CVR Pharmacology - Anti-thrombotics - Flashcards in University Pharmacy

What is haemostasis? (1)

Arrest of blood loss form damaged vessels. Vital to like. Prevents blood clotting. Dynamic mechanism

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What is haemostasis? (2)

During haemostasis, platelets are non-adhesive and circulate singly. Durinv vessel wall injury platelets aggregate, become stabilised by fibrin, arrest bleeding from severed vessels (clotting). Important to treatment prophylactically

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What is thrombosis?

Formation of occlusive thrombi leading to MI, ischaemic stroke

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Outline vascular control of platelet function

Interactions between platelets, endothelial cells and smooth muscle cells. Platelets release TXA2 (cause smooth muscle contraction, NA (also produced by endothelium, causes dilation of vessels), PGI2 (also by endothelium, vasodilation) - at rest

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Describe features of haemostasis - aggregation of platelets and vasoconstriction (1)

Damage to blood vessel wall (blood loss). Exposure of platelets to collagen/vWF in EC matrix and later exposure to thrombin. Platelets adhere/activate. Release of mediators. Vasoconstriction/aggregation of platelets. Form soft platelet plug

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Describe features of haemostasis - aggregation of platelets and vasoconstriction (2)

Platelets circulating, express adhesion molecules (e.g. GPVI, a-2/b-1). Platelets exposed to EC, adhesion/activation. Thrombin (further activated, release of 5HT causes vasoconstriction, release of ADP/further activation, activate COX/produce TXA)

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Describe features of haemostasis - aggregation of platelets and vasoconstriction (3)

Platelet aggregation. ADP activate adjacent platelets, cause expression/conformation change, fibrinogen receptors (GPIIb/IIIa), acts as bridge/cross-links, forms soft platelet plug, arrest blood flow

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Describe features of haemostasis - clotting pathway (1)

Initiation pathway (extrinsic pathway), activated by Tissue Factor, takes place on TF-expressing cells in tissues after blood with its clotting factors, leaks out of blood vessel

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Describe features of haemostasis - clotting pathway (2)

TF + FVII - FVIIa:TF - FX - FXa - FII prothrombin) to FIIa (thrombin) - activates platelets

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Describe features of haemostasis - clotting pathway (3)

Amplification/propagation (intrinsic pathway). Initiated by thrombin, involved activation of many factors (FV/FVIII, FIX, FX), takes place on activated platelets. Propagation for cascade reaction. Produce more thrombin (by 1000 fold)

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Describe features of haemostasis - clotting pathway (4)

Thrombin cleaves precursor fibrinogen (conversion on activated platelet)- fibrin - allows polymerisation of fibrin (form stronger clot - resistant to flow/force of blood, regenerative basis for healing damaged area)

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Describe features of arterial thrombosis

Associated with atherosclerosis (white appearance), from at site of vascular injury/disturbed blood flow, large platelet component. Prophylaxis with anti-platelet drugs. Most causes of MI and 80% of strokes

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Describe features of venous thrombosis

Red clots. Associated with stasis of blood or vascular injury following surgery/trauma. Platelet component, large fibrin component, erythrocyte component. Prophylaxis with anti-coagulants. Third leading cause for CV conditions associated with death

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Describe features of plaque vulnerability, disruption and thrombosis

Vulnerable plaque, fibrous cap, lipid rich core. Cap disruption - unstable coronary artery disease - thrombosis/thrombolysis (dynamic) - stenosis

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What is are the main actions of anti-platelet drugs?

To limit growth of or decrease risk of arterial thrombosis. Act by inhibiting platelet aggregation

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What are the main indications for anti-platelet drugs? (1)

Primary prevention of atherothrombotic events in people who are at high risk. Secondary prevention of atherothrombotic events in people with ACS, angina, peripheral arterial disease

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What are the main indications for anti-platelet drugs? (2)

Secondary prevention of CV events in people after MI, stent implantation, stroke or transient ischaemic attack. Prevention of atherothrombotic events in people undergoing percutaneous coronary intervention (PCI)

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Why are anti-platelet drugs not prescribed routinely for primary prevention of CVD but considered in people at high risk of stroke or MI?

If aspirin is given to the general population, the incidence of bleeding will be high (can lead to death, thrombosis can also lead to death). Safety concerns do not outweigh the risk of thrombosis. Only considered to those at high risk

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Which factors need to be considered before up-titrating the dose for anti-platelets?

Clot formation and risk of haemorrhage

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Give examples of anti-platelet drugs

Aspirin, P2Y12 antagonists (clopidogrel, prasugrel, ticagrelor, cangrelor, elinogrel), GPIIb/IIa (αIIb/β3) antagonists (GPIs) - cross links platelets with fibrinogen

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Describe features of aspirin (1)

TXA2 (potent platelet agonist, vasoconstrictor, mitogen). Major product of platelet COX-1. Low dose aspirin irreversibly inhibits COX-1 (other NSAIDs are reversible/not cardioprotective)

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Describe features of aspirin (2)

Low dose aspirin doesn't affect vascular biosynthesis of PGI2 (endothelium synthesises COX-2, overcome aspirin inhibition of PGI2 production/predominates)

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Describe features of aspirin (3)

Cardioprotective effect of PGI2 predominates over that of TXA2

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Describe features of aspirin (4)

In high risk patients, vascular death is reduced. Side effects - blood disorders, bronchospasm, GI haemorrhage, GI irritation, increased bleeding time, skin reactions

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How long is the lifespan of a platelet in humans?

8-10 days (no nucleus in platelets)

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Describe features of P2Y12 receptor antagonists (1)

ADP (crucial role as mediator in platelet aggregation by other agonists). Present in very high concentrations in dense granules. Released when platelets are exposed to thrombin, collagen, TXA2. Reinforces aggregation

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Describe features of P2Y12 receptor antagonists (2)

Full platelet aggregation/irreversible clot formation. Amplifies aggregation initiated by P2Y1 and complete aggregation induced by all other platelet agonists (ADP, collagen, thrombin, TXA2, adrenaline, 5HT)

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Describe features of irreversible P2Y12 antagonists - clopidogrel (1)

Superior to aspirin in prevention of vascular ischaemic events/stroke/MI/vascular death. Pharmacological response in 20-30% of population (genetic polymorphisms of CYP450/CYP2C19)

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Describe features of irreversible P2Y12 antagonists - clopidogrel (2)

Delayed inhibition due to clopidogrel requiring 2 CYP450 steps before active metabolite. Main side effect - bleeding

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Describe features of irreversible P2Y12 antagonists - prasugrel (1)

Improved efficacy (x10 clopidogrel). Not affected by CYP450 variation. More rapid onset of action due to increased rate of conversion to active metabolite (1 step). Demonstrates reduction of MI/stent thrombosis in clinical trials

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Describe features of irreversible P2Y12 antagonists - prasugrel (2)

Increased risk of bleeding events. Side effects - anaemia, GI haemorrhage, rash etc.

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Describe features of P2Y12 antagonists developed by design

Ticagrelor (oral), cangrelor (IV function returns to normal 20 mins post dose), reversibly inhibits P2Y12, non-thienopyridine derivates - rapid onset of action, do not require metabolism (decrease death/MI in clinical trials)

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What are the side effects of ticagrelor and cangrelor?

Dyspnoea, haematoma, haemorrhage (GI) etc.

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Describe features of GPIIb/IIa (αIIb/β3) antagonists (1)

2 drug classes (fab fragments, abciximab, tirofiban, small molecule inhibitors, eptifibatide, all used IV), very potent, block immediate restenosis following coronary angioplasty inhibits aggregation irrespective of agonist

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Describe features of GPIIb/IIa (αIIb/β3) antagonists (2)

But major thrombocytopaenia - not for long term use

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Why are multiple drug regimens used?

Multiple pathways to platelet activation limit effect of specific pathway inhibition. Incomplete efficacy even though pharmacological inhibition is complete

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What is the drug treatment for angina?

Aspirin (75 mg). Clopidogrel (75 mg daily) should be considered for people unable to take aspirin. Often various combinations recommend depending on indication (dual anti-platelet therapy)

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What is the drug treatment for ACS?

Medically managed. Aspirin 75 mg daily plus ticagrelor 90 mg twice a day for 12 months (NICE guidelines)

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What is sub-optimal with current therapy? - limited clinical efficacy

Aspirin - despite 100% inhibition of TXA, production, meta-analysis, 25% reduction in all CV outcomes as secondary prevention. Clopidogrel - between 7-18% reduction in CV outcomes after ACS (trials)

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What is sub-optimal with current therapy? - variability in patient response and toxicity

Aspirin - resistance, 5-65% patients don't respond to drug (genetic cause?), stomach ulcers. Clopidogrel - 33% show partial responsiveness, patient-patient variability, stomach ulcers, neutropenia, thrombotic, thrombocytopaenic purpura (rare)

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What is sub-optimal with current therapy? - risk of major haemorrhage

All current drugs (aspirin, clopidogrel, prasugrel, ticagrelor, cangrelor). Not used for primary prevention, since this can outweigh risk of cardiac event

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What is the cause of a haemorrhage?

Damage to endothelial cells lining the blood vessels

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Why do anti-platelet drugs lead to increased probability of bleeding? (1)

Platelets needed for normal healing of endothelial cells. In healthy person, if platelets are taken away, there is no haemorrhage. When there is an infection/inflammation, disruption to blood vessels becomes exposed

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Why do anti-platelet drugs lead to increased probability of bleeding? (2)

Inhibition of platelet activation leads to loss of interaction between endothelium and platelets (leads to haemorrhage and oedema)

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Describe features of the Vichow's Triad

Venous thrombi. Decrease blood flow. Endothelial disturbance. Increased blood coagulability. Stasis leads to decreased blood flow, preventing dilution of coagulation proteins. Venous thrombi can affects lungs and brain (venous circulation)

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Describe features of the coagulation cascade - initiation pathway

Platelet activation, vWF adheres platelets to damaged cells, platelet aggregation/formation of loose platelet plug. TF released by injured cells. Tissue thromboplastin (III), VII - VIIa, V-Va, on platelet

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Describe features of the coagulation cascade - amplification pathway

Injury to blood vessel, contact activation. XII-XIIa, XI-XIa, IX - IXa, VIII-VIIIa, X - Xa, on platelet, prothrombin (II) to thrombin (IIa)

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Describe features of the coagulation cascade - common pathway

Thrombosis accelerates. Thrombin to fibrinogen - fibrin. Thrombin + thrombomodulin leads to protein C - Ca protein, S degrade Va/VIIIa

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Describe features of the coagulation cascade - fibrinolytic system

Fibrin leads to cross links to form stable fibrin clot. Body tries to break down clot - tPa found to fibrin - plasminogen - plasmin - clot breaks into soluble fragments

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How does clotting of blood occur?

Fibrinogen is converted to fibrin by thrombin. Ca 2+ leads to polymerisation of fibrin - FXIII - formation of stable clot

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Describe features of the prevention of inappropriate clot formation (1)

Endothelial cell NO and prostacyclin (inhibit platelet activation and aggregation). Tissue Factor Pathway Inhibitor (from endothelial and other cells, inactivates/forms a complex with factor Xa, inactivates membrane-bound TF-VIIa complex)

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Describe features of the prevention of inappropriate clot formation (2)

(Limit process in extravascular space). APC (active protein C - activated by thrombin-thrombomodulin, with co-factor protein S inactivates factors Va/VIIIa). Anti-thrombin III (activated by heparans on endothelial cells and heparin)

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Describe features of the prevention of inappropriate clot formation (3)

(Inactivates thrombin and factors, IXa, Xa and XIIa when not in clot or combined in prothrombinase)

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Describe features of APC, fibrinolysis and plasmin (1)

Endothelium - thrombin/thrombomodulin - inactive protein C, APC, APC + S inactivates Va/VIIIa - inhibits plasminogen activator inhibitor - inhibits tissue plasminogen activator (damaged endothelium stimulated by bradykinin, thrombin, kallikrein)

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Describe features of APC, fibrinolysis and plasmin (2)

Plasmin inhibits a2-antiplasmin - fibrin degradation products (FDPs) and D-dimers

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Describe features of anti-coagulant therapy

Inhibit coagulation cascade, prophylaxis and treatment (venous thrombi), prevent propagation and blood clot (doesn't dissolve clot)

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What are the established anti-coagulants?

Heparin and warfarin

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Describe features of heparin

Mixture of glycosaminoglycans. Large charged molecules. Inhibits serine-protease factors XIIa, XIa, Xa, IXa and thrombin directly or potentiation of plasma serine-protease inhibitor or anti-thrombin III. Used for prevention/rapid treatment

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What are the pros of unfractionated heparin?

Effective, cheap, short half life, reversible with protamine (antidote)

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What are the cons of unfractionaed heparin?

Continuous infusion, variable bioavailability, monitoring required (unpredicted PK), HIT, haemorrhage

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What are the pros of low molecular weight heparin - enoxaparin?

Higher bioavailability, longer half life, lower risk of HIT

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What are the cons of low molecular weight heparin - enoxaparin?

Expensive, partial reversible with protamine, haemorrhage

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What is HIT?

Heparin induced thrombocytopaenia. Antibody production against complex of platelet and factor IV, activation of platelets left (increase risk of platelet activation)

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Describe features of vitamin K antagonists (1)

Coumarin (warfarin) inhibits vitamin K dependent epoxide reductase activity which modifies FVII, FIX, FX and prothrombin (FII) during synthesis in liver

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Describe features of vitamin K antagonists (2)

Long term anti-coagulant therapy, orally active, takes 1-3 days for full effect, required frequent monitoring. 1-3% of patients have major bleeding events. Activity affected by diet/genetic variation

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Describe features of vitamin K antagonists (3)

Drug interactions (displacement from plasma albumin, alteration in metabolism in liver). Antidote with vitamin K or replace clotting factors by plasma transfusion (if haemorrhage is severe)

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Describe features of factor Xa inhibitors (1)

By injection (fondaparinux, idraparinux) - pentasaccharides, active moiety of heparin based on anti-thrombin binding sequence, act indirectly (via anti-thrombin)

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Describe features of factor Xa inhibitors (2)

Anti-thrombin is produced in liver, inactivates FX and FII (thrombin). Activity increased by heparin and indirect FX inhibitors

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Describe features of factor Xa inhibitors (3)

Orally available (rivaroxaban, apixaban, edoxaban), directly inhibit FXa, favourable safety, do not require frequency blood monitoring

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Describe features of factor Xa inhibitors (4)

IV/SC (100% bioavailability), more predictable PK than heparin, HIT rarely observed, superior to LMWH (lower thrombus risk, bleeding variation).

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Describe features of thrombin inhibitors (1)

Protein has active sites (e.g. for fibrin, platelets, coagulation factors). Converts fibrinogen to fibrin. Cleaved by coagulation factors. Direct interaction with PAR 1/4 receptors. Factor IIa inhibitors, direct thrombin inhibitors

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Describe features of thrombin inhibitors (2)

Block active site of thrombin, inhibit both clot bound and free thrombin. IV infusion - hirudin, lepirudin, desirudin (short acting) as effective as LMWH.

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Describe features of thrombin inhibitors (3)

Orally active (dabigatran, licensed for AF/DVT), as effective as warfarin, less chance of haemorrhage

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What are the advantages of taking DOAC vs other anti-coagulants? (1)

Traditional anti-coagulants (warfarin) require monthly blood tests, dietary considerations, possibility of uncontrolled bleeding. DOACs are highly effective yet require less monitoring of INR ratio

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What are the advantages of taking DOAC vs other anti-coagulants? (2)

May reduce risk of brain bleed when take for stroke prevention. DOACs being to work and clear system when needed (quick then warfarin). Antidote reversal for warfarin with vitamin K

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What are the advantages of taking DOAC vs other anti-coagulants? (3)

Only one DOAC (dabigatran) has an antidote but management and PK of DOACs is easier

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Describe features of fibrinolytics (clot busters) (1)

Activate plasminogen. Used to remove (lyse) arterial thrombi (AMI - up to 12 hrs, stroke - up to 3 hrs). High risk of haemorrhage (outweighs benefit). IV infusion

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Describe features of fibrinolytics (clot busters) (2)

Antidote (severe haemorrhage treated with transexamic acid - inhibits activation of plasminogen)

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Describe features of fibrinolytics (clot busters) (3)

Streptokinase - non-enzyme protein from streptococci, binds/activates plasminogen - plasmin, allergenic

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Describe features of fibrinolytics (clot busters) (4)

Alteplase (r-tPA) - non-allergenic, clot selective? (only activates plasminogen bound to fibrin in thrombus)

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CVR Pharmacology - Anti-thrombotics

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