Drugs Affecting the Cardiovascular and Renal Systems - Nitrates

Overview of Drugs Affecting Cardiovascular and Renal Systems

  • Focus: Nitrates

Nitrates Overview

  • Definition: Nitrates are vasodilators used to relieve angina, a type of chest pain caused by reduced blood flow to the heart.

  • Examples: Nitroglycerin

Mechanism of Action for Angina Relief

Stable Angina

  • Direct Action on Vascular Smooth Muscle:

    • Promotes uptake of nitric oxide (NO).

    • NO activates guanylate cyclase which produces cyclic GMP (cGMP).

    • cGMP leads to dephosphorylation of myosin.

  • Result: Myosin interaction with actin is inhibited, preventing contraction, leading to vascular smooth muscle relaxation.

  • Effects:

    • Vasodilation

    • Decreased vascular resistance

    • Decreased preload

    • Decreased oxygen demand

  • Target Areas: Primarily acts on veins rather than arterioles.

  • Coronary Blood Flow: Limited effect on coronary blood flow; relief primarily from peripheral blood vessel effects.

Variant Angina

  • Mechanism: Nitrates provide relaxation of coronary arteries by relieving spasms.

  • Result: Increased supply of oxygen to the heart.

Forms of Nitrates

  • Administration Routes:

    • Oral (PO)

    • Sublingual

    • Buccal

    • Transdermal

  • Absorption Considerations:

    • Dry mouth can reduce absorption of sublingual tablets.

    • Oral formulations face significant first-pass metabolism; bypassed with sublingual, buccal, and transdermal routes.

Metabolism and Excretion

  • Nitroglycerin is metabolized to:

    • Isosorbide dinitrate

    • Further to isosorbide mononitrate.

  • Excretion: Through the kidneys and lungs.

Precautions and Contraindications

  • Precautions: Monitor for hypotension in patients who are volume-depleted or anemic.

  • Contraindications:

    • Closed-angle glaucoma (increases intraocular pressure)

    • Pregnancy (safety is unknown)

    • Caution in lactation

Uses of Nitrates

Preventative Treatment for Angina

  • Long-acting formulations:

    • Nitroglycerin sustained-release capsules: 40-80 mg daily

    • Isosorbide dinitrate: 10-40 mg 2-3 times a day

    • Isosorbide mononitrate: 20 mg twice a day

Treatment for Active Anginal Attacks

  • Sublingual nitroglycerin: 0.4 - 0.6 mg per dose.

    • Administration: If pain persists after two doses, instruct patients to call 911. Max: 3 doses, each separated by 5 minutes.

  • Note: For variant angina, use long-acting forms instead of sublingual.

Additional Uses

  • Combination usage in heart failure with hydralazine.

Tolerance and Tachyphylaxis

  • Issue: Tolerance develops with continuous use, especially at high doses.

  • Cross-tolerance observed with other nitrate forms.

  • Prevention Strategies:

    • Use the lowest effective dose.

    • Schedule intermittent dosing every 7 hours (i.e., twice daily: 7 AM and 2 PM).

    • Ensure 10-12 hours drug-free period for patches.

Patient Education

  • Sublingual Tablets:

    • Used for active anginal pain with the same max dose instructions.

    • Importance of keeping the drug in original container, protected from moisture.

  • Sustained Release Capsules:

    • Not for active attacks due to slow onset.

    • Maximum dosing should be once to twice a day to prevent tolerance.

  • Transdermal Patches:

    • Long-term prevention; apply to hairless areas, rotate sites, remove at night to prevent tolerance.

    • Never cut the patch.

    • Caregiver education to prevent secondary hypotension.

Administration via Other Forms

  • Ointments: For long-term prevention; rotate application site, minimize uninterrupted use to avoid tolerance.

  • IV Form: Rarely used; in severe anginal cases in hospitals.

  • IV nitroglycerin dispensed in glass bottles due to absorption concerns with PVC tubing.

Adverse Effects

  • Headaches: Severe at onset but usually subsides; persistent headaches can be treated with Tylenol.

  • Orthostatic Hypotension: Lightheadedness possible; educate to avoid rapid position changes and lie down if experiencing hypotension.

  • Reflex Tachycardia: Address by adding beta blockers or selected calcium channel blockers (e.g., diltiazem, verapamil).

Drug Interactions

  • Caution with any agents that lower blood pressure (e.g., beta blockers, calcium channel blockers, diuretics, antipsychotics).

  • Contraindicated with erectile dysfunction medications (e.g., sildenafil, tadalafil); extremely dangerous.

  • Alcohol: Should be avoided since it lowers blood pressure.

  • Anticholinergic Drugs: Reduce absorption of sublingual and buccal nitroglycerin.

  • Aspirin: Potentiates effects of nitrates; recommend Tylenol for headaches.

  • Heparin: Nitrates may reduce the effects of heparin.