Drugs in the bloodstream Flashcards
What enzyme does warfarin inhibit
Vitamin K epoxide reductase
Warfarin Pharmacokinetic
99%plasma prtein bound
almost entirely metabolised by he liver, metabolites excreted in urine + faeces
Elimiation t1/2 35 to 45 hours
Significant drug interactions- either from being displaced from plasma proteins or liver indction/inhibition
What drugs cause inhibition of warfarin metabolism (and so potentiate effects)/
Cimetidine
ALcohol
Allopurinol
Erythromycin
Ciprofloxacin
Metronidazole
What can displace warfarin from plasma proteins?
NSAIDS
WHat drugs induce enzymes and thus inhibit warfarin action?
Barbituates
rifampacin
CArbamazepine
What does cholestyramine do with warfarin?
INhibits effect as decreased fat soluble lipid absorption
What is INR
the ratio of a patients prothrombin time to a normal control sample
How do you treat high INRs? (INR >8 and RF)
Stop warfarin
Can give FFP (15ml/kg) but does not fully revers
Administer Vit K 5mg- will work within 12 hours and 10mg will saturate stores, preventing re-warfarinisation
Prothrombin complex can be used for complete reversal
Risks of warfarin in pregnancy?
- Crosses the placenta and may cause fetal haemorrhage
- Spont. abortion
- Stillbirth
- Neonatal death
-Teratogenicity (5% incidence of birth defects)
In later pregnancy central nervous system disorders are more prevalent
What is heparin?
Heparin is a glycosaminoglycan, mucopolysaccharide
Organic acid and occurs naturally in the liver and mast cells,
mainly made from porcine intestinal mucosa
molecula weight is 12-15kDa
What is the MOA of heparin
Binds reversibly and potentiates antithrombin 3- plasma serine protease inhibitor.
What does ATIII inhibit
Mainly coag factors 2, 9 and 10 but can also inhibi 12, 11 and plasmin.
Antiplatelet effects also occur through effects on fibrin
Pharmacokinetics of UFH?
Only given SC or IV- negative charge stops oral absorption
Highly plasma protein boung, individual variation leading to differences in efficacy
Low lipid solubility- does not cross BBB or placenta
t1/2 is 30-60 mins
Metabolised by hepatic heparinase
Excreted in the urine
What are lmwh?
Short chain polysaccharides with a predictable anticoag action
Avg weight is <8000kDa
What does LMWH act on
Full anti xa action but less anti 2a action due to shorte chain lengths
Half life of LMWH and why
2-3x longer than unfractionated due to a lower affinity for heparin binding proteins
How can you monitor effect of LMWH
Xa assays
Advantages of LMWH?
ONce daily dosing
no need to monitor aptt
smaller risk of bleeding- less plt interaction
Smaller risk of osteoporosis
Smaller risck of HIT
LEss effect on thrombin
Commonest adverse reactions to heparin ?
Haemorrhage, hyperkalaemia and hypotension if admin. quickly
WHat is HIT
An immune mediated thromboctopenia where heparin is recognised as foreign.
Heparin binds to plt factor 4 stimulating IgG ab formation and predisposition to thrombosis.
Most are asymptomatic.
WHen does the platelet count normally fall in HIT
5-14 days after heparin is started, or quicker if pt has received heparin in the last 3 months
What is danaparoid?
Factor Xa inhibitor, heparinoid. Can be used in HIT. Mixture of heparan, dermatan and condroitin suphatea
Advers effects of danaparoid?
Low platelets due to some structural similarities with heparin, exacerbations of asthma
What is fondaparinux?
A synthetic pentasaccharide similar to heparin
Xa inhibition
T1/2 is 21hrs, renally excreted
Risk of HIT is substantially lower
What is rivaroxaban?
Xa inhibitor
What is normal plt turnover?
10% per day,
WHen will plt function return to normal after aspirin?
7-10 days
Aspirin pharmacokinetics?
Weak acid with a pKA of 3
REadily absorbed in stomach, but greater SA means more in SI
85% plasma protein bound
Half life 15-20 minutes
HYdrolysed to acetic acid and salicyclate.
Converted ot water soluble products in the liver and then excreted by the kidneys
What are the water soluble products of aspirin
Salicykuric acid + glucuronide
Aspiring does what in acute overdose?
Uncouples oxidative phosphorylation- increases o2 consumption and co2 production
Initially MV increases, then direct stimulation of resp centre increases RR and leads to a respiratory alkalosis
Impaired aerobic metabolism then leads toa metabolic acidosis
Symptoms of aspirin ovedose
Tachycardia
Pyrexia
Swaeting
Blurred vision
HYperventilation
Tinnitus
Treatment of aspirin OD?
ACtivated charcoal early
IV fluids
ALkalinisation of urine with sodium bicarb in significant OD
HD in severely poisoned patients ie
levels >100
neurotoxicity
renal failure
pulmonary oedema
CV instability
What is clopidogrel and how does it work
Blocks the ADP induced platelet activation pathway (P2Y12ADP)
Prevents platelet activation caused by shear stress after surgery
Irreversible plt effects
Pharmacokinetics clopidogrel
It is a prodrug activated by oxidation of the thiophene ring by CP450
Rapidly absorbed, extensively metabolised . half life around 8 hours
Uses of clopidogrel?
POst MI
Prevention of thrombosis post stent
Prevention of vascular ishaemic events in pts with symptomatic atherosclerosis
AT what dose of clopi does maximal plt inhibition occur?
400mg, can be fully reversed with a plt transfusion
MOA of GP2b3a antagonists
Block common pathway preventing binding of fibrinogen
reduced plt activity, thrombin effects and neointima formation in damaged arteries
Reduces plt aggregation at 50% occupation and abolish aggregation at 80% occupancy
What is Dipyridamole?
Pyrimidopyrimidine derivative
ANtiplt- inhibits adhesion to the vessel wall
Vasodilates- particularly at the coronary artery
Excreted by the bilary tree
Half life 1 hours
MOA of dipyridamole?
PDE inhibito so potentiates prostacyclin
Stimulates prostacyclin
Inhibits the metabolism of adenosine
