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Respiratory System

To this group are concerned drugs that are used for the treatment of (1) bronchial constriction, (2) cough, (3) depression of respiratory, (4) pulmonary edema, (5) for the bettering of sputum expelling.

Bronchodilators and other agents used in bronchial asthma.

Bronchial asthma is physiologically characterized by widespread narrowing of the airways. It is a disease mediated by reaginic (IgE) antibodies bound to mast cells in the airway mucosa. Bronchial spasm appears in result of disorders in neural and humoral regulation of bronchial muscle’s tonus. To neural factors are considered depression of β2-adrenoreceptors and activation of M-cholinoreceptors. Humoral factors, that provoke bronchial spasm, are mediators of allergic reactions (histamine, serotonin, substance of anaphylaxis, etc.), that are excreted by basophilic cells and thrombocytes. Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissation in the airway lumen of abnormally thick, viscid plugs of mucus. Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy; reversal of the edema and cellular infiltration requires sustained treatment with anti-inflammatory agents. In case, when asthma has infective-allergic nature, anti-microbe drugs are also used.

Classification of bronchi widening (broncholytics) drugs:

1.	β-adrenomimetics

1.1 non-selective β1+β2-adrenomimetics (orciprenaline, isadrine) and α+β-adrenomimetics (adrenaline, ephedrine);

1.2 selective β2-adrenomimetics (salbutamol, fenoterol, terbutalin).

2. M-cholinolytics (ipratropium bromide, atropine, platyphylline);

3.	Myotrope drugs (euphylline, theophylline, no-spa);

4.	Anti-inflammatory, anti-allergic and desensitizative drugs (glucocorticoids, cromolyn-sodium, ketotifene, H1-histaminoblockers);

5.	Complex drugs (theophedrine, solutane, antasman).

The adrenoceptor agonists, have several pharmacologic actions that are important in the treatment of asthma i.e., they relax airway smooth muscle and inhibit release of some bronchoconstricting substances from mast cells. As in other tissues, the β-agonists stimulate adenylate cyclase and catalyze the formation of cAMP in the airway tissues. Although there is no evidence for direct sympathetic innervation of human airway smooth muscle, there is ample evidence for the presence of adrenoreceptors on airway smooth muscle. The adrenomimetic agents that have been widely used in the treatment of bronchial asthma include adrenaline, ephedrine, isadrine, and a number of 2-selective agents.

Adrenaline (epinephrine) is an effective, rapidly acting bronchodilator when injected subcutaneously. Because adrenaline stimulates  as well as α receptors, tachycardia, arrhythmias, worsening of angina pectoris, and hypertension are troublesome adverse effects. Compared with adrenaline, ephedrine has a longer duration (4-6 hours), oral activity, more pronounced central effects, and much lower potency. Ephedrine acts at indirect way – it stimulates the releasing of noradrenaline from presynaptic membrane. It is prescribed in fixed-dose combination with spasmolytics (theophylline), H1-histaminoblockers (dimedrole) in commercial formulations.

Isadrine (isoproterenol) is a potent bronchodilator; when inhaled as a microaerosol, it causes maximal bronchodilation within 5 minutes. Isadrine has a 60- to 90-minute duration of action. It stimulates both β1 and β2 receptors, that’s why it causes tachycardia, arrhythmias, and evokes the attack of angina pectoris. Because nonselective adrenomimetics cause more cardiac stimulation (mediated by 1 receptors), they are replaced by selective β2-adrenomimetics.

The βselective adrenoceptor agonist drugs are the most widely used adrenomimetics for the treatment of asthma at the present time. These agents are effective after inhaled or oral administration and have a long duration of action and significant 2 selectivity. Salbutamol (albuterol), terbutaline, and fenoterol are available as metered-dose inhalers. Bronchodilation is maximal by 30 minutes and persists for 3-4 hours. Salbutamol and terbutaline are also prepared in tablet form. One tablet two or three times daily is the usual regimen. Of these agents, only terbutaline is available for subcutaneous injection. The indications for this route are similar to those for subcutaneous adrenaline severe asthma requiring emergency treatment. The principal adverse effects of selective β2-adrenomimetics are skeletal muscle tremor, nervousness, and occasional weakness.

Interest in the potential value of M-cholinolytics has recently been increased by demonstration of the importance of the vagus in bronchospastic responses of laboratory animals and by the development of a potent agent that is poorly absorbed after aerosol administration to the airways and is therefore not associated with systemic atropine effects.

M-cholinolytics competitively inhibit the effect of acetylcholine at muscarinic receptors. In the airways, acetylcholine is released from efferent endings of the vagus nerves, and M-cholinolytics can effectively block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity. Very high concentrations are required to inhibit the response of airway smooth muscle to nonmuscarinic stimulation. This selectivity of muscarinic antagonists limits their usefulness in preventing bronchospasm.

M-cholinolytics are effective bronchodilators. When given intravenously, atropine, the prototypical M-cholinolytic, causes bronchodilation at a lower dose than that needed to cause an increase in heart rate. Deposition of the aerosol in the mouth frequently causes a local drying effect. Adverse effects due to systemic absorption include urinary retention, tachycardia, loss of visual accommodation, and agitation.

Systemic adverse effects limit the quantity of atropine sulfate that can be given, but the development of a more selective quaternary ammonium derivative of atropine, ipratropium bromide (atrovent), permits delivery of high doses to muscarinic receptors in the airways because the compound is poorly absorbed and does not readily enter the central nervous system. Its effect appears after 20-30 minutes, reaches maximum within 1,5-2 hours and lasts 4-8 hours.

Theophylline as well as caffeine are the derivatives of methylxanthines. At high concentrations, it inhibits the enzyme phosphodiesterase, which hydrolyzes cyclic nucleotides. This inhibition results in higher concentrations of intracellular cAMP. This effect could explain the cardiac stimulation and smooth muscle relaxation produced by these drugs, but it is not certain that sufficiently high concentrations are achieved in vivo to inhibit phosphodiesterase. Another proposed mechanism is the inhibition of cell surface receptors for adenosine that has been shown to cause contraction of isolated airway smooth muscle and to enhance histamine release from cells present in the lung. These effects are antagonized by theophylline, which blocks cell surface adenosine receptors. Besides broncholytic effect, theophylline dilates vessels of the lung, kidneys, heart, skeleton muscles, lowers hemodynamic loading on heart. It causes direct cardiotonic action and increases oxygen needs.

A lot of complex drugs include theophylline. Euphylline (theophylline + ethylendiamine), xantinole nicotinate (theophylline + nicotinic acid), etc are the most known. Euphylline is well absorbed (90%) after enteral introducing. For removing of bronchial asthma attack it is introduced intravenously or intramuscularly, however it causes irritate action. Therapeutic effect lasts 6 hours. Metabolism is done in liver; it is slower during the depression of hepatic enzymes, evoked by drugs (e.g., H2-histaminoblockers). In such cases smaller doses of euphylline are needed. It is excreted by kidneys in form of metabolites (90%) and in non-transformed form (10 %). Adverse effects include excitation of the CNS (anxiety, insomnia, tremor, cramps), tachycardia, arrhythmia, sometimes-cardiac insufficiency. Xantinole nicotinate is used for the treatment of diseases that accompanied by vessel contraction (e.g., atherosclerosis).

Another spasmolytics are papaverine, no-spa. They have a direct relaxant effect on vascular, bronchial and other smooth muscle due to inhibition of the enzyme phosphodiesterase and accumulation of cAMP in the smooth muscles. These agents are indicated for the treatment of spasm of the gastrointestinal tract, bronchi, etc. As the rule, papaverine and no-spa are used in combination with another broncholytics. Anti-allergic, desensitizative and anti-inflammatory drugs include cromolyn sodium, ketotifen, corticosteroids.

Cromolyn sodium differ from most antiasthmatic medications in that it is only of value when taken prophylactically. Cromolyn inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity reactions. When used as aerosol (metered-dose inhalers), it effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) may reduce the overall level of bronchial reactivity; however, this drug has no effect on airway smooth muscle tone and is ineffective in reversing asthmatic bronchospasm. Cromolyn is poorly absorbed from the gastrointestinal tract. For use in bronchial asthma, it must be applied topically by inhalation. When given by inhalation or orally, less than 10% is absorbed, and most is excreted unchanged.

Ketotifen has antihistamine and antiallergic activities. It inhibits mast cell release of histamine, leukotrienes, and other substances that cause hypersensitivity. In addition, ketotifen blocks H1-receptors. Agent is well absorbed from gastrointestinal tract. The serum half-life is about 20 hours. Ketotifen is used for the prevention of acute bronchospasm. Adverse effects include drowsiness and thrombocytopenia. Like cromolyn, corticosteroids do not relax airway smooth muscle directly but reduce bronchial reactivity, increase airway caliber, and reduce the frequency of asthma exacerbations if administered for some time. Their effect on airway obstruction may be due in part to their potentiation of the effects of β-receptor agonists, but their most important action is their inhibition of the eosinophilic airway mucosal inflammation in asthmatic airways. The principal anti-inflammatory action is the inhibition of the release of arachidonic acid from cell membranes and therefore reduction of the production of leukotrienes, prostaglandins, and cytokines. Aerosol treatment is the most effective way to decrease the systemic adverse effects of corticosteroid therapy. Inhalation of lipid-soluble corticosteroid such as beclometasone makes it possible to deliver corticosteroids to the airways with minimal systemic absorption. Effect develops gradually, so it is not used for turning out of attack. Because of severe adverse effects when given chronically, oral and parenteral corticosteroids (prednisolone, beclometasone, triamcinolone) are generally reserved for patients who require more urgent treatment, i.e., those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy.

Adverse effects during short courses (less than 7 days) usually are absent, during prolonged using – hyperglycemia, hypertension, osteoporosis, adrenal cortex insufficiency, etc may appear. A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis.

Combined drugs (theophedrine, solutane, antasman, etc.) are used for turning out and prophylaxis of bronchial asthma attacks. Principe of combining is based on synergetic interaction of the drugs with different mechanism of action. For example, solutan (alkaloids of belladonna + ephedrine + sodium iodide, etc), aerosol of berodual (fenoterol + ipratropium bromide), tablets of theophedrine (theophylline + ephedrine + extract of belladonna), etc.

Antitussive and expectorant drugs.

Self-cleaning of mucosa of the respiratory ways from strange bodies is done by fastening of bronchial glands secretion, increasing of epithelium’s activity and bronchioles motility. Irritation of reflective zones, especially in region of trachea’s bifurcation, is accompanied by cough. Couch is a protective reaction, which promotes deleting of irritate agent from breathing ways. But during inflammation of the mucosa, secret becomes glutinous due to cumulated proteins, leukocytes and is hardly excreted. Drugs that depress cough (anti-cough, antitussive) and drugs that better excretion of sputum (expectorants) are used for weakening of cough.

Antitussive drugs are divided into 2 groups: (1) drugs of central action (codeine, ethylmorphine, glaucin); (2) drugs of peripheral action (libexine).

Codeine and ethylmorphine are the phenanthrene-derivative opiate agonists that have antitussive properties. They cause suppression of the cough reflex by a direct effect on the cough centre in the medulla of the brain. Also these agents have mild analgesic and sedative effects. Codeine and ethylmorphine are well absorbed from the GI tract. Following oral administration, peak antitussive effects usually occur within 1-2 hours and antitussive activity may persist for 4 hours. High doses of codeine and ethylmorphine can cause depression of breathing centre, lowering of lung ventilation, and constipation. Prolonged therapy may results in addiction (dependence). Glaucin is an alkaloid of glaucium flavum. It depresses cough centre. But it doesn’t inhibit breathing, doesn’t cause drug addiction and constipation. It possesses adrenolytic effect and may lower AP, so it is not recommended during hypotonia.

Libexine apparently inhibits cough production by anesthetizing stretch receptors of vagal afferent fibers in the bronchi, pharyngis, and trachea that mediate the cough reflex.

Antitussives are used in the symptomatic relief of nonproductive cough during bronchitis, bronchial asthma, pneumonia, etc. Since the cough reflex may be a useful physiologic mechanism, which clears the respiratory passages of foreign material and excess secretions and may aid, in preventing or reversing atelectasis, cough suppressants should not be used indiscriminately.

According to the mechanism of action expectorants are divided into: (1) drugs that stimulate the sputum expectoration (secretomotoric drugs) and (2) mucolytic agents. Expectorants have been used in the symptomatic management of conditions such as chronic bronchitis, bronchiectasis, and bronchial asthma that are associated with high sputum viscosity and hard expulsion of sputum.

Secretomotoric drugs are subdivided into agents of reflective action and agents of resorptive action. It is postulated that expectorants of reflective action irritate the stomach mucosa. Because stomach mucosa as well as bronchi is innervated by nervus vagus, the irritation of stomach activates the centre of nervus vagus in medulla that results in hastening of bronchial gland secretion, stimulation of bronchial epithelium and bronchioles peristaltic. It is accompanied by diluting of sputum and mucus and their expelling by cough. Due to irritative properties, reflective expectorants in high doses may cause vomiting. Drugs of reflective action are administered primarily in form of infusions, decocts, tinctures, extracts, mixtures, some (e.g., thermopsis) in form of tablets. For examples, infusion of thermopsis grass, althea roots, tablets mucaltin (contains the extract of althea root), etc.

To drugs of resorptive action are concerned substances with iodine, ammonium chloride, sodium bicarbonate, etc. After absorption those drugs are excreted by bronchial glands, stimulating secretion and motor function of epithelium and bronchioles. Finally, they decrease the viscosity of mucus and promote it expelling. Prolong iodine therapy may cause symptoms of iodism: rhinitis, salivation, lacrimation, rash. Hypersensitivity reactions to iodides may occur and may be manifested by angioedema, fever, arthralgia, and eosinophilia.

Mucolytics act directly on glutinous secret. They reduce the viscosity of purulent and nonpurulent pulmonary secretions and facilitate their removal by coughing or postural drainage. Mucolytics are proteolytic enzymes (trypsin, chymotrypsin, deoxyribonuclease), acetylcysteine, bromhexine, etc. Trypsin hydrolyzes peptides, amides. Deoxyribonuclease hydrolyzes phosphodiester bonds in DNA and proteins. Bromhexine depolymerases and hydrolyzes fibers of mucopolysaccharides. Also bromhexine promotes the synthesis of surfactant (a surface-active agent that stabilize alveolar volume). Acetylcysteine reduces disulfide linkages of mucoproteins. Predominantly mucolytics are administrated in inhalation route, except bromhexine that is used orally. Mucolytics are used in the adjunctive treatment of patients with abnormal, viscid, or thick mucous secretions in such conditions as pneumonia, bronchitis, emphysema, tracheobronchitis, bronchiectasis, etc. In general mucolytics are combined with anti-microbe drugs, broncholytics.

Stimulators of the breathing (analeptics)

Stimulators of respiratory and cardio-vascular centres of medulla are used during depression of these centres. Because they restore life-important functions (breathing and blood circulation) they are called analeptics (animate substances). Most analeptics in higher doses may cause cramps. Analeptics are the antagonists of narcosis and soporific substances, alcohol, narcotic analgesics and cause “awakening” effect, which is characterized by smaller deepness and durability of narcosis and sleep, restoring of reflexes, muscular tonus and consciousness. Mechanism of analeptic's action is related with increased excitability of neurons.

Analeptics are divided into 3 groups:

1.	Agents of direct action on breathing centre (bemegrid, ethimisole, strychnine, caffeine);

2.	Agents of reflective action (lobelin, cytiton)

3.	Agents with combined action (cordiamine, camphor, CO2);

Bemegrid is used basically during poisoning by barbiturates and narcosis substances, for quick turning out from narcosis. It is injected slowly intravenously by 5-10 ml of 0,5 % solution every 3-5 minutes up to restoring of breathing, blood circulation and reflexes. Injecting has to be stopped on the first appearance of cramp contraction of muscles.

Ethimisole engages especial place, because together with excitation of medulla centres it causes depressive action on the cortex. It is used basically during poisoning by narcotic analgesics, and also in psychiatric practice as sedative drug. Ethimisole stimulates the production of adrenocorticotrope hormone of pituitary that increases the serum corticosteroids level and results in anti-inflammatory and anti-histamine effects. That’s why ethimisole is used for the treatment of bronchial asthma and arthritis.

Caffeine is described in chapter “Psychostimulators”. Analeptic effect appears during injection of high doses that simulate centres of medulla. It causes expressed cardiotonic action. Caffeine is administered for the treatment of alcohol poisoning and during combine respiratory and cardiac insufficiency.

Strychnine is an alkaloid from strychnos. It stimulates all parts of the central nervous system, and was used as an antidote for depressant poisons. It caused the bettering of vision, hearing, tactile sensitiveness, muscular tonus, and metabolism. So, strychnine causes general tone action and sometimes used for the treatment of chronic fatigue, hypotension, functional impairment of vision and hearing, etc. Strychnine blocks the inhibitory neurotransmitter, glycine, and thus can cause convulsions. It is a potent chemical capable of producing acute or chronic poisoning of humans or animals.

Cytiton and lobelin are the N-cholinomimetics. They stimulate respiratory centre in reflective way due to excitation of N-cholinoreceptors in the carotid sinus (carotid bulb). After intravenous injection of N-cholinomimetics one can see quick but short respiratory stimulation. They are used for the treatment of reflective respiratory depression during different traumas, inspiration of irritating substances and carbon monoxide. Cytiton raises the blood pressure, thus it is recommended for the shock, collapse. Analeptics of combined action both directly and indirectly (through the carotid sinus) stimulate respiratory centre. Cordiamine is a derivative of nicotinic acid. It stimulates breathing and blood circulation due to the stimulation of medulla centres. Also it directly stimulates heart activity. It is administered during weakening of breathing and blood circulation, caused by intoxication, infection disease, shock, etc.

Camphor is a ketone distilled from the tree of Cinnamonum camphora, and also prepared synthetically from oil of turpentine. Part of camphor is excreted through breathing ways that promotes expelling of the sputum. Locally agent causes irritate and antiseptic action. It directly stimulates centres of the medulla. Also camphor stimulates the contractility and metabolism of myocardium. Camphor increases blood pressure due to narrowing of the vessels in abdominal organs. In the same time it dilates vessels of the brain, lungs, and heart. It is used in form of oil solutions subcutaneously for the treatment of acute and chronic cardiac insufficiency, collapse, depression of the breathing centre, etc. Locally it is administered in form of ointments during inflammatory processes, itch, for prophylaxis of bedsores, etc.

Carbonic dioxide (CO2) is a potent respiratory stimulant. Inspiration of 3% CO2 increases the lung ventilation in 2 times. Carbonic dioxide can be used for inhalation separately or in combination with oxygen (carbogen). Carbonic dioxide activates the cardio-vascular centre. In the same time it dilates the smooth muscles due to the direct action. Carbonic dioxide is used for the stimulation of respiratory during poisons by narcosis substances, carbon monoxide (CO), during asphyxia of newborns. In higher doses CO2 can cause hypercapnia, acidosis, and paralysis of breathing centre.

Drugs, used during pulmonary edema

Edema of lungs is accompanied by acute respiratory insufficiency, so it needs emergency therapy. Pulmonary edema can be an aggravation of left-ventricular cardiac insufficiency, poisoning by irritate gases, during uremia, anaphylactic shock, infections, craniofacial traumas, coma, etc.

The most characteristically features of pulmonary edema are fear, cyanosis, bubbling respiratory with pink foamy sputum. The main danger of pulmonary edema is foaming of edema’s liquid in respiratory ways, which causes hypoxia. So, inhalation of anti-foaming drugs, oxygen and also sucking of the foam are necessary. Anti-foaming substances are ethyl spirit and anti-foamsilane. They diminish the foam’s surface tension and transform foam into liquid, which volume considerably smaller. They are administered in form of inhalations with oxygen. Anti-foamsilane doesn’t irritate breathing ways, doesn’t depress CNS and acts quicker than spirit. If pulmonary edema is associated with cardiac insufficiency, cardiac glycosides (strophantine, corglycon) are indicated. During edema that is associated with hypertension one can use ganglioblockers (hygronium, benzohecsonium), α-adrenolytics (phentolamine, aminazine), myotrope vessel narrowing drugs (sodium nitroprusside). Adrenomimetics (mesathon, ephedrine) are used in case of hypotension. In addition during pulmonary edema are indicated diuretics (furosemide) that cause dehydration of lung parenchyma, glucocorticoids (prednisolone) that possess anti-edema and anti-inflammatory action, narcotic analgesics (morphine) that lower venous input to heart and blood-filling of lungs, depress short breathing and coughing, cause sedative action.

title: Respiratory System


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Pharmacology/Gastrointestinal tract

Many drugs discussed elsewhere in this collection have applications in the treatment of gastrointestinal diseases. M-cholinolytic agents inhibit the food-stimulated secretion of gastric acid and also affect intestinal smooth muscle; these drugs are useful in some forms of functional bowel disease. M-cholinomimetics stimulate smooth muscle and are used to promote gastrointestinal motility. Several other groups of medications are used almost exclusively in gastrointestinal disease; these are grouped and discussed below according to their therapeutic uses.

Drugs regulating appetite
These drugs are divided into drugs that increase and decrease appetite. Action is related with influence on the appetite control center (centers of hunger and satiation), located in hypothalamus.

Drugs that increase an appetite include bitters (amara). Bitters are the substances that possess strong bitter taste. Bitters irritate taste receptors of oral cavity and stomach mucosa that cause reflective increasing of gastric juice secretion and promote digestion. Bitters are used for the treatment of the atrophic gastritis, hypoacidity (lower than normal level of hydrochloric acid), and anorexia (aversion to food). Bitters are should be used for 15-30 minutes before meals. Agents include bitter (amara) tincture, tincture of wormwood (absinthium), etc. Some taste substances (e.g., mint, pepper, and mustard) also exhibit features of bitters. They contain ether oil that stimulates an appetite. Bitters will be prohibited during hyperacidity, ulcer disease of stomach. Cyproheptadine (peritol) is an antihistamine (H1) drug that stimulates the center of hunger in the CNS. It is used for the treatment of anorexia.

Appetite suppressants are sympathomimetic agents. They are phepranone (amphepramone), desopimon, and mazindol. These agents have pharmacological effects similar to those of phenamine, including CNS stimulation and elevation of blood pressure. It is believed that the main effect of these medications is decreasing of the appetite control center activity. Phepranon and desopimon (relatives of phenamine) are weaker than phenamine as appetite suppressants, but less stimulate CNS and cardiovascular system, seldom causing drug addiction. Appetite suppressants are indicated in the management of exogenous obesity for short-term use (a few weeks) in conjunction with a regimen of weight reduction based on caloric restriction, exercise, and behavior modification. Adverse effects include insomnia, tachycardia, increasing of blood pressure, sleeplessness, accustoming and drug addiction. They are contraindicated during hypertonia, disorders of cerebral blood circulating, thyrotoxicosis, diabetes mellitus, and epilepsy.

Substances stimulating and inhibiting secretive function of the stomach
Drugs that stimulate stomach juice secretion are the next: pepsin, natural gastric juice, abomin, and panzynorm (see chapter “Enzyme preparations and enzyme inhibitors”). They normalize secretion and motility of gastrointestinal tract and are indicated for replacement therapy of stomach upset such as achlorhydria (absence of hydrochloric acid in the gastric juice) or hypoacidity. Pentagastrin is a synthetic analog of the natural hormone, gastrin. Pentagastrin as well as gastrin stimulate the secretion of hydrochloric acid, pepsin, and increases GI motility. It is useful as a diagnostic test for achlorhydria and hypersecretion of stomach juice.

Drugs, decreasing the secretive function of stomach, include M-cholinolytics, ganglioblockers, and blockers of H2-histamine receptors, antacids, adsorbents, astringents, and local anesthetics. Gastric acid secretion is under the control of histamine, acetylcholine, and gastrin. The final common pathway is through the proton pump, H/K ATPase.

H2(histamine)-receptors antagonists, e.g., cimetidine, ranitidine, famotidine, and nizatidine blockade H2-receptors of stomach mucosa that leads to reduction in basal, food-stimulated, and nocturnal secretion of gastric acid. Many trials have demonstrated their effectiveness in promoting the healing of duodenal and gastric ulcers and preventing their recurrence. H2-antagonists are rapidly and well absorbed following oral administration. Food delays and may slightly decrease absorption of the drugs. For active ulcer, any H2-blocker can be given twice daily or once at bedtime. Reversible hematologic abnormalities have been a rare occurrence with all members of this class of drugs. Cimetidine may cause reversible gynecomastia. This has been reported only rarely with ranitidine and famotidine. Cimetidine also slows hepatic microsomal metabolism of some drugs, such as neodicumarin, euphylline, diazepam, and diphenine. Ranitidine appears to have less effect and famotidine and nizatidine no effect on hepatic drug metabolism.

Cholinoreceptor antagonists such as M-cholinolytics (e.g., atropine, pirenzepine) and ganglioblockers (e.g., pirilen, pentamine) decrease the influence of nervus vagus that results in lowering of gastric juice secretion. Ganglioblockers are now rarely used because they’re adverse effects. Pirenzepine, an antimuscarinic agent with activity relatively selective for gastric M1-receptors, is approved for ulcer therapy. It may causes the disorder of accommodation, dryness of mouth, but less frequent than others M-cholinolytics.

Omeprazole irreversibly inhibits the gastric parietal cell proton pump, (H/K ATPase). Inactivation of this enzyme system blocks the final step in the secretion of hydrochloric acid by these cells. The drug requires activation in the acid environment of the secretory canaliculus of the parietal cell, i.e., it is a prodrug. Omeprazole inhibits basal and stimulated gastric acid secretion. Omeprazole is a more potent inhibitor of such secretion than are H2-receptor antagonists. Although omeprazole has a short terminal plasma half-life, the drug has a long duration of action (about 3 days). Omeprazole increases plasma gastrin concentrations via a negative feedback mechanism resulting from decreased gastric acid secretion. Omeprazole is approved for the treatment of gastric and duodenal ulcers as well as for prevention of recurrence of duodenal ulcers. The initial dose is 20 mg once daily. Omeprazole is well-tolerated drug. However, increase in gastric carcinoid tumors has been observed during long-term omeprazole exposure in animals.

Gastric antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their usefulness in peptic ulcer disease appears to lie in their ability to reduce gastric acidity. Antacid-induced increases in gastric pH inhibit the proteolytic action of pepsin. Some antacids, such as aluminum hydroxide, have astringent action. Most antacids in current use have as their principal constituent magnesium or aluminum hydroxide, alone or in combination, and occasionally in combination with sodium bicarbonate or a calcium salt.

Antacids include sodium bicarbonate, magnesium oxide, calcium carbonate, aluminum hydroxide, and a lot of complex drugs (e.g., almagel, maalox, phosphalugel, vicair, de-nol, etc). Sodium bicarbonate possesses the most quick but short period of action. During interaction with acid, carbon dioxide is formed, which stretches stomach and causes secondary wave of secretion. Absorbing into blood, sodium bicarbonate may causes systemic alkalosis. Magnesium oxide, aluminum hydroxide act slower, more durable, and more active than sodium bicarbonate. Magnesium oxide may cause purgative effect, however aluminum hydroxide may cause constipation. Calcium carbonate is slowly solubilized in the stomach. In high doses it may cause hypercalcemia and alkalosis.

There are many complex antacids. They are almagel (aluminum hydroxide and magnesium oxide), maalox (aluminum and magnesium hydroxide). These agents possess antacid, adsorptive, astringent, and envelop activities. Also agents that contain bismuth such as vicair (bismuth subnitrate, magnesium carbonate, sodium bicarbonate, and powder of frangula bark), de-nol (bismuth subcitrate) are well known. Bismuth salts have antacid and astringent effects. In addition, de-nol has mild activity against Helicobacter pylori that is associated with gastritis and peptic ulcer. Antacids are used as an adjunct to physical and emotional rest, other drugs for the relief of peptic ulcer pain and to promote the healing of peptic ulcers, hyperacid gastritis. Antacids also are used for the relief of dyspepsia, heartburn, and sour stomach.

Sucralfate is a gel (aluminum salt), which in acid surrounding forms glutinous and sticky substance, covering the ulcerous surface and protecting it from damages. Sucralfate is not absorbed.

A great meaning in treatment of gastritis and ulcer disease of stomach and duodenum is taken by gastric protectors – drugs that increase protection function of sputum and stableness of mucous layer (carbenoxolone, misoprostole). Carbenoxolone increases secretion of sputum, forming it more glutinous. It may cause retention of water in organism, hypertension. Misoprostole is a synthetic prostaglandin E1 that increase stability of gastric mucous, lower secretion of hydrochloric acid and fasten secretion of sputum. Now are widely used drugs, which promote stomach mucosa regeneration. To them are concerned solcoseril, vitamin U, anabolic steroids (retabolil, phenobolil, etc.), riboxin and methyluracil.

Emetic and anti-emetic drugs
Vomiting is a protective stomach reaction directed on its cleaning. Coordination of the complex motor activity of the stomach and abdominal musculature takes place in the vomiting center, which is located in the reticular formation in the medulla. The vomiting center receives input from the chemoreceptor trigger zone located on the floor of the fourth ventricle, the vestibular apparatus, and other areas.

Vomiting can be evoked for turning out irritate and toxic substances from the stomach. For that purpose apomorphine is used. It stimulates dopamine receptors of trigger zone. Apomorphine is characterized by short period of nausea. It is contraindicated during unconscious state, burns of esophagus and stomach by acid and alkaline. Sometimes it is used during treatment of alcoholism for forming of negative conditional reflex on alcohol. Nausea and vomiting may be manifestations of a wide variety of conditions, including pregnancy, motion sickness, gastrointestinal obstruction, peptic ulcer, drug toxicity, myocardial infarction, cancer chemotherapy, etc. So choosing of antiemetic drugs is determined by reasons, caused vomiting.

The major categories of antiemetic agents include H1-antihistamines, neuroleptics, M-cholinolytics, metoclopramide, and ondansetron. The antihistamines with good antiemetic activity (e.g., dimedrole diprazin) possess significant antimuscarinic and sedative effects (see chapter “Agents for the treatment of hypersensitivity”). It appears probable that both of these actions and the H1-blocking effect contribute to the antiemetic efficacy. They are particularly effective for the nausea and vomiting associated with motion sickness, perhaps because of specific depression of conduction in the vestibulocerebellar pathway. Anticholinergic agents, especially atropine, scopolamine (aeron), are also used to prevent motion sickness.

The neuroleptics block dopamine receptors in the trigger zone as well as other areas of the brain (see chapter “Neuroleptics”). Aminazine and galoperidol are often used as antiemetics. Extrapyramidal symptoms (parkinsonism) can be severe when large doses of neuroleptics are used. Thiethylperazine is a phenothiazine derivative (as aminazine). Agent is a strong antiemetic, however it causes mild extrapyramidal disorders. Metoclopramide promotes gastrointestinal motility. In addition to its M-cholinomimetic properties, metoclopramide is a potent dopamine antagonist. It does not increase gastric or pancreatic secretion. These drugs hasten esophageal clearance, raise lower esophageal sphincter pressure, accelerate gastric emptying, and shorten small intestine transit time. Metoclopramide's central dopamine antagonist effect is thought to be responsible for its significant antiemetic properties. Metoclopramide injection is indicated for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy, in postoperative period. Oral metoclopramide is indicated in adults for the symptomatic treatment of heartburn and reflux esophagitis, for correcting the slow gastric emptying. The most common side effects of metoclopramide are somnolence and nervousness. Parkinsonism has also been reported.

Ondansetron is a selective inhibitor of serotonin (5-HT3) receptors. The antiemetic activity of ondansetron appears to be mediated both centrally and peripherally via inhibition of 5-HT3 receptors. Ondansetron is used orally or intravenously for the prevention of nausea and vomiting associated with emetogenic cancer chemotherapy. Ondansetron appear to be more effective and better tolerated than the pharmacologically less selective metoclopramide and therefore may be preferred for the management of acute emetic effects in many patients.

Substances influencing on motility of intestine
They are divided into drugs, depressing intestine motility (antidiarrheal agents), and drugs, increasing intestine motility (laxatives).

Diarrhea is a symptom of many diseases (poisoning, infections, diseases of stomach and pancreas, etc.). For the diarrhea therapy it reason is necessary to confirm. If diarrhea is caused by infection process, antimicrobe agents must be taken. In the treatment of uncomplicated diarrhea that caused by modification of the intestinal flora by drugs (e.g., antibiotics) or during different diseases one can use chilac, biphidumbacterin, etc. These agents contain an acid-producing intestine bacterium (e.g., Lactobacillus acidophilus) or its extract prepared in a concentrated, dried, and viable culture for oral administration.

As drugs for symptomatic diarrhea therapy are used astringents, enveloping and adsorptive substances, which possess non-specific anti-inflammatory and protect intestine mucosa from irritate agents. M-cholinolytics, ganglioblockers, and spasmolytics of myotrope action (papaverine, no-spa, dibasole, etc.) decrease the tonus of smooth muscles of intestine wall that results in lowering of intestine motility. Loperamide is a synthetic piperidine-derivative antidiarrheal agent. Drug binds with opioid receptors of intestine (like morphine) and enhances contractions of intestinal circular musculature, thus increasing segmentation and retarding forward motion through the intestine. Loperamide is potent, specific, and long acting antidiarrheal agent. It has no analgesic activity. Loperamide is used in the control and symptomatic relief of acute nonspecific diarrhea and of chronic diarrhea associated with inflammatory bowel disease. Adverse effects of loperamide are constipation, dizziness, and nausea. Also it has M-cholinolytic activity.

Drugs that increase the motility of intestine include M- and M-, N-cholinomimetics (aceklidine, proserine, halantamine, etc.). These agents stimulate tonus of nervus vagus that leads to the activation of smooth muscles of intestine wall and intestine motility in general. Direct stimulating action on the intestine wall have purgatives.

Purgatives are the substances that fasten movement of intestinal content and promote defecation. In dependence of mechanism of action they are divided into next groups:

(1) drugs, acting basically on small intestine (castor oil);

(2) drugs, acting basically on large intestine (leaves of senna, bark of frangula, phenolphtalein, bisacodyl);

(3) drugs, acting on all parts of intestine (salt laxatives – magnesium sulfate);

(4) bulk laxatives (agar, methylcellulose, bran)

(5) stool softeners (mineral oil, vaselin).

Castor oil is hydrolyzed in the upper small intestine to ricinoleic acid, a local irritant that increases intestinal motility. The onset of action is prompt (2-6 hours) and continues until the compound is excreted via the colon. It is administered during acute constipation. Castor oil is contraindicated during poisoning by fat-dissolved substances.

Bark of frangula, leaves of senna contain emodin alkaloids that are liberated after absorption from the intestine and are excreted into the colon, where peristalsis is stimulated. Thus, their onset of activity is delayed for 6-10 hours. So, they are usually administrated in evening. These agents are used for the treatment of chronic constipation. Adverse effects include spasm of intestine, meteorism. Phenolphthalein and bisacodyl, which are synthetic drugs, are also potent colonic stimulants. They are absorbed in small intestine and excreted in large intestine, increasing it’s peristaltic.

Saline cathartics (magnesium sulfate) distend the bowel and stimulate its contractions. These nonabsorbable salts hold water in the intestine by osmotic force and cause distention. In result magnesium sulfate increases the motility of all intestine. Saline cathartics serve for removal of ingested toxin and as colonic lavage solutions, chiefly in preparation for radiological or endoscopic procedures. It has to be administrated with enough volume of warm water (1-2 glasses). Potent laxative effect develops after 2-4 hours. Magnesium sulfate is taken seldom because it impairs the absorption of nutritious substances in intestine.

'''Bulking laxatives. Agar and methylcellulose''' are swelling in the large intestine lumen that is associated with their enlargement. They distend the intestine and thereby stimulating its peristaltic activity. Bran (by-product of the milling of wheat, containing the indigestible cellulose) and other forms of vegetable fiber have the same effect. Bulking laxatives are taken for chronic constipation.

Stool softeners become emulsified with stool. They serve to soften stool and make passage easier. Examples are mineral oil, glycerin. They have weak laxative effect. Adverse effects include impairment of food digestion, uncontrolled defecation, and soil of clothes.

Purgatives are contraindicated during acute appendicitis and cholecystitis, peritonitis, mechanical impassability of intestines, pinched hernia, bleeding in GI tract, menorrhagia. They are to be carefully used during pregnancy due risk of abortion.

Hepatotropic drugs
Hepatotropic drugs consist of three groups. They are (1) bile-drive drugs, (2) hepatoprotectors, and (3) choleolytics.

Bile-drive drugs regulate the bile production and bile output. Lack of gall causes disorder of emulsion and absorption of lipids, fat-dissolved vitamins as well as development of putrid microflora in intestine and depression of its motility. Bile-drive drugs are divided into two main groups.

1. Drugs that stimulate bile production (cholesecretics). Drugs of resorptive type action, which activate hepatocytes. Also they irritate the intestine chemoreceptors that in reflective way promotes bile secretion. In addition, drugs including bile can act as substitutive agents. Cholesecretics are indicated during insufficiency of bile production. They will be contraindicated during acute and considerable lever defeats, obturating of bile ducts by gallstone, etc., because they form additive loading on liver and may increase jaundice.

1.1	drugs that contain bile: allohole (consist of bile, garlic and nettle extracts, and activated carbon), cholenzyn (bile, dry powder of cattle pancreas and intestine), etc.

1.2	drugs of plant origin: cholosas (syrupus of wild rose hips), corn oil, etc. 1.3	synthetic drugs: nicodin (nicotinamide + formaldehyde), cycvalone, etc.

2. Drugs promoting bile excretion into duodenum

2.1 drugs that increase tonus and motility of gallbladder, and accelerate its emptying (cholekinetics): cholecystokinine, pituitrine, magnesium sulfate, sorbit, etc. They are used for the hypotonia of gallbladder and bile ducts.

2.2 drugs that decrease tonus of bile ducts and Oddi’s sphincter (spasmolytics): atropine, platyphylline, papaverine, no-spa, etc.

They are used for removing of liver colic, Oddi’s sphincter spasm.

That classification is quite comparative, because drugs, stimulating the gall formation, at the same time increase its excretion. And drugs, increasing the gall excretion, promote gall formation. The most important factor during treating of liver and gall-ducts diseases, is the bettering of gall outflow, what deletes it’s stagnation and absorption to blood, lower risk of infection’s development in gall-ducts, and forming of gall-stones.

Hepatoprotectors are the drugs that increase the resistance of hepatocytes membrane, induce the hepatocytes enzymes, and promote restoration of liver function (synthesis of proteins, detoxication). As the rule, these drugs possess antioxidant properties. These features are possessed by legalon, essentiale. The last one includes essential (important) phospholipids, vitamins (B6, B12, PP, etc.). Hepatoprotectors are used for the treatment of hepatitis, cirrhosis.

Choleolytics are the drugs that cause desaturation of the bile by increasing the ratio of bile acids to cholesterol. The reduced cholesterol saturation allows for the gradual solubilization of cholesterol from gallstones, resulting in their eventual dissolution. Choleolytics are chenodeoxycholic acid (chenofalk, chenodiol) and ursodesoxycholic acid (ursofalk). Choleolytics are indicated for dissolution of cholesterol gallstones in selected patients with uncomplicated gallstone disease and functioning gallbladder.

Drugs influencing on outsecretive (exocrine) function of pancreas
They are divided into agents, which stimulate exocrine function of pancreas (bitters, acid hydrochlorici), agents for replacement therapy (pancreatin, panzynorm forte, festal, mezym forte), and agents, which inactivate pancreas enzymes. Uses of replacement therapy drugs are discussed in chapter “Enzyme preparations and enzyme inhibitors”. Agents, inhibiting pancreas enzymes are discussed below.

Enzymes of pancreas take part in destruction of proteins, fats and hydrocarbons. Usually in pancreas enzymes are present in nonactive (pre-enzyme) form, which is transformed to active form in the intestine lumen only. During acute pancreatitis, activation of enzymes especially proteolytic begins in gland tissues that lead to “self-destruction” of pancreas. Treatment of acute pancreatitis is directed on lowering of pancreatic secretion, using M-cholinolytics (atropine, etc.) and inactivation of proteolytic enzymes (tripsine and kallikrein) by using their inhibitors (contrycal, trasilol). Contrycal is obtained from cattle lung or pancreas tissues. Its activity is expressed in international unites (IU). Contrycal is injected intravenously droply. The most serious adverse effect of this agent is allergic reactions.

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title: Pharmacology/Gastrointestinal tract


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Antimicrobial Agents I

Antimicrobial are the chemical agents, used to destroy or inhibit the growth of pathogenic micro organism. Antimicrobial drugs are the greatest contribution of the present century to therapeutics. As the class they are one of the most frequently used in medicine. J. Zemmelweiss, the Hungarian obstetrician used lime for medicine stuff hands washing. An English surgeon J. Lister suggested phenol as an antiseptic to surgery. Further development of antiseptics was based on Paster’s discovery of pathogenic microorganisms and researches of R. Koch, I.I. Mechnikov and others.

Drug in this class differ from all others in that they designed to inhibit or to kill the infecting organism and to have minimal effect on the recipient. If agent primary inhibit the germ growing, it acts bacteriostatic. Direct lethal action is the feature of bacteriocidic activity. A practical distinction between these two mechanisms action is futile as these are often concentration dependent action.

Antimicrobial preparations are subdivided into the following groups: disinfectants, antiseptics and chemotherapeutic agents.

Disinfectants are chemical agents that inhibit or kill microorganisms on inanimate objects (walls, floor, air, and medical tools). The process of disinfection prevents infection by reducing the number of potentially infective organisms either by killing, removing, or diluting them. Antiseptics are agents with sufficiently low toxicity for host cells that they can be used directly on skin, mucous membranes, or wounds. Disinfectants and antiseptics can be used both for disinfecting of medical tools and human skin depending on their concentration. There is considerable overlap and many agents are used in either way.

Chemotherapeutic agents are used for germs killing inside the organism. Disinfectants and antiseptics differ from chemotherapeutic agents by their low parasite selectivity and high toxicity for systemic use.

A good desinfectant/antiseptic should be: active against all pathogens (bacteria, fungi, viruses, protozoa), active even in the presence of blood, pus and exudates. A desinfectant in addition should be not corrode instruments. An antiseptic also should be: non-irritating to tissues, produce minimum toxicity.

Spectrum activity of agent is the list of microorganisms, that sensitive to him. Spectrum activity of majority of antiseptic/disinfectants is wide, reflecting nonselectivity of action.

Evaluation of effectiveness of antiseptics, disinfectants although seemingly simple in principle, are very complex. Factors in any evaluation include the intrinsic resistance of the microorganism, the number of present microorganisms, mixed populations of microorganisms, amount of present organic material (e.g. blood, feces, tissue), concentration and stability of disinfectant or sterilant, time and temperature of exposure, pH, and hydration and binding of the agent to surfaces.

CLASSIFICATION OF DISINFECTANTS AND ANTISEPTICS

1. Halogens (chlorinated lime, chloramine B, chlorhexidine, iodinole, iodovidone)

2. Oxidizing agents (hydrogen peroxide, potassium permanganate)

3. Acids (salicylic acid, boric acid)

4. Phenol derivatives (phenol, cresol, resorcinol, vagotil)

5. Aldehydes and alcohols (formaldehyde, glutaraldehyde, ethanol, isopropanol)

6. Metallic salts (silver nitrate, zinc sulfate, and copper sulfate)

7. Dyes or tints (brilliant green, rivanol, methylene blue)

8. Detergents (roccal, aethonium, cerigelum, decamethoxinum, soaps)

9. Derivatives of different chemical groups (furacilinum)

10. Agents from plant source (novoimaninum, chlorophylliptum, and lysocim)

HALOGENS

Anti-germ activity of halogens depends on their ability to release chlorine and iodine. They form chloric and iodic acids in water solutions. The latter release atomic oxygen and haloids. These ions denature proteins of germs and act bactericidically.

Chlorine is a strong oxidizing agent and universal disinfectant that is most commonly provided as a 5.25% sodium hypochlorite solution, a typical formulation for household bleach. Chlorine is used to disinfect urban water supplies. Because chlorine is inactivated by blood serum, feces, and protein-containing materials, surfaces should be cleaned before chlorine disinfectant is applied. Solutions of chlorine are corrosive to aluminum, silver, and stainless steel.

Chlrophores (chlorinated lime, chloramine B) are compounds that slowly release hypochlorous acid (HOCl). Because of ease of handling, they are used in preference to gaseous chlorine. These agents retain chlorine longer and have a prolonged bactericidal action. Chlorinated lime (bleaching powder) is obtained by the action of chlorine on lime. It is used as disinfectant for medical tools, drinking water, swimming pools and sanitizer for privies. Chloramine B may be used for disinfecting of clothes, skin and instruments, which are not made from metal.

Chlorhexidine is a cationic biguanide with very low water solubility. Water-soluble chlorhexidine bigluconate is used in water-based formulations as an antiseptic. It is most effective against gram-positive cocci and less active against gram-positive and gram-negative rods. Spore germination is inhibited by chlorhexidine. It is resistant to inhibition by blood and organic materials. Chlorhexidine is used in the treatment of inflammation of the oral mucosa caused by bacterial or fungal actions, for surgeon hands washing before operation, for medical tools disinfection. Chlorhexidine has a very low skin-sensitizing or irritating capacity. Oral toxicity is low because chlorhexidine is poorly absorbed through the alimentary tract. Chlorhexidine must not be used during surgery on the middle ear because it causes sensorineural deafness. Similar neural toxicity may be encountered during neurosurgery.

Iodine is a rapidly acting, broad spectrum (bacterial, fungi, and viruses) microbicidal agent. Acts by iodinating and oxidizing germ protoplasm. Iodine in a 1:20,000 solution is bactericidal in 1 minute and kills spores in 15 minutes. It is the most active antiseptic for intact skin. It is not commonly used because of serious hypersensitivity reactions, skin, irritation that may occur and because of its staining of clothing and dressings.

Iodophors are complexes of iodine with a surface-active agent such as polyvinylpyrrolidone (iodinole, iodovidone). The amount of free iodine is low, but it is released as the diluted solution. Iodophors retain the activity of iodine. Iodophors are less irritating and less likely to produce skin hypersensitivity than tincture of iodine. They kill vegetative bacteria, mycobacterium, fungi, and lipid-containing viruses. They may be sporicidal upon prolonged exposure. Iodophors can be used as antiseptics or disinfectants, the latter containing more free iodine. Dilution may release more free iodine. An iodophor solution must be diluted according to the manufacturer's directions in order to obtain full activity.

OXIDIZING AGENT

Oxidizing agent are free atomic oxygen releasers. Atomic oxygen lead to irreversible damage of oxidizing-restoring reaction of germ. The hydrogen peroxide has high killing activity and a broad spectrum against bacteria, spores, viruses, and fungi when used in appropriate concentration. It has the advantage that its decomposition products are not toxic and does not injure the environment. Hydrogen peroxide is powerful oxidizer that is used primarily as antiseptic. Organisms with the enzymes catalase and peroxidase rapidly degrade hydrogen peroxide. The innocuous degradation products are atomic and molecule oxygen, and water. Molecule oxygen forms the foam that helps in loosing and removing slough dead tissues. Hydrogen peroxide has been proposed for wound irrigation, disinfection of respirators, acrylic resin implants, plastic eating utensils, soft contact lenses. Hydrogen peroxide has poor penetrability and a transient action.

Potassium permanganate. It liberates oxygen, which oxidizes bacterial protoplasm, and MnO2, which cause astringent and irritating effects. Solution of potassium permanganate is used for gargling, douching, and irrigating cavities, urethra and wounds. It has also been used for stomach wash in alkaloid poisoning. It promotes rusting and is not good for surgical instruments.

ACIDS

Boric acid possesses fungistatic and weak bacteriostatic properties. Drug has greater bacteriostatic activity in bases containing large amounts of water than in fatty bases. Boric acid retards the growth of fungi but is not fungicidal. Aqueous solutions of boric acid are used topically for ophthalmic irrigation to cleanse and refresh irritated eyes. It is used topically as a skin protection for relief of discomfort of chafed skin, dry skin, abrasions, or other skin irritations and has been used topically for the treatment of superficial fungal infections; however, the drug is generally considered as lacking substantial evidence of efficacy for these uses.

The risk of systemic toxicity from topical application of boric acid depends on the concentration used (more than 5%), age of the patient (children appear to be more susceptible), skin condition (increased with abraded, or macerated skin). Boric acid can produce severe and fatal poisoning, consisting of GI disturbances, erythematous skin eruptions, and signs of CNS stimulation followed by depression. Treatment of acute boric acid intoxication consists mainly of intensive symptomatic and supportive therapy.

Salicylic acid has a potent keratolytic action and a slight antifungal and antiseptic action when applied topically to the skin. In low concentrations, the drug has keratoplastic activity (activation of keratinization) and in higher concentrations (i.e., 1% or higher), the drug has keratolytic activity (causes peeling of skin). At high concentrations, salicylic acid has a caustic effect. Salicylic acid is used topically for its keratolytic effect in controlling scaling dermatoses (seborrheic, psoriasis). It has also been used in the treatment of localized hyperkeratosis, such as occurs on the palms and soles. Salicylic acid is not used systemically because of its severe irritating effect on GI mucosa and other tissues.

PHENOL DERIVATIVES

Phenol itself perhaps the oldest of the surgical desinfectant/antiseptic. It is used to disinfect urine, feces, and pus, for drug conservation. Phenol no longer used as an antiseptic because of its corrosive effect on tissues, its toxicity upon absorption, and its carcinogenic effect. When swallowed (with suicidal purpose) it causes buccal, esophageal and stomach burns, excitation, convulsions, respiratory paralysis and vascular collapse.

Phenolderivatives (cresol, resorcin, and vagotil) are less toxic than phenol. Phenolic compounds disrupt cell wall and membranes, precipitate proteins, and inactivate enzymes. They are bactericidal (including mycobacteria), fungicidal, and capable of inactivating lipophilic viruses. Cresol more active than phenol. It is used for hard surface decontamination in hospitals and laboratories, e.g., floors, beds, and counters or bench tops. Resorcin is 1/3 as potent as phenol. It also has keratolytic activity, that’s why resorcin employed on seborrheic dermatitis, eczema, acne as solution or ointment. Vagotil in addition acts on trichomonas – used for topical vaginitis treatment.

Detergents are often added to formulations to clean and remove organic material that may decrease the activity of a phenolic compound. Skin absorption and skin irritation still occur with phenolderivatives, and appropriate care is necessary in their use. They are not recommended for use in nurseries and especially bassinets, where their use has been associated with hyperbilirubinemia.

ALDEHYDES AND ALCOHOLS

The two alcohols most frequently used for antisepsis and disinfection are ethanol and isopropyl alcohol (isopropanol). They are rapidly active, killing vegetative bacteria, M tuberculosis, and many fungi and inactivating lipophilic viruses. They are not sporicidal, may not be active against hydrophilic viruses, and lack residual action because it evaporates completely. Alcohols probably act by denaturation of proteins. Alcohols have been used for skin disinfecting in case of abrasion and before hypodermic injection. The rapidity of antiseptic action increases with concentration upto 70% and decreases above 90%. At 90% concentration they form a coagulum under which bacteria could grow.

Alcohols are an irritant and should not be applied to mucous coats. They are poor disinfectant for instruments – does not kill spores and promote rusting.

Aldehydes (formaldehyde and glutaraldehyde) act by alkylation of chemical groups in proteins and nucleic acids. Activated solutions are bactericidal, sporicidal, fungicidal, and virucidal for both lipophilic and hydrophilic viruses. They are not corrosive for metal, plastic, or rubber.

Formaldehyde has a characteristic pungent odor and is highly irritating to respiratory mucous membranes and eyes. Formaldehyde solutions are used for high-level disinfection of hemodialyzers, preparation of vaccines, and preservation and embalming of tissues. Formaldehyde is available as a 37% solution in water (100% formalin). The 3,7% formaldehyde (10% formalin) solutions used for fixation of tissues and embalming may not be mycobactericidal. Including formaldehyde preparation decrease foot sweating. The urinary antiseptic hexamethylentetramine (methenamine) acts by releasing formaldehyde in acidic medium. It is used for urinary tract infections.

Those who handle formalin can develop eczematoid reaction. It has declared that formaldehyde is a potential carcinogen. Glutaraldehyde is less pungent and better sterilizing agent than formalin. Solutions of 2% glutaraldehyde are most commonly used. It is used for disinfection or sterilization of instruments such as fiberoptic endoscopes, respiratory therapy equipment, hemodialyzers, and dental handpieces.

METALLIC SALTS

Metals cause antiseptic action, because they easily combine with sulfhydryl-(SH) group of thiolic enzymes, thus stopping the oxidizing process of microorganisms. When metal-ions interact with human proteins, physical properties of the protein are usually altered; the protein may be denatured and precipitation usually occurs. When the concentration of metal is low, precipitation prevents deep tissue penetration and astringent action occurs. When the concentration of metal is high, membrane and intracellular structures are damaged and caustic or escharotic action occurs.

Metal-ions in the high concetration interact with sulfhydryl groups, inhibiting enzymes and altering cell membranes of human tissues, that’s lead to poisoning. The most distinct example is the case of mercury poisoning. Acute inhalation of elemental mercury vapors may cause chemical pneumonitis and noncardiogenic pulmonary edema. Acute gingivostomatitis may occur, and neurologic sequelae (tremor, memory loss, fatigue, insomnia, and anorexia) may also ensue. Acute ingestion of inorganic mercury salts, such as mercuric chloride, can result in a corrosive, potentially life-threatening hemorrhagic gastroenteritis followed within days by acute tubular necrosis and oliguric renal failure. In addition to intensive supportive care, acute chelation with dimercaprol (unithiol) or edetate calcium disodium (calcium EDTA) may be of value in diminishing nephrotoxicity after acute exposure to inorganic mercury salts. The sulfhydryl groups of dimercaprol form heterocyclic ring complexes with heavy metals (particularly arsenic, mercury, and gold), and these complexes prevent or reverse the binding of metallic cations to body ligands such as essential sulfhydryl-dependent enzymes. The calcium in calcium EDTA can be displaced by divalent and trivalent metals to form stable soluble complexes which can then be excreted in urine.

Silver nitrate exhibits antiseptic, germicidal, astringent, and caustic or escharotic activity. Inorganic silver salts are strongly bactericidal. Silver nitrate, 1:100, has been most commonly used, particularly as a preventive for gonococcal ophthalmitis in newborns. Silver nitrate touch is used for hypertrophied tonsillitis and aphthous ulcers.

Silver salts stain tissue black because of deposition of reduced silver. Contact of 1% silver nitrate solution with skin or other surfaces should be avoided since staining of the skin may occur. Silver nitrate is caustic and irritating to skin and mucous membranes. Cauterization of the cornea and blindness may result from repeated application of silver nitrate ophthalmic solution. Mistaken or accidental single-dose administration of 5-50% silver nitrate solutions has reportedly caused severe ocular injury including permanent corneal opacification and cataracts.

Silver sulfadiazine slowly releases silver and is used to suppress bacterial growth in burn wounds. Collargole (colloidal silver) and protargole (protein silver) also slowly release silver ions, are not irritating. They are used in cases of conjuctivitis, ulcers. Zinc sulfate exhibits astringent and mild antiseptic activity. These effects may result from precipitation of protein by the zinc ion. Zinc sulfate is used in ophthalmic solutions as an astringent for the temporary relief of discomfort from minor eye irritation. It has also been used in the treatment of angular conjunctivitis. Zinc oxide being mildly antiseptic, it is popular dermal protective and adsorbentive agent. Zinc is necessary for the proper functioning of over 200 metalloenzymes. Physiological functions that are zinc dependent include cell growth and division, sexual maturation and reproduction, night vision, wound healing, host immunity, taste acuity.

Copper sulfate as astringent and antiseptic has been used for conjuctivitis, uretritis and vaginitis treatment. Copper is necessary for the proper functioning of many metalloenzymes. Physiological functions that are copper dependent include oxidation of iron, erythro- and leukopoiesis, bone mineralization, elastin and collagen cross-linking, myelin formation, and antioxidant protection of the cell. Such polyvitamines as “Quadevitum”, “ Complivitum” are include copper sulfate (“Complivitum” also contain zinc).

Mercury is now rarely used as disinfectant/antiseptic. Mercurials are poor antiseptics with low therapeutic index. But some are still used. For example hydrargeri amidochloride (ammoniated mercury) used for skin disease treatment.

Aluminum and lead preparations are used for antiseptic rinsing and applying. Aluminum hydroxide being an antacid is indicated for relief of symptoms associated with hyperacidity (heartburn, acid indigestion, and sour stomach).

DYES (TINTS)

Brilliant green active against fungi, staphylococci, and other Gram positive bacteria. Aqueous or alcohol solution is used on furunculosis, skin abrasion, cutting, infected eczema. Staining is a disadvantage with all dyes. Brilliant green is inactivated by blood serum, feces, and protein-containing materials.

Aethacridine lactate (rivanol) influence mostly Gram positive germs. It’s water solution, ointment, paste are used for wounds and cavities washing and in dermatology.

Methylene blue has mild antiseptic activity that may inhibit bacterial proliferation. Methylene blue has been used as a urinary tract antibacterial agent (irrigation), however, more effective agents have replaced this medication. It is used as a bacteriological stain, as a dye in diagnostic procedures, such as fistula detection, and for the selective staining of certain body tissues during surgery. Methylene blue is indicated in the treatment of acquired and idiopathic methemoglobinemia. In low concentrations, it acts as a cofactor to accelerate the conversion of methemoglobin to hemoglobin in erythrocytes.

DETERGENTS

Detergents or surface-active compounds decrease surface tension of cell membrane act, thus alter it permeability. There are two kinds of detergents. They are cationic detergents (quaternary ammonium compounds) and anionic detergents (soaps).

The quaternary ammonium compounds ("quats") are bacteriostatic, fungistatic, and sporistatic. They highly effective against gram-positive bacteria and moderately active against gram-negative bacteria. Strains of Mycobacterium tuberculosis and Pseudomonas aeruginosa are often resistant and they are not effective against spore-forming organisms.

Quaternary compounds possess detergent, keratolytic, and emulsifying action. They are used for sanitation of noncritical surfaces (floors, bench tops, etc).

Quaternary compounds bind to the surface of colloidal protein in blood, serum, to fibers present in cotton, mops, cloths, and paper towels used to apply them, which can cause inactivation of the agent by removing it from solution. They are inactivated by anionic detergents (soaps). That’s why before applying quaternary ammonium compounds to the skin for preoperative disinfection, all traces of soap should be removed with water and with 70% alcohol.

The representatives of quaternary ammonium are Roccal (benzalkonium chloride), Aethonium, Cerigelum, Decamethoxinum.

Properly diluted, roccal is used for the preoperative disinfection of unbroken skin and prophylactic disinfection of the intact skin, in the treatment of superficial injuries and infected wounds. It is also used to preserve the sterility of surgical instruments and rubber articles during storage, and to preserve the sterility of ophthalmic solutions. Aethonium and decamethoxinum are used for the treatment of trophic ulcers, stomatitis, keratitis. Finally cerigel is used for hands washing of medicine staff before surgical treatment.

Soaps are anionic detergents. They are weak antiseptic and affect only Gram positive bacteria. Their usefulness primarily resides in their cleansing action. Other antiseptics can medicate soaps.

Furacilinum (nitrofurazone) is a synthetic antibacterial nitrofuran derivative. Furacilinum acts by transforming it nitrogroup into the aminogroup that lead to inhibiting bacterial enzymes involved in carbohydrate metabolism. Organic matter (e.g., blood, pus, serum) inhibits the antibacterial action of furacilinum. Furacilinum has a wide spectrum of activity against a variety of gram-positive and gram-negative organisms, however, particularly it does not inhibit fungi or viruses. Furacilinum may be active against organisms that have developed resistance to antibiotics and sulfanilamides. It is used topically in patients with burns, for prophylaxis and treatment of infections of the skin and mucous membranes, middle and external ear caused by susceptible bacteria. Furacilinum solutions have been used as a bladder irrigant in catheterized patients.

Allergic contact dermatitis is the most frequently reported adverse effect of topical furacilinum and has occurred in approximately 1% of patients treated.

Novoimaninum is antigerm agent, obtaining from the plant Hyperici perforatum. It acts primary on Gram positive microorganisms, including penicillin-resistance staphylococci. Novoimaninum has used topically as solution for abscess and infective wound treatment.

Chlorophylliptum is a mixture of chlorophyls getting form Eucalyptus leaves and Myrtace seeds. It can be used for the treatment of burns, trophic ulcers.

Lysocim is the protein structure enzyme. It is produced from hen egg protein. Lysocim breaks polycarbohydrates of cell membrane, acts mostly on Gram positive germs. In addition it stimulate host non-specific resistance, cause anti-inflammation and mucolytic action. Lysocim is used for chronic septic state, burns, conjunctivitis. It applies topically and injects intramusculary. It has not irritant action.

title: Antimicrobial Agents I


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TOC calls for hypertext
With the use of the code , the Wikimedia Ethics/TOC can be easily shared by the subpages.

No Wikimedia without hypertext! Then, Wikimedia Ethics in origin may well begin with hypertext or hyperlinking, which in turn may well begin with TOC in a way, as shown on the right. It would be immoral or improper for Wikimedia to avoid or neglect hyperlinking to the right or relevant information, just as Wikipedia should refer to the "world encyclopedia" as a highly, if not the most, relevant historical model, regardless of the substantial influence but regarding the similarity and disparity. --KYPark 17:31, 27 March 2011 sig added by Abd 00:16, 28 March 2011 (UTC)
 * Don't you think "immoral" is a bit dramatic, KYP?
 * There are many subpages, only some of which would be appropriate to include in the "TOC" page. It's not really a TOC page, but a directory of subpages considered important enough to list across all subpages, or most of them.
 * I think the links on the TOC page, by the way, are subpage links that use the current superpage base, so when this is transcluded to a Talk page, it displays, not the resource pages, but talk pages, which is why the transclusion here had redlinks, those pages didn't have Talk pages.... --Abd 00:16, 28 March 2011 (UTC)

title: Talk:Wikimedia Ethics/TOC