Haematology Drugs Flashcards
Definition of venous thrombosis and treatment
Intravascular clot(red) forms in deep veins, particularly of the legs, when flow is sluggish. Fragment may bud of (embolus) and block blood vessels, often pulmonary artery
Therapy : anticoagulant drugs
Definition of arterial thrombosis and treatment
Platelets aggregate (white) usually at site of ruptured atherosclerotic plaque, then encapsulated by clot (red)
Therapy:
- *Immediate-** dissolve existing clots with thrombolytics(fibrinolytics)
- *long term** – antiplatelet drugs (anti-thrombolytics)
Haematolgical drugs categories
Thrombolytic drugs
- rt-PA
- streptokinase
Anticoagulant drugs
- Heparins- (Unfractionated/ low molecular weight)
- Warfarin -
- Rivarobiban, apixaban - Factor Xa anatagonists
- Dabgigatran - direct thrombin inhibitors
Antiplatelet drugs
- Aspirin
- Clopidogrel
- Dipyridamole
- Tirofiban
- Abciximab
Oral anti-coagulants/ vitamin K antagoinst Example
Warfarin
Warfarin mechanism of action
- Extrinsic pathway
- Inhibits vitamin K epoxide reductase
- Prevents recycling of Vitamin K to reduced form after carboxylation of coagulation factors II, VII, IX and X
- Prevents thrombus formation
Indication of warfarin
- Treatment of venous thromboembolism
- Thromboprophylaxis in: AF/metallic heart valves/ Cardiomyopathy
Side effects of warfarin
- Bleeding (risk increases with increasing INR)
- Warfarin necrosis
- Osteoporosis
- crosses BBB
Important pharmacokinetics/pharmacodynamics of warfarin
- Orally active (more convenient than heparin)
- Numerous drug interactions / food interactions
- Reversal by giving vitamin K
- Polymorphisms in key metabolising enzymes (VKORC1 and CYP2C9)
- Needs therapeutic drug monitoring and monitored loading regimen
- Monitored with INR and dose adjusted according to indication
Patient information of warfarin
- Need for compliance / attendance at visits for monitoring
- Care needed with alcohol
- Must inform doctor before starting new drugs – avoid over the counter aspirin preparations
How to reverse side effects of warfarin
- Transfuse with plasma or coagulation factor concentrates
- Oral vitamin K- but reversal is slow- require carboxylation to resume (1-3days)
Two types of heparin
- Unfractionated heparin
- Low molecular weight heparin
Unfracionated heparin mechanism
- Intrinsic pathway
- Enhances activity of antithrombin III. (natural anticoagulant)
- Antithrombin III inhibits thrombin.
- Heparins also inhibit multiple other factors of the coagulation cascade.
- Immediate inhibition of clotting
- This produces its anticoagulant effect.
Indication of unfractionated heparin
- Treatment and prophylaxis of thromboembolic diseases, including induction of vitamin K antagonists.
- Renal dialysis (haemodialysis)
- Acute Coronary Syndrome treatment
Side effects of unfractionated heparin
- Bleeding (Major haemorrhage risk can be as high as 3.5%)
- Heparin-induced thrombocytopenia
- Osteoporosis
Important PD/PK of unfractionated heparin
- Administered by continuous intravenous infusion or subcutaneous injection
- Complex kinetics - non-linear relationship between dose / half-life and effect – needs TDM
- Effect monitored using activated partial thromboplastin time (aPTT)
- Anticoagulant effect can be reversed with protamine.
- Unfractionated heparin has a shorter duration of action than LMW Heparin.
- Used in preference to LMW Heparin, in selected patients, due to the shorter duration of action and reversability with protamine (for example, Peri-operatively.
Patient information of pharmacokinetics/ pharmacodynamics
- Risk of bleeding
- Regular blood monitoring required
Low molecular weight heparin mechanism of action
- Enhances activity of antithrombin III.
- Antithrombin III inhibits thrombin.
- Heparins also inhibit multiple other factors of the coagulation cascade.
- This produces its anticoagulant effect
- LMWH inhibits factor X only
Indication of low molecular weight heparin
- Treatment and prophylaxis of thromboembolic diseases, including induction of vitamin K antagonists.
- Renal dialysis (haemodialysis)
- Acute Coronary Syndrome treatment
- low-molecular-weight heparins do not prolong the APTT; they have a predictable anticoagulant effect and do not require monitoring unless in long-term use; in this case use the factor Xa assay to assess the degree of anticoagulation
Side effects of LMWH
- Bleeding (Major haemorrhage risk can be as high as 3.5%)
- Heparin-induced thrombocytopenia (Less risk than unfractionated heparin)
- Osteoporosis (Less risk than unfractionated heparin
Important pharmacokinetcis/ pharmaco dynamics of LMWH
- Subcutaneous injection - not orally active
- More predictable dose-response relationship than Unfractionated Heparin.
- 2-4 times longer plasma half-life than Unfractionated Heparin
- Clearance is mostly via a renal pathway, thus the half-life can be prolonged in patients with renal failure, so dose adjustment may be needed.
- Regular coagulation monitoring is not required.
- Less readily reversed with protamine, than Unfractionated Heparin.
Patient information of LMWH
- Risk of bleeding
- Requires injection
- Will need blood testing in prolonged therapy (Full Blood Count, to monitor for thrombocytopenia)
How are the anticoagulants monitored?
Warfarin- measured using INR ratio
Heparin measured using the APTT (activated partial thromboplastin time) test
Anti-platelet drugs examples
- Aspirin
- clopidogrel
- dipyrimadole
- Ticagrelori
- Tirofibran
Aspirin Mechanism of action
- Irreversible inactivation of cyclooxygenase (COX) enzyme
- This reduces platelet thromboxane (TXA2) production and endothelial prostaglandin (PGI2) production
- Reduced platelet thromboxane production reduced platelet aggregation and thrombus formation
- Reduced prostaglandin synthesis decreases nociceptive sensitisation and inflammation
Indication of aspirin
- Secondary prevention of thrombotic events
- Pain relief
Side effects of aspirin
- Bleeding (<1% Patients)
- Peptic ulceration
- Angiooedema
- Bronchospasm
- Reye’s syndrome (very rare)
Important pharcokinetics/pharmacodyanmics of aspirin
Half life becomes longer with very large doses (pharmacokinetics may be non-linear in overdose)
Avoid over the counter preparations of aspirin
Avoid over the counter preparations that contain aspirin.
Some patients may be advised to take a Proton Pump Inhibitor alongside long-term aspirin
Clopidogrel mechanism of action
- Irreversibly blocks the ADP-receptor on platelet cell membranes.
- Consequently inhibits formation of GPIIb/IIIa complex, required for platelet aggregation.
- Decreased thrombus formation.
Indication of clopidogrel
Secondary prevention of thrombotic events
Side effects of clopidogrel
- Bleeding (1-10% of Patients)
- Abdominal pain / diarrhoea (1-10% of Patients
Important pharacokinetics/pharmacodynamics of clopidogrel
avoid in liver failure
patient information of clopidogrel
- Patients may be advised to stop clopidogrel before surgical procedures.
- Patients should not stop clopidogrel without consulting their doctor if they have an arterial stent in-situ
Mechanism of action of dipyradimole
- Inhibits cyclic nucleotide phosphodiesterases à increase cyclin AMP and increases cGMP )potentiates prostacyclin and NO)
- So inhibits platelet activation
Indication of dipyradimole
dipyridamole is used in conjunction with warfarin and other anti-coagulants in the prophylaxis against thrombosis associated with prosthetic heart valves
Adverse effects of dipyridamole
- hyoptension
- nausea
- diarrhoea
- headache
Examples of glycoprotein IIb/IIIa inhibitors
- abciximab
- tirofiban
Mechanism of action of abciximab
- monoclonal antibody fragment
- directed towards the glycoprotein IIb/IIIa receptor of platlets
- binding and inactivation of this receptor prevents platelet aggregation
Indication of abciximab
- Used during surgical exploration/ clearing of intravascular blockage e.g coronary artery thrombosis
- Antigenic- can be used once only
Side effects of abciximab
- haemorrhage
- nausea
- vomitting
- hypotension
Mechanism of action of tirofiban
- Tirofiban prevents the blood from clotting during episodes of chest pain or a heart attack, or while the patient is undergoing a procedure to treat a blocked coronary artery.
- It is a non-peptide reversible antagonist of the platelet glycoprotein (GP) IIb/IIIa receptor, and inhibits platelet aggregation.
Indication of tirofiban
- For treatment, in combination with heparin, of acute coronary syndrome,
- including patients who are to be managed medically and those undergoing PTCA or atherectomy.
Dabagitran mechanism of action
- Direct thrombin inhibitor; prevents conversion of fibrinogen to fibrin
- prevents thrombus formation
Indication of dabigatran
Prophylaxis of venous thromboembolism (especially post-operative)
Thromboprophylaxis in non-valvular A
Side effects of dabigatran
- Bleeding
- Dyspepsia
Important PK/PD of dabagitran
- Rapid onset of action
- No food / few drug interactions (not metabolised via CYP 450)
- No need for therapeutic monitoring
- Currently no available antidote
Patient information of dabagitran
risk of bleeding
Rivaroxaban mechanism of action
- Inhibits conversion of prothrombin to thrombin, reducing concentrations of thrombin in the blood.
- This inhibits the formation of fibrin clots.
Indication of rivaroxiban
- Prophylaxis of venous thromboembolism (especially post-operative)
- Thromboprophylaxis in non-valvular AF
- Treatment of venous thromboembolism
Side effects of rivaroxiban
- bleeding
- nausea
Important pharmacokinetics/pharmacodynamics of rivaroxaban
- Predictable drug interactions (metabolised via CYP 450, inc CYP3A4)
- No need for therapeutic monitoring
- Currently no available antidote
Patient information about rivaroxaban
risk of bleeding
Apixaban mechanism of action
- Inhibits conversion of prothrombin to thrombin; reducing concentrations of thrombin in the blood.
- This inhibits the formation of fibrin clots
Indication of apixaban
- Prophylaxis of venous thromboembolism following hip or knee replacement surgery.
- Thromboprophylaxis in non-valvular AF.
side effects of apixaban
- bleeding
- nausea
Important pharmacokinetics/pharmaodynamics of apixaban
- Predictable drug interactions (metabolised via CYP 450 and substrate for p glycoprotein)
- 75% is metabolised by the liver, the rest being renally excreted.
- No need for therapeutic monitoring
- Currently no available antidote.
Patient information of apixaban
risk of bleeding
Examples of recombinant tissue plasminogen activators (rtPA)
Tenecteplase
alteplase
These drugs are thrombolytics/fibrinolytics
Mechanims of action of rtPA
- Recombinant form of tissue plasminogen activator
- Catalyses conversion of plasminogen to plasmin
- Promotes fibrin clot lysis
Indication of rtPA
- Acute ischaemic stroke within 4.5 hours of onset
- Myocardial infarction within 12 hours of onset
- Massive pulmonary embolism
- N.B Not all thrombolytic drugs are licenced for all of these indications
Side effecs of rtPA
Bleeding
Allergic reaction / angiooedema (1%)
Important pharmacokinetics/pharmacodynamics of rtPA
- Bolus-infusion regimen is used for alteplase
- Tenecteplase is given as a single bolus
- Pharmacodynamic interactions with other blood thinners (antiplatelets / anticoagulants)
Patient information of rtPA
- When using thrombolytic drugs, patients should be made aware of the risk-benefit ratio, which should include reference to the rate of bleeding complications
