Angina

ANG IN A dr shah murad

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 Angina results from a reduction in the oxygen supply/demand ratio.  Therefore, in order to alleviate the pain, it is necessary to improve this ratio.  This can be done either by increasing blood flow (which increases oxygen delivery or supply), or by decreasing oxygen demand (i.e., by decreasing myocardial oxygen 4 consumption).

 Pharmacologic interventions that block coronary vasospasm (coronary vasodilators) or inhibit clot formation are used to treat variant and unstable angina, respectively.  These drugs act by increasing coronary blood flow and oxygen supply

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 The goals of angina therapy are relieving symptoms and treating the underlying CAD that caused the symptoms.

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Sym ptom r eli ef Angina symptoms can be relieved by medications (nitrates, beta-blockers, and calcium channel blockers) and procedures (coronary angioplasty and coronary artery bypass grafting (CABG) surgery).

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Co ronary a rtery dise ase ( CAD) treatme nt

CAD is treated by  medications (anti-platelet, blood pressure, and cholesterol medications)  and lifestyle modifications (eating a healthy diet, exercising regularly, avoiding smoking, and maintaining a healthy weight). 8

 Angina Prevention Through Good Choices  One of the reasons that some people may shrug off the possibility of developing heart disease and angina is that it's a gradual, lifelong process that people can't see or feel. 9

 There are usually no "early angina symptoms," so people continue to make poor choices, thinking that angina will not happen to them.  Look at the odds -- 1 in 3 Americans will develop heart disease.  What are good choices for heart disease and angina prevention then? Good choices include: 10

 Get moving  Maintaining a healthy weight  Eating a well-balanced, heart-healthy diet  Controlling blood pressure and cholesterol  Preventing or managing diabetes  Not smoking

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Preventing Angina: Summary  Because of advances in medicine and technology, people with angina are living longer, more productive lives than ever before.  However, preventing angina is still the best weapon in the fight against this condition.

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 As with anything in life, there are no guarantees. You could do all the right things and still develop angina, because there are so many factors involved

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 By living a healthier life, however, you could delay angina for years or minimize its damage.  Whether you are already healthy, are at high risk for angina or heart disease, or have survived a heart attack, the advice to protect your heart is the same. 14

DRU GS USE D 1. Vasodilators

-calcium-channel blockers - nitrodilators

2. Cardioinhibitory drugs (reduce heart rate and contractility) - beta-blockers - calcium-channel blockers

3. Anti-thrombotic drugs (prevent thrombus formation) - anticoagulants - anti-platelet drugs 15

VAS ODI LAT ORS             

Alpha-adrenoceptor antagonists (alpha-blockers) Angiotensin converting enzyme (ACE) inhibitors Angiotensin receptor blockers (ARBs) Beta2-adrenoceptor agonists (b2-agonists) Calcium-channel blockers (CCBs) Centrally acting sympatholytics Direct acting vasodilators Endothelin receptor antagonists Ganglionic blockers Nitrodilators Phosphodiesterase inhibitors Potassium-channel openers Renin inhibitors

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NI TRI TE & NITRATES

 isosorbide dinitrate

 isosorbide mononitrate  nitroglycerin  erythrityl tetranitrate  Penta-erythritol tetranitrate  sodium nitroprusside

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Nitroglycerin  Has been used since the 19th century, is commonly used in the treatment of angina because it is very fast acting (within 2 to 5 minutes) when administered sublingually.  Its effects usually wear off within 30 minutes. Therefore, nitroglycerin is particularly useful for preventing or terminating an acute anginal attack. 18

 Longer-acting preparations of nitroglycerin (e.g., transdermal patches) have a longer onset of action (30 to 60 minutes), but are effective for 12 to 24 hours.  Intravenous nitroglycerin is used in the hospital setting for unstable angina and acute heart failure.

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Isosorbide dinitrate and mononitrate, and tetr an itrate  Have a longer onset of action and duration of action than nitroglycerin.  This makes these compounds more useful than short-acting nitroglycerin for the long-term prophylaxis and management of coronary artery disease. 20

 Oral bioavailability of many organic nitrates is low because of first-pass metabolism by the liver.  Isosorbide mononitrate, which has nearly 100% bioavailability, is the exception.  Therefore, oral administration of these compounds requires much higher doses than sublingual administration, which is not subject to first-pass hepatic metabolism. 21

 The metabolites of organic nitrates are biologically active and have a longer halflife than the parent compound.  Therefore, the metabolites contribute significantly to the therapeutic activity of the compound. 22

Sodium nitroprusside  is used to treat severe hypertensive emergencies and severe heart failure, has a rapid onset of action.  It is only available as an intravenous preparation, and because of its short half-life, continuous infusion is required. 23

Sid e Ef fects and Co ntr ain dic atio ns  The most common side effects of nitrodilators are headache (caused by cerebral vasodilation) and cutaneous flushing.  Other side effects include postural hypotension and reflex tachycardia.  Excessive hypotension and tachycardia can worsen the angina by increasing oxygen demand. 24

 Prolonged use of sodium nitroprusside carries the risk of thiocyanate toxicity because nitroprusside releases cyanide along with NO. The thiocyanate is formed in the liver from the reduction of cyanide by a sulfhydryl donor.

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 Cynide ion rapidly complexes with the iron in cytochrome oxidase,resulting in a block of oxidative metabolism and cell death.  Fortunately,the iron in met-hemoglobin has a higher affinity for cynide than does the iron in cytochrome oxidase.  Nitrites convert the ferrous iron in Hb to the ferric form,yielding met-hemoglobin. 26

Cyn id e p oiso nin g c an be t re ated b y 3 st eps 2. Immediate exposure to AMYL NITRITE,followed by 3. IV administration of sodium nitrite,which rapidly increases the met-hemoglobin level to the degree necessary to remove a significant amount of cynide from cytochrome oxidase. 4. IV sidium thiosulfate,which converts cyano-methemoglobin resulting from step 2 to thiocynate and met-hemoglobin. (Thiocynate is much less toxic than cynide and is 27 excreted by kidney.)

 There is clinical evidence that nitrodilators may interact adversely with cGMP-dependent phosphodiesterase inhibitors that are used to treat erectile dysfunction (e.g., sildenafil (VIAGRA).  The reason for this adverse reaction is that nitrodilators stimulate cGMP production and drugs like sildenafil inhibit cGMP degradation. When combined, these two drug classes greatly potentiate cGMP levels, which can lead to hypotension and impaired coronary 28 perfusion.

Th era peutic Indic atio ns  The primary pharmacologic action of nitrodilators, arterial and venous dilation, make these compounds useful in the treatment of hypertension, heart failure, angina and myocardial infarction.  Another beneficial action of nitrodilators is their ability to inhibit platelet aggregation. 29

Use s o f n itr odila tors  Hypertension. Nitrodilators are not used to treat chronic primary or secondary hypertension; however, sodium nitroprusside and nitroglycerine are used to lower blood pressure in acute hypertensive emergencies that may result from a pheochromocytoma, renal artery stenosis, aortic dissection, etc.  Nitrodilators may also be used during surgery to to control arterial pressure 30 within desired limits.

 Heart failure. Nitrodilators are used in acute heart failure and in severe chronic heart failure. Arterial dilation reduces afterload on the failing ventricle and leads to an increase in stroke volume and ejection fraction.

 Furthermore, the venous dilation reduces venous pressure, which helps to reduce edema.

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 Angina and myocardial infarction. Nitrodilators are used extensively to treat angina and myocardial infarction.

 They are useful in Printzmetal's variant angina because they improve coronary blood flow (i.e., increase oxygen supply) by reversing and inhibiting coronary vasospasm. 32

 These drugs also reduce systemic vascular resistance (depending on dose) and arterial pressure, which further reduces myocardial oxygen demand. Taken together, these two actions dramatically improve the oxygen supply/demand ratio and thereby reduce anginal pain.

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NO  In the cardiovascular system, NO is primarily produced by vascular endothelial cells.  This endothelial-derived NO has several important functions including relaxing vascular smooth muscle (vasodilation), inhibiting platelet aggregation (anti-thrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory).  These actions involve NO-stimulated formation of cGMP.  Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues.  These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelialindependent vasodilators.

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 There are two basic types of nitrodilators: those that release NO spontaneously (e.g., sodium nitroprusside) and organic nitrates that require an enzymatic process to form NO.  Organic nitrates do not directly release NO, however, their nitrate groups interact with enzymes and intracellular sulfhydryl groups that reduce the nitrate groups to NO or to S37 nitrosothiol, which then is reduced to NO.

 Nitric oxide activates smooth muscle soluble guanylyl cyclase (GC) to form cGMP. Increased intracellular cGMP inhibits calcium entry into the cell, thereby decreasing intracellular calcium concentrations and causing smooth muscle relaxation.  NO also activates K+ channels, which leads to hyperpolarization and relaxation.  Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation. 38

To le rance to nitr odila tors

 Tolerance to nitrodilators occurs with frequent dosing, which decreases their efficacy.  The problem is partially circumvented by using the smallest effective dose of the compound coupled with infrequent or irregular dosing.  The mechanism for tolerance is not fully understood, but it may involve depletion of tissue sulfhydryl groups, or scavenging of NO by superoxide anion and the subsequent production of peroxynitrite that may inhibit 39 guanylyl cyclase.

 Although nitrodilators can dilate both arteries and veins, venous dilation predominates when these drugs are given at normal therapeutic doses.  Venous dilation reduces venous pressure and decreases ventricular preload.  This reduces ventricular wall stress and oxygen demand by the heart, thereby enhancing the oxygen supply/demand ratio. 40

 Mild coronary dilation or reversal of coronary vasospasm will further enhance the oxygen supply/demand ratio and diminish the anginal pain.  Coronary dilation occurs primarily in the large epicardial vessels, which diminishes the likelihood of coronary vascular steal.  Systemic arterial dilation reduces afterload, which can enhance cardiac output while at the same time reducing ventricular wall stress and oxygen demand. 41

 At high concentrations, excessive systemic vasodilation may lead to hypotension and a baroreceptor reflex that produces tachycardia.  When this occurs, the beneficial effects on the oxygen supply/demand ratio are partially offset.  Furthermore, tachycardia, by reducing the duration of diastole, decreases the time available for coronary perfusion, most of which occurs during diastole 42

 Beta blockers are used in the prophylaxis of exertional angina by reducing the work the heart is allowed to perform below the level that would provoke an angina attack.  They cannot be used in vasospastic angina and can precipitate heart failure. 43

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Beta blockers decrease cardiac work by blocking receptors in the myocardium and thereby decreasing cardiac output.

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They also reduce cardiac work by decreasing blood pressure.

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All beta-1 selective and nonselective beta blockers are effective in atherosclerotic angina.

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These drugs do not cause vasodilatation.

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Although all of the "pure antagonist" beta-blockers appear to be equally effective in the prophylaxis of classic angina, only 2 (propranolol and nadolol) are presently labeled for this use

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 Beta-blockers slow the heart rate, lower blood pressure, and decrease the oxygen demands of the heart.  Limiting the heart rate and reducing the heart's oxygen needs during exercise are effective in reducing or eliminating angina symptoms.

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 Beta-blockers are usually administered in pill or injection form.  Depending on the dose and method of administration, beta-blockers usually take effect in 15 minutes to 1 hour and act from 12 to 24 hours.  Common side effects of beta-blockers include dizziness, fatigue, lightheadedness, weakness, sleep disturbances, and impotence. 47

 Unusual and potentially serious side effects can include fainting, very slow heartbeat (less than 50 beats per minute), shortness of breath, increasing chest pain, depression, skin rash, and diarrhea.

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Ca lc iu m c hannel blo ckers

Verapamil Nifedipine Nicardipine Diltiazem Isradipine Felodipine Bepridil Amlodipine Nisoldipine

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 Calcium channel blockers cause blood vessels to dilate and blood pressure to decrease, reducing the stress on the heart and decreasing or eliminating angina symptoms.

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 Calcium channel blockers are usually administered in pill or injection form.

 Depending on the dose and method of administration, calcium channel blockers usually take effect within 20 minutes to 1 hour and act for 12 to 24 hours. 51

 Physicians may prescribe calcium channel blockers in combination with beta-blockers and nitrates to control the symptoms of angina.

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Cholesterol medications  High levels of cholesterol in the blood contribute to the development of CAD plaques.  Lowering cholesterol with medication decreases the rate of CAD accumulation in the coronary arteries.

 In addition, statin medications appear to prevent CAD plaques from rupturing and causing heart attacks.

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STATINS BILE ACID SEQUESTRANTS FIBRATES NIACIN (vitamin B-3)

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 Statins: Statins lower blood lipid levels by blocking the liver from manufacturing cholesterol.  Bile acid sequestrants: Bile acid sequestrants block the reabsorption of cholesterol from the small intestine into the bloodstream.

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 Fibrates: Fibrates lower several types of cholesterol and triglycerides in the blood, although their mechanism of action is not clear

 Niacin (vitamin B3): Niacin acts on the liver to decrease production of harmful types of cholesterol, and increase production of helpful types of cholesterol in the body. 56

Anti-platelet medications  Platelets can be thought of as tiny plugs that can come together to form blood clots.  Heart attacks occur when a plaque in a coronary artery ruptures.  In response to the rupture, platelets rapidly accumulate in the artery and obstruct blood flow.  Thus, a mainstay of therapy for people with CAD is medication to prevent platelets from accumulating. 57

 These medications are usually administered as a pill.

 Anti-platelet medications usually take effect in 10 minutes to 2 hours and act for 4 to 48 hours. 58

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Common side effects of anti-platelets include stomach pain, heartburn or indigestion, nausea or vomiting, upset stomach, fatigue, muscle aches, headache, 59 change in bowel habits.

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Unusual and potentially serious side effects include chest pain, loss of hearing or vision problems, red or purple spots on the skin, bloody urine or stools, unusual bleeding, confusion or convulsions (seizures), severe diarrhea, severe nausea or vomiting, or vomiting blood, difficulty in swallowing, 60 dizziness or lightheadedness, and unexplained fever.

An ti- pla tele ts Aspirin Clopidogrel Ticlopidine

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