Antianginals

The major common determinant of myocardial oxygen consumption is:

Myocardial fiber tension

Venodilators effect preload how?

Preload is the workload presented to the heart, the blood coming back to the heart to be pumped, termed venous return. Note that venodilators decrease venous return. This decreases the wall tension and myocardial oxygen consumption. Workload before heart contraction Filling pressure or venous return of the heart, Depends on venous tone and blood volume Determines end-diastolic fiber length and tension Venodilators decrease preload

This figure demonstrates the effect that calcium channel blockers have on stable angina in patients that are exercising

Dose-response effects of Ca channel blocker (diltiazem) Diltiazem reduces double product and prolongs excercise time

If a β blocker were to be used for prophylaxis in this patient, what is the most probable mechanism of action in angina? (A) Block of exercise-induced tachycardia (B) Decreased end-diastolic ventricular volume (C) Dilation of constricted coronary vessels (D) Increased cardiac force (E) Increased resting heart rate

(A) Block of exercise-induced tachycardia

In advising the patient about the adverse effects he may notice, you point out that nitroglycerin in moderate doses often produces certain symptoms. Which of the following effects might occur due to the mechanism listed? (A) Headache due to meningeal vasodilation (B) Hypertension due to reflex tachycardia (C) Dizziness due to reduced cardiac force (D) Apnea due to cranial vasodilation (E) Diuresis due to sympathetic discharge

(A) Headache due to meningeal vasodilation

One year later, the patient returns complaining that his nitroglycerin works well when he takes it for an acute attack but that he is having frequent attacks now and would like something to prevent them. Useful drugs for the prophylaxis of exercise-induced angina include which one of the following? (A) Amyl nitrite (B) Diltiazem (C) Esmolol (D) Sublingual isosorbide dinitrate (E) Sublingual nitroglycerin

(B) Diltiazem

When nitrates are used in combination with other drugs for the treatment of angina, which one of the following combinations results in additive effects on the variable specified? (A) Beta-blockers and nitrates on end-diastolic cardiac size (B) Beta-blockers and nitrates on heart rate (C) Calcium channel blockers and beta-blockers on cardiac force (D) Calcium channel blockers and nitrates on cardiac ejection time (E) Non-dihydropyridine calcium channel blockers and nitrates on heart rate

(C) Calcium channel blockers and beta-blockers on cardiac force

A patient is admitted to the emergency department following a drug overdose. He is noted to have severe tachycardia. He has been receiving therapy for hypertension and angina. A drug that often causes tachycardia is: (A) Diltiazem (B) Clonidine (C) Isosorbide dinitrate (D) Propranolol (E) Verapamil

(C) Isosorbide dinitrate

A 60-year-old man presents to his primary care physician with a complaint of severe chest pain when he walks uphill to his home in cold weather. The pain disappears when he rests. After evaluation and discussion of treatment options, a decision is made to treat him with nitroglycerin. Which of the following is common direct or reflex effect of nitroglycerin? (A) Decreased heart rate (B) Decreased venous capacitance (C) Increased afterload (D) Increased cardiac force (E) Increased diastolic intramyocardial fiber tension

(D) Increased cardiac force

A 74-year-old man presents with a history of anterior chest pressure when he walks more than one block. The chest pain is relieved within 3 min when he stops walking. A diagnosis of stable angina in made. Which of the following drugs would be most effective in reducing the acute pain associated with walking and reduce the chance of blood clotting? (A) Esmolol (B) Nifedipine (C) Verapamil (D) Metoprolol (E) Isosorbide dinitrate

(E) Isosorbide dinitrate

arteriodilators affect what?

Afterload is the workload the heart must overcome to pump the blood out of the heart - peripheral resistance or the diastolic pressure Decreasing afterload is the main effect of arteriodilators

what causes Angina and how is it treated?

Angina is induced by ischemia, which is a lack of oxygen to the heart 1. There are agents that decrease the demand for oxygen to the heart 2. There are agents that increase the supply of oxygen to the heart. Statin drugs are in this group as well because they enhance nitric oxide (NO) synthase activity and enhance NO release.

Many different factors go into the myocardial oxygen supply

Dr. Young presents a summary of the additive determinants of myocardial oxygen consumption There are a few diastolic factors: 1. blood volume 2. venous tone There are many systolic factors: 1. peripheral resistance 2. heart rate 3. heart force 4. ejection time These factors combine to make the intramyocardial fiber tension, which determines the myocardial oxygen requirement. Myocardial oxygen supply is dependent on coronary blood flow. Coronary flow is mainly dependent on local metabolites, such as decreased oxygen, increased hydrogen ions, lactate, and adenosine, and endothelial factors (NO). Coronary flow is inversely proportional to coronary vascular bed resistance. Arteriolar tone controls vascular resistance and determines systolic wall stress. Venous tone controls the amount of blood returned to the heart and determines diastolic wall stress. The coronary vessels are extremely important for oxygen supply to the heart. Ischemia is the most potent vasodilator. Vasospastic coronary vessels can be relaxed and dilated, which can open collateral vessels. Arteriosclerotic and atherosclerotic vessels do not dilate like normal vessels. Dilator drugs may cause a "coronary steal" effect. Some drugs may shunt blood flow away from the occluded vessels. Systemic reduction of preload and afterload which decreases cardiac work and oxygen demand is the primary effect of vasodilation.

Beta blockers are another important drug for treatment of angina

Inhibition of β-1 effect in heart decreases heart rate and contractility and reduces O2 demand →Not vasodilator →Reduced heart rate prolongs diastole to increase in diastolic coronary perfusion time →Block tachycardia reflexed by nitrates & Ca antagonists (nifedipine class) Effective for *unstable and stable angina (prophylaxis); but not effective for varient angina* →Β1-blocker (eg, atenolol, metoprolol) is preferred →Avoid agents with intrinsic sympathomimetic activity (i.e., pindolol) →Caution when combined with Ca channel blocker due to additive cardiac depressant Beta-1 blockers, such as metoprolol, decrease HR, which leads to decreased BP and oxygen demand Beta-2 blockers, such as propranolol, may cause some peripheral vasoconstriction

Nifedipine

Nifedipine is another example of a calcium channel blocker It is one of the dihydropyridines, which are arteriolar dilators *Excessive dilation of the vessels may trigger reflex HR* This drug is used in stable angina and especially vasospastic angina (Prinzmetal's) Adverse effects are primarily related to excessive vasodilation and involve nausea, lightheadedness, dizziness, headache, tachycardia, and peripheral edema Other drugs in this class involve amlodipine and nicardipine

"Fixed" (Stable) is precipitated by exercise and/or excitement

Stable angina is relieved by rest It is caused by obstruction in one or more of the coronary arteries, and the lesion is usually arteriosclerotic. Nitroglycerin, calcium channel blockers, and beta blockers can be used to treat stable angina. An individual can become tolerant to nitroglycerin, so it is important to understand that there are other ways to treat angina

Nitrates and nitrites are important treatments for angina, what is the mechanism?

The mechanism involves nitric oxide (NO) synthesis from endothelial nitric oxide synthase (eNOS) and NO release, leading to guanylyl cyclase and cGMP activation, which relaxes smooth muscle by dephosphorylation of myosin light chain kinase (MLC) and relaxation of the myosin light chains Vasodilation occurs in a gradient manner In the figure, Dr. Young points out that sildenafil (Viagra), a phosphodiesterase inhibitor, can also be efficacious with reducing infarct size, but combining it with nitrates can lead to an unsafe drop in blood pressure, a fact so eloquently stated by Viagra commercials. Most prominent effect on veins is to pool the blood, which *decreases preload*. Pulmonary vascular pressures and heart size are significantly decreased due to *reduced myocardial diastolic fiber length and wall tension*. The arteries and arterioles dilate, which increases with dosage, decreasing afterload and BP In fixed (stable) angina, the above actions decrease cardiac work and the demand for oxygen. In variant or Prinzmetals angina, vasodilation, the relaxation of smooth muscle, relieves the vasospasm. This leads to increased coronary blood flow via collateral vessels in ischemic area. *Platelet aggregation also decreases*, which leads to decreased thrombosis in these vessels

calcium channel blockers are another group of drugs used to treat angina, mechanism

These drugs block slow voltage-dependent, L-type calcium channels to prevent influx calcium in smooth muscle, as well as cardiac nodal and muscle cells. They decrease myocardial contractility to reduce oxygen requirement. Decreased arteriolar tone results in decreased vascular resistance. *These drugs cause relief of coronary artery spasm and are principally used as prophylactic*. Both verapamil and diltiazem possess cardiac activity and vasodilator activity The nifedipine class has little direct effect on heart and are primarily considered vasodilators *These drugs are mainly used to relieve vasospasm in variant and stable angina*

Examples of calcium channel blockers

Verapamil and diltiazem are examples of calcium channel blockers They cause vasodilation, which decreases afterload They decrease HR and AV conduction Verapamil does this more extensively than diltiazem They also decrease myocardial contractility Usually with high doses or toxicity, they may cause CHF Again, verapamil does this more extensively than diltiazem These drugs are used in *variant and stable angina* and fast atrial and nodal arrhythmias to slow HR and AV conduction *Take caution if these drugs are used with beta blockers due to excessive reduction of contractility and possible resultant CHF*

"Unstable Angina"

is used to categorize a variety of clinical presentations involving acute ischemic syndromes that are progressive, and in the initial stages, indistinguishable from impending myocardial infarction The condition is believed to be caused by thrombosis in a blood vessel Unstable angina is very unpredictable clinically Nitroglycerin and beta blockers can be used to treat unstable angina Calcium channel blockers are not used to treat unstable angina

Adverse effects *Nitroglycerin*

include excessive dilation (decreased BP) reflex heart rate (HR), dizziness (orthostatic hypotension), vasomotor flushing, and *headache due to meningeal artery dilation*. Dizziness is exacerbated when nitrates are combined with an alpha-1 blocker. Headache can also occur and be exacerbated during the rebound effect, or reactions to when an individual is taken off of nitrates.

"Silent Ischemia"

is ischemia of the myocardium without pain or symptoms

*Nitroglycerin*

given sublingual (0.15-0.6 mg), IV, and oral spray (0.4 mg) Nitroglycerin is generally inactive PO, due to 10-20% bioavailability, hepatic metabolism, and the first-pass effect There are sustained release preps to counter the first-pass effect of nitroglycerin These are the agents with prolonged action used to prevent attacks of angina, given orally and topically: 1. Nitroglycerin Ointment (2%) 2. *Nitroglycerin Transdermal* (2.5 to 15 mg/24 hrs) 3. *Isosorbide Dinitrate* 4. Penterythritol Tetranitrate 5. Erythrityl Tetranitrate The body can develop *tolerance*, cross tolerance, and rebound with nitrates and nitrites, usually with longer acting preps, such as a transdermal patch. These drugs are used for *stable (exercise-induced) angina, variant angina, unstable angina, and acute attacks of angina* The *sublingual prep is used for acute pain*

"Variant Angina" (Prinzmetal's Angina)

occurs at rest or even during sleep and is unpredictable It is caused by vasospasm of an artery that is probably injured Nitroglycerin and calcium channel blockers can be used to treat variant angina Beta blockers are not used to treat variant angina