New pharmocological agents in the management of Angina-Nicorandil

Angina PectorisMyocardial ischaemia-coronary blood flow

inadequate to meet myocardial oxygen demand.

Angina-most common clinical presentation d/t chemical and mechanical stimulation of sensory nerve endings.

Goals of management of Angina

Decrease severity and frequency of angina

Improve prognosis

Improve patients’ life quality

Modalities of

management

Pharmacological treatment Myocardial revascularization1.Nitrates(a)Short acting –GTN,nitroglycerine(b)Long acting-Isosorbide dinitrate/mononitrate2.Beta blockers-Propanolol,Metaprolol,Atenolol

3,Calcium channel blockers-Verapamil,Diltiazem,Nifedipine

4.K+ channel opener-Nicorandil5.Others-Dipyramidole,Trimetazidine

1.Surgical revascularisation(CABG)2.Percutaneous coronary intervention(PCI)

Unmet needs of current therapyAgents like beta blockers , CCBs and nitrates

have their limitations.Beta blockers-absolute or relative

contraindication in asthma ,COPD and peripheral vascular disease.

CCBs- heart failure in patients with poor LVEF, ineffective in preventing no reflow phenomenon,ADRs(flushing & peripheral oedema)

Nitrates- long term use associated with tolerance

Nicorandil-An overviewClass- K+channel activators(Other drugs – Minoxidil, Diazoxide ,Pinacidil)• Novel drug used in treatment of

angina –having arterio and venodilating properties

• Only drug in the class approved for use in angina

• Key advantages- no tolerance, comparable efficiency and tolerability to existing agents ,potent cardioprotective action

PharmacologyHybrid compound- comprises of nicotinamide

vitamin group and an organic nitrate

Mechanism of action-(a)nitrate like action increased level of cyclic guanosine monophosphate

decrease in cytosolic calcium vascular smooth muscle relaxation dilatation of coronary epicardial arteries

(b) K+ channel activation- preferential activity on K+ ATP channels reducing

sensitivity to its inhibitor(ATP)

Increased K+efflux leading to more negative RMP

Shortens action potential and inhibits Ca influx

Decreased intracellular Calcium resulting in vasodilatation

Ischaemic preconditioningDilatation of coronary resistance arterioles

Nicorandil Dual Action

Nitrate like action K+ ATP channel opener

Dilates epicardial Venodilatation Dilates peripheral Dilates coronaryCoronary arteries arterioles microvessels

decreased preload decreased after load

Inceased coronary decreased decreased increased flow myocardial myocardial coronary O2 requirement O2 requirement bloodflow

PharmacodynamicsHemodynamic effects-Decreases ventricular volume, coronary vascular resistance and MAP ; HR and coronary blood flow increased or remain unchangedCardioprotective effects-Ischaemic preconditioning-single or multiple brief periods of ischaemia and reperfusion preceding a prolonged ischaemia- cardioprotective in nature

Clinical Efficacy & Indications

In Stable Angina-significant improvement in exercise tolerance tests compared to baseline

-effects comparable to nitrates ,CCBs and beta blockers

Unstable Angina-randomised trials revealed decreased episodes of silent and painful transient myocardial ischemia

-another study revealed efficacy better than nitrates

Acute MI--Nicorandil infusion before reperfusion and intracoronary injection is more effective than ISDN-Perserves myocardial microcirculation in reperfused AMI area-Results in better left ventricular wall motion-Recovery of ST segment elevation was 55% with nicorandil compared to 19.2% with ISDN after reperfusionIn PCI- I/v administation prevents slow coronary flow phenomenon and results in better preservation of myocardial viability

Ischaemic Heart Disease

Intravenous Nicorandil before reperfusion on AMI patients with stress hyperglycaemia improved epicardial flow and prevents occurrence of severe microvascular reperfusion injury and resulted in better outcomes

Single intravenous administration in STEMI resulted in accelerated resolution and increased coronary microvascular flow as well as reduced reperfusion injury

Dosage and administration

Recommended adult dosage- 10 mg BD ;reduced to 5 mg BD in patients prone to headache

Can be increased to 20 or 20 md BD according to clinical effect

Intravenous dosage- loading dose of 0.2 mg/kg followed by continuous administration of

0.2 mg/kg/hr

Adverse ReactionsHeadache-mild to moderate

Gastrointestinal events(nausea and vomiting)

Dizziness ,malaise and fatigue

No significant effect on glucose or lipid metabolism ,weight gain , do not produce any arrythmias

ContraindicationsKnown or idiosyncratic hypersensitivity to the drug

Cardiogenic shock

Hypotension

Left ventricular failure with low filling pressures

To be used carefully if SBP< 100 mmHg

To be discontinued if mouth ulcerations appear

Combination with PDE-5 inhibitors( sildenafil) to be avoided in view of risk for severe hypotension

Nicorandil-Place in therapyAngina does significantly impair the qualily of

life of the patientLife style modifications can improve long

term outcomeSublingual nitroglycerin remains the primary

intervention for the direct control of symptoms

Nicorandil ,along with beta blockers ,CCBs play a role in backgroung antianginal therapy

The current standard of care is reperfusion of the infarct related artery; thrombolytic therapy remains the cornerstone of management of AMI

BibliographyHarrison’s textbook of Medicine,18th Ed

Katsung Lange Pharmacology

Nikoran product monograph,Torrent pharmaceuticals