Pharm III Exam: Drugs used in the Treatment of Angina Pectoris

Types of angina?

1. atherosclerotic 2. vasospastic 3. unstable angina

Drugs used in Angina Pectoris include.

1. vasodilators a. nitrates b. Ca++ channel blocker 2. cardiac depressants a. Ca++ channel blocker b. Beta blockers 3. other drugs a. Metabolism modifiers b. metabolism rate inhibitors

In addition to well-established uses in angina, hypertension, and supraventricular tachycardia, some Ca++-channel blocker agents are used in 1. 2. 3. 4.

1.migraine 2. preterm labor 3. stroke, 4. Raynaud's phenomenon.

The efficacy of oral (swallowed) nitroglycerin probably results from the high levels of glyceryl _____ in the blood. The effects of sublingual and transdermal nitroglycerin are mainly the result of the ________ drug because these routes avoid the ______-______ effect

2 dinitrate unchanged first-pass

Oral (swallowed) normal-release formulations of nitroglycerin and isosorbide dinitrate have durations of action of __ -___ h. Sustained release oral forms have a somewhat longer duration of action. Transdermal formulations (ointment or patch) can maintain blood levels for up to ____ h. ____ develops after 8-10 h, however, with rapidly diminishing effectiveness thereafter. It is therefore recommended that nitroglycerin patches be ________ after 10-12 h. A new patch can be applied after ___ h of patch-free recovery

4-6h 24 Tolerance removed 12

Because of the high enzyme activity in the liver, the first-pass effect for nitro-glycerin is about ____%.

90&

8. A 45-year-old woman with hyperlipidemia and frequent migraine headaches develops angina of effort. Which of the following is relatively contraindicated because of her migraines? (A) Amlodipine (B) Diltiazem (C) Metoprolol (D) Nitroglycerin (E) Verapamil

Acute migraine headache is associated with vasodilation of meningeal arteries. Of the drugs listed, only nitroglycerin is commonly associated with headache. In fact, calcium channel blockers and β blockers have been used with some success as prophylaxis for migraine. The answer is D

Isosorbide mononitrate is available as a separate drug for oral use. Several other nitrates are available for oral use and, like the oral nitroglycerin preparation, have an intermediate duration of action (4-6 h). __________ nitrite is a volatile and rapid-acting vasodilator that was used for angina by the inhalational route but is now rarely prescribed.

Amyl

Vasospastic angina, variant angina, Prinzmetal's angina is caused by?

Angina precipitated by reversible spasm of coronary vessels, often at rest

A new 60-year-old patient presents to the medical clinic with hypertension and angina. He is 1.8 meters tall with a waist measurement of 1.1 m. Weight is 97 kg. Blood pressure is 150/95 and pulse 85. In considering adverse effects of possible drugs for these conditions, you note that an adverse effect that nitroglycerin and prazosin have in common is (A) Bradycardia (B) Impaired sexual function (C) Lupus erythematosus syndrome (D) Orthostatic hypotension (E) Weight gai

Both drugs cause venodilation and reduce venous return sufficiently to cause some degree of postural hypotension. Bradycardia, lupus, weight gain, and urinary retention occur with neither of them, but prazosin has been used to relieve urinary retention in men with prostatic hyperplasia. The answer is D.

Mechanisms of smooth muscle relaxation by calcium channel blockers and nitrates. Contraction results from phosphorylation of myosin light chains (MLC) by myosin light-chain kinase (MLCK). MLCK is activated by Ca2+, so calcium channel blockers reduce this step. Relaxation follows when the phosphorylated light chains are dephosphorylated, a process facilitated by cyclic guanosine monophosphate (cGMP). Nitrates and other sources of nitric oxide (NO) increase cGMP synthesis, and phosphodiesterase (PDE) inhibitors reduce cGMP metabo- lism. eNOS, endothelial nitric oxide synthase; GC, activated guanylyl cyclase; GTP, guanosine triphosphate.

Describe what's going on here.

What is Preload?

Filling pressure of the heart, dependent on venous tone and blood volume; determines enddiastolic fiber length and tension

Ivabradine, an investigational drug, inhibits the ________ sodium current in the sinoatrial node. The reduction in this ____________ induced inward pacemaker current results in decreased heart _________ and consequently decreased cardiac work.

I_funny hyperpolarization rate

What is afterload?

Impedance to ejection of stroke volume; determined by vascular resistance (arterial blood pressure) and arterial stiffness; determines systolic fiber tension

What is the primary determinant of O2 requirement?

Intramyocardial fiber tension = Force exerted by myocardial fibers, especially ventricular fibers at any given time; a primary determinant of myocardial O2 requirement

Other nitrates are similar to nitroglycerin in their pharmacokinetics and pharmacodynamics. ___________ dinitrate is another commonly used nitrate; it is available in sublingual and oral forms. Isosorbide dinitrate is rapidly denitrated in the liver and ________ muscle to isosorbide mononitrate, which is also active.

Isosorbide smooth

Another patient is admitted to the emergency department after a drug overdose. He is noted to have hypotension and severe bradycardia. He has been receiving therapy for hypertension and angina. Which of the following drugs in high doses causes bradycardia? (A) Amlodipine (B) Isosorbide dinitrate (C) Nitroglycerin (D) Prazosin (E) Verapami

Isosorbide dinitrate (like all the nitrates) and prazosin can cause reflex tachycardia. Amlodipine, a dihydropyridine calcium channel blocker, causes much more vasodilation than cardiac depression and may also cause reflex tachycardia. Verapamil typically slows heart rate and high doses may cause severe bradycardia. The answer is E

Calcium channel blockers block voltage-gated ___-_____ calcium channels, the calcium channels most important in cardiac and smooth muscle, and ________ intracellular calcium concentration and muscle ______________ (Figure 12-3). None of these channel blockers _____________ with calcium-dependent neurotransmission or hormone release because these processes use different types of calcium channels that are not blocked by L-channel blockers. Nerve ending calcium channels are of the ____, ___, ____types. Secretory cells use L-type channels, but these channels are less _________ to the calcium blockers than are cardiac and smooth muscle L-type channels.

L-type reduce contractility interferes N-, P-, and R- sensitive

What are the only methods capable of consistently increasing coronary flow in atherosclerotic angina and increasing the double product

Myocardial revascularization by coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are extremely important in the treatment of severe angina.

__________ and ________ channel blockers (but not ___ __________) can also increase oxygen delivery by reducing __________ in vasospastic angina.

Nitrates calcium Beta-blockers spasm

___________ (the active ingredient in dynamite) is the most important of the therapeutic nitrates and is available in forms that provide a range of durations of action from 10-20 min (sublingual for relief of acute attacks) to 8-10 h (transdermal for prophylaxis)

Nitroglycerin

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 a 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 myocardial fiber tension

Nitroglycerin increases heart rate and venous capacitance and decreases afterload and diastolic fiber tension. It increases cardiac contractile force because the decrease in blood pressure evokes a compensatory increase in sympathetic discharge. The answer is D.

__________(diastolic filling pressure) is a function of blood ________ and venous ______. Venous tone is mainly controlled by __________ activity. Afterload is determined by ________ blood pressure and large artery stiffness.

Preload volume tone sympathetic arterial

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) Increased double product (D) Increased cardiac force (E) Decreased ventricular ejection time

Propranolol blocks tachycardia but has none of the other effects listed. Only revascularization increases double product; drugs that decrease cardiac work increase exercise time by decreasing double product. The answer is A.

A man is admitted to the emergency department with a brownish cyanotic appearance, marked shortness of breath, and hypotension. Which of the following is most likely to cause methemoglobinemia? (A) Amyl nitrite (B) Isosorbide dinitrate (C) Isosorbide mononitrate (D) Nitroglycerin (E) Sodium cyanide

Read carefully! Nitrites, not nitrates, cause methemoglobinemia in adults. Methemoglobinemia is delibrately induced in one of the treatments of cyanide poisoning. The answer is A.

___________ of arterial smooth muscle may increase flow through partially occluded epicardial coronary vessels.

Relaxation

Certain drugs can cause severe hypotension when combined with nitrates. Which of the following interacts with nitroglycerin by inhibiting the metabolism of cGMP? (A) Atenolol (B) Hydralazine (C) Isosorbide mononitrate (D) Nifedipine (E) Ranolazine (F) Sildenafil (G) Terbutaline

Sildenafil inhibits phosphodiesterase 5, an enzyme that inactivates cGMP. The nitrates (via nitric oxide) increase the synthesis of cGMP. This combination is synergistic. The answer is F.

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

The calcium channel blockers and the β blockers are generally effective in reducing the number of attacks of angina of effort, and most have durations of 4-8 h. Oral and transdermal nitrates have similar or longer durations. Amyl nitrite and the sublingual nitrates have short durations of action (a few minutes to 30 min). Esmolol (an intravenous β blocker) must be given intravenously and also has a very short duration of action. These drugs are of no value in prophy- laxis. The answer is E

9. 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) Beta blockers and nitrates on venous tone (D) Calcium channel blockers and β blockers on cardiac force (E) Calcium channel blockers and nitrates on heart rat

The effects of β blockers (or calcium channel blockers) and nitrates on heart size, force, venous tone, and heart rate are opposite. The effects of β blockers and calcium channel blockers on the variables specified here are the same. The answer is D.

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) Constipation (B) Dizziness due to reduced cardiac force of contraction (C) Diuresis due to sympathetic discharge (D) Headache due to meningeal vasodilation (E) Hypertension due to reflex tachycardi

The nitrates relax many types of smooth muscle, but the effect on motility in the colon is insignificant. Nitroglycerin causes hypotension as a result of arterial and venous dilation. Dilation of arteries in the meninges has no effect on central nervous system function but does cause headache. The answer is D.

What is Double product?

The product of heart rate and systolic blood pressure; an estimate of cardiac work

True or false? All the calcium channel blockers in sufficient dosage reduce blood pressure and reduce the double product in patients with angina.

True

Reduced ___________ , from arteriolar dilation of resistance vessels, may contribute to an increase in _____________ and a further decrease in cardiac size.

afterload ejection

Therefore, cyanide poisoning can be treated by a 3-step procedure: (1) immediate inhalation of _______ nitrite, followed by (2) intravenous administration of sodium ______, which rapidly increases the ____________ level to the degree necessary to remove a significant amount of cyanide from cytochrome oxidase. This is followed by (3) intravenous sodium ___________ , which converts cyanomethemoglobin resulting from step 2 to ____________ and ____________.

amyl nitrite methemoglobin thiosulfate thiocyanate methemoglobin

Therapy of unstable angina differs from that of stable angina in that urgent ___________ is the treatment of choice in most patients and ___________ ____________ is the major target of drug therapy. A variety of platelet inhibitors are used in this condition.

angioplasty platelet clotting

Cyanide ion rapidly complexes with the iron in cytochrome oxidase, resulting in a _________ of oxidative metabolism and cell death. Fortunately, the iron in ____________ has a higher affinity for cyanide than does the iron in cytochrome oxidase. Nitrites convert the __________ iron in hemoglobin to the ferric form, yielding methemoglobin.

block methemoglobin ferrous

Nitrates relax the smooth muscle of the ___________, ___________ tract, and __________ tract, but these effects are too _________to be clinically significant. Intravenous nitroglycerin (sometimes used in unstable angina) reduces _________ aggregation. There are ________ clinically useful effects on other tissues.

bronchi gastrointestinal genitourinary small platelet no

In vasospastic angina, reversal of coronary spasm and increased flow can be demonstrated. Nitrates have no direct effects on __________ muscle, but significant reflex ________ and increased force of __________ are common results when nitroglycerin reduces the blood pressure. These compensatory effects result from the _________ mechanism

cardiac tachycardia contraction baroreceptor

The calcium channel blockers cause _________, ____________ __________, __________, _________ , and __________. More serious adverse effects include __________ ,____________ , and ____________ __________ depression ; these are most common with _________ and least common with the ___________.

constipation pretibial edema nausea flushing dizziness heart failure AV blockade sinus node verapamil dihydropyridines

Heart ________ and ___________ of the heart are reduced by diltiazem and verapamil. Because they block calcium-dependent conduction in the _________ node, ___________ and __________ may be used to treat AV nodal arrhythmias

contractility rate atrioventricular verapamil diltiazem

Force of cardiac ________ is another systolic factor controlled mainly by sympathetic outflow to the heart. Ejection time for ventricular contraction is _________ related to force of ______ but is also influenced by _______ to outflow. (the Decreased ejection time = increased force of contraction) Increased ejection time (prolonged systole) _________oxygen requirement.

contraction inversely contraction impedance increases

A secondary mechanism—namely, an increase in ___________ flow via collateral vessels in ischemic areas—has also been proposed

coronary

Unstable or ________angina, also known as _________ _________ ______—is characterized by increased frequency and severity of attacks that result from a combination of atherosclerotic _______ , ___________ aggregation at fractured plaques, and ____________. Unstable anginais thought to be the immediate precursor of a myocardial _________ and is treated as a medical ____________.

crescendo acute coronary syndrome plaques platelet vasospasm infarction emergency

Venodilation leads to ____________ diastolic heart size and fiber tension. _____________ dilation leads to reduced peripheral resistance and blood pressure. These changes contribute to an overall reduction in myocardial fiber _________, ____________ consumption, and the double product

decreased Arteriolar tension oxygen

Determinants of the volume of oxygen required by the heart. Both ________ and ________factors contribute to the oxygen requirement; most of these factors are directly influenced by sympathetic discharge. The following are increased during sympathetic discharge. 1. 2. 3. 4.

diastolic factors - preload - venous tone systolic factors - peripheral resistance - heart rate - heart contractile force - afterload

Atherosclerotic angina is also known as angina of _______ or ________ angina. It is associated with athero- matous ________ that partially occlude one or more coronary ________. When cardiac work increases (eg, in exercise), the __________ of flow and inadequate _______delivery results in the accumulation of metabolites, eg, _____ _________, and ________ changes that stimulate myocardial _______ endings. _______ , usually leads to complete relief of the pain within __ min. Atherosclerotic angina constitutes about____% of angina cases.

effort classic plaques arteries obstruction oxygen lactic acid ischemic pain Rest 15 90%

Beta-blockers are effective in preventing ___________ -induced angina but are ineffective against the ____________ form.

exercise vasospastic

A newer strategy attempts to increase the efficiency of oxygen utilization by shifting the energy substrate preference of the heart from ____________ to _____________.

fatty acids glucose

Nifedipine and other dihydropyridines evoke _________ vasodilation, and the resulting ___________ reflex prevents ____________ and may actually increase heart rate.

greater sympathetic bradycardia

NO stimulates soluble (cytoplasmic) _________ cyclase and causes an increase of the second messenger _____________ ; the latter results in ____________ muscle relaxation by stimulating the ___________ of myosin light-chain phosphate

guanylyl cGMP (cyclic guanosine monophosphate) smooth dephos-phosphorylation

Beta blocker actions include both beneficial antianginal effects (decreased _______ _________, ___________ _______,_______ __________) and detrimental effects (increased _________ size, longer _________ period

heart rate cardiac force blood pressure heart ejection

Recently, ____________ , a form of vitamin B12, has become the preferred method of treating __________ ____________

hydroxocobalamin cyanidepoisoning

The defect that causes anginal pain is coronary oxygen delivery relative to the myocardial ____________ requirement. This defect can be corrected—at present—in 2 ways: by increasing ___________ delivery and by ____________ oxygen requirement (Figure 12-2). Traditional pharmacologic therapies for angina include the ___________ , the _____________ channel blockers, and the _________ blockers

inadequate oxygen reducing nitrates calcium Beta

Another new group of antianginal drugs selectively reduces heart rate (and O2 requirement) with no other detectable hemodynamic effects. These investigational drugs (_____________ is the prototype) act by inhibition of the sinoatrial pacemaker current, ____.

ivabradine I_funny (HCN)

Thiocyanate is much ________ toxic than cyanide and is excreted by the _____________.

less kidney

Nitroglycerin (glyceryl trinitrate) is rapidly denitrated in the _______ and in __________ muscle—first to the 2 ______ (glyceryl dinitrate), which retain a significant _______ effect; and more slowly to the ________ , which are much ________ active.

liver smooth dinitrates vasodilating mononitrates less

Nitrites are of significant toxicologic importance because they cause _______________ at high blood concentrations. This same effect has a potential antidotal action in _________ poisoning The _________ do not cause methemoglobinemia.

methemoglobinemia cyanide nitrates

Some studies suggest that of the vascular beds, the veins are the ________ sensitive, arteries ________ so, and arterioles __________ sensitive.

most less least

Several studies have suggested that patients receiving prompt-release nifedipine may have an increased risk of __________ __________. _________-release formulations do not seem to impose this risk. These observations have been explained as follows: Rapid-acting vasodilators—such as ________ in its prompt-release formulation—cause ___________ and ___________ reduction in blood pressure. The drop in blood pressure evokes increased _____________ outflow to the cardiovascular system and increases heart ________ and force of ____________ by the mechanism shown in Figure 6-4. These changes can markedly increase cardiac ___________ requirement. If coronary blood flow does not increase sufficiently to match the increased requirement, ___________ and _______________ can result

myocardial infarction Slow nifedipine significant sudden sympathetic rate contraction oxygen ischemia infarction

Several types of calcium channel blockers are approved for use in angina; these drugs are typified by ___________, a ___________ , several other dihydropyridines, and the _____________ and _______________. Although calcium channel blockers differ markedly in structure, all are orally active and most have half-lives of ____ h.

nifedipine dihydropyridine diltiazem verapamil 3-6

The __________, __________ blockers, and ____ blockers all reduce the oxygen requirement in atherosclerotic angina.

nitrates calcium βeta

In the past, the ___________ were responsible for several occupational diseases in explosives factories in which workplace contamination by these volatile chemicals was severe. The most common of these diseases was "______ _________," that is, the alternating development of tolerance (during the work week) and loss of tolerance (over the weekend) for the vasodilating action and its associated tachycardia and resulting in headache (from cranial vasodilation), tachycardia, and dizziness (from orthostatic hypotension) every Monday.

nitrates Monday disease

Nitrates release _______ _______ within smooth muscle cells, probably through the action of the mitochondrial enzyme _________ ____________ 2.

nitric oxide alde-hyde dehydrogenase-2 (ALDH2)

The primary mechanism of therapeutic benefit in atherosclerotic angina is reduction of the ________ requirement.

oxygen

Because beta-vblockers reduce cardiac work and ____________ demand, all β blockers are effec- tive in the prophylaxis of ____________ angina attacks.

oxygen atherosclerotic

The pharmacologic treatment of coronary insufficiency is based on the physiologic factors that control myocardial _________ requirement. A major determinant is myocardial fiber ________ (the higher the tension, the __________ the oxygen requirement).

oxygen tension greater

Drugs that may act by this mechanism are termed ____________ ___________ ___________ _________ inhibitors (pFOX inhibitors) and include __________ and ___________. However, more recent evidence suggests that the major mechanism of action of ranolazine is inhibition of late _________ current

partial fatty acid oxidation ranolazine trimetazidine sodium

Nitrates interact with sildenafil and similar drugs promoted for erectile dysfunction. These agents inhibit a _______________ isoform (______) that metabolizes ________ in smooth muscle The increased _______ in erectile smooth muscle relaxes it, allowing for greater inflow of blood and more effective and prolonged erection. This relaxation also occurs in vascular smooth muscle.

phosphodiester- ase PDE5 cGMP cGMP

Beta blockers are used only for __________ therapy of angina; they are of ________ value in an acute attack

prophylactic no

Like nitrates and calcium channel blockers, β blockers __________ cardiac work, the double product, and ___________ demand.

reduce oxygen

Vasospastic angina, also known as _______ angina, ____ angina, or _____ angina, is responsible for less than __% of angina cases. It involves _____ spasm of coronaries, usually at the site of an atherosclerotic plaque. Spasm may occur at ____ time, even during sleep. Vasospastic angina may deteriorate into _________ angina

rest variant Prinzmetal's 10 reversible any unstable

Myocardial ___________ corrects coronary obstruction either by bypass grafting or by angioplasty (enlargement of the coronary lumen by means of a special catheter).

revascularization

Ranolazine appears to act mainly by reducing a late, prolonged ______ current in myocardial cells. The decrease in ___________ sodium causes an increase in calcium expulsion via the Na/Ca transporter and a _________ in cardiac force and work.

sodium intracellular reduction

Angina pectoris refers to a __________ or ___________-like pain caused by cardiac ischemia. The pain is usually located ___________ but is sometimes perceived in the neck, shoulder and arm, or epigastrium. Women develop angina at a ______ age than than men and are ________ likely to have classic substernal pain. Drugs used in angina exploit two main strategies: reduction of ________ demand and _________ of oxygen delivery to the myocardium.

strangling pressure substernally later less oxygen increase

The standard form for treatment of acute anginal pain is the __________ tablet or _________ , which has a duration of action of ____ - ____ min Sublingual i__________ _______ is similar with a duration of 30 min.

sublingual spray 10-20 sosorbide dinitrate

The combination of nitrates (through increased production of cGMP) and a PDE5 inhibitor (through decreased breakdown of cGMP) causes a __________ relaxation of vascular smooth muscle with potentially dangerous ___________ and inadequate perfusion of critical organs.

synergistic hypotension

The most common toxic effects of nitrates are the responses evoked by vasodilation. These include ________ (from the baroreceptor reflex), __________ ____________ (a direct extension of the venodilator effect), and throbbing ___________ from meningeal artery vasodilation.

tachycardia orthostatic hypotension headache

Heart rate contributes to total fiber _________ because at fast heart rates, fibers spend more time at _______ tension levels. Furthermore, at faster rates, diastole time is ___________, and diastole constitutes the time available for coronary perfusion (coronary blood flow is during systole).

tension systolic decreased low

Calcium blockers relax blood vessels and, to a lesser extent, the ________, ___________, ___________.

uterus, bronchi, and gut.

Calcium blockers are effective as prophylactic therapy in both effort and ___________ angina; __________ has also been used to abort acute anginal attacks but use of the prompt-release form is discour- aged. In severe _____________ angina, these drugs are particularly valuable when combined with nitrates

vasospastic nifedipine atherosclerotic

Smooth muscle relaxation by nitrates leads to an important degree of ___________ , which results in reduced cardiac size and cardiac output through reduced ______________.

venodilation preload

The combination of _________ and ____________ is useful because the adverse undesirable compensatory effects evoked by the nitrates (tachycardia and increased cardiac force) are prevented or reduced by β blockade

β blockers nitrates