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