1. VASODILATORS & THE TREATMENT OF ANGINA PECTORIS
Angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. The name denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and the b blockers, which are not vasodilators, are also useful in prophylaxis. New groups of drugs under investigation include fatty acid oxidation inhibitors and selective cardiac rate inhibitors.
Pharmacology I
Spring Semester, 2017

2. Definition of Angina Pectoris
Angina pectoris is acute cardiac pain caused by inadequate blood flow as a result of myocardial ischemia.
In most cases, atherosclerosis is the main etiology of CHD (classic)
The decreased blood flow causes a decrease in oxygen to the myocardium, which is the cause of the pain ( accumulation of metabolites).
Anginal attacks may last for a few minutes and can lead to myocaradial infarction (heart attack).
coronary heart disease (CHD): heart disease caused by impaired coronary blood flow.

3. responsible for more than 500,000 deaths annually
The name denotes chest pain caused by accumulation of metabolites resulting from myocardial ischemia.
The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels.
Ischemic heart disease is the most common serious health problem in the world.
This condition afflicts 11 million individuals in the United States with an incidence rate of 1.5%
responsible for more than 500,000 deaths annually

4. Forms of CHD: 1) Chronic ischemic heart disease:
-Ischemia without symptoms (silent ischemia).
-Stable angina (aka. exertional, atherosclerotic or classic angina).
-Variant angina (aka. Prinzmetal’s, angiospastic, or vasospastic angina)
2) Acute coronary syndrome (ACS):
-Unstable angina pectoris
-Myocardial infarction (MI).
Angina pectoris is a general term for the conditions in which oxygen supply<demand causing chest pain.

5. Types of Angina There are three types of angina:
Classic (stable) angina: (atherosclerotic angina)
occurs with stress and exertion and is caused by atheromatous obstruction of the large coronary vessels
Unstable angina: occurs over the course of a day with progressive severity, frequency and is caused by the narrowing or partial occlusion of coronary arteries by thrombi/platelets aggregation . This often indicates an impending heart attack— a medical emergency.
Variant (Prinzmetal, vasospastic) oxygen delivery decreases as a result of reversible coronary vasospasm
In classic angina, the imbalance occurs when the myocardial oxygen requirement increases, as during exercise, and coronary blood flow does not increase proportionately. The resulting ischemia usually leads to pain. Classic angina is therefore "angina of effort." (In some individuals, the ischemia is not always accompanied by pain, resulting in "silent" or "ambulatory" ischemia.)
Unstable angina, an acute coronary syndrome, is said to be present when there are episodes of angina at rest and when there is a change in the character, frequency, and duration of chest pain as well as precipitating factors in patients with previously stable angina.
Unstable angina is caused by episodes of increased epicardial coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. In most cases, formation of labile nonocclusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. The course and the prognosis of unstable angina are variable, but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death.

6. Pathophysiology of Angina
Determinants of Coronary Blood Flow & Myocardial Oxygen Supply
Increased myocardial demands for oxygen in the normal heart are met by augmenting coronary blood flow. Coronary blood flow is directly related to the perfusion pressure (aortic diastolic pressure) and the duration of diastole.
Determinants of Vascular Tone
Arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress. Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure.
Because coronary flow drops to negligible values during systole, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia.
Coronary blood flow is inversely proportional to coronary vascular bed resistance. Resistance is determined mainly by intrinsic factors¾including metabolic products and autonomic activity¾and by various pharmacologic agents.
Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance.
Vascular Tone: In systole, intraventricular pressure must exceed aortic pressure to eject blood; arterial blood pressure thus determines the systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Venous tone thereby determines the diastolic wall stress.

7. Drugs may relax vascular smooth muscle in several ways:
(1) Increasing cGMP
(2) Decreasing intracellular Ca2+
(3) Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane
(4) Increasing cAMP in vascular smooth muscle cells

8. Control of smooth muscle contraction
Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown).

9. Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in smooth muscle cells. (MLCK*, activated myosin light chain kinase [see Figure 12-1]; guanylyl cyclase*, activated guanylyl cyclase; ?, unknown intermediate steps. Steps leading to relaxation are shown with heavy arrows.)

10. (2) Decreasing intracellular Ca2+
Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase.
(Beta blockers and calcium channel blockers reduce Ca2+ influx in cardiac muscle, thereby reducing rate, contractility, and oxygen requirement unless reversed by compensatory responses.)

11. (3) Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane
- The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability.
- Potassium channel openers, such as minoxidil sulfate, increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain newer agents under investigation for use in angina (eg, nicorandil) may act, in part, by this mechanism.

12. (4) Increasing cAMP in vascular smooth muscle cells
As shown in Figure 12–1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by 2 agonists, drugs that are not used in angina.

13. BASIC PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA
Three of the four drug groups currently approved for use in angina
(organic nitrates, calcium channel blockers, and B-blockers) decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility). The fourth group, represented by ranolazine

15. NITRATES & NITRITES Chemistry Nitroglycerin- the prototype
The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces. Therefore, it should be kept in tightly closed glass containers. It is not sensitive to light.
pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates.
These agents are simple nitric and nitrous acid esters of polyalcohols
Although nitroglycerin is used in the manufacture of dynamite, the formulations used in medicine are not explosive.
All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates.

16. Pharmacokinetics
First Pass Metabolism oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (typically < 10–20%).
Sublingual route preferred
SL dose is limited the total duration of effect is brief (15–30 minutes).
If much longer duration of action is needed  oral preparations
The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (typically < 10–20%).
For this reason, the sublingual route, which avoids the first-pass effect, is preferred for achieving a therapeutic blood level rapidly.
However, the total dose administered by this route must be limited to avoid excessive effect; therefore, the total duration of effect is brief (15–30 minutes).
When much longer duration of action is needed, oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites.

18. Pharmacokinetics Other routes: transdermal and buccal.
Amyl nitrite: is now obsolete for angina
dinitro derivatives  significant vasodilator efficacy; they probably provide most of the therapeutic effect of orally administered nitroglycerin.
The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for clinical use as isosorbide mononitrate. (bioavailability of 100%)
Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slow-release preparations.
Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering.
Because of its unpleasant odor and short duration of action, amyl nitrite is now obsolete for angina
the dinitro derivatives have significant vasodilator efficacy; they probably provide most of the therapeutic effect of orally administered nitroglycerin.
The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for clinical use as isosorbide mononitrate. It has a bioavailability of 100%.

19. Pharmacodynamics MECHANISM OF ACTION IN SMOOTH MUSCLE
Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is released, which is then converted to nitric oxide.
A different unknown enzymatic reaction releases nitric oxide directly from the parent drug molecule.
nitric oxide (or an S-nitrosothiol derivative) causes activation of guanylyl cyclase and an increase in cGMP, which are the first steps toward smooth muscle relaxation.
The production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved.
All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin.
Veins respond at the lowest concentrations, arteries at slightly higher ones.
Arterioles and precapillary sphincters are dilated less than the large arteries and the veins, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide.
The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload.
Pulmonary vascular pressures and heart size are significantly reduced.
In the absence of heart failure, cardiac output is reduced.
Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result.
Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite.
In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect
Compensatory responses: tachycardia & fluid retention

20. ORGAN SYSTEM EFFECTS
Effects of vasodilators on contractions of human vein segments studied in vitro. Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+). Panel B shows the relaxation induced by nitroglycerin (NTG), 4 umol/L. The relaxation is prompt. Panel C shows the relaxation induced by verapamil, 2.2 umol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.)
Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone.
It has practically no direct effect on cardiac or skeletal muscle.

21. Other Effects
Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. This may result from ingestion of sodium nitrite is used as a curing agent for meats
amyl nitrite and isobutyl nitrite by inhalation as purported recreational (sex-enhancing) drugs has become popular with some segments of the population (release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase -vasodilation- which enhances erection)
Fortunately, the plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults. However, sodium nitrite is used as a curing agent for meats. In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate, eg, from well water, to nitrite ion. Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity.

22. Use of NaNO2 in CN- Toxicity
Cyanide poisoning - complexing of cytochrome iron by the CN– ion.
Methemoglobin iron has a very high affinity for CN–; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome.
IV administration of sodium thiosulfate (Na2S2O3) formation of thiocyanate ion (SCN–), a less toxic ion that is readily excreted.
Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously.
One therapeutic application of this otherwise toxic effect of nitrite has been discovered. Cyanide poisoning results from complexing of cytochrome iron by the CN- ion. Methemoglobin iron has a very high affinity for CN-; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome. The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN-), a less toxic ion that is readily excreted. Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously

23. Side effects & Tolerance
ACUTE ADVERSE EFFECTS
The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation:
orthostatic hypotension, tachycardia, and throbbing headache.
Nitrates are contraindicated if intracranial pressure is elevated.
continuous exposure to nitrates  complete tolerance (tachyphylaxis) intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous IV infusions are used for more than a few hours without interruption
With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis), and the intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few hours without interruption
Glaucoma, once thought to be a contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure

24. Clinical Use of Nitrates

25. Clinical Use of Nitrates
Because of its rapid onset of action (1–3 minutes), sublingual (SL) nitroglycerin is the most frequently used agent for the immediate treatment of angina.
duration of action is short (< 20–30 minutes), it is not suitable for maintenance therapy.
Slowly absorbed preparations of nitroglycerin include a buccal form, oral preparations, and several transdermal forms - provide blood concentrations for long periods but lead to the development of tolerance
a nitrate-free period of at least 8 hours between doses should be observed to reduce or prevent tolerance.
Nitroglycerin sublingual tablets should not be chewed, crushed, or swallowed. They work much faster when absorbed through the lining of the mouth. Place the tablet under the tongue or between the cheek and gum, and let it dissolve. Do not eat, drink, smoke, or use chewing tobacco while a tablet is dissolving.
Nitroglycerin sublingual tablets usually give relief in 1 to 5 minutes. However, if the pain is not relieved, you may use a second tablet 5 minutes after you take the first tablet. If the pain continues for another 5 minutes, a third tablet may be used. If you still have chest pain after a total of 3 tablets, contact your doctor or go to a hospital emergency room right away. Do not drive yourself and call 911, if necessary.
The onset of action of intravenous nitroglycerin is also rapid (minutes), but its hemodynamic effects are quickly reversed by stopping its infusion →used in treatment of severe, recurrent rest angina.

26. CALCIUM CHANNEL-BLOCKING DRUGS
Nifedipine is the prototype of the dihydropyridine family
The CCBs are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism.
Verapamil and diltiazem are also used by the IV route
Nifedipine is the prototype of the dihydropyridine family of calcium channel blockers; it is the most extensively studied of this group, but the properties of the other dihydropyridines can be assumed to be similar to it unless otherwise noted
The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism.
Verapamil and diltiazem are also used by the intravenous route

27. Oral Bioavailability (%)
Table Clinical pharmacology of some calcium channel-blocking drugs.
Drug
Oral Bioavailability (%)
Half-Life (hours)
Indication
Dosage
Dihydropyridines
Amlodipine
65-90
30-50
Angina, hypertension
5-10 mg orally once daily
Felodipine
15-20
11-16
Hypertension, Raynaud's phenomenon
Isradipine
15-25 8
Hypertension
mg orally twice daily
Nicardipine 35
2-4
20-40 mg orally every 8 hours
Nifedipine
45-70 4
Angina, hypertension, Raynaud's phenomenon
3-10 mcg/kg IV; mg orally every 8 hours
Nimodipine 13
1-2
Subarachnoid hemorrhage
40 mg orally every 4 hours
Nisoldipine
< 10
6-12
20-40 mg orally once daily
Nitrendipine
10-30
5-12
Investigational
20 mg orally once or twice daily
Miscellaneous
Diltiazem
40-65
3-4
mcg/kg IV; mg orally every 6 hours
Verapamil
20-35 6
Angina, hypertension, arrhythmias, migraine
mcg/kg IV; mg orally every 8 hours
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28. Pharmacodynamics MECHANISM OF ACTION
the L-type calcium channel is the dominant type in cardiac and smooth muscle and is known to contain several drug receptors.
nifedipine and other dihydropyridines (DHPs) bind to one site, while verapamil & diltiazem (non-DHPs) appear to bind to closely related but not identical receptors in another region.
Binding of a drug to the verapamil or diltiazem receptors also affects dihydropyridine binding.

29. - smooth muscle with a long-lasting relaxation
DHPs have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do non-DHPs
The drugs act from the inner side of the membrane and bind more effectively to channels in depolarized membranes.
Binding of the drug reduces the frequency of opening in response to depolarization.
The result is a marked decrease in transmembrane calcium current, resulting in
- smooth muscle with a long-lasting relaxation
- cardiac muscle with a reduction in contractility throughout the heart and
- decreases in SA node rate and in AV node conduction velocity
Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells

30. Other Effects
CCBs minimally interfere with stimulus-secretion coupling in glands and nerve endings
Verapamil has been shown to inhibit insulin release in humans, but the dosages required are 
CCBs inhibit platelets aggregation in animals
Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients
5. Other effects¾ Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channels in different tissues, as noted above. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina. A significant body of evidence suggests that the calcium channel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. Clinical studies have not established their role in human blood clotting and atherosclerosis. Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells; other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients

31. Toxicity of CCBs
immediate-acting nifedipine increased the risk of myocardial infarction in patients with hypertension.
Short-acting DHPs, comincrease the risk of adverse cardiac events in patients with hypertension with or without diabetespared with ACE-Is, have been reported to.
Slow-release and long-acting vasoselective calcium channel blockers are usually well tolerated.
Patients receiving b-adrenoceptor-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel blockers.
Minor toxicity (troublesome but not usually requiring discontinuance of therapy) includes flushing, dizziness, nausea, constipation, and peripheral edema.
cardiac depression, including cardiac arrest, bradycardia, AV block, and heart failure - rare in clinical use.

32. Clinical Uses of Calcium Channel–Blocking Drugs
angina,
hypertension
supraventricular tachyarrhythmias.
hypertrophic cardiomyopathy,
migraine,
Raynaud's phenomenon

33. Choice of CCBs
Nifedipine does not decrease AV conduction and therefore can be used more safely than verapamil or diltiazem in the presence of AV conduction abnormalities
In the presence of overt heart failure, all CCBs can cause further worsening of heart failure as a result of their negative inotropic effect
Amlodipine, however, does not increase the mortality of patients with heart failure due to left ventricular systolic dysfunction and can be used safely in these patients
The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties..
A combination of verapamil or diltiazem with b blockers may produce atrioventricular block and depression of ventricular function.

34. BETA-ADRENORECEPTOR–BLOCKING DRUGS (BBs)
Although they are not vasodilators, BBs are extremely useful in the management of angina pectoris associated with effort.
↓ heart rate, BP, and contractility →↓myocardial oxygen requirements at rest and during exercise.
↓ heart rate is also associated with ↑ in diastolic perfusion time that may ↑ coronary perfusion.
may also be valuable in treating silent or ambulatory ischemia.
↓ mortality of patients with recent myocardial infarction and
improve survival and prevent stroke in patients with hypertension.
Beta blockers may also be valuable in treating silent or ambulatory ischemia. Because this condition causes no pain, it is usually detected by the appearance of typical electrocardiographic signs of ischemia. The total amount of "ischemic time" per day is reduced by long-term therapy with a b blocker

35. NEWER ANTIANGINAL DRUGS
Ranolazine: pFOX inhibitor
Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases.
Partial inhibition of the enzyme required for fatty acid oxidation (long chain 3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tissue
The metabolic modulators (eg, ranolazine, trimetazidine) are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium. Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases. Partial inhibition of the enzyme required for fatty acid oxidation (long chain 3-ketoacyl thiolase, LC-3KAT) appears to improve the metabolic status of ischemic tissue. However, blockade of a late sodium current that facilitates calcium entry may play a larger role in the action of ranolazine.

36. CLINICAL PHARMACOLOGY OF DRUGS USED TO TREAT ANGINA
First-line: modification of risk factors such as smoking, HTN, hyperlipidemia obesity, & clinical depression.
antiplatelet drugs (aspirin, clopidogrel) &
lipid-lowering agents, especially statins are very important to prevent myocardial infarction (MI) & death.
ACEIs also ↓ the risk of adverse cardiac events in patients at high risk for CAD.
First-line therapy of CAD depends on modification of risk factors such as smoking, HTN, hyperlipidemia obesity, & clinical depression.
In addition, antiplatelet drugs (aspirin, clopidogrel) & lipid-lowering agents, especially statins are very important to prevent myocardial infarction (MI) & death.
ACEIs also ↓ the risk of adverse cardiac events in patients at high risk for CAD.
In patients with unstable angina and non-ST-segment elevation MI, aggressive therapy consists of coronary stenting, antilipid drugs, heparin, & antiplatelet agents