Veterinary Pharmacology of the Blood PDF

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE BLOOD Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] BIBLIOGRAPHY (all the tables and figures provided at...

PHARMACOLOGY AND THERAPEUTICS II PHARMACOLOGY OF THE BLOOD Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected] BIBLIOGRAPHY (all the tables and figures provided at this presentation belong to this book except in particular indicated cases) TABLE OF CONTENTS Hemostasis and the clotting cascade – revision of concepts Heparin Warfarin and Coumarin Derivatives Thrombin and Factor Xa inhibitors Agents for Treating Coagulopathies Antiplatelet drugs (aspirin and clopidogrel) Fibrinolytic drugs Antifibrinolytic drugs HEMOSTASIS  Vascular and HEMOSTASIS Platelet phases Coagulation phase Involvement of prostaglandins Vascular and Platelet phases HEMOSTASIS AND ANTI-COAGULANTS HEPARIN Heparin calcium (slow, less used) and heparin sodium (fast, more used) In vivo and in vitro anti-coagulation and anti-thrombotic properties Direct and almost instantaneous action on the coagulation process. Indications Used to prevent and treat hypercoagulability and coagulation disorders such as thromboembolism, venous thrombosis, disseminated intravascular coagulopathy (DIC), and pulmonary thromboembolism. Heparin is usually administered SC or IV because IM administration may create a hematoma. It is definitely not “a drug for which one dose fits all” HEPARIN Conventional form: unfractionated heparin (UFH). More recent use: low-molecular weight heparins (LMWH) - tinzaparin (Innohep®), enoxaparin (Lovenox®), and dalteparin (Fargmin®). HEPARIN Action It produces a change in the anti-thrombin (AT) molecule that significantly enhances its inhibitory effect on various activated coagulation factors. The predominant effect of this binding is the inhibition of thrombin (factor IIa), as well as factors IXa and Xa. But…. UFH inactivates both factor Xa and thrombin. The additional inactivation of thrombin by UFH increases the anticoagulant activity, but also increases the risk of bleeding. LMWH inactivates factor Xa because they are not large enough to bind both thrombin and AT. HEPARIN Adverse Effects Adverse effects are caused by excessive inhibition of coagulation and produce bleeding problems in patients. Heparin-induced thrombocytopenia, a problem in people, has not been cited as a problem in animals. If excessive anticoagulation and bleeding occur as a result of an overdose, protamine sulfate should be administered (“antidote”). Heparins interact with other drugs and it is not advised to mix it with other injectable drugs. It should be used cautiously in animals that are already receiving other drugs that can interfere with coagulation.  WARFARIN AND COUMARIN DERIVATIVES Warfarin sodium is the most common agent used in this group (marketed as Coumadin®). Warfarin, as well as other vitamin-K antagonists, are still used commonly as rodenticides because they produce fatal internal bleeding. Domestic animals can be intoxicated through accidental exposure. Warfarin and the other coumarin derivatives provoke in vivo inhibition of blood coagulation mechanisms. This activity is achieved by inhibiting the hepatic synthesis of vitamin K-dependent clotting factors, prothrombin, and factors VII, IX, and X.  WARFARIN AND COUMARIN DERIVATIVES In all animals studied (including people) the protein binding is high – greater than 90% (often higher than 95%). Warfarin and other coumarin derivatives are consistently well absorbed orally. Reliable and consistent oral absorption is not associated with predictable activity. The variability is caused by differences among animals in metabolism, activity of cytochrome P450 (CYP450) metabolizing enzymes, genetic differences, a possible influence of diet composition (amount of vitamin K), and interaction with other drugs. These agents are not used commonly in veterinary medicine today. THROMBIN INHIBITORS The inhibition of thrombin is a key role in producing anticoagulant effects. Thrombin is a logical target because… 1) it is involved in the final step in coagulation 2) thrombin is also an activator of platelets. Dabigatran etexilate (Pradaxa®) is the most promising of the thrombin inhibitors at this time, with little information on its use in veterinary medicine. One of the disadvantages of new anticoagulant drugs has been bleeding problems and the inability to reverse these effects until recently. VM?  FACTOR XA INHIBITORS Direct factor Xa inhibitors include rivaroxaban (Xarelto®) and apixaban (Eliquis®), both of which have become popular in human medicine. The newest agent in this group is edoxaban (Savaysa®). The inhibition of Xa appears to produce less bleeding adverse events than inhibition of thrombin. Dogs with immune-mediated hemolytic anemia (IMHA) are prone to thromboembolism and they typically have poor response to antiplatelet therapy, heparin (as LMWH), so new agents such as rivaroxaban have been studied. AGENTS FOR TREATING SPECIFIC COAGULOPATIES Desmopressin acetate (DDAVP) is a synthetic analogue of vasopressin and is used in the treatment of central Diabetes insipidus and to transiently elevate levels of vWF. The elevation in von Willebrand factor (vWF) allows surgical procedures to be performed and aids in the control of capillary bleeding from wounds in humans and animals with certain forms of vW disease. When DDAVP is administered, it releases stored vWF from endothelial cells and macrophages and rapidly raises vWF levels. This effect is reduced if the drug is given repeatedly, because the storage pools will be depleted. The duration of elevation is approximately 2 hours. Source: My Hematology ANTIPLATELET DRUGS – ASPIRIN® + CLOPIDOGREL Platelets have a central role in the initiation and propagation of thrombus formation. They release a variety of substances that promote coagulation, and they also form the initial platelet plug. A variety of drugs can be used to reduce platelet function. Clinically this should be beneficial in the prevention of thrombotic disease. The most common indications in veterinary medicine are to prevent thrombi associated with feline cardiomyopathy and to reduce the severity of pulmonary endarteritis associated with heartworm disease.  ACETYLSALICYLIC ACID – ASPIRIN® It is an NSAID that inhibits COXs, especially COX1, even in low doses. After oral administration, aspirin is absorbed into the portal vein where most of the platelet acetylation of COX1 occurs, impairing the activation and aggregation of platelets. Clinical doses are varied because of inconsistency of experimental results. Sometimes in combination with clopidogrel. Many dogs do not respond to low-dose aspirin and as many as 30% are not responsive. Cats have inconsistent response to low doses, and it is less effective than clopidogrel. CLOPIDOGREL Clopidogrel is a prodrug that undergoes biotransformation into its active metabolite. The active metabolite is a P2Y12 receptor inhibitor, thereby preventing ADP from exerting its strong cyclic AMP-dependent aggregating action. Its onset of action is, therefore, slow. Clopidogrel is primarily metabolized by two main pathways: 1) leading to the formation of the inactive carboxylic acid metabolite (SR26334) 2) leading to the active metabolite, a thiol derivate, through the formation of 2-oxo- clopidogrel. This active metabolite is responsible for the antiplatelet effects. Because aspirin is inconsistent as an antiplatelet drug in animals, the interest of clopidogrel in veterinary medicine increased. It is used as an antiplatelet drug for patients with heart disease, thromboembolic disorders, heartworm disease, immune-mediated hemolytic anaemia, and cats at risk of cardiogenic arterial thromboembolism. This drug has been safely administered to cats, rabbits, dogs, and calves. FIBRINOLYSIS FIBRINOLYSIS PHASE Plasminogen is present in a platelet clot, and fibrinolysis is initiated when plasminogen is activated into plasmin by endothelial cells and fibroblasts. Plasmin also degrades other substances in the clot and surroundings like prothrombin, fibrinogen and clotting factors. https://medical-dictionary.thefreedictionary.com/Fibrinolysis+system FIBRINOLYTIC AGENTS  FIBRINOLYTIC AGENTS The use of these agents is expensive, and there is little evidence available to show that the benefits outweigh the risks. Although it is an important component of the emergency treatment in people for acute ischemic strokes, myocardial infarction, deep vein thrombosis, and pulmonary thromboembolism, it has not been very successful in animals. The most common clinical presentations where this treatment is considered is feline arterial thromboembolism and canine pulmonary thromboembolism. Pharmacological acceleration of fibrinolysis involves drugs that enhance the conversion of the inactive precursor plasminogen to the active fibrinolytic enzyme plasmin. Thus, when a plasminogen-activating agent comes in contact with the clot, plasminogen is activated to plasmin locally with selective fibrinolysis. Streptokinase Tissue-type plasminogen activator (t-PA)  ANTIFIBRINOLYTIC AGENTS Fibrinolysis produces the breakdown of fibrin clots through the conversion of plasminogen to plasmin. There is a balance between clot- forming processes and fibrinolysis in normal animals. Excessive fibrinolysis can lead to excessive bleeding disorders. Drugs available for treatment of hyperfibrinolytic conditions are aminocaproic acid and tranexamic acid. These synthetic lysine compounds decrease fibrinolysis by binding to fibrin and competing for lysine-binding sites to inhibit plasminogen and plasmin. Aminocaproic acid prevents the association of fibrin with plasminogen. Tranexamic acid is an analogue of aminocaproic acid and has the same properties, and is used for the same indications. The adverse effects include thrombosis and an increased risk of neurological events, including seizures. THANK YOU VERY MUCH! Catarina Jota Baptista Assistant Professor DVM, MSc, PhD in Veterinary Sciences [email protected]