Cardiology Pharmacology Quiz

CV Pharmacology: Blood Coagulation

• Blood coagulation is a complex process involving proteins and enzymes, primarily focusing on platelet activation and fibrin formation.
• A balance of pro- and anti-coagulation signalling is crucial, with endothelial cells playing a protective role through heparan sulfate membrane glycoproteins and signalling molecules like prostaglandin I₂ (PGI₂) and nitric oxide (NO).
• Tissue plasminogen activator (tPA) converts ADP to adenosine, contributing to this balance.
• Platelet activation and fibrin formation typically occur concurrently.
• Platelets aggregate and activate the coagulation cascade, forming a "haemostatic plug."
• The coagulation pathway involves the intrinsic and extrinsic pathways, which converge on factor X, leading to prothrombin conversion into thrombin.
• Thrombin, an enzyme, cleaves fibrinogen, forming insoluble fibrin, which then binds to platelets and other fibrin strands, creating a stable clot.
• Thrombosis arises from pathological coagulation within a blood vessel, forming a blockage (thrombus). Thrombi can detach and become emboli.
• Venous thrombi are typically high in fibrin, while arterial thrombi often involve platelets.

Lecture Objectives

• Introduction to coagulation signalling
• Anticoagulants (oral and intravenous)
• Antiplatelet drugs (e.g., aspirin, P2Y12 receptor antagonists)
• Fibrinolytics and procoagulants
• Drugs for hyperlipidaemia (e.g., statins, fibrates)

Haemostasis

• Cessation of bleeding from damaged blood vessels relies on a complex system.
• Platelets and fibrin form a crucial component.
• The balance of pro- and anti-coagulants is critical in maintaining a healthy circulatory system.

Haemostatic Plug

• Platelets aggregate, and the coagulation cascade involves fibrin formation, creating a haemostatic plug within a blood vessel. This plug stops bleeding by forming a physical barrier.

Coagulation Pathway

• Tissue damage or external contact initiates the extrinsic pathway, leading to the conversion of prothrombin to thrombin.
• The intrinsic pathway involves factors XII, XI, and IX and also leads to thrombin formation.
• Both pathways converge on factor X, activating the cascade to produce thrombin.
• Thrombin catalyzes fibrin formation from fibrinogen, leading to a stable blood clot.
• Antithrombin III plays a role in regulating this activation.

Fibrin Formation

• Thrombin cleaves fibrinogen, causing it to change into fibrin.
• Fibrin is insoluble and forms strands that bind platelets and other fibrin fibres, creating a strong hemostatic plug

Platelet Aggregation

• Platelets, activated by various stimuli (e.g., thrombin, collagen, von Willebrand factor, PAF, ADP, TXA2), aggregate, forming a crucial part of the hemostatic plug.

Thrombosis

• Pathological coagulation within a blood vessel leads to thrombosis.
• Thrombi may detach and become emboli, potentially blocking smaller vessels.
• Various factors contribute, including hypercoagulability, blood flow issues, and blood vessel damage (Virchow's Triad).

Antithrombosis Drugs and Strategies

• Anticoagulants limit thrombin formation
• Antiplatelet drugs inhibit platelet activation.
• Fibrinolytics (thrombolytics) break down fibrin clots.
• All antithrombotic drugs increase bleeding risk.

Anticoagulants

• Warfarin is a vitamin K antagonist, inhibiting the production of clotting factors.
• Warfarin requires close monitoring and is associated with potential drug interactions.

International Normalised Ratio (INR)

• Prothrombin time measures blood clotting time, and INR standardizes this against a normal value.
• INR levels help monitor the effectiveness of anticoagulant therapy, while maintaining a therapeutic range.

Anticoagulants - Warfarin

• Vitamin K antagonists such as warfarin inhibit the enzyme VKORC1 and block vitamin K production, preventing active form of vitamin K from forming
• Vitamin K is essential for clotting factor synthesis.
• A critical antidote for warfarin overdose is vitamin K or prothrombin complex concentrate.

Warfarin - Problems

• Warfarin's low therapeutic index necessitates close monitoring to prevent overdose, and it has numerous drug interactions.
• Initial bridging with heparin is often necessary when starting warfarin.
• Warfarin is a teratogen with potential risks for liver damage and increased bleeding.

Anticoagulants - Warfarin Alternatives

• Newer anticoagulants like rivaroxaban and apixaban are often favoured due to quicker onset and lower risk of drug interactions, using selective inhibition.
• Dabigatran, which directly inhibits thrombin, is another important option.

IV Anticoagulants

• Heparins, like fondaparinux, are typically given intravenously in acute situations to prevent clot formation when quick action is required
• Fondaparinux is an effective alternative to traditional heparins.

Antiplatelet Drugs

• Antiplatelet drugs such as aspirin, and P2Y12 antagonists block molecules involved in platelet activation and aggregation.
• Phosphodiesterase inhibitors (e.g., dipyridamole) reduce platelet activation by modulating cyclic nucleotides.

Anti-platelet drugs: TXA₂ & GPIIb

• Platelet activation is involved in initiating thrombus formation, and antiplatelet medication inhibits molecules essential in aggregation/activation
• TXA₂, a key substance in platelet activation, is inhibited by certain drugs.
• GPIIb/IIIa receptors are targeted since fibrinogen binding prevents clot formation
• Anti-platelet drugs block these, preventing blood clot formation or breakdown

Anti-platelet drugs - aspirin

• Aspirin is a cyclooxygenase inhibitor, affecting platelets in the process of clot formation.
• Aspirin irreversibly inhibits platelets, which makes aspirin very effective as a preventive for clot formation.
• Aspirin resistance is a possibility in some patients.

Anti-platelet drugs: P2Y12 receptors and PAR

• P2Y12 receptors are critical in platelet activation in response to drugs
• PAR receptors are targeted for inhibiting thrombus initiation within platelets.

Antiplatelet drugs - P2Y12 receptor antagonists

• P2Y12 receptor antagonists like clopidogrel and prasugrel stop ADP from activating platelets.
• Clopidogrel is the second most common antiplatelet medication after aspirin.

Dipyridamole

• Dipyridamole is a phosphodiesterase inhibitor used to prevent platelet activation and is prescribed in specific circumstances.
• It's frequently used alongside aspirin, mainly in cases of vascular damage/clot.

GPIIb/IIIa receptor inhibitors

• GPIIb/IIIa inhibitors (e.g., abciximab) block fibrinogen binding to platelets; use is restricted to cardiac surgery and as adjunctive therapy.

Antiplatelet drugs - summary

• Various antiplatelet medications target different steps in platelet activation and aggregation, including ADP, PAR, and fibrinogen binding.

Fibrinolytics & Procoagulants

• Fibrinolytics (thrombolytics) break down existing clots.
• These drugs activate plasminogen, which converts to plasmin to digest fibrin.
• Procoagulants help stop bleeding and involve compounds like vitamin K and tranexamic acid.

Fibrinolytics/Thrombolytics

• Anticoagulants and antiplatelet drugs may be insufficient and thus fibrinolytics are used to break down existing clots.
• These drugs can be useful for treating conditions such as stroke and deep vein thrombosis (DVT)

Stroke

• Stroke is a cerebrovascular disorder causing significant global mortality and disability due to loss of blood flow to the brain, often due to thromboembolism.

Clot Breakdown

• tPA activates plasminogen to plasmin, which breaks down fibrin in the clot, leading to resolution of the clot.

Fibrinolytics

• Recombinant tPA (alteplase) and other fibrinolytics are among the primary medications used to break down blood clots rapidly, to promote clot dissolution and to maintain blood flow.

Procoagulants

• Procoagulants, especially tranexamic acid, are used to reduce bleeding by inhibiting fibrin breakdown and preventing clot degradation.
• Vitamin K and desmopressin also play a role to help stop bleeding.

Treatment Summary

• Treatment strategies for arterial and venous thrombosis involve different approaches, including anticoagulants, antiplatelet drugs, and in certain cases, fibrinolytics.

Hyperlipidaemia

• Hyperlipidaemia is characterized by abnormally high levels of lipids and lipoproteins in the blood, predominantly cholesterol.
• This can lead to the development of atherosclerosis.

Atherosclerosis

• Oxidized LDL cholesterol contributes to atheroma formation in arteries.
• HDL plays a role in removing cholesterol, and high cholesterol levels may lead to cholesterol deposition.
• Atheroma formation results in an inflammatory response and cell necrosis.
• A clot over a damaged artery leads to atherosclerosis.

Statins

• Statins, HMG-CoA reductase inhibitors, are crucial in blocking cholesterol production within the body and are a common form of treatment for hyperlipidaemia.

Fibrates

• Fibrates are PPARα agonists, promoting lipid catabolism, and they help lower triglycerides.

Others

• Ezetimibe is an enterocyte cholesterol transport inhibitor that can be used alongside other medications to lower cholesterol.
• Nicotinic acid (niacin) influences triglyceride and HDL cholesterol levels, though its use varies for various conditions.

Summary

• Thrombosis is treated with anticoagulants, antiplatelet drugs, and/or fibrinolytics depending on the type of thrombosis (arterial or venous).
• Hyperlipidemia and atherosclerosis are addressed with statins, fibrates, and other medications.
• Procoagulants are used to mitigate bleeding.

MBBS Learning Outcomes & Further Reading

• Students should learn the mechanisms of anticoagulants and how they function.
• Rang and Dale's Pharmacology and other relevant medical texts can be useful resources for further study.

Test your knowledge of drugs used in cardiology, including antiplatelet agents, anticoagulants, and fibrinolytics. This quiz covers drug mechanisms, uses, and classifications critical for managing cardiovascular conditions. Challenge yourself with questions about drug interactions and effects!