Drugs Used In Hemostasis And Thrombosis Flashcards
What is hemostasis?
The term ‘haemostasis’ refers to the normal response of the vessel to injury by forming a clot that serves to limit haemorrhage
What is thrombosis?
Thrombosis is pathological clot formation that results when haemostasis is excessively activated in the absence of bleeding
How do drugs modify hemostasis and thrombosis?
Drugs can be used to modify haemostasis and thrombosis in three ways: (1) By modifying coagulation (2) By modifying platelet aggregation (3) By modifying fibrinolysis
What is the action of anti-coagulants in thrombosis?
Anticoagulants prevent thrombus formation or extension of an existing thrombus in the slower moving venous side of the circulation
What is the action of anti-platelet agents in thrombosis?
Anti-platelet agents inhibit adhesion, activation and aggregation of platelets and therefore prevent thrombosis. They are mostly used for prevention of arterial thrombosis
What is the action of thrombolytic drugs?
Thrombolytic drugs are used to lyse thrombi in blood vessels in arterial and venous thrombosis, and are useful in conditions such as acute myocardial infarction occurring due to coronary thrombosis
What is the action of anti-thrombolytic drugs?
Anti-thrombolytic drugs inhibit thrombolysis and are used in conditions where there is need to inhibit excessive thrombolysis e.g. treatment of excessive effect of thrombolytic drugs
What is an embolus?
Any detached, travelling intravascular mass (solid, liquid or gas) carried by circulation which is capable of clogging capillary beds
What are the forms of vitamin K?
K1 (Phytomenadione) – found in plants
K2 (Menaquinone) – synthesized by bacteria e.g. E.coli in the mammalian gut
K3 (Menadiol) – synthetic and water soluble
Vitamin K1 and K2 are fat soluble and require bile for absorption while vitamin K3 does not require bile for absorption
What is the role of vitamin K in coagulation?
Vitamin K in the reduced form is required as a co-factor for the final stages of the synthesis of clotting factors II, VII, IX and X (gamma carboxylation of the glutamate residues on these proteins)
When vitamin K is deficient or inhibited, the clotting factors formed are not functional
What are the clinical uses of vitamin K?
- Bleeding resulting from vitamin K antagonists such as warfarin (phytomenadione is preferred as it has a rapid action)
- Haemorrhagic disease of the newborn
- Vitamin K deficiency: e.g. caused by obstructive jaundice, mal-absorption syndromes and reduced gut flora (as in neonates and use of broad spectrum antibiotics)
Use the water soluble vitamin K3 for deficiency arising from biliary obstruction and mal-absorption syndromes
List the categories of anti-coagulants with examples
There are four categories of anti-coagulants:
1. Oral: Vitamin K antagonists e.g. warfarin
2. Oral: Direct thrombin inhibitors and direct Xa inhibitors
3. Parenteral: Heparin and low molecular weight heparins
4. Parenteral: Hirudin and its analogues
What are the clinical uses of anti-coagulants?
Anticoagulants are used in the prevention and treatment of deep vein thrombosis in the legs and pulmonary embolism
They are of less use in preventing thrombus formation in arteries
What are the goals of anti-coagulant therapy?
- To stop expansion of established clots
- To prevent thromboembolism complications
- To prevent formation of new thrombi
NB: Anticoagulants do not lyse established thrombi
What is the MoA of warfarin?
The first oral anticoagulant to be used clinically and is the most widely used
Warfarin is an antagonist of vitamin K (structurally similar)
It inhibits vitamin K reductase, the enzyme that reduces vitamin K. This impairs the gamma carboxylation of clotting clotting factors II, VII, IX and X and thus the clotting factors formed are not functional
Describe the pharmacokinetics of warfarin
Well absorbed from the GIT
99% protein bound to albumin
Unbound warfarin readily crosses membranes including the placenta
Metabolised in the liver
Half-life is 2 days
Outline the time course of effects for warfarin
Initial response starts at 8-12 hours
It takes about 72 hours for the full anticoagulant effect to be seen (warfarin has no effect on clotting factors already present prior to the time of drug administration)
On discontinuation of treatment, coagulation remains inhibited for 2-5 days due to the long half-life
What are the clinical uses of warfarin?
Prophylaxis against venous thrombosis
Prevention of thromboembolism in patients with prosthetic valves
Prophylaxis against thrombosis in the atria in atrial fibrillation
Due to slow onset of action, warfarin is not used in emergency situations (heparin is used instead)
Warfarin is the drug of choice for long-term anticoagulation for all patients except pregnant women who should be treated with heparin
How and why is warfarin monitored in therapy?
Monitored by measuring prothrombin time (expressed as INR). The therapeutic target is INR 2-3.
Warfarin has a narrow therapeutic index thus close monitoring is required
What are the adverse effects of warfarin?
Adverse effects: (1) Haemorrhage (2) Cutaneous reactions: purpura, dermatitis, alopecia, pruritic lesions (3) Fetotoxic and teratogenic
How do you treat a warfarin overdose?
Vitamin K
What are the contraindications of warfarin?
(1) Vitamin K deficiency (2) Liver disease (3) Alcoholism (4) Pregnancy (5) Lactation
Explain how and list the drugs that increase the anti-coagulant effect of warfarin
- Drugs that displace warfarin from albumin: aspirin, salicylates, phenylbutazone, sulfonamides
- Drugs that inhibit metabolism of warfarin: cimetidine, disulfiram, phenylbutazone, metronidazole, imipramine, ciprofloxacin
- Drugs that reduce synthesis of clotting factors: broad spectrum antibiotics e.g. ampicillin (inhibit bacterial synthesis of vitamin K)
Which drugs have their effect on bleeding enhanced by warfarin?
Other anti-thrombotic drugs
Explain how and list the drugs that reduce the effect of warfarin
- Inducers of drug metabolizing enzymes e.g. barbiturates, carbamazepine, phenytoin, rifampicin, griseofulvin
- Drugs that promote synthesis of clotting factors: vitamin K, hormonal contraceptives
- Drugs that decrease absorption of warfarin: cholestyramine, colestipol
How do oral direct thrombin inhibitors and oral direct Xa inhibitors differ from warfarin?
In comparison with warfarin, these drugs:
- Have equivalent anticoagulant efficacy
- Have lower bleeding rates
- Have a rapid onset of action
- Have a wider therapeutic window
- Do not require monitoring for dosage optimization
- Have fewer drug interactions
List the oral direct Xa inhibitors
Include rivaroxaban and apixaban
What is the MoA of oral direct Xa inhibitors?
Inhibit factor Xa, in the final common pathway of clotting
They are given as fixed doses and do not require monitoring for dosage optimization
They have a rapid onset of action and shorter half-lives than warfarin
The main toxicity is bleeding and there is no antidote
What are the clinical uses of oral direct Xa inhibitors?
Clinical uses
- Prevention of embolic stroke in patients with atrial fibrillation without valvular heart disease
- Prevention of venous thromboembolism following hip or knee surgery
- Treatment of venous thromboembolic disease
Give examples of oral direct thrombin inhibitors
Include dabigatran
What are the advantages of oral direct thrombin inhibitors?
Advantages of oral direct thrombin inhibitors include
1. Predictable pharmacokinetics and bioavailability, which allow for fixed dosing and predictable anticoagulant response, thus routine coagulation monitoring not necessary
2. Rapid onset and offset of action allowing for immediate anticoagulation
What are the clinical uses of dabigatran?
Prevention of embolic stroke and systemic embolism with non-valvular atrial fibrillation
Treatment of venous thromboembolism following 5–7 days of initial heparin or LMWH therapy
Venous thromboembolism prophylaxis following hip or knee replacement surgery
What are the adverse effects of dabigatran?
The primary toxicity of dabigatran is bleeding
Other adverse effects include gastrointestinal adverse reactions and gastrointestinal bleeding
There is no antidote for dabigatran
Describe the standard heparin
A large polymer composed of repeating units of two disaccharides with a molecular weight of 3000-40,000 daltons
An acidic molecule
Has many negatively charged groups and is therefore highly polar
In the body, heparin is found in mast cells, plasma and endothelial cells
What is the time course and MoA of standard heparin?
Heparin augments the effects of anti-thrombin III
Anti-thrombin III is a naturally occurring inhibitor of clotting factors IIa, IXa, Xa and XIIa and thereby suppresses fibrin formation
Heparin binds to anti-thrombin III and accelerates its rate of activity making it instantaneous
Effects occur quickly (within minutes) because it acts directly to inhibit clotting factor activity
Explain the pharmacokinetics of standard heparin?
Heparin is not absorbed from the GIT due to its large size and polarity
Administered IV or SC (not given IM because of the potential for haematoma formation)
Metabolized in the liver and the metabolites are excreted in urine
Half-life is 40-90 minutes, and is dose dependent
What are the clinical uses of standard heparin?
- Anticoagulant of choice in pregnancy and in situations that require rapid onset of anticoagulant effects
- Used in the management of pulmonary embolism, massive deep vein thrombosis, evolving stroke
- Used in open heart surgery and renal dialysis to prevent coagulation in the extracorporeal circulation device
- Used for prevention of post-operative veno-thrombosis
- Used in the management of disseminated intravascular coagulation
What are the adverse effects of standard heparin?
Adverse effects: (1) Haemorrhage (2) Thrombocytopaenia (3) Hypersensitivity reactions: chills, fever, urticaria (4) Osteoporosis (with long term therapy)
How do you treat a standard heparin overdose?
Treatment of heparin overdose: Treated with protamine sulphate a strong basic protein that forms an inactive complex with heparin
What are the contraindications of standard heparin?
Contra-indications: (1) Thrombocytopaenia (2) Surgery of the eye, brain and spinal cord (3) Lumbar puncture
How and why is standard heparin monitored in therapy?
Heparin therapy is monitored by measuring activated partial thromboplastin time (APTT) [target: 1.5x the normal APTT]
Monitoring is required because of the unpredictable pharmacokinetics of standard heparin
List the low molecular weight heparins
Include enoxaparin and dalteparin
Describe the action, adverse effects, pharmacokinetics and clinical use of low molecular weight heparins
LMW heparins act on anti-thrombin III to inhibit factors X and XI, and they have little effect on thrombin (factor II)
As effective as standard heparin
Associated with lower risk of haemorrhage
Less likely to produce hypersensitivity reactions, thrombocytopaenia and osteoporosis
Have longer half-lives compared to standard heparin and have more predictable pharmacokinetics
Do not require APTT monitoring
Can be used on an outpatient basis
Given subcutaneously
List the hirudin analogues
bivalirudin,
desirudin and
lepirudin
What is the MoA of hirudin and its analogues?
Hirudin and its analogues (bivalirudin, desirudin and lepirudin) directly bind to and inhibit thrombin (they do not require anti-thrombin III)
All are administered parenterally (IV or SC, and not IM)
What is the clinical use of hirudin and its analogues?
They are used in patients with unstable angina undergoing angioplasty and percutaneous coronary interventions
Lepirudin is used as an alternative to heparin in patients who develop heparin induced thrombocytopaenia
What are platelet aggregation inhibitor?
These drugs decrease the formation or the action of chemical signals that promote platelet aggregation
They inhibit thrombus formation in arteries
List the examples of platelet aggregation inhibitors
- Aspirin
- Adenosine diphosphate (ADP) receptor inhibitors: clopidogrel, ticlopidine, prasugrel and ticagrelor
- Glycoprotein IIb/IIIa receptor inhibitors: abciximab, eptifibatide and tirofiban
What is the MoA of aspirin?
MOA: Inhibits the synthesis of thromboxane A2 (TXA2) in platelets by irreversible inhibition of cyclo-oxygenase, a key enzyme in TXA2 synthesis pathway. TXA2 is one of the factors required in platelet aggregation.
Because platelets lack nuclei, they cannot synthesize new enzyme. Thus the lack of TXA2 persists for the lifetime of the platelet (7-10 days).
Given orally
Explain the dose usage of aspirin
When used to inhibit platelet aggregation, aspirin is used at much lower doses than those required for anti-inflammatory action
At higher doses (> 325mg/day), aspirin will have reduced anti-thrombotic action by decreasing endothelial synthesis of prostacyclin
Low doses impair prostaglandin synthesis in platelets more than in endothelial cells and thus the anti-thrombotic effect is preserved
How is aspirin used as a platelet aggregation inhibitor?
Uses of aspirin as a platelet aggregation inhibitor
1. Prophylactic treatment of transient cerebral ischaemia
2. Primary and secondary prophylaxis of myocardial infarction
3. In the management of acute myocardial infarction
4. In the management of unstable angina
What are the adverse effects of aspirin?
Adverse effects
Increased incidence of haemorrhagic stroke
Gastro-intestinal bleeding (hence contraindicated in peptic ulcer disease)
List the ADP receptor inhibitors
Include ticlopidine, clopidogrel, prasugrel and ticagrelor
What is the MoA of ADP receptor inhibitors?
MOA: These drugs reduce platelet aggregation by irreversibly inhibiting the platelet ADP receptor (P2Y12 receptor) (except ticagrelor is a reversible inhibitor) thus blocking ADP binding to platelets ADP is one of the main platelet-activating factors and is required for binding of platelets to fibrinogen and to each other
What are the adverse effects of ADP receptor inhibitors?
Adverse effects: Haemorrhage, dyspepsia, nausea
What are the clinical uses of ADP receptor inhibitors?
Clinical uses
1. Management of unstable angina
2. Primary and secondary prophylaxis of myocardial infarction
3. Prophylaxis of transient cerebral ischaemia and ischaemic stroke
4. Prevention of atherosclerotic events in peripheral arterial disease
ADP receptor inhibitors can be used as alternatives to aspirin or in combination with aspirin
Clopidogrel is the most widely used ADP receptor inhibitor
Ticlopidine causes leukopenia and thrombocytopaenia; it is therefore no longer used
Prasugrel and ticagrelor are approved for patients with acute coronary syndromes (in combination with aspirin)
What is the contraindication of ADP receptor inhibitors?
Prasugrel is contraindicated in patients with history of cerebrovascular accident because of increased bleeding risk
List the platelet glycoprotein IIb/IIIa receptor inhibitors
Include abciximab (monoclonal antibody), eptifibatide (peptide) and tirofiban (non-peptide). They are all given intravenously
What is the MoA of platelet glycoprotein IIb/IIIa receptor inhibitors?
MOA: The glycoprotein IIb/IIIa receptor complex on platelets acts as a receptor for fibrinogen. Activation of the glycoprotein IIb/IIIa receptor complex is the final common pathway for platelet aggregation. Inhibition of the receptor prevents platelet aggregation by blocking the binding of fibrinogen to platelets
What are the clinical uses of platelet glycoprotein IIb/IIIa receptor inhibitors?
Management of acute coronary syndromes (unstable angina and myocardial infarction)
To prevent thrombosis in patients undergoing percutaneous coronary intervention
What are the adverse effect of platelet glycoprotein IIb/IIIa receptor inhibitors?
Bleeding
Abciximab also causes hypersensitivity reactions
List the thrombolytic (fibrinolytic) drugs
Include streptokinase, alteplase, reteplase, tenecteplase and urokinase
Promote lysis of thrombi (clots)
All are given intravenously
What is the MoA of thrombolytic drugs?
MOA: Convert plasminogen to plasmin. Plasmin digests the fibrin meshwork of clots
What are the adverse effects of thrombolytic drugs?
Major adverse effect of thrombolytic drugs is haemorrhage
What is streptokinase?
A protein derived from beta-haemolytic streptococci
Acts on both circulating plasminogen and fibrin-bound plasminogen
What are the ADR of streptokinase?
Causes allergic reactions (anaphylaxis, urticaria, fever, bronchospasm). Thus avoid re-use between 5 days and 12 months
Describe the action of alteplase
Alteplase is recombinant tissue type plasminogen activator (tPA), which is selective for plasminogen bound to fibrin in thrombi. Hence the incidence of bleeding is less than with streptokinase. Alteplase is not antigenic and therefore can be re-used within 1 year
What is urokinase? State its action, indication and clinical use
Prepared from cultured kidney cells using recombinant technology
Activates both circulating and fibrin-bound plasminogen
Used in the treatment of pulmonary embolism
Less antigenic than streptokinase and so it is indicated in patients sensitive to streptokinase
List the clinical uses of thrombolytic drugs
- Lysis of coronary artery thrombi associated with acute myocardial infarction
- Deep vein thrombosis
- Pulmonary embolism
- Acute ischaemic stroke (thrombotic stroke)
What are the contraindications of thrombolytic drugs?
Recent haemorrhage, trauma or surgery, coagulation defects, bleeding diathesis, severe uncontrolled hypertension, recent stroke, recent symptoms of peptic ulcer disease, severe liver disease, oesophageal varices, acute pancreatitis, heavy vaginal bleeding and coma
List the antifibrinolytic agents
- Aminocaproic acid
- Tranexamic acid
What is the action of aminocaproic acid?
Aminocaproic acid, which is chemically similar to the amino acid lysine, is a synthetic inhibitor of fibrinolysis
It competitively inhibits plasminogen activator
Given orally or IV
What are the adverse effects of amino caproic acid?
Adverse effects: Intravascular thrombosis, hypotension, myopathy, abdominal discomfort, diarrhea, and nasal stuffiness
What are the contraindications of aminocaproic acid?
Contraindications: Disseminated intravascular coagulation
What are the clinical indications of aminocaproic acid?
Clinical indications
1. Haemophilia
2. Bleeding from fibrinolytic therapy
3. Prophylaxis for re-bleeding from intracranial aneurysms
4. Post-surgical gastrointestinal bleeding
5. Post-prostatectomy bleeding
6. Bladder hemorrhage secondary to radiation- and drug-induced cystitis
What is the action of tranexamic acid?
Tranexamic acid is an analog of aminocaproic acid and also acts by inhibiting plasminogen activator
Given intravenously
What are the adverse effects of tranexamic acid?
Adverse effects: Nausea, diarrhoea, orthostatic hypotension and intravascular thrombosis
What are the clinical indications of tranexamic acid?
Indications: (1) To prevent hyper-plasminaemic bleeding states that result from damage to tissues rich in plasminogen activator e.g. after prostatic surgery, tonsillectomy (2) In haemophiliacs after dental extraction (3) To reduce bleeding after ocular trauma (4) Overdosage with thrombolytic agents (5) Thrombocytopaenia (6) Upper GIT haemorrhage
List the hemostatic agents
Desmopressin
What is the action and routes of administration of desmopressin?
Desmopressin is a longer acting analogue of vasopressin
Stimulates the release of factor VIII and von Willebrand factor
Routes of administration: Intranasal, oral, sublingual and IV
What are the clinical indications of desmopressin?
Indications: (1) Haemophilia A (2) von Willebrand’s disease (mild disease)
