Antianginal Drugs Flashcards
Drugs Used to Treat Angina
- Vasodilators (increase oxygen supply and decrease Oxygen demand)
Calcium-channel blockers
Nitrates
- Cardioinhibitory Drugs (decrease oxygen demand)
B-blockers
Calcium-channel blockers
- Ranolazine (Na+ channel blocker)
- Anti-thrombotic Drugs (see ‘Disorders of Coagulation’ lecture)
Anticoagulants
Anti-platelet drugs
Calcium Channel Blockers (CCB)
Name the five CCB
Dihydropyridine vs Non-dihydropyridines
Verapamil (diphenalkylamine)
Diltiazem (benzothiazepine)
Nifedipine (dihydropyridine)
Amlodipine (dihydropyridine)
Felodipine (dihydropyridine)
Clinical Applications
CCBs are used to treat hypertension, angina and arrhythmias. CCBs can be used to treat chronic stable, unstable and Prinzmetal’s (variant) angina.
Due to the induction of reflex tachycardia, the dihydropyridines are used in combination with -blockers when initial treatment with a -blocker is not successful or, as a - blocker substitute when -blockers are contraindicated.
Mechanism of Action
CCBs block voltage-sensitive calcium channels (L-type) located on vascular smooth muscle, cardiac myocytes and cardiac nodal tissue thereby reducing calcium entry into these cells. As a result CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation and decreased heart rate.
CCBs lower blood pressure by decreasing peripheral vascular resistance. As a consequence, CCBs may evoke a reflex tachycardia.
The anti-anginal effects of CCBs are derived both from their vasodilator and cardiodepressant actions. Increased vasodilation results in an increase in oxygen supply. Verapamil and diltiazem, due to their cardioselectivity are able to decrease heart rate and contractility, resulting in a reduction in oxygen demand. CCBs are also able to dilate coronary arteries and thus prevent or reverse the coronary vasospasm that occurs in Prinzmetal’s (variant) angina.
Choice of CCB
Hemodynamic difference among CCBs may influence the choice of a particular agent. The dihydropyridines (felodipine and amlodipine) are more selective for vascular smooth muscle and have less effect on cardiac muscle than verapamil and diltiazem. The dihydropyridines are thus more likely to evoke a reflex tachycardia. Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output.
Dihydropyridines – have a minimal effect on cardiac conduction or heart rate and are used mainly for their vasodilator effects. They are able to relieve the symptoms of variant angina. NB. Short acting dihydropyridines (nifedipine) should be avoided unless combined with a -blocker due to the strong reflex tachycardia that is induced. Long-acting dihydropyridines appear to have reduced reflex responses.
Verapamil – has a greater negative inotropic action than other CCBs, but is a weaker vasodilator. It is able to reduce oxygen demand by decreasing heart rate and contractility and is able to relieve the symptoms of chronic stable, unstable and variant angina.
Diltiazem – is intermediate between verapamil and the dihydropyridines in its selectivity for vascular calcium channels. Diltiazem is able to relieve coronary vasospasm by dilating coronary arteries and is particularly useful in relieving the symptoms of variant angina.
Adverse Effects, Contraindications and Pharmacokinetics of CCB
Pharmacokinetics
Orally administered.
Only the sustained-release preparations of felodipine and amlodipine are approved for the treatment of angina due to evidence suggesting an increase in mortality with the use of the immediate-release preparations.
Adverse Effects - Dihydropyridines
Reflex tachycardia
Other effects: Dizziness, flushing, headache, hypotension, constipation, and peripheral edema (eg, pedal edema)
Adverse Effects – Verapamil and Diltiazem
Cardiac conduction abnormalities: Bradycardia, AV block and heart failure
Other effects: Anorexia, nausea, peripheral edema, and hypotension
Constipation: Verapamil causes constipation in ~7% of patients
Contraindications
Bradycardia, conduction defects, heart failure: Patients with any of these cardiac abnormalities should not be given CCBs, especially verapamil and diltiazem. Verapamil can increase digoxin levels and should be used with caution in patients taking this drug.
Name the four Nitrates Used in Angina and their Clinical Applications
Isosorbide Dinitrate
Isosorbide Mononitrate
Nitroglycerin
Sodium Nitroprusside
CLINICAL APPLICATIONS
Variant angina
Stable and unstable angina
Nitroglycerin: first-line therapy for the treatment of acute anginal symptoms.
Isosorbide mononitrate: used orally for prophylaxis of angina.
Sodium nitroprusside: used in ICU and emergency settings.
Nitrates Mechanism of Action
In the cardiovascular system, nitrous oxide (NO) is primarily produced by vascular endothelial cells. NO activates the enzyme guanylyl cyclase which is important in the conversion of GTP into cGMP. Increased intracellular cGMP inhibits Ca2+ entry into the cell, thereby decreasing intracellular Ca2+ concentrations and causing smooth muscle relaxation. NO also activates K+ channels, which leads to hyperpolarization and relaxation. Finally, NO acting through cGMP can stimulate a cGMP-dependent protein kinase that activates myosin light chain phosphatase, the enzyme that dephosphorylates myosin light chains, which leads to relaxation.
NO has several important functions including:
- relaxing vascular smooth muscle (vasodilation)
- inhibiting platelet aggregation (anti-thrombotic)
- inhibiting leukocyte-endothelial interactions (anti-inflammatory)
Nitrates are drugs that are able to mimic the actions of endogenous NO by releasing NO or forming NO within tissues. These drugs act directly on the vascular smooth muscle to cause relaxation and therefore serve as endothelial-independent vasodilators.
Nitrates have more effect on veins than arteries and thus decrease venous pressure and ventricular preload, which results in a decrease in the oxygen demand by the heart. Arterial dilation will reduce afterload, which can both increase cardiac output at the same time as reducing oxygen demand. By dilating coronary arteries, nitrates can relieve the symptoms of variant angina.
At high concentrations, there is a risk of reflex tachycardia occurring due to excessive peripheral vasodilation.
Tolerance with Nitrates and Pharmacokinetics
Tolerance
Tolerance develops rapidly to nitrates. This is thought to occur due to the vessels becoming desensitized to the vasodilatory effects of the nitrates. Tolerance can be overcome by using the smallest possible dose of nitrate along with infrequent or irregular dosing. A daily ‘nitrate-free’ interval (10-12 h) is very successful at preventing tolerance. The patients usually is exposed to the nitrate throughout the day (eg, a 12 h nitroglycerin patch) and then stops taking the drug (ie. removes the patch) during the night.
Pharmacokinetics
Isosorbide mononitrate and dinitrate: these drugs have a longer t1/2 (>1 h) than nitroglycerin and are more useful in the long-term management and prophylaxis of angina.
Isosorbide mononitrate has near to 100% bioavailability making it unusual, as oral bioavailablity of the other nitrates is low due to high first-pass metabolism. The metabolites of both drugs also have activity as well as a longer t1/2 than the parent compound making them contribute significantly to the activity of the drug.
Sodium nitroprusside, has a rapid onset of action. It is only available as an intravenous preparation, and because of its short half-life, continuous infusion is required. It is very useful in ICU and emergency settings.
Nitroglycerin, has a rapid onset of action (2-5 min), when taken sublingually, but its effects only last ~30 min. Longer-acting (12-24 h) preparations are available (transdermal patches). Nitroglycerin can be given IV for the treatment of unstable angina.
Adverse Effects and Contraindications
Adverse Effects
Hypotension: Most serious toxicity
Reflex tachycardia: At high doses nitrates can exert strong reflex tachycardic effect due to prompt vasodilation. Both excessive hypotension and tachycardia can worsen angina by increasing oxygen demand.
Headache: Cerebral vasodilation
Other effects: Facial flushing
Sodium Nitroprusside: Cyanide toxicity is rare but can occur as the parent compound releases both NO and cyanide. It can be treated with sodium thiosulfate infusion, which converts cyanide ions to inactive thiocyanate.
Contraindications
Nitrates should not be taken alongside sildenafil (cGMP-dependent phosphodiesterase), which is used to treat erectile dysfunction. Sildenafil inhibits the breakdown of cGMP leading to an increase in cGMP levels. Nitrates also increase cGMP, by stimulating production. Together the drugs can lead to excessive cGMP levels resulting in hypotension and impaired coronary perfusion.
Name the three B-Blockers Used in Angina and their Clinical Applications and Mechanism of Action
Propranolol, Metoprolol, Atenolol
Clinical Applications
B-blockers are used in the treatment of hypertension, angina, myocardial infarction, arrhythmias and heart failure.
Angina. B-blockers are recommended in all patients with stable angina who have had an ACS or who have left ventricular dysfunction, unless contraindicated.
Mechanism of Action
By antagonizing receptors, B-blockers are able to:
(1) decrease myocardial contractility, heart rate and cardiac output (by blocking cardiac B1 receptors);
(2) reduce renin secretion thus decrease circulating angiotensin II levels (by blocking B1 receptors on juxtaglomerular cells)
There is no reflex tachycardia evoked by B-blockers due to their negative inotropic/chronotropic actions.
The antianginal effects of B-blockers are attributed both to their negative inotropic and antihypertensive actions. They reduce the workload of the heart and thus reduce oxygen demand. They have been shown to reduce both the frequency and severity of angina attacks.
Studies have also demonstrated that B-blockers are able to decrease mortality after an MI.
Adverse Effects, Contraindications and Pharmacokinetics/Pharmacodynamics of B-Blockers
Pharmacodynamics
Propranolol – non-selective B-blocker
Metoprolol & atenolol – cardioselective B-blockers (selective for B1 receptors). Less likely to cause bronchospasm and vasoconstriction and may be safer in patients with asthma, COPD, and diabetes. Most commonly used B-blockers in treatment of angina.
Pharmacokinetics
- *Propranolol –** oral admin. Extensive first-pass metabolism.
- *Metoprolol & atenolol –** oral admin. Metoprolol = extensive first-pass metabolism
Adverse Effects
Drug withdrawal: Abrupt cessation of B-blocker therapy may produce unstable angina, MI or even death in patients with coronary disease. In patients without heart disease, abrupt discontinuation of B-blockers may be associated with tachycardia, sweating, and generalized malaise in addition to increased blood pressure. These effects are likely due to upregulation of B-receptors during blockade. For these reasons, it is always important to taper the dose gradually over 1-2 weeks before discontinuation.
Cardiovascular effects: Bradycardia, reduced exercise capacity, heart failure, hypotension, AV block.
Disturb lipid metabolism
Hypoglycemia
Bronchoconstriction
CNS effects
Contraindications
Variant angina: Variant angina is treated by agents (nitrates or Ca2+ channel blockers) that can cause coronary artery vasodilation. B-blockers by reducing oxygen demand are unable to treat variant angina which is mainly caused due to a problem with oxygen supply. Non-selective B-blockers, such as propranolol, can also exacerbate variant angina by blocking B2-mediated vasodilation.
Reactive airway disease (asthma, COPD): Non-selective B-blockers (propranolol) should be avoided.
Patients with sinus bradycardia and partial AV block: Symptoms will be exacerbated by B-blocking effects
Heart Failure: Patients who have heart failure should initially be started on a very low dose of B-blockers due to the risk of exacerbation of symptoms.
Ranolazine
(Na+ Channel-blocker)
Clinical Applications
Ranolazine is an alternative option for patients with chronic angina that have failed all other therapies.
Mechanism of Action
Ranolazine blocks late inward Na+ currents in cardiomyocytes. An increase in intracellular Na+ facilitates the inward current of Ca2+ via the Na+/Ca2+ exchanger. Increased intracellular Ca2+ results in contraction of the myocytes and impaired relaxation, leading to worsening ischemia. Ranolazine, by blocking the Na+ current, prevents Ca2+ overload within the cell, leads to improved coronary blood flow. It is also thought to have some effects on fatty acid oxidation. Ranolazine, does not have any significant effects on either heart rate or arterial pressure.
Pharmacokinetics
Ranolazine is metabolized by CYP 3A4.
Adverse Effects
QT prolongation: This is the main concern with this new drug.
Other effects: Nausea, vomiting, dizziness, constipation.
Contraindications
QT Prolongation: Ranolazine is contraindicated in patients with prolonged QT intervals due to the risk of torsades de pointes and ventricular tachyarrhythmias.
Treatment of Stable, Unstable, and Prinzmetal’s Angina
Stable Angina
Acute attacks: Nitroglycerin or rest can relieve the symptoms of acute attacks.
Maintenance Therapy
Long-acting nitrates plus B-blockers are preferred therapy
Ca2+ channel blockers are used when B-blockers are not successful or contraindicated.
Ranolazine is used when nitrates, B-blockers, and Ca2+ channel blockers are unsuccessful
Aspirin and aggressive cardiovascular risk reduction should be carried out in all patients.
Unstable Angina
Unstable angina occurs between stable angina and an MI. Chest pain occurs more frequently and is precipitated more easily.
Symptoms can be relieved by rest or nitroglycerin.
In addition long-term therapy with nitroglycerin and B-blockers should be considered.
Variant (Prinzmetal’s) Angina
Variant angina is due to coronary artery vasospasm. Events are unrelated to increases in physical exertion, heart rate or blood pressure.
Symptoms respond to nitroglycerin and Ca2+ channel blockers. Choice of drug is based on each individual patient.
