Drug of the month: Nitric oxide & nitrous oxide– Same family, different stories
Shirlin M S
Clinical pharmacist, Clinical pharmacy, Heart city, Kauvery Hospital, Trichy, Tamil Nadu
Abstract
Nitric oxide (NO) and nitrous oxide (N₂O) are diatomic gases with fundamentally distinct physiological mechanisms and clinical profiles despite their phonetic similarity. Nitric oxide functions as an endogenous signaling molecule and a potent vasodilator, playing a critical role in vascular homeostasis through the stimulation of soluble guanylate cyclase and the production of cyclic guanosine monophosphate (cGMP). In contrast, nitrous oxide is an inhalational anesthetic and analgesic agent acting primarily on the central nervous system via NMDA receptor antagonism, lacking significant direct hemodynamic effects. In cardiovascular medicine, the therapeutic potential of NO is harnessed through nitric oxide donors—pharmacological compounds such as organic nitrates (e.g., nitroglycerin) and nitroprusside. These agents induce the release of NO in vivo to cause smooth muscle relaxation and vasodilation. The clinical significance of NO donors is paramount in the management of ischemic heart disease, acute decompensated heart failure, and hypertensive emergencies, where they function to reduce myocardial oxygen demand and optimize hemodynamics by decreasing preload and afterload. This review delineates the pharmacological distinctions between NO and N₂O and underscores the essential role of NO donors in contemporary cardiac therapy.
Key words: Nitric oxide (NO); Nitrous oxide (N₂O); Cyclic guanosine monophosphate (cGMP).
| Parameters | Nitric Oxide | Nitrous Oxide |
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| Category | Selective Pulmonary Vasodilator | General Anaesthetic |
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Nitric Oxide Donors
Nitric oxide (NO) is an endogenous, highly unstable free radical diatomic gas with diverse physiological and therapeutic roles, including vasodilation, neurotransmission, wound healing, angiogenesis, bone metabolism, apoptosis, insulin secretion, and inhibition of platelet aggregation. Its biological effects may be protective or harmful depending on concentration, duration of exposure, site of action, and the cellular environment. Nitric oxide also acts on cardiac muscle to decrease contractility and heart rate. NO contributes to the regulation of cardiac contractility. Owing to its small size, neutral charge, and relative lipophilicity, NO readily diffuses across cell membranes without the need for receptors, acting in a concentration-dependent manner. However, the direct clinical use of NO gas is limited by its instability, uncontrolled release, short half-life, and potential toxicity. To address these challenges, various NO-donor compounds have been developed that can store and release NO in a controlled and site-specific manner, sometimes triggered by external stimuli such as visible or near-infrared light and ultrasound. These NO donors include organic nitrates, nitrites, inorganic metal nitrosyl complexes, N-diazeniumdiolates (NONOates), S-nitrosothiols, furoxans, and nitrobenzene’s, which exert their effects by mimicking endogenous NO signaling. While therapeutically useful, excessive NO levels can lead to cytotoxicity, enzyme inhibition, DNA damage, and lipid peroxidation. Clinically, organic nitrates such as nitroglycerin and sodium nitroprusside have been used for over a century, with newer agents including isoamyl nitrite, isosorbide mononitrate (ISMN) and dinitrate (ISDN). ISMN has a long half-life, a main metabolite of ISDN. Isosorbides primarily exert their maximal effect on venous capacitance vessels, making them effective in reducing cardiac preload and improving circulation. Inhaled nitric oxide is indicated for term and near-term neonates with hypoxic respiratory failure and pulmonary hypertension to improve oxygenation via selective pulmonary vasodilation. Administered as an adjunct to ventilatory support, this agent serves as a bridge therapy to reduce the need for extracorporeal membrane oxygenation (ECMO).Sildenafil works to inhibit the enzyme phosphodiesterase 5 (PDE5), which increases the cGMP concentration by inhibiting the conversion to GMP which enhances signaling through the nitric oxide pathway. The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist.
Role of Organic nitrates
Effect on endothelial function: NO is an endothelial-derived relaxing factor (EDRF), depends on a healthy and functional endothelium to maintain the vascular tone. NO released from the endothelial cells increases the level of cyclic guanosine monophosphate (cGMP) within the cells by activating enzyme guanylate cyclase causing vasodilatation and platelet disaggregation. EDRF insufficiency in coronary artery disease (CAD) is caused by endothelial dysfunction and inadequate cGMP/NO pathway activation. A complete lack of NO (synthesis), reduced availability of bioactive NO, or increased NO inactivation can all be indicators of NO deficiency. One source of NO is exogenous nitrates, like GTN.
Effects on coronary and peripheral circulation: Nitrates are potent vasodilators dilating coronary arteries and arterioles greater than 100mcm in diameter. They relieve angina symptoms by facilitating blood flow from epicardial to endocardial vessels and enhance collateral flow by selectively relaxing the epicardial vessels, thereby relieving myocardial ischemia through improved regional myocardial blood flow. Nitrates enhance blood flow through dynamic stenosis and alleviate coronary spasm by preferentially dilating coronary arteries.
- Nitrates lower the oxygen demand by lowering the preload and theworkload by enhancing venous capacitance and peripheral blood pooling
- Nitrates lowerthe oxygen requirementby decreasing the afterload through a decrease in aortic systolic pressure, while peripheral arterial pressure remains stable.
Effect on platelets: Exogenous nitrates undergo denitration to form NO, which stimulates platelet guanylate cyclase. This, in turn, raises the platelet cGMP level, leading to decreased fibrinogen binding to the glycoprotein IIb/IIIa receptor. This leads to the disaggregation of platelets. The most common side effects include thrombocytopenia, hypokalaemia, hypotension, atelectasis, and hyperbilirubinaemia.
Limitations and Tolerance
A significant limitation to the chronic use of organic nitrates is the development of tolerance, often within 24 hours of continuous use. This phenomenon, often termed “tachyphylaxis,” is thought to be caused by the depletion of intracellular thiols (necessary for bioactivation), neurohormonal activation, and increased oxidative stress. Strategies to mitigate tolerance include the use of nitrate-free intervals to allow enzyme recovery
Significance of NO Donors in cardiology
Management of Angina pectoris: In the treatment of stable and unstable angina, organic nitrates (e.g., nitroglycerin) are first-line therapies. By dilating the venous capacitance vessels, they reduce ventricular preload (venous return), which decreases left ventricular wall stress and myocardial oxygen demand. Additionally, at higher doses, nitrates dilate epicardial coronary arteries, alleviating vasospasm and improving blood flow to ischemic myocardium
Acute Decompensated Heart Failure (ADHF): In patients with ADHF, afterload reduction is often necessary to improve cardiac output. Sodium nitroprusside is frequently utilized in this setting due to its balanced arterial and venous dilation properties. By reducing systemic vascular resistance (afterload), the failing ventricle is able to eject blood more efficiently, thereby improving forward flow and reducing pulmonary congestion.
Hypertensive Emergencies: Vascular tone regulates BP control, which is directly influenced by the vascular endothelium which is characterized mainly by a reduction in the ability of endothelial cells to release NO. For the rapid control of severe hypertension, intravenous NO donors offer titratable and immediate hemodynamic effects. Sodium nitroprusside is particularly effective due to its rapid onset and offset of action, overshoot while promptly reducing blood pressure to safe levels.
Conclusion
In summary, the pharmacological disparity between nitric oxide and nitrous oxide is profound, necessitating a clear clinical distinction between a targeted hemodynamic modulator and a central nervous system anesthetic. However, the clinical application of these agents is not without challenges; the phenomenon of nitrate tolerance necessitates sophisticated dosing strategies, and the potency of these drugs requires vigilant monitoring to prevent refractory hypotension or cyanide toxicity. Furthermore, the reliance on exogenous NO donors underscores the broader pathological significance of endothelial dysfunction in cardiovascular disease. As research continues to elucidate the complexities of NO signaling and develop novel donor compounds aimed at overcoming tolerance and enhancing bioavailability, the therapeutic relevance of this pathway remains dynamic. Ultimately, the continued evolution of NO donor therapy affirms its status as a cornerstone of cardiology, bridging the gap between molecular physiology and acute patient care
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