Anticoagulant Drugs 1 to 10
Describe the pharmacokinetics of Aspirin?
Prompt: What’s the significance of it being a weak acid?
- Aspirin has pKa 3.5; Rapidly absorbed from stomach and upper small intestine -> peak plasma level in1-2 hrs.
- Half life: 15 min. Rapidly hydrolysed -> Acetic Acid+Salicylate by esterases in tissue and blood.
- Salicylate non-linearly bound to albumin. Alkalinisation of urine increases rate of excretion of free salicylates and its water soluble conjugates.
- Small Vd, capacity limited metabolism
Pass: Specific BZD receptor antagonist at GABA receptor
What are the adverse effects of therapeautic doses of Aspirin?
Prompt: What are the respiratory effects of aspirin?
Prompt: Are there any other systems affected?
- CNS: Headache, tinnitus, dizziness
- CVS: Fluid retention, H/T, oedema
- GIT: Abdo pain, N,V, Ulcers, Bleeding
- Haem: Thrombocytopenia, neutropenia, Aplastic a
- Hepatic: Abn LFTs, liver failure
- Pulmon: Asthma
- Skin: All types of rashes, pruritis
- Renal: Impairment and failure, hyperK, proteinuria
Pass: GIT + allergy + bronchospasm
What are the pharmacodynamic differences between low molecular weight and unfractionated heparin?
- Enoxaparin predominantly binds and inhibits factor Xa function
- UFH binds to AT that inhibits factors II, IX, X
Pass: Na channel block, class 1C
What are the advantages of low molecular weight heparin over unfractionated heparin?
- Single daily or divided subcutaneous doses – facilitates patient mobility and OPD management.
- Routine monitoring not required (not mentioned in book)
- Reduced bleeding risk.
- Lower incidence of HITP.
- Improved efficacy over UFH in ACS.
- Increased bioavailability
- Dosage differences and bleeding risk as well as factors II and IX less inhibited by LMWH
- at least that APTT is not accurate measurement of anticoagulation
What is the mechanism of action of warfarin?
- Blocks synthesis of Clotting Factors II, VII, IX, X and Anticoagulant proteins C and S
- Coupled to Deactivation of Vitamin K
Pass: Blocks factors II, VII, IX, X
What drug interactions with warfarin prolong the INR?
Prompt: What is the mechanism?
- Pharmacokinetic: (Increased INR)
- Inhibit transformation of Warfarin: S-Metronidazole, Fluconazole, Bactrim; R & S-Amiodarone, Disulfiram, Cimetidine
- Displace albumin bound warfarin: phenylbutazone, sulphinpyrazone
- Pharmacodynamic: (Increased INR)
- Aspirin – affects platelet function
- 3rd generation Cephalosporins – reduce gut flora producing Vit K
- Heparin – directly prolongs INR
Pass: 2 examples
How is the action of Warfarin reversed?
- Vitamin K
- Prothrombin complex – Prothrombin X
- Recombinant Factor VIIa
How does TPA work?
- Binds to fibrin in a thrombus and converts entrapped inactive plasminogen to active plasmin to initiate local fibrinolysis
What are the indications for TPA use?
- PE with haemodynamic instability
- Acute Ischaemic Stroke:
- Severe DVT
Pass: AMI, stroke and 1 other
How does tPA work?
- tPA activates plasminogen already bound to fibrin, to form plasmin.
- Plasmin degrades fibrin to fibrin split products.
- This theoretically confines fibrinolysis to formed thrombus.
- Short half life means heparin is an essential adjunct
Pass: 2/3 mechanisms
How does tPA differ from streptokinase?
- tPA is a naturally occurring human enzyme. Streptokinase is not an enzyme itself- it is a bacterial product that combines with plasminogen to form an enzymatic complex catalyses conversion of plasminogen to plasmin.
- Long half life means that heparin is not required (and may increase bleeding risk). Prior streptococcal infection may result in antibodies that cause fever, allergic reactions and therapeutic resistance
What is the mechanism of action of clopidogrel?
- Irreversible blockade of platelet ADP receptors, leading to inhibition of platelet activity
- Note there is no anti-prostaglandin effect cf aspirin
How long is this effect?
What are the indications for clopidogrel?
- Pre/post stent
- Stroke prevention
With regard to aspirin, what are its pharmacokinetic properties?
- pKa 3.5.
- Rapidly absorbed from stomach and upper small intestine.
- Peak levels at 1-2 hours.
- ASA is absorbed as such; hydrolysed in blood to salicylate and acetate.
- Bound to plasma protein; saturatable, therefore increased free ASA with increased plasma concentration.
- Saturatable metabolism and excretion; zero order.
- t ½ for 600mg ~ 3-5 hours
- t ½ for 3.6g ~ 12-16 hours.
- Has active metabolite with long t ½ (12 hours).
- Alkaline urine increases ionized free salicylate excretion
Pass: 4 out of 6 BOLD
What are its adverse effects?
- GIT upset; gastritis; ulceration ( due to reduced protective PG synthesis)
- Abnormal LFTs; hepatitis
What are its toxic effects in overdose?
- Vomiting; tinnitus; vertigo; loss of hearing
- Metabolic acidosis
- Clotting disturbance
- CVS collapse
- Renal & respiratory failure
What is the mechanism of aspirin’s antiplatelet action?
- Irreversible inhibition of COX
- Inhibits synthesis of thromboxane A2
What other types of anti-platelet agents are there?
- Inhibitors of ADP pathway
- 2b,3a blockers
- beta blockers
- Other NSAIDs
What are the clinical indications for anti-platelet agents?
- Pregnancy: prophylaxis pre-eclampsia
- Post acute coronary intervention
How does unfractionated heparin work?
- Heterogenous mixture of sulfated mucopolysaccharides which binds to endothelial cell surfaces
- Binds to ATIII – conformational change so active site exposed for more active interaction with proteases to inhibit them from clotting (VIIa, IX a, Xa, II a) Heparin speeds up process 1000x.
- Heparin not consumed in process
How does the mechanism of action of LMW heparins differ?
- Inhibit activated factor X but less effect on AT and coagulation
- Increased bioabilability from SQ site of injection
- Need less frequent dosing (1-2/day)
- Don’t need to follow APTT
What are the adverse effects?
- Bleeding – incr. in elderly, renal failure
- Transient thrombocytopenia 25% patients, severe in 5%
- Heparin induced thromocytopenia – heparin induced Ab against heparin platelet factor 4 complex
- Long term – osteoporosis, spontaneous fractures, mineralocorticoid deficiency
What is the mechanism of action of aspirin?
Irreversibly inhibits cyclooxygenase (COX I and II) — reduces prostaglandin synthesis from arachidonic acid
Describe what happens to aspirin in the gut following oral administration.
How is aspirin eliminated from the body?
Hydrolysed by tissue esterases to salicylate and acetic acid
salicylate conjugated with glucuronide or glycine to form salicyuric acid
first order kinetics at low doses – zero order kinetics at higher doses
Then renally excreted — pH dependent resorption, amount excreted related to urine volume
What are the adverse effects of aspirin?
Bleeding — inhibition of thomboxane production in the platelet
Peptic ulceration — reduction of PGE1 and PGI2 that increase gastroprotective mucous production by the gastric mucosa
CNS — tinnitus, nausea, vomiting, seizures, respiratory alkalosis — direct CNS toxicity
Metabolic acidosis — uncoupling of oxidative phosphorylation
Allergy — idiopathic
Renal failure — inhibition of PGE1 production in renal medulla
Pass: Three examples