Nicorandil (DB09220): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Nicorandil is a unique anti-anginal agent distinguished by a rationally designed dual mechanism of action, functioning as both an adenosine triphosphate (ATP)-sensitive potassium (KATP​) channel activator and a nitric oxide (NO) donor.[1] This hybrid pharmacology confers a balanced vasodilator effect, reducing both cardiac preload through venodilation and afterload through arterial dilation, thereby improving the myocardial oxygen supply-demand balance.[3] Its primary indication is the prevention and long-term treatment of chronic stable angina pectoris.[5] However, its therapeutic role has been redefined in many regions, including the United Kingdom and the European Union, where it is now recommended as a second-line therapy. This repositioning is a direct consequence of a significant and serious risk of muco-cutaneous ulcerations, which can be severe, treatment-refractory, and may lead to complications such as perforation and fistula formation.[7] The only effective management for these ulcers is the cessation of nicorandil therapy.

The drug exhibits a complex global regulatory status; it is widely prescribed in Europe, Japan, and other parts of Asia but remains unapproved by the United States Food and Drug Administration (FDA).[1] Pharmacokinetically, it is characterized by good oral bioavailability and a short elimination half-life, necessitating a twice-daily dosing regimen for chronic management.[8] While its role in chronic angina has been circumscribed by safety concerns, a substantial body of recent evidence from clinical trials and meta-analyses has illuminated its potential in acute and procedural cardiology. Emerging data strongly support its use for cardioprotection during percutaneous coronary intervention (PCI), where it has been shown to reduce periprocedural myocardial injury and contrast-induced nephropathy.[10] These findings suggest an evolving therapeutic identity for nicorandil, potentially shifting its future application from long-term chronic management to short-term use in high-risk procedural settings where its unique cardioprotective and renoprotective mechanisms can be maximally leveraged.

Chemical Identity and Physicochemical Properties

A precise understanding of nicorandil's chemical and physical nature is fundamental to appreciating its pharmacological activity and formulation characteristics.

Nomenclature and Identifiers

To ensure unambiguous identification, nicorandil is cataloged under a variety of internationally recognized names and database identifiers.

• Primary Name: Nicorandil [1]
• DrugBank ID: DB09220 [1]
• Type: Small Molecule [5]
• CAS Number: 65141-46-0 [1]
• IUPAC Name: 2-(pyridine-3-carbonylamino)ethyl nitrate [1]
• Chemical Class: Pyridinecarboxamide, Nitrate ester. It is classified as a niacinamide derivative and is functionally related to nicotinamide.[1]
• Synonyms and Alternative Names: A comprehensive list includes Ikorel, SG-75, Dancor, Sigmart, Adancor, Perisalol, Nicorandilum, 2-Nicotinamidoethyl nitrate, N-[2-(Nitroxy)ethyl]pyridine-3-carboxamide, and N-(2-Hydroxyethyl)nicotinamide nitrate (ester).[5]
• Database Identifiers:
• PubChem CID: 47528 [8]
• ChemSpider ID: 43240 [8]
• UNII: 260456HAM0 [1]
• KEGG ID: D01810, C13280 [1]
• ChEBI ID: CHEBI:31905 [1]
• ChEMBL ID: CHEMBL284906 [1]
• European Community (EC) Number: 265-514-1 [1]

Molecular Structure and Properties

The molecular architecture of nicorandil is central to its dual pharmacological action. The structure combines a nicotinamide moiety with a nitrate ester group, a deliberate design that confers its unique therapeutic profile.

• 2D Molecular Structure:

[16]

• Molecular Formula: C8​H9​N3​O4​ [12]
• Molecular Weight: Sources cite values of 211.17 g/mol (average), 211.18 g/mol, and 211.06 g/mol. Its monoisotopic mass is 211.059306 Da.[12]
• Chemical Descriptors:
• SMILES: C1=CC(=CN=C1)C(=O)NCCO[N+](=O)[O-] [1]
• InChI: InChI=1S/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12) [1]
• InChIKey: LBHIOVIQHSOQN-UHFFFAOYSA-N [1]

The molecular architecture of nicorandil is a clear example of rational drug design, where two distinct pharmacophores are covalently linked into a single molecule to achieve a synergistic therapeutic effect. The core pyridinecarboxamide structure, a derivative of nicotinamide (a form of vitamin B3), serves as the scaffold responsible for its activity as a KATP​ channel opener.[1] Appended to this is a 2-(nitrooxy)ethyl group, a classic organic nitrate structure analogous to that found in drugs like nitroglycerin. This nitrate ester moiety is the source of its second mechanism: nitric oxide donation.[1] This hybrid design allows nicorandil to simultaneously target two separate but complementary pathways involved in vasodilation—arterial relaxation via ion channel modulation and venous relaxation via the NO-cGMP pathway—providing a more "balanced" hemodynamic effect than either a pure potassium channel opener or a traditional nitrate alone.

• Physicochemical Properties: The drug's physical and chemical properties, summarized in Table 1, are consistent with a molecule designed for oral administration and good bioavailability, as predicted by its adherence to Lipinski's Rule of Five.[18] Table 1: Physicochemical Properties of Nicorandil

Property	Value	Source(s)
Appearance	White crystalline powder or white needles; faint, characteristic odour	12
Melting Point	88.5-93.5 °C	12
Solubility	Freely soluble in methanol, ethanol, acetone, glacial acetic acid; Slightly soluble in water, chloroform; Almost insoluble in ether, benzene	12
XLogP	0.42	18
Topological Polar Surface Area (TPSA)	94.36 A˚2	18
Hydrogen Bond Donors	1	18
Hydrogen Bond Acceptors	3	18
Rotatable Bonds	6	18
Acid Dissociation Constants (pKa)	pKa1​ (acidic) = 10.97; pKa2​ (basic) = 3.07	13

Developmental History and Therapeutic Context

Discovery and Origin

Nicorandil was developed by Chugai Pharmaceutical Co., Ltd., a pharmaceutical company based in Japan.[12] It received its first regulatory approval in Japan in September 1983, establishing it as one of the pioneering drugs in the class of potassium channel activators.[20] Its development marked a significant step in the evolution of anti-anginal pharmacotherapy.

Evolution of Anti-Anginal Therapy

The development of nicorandil is best understood within the historical context of angina treatment. The therapeutic principle of nitrate-induced vasodilation has been a cornerstone of cardiology for over a century, beginning with the discovery of nitroglycerin's potent physiological effects by Ascanio Sobrero in 1847 and its first documented clinical use for relieving angina pectoris by William Murrell in 1876.[4] For decades, organic nitrates were the primary agents for angina relief, but their precise mechanism remained elusive. The seminal discoveries in the 1980s by Robert Furchgott, Louis Ignarro, and Salvador Moncada, who identified nitric oxide (NO) as the endothelium-derived relaxing factor (EDRF), finally provided the molecular basis for nitrate action, revealing the critical role of the NO-cyclic guanosine monophosphate (cGMP) signaling pathway in mediating vasodilation.[4]

Nicorandil was engineered to leverage this well-established nitrate pathway while simultaneously introducing a novel mechanism to address the limitations of traditional nitrates. Chronic use of agents like nitroglycerin is associated with the development of pharmacological tolerance, which diminishes their efficacy, and the risk of rebound angina upon withdrawal.[4] Nicorandil was designed as a hybrid agent to overcome these issues. By combining the NO-donating nitrate moiety with a nicotinamide structure that activates ATP-sensitive potassium (

KATP​) channels, it offered a dual approach to vasodilation.[4] This novel KATP channel-opening action primarily targets arterial resistance vessels, complementing the predominantly venous effects of nitrates, and is not associated with the development of tolerance.[2] Thus, nicorandil's creation represents a strategic bridge between classical pharmacology and modern molecular targeting, aiming to produce a more effective and reliable anti-anginal agent with a balanced hemodynamic profile.

Comprehensive Pharmacological Profile

Pharmacodynamics: A Dual Mechanism of Action

Nicorandil's therapeutic efficacy stems from its unique ability to induce vasodilation through two distinct yet complementary molecular pathways. This dual action results in a balanced reduction of both cardiac preload and afterload.

The KATP Channel Opening Pathway (Arterial Vasodilation)

Nicorandil functions as a potent activator of ATP-sensitive potassium (KATP​) channels, which are critical regulators of vascular smooth muscle tone.[1]

1. Channel Binding and Selectivity: KATP​ channels are complex proteins composed of inwardly rectifying potassium channel (Kir6.x) subunits that form the pore, and regulatory sulfonylurea receptor (SUR) subunits.[5] Nicorandil's binding site is located on the SUR2 subunit.[5] It exhibits significant selectivity for the SUR2B/Kir6.2 channel isoform ( EC50​ ≈ 10 µM), which is predominantly expressed in vascular smooth muscle, over the SUR2A/Kir6.2 isoform (EC50​ > 500 µM) found in cardiac and skeletal muscle.[12] This vascular selectivity is crucial, as it allows nicorandil to exert its primary effects on blood vessel tone with no significant direct action on myocardial contractility or conduction.[12]
2. Cellular Effect: The binding of nicorandil to and activation of these channels increases the transmembrane conductance of potassium ions (K+), leading to an efflux of K+ from the vascular smooth muscle cell.[1] This net outward movement of positive charge results in hyperpolarization of the cell membrane.[5]
3. Vasodilation: Membrane hyperpolarization leads to the closure of voltage-gated L-type calcium channels, thereby reducing the influx of extracellular calcium (Ca2+) into the cell.[8] Since smooth muscle contraction is dependent on intracellular Ca2+ concentration, this reduction in Ca2+ influx leads to the relaxation of arterial smooth muscle.[5]
4. Hemodynamic Consequence: This mechanism produces potent arterial and arteriolar dilation, which reduces total peripheral resistance. This reduction in the pressure against which the left ventricle must eject blood is known as a decrease in afterload.[2]

The Nitric Oxide (NO) Donor Pathway (Venous Vasodilation)

In parallel with its channel-opening activity, nicorandil's structure incorporates a nitrate ester moiety, enabling it to function as a nitric oxide (NO) donor, akin to traditional organic nitrates.[1]

1. NO Release and sGC Activation: Within the body, nicorandil is metabolized to release NO. This NO diffuses into vascular smooth muscle cells and binds to its intracellular receptor, the enzyme soluble guanylate cyclase (sGC).[8]
2. cGMP Production: The activation of sGC catalyzes the conversion of guanosine triphosphate (GTP) to the second messenger cyclic guanosine monophosphate (cGMP).[1]
3. Downstream Signaling and Vasodilation: Elevated intracellular cGMP levels activate cGMP-dependent protein kinase (PKG). PKG promotes smooth muscle relaxation through several downstream mechanisms, including:

• Inhibition of the RhoA/Rho-kinase pathway, which decreases the calcium sensitivity of the contractile apparatus.[8]
• Phosphorylation and activation of pumps that actively extrude Ca2+ from the cell.[8]
• Activation of potassium channels, leading to hyperpolarization.[8]

4. Hemodynamic Consequence: This NO-mediated pathway has a more pronounced effect on the venous side of the circulation, causing significant venodilation. This increases the pooling of blood in the peripheral capacitance vessels, which decreases the volume of blood returning to the heart. This reduction in ventricular filling volume and pressure is known as a decrease in preload.[1]

Integrated Hemodynamic Effects

The combination of these two mechanisms results in a "balanced" and comprehensive vasodilator effect.[4] By reducing both afterload (via

KATP​ channel opening) and preload (via NO donation), nicorandil effectively decreases the overall workload and wall stress of the myocardium, thereby reducing its oxygen demand.[2] Concurrently, it directly dilates both normal and stenotic epicardial coronary arteries, enhancing coronary blood flow and improving myocardial oxygen supply.[1] This dual action improves the myocardial oxygen supply-demand balance without inducing the "coronary steal" phenomenon, where blood is diverted away from ischemic areas—a potential concern with non-selective arteriolar dilators.[3]

An important nuance in its pharmacodynamics is the potential dose-dependent nature of its actions. Some evidence suggests that at lower plasma concentrations, the nitrate-like effects on large coronary arteries and veins predominate, while at higher concentrations, the KATP​ channel-opening effects on coronary resistance vessels become more significant.[8] This implies that dose titration may alter not only the magnitude but also the balance of nicorandil's hemodynamic effects, a factor that may contribute to the clinical strategy of starting at a low dose and titrating upwards.

Cardioprotective and Ancillary Mechanisms

Beyond its immediate hemodynamic effects, nicorandil exhibits several ancillary properties that contribute to a broader cardioprotective profile, particularly in the context of myocardial ischemia.

• Ischemic Preconditioning: A key aspect of nicorandil's cardioprotective action is its ability to pharmacologically mimic the phenomenon of ischemic preconditioning, where brief, non-lethal episodes of ischemia render the myocardium more resistant to a subsequent, prolonged ischemic insult.[2] This effect is primarily mediated by the activation of mitochondrial ATP-sensitive potassium ( mitoKATP​) channels.[2] Opening these channels is believed to preserve mitochondrial integrity and function, conserve cellular ATP stores, and inhibit apoptosis (programmed cell death) during ischemia-reperfusion injury, ultimately leading to a reduction in myocardial infarct size.[2]
• Angiogenesis: Preclinical studies have suggested that nicorandil may promote the growth of new coronary capillaries and arterioles (angiogenesis).[2] This effect is associated with the upregulation of key proangiogenic factors, including Vascular Endothelial Growth Factor (VEGF) and basic Fibroblast Growth Factor (bFGF), potentially offering a long-term mechanism for improving myocardial perfusion.[2]
• Antioxidant and Anti-inflammatory Effects: Nicorandil may exert protective effects by mitigating oxidative stress. It has been shown to prevent the accumulation of damaging reactive oxygen species (ROS) and may increase the activity of antioxidant enzymes such as superoxide dismutase 2 (SOD2).[1] It may also possess anti-inflammatory properties.[27]
• Anti-arrhythmic Potential: In experimental models, nicorandil has been shown to normalize prolonged cardiac action potential duration and shorten the QT interval.[8] By modulating cardiac electrophysiology, it may help prevent the development of malignant ventricular arrhythmias, particularly those triggered by ischemia.[8]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of nicorandil is characterized by rapid absorption, low protein binding, and a relatively short half-life, which dictates its clinical dosing schedule. Key parameters are summarized in Table 2.

Table 2: Summary of Nicorandil Pharmacokinetic Parameters

Parameter	Value	Source(s)
Route of Administration	Oral	6
Bioavailability (F)	75% to 80%	8
Time to Peak Concentration (Tmax​)	30 to 60 minutes	6
Plasma Protein Binding	25%	8
Volume of Distribution (Vd​)	1.40 L/kg	13
Metabolism	Hepatic; primarily via denitration	5
Major Metabolite	2-nicotinamidoethanol (inactive)	5
Elimination Half-life (t1/2​)	~1 hour	8
Excretion	Primarily renal (21% of dose)	8
Clearance (CL)	8.90 mL/min/kg	13

Nicorandil is well absorbed following oral administration and does not undergo significant first-pass metabolism, contributing to its high bioavailability.[6] Its rapid absorption leads to a quick onset of action. The relatively short elimination half-life of approximately one hour is a critical determinant of its clinical use.[8] To maintain continuous therapeutic plasma concentrations for the prophylaxis of chronic angina, a twice-daily (BID) dosing regimen is necessary. A single daily dose would result in a prolonged period without adequate therapeutic coverage due to the drug's rapid clearance from the body. Metabolism occurs primarily in the liver through a denitration pathway, which removes the nitrate group to form a pharmacologically inactive metabolite, 2-nicotinamidoethanol. This metabolite is subsequently processed through standard nicotinamide metabolic pathways before being excreted by the kidneys.[5]

Clinical Efficacy and Therapeutic Applications

Management of Chronic Stable Angina Pectoris

• Primary Indication: Nicorandil is indicated for the prevention and long-term treatment of chronic stable angina pectoris, a condition characterized by chest pain resulting from transient myocardial ischemia.[5] It is often used for patients who remain symptomatic despite optimal treatment with other anti-anginal drugs.[1]
• Role as a Second-Line Agent: Despite its proven efficacy, the regulatory standing of nicorandil for chronic use has been revised in the United Kingdom and the European Union. Following a comprehensive review of its risk-benefit profile, health authorities issued updated guidance positioning nicorandil as a second-line therapy.[7] It is now recommended only for patients whose angina is inadequately controlled by first-line anti-anginal therapies (such as beta-blockers or calcium channel antagonists) or for those who have a contraindication or intolerance to these agents. This significant change was driven primarily by the recognition of the serious risk of muco-cutaneous ulcer complications associated with its long-term use.[7]
• Evidence from Landmark Trials (IONA Study): The primary evidence supporting nicorandil's prognostic benefit in chronic stable angina comes from the Impact of Nicorandil in Angina (IONA) study.[3] This large-scale, randomized, double-blind, placebo-controlled trial enrolled 5,126 patients with stable angina who were at high risk for cardiovascular events. The study demonstrated that treatment with nicorandil (20 mg twice daily) on top of standard anti-anginal therapy resulted in a statistically significant reduction in the composite primary endpoint of coronary heart disease (CHD) death, non-fatal myocardial infarction, or unplanned hospital admission for cardiac chest pain. The event rate was 13.1% in the nicorandil group compared to 15.5% in the placebo group over a mean follow-up of 1.6 years (hazard ratio 0.83; 95% confidence interval 0.72-0.97).[3] The benefits observed in the IONA study are thought to be linked to the profound cardioprotective effects mediated by the activation of mitochondrial KATP​ channels, which go beyond simple vasodilation.[2]

Emerging Applications in Interventional Cardiology and Acute Coronary Syndromes

While its role in chronic management has been qualified, a growing body of evidence highlights a promising new role for nicorandil in acute and procedural settings, where its unique cardioprotective mechanisms can be leveraged over a short duration.

• Cardioprotection during Percutaneous Coronary Intervention (PCI): Several meta-analyses have consolidated evidence showing that periprocedural administration of nicorandil can protect the heart and kidneys during PCI.
• A 2018 meta-analysis of 14 randomized controlled trials (RCTs) involving 1,947 patients with stable coronary artery disease undergoing elective PCI found that nicorandil significantly reduced the incidence of postprocedural myocardial infarction (MI) (relative risk = 0.58) and contrast-induced nephropathy (CIN) (RR = 0.36).[11]
• A more recent meta-analysis of 14 studies with 1,762 patients confirmed that nicorandil significantly lowered the risk of periprocedural myocardial injury (PMI) (RR = 0.73) and major adverse cardiovascular events (MACE) (RR = 0.76).[27]
• Prevention of Contrast-Induced Nephropathy (CIN): The potential for nicorandil to prevent CIN—a form of acute kidney injury caused by iodinated contrast media used during angiography—is a significant area of clinical investigation.[30]
• A meta-analysis of 12 studies with 3,834 participants, published in the Journal of the American College of Cardiology, demonstrated a significantly lower incidence of CIN in patients receiving nicorandil compared to controls (odds ratio: 0.40). The benefit was particularly pronounced in the subgroup of patients with pre-existing chronic kidney disease (CKD) (OR: 0.36).[31]
• Another recent meta-analysis of 12 RCTs with 2,787 participants reached a similar conclusion, reporting that nicorandil was protective against CIN (RR 0.38) in patients undergoing coronary procedures.[32]
• Use in ST-Elevation Myocardial Infarction (STEMI): The administration of nicorandil during primary PCI for acute STEMI has been evaluated in several trials.
• The CHANGE trial, a multicenter, prospective, randomized, double-blind clinical trial (NCT03445728), investigated intravenous nicorandil given before reperfusion in 238 STEMI patients. The results showed that nicorandil significantly reduced myocardial infarct size as measured by cardiac magnetic resonance (CMR), improved left ventricular ejection fraction, and lowered the incidence of the no-reflow/slow-flow phenomenon compared to placebo.[34]
• A meta-analysis of recent trials found that intracoronary nicorandil treatment during PCI for STEMI significantly decreased the incidence of arrhythmia (RR = 0.52), reduced re-hospitalization rates (RR = 0.56), and improved coronary blood flow. However, it did not demonstrate a significant effect on cardiovascular death, heart failure, or chest pain.[10]

This accumulating evidence suggests a notable paradigm shift in the therapeutic identity of nicorandil. Initially developed and studied as a long-term prophylactic agent for chronic angina, its future may increasingly lie in the acute care setting. The very mechanisms that confer its cardioprotective benefits—mimicking ischemic preconditioning, mitigating ischemia-reperfusion injury, reducing oxidative stress, and improving microvascular circulation—are most impactful during acute ischemic events like STEMI or controlled ischemic insults like PCI. While the risk of ulceration tempers enthusiasm for its chronic use, the risk-benefit calculus for short-term, high-stakes procedural use appears highly favorable, positioning nicorandil as a valuable adjunct in the catheterization laboratory.

Clinical Practice: Dosage, Administration, and Patient Management

Recommended Dosing Regimens

The administration of nicorandil requires careful dose initiation and titration to balance efficacy with tolerability, particularly concerning the common side effect of headache.

• Starting Dose: The standard recommended starting dose is 10 mg twice daily. However, for patients known to be susceptible to headaches, a lower starting dose of 5 mg twice daily is advised. This initial dose can be maintained for approximately one week to allow for acclimatization before titrating upwards.[6]
• Therapeutic Dose: The usual therapeutic maintenance dose is in the range of 10 mg to 20 mg twice daily, administered orally.[3]
• Maximum Dose: Depending on the clinical response and patient tolerance, the dosage may be titrated upwards to a maximum of 30 mg or 40 mg twice daily if necessary to achieve adequate angina control.[3]
• Special Populations:
• Elderly: No specific dose reduction is required for elderly patients, but it is prudent practice to use the lowest effective dose.[6]
• Pediatric: The use of nicorandil in children is not recommended, as its safety and efficacy have not been established in this population.[6]

Administration Guidelines

• Route and Frequency: Nicorandil is administered orally, typically as one tablet in the morning and one in the evening to provide continuous coverage.[6]
• Relation to Food: The medication can be taken with or without food.[9]
• Method of Administration: Tablets should be swallowed whole with a drink of water. The tablets are scored, which allows them to be broken in half to facilitate 5 mg dosing or to aid patients who have difficulty swallowing whole tablets.[9]
• Duration of Therapy: For chronic angina, treatment with nicorandil is generally considered long-term, potentially for life. Patients should be advised not to discontinue the medication without consulting their physician, as this can lead to the recurrence of angina symptoms.[9]

Management of Overdose

• Symptoms: An acute overdose of nicorandil is expected to manifest as excessive peripheral vasodilation. The primary clinical signs would be a significant decrease in blood pressure (hypotension), leading to symptoms of dizziness and weakness, accompanied by a reflex tachycardia (an accelerated heart rate).[6]
• Management: There is no specific antidote for nicorandil overdose. Management is supportive and aimed at correcting the hemodynamic instability. This includes:
• Monitoring of cardiac function.
• General supportive measures.
• If necessary, expansion of the circulating plasma volume through the infusion of suitable intravenous fluids.
• In life-threatening situations of profound shock, the administration of vasopressor agents should be considered to restore blood pressure.[3]

Safety and Tolerability Profile

The safety profile of nicorandil is characterized by common, generally manageable vasodilator-related side effects and a rare but very serious risk of muco-cutaneous ulceration, which has significantly influenced its clinical use.

Table 3: Summary of Major Adverse Drug Reactions by System Organ Class and Frequency

Frequency	Adverse Reaction
Very Common (≥1/10)	Nervous System: Headache (typically transient, dose-related, and most common at treatment initiation) 3
Common (≥1/100 to <1/10)	Nervous System: Dizziness 35
	Cardiac: Increased heart rate, palpitations 5
	Vascular: Cutaneous vasodilation (flushing) 36
	Gastrointestinal: Nausea, vomiting, gastrointestinal ulcerations (stomatitis, aphthosis, mouth/tongue ulcer, small/large intestinal ulcer, anal ulcer) 35
	General: Feeling of weakness 36
	Infections: Skin abscess 35
Uncommon (≥1/1,000 to <1/100)	Vascular: Decrease in blood pressure 35
	Gastrointestinal: Gastrointestinal perforation, fistula (anal, genital, GI, skin) 35
	Eye Disorders: Corneal ulcer, conjunctival ulcer, conjunctivitis 35
	Skin: Angioedema 3
Rare (≥1/10,000 to <1/1,000)	Skin: Rash, pruritus 36
	Musculoskeletal: Myalgia (aching muscles) 35
Very Rare (<1/10,000)	Metabolism: Hyperkalemia 36
	Hepatobiliary: Liver disorders (hepatitis, cholestasis, jaundice) 35

Focus on Ulceration Risk

The most significant safety concern with nicorandil is its association with severe and persistent ulceration. This adverse effect is a class-defining issue that has fundamentally altered the drug's regulatory status and clinical positioning.

• Pervasive Nature: Nicorandil can cause painful ulcers affecting a wide range of tissues. This includes the eyes (conjunctivitis, corneal ulcers), the skin, and the entire gastrointestinal tract from the mouth (stomatitis) to the anus (anal ulcers). Ulcers can also occur at stoma sites in patients with a colostomy or ileostomy.[7]
• Serious Complications: These ulcers are not benign. They can progress to life-threatening complications, including gastrointestinal perforation, hemorrhage, the formation of fistulae (abnormal passages between organs or to the skin), and abscesses.[7]
• Risk Factors: The risk of gastrointestinal ulceration is notably increased in patients with underlying diverticular disease. Concomitant use of other ulcerogenic drugs, particularly non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, and corticosteroids, significantly elevates this risk.[36]
• Management: A critical feature of nicorandil-induced ulcers is their refractoriness to conventional treatments, including topical steroids and even surgical intervention. The only effective management is the complete cessation of nicorandil therapy. Upon withdrawal of the drug, the ulcers typically begin a slow healing process. Therefore, if a patient on nicorandil develops any form of ulceration, the medication must be stopped immediately.[7]

Contraindications and High-Risk Populations

The use of nicorandil is strictly contraindicated in several clinical scenarios due to the high risk of severe adverse events.

• Absolute Contraindications:
• Patients with cardiogenic shock, severe hypotension, or left ventricular failure with low filling pressures.[6]
• Patients with hypovolemia (depleted blood volume) or acute pulmonary oedema.[6]
• Concomitant use with phosphodiesterase-5 (PDE5) inhibitors (e.g., sildenafil, tadalafil, vardenafil) used for erectile dysfunction, or soluble guanylate cyclase (sGC) stimulators (e.g., riociguat) used for pulmonary hypertension. This combination can lead to a profound and dangerous drop in blood pressure.[36]
• Warnings and Precautions (High-Risk Populations):
• Patients with a known hypersensitivity to nicorandil or any of its excipients.[38]
• Patients with low blood potassium levels, especially if they are taking potassium supplements, due to the risk of hyperkalemia.[36]
• Patients with kidney problems.[38]
• Patients with the genetic condition glucose-6-phosphate dehydrogenase (G6PD) deficiency.[36]
• Patients with digestive conditions affecting the large intestine, such as diverticular disease, due to the increased risk of fistula formation or bowel perforation.[36]

Drug Interaction Profile

Nicorandil's drug interaction profile is a direct reflection of its dual pharmacology and its specific adverse effect profile. Clinicians must be vigilant for interactions that potentiate its hemodynamic effects, increase the risk of ulceration, or affect electrolyte balance.

Table 4: Clinically Significant Drug-Drug Interactions

Interacting Drug/Class	Potential Effect	Management/Recommendation	Source(s)
Phosphodiesterase-5 (PDE5) Inhibitors (e.g., sildenafil, tadalafil)	Profound, severe hypotension	CONTRAINDICATED	36
Soluble Guanylate Cyclase (sGC) Stimulators (e.g., riociguat)	Profound, severe hypotension	CONTRAINDICATED	36
Antihypertensive Agents (e.g., beta-blockers, calcium channel blockers)	Additive hypotensive effects (dizziness, fainting)	Use with caution; monitor blood pressure	6
Other Vasodilators	Additive hypotensive effects	Use with caution	39
Tricyclic Antidepressants (e.g., amitriptyline)	Potentiated hypotensive effects	Use with caution	39
Non-Steroidal Anti-inflammatory Drugs (NSAIDs) (e.g., ibuprofen, aspirin)	Increased risk of GI ulceration, perforation, and hemorrhage	Use with caution; consider alternative analgesics (e.g., paracetamol). Avoid regular concomitant use if possible.	39
Corticosteroids (e.g., prednisolone)	Increased risk of GI ulceration, perforation, and hemorrhage	Use with caution; monitor for GI symptoms.	7
Potassium-Increasing Drugs (ACE inhibitors, ARBs) and Potassium Supplements	Increased risk of hyperkalemia	Use with caution, especially in patients with renal impairment. Monitor serum potassium levels.	36
Dapoxetine	Increased risk of orthostatic hypotension	Use with caution	39

The contraindication with PDE5 inhibitors and sGC stimulators is a classic pharmacodynamic interaction for any NO-donating drug. These agents inhibit the breakdown or stimulate the production of cGMP, respectively, leading to a synergistic and dangerous accumulation of this second messenger when combined with an NO donor like nicorandil, resulting in severe vasodilation and hypotension.[36] Similarly, the caution regarding hyperkalemia when co-administered with drugs like ACE inhibitors or ARBs is a logical consequence of its

KATP​ channel activity, which influences potassium flux. The interaction with NSAIDs and corticosteroids is particularly concerning as it potentiates the risk of nicorandil's most severe idiosyncratic toxicity, gastrointestinal ulceration, suggesting a synergistic mechanism of mucosal injury.[39] Prescribing nicorandil therefore requires a multi-faceted clinical assessment that considers its nitrate-like properties, its ion channel effects, and its unique GI toxicity profile.

Regulatory Landscape and Global Availability

International Regulatory Status

Nicorandil has a varied regulatory status across the globe, highlighting different assessments of its risk-benefit profile by national health authorities.

• Approved Regions: The drug is approved and marketed for the treatment of angina in the United Kingdom, Australia, most of Europe, Japan, South Korea, Taiwan, India, and the Philippines.[1] It has been an approved drug in the UK since at least 2009.[18]
• United States FDA Status: Nicorandil is not an approved drug by the U.S. Food and Drug Administration (FDA) and is therefore not commercially available in the United States.[1]
• Regulatory Updates (UK/EU): A significant regulatory action occurred in January 2016 when the UK's Medicines and Healthcare products Regulatory Agency (MHRA), along with EU regulators, issued updated advice. Based on a review of safety data, particularly the risk of serious ulcer complications, nicorandil's indication was restricted. It was officially repositioned as a second-line treatment for stable angina, reserved for patients who have failed or are intolerant to first-line therapies.[7]

Commercial Formulations and Brand Names

Nicorandil is marketed globally under a multitude of brand names, reflecting its widespread use outside of the United States. Common commercial formulations are 10 mg and 20 mg oral tablets. A partial list of brand names includes:

• Ikorel: United Kingdom, Australia, most of Europe, Ireland, France [8]
• Sigmart: Japan, South Korea, Taiwan, China [8]
• Dancor: Switzerland, Portugal, Austria [8]
• Adancor: Egypt, Oman, France [15]
• Angedil: Romania, Poland [8]
• Nikoran: India [8]
• Aprior: Philippines [8]
• Cordinic: Russia [8]
• Nitorubin: Japan [8]
• PCA: India [8]
• Zynicor: India [43]
• K-Cor: India [43]
• Randil: Egypt [43]
• Nocardin: Greece [43]

Chemical Synthesis Pathways

The chemical synthesis of nicorandil can be accomplished through several routes, with modern methods focusing on improving safety and efficiency for industrial-scale production.

Primary Synthesis Route from 2-Aminoethanol

A widely described laboratory- and industrial-scale synthesis begins with the readily available starting material, 2-aminoethanol. This multi-step process is designed to selectively nitrate the hydroxyl group while the amino group is temporarily protected.[12]

1. Protection of the Amino Group: The first step is to protect the primary amine of 2-aminoethanol to prevent it from reacting in the subsequent nitration step. This is commonly achieved by reacting 2-aminoethanol with phthalic anhydride. The reaction forms a stable cyclic imide, N-(2-hydroxyethyl)-phthalimide. This step proceeds with high yield (e.g., 98%).[44]
2. Nitration of the Hydroxyl Group: The protected intermediate, N-(2-hydroxyethyl)-phthalimide, is then subjected to nitration. This is typically carried out using a potent nitrating mixture, such as cold fuming nitric acid in concentrated sulfuric acid. This step is highly exothermic and requires strict temperature control, typically maintaining the reaction between 15-20°C, as higher temperatures can lead to uncontrollable, explosive reactions.[44] The product of this step is N-(2-nitroxyethyl)-phthalimide.
3. Deprotection of the Amino Group: The phthalimide protecting group is subsequently removed to liberate the primary amine. This is accomplished by reacting the nitrated intermediate with hydrazine hydrate. The reaction forms a stable phthalylhydrazide precipitate, which is filtered off, leaving the desired intermediate, 2-nitroxyethylamine (often as its hydrochloride salt), in solution.[44]
4. Final Condensation: In the final step, 2-nitroxyethylamine is condensed with nicotinoyl chloride hydrochloride. This acylation reaction is typically performed in the presence of a base, such as dry pyridine, which neutralizes the HCl generated. This forms the amide bond, yielding the final product, N-[2-(nitroxyethyl)]-pyridine-3-carboxamide, which is nicorandil.[44]

Alternative Synthesis via Direct O-Nitration

More recent patented methods have been developed to streamline the synthesis and improve safety, particularly by avoiding the use of highly reactive and hazardous nitrating mixtures at low temperatures. One such process involves the direct O-nitration of the immediate precursor, N-(2-hydroxyethyl)nicotinamide.[45]

In this improved method, the nitrating agent is a mixture of non-fuming nitric acid (e.g., 68% HNO3​), acetic acid, and acetic anhydride. This mixture is prepared first, and then the substrate, N-(2-hydroxyethyl)nicotinamide, is added in a controlled manner (semi-batch procedure) at a more manageable temperature range of 10-30°C (preferably 22°C). This process is advantageous because it avoids the more dangerous reagents and extreme temperatures of the traditional method, making it safer and more suitable for large-scale industrial production.[46]

Synthesis of Recent Evidence and Future Directions

The clinical understanding and application of nicorandil are continuously evolving. While its foundational role in chronic angina has been established for decades, a recent surge in high-quality clinical evidence, particularly from systematic reviews and meta-analyses, is reshaping its therapeutic identity and pointing toward new horizons.

Table 5: Overview of Key Clinical Trials and Meta-Analyses

Study/Analysis	Focus Area	Key Finding(s)	Source(s)
IONA Study	Chronic Stable Angina (High-Risk)	Nicorandil reduced the composite endpoint of CHD death, non-fatal MI, or unplanned hospitalization for chest pain (HR 0.83).	2
CHANGE Trial (NCT03445728)	STEMI during Primary PCI	Intravenous nicorandil before reperfusion reduced infarct size, improved LVEF, and lowered the incidence of no-reflow phenomenon.	34
Meta-Analysis (Ye Z et al., 2017; updated 2024)	Periprocedural Myocardial Injury (PMI) during PCI	Nicorandil significantly reduced the incidence of PMI (RR ~0.73) and MACE (RR ~0.76).	27
Meta-Analysis (JACC, 2024)	Contrast-Induced Nephropathy (CIN) Prevention	Nicorandil significantly lowered the incidence of CIN (OR 0.40), especially in patients with CKD (OR 0.36).	31
Meta-Analysis (Shi L et al., 2020)	STEMI during Primary PCI	Intracoronary nicorandil decreased arrhythmia (RR 0.52), re-hospitalization (RR 0.56), and improved coronary blood flow. No effect on mortality.	10
Retrospective Cohort Study (Eur Heart J, 2023)	Long-term Outcomes in CHD	Combination of nicorandil and beta-blockers was associated with a lower long-term incidence of MACE and stroke compared to beta-blockers alone.	48

Insights from Recent Meta-Analyses

The collective weight of recent evidence strongly suggests that the greatest clinical utility of nicorandil may lie in its short-term application during periods of acute myocardial stress.

• Robust Cardioprotection in PCI: There is now consistent, high-level evidence from multiple meta-analyses that periprocedural nicorandil administration significantly reduces the risk of myocardial injury and CIN in patients undergoing elective PCI.[11] This makes a compelling case for its routine consideration as an adjunctive therapy in the catheterization laboratory.
• Effective Renoprotection: The evidence for nicorandil in preventing CIN is particularly strong and clinically relevant. Given that CIN is a common and serious complication with limited preventive options, nicorandil's demonstrated efficacy, especially in high-risk patients with pre-existing renal dysfunction, represents a major potential therapeutic advance.[31]
• Benefit in Acute STEMI: In the high-stakes setting of acute STEMI, nicorandil has been shown to confer tangible benefits. The reduction in infarct size demonstrated in the CHANGE trial is a critical surrogate for long-term prognosis, and the observed improvements in microvascular flow and reduction in arrhythmias address key pathophysiological challenges in STEMI management.[10] While a mortality benefit has not been consistently shown, these improvements in intermediate outcomes are clinically meaningful.

Unresolved Questions and Future Research

Despite these advances, several critical questions remain, which should guide future research efforts.

• Mechanism of Ulceration: The precise molecular mechanism driving nicorandil-induced ulceration remains poorly understood.[1] Is this severe adverse effect a consequence of its KATP​ channel activation, its NO-donating properties, or an off-target effect? Elucidating this mechanism is paramount and could potentially lead to strategies to mitigate this risk or identify patients who are not susceptible.
• Optimization for Acute Settings: While the benefit of nicorandil in procedural settings is clear, the optimal dosing regimen, route of administration (oral, intravenous, or intracoronary), and timing are not yet standardized. Future large-scale, prospective RCTs are needed to define the best protocols for maximizing cardioprotection and renoprotection during PCI and STEMI.
• Re-evaluating Long-Term Risk vs. Benefit: The IONA trial and a recent large retrospective study suggest a long-term prognostic benefit in CHD patients.[3] This stands in contrast to the regulatory downgrading of the drug due to ulcer risk. Future research should aim to identify specific subpopulations of chronic angina patients (e.g., those with high inflammatory burden or microvascular dysfunction) in whom the long-term cardioprotective benefits might decisively outweigh the risk of ulceration.
• Path to FDA Approval: The lack of FDA approval remains a significant barrier to its use in the United States. The robust and growing data on CIN prevention could form the basis of a new drug application for a specific, niche indication. A well-designed pivotal trial focused on preventing CIN in high-risk patients undergoing coronary procedures could provide a viable pathway for nicorandil to enter the US market, where its benefits in the acute setting can be realized.

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