Pharmacology of Vascular Smooth Muscle and Angina

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Questions and Answers

What is the primary mechanism through which nitroglycerin exerts its effect on smooth muscle?

Activation of protein kinase A

Activation of adrenergic receptors

Inhibition of calcium channels

Release of nitric oxide (correct)

What enzyme is primarily responsible for the de-nitration of nitroglycerin?

Aldose reductase

Glutathione peroxidase

Nitric oxide synthase

Aldehyde dehydrogenase isoform 2 (ALDH2) (correct)

Which of the following effects does nitroglycerin have on the cardiovascular system?

Increases arterial pressure

Increases ventricular preload

Promotes sodium retention

Reduces cardiac output (correct)

What is a common side effect associated with the use of nitroglycerin?

Throbbing headache Signup and view all the answers

How does increased potassium permeability affect the membrane potential of vascular smooth muscle cells?

It stabilizes the membrane potential near the resting potential. Signup and view all the answers

What is the primary action of nitrates and calcium channel blockers in treating angina?

Decrease myocardial oxygen requirement. Signup and view all the answers

What compensatory response occurs due to the reduction of arterial pressure caused by nitroglycerin?

Increased cardiac contractility Signup and view all the answers

How do nitrates affect erectile tissue?

Activate guanylyl cyclase Signup and view all the answers

What is the significance of nitroglycerin's storage requirements?

It is sensitive to light and must be tightly closed. Signup and view all the answers

What is one possible consequence of increased venous capacitance from nitroglycerin use?

Orthostatic hypotension Signup and view all the answers

Why is the sublingual route of nitroglycerin administration preferred?

It avoids the first-pass effect. Signup and view all the answers

Which of the following statements about nitrates is true?

Tolerance development varies among different nitrates. Signup and view all the answers

Which statement accurately reflects the action of nitric oxide in smooth muscle relaxation?

It activates soluble guanylyl cyclase to increase cGMP levels. Signup and view all the answers

What is the primary route of excretion for the metabolites of nitrates?

Renal excretion as glucuronide derivatives. Signup and view all the answers

Which aspect of pharmacokinetics is important for the effectiveness of sublingual nitroglycerin?

Rapid therapeutic blood level due to bypassing liver metabolism. Signup and view all the answers

Which of the following statements about half-lives of nitrates is correct?

Unchanged organic nitrates have half-lives of 2–8 minutes. Signup and view all the answers

What is the primary action of Ranolazine in the treatment of angina?

It reduces late sodium current. Signup and view all the answers

What effect does Trimetazidine have on fatty acid metabolism in ischemic myocardium?

It partially inhibits the fatty acid oxidation pathway. Signup and view all the answers

How does Ivabradine primarily reduce the cardiac rate?

By inhibiting hyperpolarization activated sodium channels. Signup and view all the answers

Which of the following is NOT a characteristic of Fasudil?

It is approved for widespread clinical use in angina. Signup and view all the answers

What is the uncertain mechanism by which Allopurinol aids patients with atherosclerotic angina?

It improves endothelium dependent vasodilation. Signup and view all the answers

In which patient population does Ranolazine show a QT interval change?

Patients with coronary artery disease. Signup and view all the answers

What is a significant benefit of Ivabradine compared to conventional antianginal therapies?

It reduces gastrointestinal side effects. Signup and view all the answers

What characteristic of Rho kinases (ROCK) is related to angina?

They inhibit vascular relaxation. Signup and view all the answers

What is the primary mechanism by which nitrates relieve effort angina?

Decrease myocardial oxygen demand Signup and view all the answers

What effect do nitrates have on coronary arteries in variant angina?

They relax the smooth muscle Signup and view all the answers

Which of the following correctly describes the use of nitrates in acute coronary syndromes?

Precise beneficial mechanisms are not fully understood Signup and view all the answers

What is the duration of action for sublingual nitroglycerin?

Short duration, not more than 20-30 minutes Signup and view all the answers

What is necessary to prevent tolerance when using long-acting nitrates?

A nitrate-free period of at least 8 hours Signup and view all the answers

Which of the following describes Nicorandil?

A nicotinamide nitrate ester with vasodilating properties Signup and view all the answers

What distinguishes Molsidomine from traditional nitrates?

No tolerance develops with its use Signup and view all the answers

Which of the following is a potential side effect of excessive nitrate use?

Reflex tachycardia Signup and view all the answers

What is the principal mechanism of action for the benefit achieved with nitrates and calcium channel blockers in vasospastic angina?

Prevention of coronary artery spasm Signup and view all the answers

In patients with stable chronic angina, what is generally recommended if they are refractory to three drug combinations?

Coronary angiography and revascularization Signup and view all the answers

Which combination of therapies is typically used for the treatment of unstable angina?

Aspirin combined with clopidogrel Signup and view all the answers

What is the primary indication for the insertion of stents in patients with peripheral artery disease?

To restore blood flow in obstructed vessels Signup and view all the answers

What effect does supervised exercise therapy have on patients with intermittent claudication?

Reduces claudication and increases pain-free walking distance Signup and view all the answers

Which medication should be added to the regimen if percutaneous coronary intervention with stenting is performed?

Glycoprotein IIb/IIIa inhibitors Signup and view all the answers

What proportion of patients treated with nitrates and calcium channel blockers experience complete abolition of angina attacks?

70% Signup and view all the answers

In the context of unstable angina, what is the significance of recurrent platelet-rich thrombus formation?

It is the principal mechanism behind recurrent ischemic episodes Signup and view all the answers

Study Notes

### Stabilizing or Preventing Depolarization of the Vascular Smooth Muscle Cell Membrane

Potassium permeability is increased to stabilize the membrane potential of excitable cells near the resting potential
cGMP may increase permeability of Ca2+activated K+ channels
Potassium channel openers such as minoxidil sulfate increase permeability of K+ channels

Drugs used to treat Angina

Organic nitrates, calcium channel blockers, and β blockers are used treat Angina
Drugs decrease myocardial oxygen requirement by reducing one or more of the major determinants of oxygen demand such as heart size, heart rate, blood pressure, and contractility
Nitrates and calcium channel blockers may also cause a redistribution of coronary flow and increased oxygen delivery to ischemic tissue
Nitrates and calcium channel blockers may also reverse coronary artery spasm which is helpful in variant angina
Nitrates are used to treat acute anginal pain and for prophylaxis
Calcium channel blockers and β blockers are used for prophylaxis

Nitrates and Nitrites

Nitroglycerin is available in sublingual tablet form
Nitroglycerin may lose potency due to volatility and can adsorb to plastic surfaces
Nitroglycerin must be stored in tightly closed glass containers
Nitroglycerin is not sensitive to light
Different nitrates have identical mechanisms of action and similar toxicities, but development of tolerance may vary

### Pharmacokinetics of Nitrates

Low bioavailability (10-20%)
Liver nitrate reductase removes nitrate groups and inactivates the drug
Sublingual route avoids the first-pass effect and allows for rapid therapeutic blood levels
Nitroglycerin and isosorbide dinitrate are limited by total dose administered by this route to avoid excessive effects
Other routes of administration include Nitroglycerine: transdermal and buccal absorption from slow-release preparations
Unchanged organic nitrate compounds have short half-lives (2–8 min)
Partially de-nitrated metabolites have longer half-lives (up to 3 hours)
Isosorbide mononitrate and isosorbide dinitrate are absorbed orally
5-mononitrate metabolite is an active metabolite of isosorbide dinitrate
Bioavailability is 100% for Isosorbide mononitrate and isosorbide dinitrate
Renal excretion, primarily as glucuronide derivatives of the denitrated metabolites

Pharmacodynamics of Nitrates

Nitroglycerin activation occurs through de-nitration by glutathione S-transferase
Aldehyde dehydrogenase isoform 2 (ALDH2) and possibly isoform 3 (ALDH3) activate and release NO from nitroglycerin, different enzymes may be involved in the de-nitration of isosorbide dinitrate and mononitrate
Free nitrite ion (NO2-) is released and converted to nitric oxide (NO)
NO (complexed with cysteine) combines with the heme group of soluble guanylyl cyclase activating the enzyme and increasing cGMP → smooth muscle relaxation.
Prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved.

Organ System Effects of Nitrates

Veins and arteries relax in response to nitroglycerin
Venous dilation increases venous capacitance and decreases ventricular preload
Pulmonary vascular pressures and heart size are significantly reduced
Cardiac output is reduced
Increased venous capacitance may lead to orthostatic hypotension and syncope
Dilation of coronary arteries may improve oxygen delivery in the presence of atheromas or collateral vessels
Temporal artery pulsations and a throbbing headache are common effects of nitroglycerin and amyl nitrite
Preload is often abnormally high in heart failure, the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output
Nitroglycerin also exerts a weak negative inotropic effect on the heart via nitric oxide
Compensatory responses to decreased arterial pressure include tachycardia and increased cardiac contractility
Retention of salt and water may also be significant, especially with intermediate and long-acting nitrates
Compensatory responses contribute to the development of nitrate tolerance
Nitrites readily release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase
The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation which enhances erection

Nitrate Effects in Angina of Effort

Decreased venous return to the heart → reduction of intra-cardiac volume
Decreased arterial pressure
Decreased intraventricular pressure and left ventricular volume associated with decreased wall tension (Laplace relation) and decreased myocardial oxygen requirement
Rare instances, paradoxical increase in myocardial oxygen demand may occur as a result of excessive reflex tachycardia and increased contractility
The reduction in oxygen demand is the major mechanism for the relief of effort angina.

Nitrate Effects in Variant Angina

Benefits patients by relaxing the smooth muscle of the coronary arteries and relieving coronary artery spasm.

### Nitrate Effects in Acute Coronary Syndromes

Useful in the treatment of the acute coronary syndrome of unstable angina, but the precise mechanism for beneficial effects is not clear.
Nitrates may exert their beneficial effects both by dilating the epicardial coronary arteries and by simultaneously reducing myocardial oxygen demand.
Nitroglycerin also decreases platelet aggregation, and this effect may be important in acute coronary syndrome.

Clinical Use of Nitrates

Rapid onset of action (1–3 minutes)- sublingual nitroglycerin →immediate treatment
Short duration of action (not exceeding 20–30 minutes)- not suitable for maintenance therapy
IV nitroglycerin -rapid onset (mins) restricted to severe, recurrent rest angina
Slowly absorbed preparations of nitroglycerin provide blood concentrations for long periods but may lead to tolerance
Transdermal administration may provide blood levels of nitroglycerin ≥ 24 hrs, the beneficial effects do not persist >8–10 hr
A nitrate free period -at least 8 hours between doses of long acting and slow release forms should be observed to prevent tolerance.

Other Nitrovasodilators

Nicorandil is a nicotinamide nitrate ester with vasodilating properties in coronary arteries
Nicorandil treats angina by activating Na+/Ca2+ exchanger and decreasing intracellular Ca2+ overload
Activation of cardiac KATP channels
Reduces both preload and afterload
Molsidomine - prodrug that is converted to a nitric oxide releasing metabolite
Molsidomine efficacy is comparable to that of the organic nitrates and no tolerance.

Newer Antianginal Drugs

Ranolazine reduces a late sodium current (INa) that facilitates calcium entry via the sodium/calcium exchanger
Ranolazine decreases intracellular calcium concentration
Ranolazine decreases diastolic tension, cardiac contractility, and work
Ranolazine is effective in stable angina
Ranolazine prolongs the QT interval in patients with coronary artery disease (but shortens it in patients with long QT syndrome, LQT3)
Ranolazine may inhibit the metabolism of digoxin and simvastatin.
Trimetazidine - a metabolic modulator known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium
In ischemic myocardium the metabolism shifts to oxidation of fatty acids which increases oxygen requirement
Partial inhibition of the enzyme required for fatty acid oxidation (longchain 3-ketoacyl-thiolase, LC3KAT) appears to improve the metabolic status of ischemic tissue.
Trimetazidine inhibits LC3KAT - efficacy in stable angina
Ivabradine is relatively selective sodium channel blockers
Ivabradine decreases cardiac rate by inhibiting the hyperpolarization activated sodium channel in the sinoatrial node
Ivabradine appears to reduce angina attacks with efficacy similar to calcium channel blockers and β-blockers
The lack of effect on gastrointestinal and bronchial smooth muscle is an advantage of ivabradine
Ivabradine is used in angina and heart failure
Rho kinases (ROCK) are enzymes that inhibit vascular relaxation
Excessive activity of these enzymes is implicated in coronary spasm, pulmonary HT
Fasudil inhibits smooth muscle Rho kinase and decreases coronary vasospasm in experimental animals
Fasudil has improved performance in stress tests in clinical trials of patients with CAD.
Fasudil is investigational in angina.
Allopurinol inhibits xanthine oxidase, an enzyme that contributes to oxidative stress and endothelial dysfunction
Studies suggest that high dose allopurinol (eg, 600 mg/d) prolongs exercise time in patients with atherosclerotic angina
The mechanism is uncertain, but the drug appears to improve endothelium-dependent vasodilation.
Allopurinol is not currently approved for use in angina.
Most experts recommend coronary angiography and revascularization (if not contraindicated) in patients with stable chronic angina refractory to three drug combinations

Vasospastic Angina

Nitrates and the calcium channel blockers, but not β blockers, are effective drugs
Approximately 70% of patients treated with nitrates plus calcium channel blockers, angina attacks are completely abolished
Prevention of coronary artery spasm (with or without fixed atherosclerotic coronary artery lesions) is the principal mechanism for this beneficial response
All presently available calcium channel blockers appear to be equally effective
Surgical revascularization and angioplasty not indicated in patients with variant angina.

Unstable Angina & Acute Coronary Syndromes

Unstable angina with recurrent ischemic episodes at rest, recurrent platelet-rich thrombus formation is the principal mechanism
Aggressive antiplatelet therapy with a combination of aspirin and clopidogrel are recommended
If percutaneous coronary intervention with stenting is required, glycoprotein IIb/IIIa inhibitors such as abciximab should be added
Therapy with nitroglycerin and β-blockers should be considered in addition
Calcium channel blockers should be added in refractory cases for relief of myocardial ischemia
Primary lipid-lowering and ACE inhibitor therapy should also be initiated.

Treatment of Peripheral Artery Disease & Intermittent Claudication

Atherosclerosis can result in ischemia of peripheral arteries
If blood flow is limited, pain (claudication) occurs in skeletal muscles, especially in the legs, during exercise and disappears with rest
Peripheral artery disease (PAD) is associated with increased mortality, can severely limit exercise tolerance, and can increase risk of chronic ischemic ulcers, susceptibility to infection, and the need for amputation.
Intermittent claudication results from obstruction of blood flow by atheromas in large and medium arteries
Insertion of stents in the obstructed vessels is usually indicated and can save a limb
Supervised exercise therapy is of benefit in reducing claudication and increasing pain free walking distance.

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Description

Explore the mechanisms that stabilize or prevent depolarization of vascular smooth muscle cell membranes. This quiz covers potassium permeability, the role of cGMP, and various drugs used to treat angina, including their effects on myocardial oxygen requirements and coronary flow.