive absorption of drugs, best in uncharged form, is governed by pKa value.
rises in pH (antacids, hydrogen, antagonists, PPIs) may influence absorption of other drugs.
magnesium carbonate (antacid) and tetracycline- separate administration by 2-3 hours
-> binding:
colestyramine ( bile acid sequestrant) bind drugs such as digoxin, methotrexate, vitamin A/D/K
take other drugs at least on hour drugs one hour before or 4-6 hours after
absorption: MDR1
MDR1: multiple drug resistant transporter. it has other names:
P-glycoprotein or ATP binding cascade (ABC).
may be reduced e.g. rifampicin.
may be inhibited e.g. verapamil, amiodarone
Efflux: pumps drugs out into lumen
Digoxin is a substrate and induction of MDR1 reduces bioavailiability
effect of induction of P-glycoprotein on absorption of digoxin
digoxin is used in treating heart failure and arrhythmias, and is a substrate for P-glycoprotein.
Rifampicin is an antibiotic that is an influencer of P-glycoprotein. rifampicin is an antibiotic that is an influencer of P-glycoprotein.
Pre-treatment with rifampicin for several days increases the efflux process from the enterocyte (intestinal epithelial cell) to the intestinal lumen and therefore decreases the absorption of digoxin
displacement
many drugs are protein bound, but only act in free form. acidic drugs (phenytoin, warfarin, NSAIDs etc.)
drugs may compete for binding sites, resulting in displacement, transient increases in toxicity but then increased elimination.
drug metabolism
- liver enzymes bulk of drug metabolism
- Phase 1 reactions (oxidation, reduction hydrolysis) makes molecules more reactive.
- phase 2 reactions involve combining with other molecules (e.g. glucuronic acid) to inactive form for excretion
- induction
- inhibition
cytochrome P450-mediated metabolism
many drugs metabolised by multiple CYPs. some drugs metabolised by single CYPs- these are most likely to be involved in clinically-relevant interactions.
2 possible interaction mechanisms:
inhibition and induction
enzyme inhibition
- more of an issue then induction because effects occur straight away and increase as dose increases.
- some classic inhibitors amiodarone, allopurinol, cimetidine, amlopidine, diltiazem, verapamil, ciprofloxacin, erithromycin, ketoconazole etc.
- drugs of NTR
enzyme inhibition: cytochrome P450 inhibition
H2 receptor antagonists e.g., cimetidine (numerous). antifungal agents (miconazole) (CYP3A4).
macrolides e.g. erythromycin, clarithromycin (CYP3A4). rapid onset: 1-2 days. often reverse quickly on stopping. warfarin: increase in INR~ risk of bleeding
warfarin and Quinolone antibiotics
severe
ciprofloxacin
may interfere with Cytochrome P450-dependent metabolism.
may alter gut flora and reduce vitamin K levels. patient is more likely to bleed.
simvastatin interactions with macrolides and calcium channel blockers
contraindicated with macrolides (severe)
increases side effects
interaction with amlodipine, verapamil, diltiazem .
for amlodipine plus statin:
20mg simvastatin as maximum dose. the risk of an interaction with amlodipine is much lower with atorvastatin than simvastatin
metabolism: induction
enzyme induction: increase activity of metabolising enzymes e.g. rifampicin carbamazepine reduces plasma conc of warfarin. may take a week or 2 for effect effect may persist on stopping inducer
NSAIDs and warfarin
significant interactions
aspirin is antiplatelet - enhanced bleeding effects.
NASIDs# associated with gastric bleeding, enhanced by warfarin
avoid NSAIDs and warfarin.
ensure patients on warfarin don’t self medicate with NSAIDs
clopidogrel and proton pump inhibitors (PPIs)
- omeprazole makes clopidogrel less effective: avoid omeprazole or esomeprazole
- due to both being biotransformed by same cytochrome P450
- clopidogrel is no longer converted to active metabolite. pantoprazole does not affect those cytochrome P450 and evidence suggests that it does not interact
pharmacodynamic interactions
- these are interactions where the effects of one drug are changes by the presence of another drug at its site of action.
- additive or synergistic interactions e.g. alcohol and CNS depressants, combining antihypertensives, QT prolonging drugs etc.
- antagonistic interactions e.g. propanolol and salbutamol, oxybutynin and donepezil, warfirin and chamomile tea
cranberry juice interactions
possibility of interaction with warfarin. some research suggests cranberry juice inhibits the CYP2C6 enzyme, which would cause bleeding due to increased warfarin plasma concentrations. clinical studies failed to demonstrate interaction.
warfarin and food rich in vitamin K
may reduce the activity of warfarin. avoid significant changes in diet
grapefruit juice
atorvastatin, transplant drugs, calcium channel blockers, amiodarone.
furanocoumarins inhibit CYP3A4 and P-glycoprotein transport
beneficial interactions
combinations of antihypertensive drugs
e.g. calcium channel blockers and ACE inhibitors (CCBs/ACEIs)
combinations of drugs to manage Parkinson’s disease e.g. carbidopa/levodopa
some key interactions
warfarin and NSAIDs: leading to enhanced bleeding
warfarin and antibiotics (esp erythromycin and ciprofloxacin): leading to enhanced bleeding
simvastatin and macrolides: avoid
Slimvastatin and amlodipine: caution dose (max dose of simvastatin 20mg)
ENZYME INHIBITORS LEAD TO INCREASED BLEEDING.
ENZYME INDUCERS LEAD TO FAILURE OF THERAPY
