Drugs Acting on Potassium Channel

Potassium channel openers

Include:

• Minoxidil
• Diazoxide
• Nicornadil
• Pinacidil
• Cromakalim

The chemical and electrical gradients for K⁺ across 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 K⁺ channel
• ATP activated K⁺ channel
• 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, K⁺ channel 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.

Nicornadil

• This Drug activates ATP sensitive K⁺ channels thereby hyperpolarizing vascular smooth muscle.
• The vasodilator action is partly antagonized by K⁺ channel 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 K_ATP 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. K_ATP 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⁾
• K_ATP 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 K_ATP 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

Dipyridamole

• 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 PGI₂ and 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⁾

Trimetazidine

• This drug acts by nonhemodynamic mechanisms
• There is no effect on determinants of myocardial O₂ consumption, 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

Ranolazine:

• 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

Ivabradine

• 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 I_f 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 I_f 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

Oxyphedrine

• 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

Summary

Subclass	Mechanism of action	Clinical applications	pharmacokinetics	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 tachyphylaxis	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 Verapamil             Diltiazem Nifedipine 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   Oral  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 Propranolol       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 Nicorandil
Other antanginal drugs Ranolazine         Ivabradine	Blocks late Na+ current in myocardium Reduces cardiac work   Blocks pacemaker Na+ current (If) in sinoatrial node, reduces heart rate	Angina           Investigational, angina, heart failure	Oral Duration: 10-12 h         Oral Administered twice daily	QT prolongation on ECG Inhibits CYP3A and 2D6     Unknown

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