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Ministry of Public Health of UkraineMinistry of Education, Science, Youth, and Sports of Ukraine

Sumy State University

DRUGS INFLUENCING THE FUNCTIONS OF INTERNAL ORGANS

Course of Lectures on Pharmacology Part 1

Sumy Sumy State University

2012

Drugs influencing the functions of internal organs : course of lectures on Pharmacology / compilers : I. Yu. Vysotsky, R. A. Chramova, A. A. Kachanova, V. L. Vigunov. – Sumy : Sumy State University, 2012. – 85 p.

Biophysics, biochemistry, pharmacology, and biomolecular engineering department

Навчальне видання

ЗАСОБИ, ЯКІ ВПЛИВАЮТЬ НА ФУНКЦІЇ ВНУТРІШНІХ ОРГАНІВ

Конспект лекцій з курсу фармакології для студентів спеціальності 7.110101 «Лікувальна справа»

денної форми навчанняЧастина 1

(Англійською мовою)

Відповідальний за випуск І. Ю. ВисоцькийРедактор М. В. Буката

Комп’ютерне верстання А. А. Качанової

Підписано до друку , поз.Формат 60х84/16. Ум. друк. арк. 4,88. Обл.-вид. арк. 4,77. Тираж 100 пр. Зам. №

Собівартість видання грн к.

Видавець і виготовлювач Сумський державний університет,

вул. Римського-Корсакова, 2, м. Суми, 40007Свідоцтво суб’єкта видавничої справи ДК № 3062 від 17.12.2007.

Ministry of Public Health of UkraineMinistry of Education, Science, Youth, and Sports of Ukraine

Sumy State University

DRUGS INFLUENCING THE FUNCTIONS OF INTERNAL

ORGANS

Course of Lectures on Pharmacologyfor the students of speciality 7.110101 “Medical science”

of the full-time course of study Part 1

Approvedby the session of biophysics, biochemistry, pharmacology, and biomolecular engineering department as a course of lectures on PharmacologyMinutes № 22 of 6.06.2012

SumySumy State University

2012

DRUGS INFLUENCING RESPIRATORY SYSTEM

Drugs used in different acute and chronic diseases of respiratory organs are classified into the following groups:

1. Drugs which are used in bronchial obstruction syndrome.2. Expectorant drugs. 3. Antitussive drugs.4. Breathing stimulators. 5. Drugs which are used in acute respiratory insufficiency.

Drugs Used in Bronchial Obstruction Syndrome

Bronchial obstruction syndrome is condition which is accompanied by recurrent attacks of expiratory dyspnoea (difficult exhale) owing to spasm of bronchial smooth muscles, oedema of bronchi, and increased bronchial secretion.

In 2/3 cases, the cause of bronchial obstruction syndrome is bronchial asthma.

There are two forms of asthma:- atopic (allergic); - nonatopic (infectious).

Drugs used in bronchial obstruction syndrome are classified into three groups:

1. Bronchial spasmolytics.2. Drugs eliminating the oedema of bronchi mucous membrane:

- stabilizers of tissue basophil membranes; - glucocorticoids.

3. Expectorants and mucolytics.

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Broncholial SpasmolyticsThe smooth muscles tone of bronchi is under control of

parasympathetic nervous system, excitation of which results in spasm of bronchi. Sympathetic innervation of bronchi is absent. However, both α- and β2-adrenergic receptors are located in bronchial smooth muscles. These receptors are excited by catecholamines of blood or by administered adrenoceptor agonists. Excitation of α-adrenoceptors results in spasm of bronchi, while excitation of β2-adrenoceptors causes the bronchodilation.

Drugs classification1. Adrenoceptor agonists.

1.1. Adrenoceptor agonists with direct action:- α, β-adrenoceptor agonist: adrenaline ;- nonselective β1,2-adrenoceptor agonists: isadrinum,

orciprenaline;- selective β2-adrenoceptor agonists: salbutamol, fenoterol ,

terbutaline, salmeterol , formoterol .1.2. Adrenoceptor agonists with indirect action (sympathomimetic):

ephedrine . 2. M-cholinergic antagonists: atropine, platyphyllin ,

ipratropium bromide , metacin. 3. Myotropic antispasmodics: theophyline , euphill inum

(aminophyline). 4. α-adrenoceptor antagonists: phentolamine, pyrroxane,

prazosin. 5. Calcium channel blocker: fenigidin . 6. Leukotriene receptor inhibitors: zafirlukast , montelukast .

Adrenoceptor Agonists

Adrenaline is nonselective α- and β-adrenoceptor agonists. It should be noted that β-adrenoceptors are more sensitive to adrenaline than α-adrenoceptors.

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Excitation of β2-adrenoceptors of smooth muscles and tissue basophils results in activation of adenylate cyclase and increase of cAMP level. Owing to this level of free calcium ions in the cells decreases and relaxation of bronchial smooth muscles develops. The release of histamine, serotonin, and other bronchoconstrictors also decreases.

Adrenaline is administered parenterally. Optimal mode is intramuscular because the excitation of β2-adrenergic receptors in vessels of skeletal muscles results in vasodilatation and increase of adrenaline absorption speed. In case of subcutaneous administration, α-adrenergic receptors are excited, that results in vasoconstriction.

In case of intramuscular administration, bronchodilation develops in 3–7 minutes and lasts up to 30–40 minutes.

Side effects are increase of blood pressure, tachycardia, elevation of minute blood volume, hyperglycemia, tremor, etc.

Adrenaline is used for interruption of asthma attacks.

Ephedrine is indirect adrenoceptor agonist (sympathomimetic). The drug stimulates noradrenaline release by sympathetic nervous terminals, inhibits mediator reuptake, and sensitizes adrenergic receptors to catecholamines.

In frequent ephedrine use, tachyphylaxis develops owing to exhaustion of noradrenaline storage in adrenergic fibers.

In comparison with adrenaline, broncholytic activity of ephedrine is less, but duration of action is longer. Drug is administered parenterally, in inhalations, and perorally. In case of peroral intake, the effect develops in 40–60 minutes. Duration of action is up to 6 hours. In intramuscular administration, effect develops in 10–15 minutes and lasts up to 4 hours.

Ephedrine is used both for interruption and for prevention of bronchospasms.

Side effects of ephedrine are excitation of central nervous system, insomnia, increase of blood pressure, tachycardia, elevation of minute blood volume, hyperglycemia, tremor, etc.

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Isadrinum is direct β1- and β2-adrenoceptor agonist. Drug is administered in inhalations, sublingually, and parenterally. For interruption of bronchospasm, it is administered in inhalations. In this case, effect develops in 1–3 minutes and lasts up to 1–1.5 hours. In peroral intake, isadrinum undergoes fast degradation. Sublingual and intravenous modes of administration are used in disturbances of heart rhythm.

Salbutamol , fenoterol , terbutaline , salmeterol ,

formoterol are selective β2-adrenoceptor agonists. These drugs have no pronounced effects of β1-adrenergic receptors stimulation, such as tachycardia, disturbances of cardiac rhythm, hypertension, and tremor.

Selective β2-adrenoceptor agonists are administered parenterally (subcutaneously, intramuscularly, or intravenously), in inhalations, and perorally. Bronchodilatation develops in 3–5 minutes after inhalations and in 20–30 minutes in case of parenteral administration. In case of peroral intake, the effect develops in 1 hour.

Selective β2-adrenoceptor agonists are used both for cessation and for prevention of asthma attacks.

It must be remembered that high doses of selective β2-adrenoceptor agonists can excite also β1-adrenoceptors with development of tachycardia, disturbances of coronary blood circulation, heart failure, hyperglycemia, tremor, etc. Long-term use of β2-adrenoceptor agonists is accompanied by decrease of β2-receptors sensitivity with reduction of broncholytic effect. In this case, M-cholinergic antagonists, glucocorticoids and other drugs are prescribed for restoration of β2-adrenoceptors sensitivity.

α-Adrenoceptor AntagonistsThe efficacy of α-adrenoceptor antagonists in bronchial asthma is

caused by blockade of α1 adrenergic receptors and is significantly less than efficacy of β-adrenoceptor agonists. But α-adrenoceptor antagonists can be useful in patients with tachyphylaxis to β-6

adrenoceptor agonists or in patients with accompanied hypertension or chronic heart failure.

M-Cholinergic AntagonistsAtropine , platyphyllin , and metacin were first effective

drugs for treatment of asthma. But short duration of action, predominant influence upon the upper sections of the bronchi, increase of viscosity of the sputum, and numerous side effects have become an occasion for restrict of its use in treatment of asthma.

Nowadays, M-cholinergic antagonists for inhalation are used in medical practice. These drugs are ipratropium bromide (atrovent) and troventol . Both drugs are quaternary compounds with low solubility in lipids. Therefore, these drugs have selective influence upon M-cholinoceptors of bronchi. Atrovent is used for inhalations in aerosol and in capsules for inhalations. Troventol is used in aerosol. Effect develops in 20–40 minutes after inhalation and lasts up to 8 hours.

Atrovent and troventol are used for prevention of bronchospasms in chronic obstructive bronchitis, acute and chronic pneumonia, and in bronchial asthma. Efficacy of drugs is higher in elderly patients.

Side effects of atrovent and troventol are dry mouth, disturbances of accomodation, increase of viscosity of sputum, etc.

Myotropic Antispasmodic DrugsTheophyline and euphillinum (aminophyline) are

methylxanthines which are used for treatment of bronchial asthma. Drugs block the activity of phosphodiesterase – enzyme which

catalyzes the transformation of cAMP to inactive 5-AMP. Stabilization of cAMP level causes the decrease of calcium entrance into the cells and reduction of bronchial tone.

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Simultaneously, drugs also block adenosine receptors. Adenosine is agonist of purinergic receptors A1 and A2. Bronchospasm develops if the activity of A1-receptors is more than activity of A2-receptors. In patient with bronchial asthma the quantity of A2-receptors is reduced. Methylxanthines restore quantity of A2-receptors, that results in bronchodilation. Methylxanthines also stabilize the membranes of basophiles and reduce the release of allergy mediators.

Methylxanthines stimulate respiration and heart activity, decrease the blood pressure in pulmonary artery, have weak diuretic activity owing to increase of kidney blood flow, stimulates central nervous system, and irritate mucous membrane of stomach.

Drugs are administered intravenously slowly, intramuscularly, perorally or rectally. The blood therapeutic concentrations are maintained during 4–5 hours. Drugs are administered 4–6 times per day. Drugs are administered parenterally for interruption of asthmatic status.

Methylxanthines side effects are nausea, tachycardia, tremor, headache, insomnia, etc.

GlucocorticoidsGlucocorticoids (beclomethasone , triamcinolone ,

flunisolid , etc.) influence upon different links of asthma pathogenesis.

Glucocorticoids suppress exudation and limit oedema of bronchi mucous membrane. This is the result of prostaglandins synthesis reduction and potentiation of catecholamine activity. Also, glucocorticoids have antiallergic activity.

Drugs are administered perorally, intramuscularly, intravenously, and in inhalations.

Inhalation forms of glucocorticoids are used only for treatment of chronic asthma, because effect develops slowly. In case of acute bronchospasm or asthmatic status, glucocorticoids are administered parenterally in individual doses 2–4 times per day.

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The adverse effects of systemic administration of the corticosteroids include adrenal suppression, cushingoid changes, growth retardation, cataracts, osteoporosis, CNS effects and behavioural disturbances, and increased susceptibility to infection. Inhaled corticosteroids are generally well tolerated. In contrast to systemically administered corticosteroids, inhaled agents are either poorly absorbed or rapidly metabolized and inactivated and thus have greatly diminished systemic effects relative to oral agents. The most frequent side effects are local; they include oral candidiasis, dysphonia, sore throat and throat irritation, and coughing. Caution should be exercised when taking corticosteroids during pregnancy, as glucocorticoids are teratogenic.

Stabilizers of Tissue Basophiles Membranes

This group includes such drugs as sodium cromoglycate , nedocromil-sodium , and ketotifen . Drugs are used only for prevention of asthma attacks. Stabilizers of tissue basophiles membranes are ineffective in case of acute bronchospasm.

These drugs inhibit phosphodiesterase and prevent the calcium ions entrance owing to blockade of open calcium channels. In the result, drugs suppress the release of histamine and leukotrienes. There is evidence, that drugs also block chlorine channels of basophiles. It is known, that transport of chlorine ions into the basophiles results in hyperpolarization of membrane, which is necessary for penetration of calcium ions into the cells. Drugs predominantly influence upon pathochemical stage of allergic reactions. Stabilizers of tissue basophiles membranes decrease the oedema of bronchi mucous membrane and prevent bronchospasm.

Sodium cromoglycate and nedocromil-sodium are used as liquids or powders for inhalations. Drugs effect develops in 2 hours after inhalation and lasts up to 4–6 hours. Drugs are administered 2–4 times per day.

Stabilizers of tissue basophiles membranes are used for treatment of atopic asthma. Pronounced effect develops in 2–8 weeks

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after initiation of treatment. These drugs are commonly prescribed together with bronchodilators and expectorants.

Anti-inflammatory activity of nedocromil-sodim is in 10 times more than one of sodium cromoglycate. Nedocromil-sodium is effective in both allergic and non-allergic asthma. Maximum therapeutic activity of drugs develops in 5–7 days after initiation of treatment. Drug is prescribed 2 times per day.

The special forms of nedocromil-sodium and sodium cromoglycate is developed for treatment of allergic rhinitis (Lomusol, Rynacrom, Tilorin) and conjunctivitis (Opticril, Tilavist).

Mechanism of ketotifen action is identical to nedocromil-sodium. But ketotifen additionally blocks H1-histamine receptors. Drug is administered perorally after meal. Approximately 90% of administered dose is absorbed from digestive tract. Ketotifen has the high degree of binding with plasma proteins – up to 75%. Drug is prescribed 1–2 times per day. Ketotifen undergoes biotransformation in liver. Its metabolites are excreted with urine and bile. Side effects are dry mouth, decrease of bronchial secretion, drowsiness, increase of appetite.

Leukotriene ModulatorsZafirlukast and montelukast are cysteinyl leukotriene

(CysLT) receptor antagonists; and zileuton, a leukotriene synthesis inhibitor.

CysLTs include leukotrienes C4, D4, and E4. These mediators are products of arachidonic acid metabolism and make up the components of slow-reacting substance of anaphylaxis. The cysteinyl leukotrienes are generated in basophiles, macrophages, and eosinophils. These mediators have long been suspected of being key participants in the pathophysiology of asthma. The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLT1

receptors. Zafirlukast and montelukast are competitive antagonists of these receptors.

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In contrast, zileuton suppresses synthesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes.

Montelukast, zafirlukast, and zileuton are indicated for the prophylaxis and chronic treatment of asthma. They should not be used to treat acute asthmatic episodes. All three agents are administered orally.

EXPECTORANT DRUGS

This group includes big amount of agents, which decrease the viscosity of sputum and facilitate its discharge. These drugs should be used as agents for symptomatic therapy of serious cough with little amount of viscous sputum (acute respiratory diseases, pleuritis, whooping cough, etc.). Expectorants improve the bronchi drainage and gaseous exchange, decrease the inflammation and irritation of nervous ending in mucosa.

Classification of expectorants1. Expectorant drugs with direct action: root of

marshmallow, leaves of plantain , mucaltinum, pertussinum, potassium iodide , terpinhydrate, sodium benzoate, sodium hydrocarbonate .

2. Expectorants with reflex type of action: grass of Thermopsis , grass of Labrador-tea , root of milkwort , ipecacuanha, licorice, elecampane .

3. Mucolytics: acetylcysteine , bromhexinum, ambroxol , desoxyribonuclease, crystall ine trypsin , crystall ine chymotrypsin .

Expectorant Drugs with Direct ActionThe majority of representatives are agents of plant origin. It is

thought that after absorption into blood, these drugs are partly secreted by bronchial glands and have the covering and anti-

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inflammatory action. Also these agents increase the production of bronchial secretion.

Because the plant agents have the insufficient action upon the viscosity of sputum, these drugs are commonly combined with iodides, bromides, terpinhydrate, sodium benzoate, sodium hydrocarbonate, etc. Iodine ions, secreted by bronchial glands, increase the secretion of water and decrease the viscosity of sputum.

Expectorant effect of sodium hydrocarbonate in cases of peroral administration of small doses (0.25 g) is doubtful, because agent is neutralized by hydrochloric acid of stomach.

The combination of peroral administration of expectorants with inhalation therapy is more productive. The sodium hydrocarbonate is the main component of common solution for inhalations. This agent has neutralized and loosening effects concerning acidic mucopolysaccharides and decreases its viscosity. Bromides or iodides can be also added to inhalation solutions.

Expectorant Drugs with Reflex ActionThis group includes the drugs of plant origin which contain

saponins. For expectorant effect, these drugs are used perorally. Saponins irritate the mucous membrane of stomach and reflexively cause the weak stable activation of vomiting centre. The expectorant doses of these agents are less than the threshold vomitive doses; therefore vomiting and significant nausea do not arise. But mild nausea reflexively activates the parasympathetic nervous system that is accompanied by increasing of secretion of salivary, gastric, and bronchial glands; decreasing of viscosity of sputum, and facilitating of sputum discharge. The activity of bronchi ciliary epithelium is increased. The releasing of lysosomal enzymes from epithelium cells promotes the proteolysis of sputum proteins. Expectorants with reflex action are used in acute respiratory diseases with poor secretion.

The high doses of these agents cause the nausea and vomiting.

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Mucolyt icsThis group includes such drugs as acetylcysteine ,

bromhexinum, ambroxol, desoxyribonuclease , crystalline trypsin, crystall ine chymotrypsin, etc.

Molecule of acetylcycteine contains the free HS-group. Owing to it, this agent can reduce the disulfide groups of glycoproteins. The breakage of disulfide bonds is accompanied by depolymerization of protein components of sputum which promotes the discharge of sputum. Unlike proteolytic enzymes (trypsin, chymotrypsin), acetylcysteine does not aggressively influence upon the epithelium and does not increase the size of defects in mucous membranes. Nowadays, acetylcysteine is one of the basic agents in treatment of chronic bronchitis, pneumonias, and bronchiectatic disease. The drug is used in inhalations (from 1–2 inhalations per week to 3–6 inhalations per day). Also, acetylcysteine is administered intramuscularly or intravenously. The drug is contraindicated in bronchial asthma.

Bromhexinum and ambroxol increase the activity of epithelial lysosomes, secretion of proteolytic enzymes, and synthesis of surfactant by pulmonary tissue (in turn, surfactant provides elasticity of pulmonary tissue and promotes the discharge of sputum from pulmonary tract). Also bromhexinum and ambroxol increase the synthesis of immunoglobulins G and A; and lysozyme. Both drugs show the mild antitussive activity.

Bromhexinum is used as aerosol for inhalations and in tablets for peroral administration 3–4 times daily. The effect develops in a day, but maximum effect is observed in 5–10 days from the beginning of use. This drug is well tolerated by patients. Ambroxol is administered perorally 2–3 times per day. Sometimes, ambroxol may be the cause of nausea and vomiting.

ANTITUSSIVE DRUGSAntitussive drugs suppress cough reflex in result of either

inhibition of cough centre or decrease of sensitivity of nervous endings in respiratory tract.

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The excessive, exhausting cough promotes irritation of mucous membranes, its hyperemia, impairs the condition of patient. In such cases, the cough attacks are not productive and are not accompanied by discharge of sputum.

The excessive inhibition of cough centre by antitussive agents is also inadmissible, because in this case the discharge of sputum is broken. Therefore, the doses of antitussive drugs should be correctly chosen. These agents are used in bronchitis, pneumonias, bronchiectatic disease.

Classification of antitussive drugs

1. Drugs with central action, which suppress the cough centre: a) opioid analgesics: codeine, ethylmorphine , etc.;b) non-opioid antitussive drugs: glaucine, tussuprex, oxeladine, butamirate ;2. Drugs with peripheral action, which block the sensitive nervous endings in respiratory tract: libexinum, falimint . Codeine is alkaloid of opium. Drug has moderate analgesic

action and expressed antitussive action. The duration of effect is 3–4 hours. The therapeutic doses of codeine do not suppress the respiratory centre. Long use of codeine can be accompanied by constipations and urinary retention. Codeine is contraindicated for children under 2 years. Prolonged use of codeine can cause the development of addiction.

Ethylmorphine is agent which is manufactured by chemical modification of morphine. The antitussive activity of ethylmorphine is 1.5–2 times higher than one of codeine.

The introduction of the drugs with selective inhibition of cough centre in medical practice, which do not cause addiction, was an important achievement in antitussive agents creating. These agents are called non-opioid antitussive drugs.

Glaucine has the moderate antitussive action and decreases the oedema of bronchi mucous membranes. Drug has the antispasmodic action upon the smooth muscles of inner organs. The

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tolerance and dependence to glaucine do not develop. Sometimes, glaucine can cause the drowsiness, dizziness, and weakness.

Libexinum is antitussive agent with peripheral action. The base of its antitussive effect is local anaesthetic action. Also libexinum has the bronchial antispasmodic action. It is supposed, that libexinum has mild inhibitory influence upon the cough centre. Libexinum is administered perorally 3–4 times per day. The drug is well tolerated by adults and children.

DRUGS USED IN PULMONARY OEDEMAAcute pulmonary oedema is a medical life-threatening

emergency requiring immediate care. In most cases, heart problems cause pulmonary oedema. But fluid can accumulate for other reasons, including pneumonia, exposure to certain toxins and medications, and exercising or living at high elevations. Depending on the cause, pulmonary oedema symptoms may appear suddenly or develop slowly over weeks or months. Signs and symptoms that come on suddenly are usually severe and may include: extreme shortness of breath or difficulty breathing; feeling of suffocating or drowning; wheezing or gasping for breath; anxiety, restlessness, sense of apprehension; cough that produces frothy sputum that may be tinged with blood; excessive sweating; pale skin; chest pain when pulmonary oedema is caused by coronary artery disease.

Although pulmonary oedema can sometimes result in death, the outlook is often good when patient receives prompt treatment for pulmonary oedema along with therapy for the underlying problem.

Administering oxygen is the first step in the treatment for pulmonary oedema. Depending on patient condition and the reason of pulmonary oedema, patient may also receive one or more of the following medications:

Preload reducers. Nitroglycerin and diuretics, such as furosemide (Lasix), are commonly used. These medications dilate the veins in lungs and elsewhere in body, which decreases fluid pressure going into heart and lungs.

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Afterload reducers. Nitroprusside , some drugs which block -adrenoceptors (phentolamine, tropaphenum, aminazine ), enalapril and captopril dilate the peripheral vessels and take a pressure load off the left ventricle.

Morphine . This narcotic for years is a mainstay in treating cardiac pulmonary oedema, may be used to relieve shortness of breath and associated anxiety.

Foam extinguishers. Ethyl alcohol and antifoamsilane eliminate the foam being produced in the lumen of alveoli. They decrease the surface tension of the foam vesicles and turn them into fluid which occupies smaller volume.

Glucocorticoids. Prednisolon, dexamethasone, triamcinolone are used in the treatment of pulmonary oedema because they decrease the permeability of blood-air barrier. Table 1 – Drugs for prescription

Drug name Single dose and mode of administration

Drug product

Codeini phosphas Orally 0.01–0.03 g 1–3 times per day

Powders

Libexinum Orally 0.1–0.2 g 3–4 times per day

Tablets 0.1 g

Acetylcysteinum Orally 0.2 g 3 times per day;intramuscularly 0.1–0.2 g 2-3 times per day

Tablets 0.2 g;ampoules 2 ml of 10% solution

Bromhexinum Orally 0.008 g 3–4 times daily

Tablets 0.008 g

Euphyllinum Orally 0.15 g 2–3 times per day;intramuscularly 0.24–0.36 g 1–3 times per day;intravenously slowly or drip intravenously (in 200–400 ml of 0.9% solution of NaCl) 0.12–0.24 g

Tablets 0.15 g;

ampoules 1 ml of 24% solution;ampoules 10 ml of 2.4% solution

Cromolinum-natrium

For inhalation: 1 capsule 4 times daily

Capsules 0.02 g

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Adrenalini hydrochloridum

Subcutaneously or intramuscularly (sometimes intravenously) 0.0003–0.0007 g

Ampoules 1 ml of 0.1% solution

Salbutamolum 1–2 inhalations of aerosol 2–3 times daily or for interruption of acute bronchospasm

Aerosol 10 ml

Furosemidum Intramuscularly or intravenously 0.02 g

Ampoules 2 ml of 1% solution

Hygronium Drip intravenously 0.1 g (in 100 ml of 0.9% solution of NaCl)

Ampoules 0.1 g of dry substance

CARDIOTONIC DRUGSCardiotonic drugs are drugs which increase contraction of

myocardium and normalize the functions of heart. Cardiotonics are divided into cardiac glycosides and non-glycoside cardiotonics.

Cardiac GlycosidesCardiac glycosides are nitrogen-free compounds with

cardiotonic activity. Cardiac glycosides are contained in such plants as foxglove, lily of the valley, spring adonis, strophanthus, etc. It is known 15 species containing cardiac glycosides and used in medicine.

The following drugs are most widely used in medicine: digitoxin, digoxin, celanidum, strophanthin, corglycon, infusion of adonis herb .

Cardiac glycosides influence cardiovascular, urinary, and nervous systems. Respectively, effects of cardiac glycosides are divided into cardial and extracardial ones.

Cardial effects are the following:

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1. Positive inotropic effect. Cardiac glycosides increase and shorten systole, increase stroke volume and cardiac output, and decrease the amount of residual blood in the cavity of the heart.

2. Positive tonotropic effect. Cardiac glycosides increase the tone of myocardium and decrease the size of enlarged heart. It promotes more complete expulsion of blood from the ventricles.

3. Negative chronotropic effect. Cardiac glycosides decrease heart rate and prolong diastole. As a result, blood supply to the heart improves.

4. Negative dromotropic effect. Cardiac glycosides decrease the impulse conduction through conductive heart system, especially through atrioventricular node.

5. Positive bathmotropic effect. Cardiac glycosides increase the excitability of myocardium and may promote the ventricular tachyarrhythmias.

The first three effects are the base of therapeutic action of cardiac glycosides. The forth and the fifth effects are undesirable effects, which develop predominantly in case of glycosides overdose.

Mechanism of action

Cardiac glycosides interact with membrane Na+, K+-ATPase of cardiac hystiocytes. Owing to this interaction, the partial blockage of ATPase activity develops. It results in increase of intracellular Na+

ions concentration and simultaneous reduction of K+ concentration. This change in intracellular ions balance causes the increase of Ca2+

ions concentration in cardiac hystiocytes. The increase of free calcium concentration in the cardiac hystiocytes causes the reduction of inhibitory influence of troponin upon the contractile proteins of myocardium that leads to increase of cardiac contractility. This phenomenon is called positive inotropic effect. Force of cardiac contraction increases. All systole phases are shortened. Amount of residual blood in the ventricles cavities is decreased. On ECG, tine R increases, and complex QRS narrows.

Positive inotropic effect develops if inhibition of Na+,K+-ATPase equals approximately 35%. If enzyme inhibition is less, 18

cardiotonic effect doesn’t develop. Toxic effects develop if enzyme inhibition equals or is more than 60%.

Prolongation of diastole and decrease of heart rate (negative chronotropic effect) is the result of increased vagal influence upon heart. Increase of cardiac contraction force is accompanied by enhance of stroke volume and excitation of baroreceptors of aortic arch and carotid glomeruli. Excitation carries out to vagus centre. Increase of vagal tone results in decrease of excitability and automatism of sinus node and decrease of heart rate. On ECG, prolongation of interval PP is registered.

During treatment by cardiac glycosides, the conductibility through atrioventricular node slows down (negative dromotropic effect). Mainly, it is the result of increased vagal tone. Negative dromotropic effect is most typical for digitalis drugs. On ECG, prolongation of interval P–Q is observed.

Positive bathmotropic effect is ability of toxic doses of cardiac glycosides to increase excitability of myocardium which results in geterotopic focus of excitation. It is the result of significant electrolyte change in cells which develop in toxic doses. On ECG, extrasystoles are registered.

Cardiac glycosides also have several extracardial effects. In heart insufficiency, myocardium doesn’t fulfil pump function that results in decrease of cardiac output and phlebostasis. Administration of cardiac glycosides results in increase of cardiac output and decrease of venous blood pressure. Blood volume in veins and hepatic portal system is decreased. Blood pressure is normalized. General blood flow and cerebral one are improved. The oxygen deficiency, blood concentration of carbon dioxide, excitability of respiratory and vasomotor centres, and dyspnoea are decreased.

Diuresis increases owing to rise of blood flow and enhancement of glomerular filtration. Additionally, cardiac glycosides have direct influence upon renal tubules: drugs block K+, Na+-ATPase and decrease reabsorbtion of sodium and water. Administration of cardiac glycosides results in reduction of oedemas. Cardiac glycosides have sedative effect in central nervous system.

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Cardiac glycosides stimulate smooth muscles of inner organs and that leads to increase of intestinal peristalsis, increase of tone of bladder, bronchi, and uterus.

Chemical structure of cardiac glycosides

Molecule of cardiac glycosides consists of two parts: sugary part (glycone) and nonsugary one (aglycone). Glycone influence drugs pharmacokinetics: solubility, ability to penetrate through biological membranes, binding with plasma proteins, cumulation, etc. Aglycone influence cardiotropic properties of drugs. Aglycone consists of steroid part and lactone ring. Dependently of quantity of ketone and alcogol groups in glycone structure, cardiac glycoside may be polar or nonpolar. Polar glycosides are strophanthin and corglycon; relatively polar drugs are digoxin and celanidum; nonpolar glycoside is digitoxin. Polar glycosides are poorly absorbed in gastrointestinal tract, don’t undergo biotransformation, and are excreted with urine. Nonpolar glycosides are well absorbed in intestine, bind with plasma proteins, undergo hepatic biotransformation, and are excreted predominantly through intestine. Nonpolar glycosides have high ability to cumulation.

According to pharmacokinetics, cardiac glycosides are divided into three groups:

- drugs with fast onset of effect and short duration of action which are characterized by low ability to cumulation: strophanthin and corglycon ;

- agents with moderate speed of effect development and intermediate duration which are characterized by reasonable degree of cumulation: digoxin and celanidum ;

- glycosides with slow onset of effect and long duration of action which are characterized by high degree of cumulation: digitoxin .

Drugs of the first group (strophanthin and corglycon) predominantly are used in acute heart failure. These drugs are administered intravenously slowly. Prior administration, solution of 20

glycosides is diluted in 10–20 ml of isotonic sodium chloride solution or isotonic glucose solution. Fast intravenous administration can result in spasm of vessels and increase of preload and afterload on the heart. Strophanthin effect develops in 5–10 minutes after administration, and reaches maximum in 30–90 minutes. Approximately 85–90% of administered dose is eliminated during the first day.

Digitoxin is used perorally or rectally in chronic heart failure. In case of peroral use, onset of drug action is in 2 hours and maximum effect develops in 12 hours. Only 7–10% of administered dose is excreted during the first day after administration. Digitoxin is completely excreted from the body in 2–3 weeks.

Drugs of the second group (digoxin and celanidum) occupy an intermediate position. These drugs are administered both intravenously and perorally in acute and chronic heart failure. Drugs effects develop in 0.5–2 hours after intravenous administration. Maximum effect develops in 1–5 hours. Drugs are completely excreted in 2–7 days.

Indications for use1. Treatment of chronic heart failure. 2. Supraventricular tachyarrhythmias (digitalis drugs). 3. Acute heart failure (strophanthin, corglycon). But in recent

years, use of cardiac glycosides in acute heart failure is significantly restricted owing to use of safer drugs than cardiac glycosides (dobutamine, dopamine, amrinon, etc.).

The principles of dosage of cardiac glycosidesThe coefficient of daily excretion characterizes the size of daily

excretion of cardiac glycosides from the patient’s body. This is percentage ratio of dose which was introduced into the body during the day to quantity of glycoside, which was excreted from the body during day. For example, coefficient of daily excretion of digitoxin equals 7–10%, for strophantin – 40–50%.

The treatment of chronic heart failure is carried out in two phases: phase of initial digitalization and supporting phase. During the initial digitalization the full effective dose of glycoside is

21

received in organism. The realization of phase of saturation is crucial task, as the sensitivity of the patients to glycosides is individual, and the effective dozes of drugs are close to toxic. This phase may be carried out with different velocity. The moderate (during 3 days) and slow (during 8 days) types of initial digitalization are most commonly used in practice. Fast type of digitalization (during 1 day in organism of patient the full effective dose is introduced) creates the biggest threat of intoxication. During the second step (supporting phase) patient was been treated with supportive dose. The calculation of supportive dose is performed according to ratio: supportive dose = dose of saturation (full effective dose) · coefficient of daily excretion.

Daily supportive dose is not divided into several receptions.

Symptoms and treatment of glycosides overdoseIn glycoside overdose, disturbances of heart rate observed in

90–95% of patients. Ventricular arrhythmias (extrasystoles, paroxysmal ventricular tachycardia, and ventricular fibrillation) are most common among them. The cause of ventricular arrhythmias is decrease of potassium concentration and simultaneous increase of calcium ions concentration in cardiac hystiocytes. Also, complete or partial atrioventricular blocks can develop.

Less dangerous complications include nausea, vomiting, epigastric pain, xanthopsia (seeing of objects in yellow or green colour), “rings” and “balls” before eyes, psychical disturbances (excitement and hallucinations), and headache.

In case of overdose, the cardiac glycosides therapy is stopped. Non-glycoside cardiotonic (dopamine or dobutamine) should be prescribed.

Drugs binding glycosides and reducing their blood circulation should be prescribed. They are agents decreasing glycoside absorption in gastrointestinal tract: tannin , cholestyramine , charcoal , laxative drugs. These drugs are prescribed independently of glycoside administration mode, because cardiac glycosides undergo enterohepatic circulation. Drugs binding

22

glycosides in the blood are unithiolum and antibodies or their Fab-fragments to digitalis .

Potassium- and magnesium-containing drugs, such as potassium chloride, asparkam, panangin , polarizes mixture (potassium chloride , insulin, and glucose), magnesium sulfate , and trilon B are used for treatment of glycoside intoxication. Potassium and magnesium slow down the impulci conduction, therefore they are not prescribed to patients with bradycardia and atrioventricular blockage. Intravenous administration of potassium-containing drugs should be fulfilled under control of ECG.

For treatment of ventricular tachyarrhythmias, lidocaine and dipheninum are used. In some cases, atrioventricular blockage may be reduced by administration of atropine .

Non-Glycoside Cardiotonics

According to mechanism of action, non-glycoside cardiotonics are divided into the following groups:

1. Drugs stimulating β1-adrenoceptors: dopamine, dobutamine .

2. Phosphodiesterase inhibitors: amrinone, milrinone, sulmazol .

3. Drugs with different mechanisms of action: levosimendan, vesnarione .

Dopamine is noradrenaline precursor. In average therapeutic doses, dopamine stimulates dopaminergic receptors and β1-adrenergic receptors of heart. It results in increase of cardiac contraction force. Owing to excitation of dopanergic receptors of smooth muscles of vessels, drug dilates renal and mesenteric vessels. In high doses, dopamine can also excite α-adrenoceptors. Dopamine

23

is used in severe cardiovascular insufficiency, shock, severe arterial hypotension.

Dobutamine is more selective agent which excites β1-adrenoceptors. Drug stimulates heart work without influence upon the vessels. Dobutamine is used in acute heart failure.

Both dopamine and dobutamine are administered intravenously driply.

Recently, cardiotonic drugs with favourable influence upon coronary circulation were approved in medical practice. Amrinone and milrinone are among them. Drugs inhibit phosphodiesterase activity and promote accumulation of cAMP in myocardium. It results in increase of intracellular calcium concentration and cardiotonic effect. Drugs are used in heart failure resistant to therapy with cardiac glycosides.

Amrinone is administered perorally or intravenously. Duration of action is 4–7 hours. Amrinone side effects are thrombocytopenia, dyspepsia, hypotension, arrhythmias, disturbances of renal function, etc.

Cardiotonic activity of milrinone is 20 times more than amrinone. Drug is administered intravenously. Duration of action is 48–72 hours. Milrinone is used for short-term therapy of acute heart failure.

Sulmazol inhibits phosphodiesterase activity and blocks A1

adenosine receptors of heart. It results in cardiotonic effect. Furthermore, drug increases activity of microfibrillar ATPase.

Levosimendan increases activity of Ca2+-dependent ATPase of endoplasmatic reticulum in cardiac hystiocytes. Drug increases the force of cardiac contraction and relax arteries and veins. Agent is administered intravenously driply in acute decompensated severe chronic heart failure. Levosimendan is intended for use only in specialized cardiac hospitals.

Vensarinone influences activity of cytokines. Drug is an orally active inotropic agent used for the treatment of chronic heart failure.

Table 2 – Drugs for prescription

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Drug product

Digitoxinum Orally 0.0001 g once a day;for rectal use 0.00015g once a day

Tablets 0.0001 g;suppositories 0.00015 g

Digoxinum Orally 0.000125–0.00025 g once a day;intravenously slowly 0.000125–0.00025 g with 10–20 ml of isotonic sodium chloride solution once daily

Tablets 0.00025 g;

ampoules 1 ml of 0.025% solution

Celanidum Orally 0.00025 g 3 times per day;intravenously slowly 0.0002 g with 10–20 ml of isotonic sodium chloride solution once a day

Tablets 0.00025 g;


Strophantinum Intravenously slowly 0.00025 g with 10–20 ml of isotonic sodium chloride solution once a day


Table 2 - continuationDrug name Single dose and mode of

administrationDrug product

Unithiolum Intramuscularly 0.25 g Ampoules 5 ml of 5% solution

“Asparcamum” or “Pananginum”

Orally 1–2 tablets 3 times per day

Tablets

Lidocainum Intravenously slowly 0.05–0.1 g;intravenously drop-by-drop 0.05–0.1 g with 100 ml of isotonic sodium chloride solution

Ampoules 2 ml of 10% solution; 2 or 10 ml of 2% solution

Dipheninum Orally 0.117 g 1–3 times per day

Tablets 0.117 g

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ANTIHYPERTENSIVE DRUGSAntihypertensive drugs are agents with different chemical

structure which reduce increased blood pressure. Hypertensive disease is the most prevalent disease of

cardiovascular system. Nearly 10–30% of word population suffers from hypertension. The frequency of disease is higher in Japan and in highly developed countries of Europe and America. Approximately 80% of all cases of hypertension are accounted for essential hypertension. Another 20% of cases are symptomatic hypertension (renal, endocrinal, etc.).

Different view points exist about primary mechanisms of hypertensive disease. Most common etiotropic factors are psycho-emotional overload and age-related changes in diencephalon-hypothalamus structures of brain. Heredity also plays an important role. In the initial stages of disease, excessive sympathoadrenal system activation is observed. That results in increase of cardiac output, increase of vessels tonus, activation of renin-angiotensin-aldosterone system. Renal changes cause the decrease of sodium and water excretion that results in increase of blood volume. Sodium ions are accumulated in vessels wall that causes the vessels oedema. Simultaneously, ionized calcium level increases in cells of smooth muscles of vessels. Owing to described change, muscular cells sensitivity to vasopressors (catecholamines, angiotensin II, etc.) increases. Hypertrophy of vessels muscular layer develops gradually. These processes are predominantly expressed in small arterioles.

Drug classificationAntihypertensive drugs are divided into the following groups:

I. Basic antihypertensive drugs1. β-adrenoceptor antagonists. 2. Inhibitors of angiotensin-converting enzyme and blockers of

angiotensin II receptors.

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3. Diuretics. 4. Blockers of calcium channels.

II. Ancillary drugs:1. α-adrenoceptor antagonists. 2. Central α2-adrenoceptor agonists. 3. Ganglion blockers. 4. Sympatholytic drugs. 5. Myotropic antispasmodic drugs. 6. Agonists of imidazoline receptors.

Basic Antihypertensive Drugs

β-Adrenoceptor Antagonists

Owing to likeness of chemical structure of β-adrenoceptor antagonists with catecholamines, these drugs interact with β-adrenoceptors and prevent or eliminate the influence of catecholamines upon innervated organs.

β1-adrenoceptors are located in myocardium cells, in cardionector, in cells of juxtaglomerular apparatus of kidney, and in fatty tissue. β2-adrenergic receptors are located in cells of smooth muscles of bronchi, vessels of skeletal muscles, uterus, liver, pancreas, and membranes of presynaptic ending of sympathetic fibres. In central nervous system, both β1- and β2-adrenergic receptors are located.

According to selectivity to types of β-adrenoceptors, drugs are divided into selective β1-adrenoceptor antagonists and nonselective β1,2-adrenoceptor antagonists. But if β1-blockers are used in high doses, selectivity is worsened. Therefore, correct drug dosage is important.

β-blockers have intrinsic sympathomimetic activity or haven’t it. Along with adrenergic blocking activity, β-blockers with intrinsic sympathomimetic activity can stimulate β-adrenoceptors within physiological limits. Due to this, heart rate doesn’t significantly decrease at rest. Drugs influence upon activity of sinus node is

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manifested only during increased physical and emotional stress (that is in case of high catecholamine activity).

On the base of these typical properties, β-adrenoceptor antagonists are classified into several groups:

1. Nonselective β-adrenoceptor antagonists or β1,2-adrenoceptor antagonists:

1.1. Nonselective β-adrenoceptor antagonists without intrinsic sympathomimetic activity: propranolol (anaprilinum), nadolol (korgard) .

1.2. Nonselective β-adrenoceptor antagonists with intrinsic sympathomimetic activity: pindolol , oxprenolol , sotalol .

2. Cardioselective β-adrenoceptor antagonists or β1-adrenoceptor antagonists:

2.1. Drugs without intrinsic sympathomimetic activity: metoprolol , atenolol , nebivolol , betaxolol .

2.2. Drugs with intrinsic sympathomimetic activity: acebutalol , talinolol .

Several β-adrenoceptor antagonists have membrane stabilizing activity: propranolol , oxprenolol , acebutalol , etc. This activity is the result of decrease of membrane permeability for Na+

and K+ ions in myocardium conductive system. It promotes antiarrhythmic effect of β-adrenoceptor antagonists.

β-blockers also differ in degree of molecules lipophilicity and ability to penetrate through membranes. Atenolol is an example of drug with expressive hydrophilic properties which can’t penetrate through hematoencephalic barrier. Atenolol lacks sedative effect, has low speed of gastrointestinal absorption and long duration of action. Atenolol is administered once a day. Propranolol is characterized by high ability to penetrate through blood-brain barrier. Agent has anxyolitic activity.

In recent years, nebivolol is widely used in medicine. Except β-adrenergic blocking activity, agent stimulates synthesis of nitrous oxide. It improves coronary circulation and reduces peripheral vessels resistance. 28

Antihypertensive effect of β-adrenoceptor antagonists

Drugs block β1-adrenoceptors in the heart that results in decrease of heart rate, force of cardiac contraction, and cardiac output. In case of single drug administration, there is 10–25% decrease of cardiac output level. But in case of regular use, this value is 5–15%. Drugs with intrinsic sympathomimetic activity affect cardiac output in less degree; but it doesn’t influence upon their hypotensive activity.

Drugs ability to block β1-adrenoceptors of juxtaglomerular apparatus cells is also important for hypotensive effect. It results in decrease of renin secretion, reduction of angiotensin II synthesis and aldosterone release.

Lipophilic β-adrenoceptor antagonists penetrate through blood-brain barrier and cause sedation. Prolonged use of these agents results in inhibition of central links of sympathetic nervous system tone regulation.

Nonselective β1,2-adrenoceptor antagonists block presynaptic β2-adrenergic receptors that results in reduction of noradrenaline secretion and decrease of vessels postsynaptic α-adrenoceptors excitation.

β-adrenoceptor antagonists are administered perorally or parenterally. Lipophilic drugs (anaprilinum, oxprenolol , etc.) are readily absorbed in gastrointestinal tract. Agents bind with plasma proteins and undergo biotransformation. The main route of metabolites excretion is liver. These agents are administered three times per day.

Hydrophilic β-blockers (pindolol , atenolol , nadolol , etc.) are poorly absorbed in gastrointestinal tract. Degree of their binding with plasma proteins is low. Drugs are excreted in unchanged state through kidneys. Hydrophilic β-adrenoceptor antagonists are prescribed 1–2 times per day.

β-adrenoceptor antagonists are prescribed in essential and symptomatic hypertension. Initial hypotensive effect develops in

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several hours after drug intake. Stable decrease of blood pressure is developed gradually; therefore efficacy of β-blockers should be assessed in 3–4 weeks after start of intake. It is appropriate to prescribe β-blockers to patients with hyperkinetic syndrome, which develops owing to physical load. In most cases, β-blockers are prescribed in combination with other hypotensive agents. For instance, a combination of β-adrenoceptor antagonists with diuretics is widely used in medicine for treatment of hypertensive disease.

Also, β-adrenoceptor antagonists are used for treatment of tachyarrhythmias (predominantly supraventricular localization), effort angina, hypertrophic cardiopathy, and thyrotoxicosis. Drugs also are prescribed for treatment of parkinsonism of vascular origin.

The most common side effects of nonselective β-blockers are bronchospasm and disturbances of peripheral blood circulation (intermittent claudication).

Other side effects of β-blockers therapy include bradycardia, atrioventricular blockage, and aggravation of heart failure. β-adrenoceptor antagonists intake by patients with diabetes mellitus can result in hypoglycemia.

Sudden interruption of β-adrenoceptor antagonists intake after long-time therapy can result in return syndrome. The main manifestations of which include hypertensive crisis, angina attacks, and tachyarrhythmias. Phasing out of the drug with the use of another scheme of treatment is most simple and safe way of prevention of return syndrome.

Calcium Channel BlockersCalcium channel blockers are divided into 3 generations:I generation: verapamil, nifedipine, dilt iazem . II generation: gallopamil , amlodipine , felodipine ,

nicardipine, clentiazem.III generation: naftopidil , emopamil .

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In comparison with the first generation, drugs of the second generation are characterized by longer duration of action, higher tissue specificity, less number of side effects.

The third generation is characterised by presence of special kinds of activity: naftopidil has α-adrenergic blocking activity; emopamil has sympatholytic activity.

Calcium channel blockers block potential-dependent calcium channels in membranes of cardiac hystiocytes and smooth muscles of vessels. It results in decrease of total peripheral vascular resistance and decrease of cardiac contraction. Also, calcium channel blockers decrease platelets aggregation, suppress automatism of sinus node and ectopic foci of rhythm in atrium, and slow down conduction through atrioventricular node.

Several types of calcium channels are known: T, N, P, and L. Blockers of calcium channels inhibit the slow L-channels. Intake of these drugs results in significant reduction of cytoplasmic calcium concentration and relaxation of smooth muscles of arteries. It is proved that intracellular calcium concentration is increased in hypertensive patients. Influence of drugs on venous vessels expressed insignificantly.

In the result of cardiac contraction decrease, calcium antagonists promote regression of left ventricle hypertrophy.

Calcium channel blockers are administered parenterally, orally, and sublingually. Duration of action of the first generation drugs is 4–6 hours. Second generation drugs act up to 12 hours. Calcium antagonists undergo high degree of liver biotransformation.

The main indications for use of calcium channel blockers are hypertensive disease, hypertensive crisis, ischaemic heart disease, and supraventricular tachyarrhythmias.

Side effects of calcium antagonists are headache, dizziness, flushing, constipation; oedemas of feet, shins, and elbows owing to vascular stasis and disturbances of microcirculation. Also, both bradycardia (for verapamil) and tachycardia (for nifedipine) are possible.

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Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors are divided into two generations:

- I generation: captopril ;- II generation: enalapril , l isinopril , ramipril ,

benazepril , fosinopril , perindopril , trandolapril .Drugs of the second generation are characterized by high activity,

lack of sulfhydryl groups in molecules, higher duration of action, less frequency of side effects.

Renin is synthesized in juxtaglomerular cells in the result of sympathetic stimuli, reduction of renal blood flow, decrease of blood pressure, and increase of sodium concentration in distal convoluted tubules. Renin influence angiotensinogen with formation of angiotensin I. Angiotensin-converting enzyme (kinase II) transforms angiotensin I to angiotensin II. Synthesis of angiotensin II occurs in heart, brain, lungs, and other organs. High concentration of ACE is found in vascular endothelium. Angiotensin II stimulates aldosterone release, that results in increase of sodium and water reabsorption and potassium excretion.

4 types of angiotensin II receptors are found in different tissues. The main cardiovascular effects are the results of excitation of angiotensin receptors of the type 1 – AT1. Angiotensin II causes significant vasoconstriction and stimulates cardiac contraction. Additionally, angiotensin acts as growth factor of cardiac hystiocytes, increases secretion of vasopressin, prolactin, and adrenocorticotropin.

It is also important to note that ACE also catalyzes inactivation of bradykinin and enkephalin. Both bradykinin and enkephalin relax vessels, decrease blood pressure, increase sodium and water excretion, and suppress platelets aggregation.

ACE inhibitors decrease angiotensin II synthesis and prevent its effects. Additionally, drugs promote bradykinin and enkephalin protection that results in increase of effects of these substances. Owing to this mechanism, ACE inhibitors cause the following effects:32

- both venous and arterial tone is decreased;- blood pressure is lowered;- both preload and afterload upon the heart is diminished; - blood circulation in heart, kidneys, and other inner organs is

improved;- diuresis is increased.

It should be noted that the application of ACE inhibitors is accompanied by decrease of hypertrophy of myocardium and of vessels wall.

ACE inhibitors are prescribed orally. Enalapril (Vasotec) and lisinopril also are administered intravenously. After oral administration, drugs are easily absorbed from gastrointestinal tract. Therapeutic effect of captopril develops in 1 hour after intake. Onset of effects of other drugs is 2 hours after peroral administration. Duration of captopril action is 6 hours; duration of action of other drugs is up to 24 hours. In this regard, captopril is prescribed 4 times daily; other drugs are prescribed once a day. The main route of drugs elimination is kidneys. But such agents as ramipril , benazepril , and perindopril are predominantly excreted by liver (approximately 60% of the administered dose).

ACE inhibitors increase blood circulation in myocardium, liver, brain, and kidneys. The drugs efficacy is proportional to blood renin concentration. And while drugs reduce blood pressure in patients with normal renin activity, drugs efficacy in this case is less.

ACE inhibitors are used for treatment of hypertensive disease. Drugs may be combined with central hypotensive agents, calcium channel blockers, β-adrenoceptor antagonists, and diuretics. Captopril sublingually may be used for cessation of hypertensive crisis.

Nowadays, ACE inhibitors are used for treatment of chronic heart insufficiency. Owing to reduction of arterial and venous tone, drugs decrease preload and afterload upon the heart, and blood pressure in ventricles. In three months after the initiation of treatment with ACE inhibitors, hypertrophy of the left ventricle is significantly decreased.

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ACE inhibitors are also used in postinfarction cardiosclerosis and diabetic nephropathy.

Side effects of ACE inhibitors include excessive hypotension, dry cough, angioedema, neutropenia, headache, and dizziness.

Blockers of Angiotensin Receptors

Angiotensin receptor blockers include losartan , valsartan, candesartan, irbesartan, telmisartan, etc.

Drugs block angiotensin receptors in vessels, adrenal gland and other organs, decrease aldosterone and norepinephrine blood concentrations. Angiotensin receptor blockers also increase kidneys excretion of sodium and have diuretic action.

In the result, total peripheral vascular resistance, systemic blood pressure, and pressure in the pulmonary circulation are reduced. Hypotensive activity of angiotensin receptor blockers is identical to one of ACE inhibitors.

Drugs are used perorally once a day. Bioavailability is approximately 30%. Antihypertensive effect develops during 6 hours and lasts up to 24 hours. Unchanged drugs and its metabolites are excreted through liver.

Indications for use of angiotensin receptor blockers include hypertensive disease, renovascular hypertension, for diagnosis of increased activity of renin-angiotensin system.

Side effects of angiotensin receptor blockers are headache, vertigo, potassemia, cough, and allergic reactions. Teratogenic activity is typical for these drugs. Therefore, angiotensin receptor blockers are contraindicated in pregnancy.

DiureticsDiuretics are dichlothiazidum, furosemide, clopamide,

spironolactone, triamterene , etc. Drugs action upon nephron is accompanied by reduction of

sodium and water reabsorption and decrease of volume of 34

extracellular fluid. Diuretics significantly potentiate hypotensive effect of other antihypertensive drugs. Drugs are widely used for monotherapy of initial stage of hypertensive disease. Diuretics commonly combine with one another for potentiation of effect. Thiazides (dichlothiazidum ), non-thiazide sulfonamides (oxodolinum, clopamide, indapamide ), and potassium-sparring diuretics (triamterene, amiloride, spironolactone ) are most widely used diuretics for treatment of hypertensive disease. Strongly acting loop diuretics (furosemide, ethacrinic acid, torsemide) are used in case of aggravation of II and III stages of hypertensive disease and for urgent therapy of hypertensive crisis.

Initial decrease of blood pressure owing to diuretics use is the result of increased sodium and water excretion and reduced volume of circulating blood. In 6–8 weeks after initiation of treatment with diuretics, diuretic effect is gradually reduced and cardiac output is normalized. It is the result of renin activity increase owing to reduction of plasma volume and blood pressure. Under these conditions, hypotensive effect of diuretics develops owing to decrease of peripheral vessels resistance. Reduction of vessels tone is the result of gradual decrease of intracellular sodium and increase of intracellular potassium in cells of vessels wall. Despite of increased activity of renin-angiotensin system, resistance of peripheral and renal vessels reduces. Diuretics decrease both systolic and diastolic blood pressure and maintain or even increase cardiac output. Therapy with diuretics doesn’t cause postural hypotension.

Supporting Antihypertensive Drugsα-Adrenoceptor Antagonists

α-adrenoceptor antagonists are divided into:- α1-adrenoceptor antagonists: prazosin, doxazosin ,

terazosin ;- α1,2-adrenoceptor antagonists: phentolamine,

tropaphenum, pyrroxane .Nonselective α-adrenoceptor antagonists relax vessels owing to

blockage of both α1 and α2-adrenoceptors. But these drugs aren’t used for systemic treatment of hypertensive disease, because they

35

don’t promote stable hypotensive effect. Shortness of effect is the result of blockage of presynaptic α2-adrenoceptors which regulate negative feedback. Blockage of these receptors results in excessive noradrenaline release and restoration of adrenergic transmission in vessels. Nonselective α-adrenoceptor antagonists are used in pheochromocytoma (tumor of adrenal gland medulla), hypertensive crisis, and pulmonary oedema.

Stable and prolonged blockage of postsynaptic α-adrenergic receptors is observed in prescribing of selective α1-adrenoceptor antagonists, because these agents don’t affect negative feedback in adrenergic synapses. Blockage of α1-adrenoceptors in vessels results in decrease of general peripheral resistance, venous return, and preload upon the left ventricle. Hypotensive effect of α1-adrenoceptor antagonists isn’t accompanied by tachycardia and increase of cardiac output. Prazosin and doxazosin additionally have moderate antispasmodic influence upon smooth muscles of vessels. Both drugs also decrease level of low-density lipoproteins and of very low density lipoproteins. This effect is very useful in case when arterial hypertension is accompanied by hyperlipidemia.

Selective α1-adrenoceptor antagonists are easily absorbed in gastrointestinal tract. The main route of drugs excretion is liver. Prazosin is prescribed two times per day, doxazosin – once a day.

Indications for use of selective α1-adrenoceptor antagonists are the following: hypertensive disease, chronic heart failure, chronic renal failure, and stagnation in the pulmonary vessels.

Side effects include headache, excessive hypotension, drowsiness, diarrhoea, dry mouth, and polyarthritis.

Central α 2-Adrenoceptor Agonists

Clophelinum and methyldopa excite α2-adrenoceptors in membranes of neurons of vasomotor centre, it is accompanied by decrease of centre activity. Antihypertensive effect is the result of inhibition of pressor part of vasomotor center and general decrease of sympathetic tone. It is accompanied by decrease of peripheral vessels 36

resistance and heart rate, reduction of catecholamines secretion, and temporally decrease of renin production.

Clophelinum (clonidine ) is potent and fast-acting hypotensive agent. Stable hypotension may be preceded by short-term increase of blood pressure owing to excitation of α2-adrenergic receptors in vessels. This phase lasts up to 5–10 minutes. Hypotensive effect of clophelinum lasts up to 10–12 hours. As a rule, clonidine therapy is started with small doses, it is taken 2–4 times a day. Gradually clonidine dose is increased.

So-called return syndrome develops in case of sudden cessation of clophelinum therapy. It starts in 18–36 hours after stop of drug intake and lasts from 1 to 5 days. Symptoms of return syndrome include hypertension up to hypertensive crisis, tachycardia, encephalopathy, disturbances of heart rate, abdominal pain. Gradual decrease of clonidine dose prevents development of return syndrome. Period of gradual drug cancellation lasts at least 7 days.

Clophelinum is administered orally and parenterally. Agent is prescribed in hypertensive disease and hypertensive crisis. Clonidine has hypnotic and sedative effects on CNS, decrease the body temperature. Agent potentiates effects of ethyl alcohol, hypnotics, tranquilizers, and neuroleptics. Clophelinum increases appetite, decreases secretion of salivary glands. The following side effects are possible in case of therapy with clophelinum: postural hypotension, dry mouth, constipation, urinary retention, vision disturbances, retention of sodium and water, etc. Long-term therapy with clophelinum results in tolerance.

Methyldopa transforms to α-methyl-norepinephrine which stimulates postsynaptic α2-adrenoceptors in membranes of neurons of vasomotor centre. It results in relaxation of vessels, decrease of general peripheral resistance, and reduction of cardiac output. Drug causes relaxation of renal vessels and increase of diuresis. Methyldopa has sedative and hypnotic effects. Drug is administered orally and parenterally once a day. Side effects are weakness, fatigue, disorders of attention, drowsiness, dry mouth, nasal stuffiness, dizziness, dyspepsia, and skin rash.

37

Ganglion Blockers

Ganglion blockers include such drugs as pentaminum, benzohexonium, pirilenum, hygronium, and arfonade . Drugs block Nn-cholinergic receptors in ganglia and prevent propagation of sympathetic vasoconstrictive impulses to vessels. Administration of ganglion blockers is accompanied by significant dilation of arterioles, venules, and capillaries which results in decrease of blood pressure. Cardiac output and stroke volume are decreased mainly due to reduction of venous return of blood. Dilation of veins is accompanied by reduction of preload upon the heart. Blood is deposited in vessels of mesentery and lower extremities. Blood pressure decreases in pulmonary circulation and in right ventricle. Owing to dilation of resistive vessels, peripheral vessels resistance and afterload upon the left ventricle are reduced.

Ganglion blockers are used for controlled hypotension; for treatment of pulmonary oedema and brain oedema; for interruption of hypertensive crisis. Nowadays, ganglion blockers are used seldom for treatment of hypertensive disease, because drugs administration results in large number of side effects: decrease of tone and motility of gastrointestinal tract and bladder, constipation, disturbances of accomodation, dry mouth. Serious complication of ganglion blockers administration is postural hypotension. Tolerance develops in case of regular administration of ganglion blockers.

Sympatholytics

Sympatholytics reserpine and octadine suppress adrenergic transmission on the level of presynaptic membranes. These drugs exhaust noradrenaline storage.

Reserpine is alkaloid of Rauwolfia. Agent affects deposition of noradrenaline in vesicles and promotes mediator inactivation by cytoplasmic MAO. It results in vasodilation, decrease of general peripheral resistance, bradycardia, and decrease of cardiac output. 38

Reserpine also reduces noradrenaline storage in central nervous system. It results in decrease of vasomotor centre tone, reduction of limbic system activity and reticular formation of brain axis. Therefore, reserpine has psychosedative, hypnotic, and depressive effects. Hypotensive effect develops in 1–2 weeks after start of drug intake. After cessation of drug administration, hypotensive effect persists during 3–4 weeks. Phenomenon of return is absent. Reserpine does’t cause postural hypotension. Side effects include depression, parkinsonism, hypersalivation, aggravation of ulcer disease and gastritis, diarrhoea, increase of bronchial tone, bradycardia, nasal congestion, etc.

Octadine affects noradrenaline release and prevents its neuronal reuptake. Agent has low solubility in lipids and doesn’t penetrate into central nervous system. Octadine reduces cardiac output, decreases general peripheral resistance and venous return. Drug is prescribed orally once a day. Hypotensive effect develops in 4–7 days after initiation of treatment. After cessation of octadine administration, hypotensive effect persists during 1–2 weeks. Octadine can cause postural hypotension. Other side effects include bradycardia, disturbances of atrioventricular conduction, increase of bronchial tone, diarrhoea, etc.

Potassium Channel ActivatorsPotassium channel activators diazoxide and minoxidil open

potassium channels in membranes and promote K+ entrance from cells. It results in hyperpolarization of membrane and inactivation of calcium channels. Sensitivity of smooth muscles to vasoconstrictive agents (catecholamines, angiotensin II, etc.) is decreased. Potassium channel activators influence only upon arterioles.

Minoxidil is one of the most potent drugs of this group. Drug is used for treatment of the most severe and malignant forms of

39

hypertension, which are resistant to other hypotensive agents and its combinations. Minoxidil significantly reduces blood pressure and decreases preload. Minoxidil is administered orally. Hypotensive effect lasts up to 24 hours. Side effects of minoxidil are hirsutism, lesion of pericardium, skin rash, and headache. Drug causes retention of sodium and water.

Diazoxide is administered intravenously for cessation of hypertensive crisis. Effect develops in 2–5 minutes and lasts up to 6–10 hours. Diazoxide also suppresses the heart activity. Drug inhibits secretion of insulin and causes hyperglycemia. Side effects include sodium and water retention, increase of uric acid level in blood.

Nitric Oxide Donators

Sodium nitroprusside is hypotensive agent influencing upon resistive and capacitive vessels. Hypotensive effect of drug doesn’t result in increase of cardiac output. Sodium nitroprusside releases nitrous oxide which stimulates cytosolic guanylate cyclase. In the result, level of cGMP increases and causes the reduction of intracellular calcium level. Tone of smooth muscles of vessels is decreased. Drug is administered intravenously driply in hypertensive crisis, for controlled hypotension, and in pulmonary oedema. Hypotensive effect develops in 2–3 minutes. Drug administration is accompanied by tachycardia, headache, dyspeptic disorders, and muscular twitching.

Miscellaneous Drugs

Apressinum (hydralazine) relaxes resistive vessels, decreases general peripheral resistance, and decreases blood pressure. Drug is prescribed orally. Apressinum is easily absorbed in gastrointestinal tract. For dosage of drug, it is necessary to remember that speed of metabolism is different in different patients. On average, the effect lasts 6–8 hours. Side effects of apressinum include tachycardia, heart pain, arrhythmias, headache, disturbances 40

of water-salt balance, autoimmune reactions (rheumatoid arthritis, systemic lupus erythematosus), dyspepsia, etc.

Dibazolum (bendazole) relaxes vessels, reduces general peripheral resistance and cardiac output. It results in decrease of blood pressure. Hypotensive effect of dibazolum is moderate. In case of hypertensive disease treatment, dibazolum is combined with other hypotensive agents. Drug also may be administered intramuscularly or intravenously for cessation of hypertensive crisis. Side effects appear seldom.

Magnesium sulfate is administered intravenously or intramuscularly in hypertensive crisis. Except myotropic antispasmodic action, drug also suppresses neurotransmission through vegetative ganglia. In high doses, magnesium sulfate also inhibits vasomotor centre activity. Drug has sedative effect and inhibits convulsions. Overdose of drug results in respiratory depression. In this case, calcium chloride should be administered, because calcium is antagonist of magnesium.

Papaverine is alkaloid of opium. It is myotropic antispasmodic agent which inhibits activity of phosphodiesterase. Owing to such mechanism drug causes accumulation of intracellular cAMP, which causes relaxation of vessels.

Drugs Used for Cessation of Hypertensive CrisisTreatment of hypertensive crisis is a task of urgent therapy. In

this case, preference is given to drugs with fast onset of action, which are administered parenterally. For cessation of crisis may be used such drugs as sodium nitroprusside , nitroglycerin, diazoxide, labetalol , furosemide, magnesium sulphate , pentaminum, clophelinum, enalapril , dibazolum , etc. Aminazinum (intramuscularly, 50–100 mg) or droperidol(intramuscularly or intravenously, 5 mg) are administered in patients

41

with high tone of sympathoadrenal system, vomiting, anxiety, and other symptoms of encephalopathy. Such drugs as captopril , nifedipine, clophelinum are used for peroral or sublingual administration in patients with hypertensive crisis.

HYPERTENSIVE DRUGSDrugs which increase blood pressure are used in shock,

collapse, and arterial hypotension. The cause of blood pressure decrease should be identified before drug administration. Pathogenetic therapy in any cases includes administration of drugs increasing blood pressure.

Classification of hypertensive drugs1. Drugs which stimulate vasomotor centre – analeptics:

coffeinum, cordiaminum, camphor, sulfokamfokain . 2. Drugs which tone central nervous system and cardiovascular

system: tinctures of Ginseng , Schizandra; extracts of Eleuterococcus, Rhodiola; pantocrinum .

3. Drugs with peripheral vasoconstrictor and cardiotonic activity.

3.1. Drugs which stimulate both α- and β-adrenergic receptors in vessels and heart: noradrenaline , adrenaline , ephedrine .

3.2. Drugs which stimulate α-adrenergic receptors: mesatonum .

3.3. Gormonal drugs: vasopressin , pituitrinum .3.4. Agonists of dopanergic receptors: dopamine .3.5. Drugs with peripheral action: angiotensinamide . 3.6. Cardiotonic drugs: strophantin , dobutamine . 4. Drugs which increase blood volume: polyglucinum,

rheopolyglucinum .

Agonists of Dopaminergic Receptors

42

Dopamine acts dependently of administered dose. Low doses of dopamine (1–5 mg/kg in 1 minute) stimulate peripheral dopaminergic receptors, relax renal and mesenteric vessels. Intermediate doses of dopamine (5–20 mg/kg in 1 minute) stimulate β1-adrenergic receptors of heart and increase cardiac output and heart rate. Renal blood flow increases. Blood pressure does not change significantly. Administration of high doses of drug (more than 20 mg/kg in 1 minute) results in excitation of α-adrenergic receptors. Resistance of renal vessels is increased. Heart rate and force of cardiac contraction are increased too. Dopamine can cause cardiac arrhythmia. Drug is administered intravenously driply in different forms of shock.

Drugs with Peripheral Action

Angiotensinamide is amide of natural angioconstrictor angiotensin II. Vasoconstrictive effect of angiotensinamide is 40 times greater than those of noradrenaline. Hypertensive effect of angiotensinamide is the result of excitation of angiotensin receptors of arterioles. Venous tone increases only insignificantly.

Angiotensinamide stimulates synthesis of aldosterone that results in sodium and water retention in organism. Owing to this, extracellular fluid volume increases and blood pressure increases. Moreover, angiotensinamide stimulates adrenaline release, increases tone of vasomotor centre, stimulates transmission through sympathetic ganglia, and increases peripheral effects of noradrenaline.

Angiotensinamide is used in acute arterial hypotension. Drug is administered intravenously drop by drop. Side effects are headache, allergic reactions, narrowing of the renal vessels, etc.

Drugs Increasing Blood Volume

43

Administration of blood, plasma, or plasma expanders has significant effect in hypotension with hypovolemia. These agents are especially effective in patients with hemorrhage and dehydration of organism. Antiaggregants and anticoagulants should be administered together with them.



Drug product

Hygronium Drip intravenously 0.04–0.08 g (as 0.1% solution in isotonic NaCl)

Ampoules 0.1g of dry substance

Pentaminum Intramuscularly 0.05–0.1 g;intravenously slowly 0.01–0.025 g (in 10–20 ml of isotonic solution of NaCl)

Ampoules 1 or 2 ml of 5% solution

Benzohexonium Orally 0.1–0.2 g 3–6 times daily;subcutaneously or intramuscularly 0.025 g 1–2 times daily

Tablets 0.1 g;


Tropaphenum Subcutaneously or intramuscu-larly 0.01–0.02 g; intravenously slowly 0.01 g in 10–20 ml of isotonic NaCl

Ampoules 0.02 g of dry substance

Anaprilinum Orally 0.01–0.04 g;intravenously slowly 0.001 g in 10–20 ml of isotonic NaCl

Tablets 0.01 or 0.04 g;ampoules 1 or 5 ml of 0.1% solution



Metoprololum Orally 0.05–0.1 g Tablets 0.05 or 0.1 gPrazosinum Orally 0.0005–0.002 g Tablets 0.001, 0.002

or 0.005 g

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Octadinum Orally 0.025–0.05 g Tablets 0.025 gReserpinum Orally 0.00005–0.0001 g Tablets 0.0001 or

0.00025 gClophelinum Orally 0.00075–0.00015 g;

subcutaneously or intramus-cularly 0.00005–0.0001 g;intravenously 0.00005-0.0001 g in 10–20 ml of isotonic NaCl

Tablets 0.000075 or 0.00015 g;ampoules 1 ml of 0.01% solution

Methyldophum Orally 0.25 g Tablets 0.25 gPhenigidinum Orally 0.01–0.02 g Tablets 0.01 gDiazoxidum Intravenously fast 0.075–0.3 g Ampoules 20 ml (0.3 g)Magnesii sulfas Intramuscularly of

intravenous-ly slowly 1–5 gAmpoules 5, 10 or 20 ml of 20% or 25% solution

Captoprilum Orally 0.025–0.05 g Tablets 0.025 gLosartanum Orally 0.1 g Tablets 0.1 gDichlothiazidum

Orally 0.025–0.05 g Tablets 0.025 or 0.1 g

Furosemidum Orally 0.04 g;intramuscularly or intravenous-ly 0.02 g

Tablets 0.04 g;ampoules 2 ml of 1% solution

Spironolactonum

Orally 0.025–0.05 g Tablets 0.025 g

Noradrenalini hydrotartras

Drip intravenously 0.004–0.008 g in 1 L of isotonic NaCl


Mesatonum Orally 0.01–0.025 g;subcutaneously or intramuscu-larly 0.003–0.005 g;intravenously slowly 0.001–0.003 g in 10–20 ml of isotonic NaCl (drip intravenous introduction is possible)

Powders; ampoules 1 ml of 1% solution

45

DRUGS FOR TREATMENT OF ISCHAEMIC HEART DISEASE (ANTIANGINAL DRUGS)

Antianginal drugs eliminate the imbalance between myocardium oxygen demand and oxygen delivery. In the result, drugs interrupt angina attacks or relief ischaemic heart disease.

Classification of antianginal drugs1. Drugs which decrease the myocardium oxygen demand and

improve the blood supply. 1.1. Organic nitrates: nitroglycerin, nitrosorbidum

(isosorbide dinitrate), isosorbide mononitrate , erynitum, sustac-mite, sustac-forte , trinitrolong, nitrong .

1.2. Calcium channel blockers: verapamil , gallopamil , nifedipine, nicardipine, amlodipine , diltiazem, nisoldipine .

1.3. Potassium channels activators: nicorandil , pinacidil . 1.4. Different drugs: amiodarone, molsidomine . 2. Drugs decreasing myocardial oxygen demand. 2.1. β-adrenoceptor antagonists: anaprilinum, nadolol,

oxprenolol , metoprolol , talinolol , nebivolol , acebutalol . 2.2. Bradicardic drugs: alinidine, falipamil . 3. Drugs increasing oxygen delivery to myocardium. 3.1. Myotropic coronary vasodilating drugs: carbochromen,

dipyridamole , papaverine , nospa . 3.2. Coronary vasodilating drug with reflex action: validolum .

Drugs Decreasing the Myocardium Oxygen Demand and Imroving the Blood Supply

Organic Nitrates

Organic nitrates interact with sulfhydryl groups of cysteine which is located in membranes of endotheliocytes. In the result of this interaction, NO2 is synthesized with the following transformation 46

into NO. Nitric oxide stimulates guanylyl cyclase of smooth muscles cells and causes the increase of cGMP level. cGMP participates in regulation of smooth muscles contraction, reducing calcium intracellular concentration. It results in dephosphorylation of myosin light chains and relaxation of smooth muscles. Nitrates stimulate prostaglandins synthesis and suppress thromboxane A2 synthesis. It results in decrease of adhesion and aggregation of platelets and microcirculation improvement.

Besides peripheral action, nitrates also have expressive influence upon the central regulation of adrenergic innervation. Drugs decrease adrenergic influence upon heart and vessels that also promotes vasodilatation.

The main factor of anti-ischaemic effect of nitrates is their ability to decrease venous blood return to heart. This effect is the result of dilation of capacitive vessels and blood deposition in peripheral veins. Owing to this, cardiac preload is decreased. Reduction of arterioles tone is less expressive, but also useful because it results in decrease of cardiac afterload.

Decrease of both preload and afterload is accompanied by decrease of heart work and reduction of oxygen demand.

Improvement of coronary blood flow is of secondary importance. But in comparison with other coronarolytics, nitrates have their own characteristics. Drugs dilate large coronary arteries and promote increase of perfusion pressure at the entrance to sclerous segments of vessels. Speed of blood flow in the ischaemic areas increases. Steal phenomenon isn’t typical for nitrates.

It is necessary to note, that redistribution of intracardial blood flow is for the benefit of the most vulnerable subendocardial sections.

Nitrates also delete vessels of brain, internal organs, retina, etc. Because nitrates are myotropic antispasmodics, they cause relaxation of smooth muscles of inner organs (gastrointestinal tract, bronchi, etc.).

The used medicinal forms of nitrates determine the mode of drugs administration, speed of effect development, and duration of antianginal action. In case when drug is used for prevention of

47

angina attacks, speed of effect development isn’t critical. But it is decisive factor in case of interruption of angina attacks. For interruption of stenocardia attacks the following medicinal forms of nitroglycerin for sublingual administration are used: tablets, alcoholic and oil solutions (dosed by drops), spray for irrigation of mouth, and capsules. These medicinal forms are used only sublingually, because nitroglycerin is destroyed in the first passage through the liver. Medicinal form of nitroglycerin for intravenous administration is also used.

In sublingual administration, nitroglycerin avoids the first passage through the liver. Drug is readily absorbed into superior vena cava system and comes to systemic blood circulation. The bioavailability of nitroglycerin in sublingual administration is more than 90%. It is necessary to note, that nitroglycerin absorption significantly depends on salivation intensity. Bioavailability of nitroglycerin is decreased in dry mouth. Therefore, in patients with salivation disturbances use of nitroglycerin spray is preferable.

In sublingual administration, maximum concentration of nitroglycerin in the blood is observed in 2–3 minutes. Duration of nitroglycerin action is 15–20 minutes. In 20–30 minutes, only trace of drug is determinated in the blood. Nitroglycerin undergoes biotransformation in the liver by conjugation with glutathione. Metabolites are excrated through the liver and lungs.

Medicinal forms slowly releasing nitroglycerin are used for prevention of angina attacks. Among them are tablets “Sustac-mite” and “Sustac-forte”, polymer plates “Trinitrolong”; spray, ointment, and plaster discs with nitroglycerin. In use of cutaneous form of nitroglycerin (ointment and plaster discs), effect develops slowly and lasts 8–24 hours.

Group of nitrates with prolonged effect includes nitrosorbidum, isosorbide mononitrate , and isosorbide dinitrate . The efficacy of these drugs is less than nitroglycerin efficacy.

Nitrates are used for interruption and for prevention of angina attacks. Drugs also are administered intravenously by drops for treatment of myocardial infarction in acute period.48

Most dangerous complication of nitrates therapy is postural hypotension. Reflex tachycardia, the increase of intracranial and intraoccular pressure, headache, feeling the heat, and hyperemia of face are observed. Hemorrhagic stroke cases also are described. Tolerance develops approximately in 58% of patients with regular intake of nitroglycerin during 1.5–2 months. At present, the most effective method for restoring nitroglycerin responsiveness is to discontinue drug administration for at least 6 to 8 hours each day.

Sudden cessation of long-term therapy with nitrates results in return phenomenon. In this case, the increase of intensively of chest pain and the increase of frequency of angina attacks are developed. Also return-phenomenon can result in myocardial infarction and sudden death. Therefore, cessation of nitrates therapy should be done by gradually reducing the dose of drug and the frequency of its intake.

Calcium Channel Blockers

Calcium channel blockers are divided into 3 generations:- I generation: verapamil, nifedipine , dilt iazem ;- II generation: gallopamil , amlodipine , felodipine ,

nicardipine, nisoldipine ;- III generation: naftopidil , emopamil .

According to chemical structure, calcium channel blockers are divided into 3 subgroups:

- phenylalkylamine derivatives: verapamil , gallopamil ;- dihydropyridine derivatives: nifedipine, nicardipine,

nisoldipine, isradipine, felodipine , amlodipine ;- benzothiazepine derivatives: dilt iazem, clentiazem .

In comparison with the first generation drugs, the second generation drugs have longer duration of action and more selective influence upon calcium channels of vessels. The third generation

49

includes drugs with additional properties: naftopidil has α-adrenergic blocking activity, emopamil – sympatholytic activity.

All three generations have antianginal, antiarrhythmic, and antihypertensive activity.

Calcium channel blockers inhibit calcium ions penetration through L-type of slow calcium channels into the muscular cells of vessels and heart. A decrease of free calcium ions concentration in the cardiac hystiocytes results in reduction of energy consumption of ATP for mechanical work of myocardium. Heart force decreases. It results in reduction of myocardial oxygen consumption. Decrease of heart work is also the result of relaxation of peripheral arteries and reduction of afterload. Relaxation of coronary vessels also contributes to antianginal effect.

Calcium channel blockers improve the subendocardial blood flow and enhance collateral circulation.

Calcium channel blockers are administered enterally, sublingually, and parenterally. Drugs are completely (more than 90%) and rapidly absorbed from the gastrointestinal tract. But in the first passage through liver drugs undergo first-pass elimination. Bioavailability of calcium channel blockers is only 35% (for nifedipine, nitrendipine, and amlodipine it varies from 65 to 90%). Nearly 90% of amount of drugs, which reach systemic circulation, binds with plasma proteins. Calcium channel blockers easily penetrate in various tissues and organs including central nervous system. Drugs of the first generation have duration of action 4–6 hours. II generation of calcium channel blockers acts 12 hours. Calcium channel blockers are almost 100% metabolized by liver with the formation of inactive metabolites. Exceptions are verapamiland dilt iazem , metabolites of which show some pharmacological activity. Metabolites of calcium channel blockers are excreted by kidneys (80–90%) and partly – by liver.

Calcium channel blockers are used for treatment of all types of angina (variant angina and angina of effort). Derivatives of phenylalkylamine and benzothiazepine are predominantly used in treatment of angina which is accompanied by supraventricular tachycardia. Dihydropyridine derivatives are used in angina which is 50

accompanied by bradycardia, disturbances of atrioventricular conduction, or arterial hypertension.

In addition, calcium channel blockers are used in treatment of hypertensive disease, supraventricular tachyarrhithmias, auricular flutter and atrial fibrillation.

Side effects of calcium channel blockers include headache, dizziness, arterial hypotension, constipations, bradycardia (for phenylalkylamine derivatives) or tachycardia (for dihydropyridine derivatives).

Potassium Channel Activators

This group includes nicorandil and pinacidil . Potassium channel activators open ATP-sensitive potassium channels and promote potassium ions outflow from the cells of smooth muscles. It results in hyperpolarization of membrane and reduction of vessels tone.

Pinacidil relaxes both peripheral and coronary vessels and also decreases afterload. Drug administration is accompanied by reflex tachycardia. In addition, pinacidil decreases the level of cholesterol and triglycerides in the blood. Side effects of pinacidil are headache, tachycardia, hypertrichosis, etc. Drug is used for treatment of angina pectoris and heart failure.

Nicorandil activates potassium channels and increases the synthesis of NO (nitrate-like action). Administration of drug is accompanied by relaxation of coronary, resistive, and capacitive vessels. Both preload and afterload are reduced. Nicorandil causes reflex tachycardia. Drug is used in angina and hypertensive disease. Side effects are headeche, tachycardia, and dyspepsia.

Different Antianginal Drugs Which both Decrease the Myocardium Oxygen Demand and Improve the Blood

Supply

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http://en.wikipedia.org/wiki/ATP-sensitive_potassium_channel

This group includes amiodarone and molsidomine . Amiodarone has antianginal and antiarrhythmic effects.

Mechanism of drug action is blockage of potassium, calcium, and sodium channels. In addition, amiodarone has β- and α-adrenergic blocking activity. Amiodarone is antagonist of glucagon. Administration of amiodarone results in the reduction of heart rate, decrease of blood pressure, increase of coronary blood flow. Consequently, myocardial oxygen demand is decreased. Also, amiodarone improves coronary blood flow.

Amiodarone is administered orally or intravenously slowly. Degree of absorption in gastrointestinal tract is approximately 50%. Amiodarone undergoes biotransformation in the liver. The main rote of amiodarone excretion is bowels. Drug is used for prevention of angina pectoris attacks, for prevention and treatment of both supraventricular and ventricular tachyarrhythmias. Therapeutic effect of drug develops in several weeks after initiation of treatment.

Prolonged courses of treatment with amiodarone may be accompanied by deposition of microcrystals of the drug in the cornea of the eye, pigmentation of the skin, photodermatosis, thyroid dysfunction, bradycardia, and hypotension.

Molsidomine (Corvatone) is able to release NO which is a strong vasodilator also called “endothelium-derived relaxing factor”. Drug selectively relaxes peripheral veins, decreases adhesion and aggregation of thrombocytes, and increases the elasticity of large arteries. Molsidomine decreases both preload and afterload on the heart, reduces myocardial oxygen demand, and increases coronary blood flow.

Molsidomine is administered parenterally, sublingually, and orally. Intestinal absorption of molsidomine is about 60%. Drug does not bind with plasma proteins. In case of oral intake, effect develops in 20–30 minutes. In case of sublingual administration, drug begins to act in 5 minutes. Duration of molsidomine action is 6–8 hours. Biotransformation of molsidomine occurs in liver. Metabolites of molsidomine are excreted through kidneys and liver.

Molsidomine is used for treatment and prevention of angina pectoris attacks, and for treatment of chronic heart failure. 52

Side effects of molsidomine are headache, hyperemia of the person, nausea, spasms of muscles, etc.

Drugs Decreasing Myocardium Oxygen Demand

β-Adrenoceptor Antagonists

β-adrenoceptor antagonists are the main drugs in therapy of majority of cases of angina pectoris.

Depending on selectivity to certain types of -adrenergic receptors, -adrenergic antagonists are classified into the following groups:

1) β1 and 2-adrenoceptor antagonists (nonselective -adre-noceptor antagonists): anaprilinum (propranolol), nadolol , sotalol, oxprenolol , pindolol ;

2) β1-adrenoceptor antagonists (cardioselective -adrenoceptor antagonists): metoprolol , talinolol , atenolol , nebivolol , acebutalol .

Drugs decrease excessive influence of stress and negative

emotions upon cardiovascular system owing to blockage of β1-adrenergic receptors in myocardium. Under the influence of β-adrenoceptor antagonists, the force of cardiac contractions and heart rate are decreased. It results in decrease of myocardium oxygen demand.

It is necessary to note, that β-adrenoceptor antagonists reduce coronary blood circulation. A case of this phenomenon is blockage of β2-adrenergic receptors in coronary vessels (for nonselective agents) and reduction of stroke volume and cardiac output. Therefore, high efficacy of β-adrenoceptor antagonists in ischaemic heart disease is the result of significant reduction of myocardium oxygen demand.

Selective β1-adrenoceptor antagonists are preferable in treatment of ischaemic heart disease because these drugs cause less reduction of coronary and peripheral blood flow.

β-adrenoceptor antagonists are administered orally and pareneterally. The majority of drugs are readily (70–90%) absorbed in

53

gastrointestinal tract. Bioavailability of β-adrenoceptor antagonists is nearly 50%. Biotransformation of drugs occurs in the liver. Degree of binding with plasma proteins for different drugs varies from 5 to 90%. Duration of action for majority of drugs is approximately 8 hours; for metoprolol – 12 hours; for atenolol and pindolol – 24 hours. Lipophilic β-adrenoceptor antagonists are excreted predominantly through the liver; hydrophilic ones – through the kidneys.

Most commonly β-adrenoceptor antagonists are used for treatment of angina of effort in patients with tendency to increase of blood pressure and heart rate. As a rule, selective β-adrenoceptor antagonists are used together with drugs of other groups. β-adrenoceptor antagonists with intrinsic sympathomimetic activity are preferable for treatment of patients with bradycardia and with symptoms of heart failure.

β-adrenoceptor antagonists are also used for treatment of hypertensive disease, supraventricular tachyarrhythmisas, extrasystoles, and thyrotoxicosis.

Side effects of β-adrenoceptor antagonists are bradycardia, conduction disturbances, arterial hypotension, heart failure, bronchoconstriction, worsening of lipid spectrum (drugs increase the level of atherogenic lipoproteins), central nervous system suppression, hypoglycemia, vasospasm of limbs, and dyspeptic disorders.

Sudden stop of β-adrenoceptor antagonists therapy can result in serious aggravation of ischaemic heart disease up to myocardial infarction. Therefore, discontinuation of drug therapy should be gradual.

Bradicardic DrugsBradicardic drugs are alinidine and falipamil . Drugs

significantly decrease heart rate and myocardium oxygen demand. Bradycardia is the result of direct suppressive influence of drugs upon automatism of sinus node (drugs slow down phase of diastolic

54

depolarization). Bradicardic drugs also have antiarrhythmic effect. Drugs don’t influence circulatory dynamics.

Drugs Increasing Oxygen Delivery to Myocardium

Coronary Vasodilating Drugs with Myotropic Action

This group includes such drugs as dipyridamole , papaverine, carbochromen, and no-spa .

Dipyridamole decreases the tone of small resistance vessels owing to inhibition of reuptake of adenosine by cardiac hystiocytes and erythrocytes. Drug also inhibits the activity of adenosine deaminase. It is known, that aminasine is released in hypoxia of myocardium. Adenosine causes marked dilation of coronary arteries. Dipyridamole also suppresses the platelets aggregation and improves microcirculation. Agent doesn’t change the general peripheral resistance. Dipyridamole is used for prevention of angina attacks. It is necessary to note, that in patient with coronary atherosclerosis, dipyridamole doesn’t improve oxygen delivery to ischaemic area. Moreover, agent worsens blood circulation in ischaemic region. It is explained by the fact that in ischaemic area small coronary vessels are relaxed in maximum degree (compensatory reaction). After dipyridamole administration, small vessels are relaxed also in non-ischaemic regions of myocardium. It promotes the reduction of blood circulation in ischaemic area. This phenomenon is called steal syndrome. It is sometimes used to determine the latent coronary insufficiency.

Dipyridamole is administered orally and sometimes parenterally. Side effects are headache, dyspepsia, hypotension, etc.

Papaverine is alkaloid of opium. Drug has low coronary vasodilating activity and short duration of action. Mechanism of action is associated with inhibition of phosphodiesterase that results in increase of intracellular cAMP. Increase of cAMP concentration causes the reduction of calcium level in smooth muscles of vessels

55

and the increase of calcium level in cardiac hystiocytes. Therefore, relaxation of coronary vessels is accompanied by increase of force of cardiac contraction. In addition, papaverine decreases systemic arterial pressure, reduces the tone of cerebral vessels, and relaxes the smooth muscles of inner organs. Papaverine is used for prevention of angina attacks.

Antianginal Drugs with Reflex Action

Validolum is 25–30 % solution of menthol in menthol ether of isovaleric acid. Drug is used sublingually for interruption of slight attacks of angina pectoris. Menthol irritates the cold receptors in oral cavity which results in reflex relaxation of coronary vessels. The antianginal activity of validolum is low. If in 2–3 minutes after drugs intake pain isn’t reduced, patient should take nitroglycerin.

CardioprotectorsTrimetazidine (Preduktal , Vastarel MR) directly

influences upon cardiac hystiocytes in ischaemic area and normalizes their energy balance. Drug effect is due to inhibition of the enzyme 3-ketoacyl-CoA thiolase. Suppression of enzyme activity results in reduction of fatty acid oxidation. This leads to the activation of glucose oxidation, which favourably influences the myocardial function. Trimetazidine is prescribed 2–3 times a day. Drug is well absorbed in gastrointestinal tract and undergoes biotransformation in liver.

Adenosine triphosphate (ATP) participates in different metabolic processes. In interaction with actomyosin, it turns into ADP and inorganic phosphate. This process is accompanied by release of energy used for the heart and anabolic processes. Besides, ATP is considered as one of the mediators of adenosine receptors. In patients with ischaemic heart disease, level of ATP in myocardium is decreased. Administration of ATP increases cerebral and coronary blood supply. Considering that, the penetration of ATP across the 56

cell membranes, value of exogenous ATP as an energy source is questionable. Therefore, the medicine ATP-long was developed, which plays the role of coordinating drug: ATP together with potassium, magnesium, and histidine penetrate inside of cardiac hystiocytes. Intracellular ATP provides anti-ischaemic and antiarrhythmic affect.

Principles of Myocardial Infarction TreatmentMyocardial infarction is acute disease which develops due to

occurrence of one or more foci of heart muscle necrosis as a result of absolute or relative insufficiency of coronary circulation. In the vast majority of cases the main cause of myocardial infarction is atherosclerosis of coronary vessels. As a rule, myocardial infarction is accompanied by severe pain, fear of death, excitement, sharp activation of the sympathoadrenal system, spasm of the coronary and peripheral arteries. It creates additional load upon heart and increases the conflict between oxygen delivery and oxygen demand of myocardium. In 90% of cases, myocardial infarction is accompanied by cardiac arrhythmias and acute heart failure, which can result in ventricular fibrillation and cardiogenic shock. All medical measures in myocardial infarction should be held in a short time.

Opioid analgesics (phentanyl, morphine, promedolum , etc.), tranquilizers (diazepam), and neuroleptics (droperidol) are administered for pain relief, for elimination of fear of death and excitement. If painful syndrome isn’t reduced, opioid analgesic is administered again in 20–30 minutes. If needed, nitrous oxide with oxygen is given to patient.

Nitroglycerin is administered as intravenous infusion for relief of myocardium ischaemia. Effectiveness of this is higher the earlier the drug is introduced. It is necessary to notice, that administration of nitrates is contraindicated in collapse and shock. β-adrenoceptor antagonists are administered for decrease of heart work and reduction of tachycardia. Selective β1-adrenoceptor antagonists – metoprolol or talinolol – are preferable.

57

Lidocaine or amiodarone are administered for prevention or elimination of ventricular tachyarrhythmias.

Dopamine or dobutamine are administered as intravenous infusion for maintenance of myocardial contractile function.

Fibrinolytics (streptokinase, urokinase, alteplase , etc.) are used in the case of thrombosis of coronary artery. These drugs cause lysis of thrombi. For prevention of further thrombosis, anticoagulants (heparine, etc.) are used.

Table 4 – Drugs for prescriptionDrug name Single dose and mode of


Nitroglycerinum Sublingually 0.0005 g at an attack of angina pectoris (it is necessary previously to get to the core of a capsule by teeth);drip intravenously 0.0005–0.001 g in 100 ml of 0.9% NaCl solution

Tablets 0.0005 g;capsules 0.0005 g of 1% oil solution;


Isosorbide mononitrate

Orally 0.02-0.04 g 2–4 times per day

Tablets 0.02 or 0.04 g

Sustac-mite Orally 1 tablet 2 times daily Tablets 2.6 mg Sustac-forte Orally 1 tablet once daily Tablets 6.4 mg Validolum Sublingually 0.05–0.06 g at an

attack of angina pectorisTablets 0.06 g;capsules 0.05 g

Anaprilinum Orally 0.01–0.04 g 3 times per day;intravenously slowly 0.001 g in 10–20 ml of 0.9% solution of NaCl once a day

Tablets 0.01 or 0.04 g;

ampoules 1 or 5 ml of 0.1% solution

Amiodaronum Orally 0.2 g 1–2 times daily;intravenously slowly 0.005 g/kg in 10–20 ml of 0.9% NaCl solution once a day

Tablets 0.2 g;

ampoules 3ml of 5% solution

Verapamilum Orally 0.04–0.08 g 3 times per day;intravenously slowly 0.005–

Tablets 0.04 or 0.08 g;ampoules 2 ml of 0.25% solution

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0.01 g in 10–20 ml of 0.9% NaCl solution

Amlodipinum Orally 0.005–0.01 g once a day


ANTIARRHYTHMIC DRUGS

Cardiac arrhythmias result from alterations in the orderly sequence of depolarization followed by repolarization in the heart. Cardiac arrhythmias may result in alterations in heart rate or rhythm and arise from alterations in impulse generation or conduction. The clinical implications of disordered cardiac activation range from asymptomatic palpitations to lethal arrhythmia.

Pharmacological management of arrhythmias uses drugs that exert effects directly on cardiac cells by inhibiting the function of specific ion channels or by altering the autonomic input into the heart.

Successful antiarrhythmic drug therapy requires a combination of understanding the pathophysiology of the arrhythmia, identification of a drug that can influence the electrophysiological parameters, and careful titration of the drug dose to correct the abnormal electrophysiological events giving rise to the arrhythmia.

Before we begin to consider antiarrhythmic drugs, it is necessary to recollect the most important rules of cardiac electrophysiology.

Figure 1 shows the phases of the cardiac action potential. The characteristic action potential is the result of activation and inactivation of multiple ion channels, which allows the flow of charged ions across the membrane. The ions flow through open channels according to the electrochemical driving forces at any given moment.

The interior of the cardiac muscle cell is electrically negative with respect to the surrounding medium. This difference between the exterior and interior of a myocardial cell results from the action of several energy-requiring pumps, and the presence of large negatively charged intracellular proteins that don’t diffuse freely across the

59

membrane. The prominent example of pump is Na+,K+-ATPase, which pumps Na+ out of and K+ into the cell in a ratio of 3Na+ to 2K+.

Figure 1 - Cardiac action potential

The action potential has been divided into five phases: rapid depolarization (phase 0), early repolarization (phase 1), plateau (phase 2), rapid repolarization (phase 3), and finally the resting phase in myocytes or slow diastolic depolarization (phase 4). The latter is a property in cells with the potential for automaticity.

Phase 0 of the action potential encompasses the rapid depolarization of the myocyte induced principally by the opening of the voltage gated sodium channels. The sodium channels open rapidly in response to membrane depolarization and close within 1 to 2 milliseconds. The conformation of the channels changes, and they enter an inactivated state.

Phase 1. At the peak of the action potential upstroke, a short rapid period of repolarization occurs and the membrane potential returns toward 0 mV. This produces a spike and dome configuration of the action potential and is a result of inactivation of the fast inward

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sodium current (INa) and activation of a short-lived outward current called the transient outward current. Transient outward current composed of two distinct channels carried by either potassium or chloride.

Phase 2 (action potential plateau) is characterized by a net balance between inward (depolarizing) and outward (repolarizing) ion currents maintaining the myocyte in a depolarized state. During this phase, Ca2+ enters the cell, causing Ca2+ release from intracellular stores and linking electrical depolarization with mechanical contraction. Ca2+ enters the cell through voltage-dependent channels highly selective for Ca2+ that open when the membrane is depolarized above -40 mV. The channel (L-type calcium channel) possesses slow inactivation kinetics resulting in a long-lasting current.

Outward repolarizing K+ currents oppose the effect of the inward Ca2+ current on the plateau phase. These K+-channels are voltage sensitive, with slow inactivation kinetics.

Phase 3 (late phase of repolarization). This phase is a result of work of Na,K-ATPase, which returns the cell membrane to the resting potential. Alongside with Na,K-ATPase the Ca-pump works too. This pamp deletes surplus of Ca2+ from the cell. This is rapid process of repolarization which returns the cell to the resting membrane potential.

Phase 4. In normal atrial and ventricular myocytes, phase 4 is electrically stable, with the resting membrane potential held at approximately -90 mV and maintained by the outward potassium leak current and ion exchangers. It is during phase 4 that the Na+

channels necessary for atrial and ventricular myocyte depolarization recover completely from inactivation. In myocytes capable of automaticity, the membrane potential slowly depolarizes during this period to initiate an action potential. The cause of phase 4 in SA-node is penetration of Ca2+ ions through slowing calcium channels into the cells during diastole. It is necessary to indicate, that in ischaemic locus the cause of spontaneous depolarization is penetration of sodium ions into the cells through sodium channels (the so-called “slow” Na-current).

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Myocytes within the sinoatrial node possess the most rapid intrinsic rate of automaticity; therefore, the sinoatrial node serves as the normal pacemaker of the heart. Specialized cells within the atria, atrioventricular (AV) node, and His-Purkinje system are capable of spontaneous depolarization, albeit at a slower rate. More rapid rate of depolarization of the sinoatrial nodal cells normally suppresses all of the other cells with the potential for automaticity. The other cells will become pacemakers when their intrinsic rate of depolarization becomes greater than that of the sinoatrial node or when the pacemaker cells within the sinoatrial node are depressed. When impulses fail to conduct across the AV node to excite the ventricular myocardium (heart block), spontaneous depolarization within the His-Purkinje system may become the dominant pacemaker maintaining cardiac rhythm and cardiac output.

It is necessary to say some words about the role of nervous system in control of automaticity. The rate of pacemaker discharge within these specialized myocytes is influenced by the activity of both divisions of the autonomic nervous system. Increased sympathetic nerve activity to the heart, the release of catecholamines from the adrenal medulla, or the administration of adrenomimetic drugs will cause an increase in the rate of pacemaker activity through stimulation of β-adrenoceptors on the pacemaker cells.

The parasympathetic nervous system, through the vagus nerve, inhibits the spontaneous rate of depolarization of pacemaker cells. The release of acetylcholine from cholinergic vagal fibres increases potassium conductance in pacemaker cells, and this enhanced outward movement of K+ results in more negative potential or hyperpolarization, of the sinoatrial cells. Thus, during vagal stimulation, the threshold potential of the sinoatrial node pacemaker cells is achieved more slowly and the heart rate is slowed.

Cardiac Conduction. The cardiac impulse begins in the sinoatrial node in the high lateral right atrium near the junction of the superior vena cava and the right atrium. Excitation leaves the sinoatrial node and spreads throughout the atrium. After the excitatory wave has spread throughout the atrium, it enters the atrioventricular node. Conduction velocity slows significantly as the 62

electrical signal enters the AV node, where cellular depolarization depends on L-type Calcium current rather than inward sodium current. After passing through the AV node, the electrical signal is carried via the right and left bundle branches to the body of the right and left ventricles. The principal determinant of conduction velocity within the myocardium is the maximum rate of depolarization of phase 0 the action potential in individual myocytes. One common clinical cause of abnormal depolarization of myocardial tissue is ischaemia resulting from coronary disease.

Refractory Period. Depolarized cardiac cells are transiently unresponsive to any activation stimuli. During this interval, most Na+

and some Ca2+ channels are inactivated, and the cardiac myocytes are said to be refractory. The refractory period is subdivided into three phases, absolute, effective, and relative. The absolute refractory period is the time from the onset of the action potential until a stimulus is able to evoke a local nonconducted response. During this period, the cell is completely refractory to any stimulus regardless of its intensity. The effective refractory period (ERP) begins with the onset of the action potential, incorporates the absolute refractory period, and ends when an excitatory stimulus is able to generate a conducted signal. The ERP is determined as the shortest interval between two stimuli of equal intensity that results in the generation of a propagated response. The relative refractory period begins with the completion of the ERP and continues through the time in which a signal may be conducted slowly, prior to obtaining normal propagation of the signal. Since the cell is not fully repolarized during the relative refractory period, a stronger than normal stimulus is needed to produce depolarization and conduction of a propagated impulse. Conduction impulses generated during the relative refractory period will propagate slowly and may contribute to the genesis of cardiac arrhythmias.

Mechanisms of ArrhythmiasDisturbances in the orderly formation and conduction of the

cardiac impulse may result in heart rates that are either too fast (tachycardia), or too slow (bradycardia). In general,

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bradyarrhythmias result from the failure of impulse generation within the sinoatrial node or failure of the excitatory wave-front to conduct from the atrium to the ventricle through the atrioventricular node. In general, bradyarrhythmias are not amenable to long-term pharmacological therapy and may require permanent cardiac pacing. Tachyarrhythmias, conversely, frequently may be palliated with long-term medical therapy. In pathogenesis both brady- and tachyarrhythmias can took place both disturbances of innervation and disturbances of ionic balance. The increase of parasympathetic tone leads to development of bradyarrhythmia, while the rise of sympathetic tone can cause the tachyarrhythmia. Roughly simplifying, it is possible to tell that at tachyarrithmias take place the increased influx of ions of Na+ and Ca2+, and enhanced of K+ outflow. In any cases the disturbances of automaticity and conductivity (or both processes) are develop.

Classification of Antiarrhythmic Drugs

The antiarrhythmic drugs are divided into the following groups:I. Drugs for treatment of tachyarrhythmias. 1. Drugs which act directly upon the conductive system of the

heart and upon the contractive myocardium. 1.1. Sodium channel blockers (or class I according to classification of Vaughan Williams – one of the most widely used classification scheme of antiarrhythmic drugs):

1.1.1. Subgroup IA: quinidine sulphate, novocainamidum (procainamide), disopyramide, ajmalin.

1.1.2. Subgroup IB: lidocaine, dipheninum (phenytoin).1.1.3. Subgroup IC: flecainide, propafenone,

aetmozinum (moracizine), ethacizine. 1.2. Calcium channel blockers (class IV): verapamil , dilt iazem . 1.3. Drugs increasing the duration of action potential (class III): amiodarone, ornidum . 1.4. Miscellaneous antiarrhythmic agents:1.4.1. Potassium- and magnesium-containing drugs: potassium chloride, Asparcamum, Panangin .

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1.4.2. Adenosine . 1.4.3. Cardiac glycosides (class V): digoxin, digitoxin, celenidum .

2. Drugs which influence upon efferent innervation of the heart. 2.1. Drugs decreasing the adrenergic influences – β-adrenoceptor antagonists (class II): anaprilinum, talinolol , metoprolol , etc. 2.2. Drugs increasing the cholinergic influences (class VI): cholinesterase inhibitors (edrophonium), and α-adrenoceptor agonists (mesatonum). II Drugs for treatment of bradyarrhythmias.

1. Drugs increasing the adrenergic influences.1.1. β-adrenoceptor agonists: isadrinum . 1.2. Sympathomimetic: ephedrine .2. Drugs decreasing the cholinergic influences – M-cholinoceptor

antagonists: atropine, etc.3. Hormonal agent: glucagon .

Blockers of Sodium Channels These antiarrhythmic drugs are characterized by their ability to

block the voltage-gated sodium channel. These agents may block the channel when it is in either open or inactivated state. Inhibition of the sodium channel results in a decrease in the rate of rise of phase 0 of the cardiac membrane action potential and slowing of the conduction velocity. Additionally, these drugs, through inhibition of the sodium channel, require more hyperpolarized membrane potential (more negative) to be achieved before the membrane becomes excitable and propagate an excitatory stimulus. As a result, the ERP of fast-response fibres is prolonged.

The antiarrhythmic drugs of this group suppress the abnormal automaticity resulting from myocardial damage. Suppression of abnormal automaticity permits the sinoatrial node again to assume the role of the dominant pacemaker.

The antiarrhythmic agents that belong to class I are divided into three subgroups with slightly different properties.

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Class IA. These drugs decrease the permeability of cells membranes for Na+ through the “slow” Na-channels in ischaemic focus. This effect causes the slowing of velocity of spontaneous depolarization in these focuses (phase 4). Besides, these drugs oppress penetration of Na+ and Ca2+ ions through the “fast” channels (phase 0) and outflow of K+ ions from cells during repolarization (phase 2). These effects cause the prolongation of effective refractory period. As a result, the duration of refractory period in ectopic focus become equal to duration of refractory period in normal parts of myocardium. Drugs of group IA cause prolongation of P-Q, QRS, and QT intervals. These drugs oppress the contractility of the left ventricle and decrease the blood pressure.

The typical representatives of class IA are quinidine, novocainamide, and disopyramide .

Quinidine is an alkaloid obtained from various species of Cinchona or its hybrids, from Remijia pedunculata, or from quinine. Quinidine was one of the first clinically used antiarrhythmic agents. Because of the high incidence of ventricular proarrhythmia associated with its use and numerous other equally efficacious agents, quinidine is now used sparingly.

Quinidine has M-cholinoblockering properties which can cause a slight increase in heart rate. The anticholinergic properties of quinidine prevent both vagally mediated prolongation of the AV node refractory period and depression of conduction velocity; these effects lead to enhancement of A-V transmission. But quinidine direct electrophysiological actions on the A-V node are to decrease conduction velocity and increase the ERP. The summary result depends from dose and vagal tone.

At normal therapeutic plasma concentrations, quinidineprolongs the PR, the QRS, and the QT intervals.

Quinidine may depress cardiac contractility sufficiently to result in a decrease in cardiac output, a significant rise in left ventricular end-diastolic pressure, and overt heart failure. Quinidine can relax vascular muscle directly as well as indirectly by inhibition of α1-adrenoceptors.

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Quinidine has almost complete absorption at oral administration. Duration of quinidine action is 6–8 hours.

The indications for use of quinidine include extrasystoles that have an atrial, AV junctional, or ventricular origin; restoration of normal sinus rhythm in atrial flutter and atrial fibrillation; termination of ventricular tachycardia.

The most common adverse effects associated with quinidine administration are diarrhoea (is observed in 35% of the patients), upper gastrointestinal distress (25%), and light-headedness (15%). Other relatively common adverse effects include fatigue, palpitations, headache, angina-like pain, and rash. In some patients, quinidine administration may bring on thrombocytopenia. The cardiac toxicity of quinidine includes AV and intraventricular block, and depression of myocardial contractility. One of the few absolute contraindications for quinidine is complete AV block. It is also contraindicated in congestive heart failure and hypotension. The use of quinidine should be avoided in patients who previously showed evidence of quinidine-induced thrombocytopenia.

Novocainamidum (procainamide) is a derivative of the local anaesthetic agent novocainum (procaine). Novocainamidum has a longer half-life, does not cause CNS toxicity at therapeutic plasma concentrations, and is effective orally. Novocainamidum is a particularly useful antiarrhythmic drug.

The direct and indirect actions of novocainamidum on cardiac electrophysiology are similar to those of quinidine. The hemodynamic alterations produced by novocainamidum are similar to those of quinidine but are not as intense. The hypotensive effects of novocainamidum are less pronounced after intramuscular administration and seldom occur after oral administration.

The oral bioavailability of novocainamidum is 75–95%. The duration of action is 4–10 hours.

Novocainamidum is useful in the treatment of premature atrial contractions, paroxysmal atrial tachycardia, and atrial fibrillation. Procainamide can decrease the occurrence of all types of active ventricular dysrhythmias with acute myocardial infarction

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which are free from AV dissociation, serious ventricular failure, and cardiogenic shock. About 90% of patients with ventricular premature contractions and 80% of patients with ventricular tachycardia respond to procainamide administration.

Novocainamidum administration can results in the following adverse effects and complications. Acute cardiovascular reactions to novocainamidum administration include hypotension, AV block, intraventricular block, ventricular tachyarrhythmias. Long-term drug use leads to increased antinuclear antibody titres in more than 80% of patients; more than 30% of patients receiving long-term novocainamidum therapy develop a clinical lupus erythematosus-like syndrome. The agranulocytosis can develop as a result of therapy by novocainamidum .

Contraindications to novocainamidum are similar to those for quinidine. Novocainamidum should not be administered to patients who have shown procaine or novocainamidumhypersensitivity and should be used with caution in patients with bronchial asthma. Prolonged administration should be accompanied by haematological studies, since agranulocytosis may occur.

Disopyramide can suppress atrial and ventricular arrhythmias and is longer acting than other drugs in its class. The effects of disopyramide on the myocardium and specialized conduction tissue are a composite of its direct actions on cardiac tissue and its indirect actions mediated by competitive blockade of muscarinic cholinergic receptors. The direct depressant actions of disopyramide on the sinoatrial node are antagonized by its anticholinergic properties, so that at therapeutic plasma concentrations, either no change or a slight increase in sinus heart rate is observed. Both the anticholinergic and direct depressant actions of disopyramide on sinus automaticity appear to be greater than those of quinidine.

Disopyramide depresses conduction velocity and increases the ERP of the AV node. Its anticholinergic actions, however, produce an increase in conduction velocity and decrease in the ERP. The net effect of disopyramide on AV nodal transmission therefore will be determined by the sum of its direct depression and indirect facilitation of transmission. 68

Disopyramide directly depresses myocardial contractility. The negative inotropic effect may be detrimental in patients with compromised cardiac function. Some patients develop overt congestive heart failure.

The duration of action of disopyramide is 1.5–8.5 hours. Oral bioavailability is 87–95%.

The indications for use of disopyramide are ventricular extrasystoles, and episodes of ventricular tachycardia. Disopyramide is used for prophylaxis of arrhythmias during surgery on heart or vessels.

The major toxic reactions to disopyramide administration include hypotension, congestive heart failure, and conduction disturbances. Most other toxic reactions (such as dry mouth, blurred vision, constipation) can be attributed to the anticholinergic properties of the drug. CNS stimulation and hallucinations are rare.

Disopyramide should not be administered in cardiogenic shock, preexisting second- and third-degree AV block, uncompensated heart failure or severe hypotension, or known hypersensitivity to the drug.

Members of class IB do not influence on the SA-node and atrium. Lidocaine and dipheninum influence only on level of ventricles, where they block the Na+ channels. As a result of this action, the slowing of phase 4 in ischaemic focus develops. Besides, drugs increase permeability of membranes for K+ ions. The outflow of K+ ions is facilitated. This phenomenon causes the shortening of phase 2. Therefore, drugs decrease the duration of effective refractory period. Members of class IB do not cause the depression of contractility of the left ventricle.

Lidocaine was introduced as a local anaesthetic. Lidocaine is an effective sodium channel blocker, binding to channels in the inactivated state. Lidocaine, like other IB agents, acts preferentially in ischaemic tissue, causing conduction block and interrupting reentrant tachycardias.

Lidocaine does not depress myocardial function, even in the face of congestive failure, at usual doses. Lidocaine is commonly administered intravenously and intramuscularly. The oral way is used

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rarely. The oral bioavailability of lidocaine is low and equals 30–40%. Duration of action at intramuscular administration is 60–90 minutes, and at intravenous administration – 10–20 minutes.

Lidocaine is useful in the control of ventricular arrhythmias, particularly in patients with acute myocardial infarction and with digitalis intoxication.

The most common toxic reactions seen after lidocaineadministration affect the CNS. Drowsiness is common. Some patients have paresthesias, disorientation, and muscle twitching. In some cases psychosis, respiratory depression, and seizures can be observed. Lidocaine may produce clinically significant hypotension, but this is exceedingly uncommon if the drug is given in moderate dosage.

Contraindications include hypersensitivity to local anaesthetics of the amide type, severe hepatic dysfunction, a history of grand mal seizures due to lidocaine, and age 70 or older. Lidocaine is contraindicated in the presence of second- or third-degree heart block.

Dipheninum (phenytoin) was originally introduced for the control of convulsive disorders but has now also been shown to be effective in the treatment of cardiac arrhythmias. Dipheninum is effective in the treatment of ventricular arrhythmias. It is particularly effective in treating ventricular arrhythmias associated with digitalis toxicity, acute myocardial infarction, open-heart surgery, anaesthesia, cardiac catheterization, and angiographic studies. The ability of dipheninum to improve digitalis-induced depression of AV conduction is a special feature that contrasts with the actions of other antiarrhythmic agents.

Acute adverse effects, seen after phenytoin administration, usually result from overdosage. They are generally characterized by nystagmus, ataxia, vertigo, and diplopia. The blood dyscrasias and hepatic necrosis can develop. There is evidence that phenytoin is teratogenic in humans, but the mechanism is not clear. However, it is known that phenytoin can produce a folate deficiency, and folate deficiency is associated with teratogenesis.

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Dipheninum either should not be used or should be used cautiously in patients with hypotension, severe bradycardia, high-grade AV block, severe heart failure, or hypersensitivity to the drug.

The drugs of class IC have the most potent sodium channel blocking effects. These drugs produce a marked depression in the rate of rise of the membrane action potential and have minimal effects on the duration of membrane action potential and ERP of ventricular myocardial cells. This subgroup includes such drugs as propafenone, aetmozinum, and ethacizine . Members of IC class are most commonly used for treatment of ventricular tachyarrhythmias and have the significant proarrhythmic properties.

-Adrenoceptor Antagonistsβ-adrenoceptor antagonists competitively inhibit β-

adrenoceptors and inhibit catecholamine-induced stimulation of cardiac β1-receptors. In addition, some members of the group (for example, propranolol and acebutalol) influence Na+ permeability in phases 4 and 0. The latter actions have been called membrane-stabilizing effects. β-blockers decrease the oxygen demand of myocardium and therefore promote the normalization of ionic balance.

Anaprilinum (propranolol , inderal) is the prototype β-blocker. It decreases the effects of sympathetic stimulation by competitive binding to β-adrenoceptors. As antiarrhythmic agent, anaprilinum has two separate effects. The first is a consequence of the drug β-blocking properties and the subsequent removal of adrenergic influences on the heart. The second is associated with its direct myocardial effects (membrane stabilization). The latter action, especially at high clinically employed doses, may account for its effectiveness against arrhythmias in which enhanced β-receptor stimulation does not play a significant role in the genesis of the rhythm disturbance.

Anaprilinum slows the spontaneous firing rate of sinoatrial node by decreasing the slope of phase 4 depolarization. Membrane

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responsiveness of atrial cells and action potential amplitude are reduced, and excitability is decreased. Conduction velocity is reduced. The depressant effects of anaprilinum on the AV node are more pronounced than direct depressant effects of quinidine are. This is due to anaprilinum dual actions of β-blockade and direct myocardial depression. Anaprilinum administration results in a decrease in AV conduction velocity and increase in the AV nodal refractory period. Anaprilinum decreases Purkinje fibre membrane responsiveness and reduces action potential amplitude. His-Purkinje tissue excitability also is reduced. These changes result in a decrease in His-Purkinje conduction velocity.

β-adrenoceptor antagonists are indicated in the management of a variety of cardiac rhythm disorders. In selected cases of sinus tachycardia caused by anxiety, pheochromocitoma, or thyrotoxicosis, β-blockade will reduce the spontaneous heart rate. Anaprilinum can help control the ventricular rate in patients with atrial tachycardia, supraventricular extrasystoles, atrial flutter or atrial fibrillation.

The arrhythmias associated with halothane or cyclopropane anaesthesia have been attributed to the interaction of the anaesthetic with catecholamines, and they have been suppressed by intravenous administration of propranolol. An increase in circulating catecholamines has been observed in patients with acute myocardial infarction.

β-blockers are administered for treatment of ventricular extrasystoles and ventricular tachycardia.

The toxicity associated with β-blockers are for the most part related to them primary pharmacological action, inhibition of the cardiac β-adrenoceptors. These adverse effects are known to you (see the lecture about adrenergic drugs) and now we shall not consider them.

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Drugs Causing Repolarization Slowing (Class III)Class III antiarrhythmic drugs prolong the membrane action

potential by delaying repolarization. Amiodarone is an iodine-containing chemical substance.

Amiodarone blocks the K+ channels and inhibits the outward potassium current. Additionally, amiodarone blocks sodium and Ca2+

channels and is a noncompetitive β-receptor blocker. Amiodarone causes the significantly slowing of phase 3 repolarization and prolongs the duration of effective refractory period in all cardiac tissues. Amiodarone decreases the slope of phase 4 depolarization. Amiodarone increases AV nodal conduction time and refractory period. Amiodarone is effective for the treatment of most arrhythmias.

Amiodarone relaxes vascular smooth muscle. One of its most prominent effects is on the coronary circulation, reducing coronary vascular resistance and improving regional myocardial blood flow. In addition, its effects on the peripheral vascular bed lead to a decrease in left ventricular stroke work and myocardial oxygen consumption. Therefore, amiodarone improves the relationship between myocardial oxygen demand and oxygen supply.

The pharmacokinetics of amiodarone is characterized by the very slow beginning of action. Effect develops from 2–3 days, up to 2–3 months. The duration of action proceeds from weeks to months. Plasma half-life of amiodarone with chronic administration is equal 26–107 days. Drug is introduced by oral or intravenous way, as a rule, 1 time per day.

Amiodarone is indicated for treatment and for prophylaxis both atrial and ventricular tachyarrhythmias. But amiodarone use is limited by the multiple and severe noncardiac side effects that it produces.

Amiodarone most significant adverse effects include hepatitis, worsening of congestive heart failure, thyroid dysfunction, and pulmonary fibrosis. Pulmonary fibrosis is frequently fatal and may not be reversed with discontinuation of the drug. Corneal micro-deposits develop in most adults receiving amiodarone. As many as 10% of patients complain of halos or blurred vision. The corneal

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micro-deposits are reversible with stoppage of the drug. Photosensitization occurs in 10% of patients. With continued treatment, the skin assumes a blue-gray colouration. The discolouration of the skin regresses slowly after discontinuation of amiodarone. Under action of amiodarone euthyroid state can develop. Manifestations of both hypothyroidism and hyperthyroidism have been reported.

Amiodarone is contraindicated in patients with sick sinus syndrome and may cause severe bradycardia and second- and third-degree atrioventricular block. Amiodarone crosses the placenta and will affect the fetus, as evidenced by bradycardia and thyroid abnormalities. The drug is secreted in breast milk.

Bretylium was introduced for the treatment of essential hypertension but subsequently was shown to suppress the ventricular fibrillation often associated with acute myocardial infarction.

Bretylium slows the penetration of Ca2+ ions during phase 2 of action potential. Besides, the drug has sympatholitic properties.

Bretylium is used for treatment of ventricular tachyarrhythmias, especially at acute period of myocardial infarction, if introduction of lidocaine is not effective. Bretylium is not to be considered a first-line antiarrhythmic agent. The most important side effects associated with the use of bretylium is hypotension. Nausea, vomiting, and diarrhoea were reported in intravenous administration and can be minimized by slow infusion. The use of bretylium should be limited to no longer than 5 days.

Calcium Channel Blockers (Class IV)Class IV drugs block the slow inward Ca2+ current (L-type

calcium channel) in cardiac tissue. The most pronounced electrophysiological effects are exerted on cardiac cells that depend on the Ca2+ channel for initiating the action potential, such as those found in the sinoatrial and atrioventricular nodes. Drugs decrease the rate of rise and slope of the slow diastolic depolarization, the maximal diastolic potential, and the membrane potential at the peak

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of depolarization in the sinoatrial node. Drugs impair conduction through the AV node and prolong the AV nodal refractory period, thereby reducing the ability of the atrioventricular node to conduct rapid impulses to the ventricle. Drugs have no effect on the His-Purkinje system.

This action may terminate supraventricular tachycardias and can slow conduction during atrial flutter or fibrillation. The members of this class, which are used as anthiarrhythmic drugs, are verapamil and dilt iazem .

Verapamil in addition to its use as an antiarrhythmic agent has been employed extensively in the management of angina pectoris. Usual intravenous doses of verapamil are not associated with marked alterations in arterial blood pressure, peripheral vascular resistance, heart rate, left ventricular end-diastolic pressure, or contractility.

Oral administration of verapamil is well tolerated by most patients. Most complains are of constipation and gastric discomfort. Other complains include vertigo, headache, and nervousness. Verapamil must be used with extreme caution or not at all in patients who are receiving β-adrenoceptor antagonists. The use of verapamilin children less than 1 year of age is controversial.

The antiarrhythmic actions and uses of dilt iazem are similar to those of verapamil.

Cardiac Glycosides (Class V)Digitalis glycosides, especially digoxin , because of their

positive inotropic effect, are widely used for treatment of patients with congestive heart failure. They also continue to be used for the management of patients with supraventricular arrhythmias. The direct effect of digitalis on the electrophysiology of the myocytes is the slope increase of phase 4 depolarization. This effect enhances automaticity. The principal antiarrhythmic effect is achieved via prominent vagotonic actions. The vagotonic influence leads to inhibition of Ca2+ currents in the AV node and activation of acetylcholine-sensitive potassium channels in the atrium (these

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channels are not present in the ventricle). This results in a slowing of conduction through the AV node, hyperpolarization of the resting membrane potential, and shortening of the refractory period in atrial tissue. The principal antiarrhythmic actions are associated with the effects on the AV node. Digitalis can therefore be used on reentrant arrhythmias that use the AV node as one limb of the circuit and for limiting atrioventricular conduction during rapid atrial arrhythmias, such as atrial fibrillation.

Digitalis glycosides have theoretical advantages over other drugs that limit conduction through the AV node, by providing a positive inotropic effect on the ventricles.

Drugs Increasing the Cholinergic Influences (Class VI)

Drugs increasing the cholinergic influences include cholinesterase inhibitor edrophonium and α-adrenoceptor agonist mesatonum. These drugs are used seldom for the treatment of supraventricular tachyarrhythmias.

Miscellaneous Antiarrhythmic AgentsAdenosine is an endogenous nucleoside that is a product of

the metabolism of adenosine triphosphate. It is used for the rapid termination of supraventricular arrhythmias following rapid bolus dosing.

Adenosine receptors are found on myocytes in the atria and sinoatrial and atrioventricular nodes. Stimulation of these receptors acts via G-protein signaling cascade to open acetylcholine-sensitive outward potassium current. This leads to hyperpolarization of the resting membrane potential, decrease in the slope of phase 4, and shortening of the action potential duration. The effects on the AV node may result in a conduction block and termination of tachycardias that use the AV node as a limb of reentrant circuit. Adenosine does not affect the action potential of ventricular

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myocytes because the adenosine-stimulated potassium channel is absent in ventricular myocardium. The most profound effect of adenosine is the induction of an atrioventricular block within 10 to 20 seconds of administration. Mild sinus slowing may be observed initially followed by sinus tachycardia. Adenosine is approved for the acute management and termination of supraventricular tachyarrhythmias. Adverse effects to the administration of adenosine are fairly common. These are flushing, chest pain, and dyspnoea. Adenosine may induce profound bronchospasm in patients with reactive airway disease. This effect may last for up to 30 minutes despite the short half-life of the drug. Patients with second- or third-degree atrioventricular block should not receive adenosine.

Magnesium sulfate may be effective in terminating refractory ventricular tachyarrhythmia. Digitalis-induced arrhythmias are more likely in the presence of magnesium deficiency. Magnesium sulfate can be administered orally, intramuscularly, or intravenously.

Salts of potassium (for example, potassium chloride, “Panangin”, “Asparcamum”) are widely used for treatment of different tachyarrhytmias. The action of potassium is similar to those of stimulation of nervus vagus. In acute cases of tachyarrhythmias the solution of potassium chloride is introduced drip intravenously under the close control of ECG.



Drug product

Chinidini sulfas Orally 0.1–0.3 g 2–3 times per day.


Novocainamidum

Orally, intramuscularly, or intravenously 0.25–0.5 g 1–3 times per day

Tablets 0.25 or 0.5 g;ampoules 5 ml of 10% solution

Kalii chloridum Intravenously drop-by-drop 2 g in 450 ml of water for injection

Ampoules 50 ml of 4% solution

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“Asparcamum” or “Pananginum”

Orally 1–2 tablets 3 times per day

Tablets

Lidocainum Intravenously drop-by-drop 0.05–0.1 g

Ampoules 2 ml of 10% solution and 2 or 10 ml of 2% solution

Dipheninum Orally 0.117 g 1–3 times per day

Tablets 0.117 g

Anaprilinum Orally 0.01–0.04 g 3 times per day;intravenously slowly 0.001 g in 10–20 ml of 0.9% solution of NaCl once a day


ampoules 1 or 5 ml of 0.1% solution

Amiodaronum Orally 0.2 g 1–2 times per day;intravenously slowly

0.005 g/kg in 10–20 ml of 0.9% NaCl solution once a day

Tablets 0.2 g;

ampoules 3 ml of 5% solution

Verapamilum Orally 0.04–0.08 g 3 times per day;intravenously slowly 0.005–0.01 g in 10–20 ml of 0.9% NaCl solution



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INDEX

A

Acebutalol 28, 48, 56, 75Acetylcysteine 10–12 Adenosine 6, 57, 59, 68, 81Adenosine triphosphate 59Adrenaline 2, 3, 43, 45Aetmozinum 68, 75Ajmalin 67Alinidine 48, 57Alteplase 61Ambroxol 10–12Amiloride 35Aminazine 15Aminazinum 43Amiodarone 48, 54, 60, 68, 77, 78Amlodipine 30, 48, 51, 52Amrinone 23, 24Anaprilinum 28, 29, 48, 55, 68, 75,

76Angiotensinamide 44, 45Antifoamsilane 15Apressinum 41Arfonade 38Asparcamum 25, 68, 81, 82Asparkam 22Atenolol 28, 29, 55, 56Atropine 2, 23, 68

B

Beclomethasone 6Benazepril 32, 33Bendazole 42Benzohexonium 38Betaxolol 28Bromhexinum 10–12Butamirate 13

C

Camphor 43

Candesartan 34Captopril 15, 32, 33, 43Carbochromen 48, 57Celanidum 17, 19, 20Celenidum 68Charcoal 22Cholestyramine 22Chymotrypsin 10–12Clentiazem 31, 51Clonidine 37, 38Clopamide 35Clophelinim 38Clophelinum 37, 38, 42, 43, 46Codeine 13Coffeinum 43Cordiaminum 43Corglycon 17, 19–21Cromoglycate sodium 7, 8

D

Desoxyribonuclease 10, 11Dexamethasone 15Diazepam 60Diazoxide 40–42Dibazolum 42, 43Dichlothiazidum 35Digitoxin 17, 19, 20, 68Digoxin 17, 19, 20, 68, 80Diltiazem 30, 48, 51, 52, 68, 79Dipheninum 23, 68, 73, 74Dipyridamole 48, 57, 58Disopyramide 67, 69, 72, 73Dobutamine 21–23, 44, 60Dopamine 21–23, 44, 60Doxazosin 36, 37Droperidol 43, 60

E

Edrophonium 68, 80

79

Elecampane 10Emopamil 31, 51, 52Enalapril 15, 32, 33, 43Ephedrine 2–4, 43, 68Erynitum 47Ethacizine 68, 75Ethacrinic acid 35Ethyl alcohol 15Ethylmorphine 13Euphillinum 2, 6Extract of Rhodiola 43Extracts of Eleuterococcus 43

F

Falimint 13Falipamil 48, 57Felodipine 30, 51Fenigidin 2Fenoterol 2, 4Flecainide 68Flunisolid 6Formoterol 2, 4Fosinopril 32Furosemide 15, 35, 42

G

Gallopamil 30, 47, 51Glaucine 13, 14Glucagon 54, 68Glucose 20, 22, 59Grass of Labrador-tea 10Grass of Thermopsis 10

H

Heparine 61Hydralazine 41Hygronium 38

I

Indapamide 35Inderal 75

Infusion of adonis herb 17Insulin 22, 41Ipratropium bromide 2, 5Irbesartan 34Isadrinum 2, 4, 68Isosorbide dinitrate 47, 50Isosorbide mononitrate 47, 50

K

Ketotifen 7, 8Korgard 28

L

Labetalol 42Lasix 15Leaves of plantain 9Levosimendan 23, 24Libexinum 13, 14Licorice 10Lidocaine 23, 60, 68, 73, 74, 78Lisinopril 32, 33Losartan 34

M

Magnesium sulfate 22, 42, 81Magnesium sulphate 42Mesatonum 44, 68, 80Metacinium 2, 5Methyldopa 37, 38Metoprolol 28, 48, 55, 56, 60, 68Milrinone 23, 24Minoxidil 40Molsidomine 48, 54, 55Montelukast 2, 9Moracizine 68Morphine 13, 15, 60Mucaltinum 9

N

Nadolol 28, 29, 48, 55Naftopidil 31, 51, 52

80

Nebivolol 28, 48, 56Nedocromil-sodium 7, 8Nicardipine 31, 48, 51Nicorandil 48, 53Nifedipine 30, 32, 43, 47, 51, 52Nitroglycerin 15, 42, 47, 49, 50, 51,

59, 60Nitrong 47Nitroprusside 15Nitrosorbidum 47, 50Noradrenaline 3, 23, 29, 36, 39, 40,

43, 45Nospa 48Novocainamide 69Novocainamidum 67, 71, 72

O

Octadine 39, 40Orciprenaline 2Ornidum 68Oxeladine 13Oxodolinum 35Oxprenolol 28, 29, 48, 55

P

Panangin 22, 68, 81Pantocrinum 43Papaverine 42, 48, 57, 58Pentaminum 38, 42Perindopril 32, 33Pertussinum 9Phentanyl 60Phentolamine 2, 15, 36Phenytoin 68, 74, 75Pinacidil 48, 53Pindolol 28, 29, 55, 56Pirilenum 38Pituitrinum 44Platyphyllin 2, 5Polarizes mixture 22Polyglucinum 44Potassium chloride 22, 68, 81, 82

Potassium iodide 10Prazosin 2, 36, 37Prednisolon 15Preduktal 59Procainamide 67, 71Promedolum 60Propafenone 68, 75Propranolol 28, 55, 75, 76Pyrroxane 2, 36

Q

Quinidine 67, 69–72, 76Quinidine sulphate 67

R

Ramipril 32, 33Reserpine 39, 40Rheopolyglucinum 44Root of ipecacuanha 10Root of marshmallow 9Root of milkwort 10

S

Salbutamol 2Salmeterol 2, 4Sodium benzoate 10Sodium hydrocarbonate 10, 11Sodium nitroprusside 41, 42Sotalol 28, 55Spironolactone, 35Streptokinase 61Strophanthin 17, 19–21Strophantin 44Sulfokamfokain 43Sulmazol 23, 24Sustac-forte 47Sustac-mite 47

T

Talinolol 28, 48, 55, 60, 68Tannin 22

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Telmisartan 34Terazosin 36Terbutaline 2, 4Terpinhydrate 10Theophyline 2Tinctures of Ginseng 43Tinctures of Schizandra 43Torsemide 35Trandolapril 32Triamcinolone 6, 15Triamterene 35Trilon B 22Trimetazidine 59Trinitrolong 47Tropaphenum 15, 36Trypsin 10–12Tussuprex 13

U

Unithiolum 22Urokinase 61

V

Validolum 58, 61Vasopressin 33, 44Vasotec 33Vastarel 59Vensarinone 24Verapamil 30, 32, 47, 51, 52, 68, 79Vesnarione 23

Z

Zafirlukast 2, 9Zileuton 9

82

REFERENCES1. Bertram G. K. Basic and Clinical Pharmacology : textbook / Bert-

ram G. Katzung. – 10th edition. – San Francisco : McGraw-Hill Companies, 2007. – 1200 p.

2. Goodman S. The pharmacological basis of therapeutics / S. Good-man, A. Gilman. – 9th edition. – New York : McGraw-Hill, 1996. – 1811 p.

3. Harvey R. A. Pharmacology / A. Richard Harvey, Pamela C. Chempe – 2nd edition. – Lippincott Williams & Wilkins, 1997. – 564 p.

4. Kresyun V. A. General pharmacology : cource of lectures / V. A. Kre-syun, D. Yu. Andronov, K. F. Shemonaeva. – Odessa : OSMU, 2005. – 215 p.

5. Pharmacology : textbook / I. S. Chekman, N. O. Gorchakova, N. I. Panasenko, P. O. Bekh. – Vinnytsya : NOVA KNYHA Publi-shers, 2006. – 384 p.

6. Polevik I. V. Lectures on Pharmacology: For the Foreign Students Being Educated in English / I. V. Polevik, A. I. Beketov, M. G. Kur-chenko. – Simferopol : Вид-во «Симферопільська міська типографія», 2003. – Part 1. – 100 p.

7. Polevik I. V. Lectures on Pharmacology: For the Foreign Students Being Educated in English / I. V. Polevik, A. I. Beketov, M. G. Kur-chenko. – Simferopol : Вид-во «Симферопільська міська типографія», 2003. – Part 2. – 108 p.

8. Stefanov O. Pharmacology with General Prescription : textbook / O. Stefanov, V. Kurcher. – К. : Вид-во «Ельіньо». – 2004. – 156 p.

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CONTENTS

P.DRUGS INFLUENCING RESPIRATORY SYSTEM…......…........ .…...3Drugs Used in Bronchial Obstruction Syndrome.................................... ........3Bronchial Spasmolytics....................................................................................4

Adrenoceptor Agonists......................................................................... ........4α-Adrenoceptor Antagonists................................................................. ........6M-Cholinolytics.................................................................................... ........7Myotropic Antispasmodic Drugs.......................................................... ........7Glucocorticoids..................................................................................... ........8Stabilizers of Ttissue Basophiles Membranes...................................... ........9Leucotriene Modulators........................................................................ ......10

Expectorant Drugs.................................................................................... ......11Expectorant Drugs with Direct Action................................................. ......11Expectorant Drugs with Reflex Action................................................ ......12Mucolytics............................................................................................ ......12

Antitussive Drugs..................................................................................... ......13Drugs Used in Pulmonary Oedema.......................................................... ......15CARDIOTONIC DRUGS..................................................................... ......17

Cardiac Glycosides............................................................................... ......17Non-Glycoside Cardiotonics................................................................ ......23

ANTIHYPERTENSIVE DRUGS......................................................... ......25Basic Antihypertensive Drugs................................................................. ......26

β-Adrenoceptor Antagonists................................................................. ......26Calcium Channel Blockers................................................................... ......30Angiotensin-Converting Enzyme Inhibitors......................................... ......31Blockers of Angiotensin Receptors...................................................... ......33Diuretics................................................................................................ ......34

Supporting Antihypertensive Drugs........................................................ ......35α-Adrenoceptor Antagonists................................................................. ......35Central α2-Adrenoceptor Agonists........................................................ ......36Ganglion Blockers................................................................................ ......37Sympatholytics............................................................................................38Potassium Channel Activators.............................................................. ......39Nitric Oxide Donators........................................................................... ......39Miscellaneous Drugs...................................................................................40

Drugs Used for Cessation of Hypertensive Crisis................................... ......41HYPERTENSIVE DRUGS................................................................... ......41

......4284

Agonists of Dopaminergic Receptors...................................................Drugs with Peripheral Action............................................................... ......42Drugs Increasing Blood Volume.......................................................... ......43

DRUGS FOR TREATMENT OF ISCHAEMIC HEART DISEASE (ANTIANGINAL DRUGS)................................................. ......45Drugs Decreasing the Myocardium Oxygen Demand and Improving Blood Supply............................................................................................ ......45

Organic Nitrates.................................................................................... ......45Calcium Channel Blockers................................................................... ......48Potassium Channel Activators.............................................................. ......50Different Antianginal Drugs Which both Decrease the Myocardium Oxygen Demand and Improve the Blood Supply................................. ......50

Drugs Decreasing Myocardium Oxygen Demand................................... ......52β-Adrenoceptor Antagonists................................................................. ......52Bradicardic Drugs................................................................................. ......53

Drugs Increasing Oxygen Delivery to Myocardium................................ ......54Coronary Vasodilating Drugs with Myotropic Action......................... ......54Antianginal Drugs with Reflex Action................................................. ......55Cardioprotectors..........................................................................................55

Principles of Myocardial Infarction Treatment........................................ ......56ANTIARRHYTMIC DRUGS............................................................... ......58

Blockers of Sodium Channels.....................................................................64β-Adrenoceptor Antagonists................................................................. ......70Drugs Causing Repolarization Slowing (Class III).............................. ......72Calcium Channel Blockers (Class IV).................................................. ......73Cardiac Glycosides (Class V)............................................................... ......74Drugs Increasing the Cholinergic Influences (Class VI)...................... ......75Miscellaneous Antiarrhythmic Agents................................................. ......75INDEX........................................................................................................78REFERENCES..........................................................................................82

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