Drugs Acting on Potassium Channel

Potassium channel openers


  • Minoxidil
  • Diazoxide
  • Nicornadil
  • Pinacidil
  • Cromakalim

The chemical and electrical gradients for Kacross the plasma membrane are in opposite direction. As such, depending on the channel, this ion can move in either direction. Such movement is regulated by multiple types of K+ channels viz.:

  • Voltage dependent Kchannel
  • ATP activated Kchannel
  • Ca2+ activated K+ channel
  • Receptor operated K+ channel
  • Na+ activated K+ channel
  • Cell volume sensitive K+ channel

These channels regulate K+ movement outwards as well as inward, serve diverse functions and exhibit different sensitivities to drugs. As such, Kchannel openers exhibit considerable diversity in action. All the above drugs open ATP activated K+ channels in the smooth muscles. Their most prominent action is hyperpolarization and relaxation of vascular as well as visceral smooth muscle.


  • This Drug activates ATP sensitive K+ channels thereby hyperpolarizing vascular smooth muscle.
  • The vasodilator action is partly antagonized by Kchannel blocker glibenclamide
  • It also acts as a NO donor – relaxes blood vessels by increasing cGMP
  • Arterial dilatation is coupled with venodilatation
  • Coronary flow is increased; dilatation of both epicardial conducting vessels and deeper resistance vessels occurs
  • No cardiac effect on contractility and conduction is noted
  • Beneficial effects in angina frequency and exercise tolerance comparable to nitrates and CCBs have been obtained in stable as well as vasospastic angina
  • Nicorandil exerts a cardio protective action by stimulating ischemic preconditioning as a result of activation of mitochondrial KATP channel
  • It is well absorbed orally, nearly completely metabolized in liver and is excreted in urine
  • It exhibits biphasic elimination; the initial rapid phase t ½ is 1 hour and later slow phase t ½ is 12 hours
  • It has the ability to dilate both arteries and veins, maximises coronary flow wile concomitantly reduces myocardial work through reduction in afterload. It is successful in managing angina and hypertension. KATP channel activators are going to be future therapeutic target for pharmacological preconditioning in patients at risk for heart disease or as a therapy for vascular dysfunction. (1)
  • Nicornadil prior to reperfusion is associated with improvement of coronary reflow as well as suppression of ventricular arrhythmia, and further improves left ventricular function in patients who suffered from acute myocardial infarction undergoing primary percutaneous coronary intervention. (2)
  • Oral administration of nicornadil is associated with reduced incidence of death in the setting of secondary prevention after acute myocardial infarction. (3)
  • KATP channel openers could protect against OGD-induced neuroinflammation via inhibiting inflammasome activation and TLR4 signal transduction. (4)
  • Nicornadil exerts a direct cardioprotective effect on heart muscle cells, an effect mediated by selective activation of mito KATP channels. (5)
  • Nicornadil can increase the blood glucose level by its action probably on ATP sensitive K+ channel of β cells of pancreas. (6)
  • Nicornadil is effective regulator of intra ocular pressure in the mouse eyes. (7)
  • Nicornadil causes hyperkalemia which induces bradycardia in uraemic patients. (8)
  • NIcornadil is a safe and effective anti-anginal comparable to isosorbide mononitrate. (9)
  • IN peripheral arteries, the nitrovasodiltor effect of nicornadil is nearly comparable to the potassium agonistic effect, the concentration, which is necessary to reduce peripheral vascular resistance significantly, is comparable with dosages necessary for reduction of coronary resistance. (10)
  • In spontaneously hypertensive rats, long term administration of nicornadil can ameliorate hypertensive protinuria, without lowering blood pressure, possibly through an increase in endothelial nitric oxide synthase (eNOS) expression. (11)
  • Nicornadil is a commmon antianginal drug, which causes large ulcers resembling major aphthous stomatitis or squamous cell carcinoma. (12)
  • Nicornadil induced ulcers have been reported at doses as low as 10 mg daily and complete cessation of nicornadil may be required. (13)

Side effects are:

o   Flushing

o   Palpitation

o   Weakness

o   Headache

o   Dizziness

o   Nausea and vomiting

o   Large painful aphthous ulcers in the mouth

o   Nitrates like tolerance does not occur with nicorandil

Other antianginal drugs


  • Powerful coronary dilator
  • Increases total coronary flow by preventing uptake and degradation of adenosine which is a local mediator involved in autoregulation of coronary flow in response to ischemia
  • It dilates resistance vessels and abolishes autoregulation but has no effect on larger conducting coronary vessels
  • Venous return is not reduced
  • BP is minimally altered
  • Coronary steal phenomenon is seen. By dilating resistance vessels in nonischemic zone as well, it diverts the already reduced blood flow away from the ischemic zone
  • Dipyridamole inhibits platelet aggregation
  • By potentiating PGIand increasing cAMP in platelets, it enhances antiaggregatory influences.
  • It is employed in prophylaxis of coronary and cerebral thrombosis in post MI and post stroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves
  • Plasma dipyridamole concentration is maximal 1-2 h after ingestion. There is significant inhibition of platelet aggregation in response to both collagen and ADP at the same time. It does not have ant effect on platelt cyclic AMP content, does not affect platelt thromboxane formation. (14)
  • The administration of dipyridamole is associated with 20% reduction in systemic arterial pressure, 31% reduction in peripheral vascular resistnce, 13% increase in cardiac index, 21% decrease in cerebrovascular resistance. Regional cerenral blood flow remains unchanged, blod flow to heart increases 355% in the right ventricle and 213% in the left ventricle. Blood flow to jejunum is decreased 52% while blood flow to the kidney and liver decreased slightly. (15)
  • Dipyridamole inhibits the thymidine kinase negative Herpes simplex virus (HSV) and wild type HSV reactivation, suggesting a potential antiviral use. (16)
  • In patients with a prior ischemic stroke or transient ischemic attach, adding the antiplatelet drig dipyridamole to aspirin reduces the relative risk of vascular events (stroke, myocardial infarction or vascular deaths) by a fifth. (17)
  • The patients with silent and symtomatic ischemia has comparable severity of dipyridamole induced ischemia, extent of angiographic coronary artery disease and incidence of cardiac events. (18)
  • The addition of limited exercise to dipyridamole results in benefits during Tc099m sestamibi imaging, increasing heart to liver activity ratio, preventing vasodilator induced hypotension and improving ECG sensitivity for the detection of ischemia. (19)
  • Dipyridamole causes a modest pC)2 independent dilatation of the middle cerebral artery which is time linked to the onset of headache. (20)
  • Oral dipyridamole is safe, effective and well tolerated in patients with chronic stable angina. (21)
  • Dobutamine-atropine and dipyridamole echocardiography have similar sensitivity abd a higher specificity than that obtained by exercise ECG for the diagnosis of coronary artery disease. (22)
  • Dipyridamole and paracetamol overdose resulted in multi organ failure requiring dialysis, ionotropic support, ventilation and extensive surgical intervention for small bowel ischemia. (23)
  • Aspirin and dipyridamole inhibits the platelet aggregation for up to 3 days after cessation of mediaction. This abnormality is not detected by the bleeding time and is not associated with clinically abnormal bleeding. (24)
  • Aspirin and dipyridamole combination therapy is effective and safe for secondary prevention of stroke. (25)


  • This drug acts by nonhemodynamic mechanisms
  • There is no effect on determinants of myocardial Oconsumption, such as HR and BP, both at rest as well as during exercise
  • Angina frequency is reduced and exercise capacity is increased
  • Trimetazidine has a direct anti-ischemic effect on the myocardium without altering the rate × pressure product or coronary blood flow. Trimetazidine (20 mg three times daily) and propanolol (40 mg three times daily) have a similar efficacy in patients with stble angina pectoris. (26)
  • The treatment with trimetazidine in patients with angina pectoris is restricted to add-on to existing treatments in patients who are not adequately controlled by or intolerant to other medicines for angina pectoris. Trimetazidine should be contraindicated in patients with Parkinson disease, parkinsonian symptoms, tremors, restless leg syndrome, and other related movement disorders as well as in patients with severe renal impairment. (27)
  • Trimetazidine improves exercise tolerance and elevates the ischemic threshold comparable with neta-blocker and calcium channel blocker. The antianginal properties are independent of hemodynamic changes and dramatically improve the recovery of mechanical function after ischemia. (28)
  • In elderly patients with ischemic cardiomyopathy, trimetazidine in addition to standard medical therapy has a beneficial effect on left ventricular systolic and diastolic function and improves the quality of life. (29)
  • With the metabolic effect, devoid of any hemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with beta blocker. (30)
  • Trimetazidine can improve the total clinical efficacy and cardiac function. The long term treatment is safe. (31)
  • Treatment with trimetazidine induces a functional improvement in patients with dilated cardiomyopathy. It is associated with improvement of left ventricular function and remodelling process. Imflammatory response is limited in patients treated with trimetazidine. (32)
  • Trimetazidine has a beneficial effect on the retinal lipid peroxidation and histopathologic changes due to ischemia/ reperfusion injury. (33)
  • The improvement in exercise performance seen in patients with angina is due to cytoprotective mechanism exerted by trimetazidine on the skeletal muscle integrity. (34)
  • Trimetazidine pretreatment reduces liver damage induced by ischemia-reperfusion. It may be a useful drug in liver surgery to prevent ischemia-reperfusion injury. (35)
  • Trimetazidine does not reduce mortality in patients undergoing thrombolytic therapy; however, it might have some beneficial effect for non-thrombolysed patients. (36)
  • Trimetazidine made the warm ischemic kidneys more resistant to the deleterious impact of a single episode of ischemia-reperfusion injury and have a role in preserving the ischemic kidney from long term damage. (37)
  • In patients not adequately controlled by long acting nitrate/ β blocker/ CCB, addition of trimetazidine further reduced angina attacks and increased exercise duration.

It improves cellular tolerance to ischemia by following mechanisms:

  • Inhibiting mitochondrial long chain 3-ketoacyl-CoA-thiolase (LC3-KAT)
  • Limiting intracellular acidosis and Na+, Ca2+ accumulation during ischemia
  • Protecting against O free radical induced membrane damage
  • It is well absorbed orally, partly metabolized and largely excreted unchanged in urine
  • It is generally well tolerated

Side effects:

o   Gastric burning

o   Dizziness

o   Fatigue

o   Muscle cramps

  • Trimetazidine is also used in

o   Visual disturbances

o   Tinnitus

o   Meniere’s disease

o   Dizziness


  • Acts by inhibiting a late Na+ current in the myocardium which indirectly facilitates Ca2+ entry through Na+/Ca2+ exchanger
  • Reduction in Ca2+ overload in the myocardium during ischemia decreases contractility and has a cardioprotective effect
  • Sparing of fatty acid oxidation during ischemia in favour of more O2 efficient carbohydrate oxidation by inhibiting LC3KAT has also been demonstrated
  • It has no effect on HR and BP but prolongs exercise duration in angina patients
  • Ranolazine is an antianginal medication in patients with symptomatic coronary heart disease, should be considered as an initial antianginal agent in patients with hypotension or bradycardia. (38)
  • Ranolazine when added to concurrent antidiabetes treatment, lowers fasting blood glucose and A1C in patinets with cardiovascular disease and poorly controlled diabetes. (39)
  • Ranolazine is approved in United States for use in patients with chronic angina who continue to be symptomatic on β blockers, calcium antagonists or nitrates. (40)
  • The progressive magnitude of ischemia reduction was proportionally more substantial than the minor reduction in heart rate or rate pressure product. Ranolazine beneficial mechanism of action is more likely due to an improvement in regional coronary blood flow in areas of myocardial ischemia. (41)
  • Ranolazine is safe and effective antianginal in the management of refractory chronic angina with an advantage of decreased angina frequency, increased exercise tolerance and no deleterious effects on hemodynamics. It has a favorable effect on HbA1c levels in diabetic patients. (42)
  • Ranolazine is effective in treating chronic angina. It is ineffective in treating acute coronary syndrome patients. It is metabolized in liver and cleared by the kidney. Therefore, caution must be taken in patients with impaired hepatic or renal function. (43)
  • Ranolazine is effective for the symptomatic treatment of patients with stable angina on background therapy with maximal tolerated doses of the first line anti-anginal therapies. (44)
  • Ranolazine appears to be effective in symptomatic ventricular arrhythmias. The reduction in premature ventricular complexes in greatest among individuals with reduced ventricuklar function due to enhanced late sodium current associated with cardiomyopathy. (45)
  • Ranolazine is indicated in angina pectoris and myocardial ischemia without coronary artery disease (cardiac X syndrome); symptomatic patients with IHD and diabetes mellitus and/or some arrhythmias; symptomatic patients with IHD and diastolic dysfunction. (46)
  • Ranolazine significantly prolongs the exercise duration and time to angina, as monotherapy or when administered with conventional anti-anginal therapy. It also reduces angina attacks and consumption of nitroglycerin and is well tolerated at therapeutic doses. (47)
  • Oral absorption is slow taking 4-6 hours with a bioavailability of 30-50%
  • It is metabolized by liver mainly by CYP3A4 and excreted in urine, with an average t ½ of 7 hours

Side effects:

o   Dizziness

o   Weakness

o   Constipation

o   Postural hypotension

o   Headache 

o   Dyspepsia

o   It should not be given to patients taking CYP3A4 inhibitors


  • Pure heart rate lowering antianginal drug
  • The only significant action is blockade of cardiac pacemaker (sino-atrial) cell ‘f’ channel, which are funny cation channels that open during early part of slow diastolic (phase 4) depolarization
  • Selective blockade of If current results in heart rate reduction without any other electrophysiological or negative ionotropic or negative lucitropic (slowing of myocardial relaxation) effect
  • Heart rate reduction decreases cardiac O2 demand and prolongation of diastole tends to improve myocardial perfusion (O2 supply)
  • It has found to improve exercise tolerance in stable angina and reduce angina frequency
  • It is well absorbed orally, 40%bioavailable due to  first pass metabolism; degraded by CYP3A4 and excreted in urine with a t ½ of 2 hours
  • A significant reduction in infarct size by ivabadrine persists in absence of heart rate reduction. This protection can also be recruited when the drug is given only during early perfusion. (48)
  • Ivabradine is an effective antianginal agent alone or in combination with a beta blocker. In patients with stable coronary artery disease and left ventricular systolic dysfunction and herat rate < 70 beats/min, ivabadrine is associated with 36% reduction in hospitalozation for fatal and non fatal myocardial infarction. It has beneficial effects in systolic an ddiastolic heart failure. (49)
  • Heart rate reduction with ivabadrine is important for improvement of clinical outcome in heart failure. (50)
  • Reduction in heart rate with ivabadrine does not improve cardiac outcomes in all patients with stable coronary artery disease and left ventricular systolic dysfunction. It could be used to reduce the incidence of coronary artery disease outcomes in patients who have heart rate of 70 bpm or greater. (51)
  • Oral administration of ivabadrine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker If current while ventricular performance is maintained. (52)
  • Ivabadrine lowers heart rate and provides an attractive alternative to conventional treatment for a wide range of patients with confirmed stable angina. (53)
  • Ivabradine produces dose dependent improvement in exercise tolerance and development of ischemia during exercise. It is effective and safe during 3 months of use. (54)
  • In coronary patients with symptomatic diastolic heart failure with preserved systolic function, low dose digoxin is significantly more effective than ivabadrine and is much cheaper. (55)
  • A single dose of ivabadrine decreases the dynamic left ventricular outflow tract (LVOT) obstruction in cats with hypertrophic cardiomyopathy (HCM) but the clinical effect is negligible and inferior compared to that achieved by atenolol. (56)
  • Ivabadrine is antiarrhythmic in the acute myocardial infarction in the rat. Potential mechanism include prevention of diastolic Ca2+ leak from sarcoplasmic reticulum, upregulation of If current in left ventricle and dispersion of cardiac repolarization. (57)
  • Ivabadrine may be important agent for improving symptoms in patients with inapprpriate sinus tachycardia. (58)
  • Heart rate reduction through ivabadrine does not improve tthe endothelial function in patients with a stable coronary heart disease. (59)

Side effects include:

  • Excess bradycardia
  • Visual disturbance
  • Extrasystoles
  • Prolongation of PR interval
  • Headache
  • Dizziness
  • Nausea
  • It should not be used if HR < 60/ min, in sick sinus and in AF
  • Concurrent use of drugs which prolong QT or which inhibit CYP3A4 is contraindicated
  • Ivabradine is indicated in chronic stable angina in patients with sinus rhythm who are intolerant to β blockers or when the latter are contraindicated
  • It can also be used in inappropriate sinus tachycardia


  • This drug is claimed to improve myocardial metabolism so that heart can sustain hypoxia
  • Though used in angina and MI over 3 decades, its efficacy and status in coronary artery disease is not defined
  • Oxyphedrine depress the tonicity of coronary vessels, increase the coronary circulation volume, the oxygen uptake by the hearet and a positive iono and chronotropic action. These effects are caused by stimulation of beta-adrenoreceptors of the heart and vessels. (60)
  • It can diminish or alter taste sensation



Mechanism of action

Clinical applications


Toxicities, Interactions

Short- acting nitrates

Nitroglycerin (SL)

Isosorbide dinitrate (SL)

Releases nitric oxide (NO), increases cGMP (cyclic guanosine monophosphate), and relaxes vascular smooth muscle

Acute angina pectoris, acute coronary syndrome

Rapid onset (1min) short duration (15 min)

Slightly longer acting (20-30 min)

Tachycardia, orthostatic hypotension, headache

Intermediate -acting nitrate

Nitroglycerin (oral)

Isosorbide dinitrate and mononitrate (oral)


Same  as GTN (SL)

active metabolite dinitroglycerin


Prophylaxis of angina

Slow onset

Duration: 2-4 h

Same as GTN (SL)

Long- acting nitrate

Transdermal GTN

Same as GTN oral

Prophylaxis of angina

Slow onset

long duration of absorption: 24 h

Duration of effect: 10 h



Same as GTN (SL)

Loss of response is common after 10-12 h exposure to drug

Ultra short- acting nitrite

Amyl nitrite

Same  as GTN (SL)

Obsolete for angina

Some recreational use

Vapors are inhaled

Onset in seconds

Duration: 1-5 min

Same  as GTN (SL)

Calcium channel blockers








Amlodipine, felodipine, nicard ipine, nisoldipine




Blocks L-type Ca2+ channels in smooth muscle and heart

Decreases intracellular Ca2+

Same as verapamil

Dihydropyridine Ca2+ channel blocker

Vascular > cardiac effect




Angina (both atherosclerotic and vasospastic), hypertension, AV- nodal arrhythmias, migraine

Same as verapamil


Angina, hypertension



Oral, parenteral

Duration: 6-8 h



Shorter t1/2



 Slow release form

Duration: 6-8 h



Constipation, pretibial edema, flushing, dizziness,

Higher doses: cardiac depression, hypotension


Like verapamil

Less constipation & cardiac effect

may increase heart rate


Beta blockers





Atenolol, metoprolol, other


Blocks sympathetic effect on heart and blood pressure

Reduces renin  release


Angina, hypertension, arrhythmias, migraine, performance anxiety



Oral, parenteral

Duration: 6 h


Bronchospasm, atrioventricular block, heart failure

CNS- sedation, lethargy, sleep disturbances

Less bronchospasm

Potassium channel opener






Other antanginal drugs








Blocks late Na+ current in myocardium

Reduces cardiac work


Blocks pacemaker Na+ current (If) in sinoatrial node, reduces heart rate









Investigational, angina, heart failure



Duration: 10-12 h






Administered twice daily


QT prolongation on ECG

Inhibits CYP3A and 2D6





  1. John C Barbato. Nicornadil. The drug that keeps on giving. HYpertension. 2005;46:647-648. 
  2. Muli Wu, Zheng Huang, Hoajun Xie, Zhongjiang Zhou. Nicornadil in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: A systematic review and meta-analysis. PLoS ONE 2013;8(10):e78231. 
  3. Yasuhiko Sakata, Daisku Nakatani, Masahiko Shimizu, Shinichiro Suna, Masaya Usami, Sen Kawano, Katsuomi Iwakura et al. Oral treatment with nicornadil at discharge is associated with reduced mortality after acute myocardial infarction. Journal of Cardiology. Jan 2012;59(1):14-21. 
  4. An-Peng Zhao, Yin-Feng Dong, Wei Liu, Jun Gu, Xiu-Lan Sun. Nicornadil inhibits inflammasome activation and toll like receptor-4 signal transduction to protect against oxygen-glucose deprivation-induced inflammation in BV-2 cells. CNS Neurosciences & Therapeutics. Feb 2014;20(2):147-153. 
  5. Toshiaki Sato, Norihito Sasaki, Brian O’Rourke, Eduardo Marban. NIcornadil, a potent cardioprotective agent, acts by opening mitochondrial ATP dependent potassium channels. J Am Coll Cardiol. 2000;35(2):514-518. 
  6. Anupam Gupta, S Lata, VK Bhardwaj. Modulation of blood glucose level by nicornadil, a K+ channel opener. JARBS. 2012;4(4):337-339. 
  7. Uttio Roy Chowdhury, Bradley H Holman, Michael P Fautsch. ATP-sensitive potassium (KATP) channel openers diazoxide and nicornadil lower intraocular pressure in vivo. Invest. Ophthalmol. Vis. Sci. July 2013;54(7):4892-4899. 
  8. Hung-Hao Lee, Po-Chao Hsu, Tsung-Hsein Lin, Wen-Ter Lai, Sheng-Hsiung Sheu. Nicornadil-induced hyperkalemia in a uremic patient. Case report in Medicine. 2012. Article ID 812178, 4 pages. 
  9. Padmaja Udaykumar, Prabha Adhikari, Prathibha Periera. Safety and efficacy of nicornadil in chronic stable angina- a double blind comparative randomised trial with isosorbide mononitrate. JIACM 2003;4(3):205-9. 
  10. Marianne Brodmann, Ulrike Lischnig, Andreas Lueger, Gerhard Stak, Ernst Pilger. The effect of the K+ agonist nicornadil on peripheral vascular resistance. International Journal of Cardiology. July 2006;111(1):49-52. 
  11. Serizawa K, Yogo K, Tashiro Y, Koike N, Aizawa K, Hirata M, Ishizuka N. Nicornadil ameliorated hypertensive renal injury without lowering blood pressure in spontaneously hypertensive rats. Pharmacology 2013;91:92-103. 
  12. K Webster, P Godbold. Nicornadil induced oral ulceration. British Dental Journal. 2005;198:619-621. 
  13. CM Healy, Y Smyth, SR Flint. Persistent nicornadil induced oral ulceration. Heart. Jul 2004;90(7):e38. 
  14. D Gregov, A Jenkins, E Duncan, D Siebert, S Rodgers, B Duncan, F Bochner, J Lloyd. Dipyridamole: pharmacokinetics and effects on aspects of platelet function in man. Br J Clin Pharmacol. Oct 1987;24(4):425-434. 
  15. DJ Boarini, NF Kassell, JJ Olin, JA Sprowell. The effect of intravenous dipyridamole on the cerebrala dn systemic circulations of the dog. Stroke 1982;13:842-847. 
  16. Richard B Tenser, Andrew Gaydos, Kathleen A Hay. Inhibition of herpes simplex virus reactivation by dipyridamole. Antimicrob. Agents Chemother. Dec 2001;45(12):3657-3659. 
  17. Cathie Sudlow. Dipyridamole with aspirin is better than aspirin alone in preventing vascular events after ishemic stroke or TIA. BMJ 2007;334:910. 
  18. Leonardo Bolognese, Lidia Rossi, Gianni Sarasso, Maria Domenica Prando, Angelo Sante Bongo, Piefranco Dellavesa, Paolo Rossi. Silent versus symptomatic dipyridamole induced ischemia after myocardial infarction: clinical and prognostic significance. Journal of the american college of cardiology. April 1992;19(5):953-959. 
  19. Joao V Vitola, Jose C Brambatti, Fabio Caligaris, Carlos R Lesse, Paulo R Nogueira, Adriana I Joaquim, Mario Loyo, Fernando V Salis, Eleuses V Paiva, William A Chalela, J Claudio Meneghetti. Exercise supplementation to dipyridamole prevents hypotension, improves electrocardiogram sensitivity and increases heart to liver activity ratio on Tc-99m sestamibi imaging. Journal of nuclear cardiology. Nov 2001;8(6):652-659. 
  20. Christina Kruuse, Torsten B Jacobsen, Lisbeth H Lassen, Lars L Thomsen, Steen G Hasselbalch, Harriet Dige Petersen, Jes Olesen. Dipyridamole dilates large cerebral arteries concomitant to headache induction in healthy subjects. Journal of cerebral blood flow &  metabolism. 2000;20:1372-1379.  
  21. E Picano. Dipyridamole in chronic stable angina pectoris. A randomized, double blind, placebo controlled, parallel goup study. Eur Heart J. 2001;22(19):1785-1793. 
  22. Jose Alberto San Roman, Isidre Vilacosta, Francisco-Aviles, Juan Antonio Castillo, Maria Jesus Rollan, Vincente Peral, Luis Sanchez-Harguindey. Dipyridamole and dobutamine-atropine stress echocardiography in the diagnosis of coronary artery disease: Comparison with exercise stress test, analysis of agreement and impact of antianginal treatment. Chest 1996;110(5):1248-1254. 
  23. PS Cullis, D Watson, A Cameron, RF McKee. Dipyridamole and paracetamol overdose resulting in multi organ failure. Scott Med J. August 2013;58(3):e14-e17. 
  24. Keiko Kinouchi, Tomio Fujita, Chie Narahara, Seiji Kitamura. Platelet function in pregnant women receiving aspirin and dipyridamole. Journal of Anesthesia. July 2000;14(3):115-118. 
  25. Xia Li, Guoyu Zhou, Xueying Zhou, Shengnian Zhou. The efficacy and safety of aspirin plus dipyridamole versus aspirin in secondary prevention following TIA or stroke: A meta-analysis of randomized controlled trials. Journal of the Neurological Sciences. Sept 2013;332(1):92-96. 
  26. JM Detry, P Sellier, S Pennaforte, D Cokkinos, H Dargie, P Mathes. Trimetazidine: A new conceot in the treatment of angina. Comparison with propanolol in patients with stable angina. Trimetazidine european multicenter study group. Br J Clin Pharmacol. Mar 1994;37(3):279-288. 
  27. Assessment report for trimetazidine containing medical products. European Medicines Agency. 3 September 2012. 
  28. M Marzilli. Trimetazidine: a metabolic agent for the treatment of stable angina. Eur Heart J Suppl. 2001;3(suppl O): O12-O15. 
  29. Cristiana Vitale, Mauricio Wajngaten, Barbara Sposato, Otavio Gebara, Paola Rossini, Massimo Fini, Maurizio Volterrani, Giuseppe MC Rosano. Trimetazidine improvesleft ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J. 2004;25(20):1814-1821. 
  30. H Szwed, Z Sadowski, W Elikowski, A Koronkiewics, A Mamcarz, W Orszulak, E Skibinska, K Szymczak, J Swiatek, M Winter. Combination treatment in stable effort angina using trimetazidine and metoprolol. Results of a randomized, double-blind, multicentre study (TRIMPOL II). Eur Heart J. 2001;22(24):2267-2274. 
  31. Yang Bin, PEN Li, XUE Yin-wen, Gui-quing, MEI Qi-bing. Clinical data analysis based on trimetazidine in the treatment of coronary heart disease with heart failure. World Clinic Drugs. 2012;33(9):544-551. 
  32. P Di Napoli, AA Taccardi, A Barsotti. Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischemic dilated cardiomyopathy. Heart 2005;91:161-165. 
  33. T Demir, B Turgut, I Ozercan et al. Trimetazidine for prevention of induced ischemia and reperfusion of guinea pif retina. Clinical Ophthalmology. DEc 2009;2010(4):21-26. 
  34. Elisabetta Ferraro, Anna Maria Giammariolo, Sara Caldarola, Pasquale Lista, ALessandra Feraco, Antonella Tinari, Anna maria Salvatore, Walter Malorni, Libera Berghella, Giusepe Rosano. The metabolic modulator trimetazidine triggers autophagy and counteracts stress induced atrophy in skeletal muscle myotubes. FEBS Journal. October 2013;280(20):5094-5108. 
  35. Abdellatif Settaf, Didier Morin, Fatima Lamchouri, Aziz Elimadi, Yahia Cherrah, Jean-Paul Tillement. Trimetazidine ameliorates the hepatic injury associated with ischemia-reperfusion in rats. Pharmacological Research. March 1999;39(3):211-216. 
  36. Effect of 48-h intravenous trimetazidine on short- and long-term outcomes of patients with acute myocardial infarction, with and without thrombolytic therapy. A double-blind, placebo controlled, randomized trial. Eur Heart J. 2000;21(18):1537-1546. 
  37. Jerome Cau, Frederic Favreau, Jean Paul Tillement, Lilach O Lerman, Thierry Hauet, Jean Michel Goujon. Trimetazidine reduces early and long term effects of experimental renal warm ischemia: A dose effect study. Journal of vascular surgery. April 2008;47(4):852-860. 
  38. David S Vadnais, Nanette K Wenger. Emerging clinical role of ranolazine in the management of angina. Therapeutics and clinical risk management. Oct 2010;6:517-530. 
  39. Jeffrey W Chisholm, Allison B Goldfine, Arvinder K Dhalla, Eugene Braunwald, David A Morrow, Ewa Karwatowska-Prokopczuk, Luiz Belardinelli. Effect of ranolazine on A1C and glucose levels in hyperglycemic patients with non ST elevation acute coronary syndrome. Diabetes Care. June 2010;33(6):1163-1168. 
  40. Berbard R Chaitman. Ranolazine for the treatment of chronic angina and potential use in other cardiovascular conditions. Circulation. 2006;113:2462-2472. 
  41. Peter H Stone, Bernard R Chaitman, Karen Stocke, Junko Sano, Arthur DeVault, Gary G Koch. THe anti ischemic mechanism of action of ranolazine in stable ischemic heart disease. J Am Coll Cardiol. 2010;56(12):934-942. 
  42. Pawan D Patel, Rohit R Arora. Utility of ranolazine in chronic stable angina patients. Vasc Health Risk Manag. Aug 2008;4(4):819-824. 
  43. Mohammed Aldakkak, David F Stowe, Amadou KS Camara. Safety and efficacy of ranolazine for the treatment of chronic angina pectoris. Clinical Medicine Insights: Therapeutics. 2013;5:1-14. 
  44. Jose LOpez Sendon, Stella Lee, Mei L Cheng, Ori Ben Yehuda. Effects of ranolazine on exercise tolerance and angina frequency in patients with severe chronic angina receiving maximally tolrated background therapy: analysis from the combination asessment of ranolazine in stable angina (CARISA) randomized trial. European Journal of Preventive cardiology. Oct 2012;19(5):952-959. 
  45. Eric Yeung, Mori J Krantz, Joseph L Schuller, Rita A Dale, MArk C Haigney. Ranolazine for the suppression of ventricular arrhythmia: A case series. Annals of noninvasive electrocardiology. 17 Feb 2014. 
  46. Cocco G. Indicated and off-label use of ranolazine. E journal of ESC council for cardiology practice. 15 April 2013. 
  47. Jean-Pierre Bassand. Clinical implications of inhibition of the late sodium current: ranolazine. Eur Heart J Suppl. Feb 2006;8(suppl A): A14-A19. 
  48. Gerd Heusch, ANdreas Skyschally, Rainer Schulz. Cardioprotection by ivabradine through heart rate reduction and beyond. J Cardiovasc Pharmacol Ther. Sept/Dec 2011;16(3-4):281-284. 
  49. Kim Fox. Ivabradine: advantages throughout the cardiovascular continuum. Eur Heart J Suppl. 2010;12(suppl C):C16-C20. 
  50. Karl Swedberg, Michel Komajda, Michael Bohm, Jeffrey S Borer, Ian Ford, Ariane Dubost- Brama, Guy Lerebours, Luigi Tavazzi. Ivabadrine and outcomes in chronic heart failure (SHIFT): a randomized placeno-controlled study. The Lancet. Sept 2010;376(9744):875-885. 
  51. Kim Fox, Ian Ford, P Gabriel Steg, Michal Tendera, Roberto Ferrari. Ivabadrine for patients with stable coronary artery disease and left ventricular systolic dysfunction (BEAUTIFUL): a randomised, double blind, placeno controlled trial. The Lancet. Sept 2008;372(9641):807-816. 
  52. Xiao-Jun Du, Xinheng Feng, Xiao-Ming Gao, Tze Ping Tan, Helen Kiriazis, Anthony M Dart. If channel inhibitor Ivabadrine lowers heart rate in mice with enhanced sympathoadrenergic activities. Br J Pharmacol. May 2004;142(1):107-112. 
  53. S Sulfi, AD Timmis. Ivabadrine- the first selective sinus node If channel inhibitor in the treatment of stable angina. Int J Clin Pract. Feb 2006;60(2):222-228. 
  54. Jeffrey S Borer, Kim Fox, Patrice Jaillon, Guy Lerebours. Antianginal and antiischemic effects of ivabadrine, an If inhibitor, in stable angina. A randomized, double blind, multicentred, placebo controlled trial. Circulation 2003;107:817-823. 
  55. Giuseppe Cocco, Paul Jerie. Comparison between ivabadrine and low dose digoxin in the therapy of diastolic heart failure with preserved left ventricular systolic function. Clinics and Practice. 2013;3(2). 
  56. KA Blass, KE Schober, X Li, BA Scansen, JD Bonagura. Acute effects of ivabadrine on dynmic obstruction of the left ventricular outflow tract in cats with preclinical hypertrophic cardiomyopathy. Journal of veterinary internal medicine. May/June 2014;28(3):838-846. 
  57. Urszula Mackiewicz, Joseph Y Gerges, Sandy Chu, Monika Duda, Halina Dobrzynski, Bohdan Lewartowski, Michal Maczewski. Ivabadrine protects against ventricular arrhythmias in acute myocardial infarction in the rat. Journal of cellular physiology. June 2014;229(6):813-823. 
  58. Raccardo Cappato, Serenella Castelvecchio, Cristian Ricci, Elisabetta Bianco, Laura Vitali-Serdoz, Tomaso Gnecchi-Ruscone, Mario Pittalis, Luigi De Ambroggi, Mirko Baruscotti, Maddalena Gaeta, Francesco Furlanello, Dario Di Francesco, Pier Paolo Lupo. Clinical efficacy of ivabadrine in patients with inappropriate sinus tachycardia: A prospective, randomized, placebo controlled, double blind, cross over evaluation. Journal of American College of Cardiology. 9 October 2012;60(15):1323-1329. 
  59. Nicoline Jochmann, Franziska Schroter, Fabian Knebel, Robert Hattasch, Christine Gericke, Karl Stangl, Gert Baumann, Verena Stangl. Effect of ivabadrine induced heart rate reduction on flow mediated dilation measured with high sensitivity ultrasound in patients with stable coronary artery disease. Cardiovascular Ultrasound. 2014;12:5. 
  60. Chichkanov GG, Chumburidze VB. Mechanism of the antianginal action of oxyfedrine. Farmakol Toksikol. 1977 May-June;40(3):302-6.