MBBS Antithrombotic & Antiplatelet Medications PDF

# MBBS Antithrombotic & Antiplatelet Medications - Dr Mitchell Lai - Department of Pharmacology - [email protected] ## Haemostasis - A diagram of haemostasis. - Diagram illustrates the different steps involved in a blood clot forming when a blood vessel is cut. - The first step is **...

# MBBS Antithrombotic & Antiplatelet Medications - Dr Mitchell Lai - Department of Pharmacology - [email protected] ## Haemostasis - A diagram of haemostasis. - Diagram illustrates the different steps involved in a blood clot forming when a blood vessel is cut. - The first step is **vasoconstriction** which then leads to a **platelet plug** forming. - The platelets adhere to the damaged area, become activated and form a plug, which then forms **fibrin strands** and a **network of fibrin**. - Finally, **fibrin formation** takes place. ## Anticlotting drugs - Diagram of the different types of anticlotting drugs. - **Antiplatelet drugs** - **Anticoagulants** - **Thrombolytics** ## I. Antiplatelet drugs - Diagram of the different types of antiplatelet drugs - **Non-steroidal anti-inflammatory drugs (Aspirin)** - **Platelet GPIIB/IIIA Receptor blockers (Abciximab, Eptifibatide, Tirofiban)** - **ADP Receptor blockers (Ticlopidine, Clopidogrel)** - **PDE inhibitor (Dipyridamole)** - PDE: phosphodiesterase ## Events involves in platelet activation and aggregation - Diagram of platelet activation and aggregation. - This diagram illustrates the steps involved in platelets becoming activated and aggregating to form a blood clot. - The steps are numbered 1-4 and include information about the action of aspirin and dipyridamole. - *Need to know*: Platelets which receive these start to release (their TXA2 also) 2: - Serotonin - ADP - 1: Healthy, intact endothelium releases prostacyclin in plasma. - Prostacyclin binds to platelet membrane receptors causing synthesis of cAMP. - cAMP inhibits release of granules containing aggregating agents. - 2: Thrombin, thromboxane A2 and exposed collagen cause the release of arachidonic acid from platelet membrane. - Thromboxane A2 is synthesised from arachidonic acid and released from the platelet. - This pathway is inhibited by aspirin. - 3: Thromboxane A2 binds to receptors on other platelets thereby initiating the release of additional aggregating agents. - 4: Balance between levels of prostacyclin and thromboxane A2 influences whether platelet aggregates or circulates freely. ## Aspirin - Diagram illustrating the action of aspirin. - Aspirin effects phospholipase A2, arachidonic acid and cyclooxygenase. - It results in decreased formation of PGI2, PGE2 and PGF2a. - Actions of aspirin - Phospholipid and arachidonic acid. - Cyclooxygenase. - Hydroperoxidase. - PGG2. - PGH2 - TXA2 - PGI2 - PGE2 - PGF2a - Pharmacokinetics - The inhibitory effect of aspirin on the platelets is rapid and lasts for the life of the platelet which is approximately 7-10 days. - Clinical Uses - Prophylactic treatment of transient cerebral ischemia. - To reduce the incidence of recurrent myocardial infarction. - To decrease mortality in postmyocardial infarction patients. - Adverse Effects: - Bleeding (PGI2) - Gastric upset and ulcers (PGE2) - *Gastrointestinal bleeding* - PGF2a - bronchus / uterine contraction ## GP IIB/IIIA receptors - Diagram illustrating the activation of GP IIB/IIIA receptors. - The IIb/Illa protein is a platelet membrane surface protein. - This diagram illustrates the process of platelet aggregation, which is the final common pathway for platelet aggregation. - It illustrates the activation of GPIIB/IIIA receptors by other molecules such as Thrombin, Plasmin, TXA2, ADP, PAF and Serotonin. - Note - AT III = Antithrombin III, Factor Xa, PAF = Platelet Activating Factor, TxA2 = Thromboxane A2, ADP = Adenosine Diphosphate, LMWH = Low-molecular-weight Heparin. ## Blockade of platelet GP IIB/IIIA receptors - Diagram of the different types of GPIIB/IIIA receptor blockers.. - **Abciximab** - A humanized monoclonal antibody directed against the IIb/Illa complex, which reversibly inhibits the binding of fibrinogen and other ligands to GPIIB/IIIA. - **Eptifibatide** - An analog of the sequence at the extreme carboxyl terminal of the delta chain of fibrinogen, which mediates the binding of fibrinogen to the receptor. - **Tirofiban** - A small molecule blocker of the GPIIB/IIIA receptor. - **Clinical Uses** - Used to prevent restenosis after coronary angioplasty and are used in acute coronary syndromes. ## Other platelet aggregation inhibitors - Diagram illustrating the action of the other platelet aggregation inhibitors - **Clopidogrel and Ticlopidine** - Action Mechanism: - Clopidogrel and ticlopidine block the ADP receptor. - **Dipyridamole** - Action Mechanism: - Dipyridamole inhibits PDE, which increases cAMP. ## II. Anticoagulants - Diagram illustrating the different types of anticoagulants. - **Heparin derivatives** - **Coumarin derivative (warfarin)** - **Lepirudin hirudin** - **Antithrombin III** ## Action of thrombin - Thrombin (factor IIa) activates upstream proteins, primarily factors V, VIII and XI, resulting in further thrombin generation. - It cleaves fibrinogen, producing fragments that polymerise to form fibrin. - It also activates factor XIII, a fibrinoligase, which strengthens fibrin-to-fibrin links, thereby stabilizing the coagulum. - It also causes platelet aggregation, stimulates cell proliferation and modulates smooth muscle contraction. ## Intrinsic pathway - A diagram illustrating the intrinsic coagulation pathway. - Diagram illustrates the steps involved in the intrinsic coagulation pathway which results in the formation of fibrin. - The steps include XII, Xlla, XI, Xla, IX, IXA, VIlla, X, Xa, Va, Prothrombin, Ila, Fibrinogen, Fibrin (Soluble) and Fibrin (insoluble). ## Extrinsic pathway - A diagram illustrating the extrinsic coagulation pathway. - Diagram illustrates the steps involved in the extrinsic coagulation pathway which results in the formation of fibrin. - The steps include TFPI, Vlla-TF, VII+TF, Xa, Va, Prothrombin, Ila, Fibrinogen, Fibrin (Soluble) and Fibrin (insoluble). ## Blood coagulation - Diagram illustrating the intrinsic and extrinsic coagulation pathways. - *Just need to know* - Thrombin is in the last step. - The intrinsic pathway is inhibited by heparin, while the extrinsic pathway is inhibited by oral anticoagulant drugs and by TFPI. - Diagram illustrates the intrinsic and extrinsic pathways, and the steps involved in each. - *Recall*: - This is a multi-step pathway - Amplification of signal - More checkpoints for control ## Antithrombin III and Heparin - Diagram illustrating the actions of antithrombin III and heparin. - Antithrombin III is an endogenous anticlotting protein that irreversibly inactivates clotting factor proteases, especially thrombin (IIa), IXa, and Xa, by forming equimolar stable complexes with them. - Heparin is not a single substance but a family of sulfated glycosaminoglycans (mucopolysaccharides). - Low molecular weight heparins (LMWHs) have better bioavailability and a longer half-life compared to regular (unfractionated) heparin. ## Actions of heparins - Diagram illustrating the actions of heparins. - The active heparin molecules bind tightly to ATIII and cause a conformational change, which exposes its active site for more rapid interaction with the proteases. - To inhibit thrombin, heparin needs to bind to the enzyme as well as to AT III; to inhibit factor X it is only necessary for heparin to bind to AT III. - LMWHs increase the action of antithrombin III on factor Xa but not its action on thrombin. - *Implications*: Lack of binding site for other enzymes does not count towards IIa. ## Heparin - Diagram illustrating the clinical uses and adverse effects of heparin. - Clinical uses: - Treatment of deep-vein thrombosis, pulmonary embolism, and acute myocardial infarction. - Can be used in combination with thrombolytics for revascularization and in combination with GP IIb/IIIa inhibitors during angioplasty and placement of coronary stents. - Can be used when an anticoagulant must be used in pregnancy (e.g., treatment of venous thromboembolism (VTE). - Pharmacokinetics: - Given intravenously or subcutaneously - IM - *haematomas!!!!* - Adverse Effects: - Haemorrhage: stop heparin therapy + protamine sulfate (cationic peptide). - *Protamine sulfate* binds to excess heparin. - Thrombocytopenia. ## Heparin - Diagram illustrating the adverse effects of heparin. - 1: Haemorrhage: stop heparin therapy + protamine sulfate. - 2: Thrombosis and Thrombocytopenia. ## Vitamin K - Diagram illustrating the action of vitamin K. - Vitamin K is a fat-soluble vitamin occurring naturally in plants and is essential in the formation of clotting factors II, VII, IX and X. - Actions of vitamin K: reduced Vitamin K is an essential cofactor in the carboxylation of glutamate residues. - Clinical uses of vitamin K - Treatment and/or prevention of bleeding resulting from the use of oral anticoagulant drugs (e.g. warfarin) - Babies: to prevent haemorrhagic disease of the newborn - For vitamin K deficiencies in adults. ## Warfarin - Diagram illustrating the action of Warfarin. - Warfarin (Wisconsin Alumni Research Foundation) - Actions of Warfarin - Vitamin K reduced form (hydroquinone) - Vitamin K (quinone) - Vitamin K oxidised form (epoxide) - Warfarin. - Sweet Clover. ## Warfarin - Diagram illustrating the clinical uses, pharmacokinetics and adverse effects of warfarin. - Clinical uses of Warfarin: - Same as Heparin except in pregnant women. - Pharmacokinetics of Warfarin - Warfarin is a small and lipid-soluble molecule and is given orally, absorbed quickly and totally. - It has a small distribution volume and is strongly bound to plasma albumin - Elimination depends on metabolism by hepatic cytochrome P450. - Adverse Effects of Warfarin - Bleeding - Warfarin should never be administered during pregnancy. - Warfarin crosses the placenta and can cause hemorrhagic disorder in the fetus as fetal proteins with gamma-carboxyglutamate residues found in bone and blood may be affected by warfarin. - Drug Interactions - Warfarin can interact with barbiturates, carbamazepine and phenytoin, as well as with amiodarone, cimetidine, disulfiram and imipramine. ## III. Thrombolytic Agents - Diagram illustrating the different types of thrombolytic agents. - t-PA (alteplase) - Urokinase - Streptokinase - Anistreplase - *t-PA: tissue plasminogen activator* ## Fibrinolytic system - Diagram illustrating the fibrinolytic system. - This diagram illustrates the steps involved in the fibrinolytic system. - The process begins with plasminogen which can be activated by streptokinase, alteplase, anistreplase or urokinase to form plasmin. - Plasmin can then break down fibrin, fibrinogen and thrombin. ## Clinical uses - 1: Emergency treatment of coronary artery thrombosis. - 2: Peripheral arterial thrombosis and emboli. - 3: Ischaemic stroke (< 4.5 hr window). ## Pharmacokinetics - Intracoronary injection, intravenous injection. ## Adverse Effects - **Bleeding** - Contraindication: healing wound, pregnancy ## Summary of anticlotting drugs - Diagram illustrating the summary of anticlotting drugs. - This diagram illustrates the actions of the different types of anticlotting drugs. - It shows the formation of a thrombus, and the different types of anticlotting drugs that can be used to prevent or dissolve the thrombus. # MBBS Medications for Coronary (Ischemic) Heart Disease - Dr Mitchell Lai - Department of Pharmacology - [email protected] ## Types of Angina - Angina pectoris is a characteristic chest pain caused by insufficient coronary blood flow to meet the oxygen demands of the myocardium. - 1: **Atherosclerotic Angina** - associated with atherosclerotic plaques that partially occlude one or more coronaries. - 2: **Vasospastic Angina** - (rest angina, variant angina) - 3: **Unstable Angina** - (acute coronary syndrome) ## Determinants of cardiac oxygen requirement - Diagram illustrating the determinants of cardiac oxygen requirement. - This diagram illustrates the factors that influence cardiac oxygen requirement. - The determining factors are broken down into two categories: **Preload** and **Afterload**. - **Preload**: the diastolic filling pressure. It depends on blood volume and venous tone. - **Afterload**: the resistance to ejection of stroke volume. It is determined by the arterial blood pressure. ## Therapy of angina* - Diagram illustrating the therapy for angina. - *Antiplatelets and cholesterol-lowering medications are also used but are covered in their respective lectures* - **Vasodilators** - **Nitrates** - **Calcium channel blockers** - **Cardiac depressants** - **Beta-Blockers** - **Cardiac pacemaker retardant** - **Ivabradine** - *Blue: Covered in related lecture - *Red: Go through here* ## Nitrates - Diagram illustrating the mechanism of action of Nitrates. - Nitrates: Mechanism of action - Nitric Oxide: causes vasodilation by stimulating guanylyl cyclase. - This diagram illustrates the mechanism of action for nitrates. - In this diagram MLCK* is the active form of myosin light chain kinase and MLCK-(PO4)2 is the phosphorylated form of MLCK. - **Nitrates** → **Nitric Oxide** → **Guanylyl cyclase** → **cGMP** → **GTP** → **Myosin-LC** → **relaxation** - Nitrates increase cGMP by stimulating guanylyl cyclase, which in turn relaxes the smooth muscle and causes vasodilation. # Nitrates: Therapeutic Effects - Diagram illustrating the therapeutic effects of nitrates. - Therapeutic effects of nitrates. - *Nitrates oxide donor?* - **Action:** - Vasorelaxation - Venodilation → preload decreased → oxygen consumption decreased → therapy of angina - Arteriolar dilation → afterload decreased → oxygen consumption decreased → therapy of angina ## Glycerol Nitrates - Diagram illustrating the pharmacokinetics of Glycerol Nitrates. - The diagram illustrates the breakdown of nitroglycerin. - This diagram illustrates the breakdown of nitroglycerin, which is the most commonly used nitrate for acute treatment of angina pectoris. - Nitroglycerin is metabolized by the enzyme GSH S-transferase in the body. - **H₂C-CH-CH₂(NO₂)₃** → **Nitroglycerin (glyceryl trinitrate)** → **Significant vasodilation** - **H₂C-CH-CH₂(NO2)₂** → **glyceryl dinitrate** → **Significant vasodilation** - **H₂C-CH-CH₂(NO₂)₁** → **glyceryl mononitrate** → **Less active** - Nitroglycerin for acute treatment of angina pectoris. - Administration - Onset of action - Duration of action - **Sublingual** → **1-5 mins** → **10-30 mins** - **Transdermal** → **30-60 mins** → **7-10 hours** ## Isosorbide Dinitrate (ISDN) - Diagram illustrating the pharmacokinetics of Isosorbide Dinitrate (ISDN). - This diagram illustrates the metabolism of Isosorbide Dinitrate, where after the donation of one molecule of nitric oxide, is converted to isosorbide mononitrate. - **O₂NO-Isosorbide-ONO₂** → **Isosorbide dinitrate** - **O₂NO-Isosorbide-OH** → **Isosorbide mononitrate** - ISDN (with a comparison to ISMN) - Administration - Onset of action - Duration of action - **ISDN: Oral** → **60 mins** → **8 hours (IR), 12 hours (SR)** - **ISMN: Oral** → **30-45 mins** → **6 hours (IR), ≤24 hours (SR)** - ISDN and ISMN are both nitrates that can be used to treat angina pectoris. - Although their clinical effects are similar, their pharmacokinetics are different. - ISDN has a longer duration of action than ISMN. ## ISMN / ISDN - Diagram illustrating the clinical uses and the pharmacokinetic features of Isosorbide Mononitrate (ISMN) and Isosorbide Dinitrate (ISDN). - *effect fand in high C, too* - Clinical uses of ISMN and ISDN - For angina pectoris prophylaxis, also used in the treatment of heart failure. - Pharmacokinetic (PD) features - 1. Low plasma concentrations → venous dilatation → peripheral pooling of blood → decreased venous return and reduction in left ventricular end-diastolic pressure (preload). - 2. High plasma concentrations → also dilate the arteries → reducing systemic vascular resistance and arterial pressure → reduction in cardiac afterload. - 3. Also has a direct dilatory effect on the coronary arteries (by reducing end diastolic pressure and volume → lowers the intramural pressure → improvement in the subendocardial blood flow. ## Nitrates: Side Effects - Diagram illustrating the side effects of nitrates. - Side effects of nitrates. - Vasorelaxation - Venodilation → Hypotension - Baroreflex → Reflex tachycardia - Meningeal artery vasodilation → Headache ## β- Blockers - (see **Antihypertensive lecture**) ## MOA of Beta-Blockers for IHD / angina - Diagram illustrating the MOA of beta-blockers. - **Mechanism of action of beta-blockers** - Beta-blockers decrease heart rate and contractility, which reduces cardiac oxygen requirements. - Decrease rate and contractility reduces cardiac oxygen requirements. - *Beta-blockade* → **Adenylyl cyclase** → **CAMP** → **MLCK** → **Contraction** ## Calcium Channel Blockers - Diagram illustrating the action of calcium channel blockers. - Calcium Channel blockers - *Ca2+ channel blocker* - **Actions** - Sinoatrial nodal - Atrioventricular nodal - Supraventricular Reentry Tachycardia - Verapamil, Diltiazem - Myocardial Contractility, Cardiac Output - Oxygen Requirement - Nifedipine, Amlodipine - **Clinical Uses** - Antiarrhythmia (Non-DHP) - Anti-angina (Non-DHP & DHP) - Anti-hypertension (DHP) ## Calcium Channel Blockers - Diagram illustrating the different actions and adverse effects of calcium channel blockers. - Calcium channel blockers (continued) - Lowering BP: - Verapamil = diltiazem = nifedipine - Vasodilator: - Nifedipine > diltiazem > verapamil - Cardiac depressant: - Verapamil > diltiazem > nifedipine - Adverse Effects: - Cardiac Depression: Bradycardia, AV blocker, heart failure ## MOA of DHP Calcium Channel Blockers - Diagram illustrating the mechanism of action of DHP Calcium Channel Blockers. - MOA of DHP Calcium Channel Blockers - *Ca2+ channel blocker* - ***B2-Agonists*** - **Adenylyl cyclase** → **cAMP** → **MLCK** → **Contraction** - ***Nitrates*** → **Nitric Oxide** → **Guanylyl cyclase** → **cGMP** → **GTP** → **Myosin-LC** → **relaxation** ## DHP Calcium Channel Blockers - Diagram illustrating the clinical uses and adverse effects of DHP Calcium Channel Blockers. - *must mention all 3 + hyper a 3m ago* - Clinical uses of DHP Calcium Channel Blockers: - 1: Hypertension - 2: Stable angina (Amlodipine) - 3: Reduce risk of myocardial infarction and stroke (Amlodipine) - Adverse Effects: - 1: Hypotension - 2: Heart Failure - 3: Myocardial infarction ## Ivabradine - Diagram illustrating the pharmacological features and adverse effects of Ivabradine. - Ivabradine - **Pharmacological Features** - A 'pure' heart rate lowering agent, indicated for stable angina pectoris. - Also indicated for chronic heart failure with systolic dysfunction, in patients in sinus rhythm and whose heart rate is ≥ 75 bpm. - Specific inhibition of the cardiac pacemaker I(f) current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate. - Reduction in cardiac workload and myocardial oxygen consumption. - **Adverse Effects** - Visual problems: luminous phenomena, transient enhanced brightness in limited area of the visual field. - Dizziness (related to bradycardia) - Other bradycardia associated symptoms (hypotension, fatigue, malaise) ## Drugs commonly used in treating hypertension - A table listing the drugs commonly used in treating hypertension, as well as drugs that can be used as an alternative. - Concomitant disease - Commonly Used drugs - Alternate Drugs - **Angina Pectoris**: - Diuretics - β-blockers - ACE -I/ARB - Ca2+ channel blockers - **Congestive Heart Failure**: - Diuretics - β-blockers - ACE-I/ARB - X - **Previous Myocardial Infarction**: - Diuretics - β-blockers - ACE-I/ARB - Ca2+ channel blockers - **Chronic Renal Disease**: - Diuretics - β-blockers - ACE-I/ARB - Ca2+ channel blockers - **Asthma**: - Diuretics - X - ACE-I/ARB - Ca2+ channel blockers - **Diabetes**: - Diuretics - X - ACE-I/ARB - Ca2+ channel blockers - **Pregnancy**: - Diuretics - β-blockers - X - Ca2+ channel blockers - *ACE-I/ARB: ACE inhibitors or Ang II receptor blockers*