Anti-Platelet Drugs: Pharmacology Lecture - PDF

Gastrointestinal Block Pharmacology Team 439 Helpful video Color index: Main Text...

Gastrointestinal Block Pharmacology Team 439 Helpful video Color index: Main Text Important Dr’s Notes Female Slides Anti-Platelet Male Slides Drugs Extra We highly recommend studying physiology of platelets before this lecture Objectives: - Basic concept of Activation of platelets and aggregation - Anti-platelet drugs: A. Inhibition of thromboxane A2 synthesis via inhibiting COX-1: Aspirin B. Antagonist of ADP receptors: Clopidogrel, Ticlopidine C. GP IIb/IIIa receptor antagonists: Abciximab,Tirofiban and Eptifibatide D. Phosphodiesterase 3 (PDE) inhibitors/adenosine uptake inhibitors - Pharmacotherapeutic profile of the individual classes (mechanism, indications, adverse drugs reactions) Editing file Summary  Platelets and clots formation Platelets and vessels In healthy vessels, circulating platelets are maintained in an inactive state by nitric oxide (NO) and prostacyclin (PGI2) released by endothelial cells lining the blood vessels. Injury to the vessel wall leads to interaction between platelets, endothelial system and coagulation factors which lead to formation of the CLOT. Activation of platelets after vascular injury ❖ Injury exposes reactive subendothelial matrix proteins, platelet adherence & activation, + secretion & synthesis of vasoconstrictors & platelet activating molecules. ❖ Thus, Thromboxane A2 (TXA2) is synthesized from arachidonic acid within platelets & is platelet activator & potent vasoconstrictor. ❖ Adenosine diphosphate (ADP), secreted from platelet, a powerful inducer of platelet aggregation ❖ Serotonin (5HT), which stimulates aggregation & vasoconstriction. ❖ Activation of platelets, → aggregation & conformational change in the GPIIb/IIIa, enabling it to bind fibrinogen, which cross-links adjacent platelets → aggregation & formation of a platelet plug. ❖ Simultaneously, the coagulation system cascade is activated → thrombin generation & a fibrin clot, which stabilizes the platelet plug. Clot ➔ Thrombus: CLOT that adheres to vessel wall. ➔ Embolus: CLOT that floats in the blood. ➔ Thrombosis: Formation of unwanted clot within the blood vessels, producing life threatening condition such as: - Acute myocardial infarction (MI) - Acute ischemic stroke (AIS) - Deep vein thrombosis (DVT) - Pulmonary embolism (PE)  Drugs used in thrombosis #CVS Anticoagulants: Antiplatelets: Thrombolytics or drugs which prevent clotting drugs which prevent and Fibrinolytics: by inhibiting clotting factors inhibit platelet activation and Drugs which reduce or lysis (coagulation process). aggression. used in prevention and used as prophylactic the clot. used in the acute treatment of thrombosis. therapy in high risk patients. treatment of thrombosis. IMPORTANT Each drug site of action is specified in the pictures in drug tables Drugs target for platelet inhibition M.O.A Drug R.O.A Inhibition of thromboxane A2 Aspirin Oral synthesis via inhibiting COX-1 Inhibition of ADP-induced platelet Clopidogrel aggregation Oral Ticlopidine (ADP receptor antagonists) Abciximab GP IIb/IIIa receptor antagonists Tirofiban I.V (Inhibitors) Eptifibatide Phosphodiesterase 3 (PDE) Dipyridamole inhibitor/adenosine uptake Oral Cilostazol inhibitors  MOA of Antiplatelet Drugs (Extra) Plaque Disruption Collagen vWF Platelet adhesion and secretion Aspirin COX-1 TXA2 ADP Ticlopidine Clopidogrel Platelet recruitment and activation GPIIb/IIIa activation Abciximab Eptifibatide Tirofiban Platelet aggregation Arachidonic acid pathway inhibitors Drug Aspirin (Acetylsalicylic Acid) Irreversible inhibition of cyclooxygenase enzyme (COX-1) via acetylation, thus inhibiting synthesis of TXA2. Ishfaq: Make sure to mention COX-1 in the answer M.O.A Low dose (75-160 mg) selectively inhibits COX-1, Decreasing synthesis of platelets thromboxane (TXA2) and inhibit platelet aggregation, but spares the protective PGI2 synthesis Prophylaxis of thromboembolism e.g. unstable angina, myocardial infarction, ischemic stroke. Uses Combined with other antiplatelet aggregating: (clopidogrel) and anticoagulants (heparin). Hyperacidity (Risk of peptic ulcer) ADRs Allergy Increased incidence of GIT bleeding (aspirin prolongs bleeding time) Contraindication Peptic ulcer  ADP Pathway Inhibitors Ticlopidine Drug Clopidogrel T= more Toxic - Irreversibly block ADP receptor of platelets - Inhibits ADP-induced expression of platelet membrane M.O.A GPIIb/IIIa and fibrinogen binding to activated platelets. - ADP causes Direct aggregation of platelets and indirectly increases GPIIb/IIIa receptor expression - Pro-drugs P.k - Require metabolism by the hepatic cytochrome p450 (CYP) enzyme system to active form - Prevent thrombosis (unlike aspirin that is used as a primary prophylactic) - Prevention of vascular events in pts with: Uses Transient ischemic attacks Unstable angina pectoris Placement of a coronary stent ‫دﻋﺎﻣﺔ‬ - Patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease. Specific Indications - Patients with acute coronary syndrome (unstable angina/ MI): either those managed medically or with percutaneous coronary intervention (PCI) with or without stent. - GIT: nausea, dyspepsia, diarrhea. - Hemorrhage (prolong bleeding time) - Same but fewer than ticlopidine - Leukopenia - Longer duration of action (once daily - TTP (thrombotic thrombocytopenic purpura) dosing, ticlopidine given twice daily) ADRs Precaution: Regular monitoring of WBC Clopidogrel has replaced ticlopidine: count during first three months - More potent (Therapy with ticlopidine requires regular - Better safety profile monitoring for neutropenia) Antiplatelet Drugs: Prevent blood clots from forming in the arteries. Monitoring: Bleeding time (Antiplatelet drugs increase bleeding time) Aspirin is the most commonly prescribed antiplatelet drug. Aspirin-Clopidogrel: Clopidogrel works by reducing the “stickiness” of platelets in a similar way to aspirin & is often recommended as an alternative for people who cannot take aspirin. Given together in high risk patients May be recommended for people who have had a heart attack, a severe attack of angina, or who have undergone a coronary angioplasty & stenting. Aspirin Resistance: Resistance: recurrent thrombosis while on antiplatelet therapy. The reported incidence of resistance varies greatly, from 5 % to 75%. Although aspirin reduces the production of TXA2, it may fail to inhibit platelet aggregation because platelets continue to respond strongly to other agonists. TXA2-induced platelet aggregation is only ONE of many factors leading to thrombus formation, which is the most common, but not the only, mechanism leading to ischemic events.  Glycoprotein IIb/IIIa receptor Inhibitors (Monoclonal Antibodies) Drug Abciximab Tirofiban Eptifibatide (non-peptide drug) (peptide drug) - GP IIb/IIIa receptor Blockers (antagonists) GPIIb/IIIa is found on the surface of platelets and is the most abundant receptor. M.O.A Activated, GPIIb/IIIa binds adhesive molecules, such as fibrinogen and vWF to promote clotting. Abciximab binds to GPIIb/IIIa and stops the clot formation. - Given parenterally only (doesn’t need to be activated by the liver) P.k Abciximab has long half life while Tirofiban & Eptifibatide have short half life. - In acute MI patients - Administered IV as an adjuvant to angioplasty surgery for the prevention of ischemic complications of angioplasty. - With heparin or aspirin (using combinations will also increase bleeding risks) Uses To prevent thrombosis (Prevention of vascular events in pts with): - Acute coronary syndrome - Percutaneous coronary intervention: (angioplasty with stent) a procedure used to open clogged heart arteries. Angioplasty involves temporarily inserting and inflating a tiny balloon to help widen the artery. - Bleeding ADRs - Thrombocytopenia (immune reaction) Phosphodiesterase (PDE) Inhibitor Drug Dipyridamole Cilostazol - Vasodilator - Inhibits platelet function Phosphodiesterase (PDE3) inhibitor, by inhibiting adenosine uptake M.O.A promotes vasodilation & inhibits platelet - Inhibits cAMP metabolism aggregation. by inhibiting phosphodiesterase activity. - cAMP for anti Platelet action When given alone it has little to no beneficial effect. Prevention of intermittent Uses Thus given in combination with aspirin to prevent Claudication: muscle ischaemia during exercise caused by obstruction to arterial flow. cerebrovascular ischemia. Ishfaq: C for claudication Due to its vasodilatory properties it should be used in Precaution caution in coronary problems (because the vasodilation will cause reflex tachycardia), clopidogrel is a better choice.  Summary ADRs/ Class Drug M.O.A Uses Precautions Prophylaxis of Low dose selectively and pathway inhibitors thromboembolism e.g. Arachidonic acid Irreversibly inhibits COX-1 via unstable angina, acetylation, decreasing myocardial infarction, Hyperacidity (Risk Aspirin synthesis of platelets ischemic stroke. of peptic ulcer) (Acetylsalicylic Acid) thromboxane Combined with other Allergy (TXA2) and inhibit platelet aggregation, but spares the antiplatelet aggregating: protective PGI2 synthesis. (clopidogrel) and anticoagulants (heparin). Prevent thrombosis Ticlopidine ADP Pathway Inhibitors - Irreversibly block ADP Prevention of vascular Ticlopidine: receptor of platelets events in pts with: - GIT - Inhibits ADP-induced TIA, Unstable angina - Hemorrhage expression of platelet pectoris, Coronary stent - Leukopenia membrane GPIIb/IIIa and Clopidogrel: - TTP fibrinogen binding to activated - Patients with a history Precaution: Regular Clopidogrel of recent MI, stroke, or monitoring of WBC platelets. - ADP causes Direct aggregation of established peripheral count during first platelets and indirectly increases arterial disease. three months GPIIb/IIIa receptor expression - Patients with acute (for neutropenia) coronary syndrome To prevent thrombosis (Prevention of vascular Glycoprotein IIb/IIIa receptor Abciximab GP IIb/IIIa receptor Blockers events in pts with): (antagonists) Acute coronary GPIIb/IIIa is found on the syndrome, Percutaneous surface of platelets and is the coronary intervention Inhibitors most abundant receptor. - Bleeding Tirofiban Activated, GPIIb/IIIa binds Abciximab: - Thrombocytopenia (non-peptide drug) adhesive molecules, such as - In acute MI patients (immune reaction) fibrinogen and vWF - Administered IV as an to promote clotting. adjuvant to angioplasty Abciximab binds to GPIIb/IIIa surgery Eptifibatide and stops the clot formation. - With heparin or aspirin (but it increase bleeding (peptide drug) risks) Precautions: - Vasodilator When given alone it has Due to its Phosphodiesterase (PDE) - Inhibits platelet function little to no beneficial vasodilatory by inhibiting adenosine uptake effect. Thus given in properties it should Dipyridamole - Inhibits cAMP metabolism combination with aspirin be used in caution in by inhibiting to prevent Inhibitor coronary problems, phosphodiesterase activity. cerebrovascular clopidogrel is a better - cAMP for anti Platelet action ischemia. choice. Phosphodiesterase (PDE3) Prevention of inhibitor, promotes intermittent Cilostazol vasodilation & inhibits platelet Claudication aggregation. Ishfaq: C for claudication  MCQs Q1: A man who is taking omeprazole for his hyperacidity is in a very high risk of myocardial infarction and came to the clinic and the doctor prescribed him an antiplatelet agent, which one of the following drugs is contraindicated in this patient? A-Cilostazol B-Ticlopidine C-Aspirin D-Dipyridamole Q2: A 56-year old woman started to take an antiplatelet agent two months ago, she came back to the clinic due to an infection. CBC showed decreased neutrophils count, which drug is she most likely on? A- Ticlopidine B-Aspirin C- Abciximab D-Clopidogrel Q3: Which of the following is an ADR for Glycoprotein IIb/IIIa receptor Inhibitors? A- Dyspnea B-Thrombocytopenia C-Leucopenia D-Hyperacidity Q4: What is the MOA of Dipyridamole? C-Glycoprotein IIb/IIIa D-Arachidonic acid A- PDE inhibitor B-ADP pathway inhibitor receptor Inhibitors inhibitor Q5: A patient came to you in the emergency department with MI, you wanted to prescribe aspirin but she said she's allergic to it, what is the best alternative drug in her case? A-Clopidogrel B-Prasugrel C-Abciximab D-Tirofiban Q6:A 55 year-old diabetic man went to the clinic due to severe distal leg pain, you diagnosed him with intermittent claudications, which one of the following drugs will you prescribe? A- Eptifibatide B-Aspirin C-Dipyridamole D-Cilostazol Q7: A patient is undergoing a percutaneous coronary angioplasty, which one of the following drugs can be administered parenterally? A- Clopidogrel B-Cilostazol C-Abciximab D-Ticlopidine Q8: Which enzyme does a small dose of aspirin block? A- COX-1 B- COX-2 C- PGI2 D- A&B 1 2 3 4 5 6 7 8 C A B A A D C A  SAQ Q1)What is the mechanism of action of ticlopidine? Q2) List two Glycoproteins llb/llla receptor inhibitors drugs and two ADRs: Q3.1) Mention two drugs used in Acute Coronary Syndrome? Q3.2) Mention their MOAs Q3.3) Mention two ADRs for each class Answers A1) inhibition of ADP induced platelets aggregation (ADP receptor antagonist). A2) Abciximab,tirofiban. ADRs: bleeding, thrombocytopenia A3.1) A) Clopidogrel B) Abciximab A3.2) A) Irreversible blocking of ADP receptors B) GP IIb/IIIa receptor blocker A3.3) A) TTP and Leukopenia B) Bleeding and thrombocytopenia Feedback Form Gastrointestinal Block Pharmacology Team 439 Leaders Banan AlQady Ghada AlOthman Nawaf Alshahrani Organizers Note Takers Revisers Ghada Aljedaie Duaa Alhumoudi Dana Naibulharam Hind Almotywea Homoud Algadheb Mishal Althunayan Mais Alajami Mishal Althunayan Omar Alhalabi Norah Alasheikh Omar Alhalabi Nouf Alsubaie Yasmine Alqarni Sadem Alzayed Shatha Aldhohair Shayma Alghanoum Tarfa Alsharidi Members Abdulaziz Alderaywsh Arwa alqahtani Norah Almasaad Abdulaziz Alghuligah Feras Alqaidi Noura Bamarei Abdulrahman Almebki Lama Alahmadi Rand AlRefaei Abdulrhman Alsuhaibany Maha Alanazi Rawan Bakader Aljoharah Albnyan Manal Altwaim Salem Alshihri Aljoud Algazlan Mona Alomiriny Shahd Almezel