Pharmacology of Organic Nitrates

This set covers the physiological mechanism, classifications, pharmacokinetics, and clinical considerations of organic nitrates used in treating angina.

Organic Nitrates

A class of drugs used for the acute treatment and prevention of ischemic heart disease by reducing myocardial oxygen demand.

Nitric Oxide ($NO$)

An endogenous vasodilator produced by the endothelium; its release is triggered by the metabolic activation of nitrates.

Aldehyde Dehydrogenase 2 (ALDH2)

An enzyme found predominantly in the veins that breaks down nitrates to facilitate the spontaneous release of nitric oxide.

Cyclic GMP ($cGMP$)

A secondary messenger that increases within the vasculature in response to $NO$, leading to the relaxation of vascular smooth muscles.

Preload Reduction

The primary hemodynamic effect of nitrates at standard doses, achieved through venodilation which reduces the volume of blood returning to the heart.

Afterload Reduction

A hemodynamic effect achieved at higher nitrate doses through arteriolar dilation, reducing the resistance the heart must pump against.

Glycerol Trinitrate (GTN)

Also known as Nitroglycerin, this nitrate has a rapid onset of action but very low oral bioavailability due to extensive first-pass metabolism in the liver.

Sublingual GTN Tablets

A formulation for acute relief that bypasses the liver but is highly volatile with a limited shelf life of approximately $3$ months.

Sublingual GTN Spray

A stable formulation for immediate relief with a shelf life of up to $2$ years after opening, though the device requires priming before use.

Nitrate Tolerance

The loss of drug efficacy resulting from continuous exposure to nitrates, requiring a regular interval without the drug to restore effectiveness.

Nitrate-free Period

A mandatory interval of at least $8$ hours every $24$ hours where systemic nitrate levels return to zero to prevent or reverse tolerance.

Isosorbide Dinitrate (ISDN)

A nitrate with poor oral bioavailability that is metabolized by hepatic reductase into active mononitrate forms.

Isosorbide Mononitrate (ISMN)

The active metabolite of ISDN that is $100\%$ bioavailable when administered orally and features a significantly long half-life of $4$ hours.

Orthostatic Hypotension

A common side effect where blood pressure drops upon standing because nitrates reduce preload and interrupt the natural baroreceptor reflex.

Reflex Tachycardia

A compensatory increase in heart rate and contractility that occurs as the vasculature dilates and blood pressure drops, typically at higher nitrate doses.

Sildenafil (Viagra)

A $PDE5$ inhibitor that, when combined with nitrates, causes a massive buildup of $cGMP$, leading to life-threatening hypotension or priapism.

Phosphodiesterase 5 (PDE5)

The enzyme responsible for breaking down $cGMP$; its inhibition by drugs like Sildenafil prevents the degradation of $cGMP$.

Priapism

A medical emergency characterized by a painful erection lasting more than $2$ hours, which can cause permanent damage if not resolved within $4$ hours.

Pseudoephedrine

A vasoconstrictor that binds to alpha receptors in the periphery, used as an emergency treatment to reverse severe vasodilation or priapism.

Glucuronidation

The metabolic process by which all nitrates eventually undergo transformation before being excreted via the kidneys.