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What is the primary mechanism through which nitroglycerin exerts its effect on smooth muscle?
What is the primary mechanism through which nitroglycerin exerts its effect on smooth muscle?
What enzyme is primarily responsible for the de-nitration of nitroglycerin?
What enzyme is primarily responsible for the de-nitration of nitroglycerin?
Which of the following effects does nitroglycerin have on the cardiovascular system?
Which of the following effects does nitroglycerin have on the cardiovascular system?
What is a common side effect associated with the use of nitroglycerin?
What is a common side effect associated with the use of nitroglycerin?
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How does increased potassium permeability affect the membrane potential of vascular smooth muscle cells?
How does increased potassium permeability affect the membrane potential of vascular smooth muscle cells?
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What is the primary action of nitrates and calcium channel blockers in treating angina?
What is the primary action of nitrates and calcium channel blockers in treating angina?
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What compensatory response occurs due to the reduction of arterial pressure caused by nitroglycerin?
What compensatory response occurs due to the reduction of arterial pressure caused by nitroglycerin?
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How do nitrates affect erectile tissue?
How do nitrates affect erectile tissue?
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What is the significance of nitroglycerin's storage requirements?
What is the significance of nitroglycerin's storage requirements?
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What is one possible consequence of increased venous capacitance from nitroglycerin use?
What is one possible consequence of increased venous capacitance from nitroglycerin use?
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Why is the sublingual route of nitroglycerin administration preferred?
Why is the sublingual route of nitroglycerin administration preferred?
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Which of the following statements about nitrates is true?
Which of the following statements about nitrates is true?
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Which statement accurately reflects the action of nitric oxide in smooth muscle relaxation?
Which statement accurately reflects the action of nitric oxide in smooth muscle relaxation?
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What is the primary route of excretion for the metabolites of nitrates?
What is the primary route of excretion for the metabolites of nitrates?
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Which aspect of pharmacokinetics is important for the effectiveness of sublingual nitroglycerin?
Which aspect of pharmacokinetics is important for the effectiveness of sublingual nitroglycerin?
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Which of the following statements about half-lives of nitrates is correct?
Which of the following statements about half-lives of nitrates is correct?
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What is the primary action of Ranolazine in the treatment of angina?
What is the primary action of Ranolazine in the treatment of angina?
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What effect does Trimetazidine have on fatty acid metabolism in ischemic myocardium?
What effect does Trimetazidine have on fatty acid metabolism in ischemic myocardium?
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How does Ivabradine primarily reduce the cardiac rate?
How does Ivabradine primarily reduce the cardiac rate?
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Which of the following is NOT a characteristic of Fasudil?
Which of the following is NOT a characteristic of Fasudil?
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What is the uncertain mechanism by which Allopurinol aids patients with atherosclerotic angina?
What is the uncertain mechanism by which Allopurinol aids patients with atherosclerotic angina?
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In which patient population does Ranolazine show a QT interval change?
In which patient population does Ranolazine show a QT interval change?
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What is a significant benefit of Ivabradine compared to conventional antianginal therapies?
What is a significant benefit of Ivabradine compared to conventional antianginal therapies?
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What characteristic of Rho kinases (ROCK) is related to angina?
What characteristic of Rho kinases (ROCK) is related to angina?
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What is the primary mechanism by which nitrates relieve effort angina?
What is the primary mechanism by which nitrates relieve effort angina?
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What effect do nitrates have on coronary arteries in variant angina?
What effect do nitrates have on coronary arteries in variant angina?
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Which of the following correctly describes the use of nitrates in acute coronary syndromes?
Which of the following correctly describes the use of nitrates in acute coronary syndromes?
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What is the duration of action for sublingual nitroglycerin?
What is the duration of action for sublingual nitroglycerin?
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What is necessary to prevent tolerance when using long-acting nitrates?
What is necessary to prevent tolerance when using long-acting nitrates?
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Which of the following describes Nicorandil?
Which of the following describes Nicorandil?
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What distinguishes Molsidomine from traditional nitrates?
What distinguishes Molsidomine from traditional nitrates?
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Which of the following is a potential side effect of excessive nitrate use?
Which of the following is a potential side effect of excessive nitrate use?
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What is the principal mechanism of action for the benefit achieved with nitrates and calcium channel blockers in vasospastic angina?
What is the principal mechanism of action for the benefit achieved with nitrates and calcium channel blockers in vasospastic angina?
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In patients with stable chronic angina, what is generally recommended if they are refractory to three drug combinations?
In patients with stable chronic angina, what is generally recommended if they are refractory to three drug combinations?
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Which combination of therapies is typically used for the treatment of unstable angina?
Which combination of therapies is typically used for the treatment of unstable angina?
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What is the primary indication for the insertion of stents in patients with peripheral artery disease?
What is the primary indication for the insertion of stents in patients with peripheral artery disease?
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What effect does supervised exercise therapy have on patients with intermittent claudication?
What effect does supervised exercise therapy have on patients with intermittent claudication?
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Which medication should be added to the regimen if percutaneous coronary intervention with stenting is performed?
Which medication should be added to the regimen if percutaneous coronary intervention with stenting is performed?
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What proportion of patients treated with nitrates and calcium channel blockers experience complete abolition of angina attacks?
What proportion of patients treated with nitrates and calcium channel blockers experience complete abolition of angina attacks?
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In the context of unstable angina, what is the significance of recurrent platelet-rich thrombus formation?
In the context of unstable angina, what is the significance of recurrent platelet-rich thrombus formation?
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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.