Drugs used for failure of the coronary circulation

Drugs used for failure of the coronary circulation  

Pathological conditions associated with impaired coronary blood flow of the heart are called coronary heart disease (CHD). The most common manifestations of CHD considered angina (angina pectoris), and myocardial infarction. 

 The increased demand for oxygen and decreased coronary blood flow are typical for CHD. Therefore, the drugs used to treat coronary artery disease should either reduce the work of the heart or to increase its blood supply. 

To reduce the work of the heart it is possible to:

• reduce systemic venous pressure → decrease venous return to the heart (preload on the heart) → reduce the size of the heart → reduce the stroke volume of the heart (organic nitrates, molsidomine);
• lower the blood pressure by decreasing general peripheral resistance → reduce the afterload on the heart (β-blockers, antagonists of Ca2 +).
• reduction of pre-and afterload reduces myocardial wall stress, reduces the need of the heart for oxygen;
• need of heart for oxygen decreases with deceleration of the heart rate, while reducing myocardial metabolism.

Medications that reduce oxygen demand of the heart for oxygen  and increase oxygen delivery

1. organic nitrates:

a) nitroglycerin drugs;

b) organic nitrates of long action;

2. other donators NO;

3. calcium channel blockers (phenylalkylamine and benzodiazepines).

Organic nitrates     

 Used for the relief and prevention of strokes, heart hemodynamic unloading in acute and chronic heart failure, during  hepatic colic.

Pharmacodynamics. Nitroglycerin drugs (short action) and long action organic nitrates have the same effect but they differ only by their onsets of action.

 In general, they have a direct relaxing effect on smooth muscle.

Nitrates dilate the veins more than arteries → contribute to the accumulation of blood in the periphery → reduce preload on the heart → decrease in end-diastolic pressure, and heart size → reduce the work of  heart.

Nitrates also expand arterioles → slightly reduce peripheral resistance and cardiac afterload → reduce the heart.

Nitrates dilate blood vessels in the skin, especially in the face and neck, causing hyperemia (congestion), causing headaches.

Blood flow in the internal organs and kidneys is reduced.

 Nitrates help to eliminate congestion in the lungs through the return of blood to the systemic circulation. They significantly relax the muscles of the bronchi, bile ducts, esophagus.

Mechanism of action. Organic nitrates undergo rapid enzymatic denitration in smooth muscle cells with release of nitric oxide (NO) identical to endothelial relaxing factor.

Nitric oxide stimulates guanylate cyclase → increases the formation of cGMP, which activates protein kinase G → phosphorylates phospholamban (protein of sarcoplasmic reticulum) → activated by Ca2 + - ATPase of sarcoplasmic reticulum → transition of Ca2 + into reticulum is activated → the content of Ca2 + in the myocytes cytoplasm is reduced → vascular smooth muscle relaxes.  

Furthermore cGMP activates the K + channels → hyperpolarization of the cell membrane occurs → opening of voltage-Ca2 + channels and reducing smooth muscle fibers stop.

Pharmacokinetics. Organic nitrates are fat-soluble and therefore well absorbed in oral mucosa, intestine, and skin.

Except for the isosorbide mononitrate all the nitrates all undergo metabolism in the liver.

Therefore, their bioavailability is low. Cmax in the blood after administration: nitroglycerin in 2-3min., Isosorbide dinitrate - after 15-30min.

 Isosorbide mononitrate is completely absorbed in the intestine, and is not subject to first-pass effect.

Its bioavailability is high. Period T1 / 2 to 1-4 hours, isosorbide dinitrate 4 hours during peroral intake, Isosorbide mononitrate 5hours. Duration of action of nitroglycerin about 10min., Isosorbide dinitrate – 3-5 hours., Isosorbide mononitrate – 2-6 hours.

Transdermal forms of nitroglycerin have an increased duration of action: ointment form – 4-8h., plaster – up to 24 h.

Nitroglycerin (Nitroglycerin, Nitro Mack perlinganit)    

Indications: unstable angina, acute left ventricular failure (cardiac asthma, pulmonary edema), severe chronic heart failure, and acute myocardial infarction.

Contraindications: heart valve stenosis, hypertrophic cardiomyopathy, myocardial infarction involving the right ventricle of the heart.   

Adverse drug reactions: headache, orthostatic hypotension, skin redness, tachycardia.

During overdose of nitroglycerin there may occur vascular collapse (sudden drop in blood pressure) and fainting, increased intracranial pressure, methemoglobinemia.     

 During regular use of nitroglycerin addiction develops quickly, side effects reduce, mainly headache.

At the abrupt withdrawal of nitroglycerin there can be the following withdrawal symptoms: increased angina attacks, possible myocardial infarction.

Dosage forms: tablets for sublingual administration of 0.5 mg; capsules with oil solution of nitroglycerin 1% -0.05 ml, aerosol cans for inhalation (Nitromint, Nitrosprey (Nitrolingval, Nitromin).

Nitroglycerin for intravenous administration: Perlinganit amp. for 10ml (10mg); Nitro Mak amp for 5ml (5mg), Nitro-Pohl 5 ml - 1%: Nitroglycerin 1% - 2 ml.

It is diluted to 0.01% solution (5mkg in1 drop), administer slowly – 5 drops/min, gradually increasing the speed under control of blood pressure.

Prolonged forms: Sustaс forte, Nitrong forte, Nitrogranulong. Now rarely used.

Isosorbide dinitrate (Isosorbide dinitrate, Nitrosorbide, Isoket, Cardiket)

Dosage forms: Nitrosorbide Tab. of 10mg. Isodinit, Isoket, Cardicat, isosorbide – 20mg in a tab.

The onset of action is 20-30 min. after ingestion and 3-5min. for sublingual intake. Duration of action – 3-5 hours. Used for the relief of angina attack, as well as 30 minutes before the expected load.

Izoket spray for the relief of angina attacks.

Tablets and capsules of extended release: izoketretard, Cardiket retard.

Medications for IV administration: izoket in amp. of 10ml (10mg per amp.). 50 ml of izoket is dissolved in 500 ml of 0.9% NaCl (1drop.-5mkg).

Slow infusion (7drops./min).

Isosorbide - 5 - mononitrate (Monocinque, Mono Mack)     

Dosage forms: isosorbide -5 - mononitrate (Mono Mack, IzMo, Izomonat, Monocinque, Efoks 20). Antianginal effect develops within 30-45min., duration is from 2 to 6 hours.

Produced in tablets of 20 and 40 mg. The last dose should be taken in the afternoon. Tablets of prolonged action are taken in the morning.

Nitrates use

Angina. To treat an attack it is used "on demand" sublingual tablets or spray nitroglycerin or isosorbide dinitrate.

Drugs of different organic nitrates are used to prevent strokes.

However, the development of tolerance may be the reason for their restriction in use. Nitrates are effective during unstable angina in combination with antithrombotic drugs.

Myocardial infarction. The use of nitrates from the first hours of myocardial infarction limits the area of ​​necrosis and reduces myocardial oxygen demand by reducing heart work.

Nitrates reduce the incidence of life-threatening complications: acute heart failure, pulmonary edema, arrhythmias, early mortality.

The use of nitrates in the late phase of myocardial infarction doesn’t affect mortality significantly, but reduces the symptoms of angina.

Acute and chronic heart failure. Reducing pre-and afterload, nitrates are pathogenic agents in the treatment of heart failure.    

Biliary colic. Nitrates are effective in the treatment of spasm of the sphincter of Oddi and gallbladder.

Esophagospasm. Sublingual nitrates intake effectively stops pain caused by spasm of the esophagus.

Slow calcium channel blockers of L type      

Inhibit potential dependant Ca 2 + channels of L-type, which have the greatest functional significance for the heart and blood vessels.

 By chemical structure there can be:

• phenylalkilamins - verapamil (act mainly on the heart);
• benzothiazepines - diltiazem;
• dihydropyridines - nifedipine, amlodipine, isradipine, felodipine, lacidipin, nitrendipine, nimodipine (operating mainly in the arteries and to lesser extent on the heart);
• difenilpiperazines - Cinnarizine (expand arterial vessels of the brain).

Reduce the need of heart for oxygen and increase oxygen delivery only: verapamil and diltiazem.

Nifedipine (Nifedipine, corinfar, Cordafen)     

Pharmacodynamics. The main effect of nifedipine is associated with the dilation of the arterioles, decreasing of afterload on the heart, lower blood pressure.

Nifedipine does not cause sinoatrial and atrioventricular block sites, does not slow atrioventricular conduction.

Reflex sympathetic stimulation of the heart leads to tachycardia, increased contractility, increased coronary blood flow.

Has a mild natriuretic  effect without increasing urine output. Lowers the tone of the myometrium.     

Pharmacokinetics. Taken orally, the tablets or capsules are rapidly and completely absorbed.

Bioavailability 40-60% as a result of first-pass metabolism.

Cmax in 30 minutes. T1 / 2 - 2-4hours. Excreted by the kidneys.

When administered orally te onset of action is 30-60min, duration of action – 4-6hours. With sublingual administration – in 5-10min, maximum in 15-45min., duration – 4-8h.

Effect of tablets with sustained release is in 10-15min, the duration to 21hours. (Do not chew!).     

Indications: as antianginal drug used in the treatment of stable angina, rest angina, vasospastic angina, Prinzmetal's angina.

However, when prescribing the regular, not prolonged, nifedipine it is possible the  worsen  the angina and cause other cardiovascular complications.

Adverse drug reactions. Hyperemia of face and skin and upper part of the body, leg edema, tachycardia, headache; reduced at lowering doses and use of the drug after meals.

Possible: dizziness, nausea, hypotension, frequent urination, blurred vision, gingival hyperplasia, and depression.   

Contraindications: severe heart failure, sick sinus syndrome, hypotension, recent myocardial infarction, unstable angina, pregnancy, lactation.

Dosage forms: tablets of 0.01 and 0.02 g Retard to 0.01, 0.02 and 0.06 g  

Amlodipine (Amlodipine, normodipine, Norvasc)     

Indications: in stable and vasospastic angina. Little effect on the sinus node and the atrioventricular conduction. Inhibits platelet aggregation.

Pharmacokinetics. Absorbed slowly, almost completely. Bioavailability – 60-65% because of the effect of first-pass metabolism. Cmax – 6-12hours. T1 / 2 – 35-48h. Excreted by the kidneys.   

Side effects and contraindications are the same as for nifedipine.     

Prescription: orally 0.005 – 0.01 g (5-10mg), 1 time / day.     

Dosage forms: tab. of 0.0025, 0.005, and 0.001 g

Trimetazidine (Trimetazidine, Preductal)     

 Pharmacodynamics. It shows pharmacological effect not through hemodynamic mechanisms. It does not effect on myocardial oxygen consumption, heart rate and blood pressure.

However, the symptoms of angina decrease and tolerance to physical exercises increases. The mechanism of action of trimetazidine is associated with:

• disturbance of the oxidation of fatty acids in myocardiocytes by inhibiting 3 ketoacyl-CoA-thiolase and increase of  glucose oxidation by way of glycolysis, which requires less oxygen.
• a decrease in intracellular acidosis and accumulation of Na + and Ca2 + in cardiomyocytes during ischemia.
• protection of myocyte membranes from the damaging effect of oxygen.   

Pharmacokinetics. Quickly and efficiently absorbed in the intestine. T1 / 2 is about 6 hours. Biotransformation in the liver, excreted by kidneys.

Indications: to prevent angina strokes, dizziness caused by stroke, Meniere's disease, tinnitus. 

Contraindications: Pregnancy, lactation.    

Dosage forms: tablets of 0.02 g, Retard 0.035 g

Drugs decreasing the myocardial oxygen demand     

β - adrenoblockers: propranolol, metoprolol, oxprenolol, betaxolol, atenolol, nadolol, sotalol, bisoprolol, pindolol, acebutolol.

Antianginal action of  β - adrenergic blockers is connected to:

• reduction in myocardial oxygen demand by reducing heart rate, blood pressure, myocardial contractility;
• improve of coronary perfusion by reducing the heart rate, lengthening of diastole, diastolic pressure in the left ventricle, increased collateral flow, redistribution of blood flow in favor of ischemic myocardium;
• reduction of cardiotoxic and adverse metabolic effects of catecholamines;
• antiplatelet action (propranolol, timolol, oxprenolol).

Drugs used during myocardial infarction  

The main therapeutic measures during myocardial infarction are aimed at:

• elimination of pain. Starting with the first hours, one prescribes morphine IV (dilute 1% -1 ml (10 mg) in 10 ml of isotonic 0,9% NaCl; administrate 5 mg of morphine  IV by bolus slowly. Extra administration is possible 2-4mg of morphine). Can be assigned to other analgesics.
• elimination of arrhythmias. IV instillation of lidocaine during ventricular tachyarrhythmias.
• elimination or reduction of myocardial ischemia. IV injections of: fibrinolytic agent (alteplase, streptokinase), nitroglycerin, isosorbide dinitrate;
• oxygen therapy;
• reduction in myocardial oxygen demand, prevention of arrhythmias.
• During  satisfactory heart rate and blood pressure: a slow bolus (within 5 minutes) IV administration  of atenolol (β - blockers are contraindicated during cardiogenic shock, bradycardia, hypotension, left ventricular failure, atrio-ventricular block II-III degree);
• Treatment and prevention of thromboembolic complications. Heparin (fraxiparine, enoksiparin) parenterally. Antiplatelet therapy (aspirin, clopidogrel) inside.
• furosemide to reduce the pressure in the pulmonary artery, treatment of blood congestion in the lungs, the prevention and treatment of pulmonary edema. IV, 40 mg by bolus, further dose increases.
• Treatment and prevention of cardiogenic shock. Restoring of  blood volume 0,9% NaCl 200-250ml, possible to repeat the administration.
• IV infusion of dopamine and norepinephrine. Nitroglycerin IV.
• ACE inhibitors (captopril, IV  6.25 mg.) IV infusion Cardiotonic (dobutamin. dopamine, norepinephrine).
• Control of hyperlipidemia. Statin.

Drugs improving blood flow to the brain

1.      nimodipine, cinnarizine (calcium channel blockers). 
2.      vincamine, vinpocetine (Vinca Alkaloid and its derivatives);
3.      pentoxifylline (xanthine derivative);
4.      xantinol nicotinate (a xanthine compound and nicotinic acid);
5.      Dihydroergocristine (ergot alkaloid derivative);
6.      nicergoline (a derivative of ergot alkaloid and nicotinic acid);
7.      naftidrofuryl (serotonin receptor blocker);
8.      bencyclane;
9.      Ginkgo biloba medications