Nitrates

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Nitrates

Nitrates are organic nitric acid esters of polyalcohols. They are among the oldest cardiovascular drugs still in regular clinical use - nitroglycerin has been used for over 160 years.

Prototype and Members

Drug	Route / Formulation
Nitroglycerin (glyceryl trinitrate)	Sublingual tablet, spray, IV, transdermal patch, buccal
Isosorbide dinitrate	Sublingual, oral
Isosorbide mononitrate	Oral (active metabolite, avoids first-pass)
Pentaerythritol tetranitrate (PETN)	Oral
Amyl nitrite	Inhalation (obsolete for angina)

Mechanism of Action

Nitrates must be bioactivated enzymatically to release nitric oxide (NO). Key enzymes include:

Aldehyde dehydrogenase isoform 2 (ALDH2) - primary enzyme for nitroglycerin and PETN
Glutathione S-transferase - also contributes in smooth muscle

The NO is released as free nitrite, then converted to NO, which (complexed with cysteine) binds the heme group of soluble guanylyl cyclase, raising intracellular cGMP. Elevated cGMP activates protein kinase G (PKG), leading to:

Dephosphorylation of myosin light chains
Smooth muscle relaxation
Vasodilation - predominantly venous at low doses, arterial at higher doses

Production of PGI2/PGE and membrane hyperpolarization may also contribute. There is no direct autonomic receptor involvement, though autonomic reflexes are commonly triggered by the resulting hypotension.

Katzung's Basic and Clinical Pharmacology, 16th Edition
Braunwald's Heart Disease

Pharmacokinetics

Key point: high first-pass hepatic metabolism. The liver contains a high-capacity organic nitrate reductase. Oral bioavailability of nitroglycerin and isosorbide dinitrate is typically <10-20%.

Feature	Detail
Preferred route (acute)	Sublingual - bypasses first-pass, onset 1-3 min
Plasma half-life (unchanged drug)	2-8 minutes
Metabolite half-life	Up to 3 hours (active)
Excretion	Renal (glucuronide conjugates of denitrated metabolites)
Isosorbide mononitrate	Already the active metabolite - no first-pass problem, good oral bioavailability
Transdermal	Sustained 24-hour delivery; tolerance problem if used continuously

Sublingual tablets can lose potency from volatilization; they should be stored in tightly closed glass containers (not plastic).

Katzung's Basic and Clinical Pharmacology, 16th Edition

Cardiovascular Effects

Nitrates relax ALL smooth muscle regardless of the cause of preexisting tone. They have essentially no direct effect on cardiac or skeletal muscle.

Venous (dominant at therapeutic doses)

Venodilation → reduced venous return → decreased LV preload
Reduced LV end-diastolic volume and pressure → decreased myocardial wall tension and O2 demand

Arterial (at higher doses)

Dilation of epicardial coronary arteries (important in vasospastic angina)
Increased collateral blood flow to ischemic myocardium
Systemic arteriolar dilation → reduced afterload

Hemodynamic result in angina

Reduced myocardial O2 demand (via preload and afterload reduction)
Improved O2 supply (coronary vasodilation + collaterals)
Harrison's Principles of Internal Medicine 22E (2025)

Clinical Indications

Stable angina - sublingual NTG for acute relief; long-acting nitrates for prophylaxis
Unstable angina / NSTEMI - IV nitroglycerin
Vasospastic (Prinzmetal) angina - particularly useful (coronary vasodilation)
Acute decompensated heart failure - reduce preload and afterload
Hypertensive emergencies - IV nitroglycerin or nitroprusside
Acute MI - cautious use to reduce ischemia (avoid if hypotension or RV infarct)
Esophageal spasm - smooth muscle relaxation

Nitrate Tolerance

A major limitation of long-acting nitrate therapy.

Mechanism (multifactorial):

Depletion of tissue sulfhydryl (SH) groups (e.g., on cysteine), reducing capacity to generate NO
Increased generation of reactive oxygen species (free radicals) during nitrate metabolism
Diminished availability of calcitonin gene-related peptide (CGRP), a potent endogenous vasodilator
Neurohormonal counterregulation (RAAS activation, sympathetic stimulation)

Prevention: A nitrate-free interval of 8-12 hours each day (typically overnight for patches) prevents tolerance. Sulfhydryl donors (e.g., N-acetylcysteine) can partially restore responsiveness.

Katzung's Basic and Clinical Pharmacology, 16th Edition

Adverse Effects

Effect	Mechanism / Notes
Headache	Meningeal vasodilation - most common side effect; often diminishes with continued use
Hypotension / dizziness	Venodilation + reflex tachycardia
Reflex tachycardia	Baroreceptor response to BP drop
Flushing	Cutaneous vasodilation
Methemoglobinemia	Rare; more of a risk with amyl/isobutyl nitrites
Syncope	Particularly on standing (orthostatic)

Contraindications

Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, vardenafil) - absolute contraindication - combined use causes severe, potentially fatal hypotension (both increase cGMP)
Right ventricular infarction - preload-dependent, nitrates worsen hypotension
Severe aortic stenosis - fixed outflow obstruction; hypotension is dangerous
Hypotension (SBP <90 mmHg)
Hypertrophic obstructive cardiomyopathy - can worsen outflow obstruction

Drug Interactions

PDE5 inhibitors - see above (most critical)
Beta-blockers and calcium channel blockers - used together with nitrates to prevent reflex tachycardia and provide additive antianginal benefit
Antihypertensives / alcohol - additive hypotension

Summary Table

Property	Detail
Class	Organic nitrates (vasodilators)
MOA	NO → cGMP↑ → smooth muscle relaxation
Primary site	Veins >> arteries at low doses
Main benefit in angina	Preload reduction + coronary vasodilation
Prototype	Nitroglycerin
Key limitation	Tolerance (nitrate-free interval required)
Fatal interaction	PDE5 inhibitors

Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed. | Harrison's Principles of Internal Medicine, 22E | Lippincott Illustrated Reviews: Pharmacology | Braunwald's Heart Disease

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