Antianginal Drugs

1. Antianginal Drugs ► Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms. ► It is caused by coronary blood flow that is insufficient to meet the oxygen demands of the myocardium, leading to ischemia. ► The imbalance between oxygen delivery and utilization may result during exertion, from a spasm of the vascular smooth muscle, or from obstruction of blood vessels caused by atherosclerotic lesions. ► These transient episodes (15 seconds to 15 minutes) ► nitrates, beta blockers and calcium channel blockers are used ►Lifestyle and risk factor modifications, especially cessation of smoking, are important in the treatment of angina. ► angioplasty and coronary artery bypass surgery are also medication

4. A. Stable angina • It is called typical angina pectoris. • It is characterized by a burning, heavy, or squeezing feeling in the chest. • It is caused by atherosclerosis. • Typical angina pectoris is promptly relieved by rest or nitroglycerin • B. Unstable angina • Unstable angina lies between stable angina on the one hand and myocardial infarction on the other. In unstable angina, chest pains occur with increased frequency. The symptoms are not relieved by rest or nitroglycerin. • Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm • May be associated with myocardial infarction

5. Therapeutic rationale: Inhibit platelet aggregation and thrombus formation (increase oxygen delivery), decrease cardiac load (decrease oxygen demand), and vasodilate coronary arteries (increase oxygen delivery)C. Prinzmetal's or variant or vasospastic anginait occurs at rest and is due to coronary artery spasm. Prinzmetal's angina generally responds promptly tocoronary vasodilators, such as nitroglycerin and calcium-channel blockers.D. Mixed forms of angina Patients with advanced coronary artery disease may present with angina episodes during effort as well as at rest

6. Organic Nitrates • isosorbidedinitrateand isosorbidemononitrateare solids at room temperature, nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile. Mechanism of action • Nitrates relax vascular smooth muscle by their intracellular conversion to nitrite ions, and then to nitric oxide (endothelial relaxation factor), which in turn activates guanylatecyclase and increases the cells' cyclic guanosinemonophosphate (GMP) • Elevated cGMP ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle relaxation

7. Mechanism of Action of Nitrovasodilators Nitrates become denitrated by glutathione S-transferase to release Nitric Oxide activates GuanylateCyclase* converts GTP cGMP activates cGMP-dependent protein kinase • Activation of PKG results in phosphorylation • of several proteins that reduce intracellular calcium • causing smooth muscle relaxation

8. Effects on the cardiovascular system ► They cause dilation of the large veins, resulting in pooling of blood in the veins. This diminishes preload and reduces the work of the heart. ► Second, nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle. Pharmacokinetics • The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbidemononitrate • Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination.

9. Adverse effects ♥ headaches, ♥ High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia. ♥Sildenafilpotentiates the action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated. Tolerance • The blood vessels become desensitized to vasodilation. • So daily dose nitrate-free interval restores sensitivity to the drug. This interval is at night because demand on the heart is decreased. • Nitroglycerin patches are worn for 12 hours then removed for 12 hours. However, variant angina worsens early in the morning, perhaps due to circadian catecholamine surges. So the free interval occur in the late afternoon.

10. β-Adrenergic Blockers They suppress the activation of the heart by blocking β1 receptors reducing the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure. The demand for oxygen by the myocardium is reduced both during exertion and at rest. • Propranolol is not cardioselective. • metoprololor atenolol, are crdioselective • Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. • in the treatment of patients with myocardial infarction and have been shown to prolong survival. • used with nitrates to increase exercise duration and tolerance.

11. They are contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral vascular disease, or chronic obstructive pulmonary disease. • It is important not to discontinue beta-blocker therapy abruptly. The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.] • Bet-blockers are contraindicated in variant angina

12. Calcium-Channel Blockers • Calcium is essential for muscular contraction. Calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. • The calcium channel blockers protect the tissue by inhibiting the entrance of calcium into cardiac and smooth muscle cells of the coronary and systemic arterial beds. • All calcium-channel blockers are therefore arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular resistance. • At clinical doses, these agents affect primarily the resistance of vascular smooth muscle and the myocardium. [Note: Verapamilmainly affects the myocardium, whereas nifedipineexerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazemis intermediate in its actions.]

13. A. Nifedipine • Nifedipine a dihydropyridine derivative, functions mainly as an arteriolar vasodilator. • Other members of this class are amlodipine, nicardipine, and felodipine • Nifedipinecan cause flushing, headache, hypotension, and peripheral edema as side effects of its vasodilation activity. As with all calcium-channel blockers, constipation is a problem. Because it has little to no sympathetic antagonistic action, nifedipinemay cause reflex tachycardia if peripheral vasodilation is marked. short-acting dihydropyridines should be avoided in coronary artery disease.] • B. Verapamil • The diphenylalkylamine slows AV conduction directly, and decreases heart rate, contractility, blood pressure, and oxygen demand. Verapamilcauses greater negative inotropic effects than nifedipine, but it is a weaker vasodilator. itis contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities. It also causes constipation. • Verapamil increases digoxinlevels.

14. Blood Drugs Thrombus VS. Embolus۞ A clot that adheres to a vessel wall is called a thrombus۞ An intravascular clot that floats in the blood is termed an embolus. ۞ Both thrombi and emboli are dangerous, because they may occlude blood vessels and deprive tissues of oxygen and nutrients. Platelet Response to Vascular InjuryA. Resting platelets۞ In the absence of injury, resting platelets circulate freely, because the balance of chemical signals. ۞prostacyclin and nitricoxide, are synthesized by intact endothelial cells and act as inhibitors of platelet aggregation. ۞Prostacyclin (prostaglandin I2 binds to platelet membrane receptors leading to the synthesis of cAMP۞ cAMP decreases intracellular Ca2+ that inhibits platelet activation.

15. B. Platelet adhesion۞ When the endothelium is injured, platelets adhere the exposed collagen  C. Platelet activationReceptors on the surface of the platelets are activated by the collagen D. Platelet aggregationThe increase in cytosolicCa2+ accompanying activation is due to a release of sequestered stores within the platelet This leads to 1) the release of platelet granules containing mediators, such as ADP and serotonin that activate other platelets 2) activation of thromboxane A2 synthesis3) activation of the glycoprotein (GP) IIb/IIIareceptors that bind fibrinogen and, ultimately, regulate platelet-platelet interaction and thrombus formation .

17. E. Formation of a clotLocal stimulation of the coagulation cascade by tissue factors released from the injured tissue and by mediators on the surface of platelets results in the formation of thrombin (Factor IIa) which catalyzes the hydrolysis of fibrinogen to fibrin that forms strands stabilizes the clot and forms a hemostatic platelet-fibrin plugF. FibrinolysisDuring plug formation, the fibrinolytic pathway is locally activated. Plasminogen is enzymatically processed toplasmin (fibrinolysin) by plasminogen activators in the tissue. Plasmin limits the growth of the clot and dissolves the fibrin network as wounds heal.

18. The role of platelets

19. The role of platelets

20. The role of platelets

21. The role of platelets

23. Platelet Aggregation InhibitorsA. AspirinMechanism of actioninhibits thromboxane A2 synthesis by irreversible acetylation of COX-1 and inhibits platelet aggregation that last for the life of platelet”approximately7 to 10 days.Usesin the prophylactic treatment of transient cerebral ischemia. The dose: 81 to 325 mg side effects gastrointestinal bleeding, especially at higher doses. Ibuprofen, if taken concomitantly with, or 2 hours prior to aspirin can inhibit its action. Therefore, aspirin should be taken at least 30 minutes before ibuprofen or at least 8 hours after ibuprofen.

25. B. Ticlopidine and clopidogrelMechanism of action: They irreversibly inhibit the binding of ADP to its receptors on platelets and, thus, inhibit the activation of the GP IIb/IIIareceptors required for platelets to bind to fibrinogen and to each other.Therapeutic use:Ticlopidine is usedfor the prevention of transient ischemic attacks and strokes. Used as adjunct therapy with aspirin following coronary stent implantation to decrease the incidence of stent thrombosis. it is generally reserved for patients who are intolerant to other therapies due to its life-threatening hematologic adverse reactions Clopidogrelis approved for prevention of atherosclerotic events following recent myocardial infarction. It is also approved for prophylaxis of thrombotic events in unstable angina or myocardial infarction. Itis used to prevent thrombotic events associated with percutaneous coronary intervention with or without coronary stent.clopidogrelhas a better overall side-effect profile

27. C. Abciximab (is expensive) monoclonal antibodybinds to GP IIb/IIIaof platelets , blocking the binding of fibrinogen and von Willebrand factor blocking aggregation Abciximabis given intravenously along with heparin or aspirin as an adjunct to percutaneous coronary intervention. The major adverse effect of abciximabtherapy is the potential for bleeding, especially if the drug is used with anticoagulants. E. DipyridamoleDipyridamoleincreases intracellular levels of cAMP by inhibiting cyclic nucleotide phosphodiesterase, resulting in decreased thromboxane A2 synthesis.dipyridamoleis effective for inhibiting embolization from prosthetic heart valves.

29. Intrinsic Pathway Extrinsic Pathway Tissue Injury Blood Vessel Injury Tissue Factor XIIa XII Thromboplastin XIa XI IXa VIIa VII IX Xa X X Prothrombin Thrombin Factors affected By Heparin Fribrin monomer Fibrinogen Fibrin polymer Vit. K dependent Factors Affected by Oral Anticoagulants XIII

30. The balance between the formation and degradation of FN Nesheim, M. Chest 2003;124:33S-39S

31. AnticoagulantsA. Thrombin inhibitors: heparin , enoxaparin (LMW)Mechanism of action: Heparin serves as a true catalyst, allowing antithrombin III to rapidly combine with and inhibit circulating thrombin and Factor XaTherapeutic uses: treatment of acute deep-vein thrombosis and pulmonary embolism. . prophylactically to prevent postoperative venous thrombosis in , dialysis machines) to prevent thrombosis. treating pregnant women (do not cross the placenta due to large size).Adverse effects: Bleeding complications: treated with protamine sulfateHypersensitivity reactions: from porcine sources and, antigenic. Thrombosis: Chronic use of heparin can lead to a reduction in antithrombin III activity, thus decreasing the inactivation of coagulation factors c. Thrombocytopenia

32. Vitamin K antagonists (warfarin) Mechanism of action: Several of the protein coagulation factors (including Factors II, VII, IX, and X) require vitamin K as a cofactor for their synthesis by the liver. Warfarin inhibit vitamin K epoxidereductase that regenerate it Therapeutic uses: to prevent the progression or recurrence of acute deep-vein thrombosis or pulmonary embolism after initial heparin treatment.Prophylactically, it is used in patients with acute myocardial infarction, prosthetic heart valves, or chronic atrial fibrillation.Pharmacokinetics:99 percent bound to plasma albumin, as sulfonamides, can displace itWarfarinreadily crosses the placental barrier ( C.I in pregnancy)Adverse effects:Bleeding disorders: treated wih oral vitamin K1 Skin lesions and necrosis are rare complications of warfarintherapy and are observed primarily in women.

34. Thrombolytic drugs –mechanism of action

35. Alteplase tissue plasminogen activator, or tPA) . It is now obtained as a product of recombinant DNA technology.Mechanism of action: Alteplasehas a low affinity for free plasminogen in the plasma, but it rapidly activatesplasminogen that is bound to fibrin in a thrombus or a hemostatic plug. Thus, alteplaseis said to be fibrinselective and at low doses, it has the advantage of lysing only fibrin.Therapeutic uses: Alteplaseis approved for the treatment of myocardial infarction, massive pulmonary embolism, and acute ischemic stroke. Alteplaseseems to be superior to streptokinase in dissolving older clots Adverse effects: Bleeding complications, including gastrointestinal and cerebral hemorrhages, may occur.

37. Streptokinasepurified from culture broths of Group hemolytic streptococci.Mechanism of action: it forms an active one-to-one complexwith plasminogen. This complex converts uncomplexedplasminogen to the active enzyme plasmin . In addition to the hydrolysis of fibrin plugs, the complex also catalyzes the degradation of fibrinogen as well as clotting Factors V and VII Therapeutic uses: in acute pulmonary embolism, deep-vein thrombosis, acute myocardial infarction, arterial thrombosis, and occluded access shunts.Adverse effects:Bleeding Hypersensitivity and presence of antibody against the drug due to streptococcal infection, circulating antibodies against streptokinase decrease its activity and cause hypersensitivity

39. Anistreplase (anisoylatedplasminogen streptokinase activator complex)Anistreplaseis a preformed complex of streptokinase and plasminogen and it is considered to be a prodrug.Streptokinase must be released, and only plasminogen to which it was associated will get converted to plasmin which hydrolyzes fibrin plugs