Inotropic drugs. Chronotropic and inotropic effect Features of the influence of nerves

13.08.2020

What are negative and positive inotropic effects? These are the efferent pathways that go to the heart from the centers of the brain and together with them are the third level of regulation.

Discovery history

The influence that the vagus nerves have on the heart was first discovered by the brothers G. and E. Weber in 1845. They found that as a result of electrical stimulation of these nerves, there is a decrease in strength and heart rate, that is, an inotropic and chronotropic effect is observed. At the same time, the excitability of the heart muscle decreases (batmotropic negative effect) and, along with it, the speed with which excitation moves along the myocardium and the conducting system (dromotropic negative effect).

For the first time he showed how irritation of the sympathetic nerve affects the heart, I.F. Zion in 1867, and then studied it in more detail by I.P. Pavlov in 1887. The sympathetic nerve affects the same areas of the heart as the vagus, but in the opposite direction. It manifests itself in a stronger contraction of the atrial ventricles, heart palpitations, increased cardiac excitability and faster conduction of excitation (positive inotropic effect, chronotropic, batmotropic and dromotropic effects).

Innervation of the heart

The heart is an organ that is rather strongly innervated. An impressive number of receptors located in the walls of its chambers and in the epicardium give reason to consider it a reflexogenic zone. The most important in the field of sensitive formations of this organ are two types of populations of mechanoreceptors, which are located mostly in the left ventricle and atria: A-receptors, which respond to changes in the stress of the heart wall, and B-receptors, which are excited during its passive stretching.

In turn, afferent fibers associated with these receptors are among the vagus nerves. The free sensory endings of the nerves located under the endocardium are the terminals of the centripetal fibers that make up the sympathetic nerves. It is generally accepted that these structures are directly involved in the development of pain syndrome, radiating segmentally, which characterizes the attacks of ischemic disease. The inotropic effect is of interest to many.

Efferent innervation

Efferent innervation occurs due to both parts of the ANS. The sympathetic preanglionic neurons involved in it are located in the gray matter in the three upper thoracic segments in the spinal cord, namely in the lateral horns. In turn, preanglionic fibers move to the neurons of the sympathetic ganglion (upper thoracic). The postganglionic fibers, together with the parasympathetic vagus nerve, create the upper, middle and lower nerves of the heart.

The entire organ is pierced by sympathetic fibers, while they innervate not only the myocardium, but also the components of the conducting system. The parasympathetic preanglionic neurons involved in cardiac innervation of the body are located in the medulla oblongata. Axons related to them move among the vagus nerves. After the vagus nerve enters the chest cavity, branches that are included in the nerves of the heart depart from it.

Derivatives of the vagus nerve, which pass in the number of cardiac nerves, are parasympathetic preganglionic fibers. Excitation from them passes to intramural neurons, and then, first of all, to the components of the conducting system. The influences that are mediated by the right vagus nerve are mainly addressed to the cells of the sinoatrial node, and the left to the atrioventricular. The vagus nerves cannot directly affect the ventricles of the heart. This is the basis of the inotropic effect of cardiac glycosides.

Intramural neurons

Intramural neurons are also found in the heart in large numbers, and they can be located both singly and collected in the ganglion. The bulk of these cells are located next to the sinoatrial and atrioventricular nodes, forming, together with the efferent fibers located in the interatrial septum, the intracardiac plexus of nerves. It contains all those elements that are needed in order to close the local reflex arcs. It is for this reason that the intramural nervous cardiac apparatus is in some cases referred to as the metasympathetic system. What else is interesting about the inotropic effect?

Features of the influence of nerves

While the autonomic nerves innervate the pacemaker tissue, they can affect their excitability and thus cause changes in the frequency of generation of action potentials and heart rate (chronotropic effect). Also, the influence of nerves can change the rate of electrotonic transmission of excitation, and hence the duration of the phases of the heart cycle (dromotropic effects).

Since the action of mediators in the composition of the autonomic nervous system contains a change in energy metabolism and the level of cyclic nucleotides, in general, autonomic nerves can affect the strength of heart contractions, that is, an inotropic effect. Under the influence of neurotransmitters in laboratory conditions, the effect of changing the value of the excitation threshold of cardiomyocytes, which is designated as batmotropic, was achieved.

All of these pathways by which the nervous system influences myocardial contractile activity and cardiac pumping function are of course of exceptional importance, but are secondary to myogenic mechanisms that modulate influences. Where is there a negative inotropic effect?

The vagus nerve and its influence

As a result of stimulation of the vagus nerve, a chronotropic negative effect appears, and against its background - a negative inotropic effect (we will consider the drugs below) and dromotropic. There are constant tonic influences of bulbar nuclei on the heart: if it is cut bilaterally, the heart rate increases from one and a half to two and a half times. If the irritation is strong and prolonged, then the influence of the vagus nerves weakens over time or stops altogether. This is called the "escape effect" of the heart from the corresponding influence.

Selecting a mediator

With irritation of the vagus nerve, a chronotropic negative effect is associated with inhibition (or slowing down) of impulse generation in the driver of the heart rate of the sinus node. At the endings of the vagus nerve, when it is irritated, a mediator, acetylcholine, is released. Its interaction with muscarinic-sensitive cardiac receptors increases the permeability of the surface of the cell membrane of pacemakers for potassium ions. As a result, membrane hyperpolarization appears, slowing down or suppressing the development of slow spontaneous diastolic depolarization, as a result of which the membrane potential reaches a critical level later, which affects the slowing down of the heart rate. With strong stimulation of the vagus nerve, diastolic depolarization is suppressed, hyperpolarization of pacemakers appears, and the heart completely stops.

During vagal stimulation, the amplitude and duration of atrial cardiomyocytes decreases. When the vagus nerve is excited, the threshold for atrial irritation rises, automation is suppressed and the conduction of the atrioventricular node slows down.

Electrical stimulation of fibers

Electrical stimulation of the fibers that extend from the stellate ganglion has the effect of accelerating the heart rate and increasing myocardial contractions. In addition, the inotropic effect (positive) is associated with an increase in the permeability of the cardiomyocyte membrane for calcium ions. If the incoming calcium current increases, the level of electromechanical coupling expands, resulting in an increase in myocardial contractility.

Inotropic drugs

Inotropic drugs are drugs that increase myocardial contractility. The most famous are cardiac glycosides ("Digoxin"). In addition, there are non-glycoside inotropic drugs. They are used only in acute heart failure or when there is severe decompensation in patients with chronic heart failure. The main non-glycoside inotropic drugs are: "Dobutamine", "Dopamine", "Norepinephrine", "Adrenaline". So, the inotropic effect in the activity of the heart is a change in the force with which it contracts.

Drugs with inotropic action include cardiac glycosides, β-adrenoreceptor agonists, and phosphodiesterase inhibitors. The drugs of these groups increase the concentration of intracellular calcium, which is accompanied by an increase in myocardial contractility and an upward shift of the Frank-Starling curve (Fig. 9.10). As a consequence, stroke volume and SV increase at any end-diastolic volume (preload). These drugs are indicated for the treatment of patients with LV systolic but not diastolic dysfunction.

Figure: 9.10. Changes in the pressure - LV volume curve (Frank-Sterling curve) during therapy for heart failure. Point a corresponds to CH (the curve is shifted downward). In heart failure, the stroke volume is reduced (before the development of arterial hypotension) and the end-diastolic pressure of the LV is increased, which is accompanied by symptoms of pulmonary congestion. Therapy with diuretics or drugs that have a venodilating effect (point b on the same curve) reduces pressure in the LV without significant changes in stroke volume (SV). However, an excessive increase in urine output or severe venodilation can lead to an undesirable decrease in YO and arterial hypotension (point b). Against the background of taking inotropic drugs (point c) or vasodilators acting mainly on the arteriolar bed (as well as combined vasodilators) (point d), the SV increases and the LV end-diastolic pressure decreases (due to a more complete ejection of blood during systole). Point e reflects the possible positive effect of combination therapy with inotropic and vasodilator drugs. The dotted line shows an increase in the Frank-Starling curve against the background of therapy with inotropic and vasodilator drugs (which, however, does not reach the level of functional activity of the normal LV)

Patients with a severe form of the disease receiving treatment in a hospital are sometimes injected intravenously with β-adrenoreceptor agonists (dobutamine, dopamine) to temporarily maintain hemodynamic parameters. Long-term use of these drugs is limited due to the lack of dosage forms for oral administration and rapidly developing tolerance - a progressive decrease in their therapeutic efficacy due to a decrease in the number of adrenergic receptors in the myocardium according to the feedback principle. Phosphodiesterase inhibitors are commonly used in severe functional class III – IV heart failure requiring intravenous therapy. Despite the high efficiency of phosphodiesterase inhibitors at the beginning of treatment, the results of clinical studies indicate that therapy with these drugs does not significantly increase the life expectancy of patients.

In clinical practice, of all inotropic drugs, the most widespread are cardiac glycosides, which are prescribed both intravenously and orally. Cardiac glycosides increase myocardial contractility, decrease LV dilatation, increase CO, and help relieve HF symptoms. While taking cardiac glycosides, the sensitivity of baro-receptors increases, and, therefore, the sympathetic tone reflexively decreases, which leads to a decrease in LV afterload in patients with heart failure. In addition, cardiac glycosides can control heart rate, which has an additional positive effect in patients with concomitant atrial fibrillation. Therapy with cardiac glycosides alleviates the symptoms of heart failure, but does not increase the life expectancy of patients in this category. Drugs of this class are impractical to use in the treatment of patients with LV diastolic dysfunction, since they do not improve ventricular relaxation.

p-blockers

Previously, it was believed that β-blockers are contraindicated in systolic LV dysfunction, since their negative inotropic effect can lead to an increase in the symptoms of the disease. At the same time, the results of recent clinical studies indicate that therapy with β-blockers paradoxically promotes an increase in CO and normalization of hemodynamic parameters. The mechanism of this phenomenon has not yet been studied, but it is believed that a decrease in heart rate, weakening of sympathetic tone and the anti-ischemic effect of β-blockers can play a positive role in these cases. Currently, the use of β-blockers in the treatment of patients with heart failure remains the subject of clinical studies.

Adrenalin... This hormone is formed in the adrenal medulla and adrenergic nerve endings, is a direct-acting catecholamine, stimulates several adrenergic receptors at once: and 1 -, beta 1 - and beta 2 - Stimulation and 1 -adrenergic receptors is accompanied by a pronounced vasoconstrictor effect - a general systemic vasoconstriction, including precapillary vessels of the skin, mucous membranes, renal vessels, as well as pronounced narrowing of the veins. Stimulation of beta 1 -adrenergic receptors is accompanied by a distinct positive chronotropic and inotropic effect. Stimulation of beta 2 -adrenergic receptors causes bronchial expansion.

Adrenalin often irreplaceable in critical situations, since it can restore spontaneous cardiac activity during asystole, increase blood pressure during shock, improve the automatism of the heart and myocardial contractility, and increase heart rate. This drug relieves bronchospasm and is often the drug of choice for anaphylactic shock. It is used mainly as a first aid and rarely for long-term therapy.

Solution preparation. Epinephrine hydrochloride is available as a 0.1% solution in 1 ml ampoules (at a dilution of 1: 1000 or 1 mg / ml). For intravenous infusion, 1 ml of a 0.1% solution of epinephrine hydrochloride is diluted in 250 ml of isotonic sodium chloride solution, which creates a concentration of 4 μg / ml.

1) for any form of cardiac arrest (asystole, VF, electromechanical dissociation), the initial dose is 1 ml of a 0.1% solution of epinephrine hydrochloride, diluted in 10 ml of isotonic sodium chloride solution;

2) with anaphylactic shock and anaphylactic reactions - 3-5 ml of a 0.1% solution of epinephrine hydrochloride, diluted in 10 ml of isotonic sodium chloride solution. Subsequent infusion at a rate of 2 to 4 mcg / min;

3) with persistent arterial hypotension, the initial injection rate is 2 μg / min, in the absence of an effect, the rate is increased until the required blood pressure level is reached;

4) action depending on the rate of introduction:

Less than 1 mcg / min - vasoconstrictor,

1 to 4 mcg / min - cardiac stimulating,

5 to 20 μg / min - and-adrenostimulating,

More than 20 mcg / min - the predominant a-adrenostimulating.

Side effect: adrenaline can cause subendocardial ischemia and even myocardial infarction, arrhythmias and metabolic acidosis; small doses of the drug can lead to acute renal failure. In this regard, the drug is not widely used for long-term intravenous therapy.

Norepinephrine ... Natural catecholamine, which is a precursor to adrenaline. It is synthesized in the postsynaptic endings of the sympathetic nerves, carries out a neurotransmitter function. Norepinephrine stimulates and-, beta 1 -adrenergic receptors, almost does not affect beta 2 -adrenergic receptors. It differs from adrenaline in a stronger vasoconstrictor and pressor effect, a lesser stimulating effect on the automatism and contractile ability of the myocardium. The drug causes a significant increase in peripheral vascular resistance, reduces blood flow in the intestines, kidneys and liver, causing severe renal and mesenteric vasoconstriction. The addition of small doses of dopamine (1 μg / kg / min) promotes the maintenance of renal blood flow when norepinephrine is administered.

Indications for use: persistent and significant hypotension with a fall in blood pressure below 70 mm Hg, as well as with a significant decrease in TPR.

Solution preparation. Contents of 2 ampoules (4 mg of norepinephrine hydrotartrate is diluted in 500 ml of isotonic sodium chloride solution or 5% glucose solution, which creates a concentration of 16 μg / ml).

The initial rate of administration is 0.5-1 μg / min by titration until the effect is obtained. Doses of 1-2 mcg / min increase the CO, over 3 mcg / min have a vasoconstrictor effect. In refractory shock, the dose may be increased to 8-30 mcg / min.

Side effect. With prolonged infusion, renal failure and other complications (gangrene of the extremities) associated with the vasoconstrictor effect of the drug may develop. With extravasal administration of the drug, necrosis may appear, which requires chipping of the extravasate site with a phentolamine solution.

Dopamine ... It is the precursor to norepinephrine. It stimulates and-and beta receptors, has a specific effect only on dopaminergic receptors. The effect of this drug is largely dose dependent.

Indications for use: acute heart failure, cardiogenic and septic shock; the initial (oliguric) stage of acute renal failure.

Solution preparation. Dopamine hydrochloride (dopamine) is available in 200 mg ampoules. 400 mg of the drug (2 ampoules) is diluted in 250 ml of isotonic sodium chloride solution or 5% glucose solution. In this solution, the concentration of dopamine is 1600 μg / ml.

Intravenous doses: 1) the initial rate of administration is 1 μg / (kg-min), then it is increased until the desired effect is obtained;

2) small doses - 1-3 μg / (kg-min) are administered intravenously; while dopamine acts mainly on the celiac and especially the renal region, causing vasodilation of these areas and contributing to an increase in renal and mesenteric blood flow; 3) with a gradual increase in the speed to 10 μg / (kg-min), peripheral vasoconstriction and pulmonary occlusive pressure increase; 4) large doses - 5-15 μg / (kg-min) stimulate beta 1 -receptors of the myocardium, have an indirect effect due to the release of norepinephrine in the myocardium, i.e. have a distinct inotropic effect; 5) in doses over 20 μg / (kg-min) dopamine can cause vasospasm of the renal and mesenteric vessels.

To determine the optimal hemodynamic effect, it is necessary to monitor hemodynamic parameters. If tachycardia occurs, it is recommended to reduce the dose or stop further administration. Do not mix the drug with sodium bicarbonate, as it is inactivated. Long-term use and- and beta-agonists reduces the effectiveness of beta-adrenergic regulation, the myocardium becomes less sensitive to the inotropic effects of catecholamines, up to a complete loss of the hemodynamic response.

Side effect: 1) an increase in DZLK, the appearance of tachyarrhythmias is possible; 2) in large doses, it can cause severe vasoconstriction.

Dobutamine(dobutrex). It is a synthetic catecholamine with a pronounced inotropic effect. Its main mechanism of action is stimulation beta-receptors and an increase in myocardial contractility. Unlike dopamine, dobutamine lacks a splanchnic vasodilatory effect, but tends to be systemically vasodilated. It increases heart rate and PWD to a lesser extent. In this regard, dobutamine is indicated in the treatment of heart failure with low CO, high peripheral resistance against a background of normal or elevated blood pressure. When using dobutamine, like dopamine, ventricular arrhythmias are possible. An increase in heart rate by more than 10% of the initial level can cause an increase in the zone of myocardial ischemia. In patients with concomitant vascular lesions, ischemic necrosis of the fingers is possible. In many patients treated with dobutamine, systolic blood pressure increased by 10-20 mm Hg, and in some cases, hypotension.

Indications for use. Dobutamine is prescribed for acute and chronic heart failure caused by cardiac (acute myocardial infarction, cardiogenic shock) and non-cardiac causes (acute circulatory failure after injury, during and after surgery), especially in cases where the average blood pressure is above 70 mm Hg. Art., and the pressure in the system of the small circle is higher than normal values. Prescribed for increased ventricular filling pressure and risk of overloading the right heart, leading to pulmonary edema; with a reduced MOS due to the PEEP mode during mechanical ventilation. During treatment with dobutamine, like other catecholamines, careful monitoring of heart rate, heart rate, ECG, blood pressure and infusion rate is necessary. Hypovolemia must be corrected before starting treatment.

Solution preparation. A vial of dobutamine containing 250 mg of the drug is diluted in 250 ml of 5% glucose solution to a concentration of 1 mg / ml. Saline dilution solutions are not recommended as SG ions may interfere with dissolution. Do not mix dobutamine solution with alkaline solutions.

Side effect. In patients with hypovolemia, tachycardia is possible. According to P. Marino, ventricular arrhythmias are sometimes observed.

Contraindicated with hypertrophic cardiomyopathy. Because of its short half-life, dobutamine is given continuously intravenously. The action of the drug occurs in the period from 1 to 2 minutes. It usually takes no more than 10 minutes to create its stable concentration in plasma and to ensure maximum action. A loading dose is not recommended.

Doses. The rate of intravenous administration of the drug, required to increase the stroke and cardiac output, ranges from 2.5 to 10 μg / (kg-min). It is often required to increase the dose to 20 μg / (kg-min), in more rare cases - over 20 μg / (kg-min). Dobutamine doses above 40 mcg / (kg-min) can be toxic.

Dobutamine can be used in combination with dopamine to increase systemic blood pressure during hypotension, increase renal blood flow and urinary output, and prevent the risk of pulmonary overload observed with dopamine alone. The short half-life of beta-adrenergic receptor stimulants, equal to several minutes, allows very quick adaptation of the administered dose to the needs of hemodynamics.

Digoxin ... Unlike beta-adrenergic agonists, digitalis glycosides have a long half-life (35 hours) and are eliminated by the kidneys. Therefore, they are less manageable and their use, especially in intensive care units, carries the risk of possible complications. If sinus rhythm is maintained, their use is contraindicated. With hypokalemia, renal failure against the background of hypoxia, manifestations of digitalis intoxication occur especially often. The inotropic effect of glycosides is due to the inhibition of Na-K-ATPase, which is associated with the stimulation of Ca 2+ metabolism. Digoxin is indicated for atrial fibrillation with VT and paroxysmal atrial fibrillation. For intravenous injections in adults, it is used in a dose of 0.25-0.5 mg (1-2 ml of a 0.025% solution). Inject it slowly into 10 ml of 20% or 40% glucose solution. In emergency situations, 0.75-1.5 mg of digoxin is diluted in 250 ml of a 5% dextrose or glucose solution and administered intravenously for 2 hours. The required serum level of the drug is 1-2 ng / ml.

VASODILATORS

Nitrates are used as fast-acting vasodilators. The drugs of this group, causing the expansion of the lumen of blood vessels, including coronary vessels, affect the state of pre- and afterload, and in severe forms of heart failure with high filling pressure, significantly increase CO.

Nitroglycerine ... The main action of nitroglycerin is to relax vascular smooth muscles. In low doses, it provides a venodilating effect, in high doses, it also dilates arterioles and small arteries, which causes a decrease in systemic vascular resistance and blood pressure. Providing a direct vasodilator effect, nitroglycerin improves the blood supply to the ischemic region of the myocardium. The use of nitroglycerin in combination with dobutamine (10-20 μg / (kg-min) is indicated in patients with a high risk of developing myocardial ischemia.

Indications for use: angina pectoris, myocardial infarction, heart failure with adequate blood pressure; pulmonary hypertension; high level of OPSS with increased blood pressure.

Solution preparation: 50 mg of nitroglycerin is diluted in 500 ml of solvent to a concentration of 0.1 mg / ml. Doses are selected by titration.

Doses for intravenous administration. The initial dose is 10 μg / min (low doses of nitroglycerin). The dose is gradually increased - every 5 minutes by 10 mcg / min (high doses of nitroglycerin) - until a clear effect on hemodynamics is obtained. The highest dose is up to 3 μg / (kg-min). In case of an overdose, hypotension and exacerbation of myocardial ischemia are possible. Intermittent therapy is often more effective than long-term administration. For intravenous infusions, systems made of polyvinyl chloride should not be used, since a significant part of the drug is deposited on their walls. Systems made of plastic (polyethylene) or glass vials are used.

Side effect. Causes the conversion of part of hemoglobin into methemoglobin. An increase in the level of methemoglobin up to 10% leads to the development of cyanosis, and a higher level is life-threatening. To lower the high level of methemoglobin (up to 10%), a solution of methylene blue (2 mg / kg for 10 minutes) should be injected intravenously [Marino P., 1998].

With prolonged (from 24 to 48 hours) intravenous administration of a nitroglycerin solution, tachyphylaxis is possible, characterized by a decrease in the therapeutic effect in cases of repeated administration.

After the use of nitroglycerin with pulmonary edema, hypoxemia occurs. A decrease in PaO 2 is associated with an increase in blood shunting in the lungs.

After using high doses of nitroglycerin, ethanol intoxication often develops. This is due to the use of ethyl alcohol as a solvent.

Contraindications: increased intracranial pressure, glaucoma, hypovolemia.

Sodium nitroprusside - a fast-acting balanced vasodilator that relaxes the smooth muscles of both veins and arterioles. Has no pronounced effect on heart rate and heart rate. Under the influence of the drug, OPSS and blood return to the heart decrease. At the same time, coronary blood flow increases, CO increases, but myocardial oxygen demand decreases.

Indications for use. Nitroprusside is the drug of choice in patients with severe hypertension and low CO. Even a slight decrease in OPSS in myocardial ischemia with a decrease in the pumping function of the heart contributes to the normalization of CO. Nitroprusside has no direct effect on the heart muscle, it is one of the best drugs in the treatment of hypertensive crises. It is used for acute left ventricular failure without signs of arterial hypotension.

Solution preparation: 500 mg (10 ampoules) of sodium nitroprusside are diluted in 1000 ml of solvent (concentration 500 mg / l). Store in a place well protected from light. Freshly prepared solution has a brownish tint. The darkened solution is not suitable for use.

Doses for intravenous administration. The initial rate of administration is from 0.1 μg / (kg-min), with low SV - 0.2 μg / (kg-min). In case of hypertensive crisis, treatment begins with 2 μg / (kg-min). The usual dose is 0.5 - 5 mcg / (kg-min). The average injection rate is 0.7 μg / kg / min. The highest therapeutic dose is 2-3 μg / kg / min for 72 hours.

Side effect. With prolonged use of the drug, cyanide intoxication is possible. This is due to the depletion of thiosulfite reserves in the body (in smokers, in case of malnutrition, vitamin B 12 deficiency), which takes part in the inactivation of cyanide formed during the metabolism of nitroprusside. In this case, the development of lactic acidosis is possible, accompanied by headache, weakness and arterial hypotension. Thiocyanate intoxication is also possible. Cyanides formed during the metabolism of nitroprusside in the body are converted to thiocyanate. The accumulation of the latter occurs with renal failure. The toxic plasma concentration of thiocyanate is 100 mg / L.

Intravenous doses:

3) with persistent arterial hypotension, the initial injection rate is 2 μg / min, in the absence of an effect, the rate is increased until the required blood pressure level is reached;

4) action depending on the rate of introduction:

Less than 1 mcg / min - vasoconstrictor,

1 to 4 mcg / min - cardiac stimulating,

5 to 20 μg / min - and-adrenostimulating,

More than 20 mcg / min - the predominant a-adrenostimulating.

Indications for use: persistent and significant hypotension with a fall in blood pressure below 70 mm Hg, as well as with a significant decrease in TPR.

Indications for use: acute heart failure, cardiogenic and septic shock; the initial (oliguric) stage of acute renal failure.

Intravenous doses: 1) the initial rate of administration is 1 μg / (kg-min), then it is increased until the desired effect is obtained;

Side effect: 1) an increase in DZLK, the appearance of tachyarrhythmias is possible; 2) in large doses, it can cause severe vasoconstriction.

Side effect. In patients with hypovolemia, tachycardia is possible. According to P. Marino, ventricular arrhythmias are sometimes observed.

VASODILATORS

Indications for use: angina pectoris, myocardial infarction, heart failure with adequate blood pressure; pulmonary hypertension; high level of OPSS with increased blood pressure.

Solution preparation: 50 mg of nitroglycerin is diluted in 500 ml of solvent to a concentration of 0.1 mg / ml. Doses are selected by titration.

After the use of nitroglycerin with pulmonary edema, hypoxemia occurs. A decrease in PaO 2 is associated with an increase in blood shunting in the lungs.

After using high doses of nitroglycerin, ethanol intoxication often develops. This is due to the use of ethyl alcohol as a solvent.

Contraindications: increased intracranial pressure, glaucoma, hypovolemia.

2. Negative chronotropic (based on inotropic action).

Bradycardia due to inclusion of the vagus nerve:

a) synocardial effect

If the work of the heart increases - pressure increases - the baroreceptors of the sinoaortic zone begin to respond - impulses go to the nucleus of the vagus nerve - slowing down the heart.

b) cardiocardial effect

With an increase in the force of contraction, a stronger compression also occurs - special receptors located in the myocardium itself react - impulses to the nucleus of the vagus nerve - slowing down the heart.

Heart failure is accompanied by congestion in the venous system, especially in the mouths of the vena cava (there are receptors there). The more stagnation - the greater the effect on the sympathetic centers - an increase in the frequency of contractions. Cardiac glycosides increase heart function and eliminate congestion.

Additionally, when exposed to cardiac glycosides, hypoxia (which reduces the critical level of depolarization of the sinus node) decreases - action potentials arise more slowly - the heart rate decreases.

In total:

Increase:

efficiency, stroke volume, pumping function of the heart, coronary blood flow, minute blood volume (despite slowing down the frequency of contractions), blood circulation, pressure, blood flow velocity, urination (renal blood flow increases) - the volume of circulating blood decreases.

Decrease:

period of reaching maximum tension, residual volume, venous pressure (+ increased venous tone), portal hypertension, stagnation of blood in the tissues - edema disappears.

(fraction of elimination) Polar does not bind to proteins - fast and strong effect and rapid elimination through the kidneys

CED is a feline unit of action - the amount of the drug is sufficient to cause cardiac arrest in a cat during systole.

Digitalis preparations bind up to 80% - circulate in the enterohepatic circle:

Gastrointestinal tract - liver - with bile in the gastrointestinal tract - into the liver and so on.

Comparative characteristics of Digitalis preparations:

Lack of cardiac glycosides - very small therapeutic latitude

Subtherapeutic dose	0.8	20
Therapeutic	0.9-2.0	20-35
Toxic	3.0	45-50

Intoxication

Pronounced bradycardia with the appearance of dromotropic action (atrio-ventricular delay).

1. Decrease in potassium concentration - violation of conduction

2. Block of SH-groups of enzymes - impaired conduct

3. An increase in the PQ interval (or complete atrioventricular block) - should alert (toxic effects).

If the dose is still increased, the batmotropic effect appears.

1. Increased calcium intake - a steeper increase in depolarization

2. Decrease in potassium - decrease in the level of critical depolarization

3. Violation of atrio-ventricular conduction

All this leads to the fact that the ventricles begin to contract independently of the atria - obvious glycosidic intoxication - requires special treatment: potassium preparations, complexones that bind calcium (magnesium and sodium EDTA salts - ethylenediaminetetraacetic acid), SH-group donors, in the west - the introduction of antibodies to Digitalis (Digitalis).

1. Nausea and vomiting, including with parenteral administration (central action - receptors in the vomiting center).

2. Visual impairment, xanthopsia (seeing everything in yellow light).

3. Headaches, dizziness

4. Neurotoxic disorders before delirium Disappear only with drug withdrawal

Factors that increase sensitivity to cardiac glycosides

1 Older age

2 Severe heart failure (late stage)

3 Pulmonary failure, hypoxia

4 Renal failure

5 Electrolyte disturbances (especially hypokalemia)

6 Violations of the acid-base state (therefore combined with diuretics)

The effect is weaker than cardiac glycosides, is the drug of choice for pulmonary insufficiency (reflex respiration stimulation), is a surfactant - displaces toxins.

Disadvantages:

The oil solution - therefore injected subcutaneously - is painful, the effect develops slowly - therefore it is not used in emergency conditions.

Should not be applied. They increase the work of the heart by 20%, but at the same time increase the oxygen consumption of the heart by 5-7 times. Used for cardiogenic shock - Dopamine. Stimulates the heart + dilates blood vessels, Dobutamine is more effective (selective beta-1 mimetic).

HYPERKALIEMIA

1. Kidney disease Secreted in the distal tubules. Potassium-sparing

there is no mechanism.

2. Aldosterone deficiency

3. Overdose of K-drugs.

For the synthesis of protein and glycogen, a fairly large amount of potassium is required.

Changes in the surface potential of the cell, changes in myocardial activity, conduction disturbances with the transition to an independent rhythm, cessation of myocardial excitability due to the impossibility of the emergence of cellular potential.

HYPOCALYEMIA

Operations on the gastrointestinal tract, diarrhea, vomiting, a decrease in potassium consumption, the use of ion exchange substances, acidosis, alkalosis (not compensated for 5-6 days).

Decrease in muscle activity, decrease in conductivity and excitability of muscle tissue.

Regulation of calcium metabolism

Parathyroid hormone - calcium retention in the blood (increased reabsorption of calcium in the kidneys).

Vitamin B3 - transport of calcium from the intestine to the bone (bone ossification).

Calcitonin is the transfer of calcium from the blood to the bone.

ANTI-ARRHYTHMIC DRUGS

General pharmacology

The polarization of the cytoplasmic membrane depends on the work of sodium-potassium pumps, which are affected by ischemia - arrhythmias.

Automatism

The frequency can be changed by:

1) acceleration of diastolic depolarization

2) decrease in the threshold potential

3) change in resting potential

The mechanism of arrhythmia as an object of pharmacological action

a) change in impulse conduction

b) changes in pulse generation

c) a combination of a) and b)

Change in normal automatism. Emergence of an ectopic focus Early or late trace depolarization Slowing down of rapid responses. The emergence of slow responses. The re entry mechanism (circle of excitement - re-contraction - ventricular tachycardia).

Arrhythmogenic action is possessed by:

Catecholamines, sympathomimetics, anticholinergics, changes in acid-base balance, some general anesthetics (cyclopropane), xanthine, aminophylline, thyroid hormones, ischemia and inflammation of the heart.

Classification

1 Sodium channel blockers

group A: moderate inhibition of phase 0, deceleration of impulse conduction, acceleration of repolarization (quinidine, Novocainamide, deoxypyramide)

group B: minimal inhibition of phase 0 and slowing down of depolarization, decrease in conduction (Lidocaine, Dofenin, Mexiletin)

group C: pronounced inhibition of phase 0, and slowing down of conduction (Propafenone (Ritmonorm, Propanorm))

2 Blockers of beta-2 adrenergic receptors (Obzidan)

3 Potassium channel blockers: Ornid, Amiodarone, Sotakol

4 Calcium channel blockers: Verapamil, Diltiazem.

The main mechanisms of action of antiarrhythmic drugs.

The double arrows in the diagram represent the oppressive effect.

Group A drugs

Quinidine:

Negative inotropic effect, on the ECG: QRST and QT increase.

Pharmacokinetics of group A drugs:

Half-life \u003d 6 hours, the drug is destroyed after 4-10 hours. With the induction of cytochrome P450 (Rifampicin, barbiturates), there is an increase in the destruction of quinidine in the liver.

Side effect:

1 Negative inotropic effect

2 Heart block

3 Decrease in blood pressure

4 Irritation of gastric mucosa

5 Visual impairment

Novocainamide

Half-life \u003d 3 hours. It is used for paroxysmal arrhythmias, side effects: a decrease in blood pressure, there may be an exacerbation of glaucoma. The course of treatment is no more than 3 months, with a longer one - there may be an immune pathology like lupus.

Disopyramid_. has a prolonged action (half-life \u003d 6 hours) 7

Aimaline_. is a part of "Pulsnorm" and has a sympatholytic effect. Quinidine-like action, better tolerance.

Etmozin_. - mild, quinidine-like, short-lived effect.

Etatsizin_. - longer lasting effect.

There are drugs: Bennecor, Tyracillin.

Group B drugs

Lidocaine

It binds less strongly to sodium channels, more selective in ventricular arrhythmias (since it binds to depolarized cells, which have a greater action potential in the ventricles). Low bioavailability, half-life 1.5 - 2 hours. Introduced intravenously. It is used for ventricular arrhythmias, especially in emergency conditions, in cardiac surgery, for the treatment of glycosidic intoxication.

Mexiletin_. bioavailability up to 90%.

Half-life \u003d 6-24 hours, depending on the dose. May inhibit the metabolism of anticoagulant, psychotropic drugs.

Side effects of group B drugs: decrease in blood pressure

ECG change: decrease in the QT interval.

Group C drugs

Amiodarone

Increase the PQ interval, 100% binds to plasma proteins. Withdrawal period \u003d 20 days, therefore, the risk of overdose and cumulation increases - the drug belongs to the reserve.

Bretilius_. (Ornid)

Most effective in ventricular arrhythmias.

Calcium channel blockers

Nifedipine, Verapamil, Diltiazem.

Verapamil

Increase in PP and PQ intervals. More focused on atrial arrhythmias (possibly the use of cardiac glycosides, nitrates).

URINE (diuretics)

Basic indications

Nephron as a target of pharmacological action

1 Increased glomerular filtration (possibly mainly against the background of a decrease in hemodynamics in the patient).

2 Violation of tubular reabsorption of sodium and chlorine

3 Aldosterone antagonists

4 Antidiuretic hormone antagonists

1 Osmotic diuretics

Violate the concentration ability of the kidneys. The introduction of a large dose of a non-metabolizable substance that is poorly reabsorbed and well filtered. It is introduced into the bloodstream, which leads to an increase in the volume of hyperosmotic tubular urine and an increase in the rate of urine flow - an increase in the loss of water and electrolytes.

Mannitol

Features: spreads only in the extracellular sector. Administered intravenously, drip.

Urea

Features: spreads to all sectors, getting into the intracellular sector leads to secondary overhydration. It is used intravenously or inside.

Glycerol

It is used internally.

Indications

Urgent indications for preventing an increase in intracranial pressure in heart attacks and strokes, glaucoma (especially acute), prevention of acute renal failure (in the oliguric phase), poisoning (+ hemodilution).

Classification

2 Loop diuretics

Furosemide (lasix), bumetadine (bufenox),

Ethacrynic acid (uregide) ¦

Indocrinone ¦ Ethacrynic acid derivatives

Ticrinafen ¦

1 Sodium channels of the cell

2 Combined transport of sodium, potassium and 2 chlorine ions.

3 Exchange of sodium for hydrogen cations

4 Transport of sodium with chlorine

Sodium transport

Transcellular Paracellular

Furosemide

It is secreted by the kidneys, inhibits the sodium potential, leads to an increase in the loss of calcium and magnesium. Vasodilator effect 10-15 minutes after administration before the development of the actual diuretic effect.

Application

Acute left ventricular failure, hypertensive crisis, pulmonary edema, acute and chronic renal failure, glaucoma, acute poisoning, cerebral edema.

Side effects

Hypochloremic alkalosis (chlorine ions are replaced by bicarbonate ions), hypokalemia, hyponatremia, orthostatic reactions, thromboembolic reactions, hearing impairment, gout, hyperglycemia, mucosal irritation (ethacrynic acid).

Novurite (organic compound of mercury based on theophylline). Appointment after 1-2 weeks, maximum effect after 6-12 hours.

4 Thiazides and thiazide-like

Dichlothiazide, Cyclomethioside, Chlorthalidone (Oxodolin), Chlopamid (Barinaldix).

The target is the transport of sodium and chlorine in the initial segment of the distal tubule (electrically neutral pump) - electrolyte losses (sodium, chlorine, potassium, hydrogen protons), a delay in calcium excretion (its reabsorption increases).

Indications

1 Edema of any origin (no tolerance)

2 Arterial hypertension

3 Glaucoma, recurrent nephrolithiasis

Thiazides cause:

1 Decrease in circulating blood volume

2 Reducing the amount of sodium in the vessel wall -

a) a decrease in the edema of the vessel wall - a decrease in the total peripheral vascular resistance

b) a decrease in the tone of myocytes - a decrease in the total peripheral vascular resistance

Hypokalemia, hyponatremia, hypercalcemia, hyperglycemia, alkalosis, increased cholesterol and triglyceride levels.

5 Carbonic anhydrase inhibitors

Removal of non-volatile acids while maintaining an alkaline reserve, an increase in the loss of sodium, bicarbonate, potassium, a shift in the acidity of urine to the alkaline side, and plasma to the acidic side - acidosis. Rapid tolerance develops to Diacarb within 3-4 days - therefore it is widely used:

1 In ophthalmology for the treatment of glaucoma, since carbonic anhydrase increases the flow of fluid to the eyeball

2 As an antisecretory drug for hyperacid conditions of the gastrointestinal tract

6 Potassium-sparing diuretics

1 Aldosterone antagonists

Spironolactone (its metabolites act) is a competitive antagonist of aldosterone. Decreased excretion of potassium and hydrogen, increased excretion of sodium and water.

Application

a) Hyperaldosteronism

b) In combination with other diuretics

2 Amiloride (sodium channel blocker - potassium retention),

Triamteren

7 Xanthine derivatives

Theobromine, Theophylline, Eufillin.

1 Cardiotonic effect (increased cardiac output)

2 Expansion of the vessels of the kidneys. 1 and 2 leads to improved renal blood flow -

a) increased filtration

b) decrease in renin production - decrease in aldosterone production - decrease in sodium production

Combined: Moduretic \u003d Hydrochlorothiazide + Amiloride, Triampur \u003d Hydrochlorothiazide + Tiamtren, Adelfan \u003d Hydrochlorothiazide + Reserpine + Dihydrolazine, Ezidrex

8 Phytodiuretics

Bearberry leaf, Juniper fruits, Horsetail grass, Cornflower, Lingonberry leaf, birch buds.

DRUGS AFFECTING RESPIRATORY FUNCTION

Mechanisms of broncho-obstructive syndrome:

1 Bronchospasm

2 Edema of the bronchial mucosa as a result of inflammation

3 Blockage of the lumen with sputum:

a) there is too much sputum - hypercrinia

b) sputum of high viscosity - discrimination

Ways to combat broncho-obstructive syndrome

1 Elimination of bronchospasm

2 Reduction of edema

3 Improvement of sputum discharge

Physiological mechanisms of bronchial tone regulation

1 Sympathetic autonomic nervous system

2 Parasympathetic autonomic nervous system

Parasympathetic

M-cholinergic receptors are located throughout the bronchial tree. The receptor is associated with a membrane enzyme - guanylate cyclase. This enzyme catalyzes the conversion of GTP into the cyclic form of HMP. When the receptor is activated, cGMP accumulates - calcium channels open. Extracellular calcium enters the cell. When the concentration of calcium in the cell reaches a certain value, bound calcium leaves the depot (mitochondria, Golgi complex). The total concentration of calcium increases, which leads to a stronger contraction - the tone of the smooth muscles of the bronchi increases - bronchospasm -\u003e M-anticholinergics can be used as a treatment.

Sympathetic

The effect of activating beta-1 adrenergic receptors.

1 Heart - enlargement:

Heart rate, contraction force, heart muscle tone, atrioventricular conduction velocity, excitability ---\u003e pacing.

2 Adipose tissue - lipolysis

3 Kidneys (juxtaglomerular apparatus) - Renin release

The effect of activating beta-2 adrenergic receptors

1 Bronchi (preferred location) - dilation

2 Skeletal muscle - increased glycogenolysis

3 Peripheral vessels - relaxation

4 Pancreatic tissue - increased insulin release - decreased blood glucose concentration.

5 Intestines - decrease in tone and peristalsis

6 Uterus - relaxation.

Receptor locations are provided to illustrate potential side effects.

Beta-2 adrenergic receptors are associated with the membrane enzyme adenylate cyclase, which catalyzes the conversion of ATP to cAMP. When a certain concentration of cAMP accumulates, calcium channels close - the concentration of calcium inside the cell decreases - calcium enters the depot - muscle tone decreases - bronchodilation occurs -\u003e adrenomimetics can be used as a treatment.

One of the most characteristic examples of broncho-obstructive syndrome is bronchial asthma_ .. Bronchial asthma is a disease that is heterogeneous in its mechanism:

a) Atopic variant ("true" bronchial asthma) - bronchial obstruction in response to a meeting with a strictly specific allergen.

b) Infectious bronchial asthma - there is no clear dependence on the allergen, a specific allergen is not detected.

In the atopic variant, upon repeated encounter with the antigen, degranulation of mast cells occurs - histamine is released. Among the effects of histamine is bronchoconstriction.

There are 2 types of histamine receptors. In this case, type 1 histamine receptors located in the bronchial wall are considered. The mechanism of action is similar to the mechanism of action of M-cholinergic receptors - it would be logical to assume that histamine blockers can be used, but histamine blockers are not used. Histamine blockers are competitive inhibitors, and in bronchial asthma, so much histamine is released that it displaces histamine blockers from the connection with the receptor.

Real mechanisms for dealing with excess

the amount of histamine

1 Stabilization of mast cell membranes

2 Increasing the resistance of mast cells to degranulating agents.

Classification

1 Bronchospasmolytics

1.1 Neurotropic

1.1.1 Adrenomimetics

1.1.2 M-anticholinergics

1.2 Myotropic

2 Anti-inflammatory drugs

3 Expectorants (agents that regulate the excretion of phlegm)

Additional funds - antimicrobial (only in the presence of infection)

Adrenomimetics

1 Alpha and beta adrenergic agonists (non-selective) Epinephrine hydrochloride, Ephedrine hydrochloride, Dephedrine

2 Beta-1 and beta-2 adrenergic agonists

Izadrin (Novodrin, Euspiran), Orciprenaline sulfate (Astmopent, Alupent)

3 Beta-2 adrenergic agonists (selective)

a) the average duration of action Fenoterol (Berotek), Salbutamol (Ventonil), Terbutolin, (Brickalin), Hexoprenaline (Ipradol).

b) long-acting

Clembuterol (Contraspazmin), Salmetirol (Serelent), Formoterol (Foradil).

Adrenalin

Has a strong bronchodilatory and anti-anaphylactic activity, additionally affects the alpha-adrenergic receptors of blood vessels - spasm - reduction of edema.

1 Peripheral vasospasm (effect on alpha-adrenergic receptors) - an increase in total peripheral vascular resistance - an increase in blood pressure.

2 Effects of cardiac stimulation (tachycardia, increased excitability of the heart - arrhythmias).

3 Pupil dilation, muscle tremor, hyperglycemia, suppression of peristalsis.

Due to the large number of side effects, it is used for the treatment of bronchial asthma only if there are no other drugs. It is used to relieve asthma attacks: 0.3-0.5 ml subcutaneously. The onset of action is 3-5 minutes, the duration of action is about 2 hours. Tachyphylaxis develops rapidly (a decrease in the effect of each subsequent drug intake).

In tablet form, it is used to prevent attacks of suffocation, when administered subcutaneously or intramuscularly - to stop them. In tablet form, the onset of action is 40-60 minutes, the duration of action is 3-3.5 hours. It has a lower affinity for alpha-adrenergic receptors than adrenaline, therefore it causes less hyperglycemia and cardiac stimulation. Penetrates the blood-brain barrier and causes addiction and addiction - "ephedronic substance abuse". As a result of this effect, it is subject to special consideration and, therefore, is inconvenient to use.

Ephedrine is part of the combination drugs:

Bronholitin, Solutan, Teofedrin.

Izadrin_. - rarely used.

Orciprenaline sulfate

In inhalation form, it is used to relieve asthma attacks. Onset of action in 40-50 seconds, duration of action 1.5 hours. In tablets, it is used to prevent seizures. Onset of action in 5-10 minutes, duration of action 4 hours.

There is such a dosage form as aerosols. They contain a repellent - a substance that boils at a low temperature and helps to spray the drug. Inhalation is performed at maximum inspiration. With the 1st inhalation, 60% of the maximum effect is achieved, with the 2nd inhalation 80%, with the 3rd and subsequent inhalations, the effect increases by about 1%, but the side effects increase sharply. Therefore, for medium-acting drugs, about 8 doses per day are prescribed, and for long-acting drugs, 4-6 doses per day (1 dose is the amount of the drug that enters the patient's body in 1 inhalation). The drug used by inhalation is not normally absorbed, it acts locally.

Side effect (in case of overdose):

1 Syndrome of "rebound" ("recoil"): First, a tachyphylaxis reaction occurs and the drug stops working, then the drug's action is reversed (bronchospasm).

2 Syndrome of "blockage of the lungs" There is an expansion of not only the bronchi, but also their vessels, which leads to the sweating of the liquid part of the blood into the alveoli and small bronchi. Transudate accumulates and interferes with normal breathing, but it cannot be cough up - there are no cough receptors in the alveoli.

3 Absorption - the drug begins to act on the b-1 adrenergic receptors of the heart, which leads to the phenomena of cardiac stimulation.

Fenothyrol and Salbutamol

They are used in inhalation form to prevent and relieve asthma attacks. The onset of action in 2-3 minutes, the duration of action for Fenothyrol 8 hours, for Salbutamol 6 hours.

Inhaled M-anticholinergics

Atropine, Krasavka extract and other non-inhalation M-anticholinergics are not used, since they inhibit the bronchomotor function of the lungs and contribute to the thickening of sputum - therefore, they are not used.

Inhalation: Ipratropium bromide, Troventol.

Mechanism of action:

1 Block of M-cholinergic receptors throughout the respiratory tract.

2 Decreased synthesis of cGMP and intracellular calcium

3 Reducing the rate of phosphorylation of contractile proteins

4 Do not affect the amount and nature of sputum.

The effect of M-anticholinergics is less than that of adrenergic agonists, and therefore M-anticholinergics are used to relieve an attack of suffocation only in certain categories of patients:

1 Patients with cholinergic variant of bronchial asthma

2 Patients with increased tone of the parasympathetic nervous system (vagotonia)

3 Patients who develop an asthma attack upon inhalation of cold air or dust.

There are combination drugs: Berodual \u003d Fenoterol (beta-2 adrenomimetic) + Atrovent (M-anticholinergic). The combination achieves a strong effect as in adrenomimetics and long-term as in anticholinergics, in addition, the amount of adrenomimetic in this drug is less than in a pure adrenomimetic drug - therefore, there are fewer side effects.

Myotropic bronchospasmolytics

Purine (methylxanthine) derivatives:

Theophylline, Eufillin (80% - Theophylline 20% - ballast for better solubility).

The mechanism of action of Theophylline:

1 Inhibition of the enzyme phosphodiesterase, which catalyzes the conversion of cAMP to ATP.

2 Blockade of adenosine receptors of the bronchi (adenosine is a powerful endogenous bronchoconstrictor)

3 Decreased pulmonary artery pressure

4 Stimulation of contraction of the intercostal muscles and the diaphragm, which leads to increased ventilation

5 Increased beating of the cilia of the respiratory epithelium - increased sputum separation

The half-life of theophylline depends on several factors:

1 Adult non-smokers 7-8 hours

2 Smokers 5 hours

3 Children 3 hours

4 Elderly with pulmonary heart disease for 10-12 hours or more

Saturating dose for adults 5-6 mg / kg body weight, maintenance dose 10-13 mg / kg

Smoking 18

Patients with heart and pulmonary insufficiency 2

Children under 9 years old 24

Children 9-12 years old 20

In tablets Theophylline is used for the prevention of seizures, with intravenous administration - for the relief of asthma attacks.

Rectal suppositories and 24% solution intramuscularly are ineffective

Side effects

In overdose, the organ system involved in the side effect depends on the concentration of the drug in the blood. The maximum therapeutic concentration is 10-18 mg / kg.

Long-acting drugs: Teopek, Retofil, Teotard - 2 times a day, used for prophylactic purposes.

Anti-inflammatory drugs

a) stabilizers of mast cell membranes

b) glucocorticoids

Mast cell membrane stabilizers

Nedocromil sodium (Tayled), Cromoline sodium (Intal), Ketotifen (Zaditen).

Mechanism:

1 Stabilize mast cell membranes

2 Inhibit phosphodysterase activity

3 They inhibit the functional activity of M-cholinergic receptors.

Tiled and Intal_. 1-2 capsules are used 4 times a day, later - less often. The effect occurs within 3-4 weeks after continuous administration of the drug. The capsules are applied using a special "Spinhaler" turbine inhaler, which must be prescribed at the beginning of treatment.

Rp .: "Spinhaler"

D.S. For taking Intal capsules

Inside capsules "Intal" are not used

Ketotifen_. used in tablets 1 mg 2-3 times a day, causes side effects - drowsiness, fatigue.

Glucocorticoids

They are used as a prophylaxis for attacks in the form of inhalation. Peklomethasone, Fluticasone, Flunesolid.

DRUGS AFFECTING THE GASTROINTESTINAL TRACT

1 Influencing secretory activity

2 Influencing motor skills

In the proximal GI tract (stomach, liver, pancreas), lesions occur most frequently. This is due to the fact that these departments are the first to encounter "food aggression". Food is a kind of aggression because it contains substances that are foreign to the body.

The stomach glands are composed of 3 main types of cells:

Parietal (parietal) secrete hydrochloric acid

The main cells secrete pepsinogen

Mucocytes secrete mucus

The secretion and motility of the gastrointestinal tract is regulated by the nervous and humoral mechanisms. The basis of the nervous regulation of secretion and gastrointestinal motility is the vagus nerve. Humoral regulation is carried out with the help of general and local hormones: cholecystokinin, gastrin, secretin.

The pathology of this part of the gastrointestinal tract is usually combined.

Secretion disorders

1 Hyposecretion (insufficient secretory activity)

2 Hypersecretion (excessive secretory activity)

1 Hyposecretory disorders

It can be assumed that it is possible to use local and general hormones and mediators that directly increase secretion: histamine, gastrin, acetylcholine, but these drugs are not used in secretory insufficiency.

Cholinomimetics are not used because of their too broad action (a large number of side effects).

Histamine is not used because of its effect on the vascular bed and its short-term effect.

The gastrin drug - Pentagastrin is not used for treatment due to its short-term effect. Histamine and pentagastrin are used to study stimulated (submaximal and maximal) acidity.

Due to the lack of the possibility of stimulating secretion, replacement therapy is the basis of the treatment of secretory insufficiency.

In case of insufficient secretion of hydrochloric acid, its preparations of hydrochloric acid (Acidum hydrochloridum purum dilutum) are used. The effects of this drug:

1 Activation of pepsinogen with its conversion to pepsin

2 Stimulation of gastric secretion

3 Gatekeeper Spasm

4 Stimulation of pancreatic secretion

As a rule, there is a combined violation of the secretion of hydrochloric acid and pepsinogen.

Components of combination drugs

1 Enzymes of juices of the stomach and pancreas and drugs that stimulate their secretion

2 Components of bile and cholagogues

a) facilitating the emulsification of fats

b) an increase in the activity of pancreatic lipase

c) improving the absorption of fat-soluble vitamins (groups A, E, K)

d) choleretic action

3 Plant-derived enzymes

a) Cellulase, hemicellulase - break down fiber

b) Bromelin - a complex of proteolytic enzymes

4 Rice fungus extract - the sum of enzymes (amylase, protease and others)

5 Lipolytic enzymes produced by fungi of the genus Penicillum.

6 Defoamers are surfactants.

Drugs

Acidin-pepsin - a complex of elements of gastric juice with bound hydrochloric acid

Natural Gastric Juice - obtained from dogs through a stomach fistula and mock feeding.

Pepsidil - an extract from the gastric mucosa of slaughter pigs

Abomin - an extract from the gastric mucosa of newborn lambs or calves - is used in pediatrics.

Pancreatin is a pancreatic juice preparation. Pancurmen \u003d pancreatin + plant choleretic substance. Festal, Enzistal, Digestal \u003d pancreatin + bile extract + hemicellulase. Merkenzine \u003d Bromelain + bile extract. Kombitsin - rice fungus extract. Pancreoflet \u003d Combicin + silicones. Panzinorm \u003d pepsin + pancreatic enzymes + cholic acid

The use of drugs

1 Substitution therapy for exocrine insufficiency as a result of: chronic gastritis, pancreatitis, gastric resection.

2 Flatulence

3 Noninfectious diarrhea

4 Nutritional errors (overeating)

5 Preparation for X-ray examination

2 Hypersecretory disorders

Usually observed in the stomach.

1 Vagotonia (increased vagus tone)

2 Increased gastrin production (including tumor)

3 Increased receptor sensitivity on parietal (parietal) cells.

In general, acid-peptic aggression occurs when the balance between the defense systems and the secretion of hydrochloric acid and gastric juice is disturbed. Thus, aggression can also occur with normal secretory activity in violation of regulation.

The drugs are divided into 2 groups:

1.1 Antacids (chemically neutralize hydrochloric acid)

1.2 Antisecretory agents

1.1 Antacids

Requirements for these funds:

1 Fast interaction with hydrochloric acid

2 Bring the acidity of gastric juice to pH 3-6

3 Binding of a sufficiently large amount of hydrochloric acid (high acid capacity)

4 Lack of side effects

5 Neutral or pleasant taste.

Components of drugs

A) Central actions not only reduce acidity, but also lead to systemic alkalosis: baking soda (sodium bicarbonate)

B) Peripheral action

Calcium carbonate (chalk), magnesium oxide (burnt magnesia), magnesium hydroxide (magnesia milk), magnesium carbonate (white magnesia), aluminum hydroxide (alumina), aluminum trisilicate.

Combined drugs

Vikain_. \u003d bismuth + sodium bicarbonate (fast acting) + magnesium carbonate (long acting). Vikair_. \u003d Vicain + Calamus bark + Buckthorn bark (laxative effect). Almagel_. \u003d aluminum hydroxide + magnesium hydroxide + sorbitol (additional laxative and choleretic effect). Phosphalugel_. \u003d Almagel + phosphorus preparation (due to the fact that aluminum hydroxide binds phosphorus and, with prolonged use, this can lead to osteoporosis and similar complications). Maalox, Octal, Gastal - preparations with a similar composition.

Comparative description of some drugs

Sodium bicarbonate

Reduces the acidity of gastric juice to 8.3, which leads to impaired secretion. The remainder of sodium bicarbonate passes into the duodenum, where, together with sodium bicarbonate secreted there (which is normally neutralized by acidic chyme) is absorbed into the bloodstream and leads to systemic alkalosis. In the stomach, during the neutralization reaction, carbon dioxide is released, which irritates the stomach wall. This leads to an increase in the secretion of hydrochloric acid and gastric juice.

Magnesium oxide

Reduces acidity slightly, carbon dioxide is not formed. Magnesium chloride is formed, which can neutralize sodium bicarbonate in the duodenum. In general, the drug lasts longer.

Aluminum hydroxide

Dissolving with water forms a gel that absorbs gastric juice. The acidity stops at pH \u003d 3. In the duodenum, hydrochloric acid leaves the gel and neutralizes sodium bicarbonate.

General actions of drugs

1 Neutralization of hydrochloric acid

2 Adsorption of pepsin 1 and 2 - decrease in peptic activity

3 Enveloping action

4 Activation of prostaglandin synthesis

5 Enhanced mucus secretion. 3,4 and 5 - protective actions (their meaning is being discussed)

Clinical effect

Heartburn and heaviness disappear, pain and spasm of the gatekeeper decrease, motor skills improve, the patient's general condition improves, and the rate of healing of defects in the stomach wall can increase.

The use of antacids

1 Acute and chronic gastritis in the exacerbation phase (with increased and normal secretion) 2 Esophagitis, reflux esophagitis 3 Hernia of the esophageal opening of the diaphragm 4 Duodenitis 5 Complex therapy of stomach ulcers 6 Syndrome of non-ulcer dyspepsia (errors in diet, drugs irritating the gastric mucosa) 7 Prevention of stress ulcers in intensive care in the postoperative period

Half-life \u003d 20 minutes (maximum 30-40 minutes, up to 1 hour).

Methods for prolonging the effect:

1 Increase in dose (currently not usually used)

2 Reception after meals (after 1 hour (at the height of secretion) or 3 - 3.5 hours (when removing food from the stomach)). This achieves:

a) potentiation of the "food antacid" effect

b) slowing down the evacuation of the drug

3 Combination with antisecretory drugs.

Side effect

1 Stool problems. Aluminum and calcium-containing drugs - can lead to constipation, magnesium-containing - can cause diarrhea.

2 Means containing magnesium, calcium, aluminum can bind many drugs: anticholinergics, phenothiazides, propranolol, quinidine and others, so it is necessary to break their intake in time.

3 Milk-alkaline syndrome (while taking large amounts of calcium carbonate and milk). The concentration of calcium in the blood plasma increases -\u003e the production of parathyroid hormone decreases -\u003e the excretion of phosphates decreases -\u003e calcification -\u003e nephrotoxic effect -\u003e renal failure.

4 Long-term use of large doses of preparations containing aluminum and magnesium can cause intoxication.

1.2 Antisecretory agents

Mechanism of action of hormones and mediators

Prostaglandin E and histamine.

When they bind to receptors, the G-protein is activated -\u003e adenylate cyclase is activated -\u003e ATP is converted into cAMP -\u003e protein kinase is activated and phosphorylates proteins, which leads to a decrease in the activity of the proton pump (pumps potassium into the cell in exchange for hydrogen protons, which are released into lumen of the gastric gland).

2 Gastrin and Acetylcholine_. through receptor-activated calcium channels increase the entry of calcium into the cell, which leads to the activation of protein kinase and a decrease in the activity of the proton pump.

1.2.1 Drugs that bind to receptors

1.2.1.1 Histamine blockers of the second type (block H2-histamine receptors)

1st generation drugs: Cimetidine (Histadil, Belomet) Applied at a dose of 1 g / day

2nd generation drugs: Ranitidine 0.3 g / day

3rd generation drugs: Famotidine (Gaster) 0.04 g / day

Roxatidine (Altat) 0.15 g / day

The bioavailability is satisfactory (\u003e 50%) -\u003e administered enterally.

Therapeutic Concentrations

Cimetidine 0.8 μg / ml Ranitidine 0.1 μg / ml

Half-life

Cimetidine 2 hours Ranitidine 2 hours Famotidine 3.8 hours

There is a classic dose / effect relationship

Side effects of 1st generation drugs

1 With prolonged use, cimetidine may interact with other drugs

2 Selected cases of male genital disorder

The drugs of the 2nd and 3rd generation have no such side effects.

1.2.1.2 Anticholinergics

Pirenzepine

Gastroselective long-acting antimuscarinic drug (applied 2 times a day). More selective than Atropine -\u003e fewer side effects. Due to the relativity of selective action with prolonged use, side effects are possible: dry mouth, glaucoma, urinary retention

1.2.1.3 There are no antigastrin drugs

Proton pump blockers

Omepradol

The most powerful drug, selective. In tablets - an inactive drug, it is activated in an acidic environment - therefore only in the stomach. The active form of the drug binds to the thiol groups of the proton pump enzymes.

Auxiliary antisecretory drugs

1 Prostaglandins

2 Opioid

Dalargin_. - (drug without central effect)

Application

a) prevention of dystrophic changes in the gastrointestinal tract

b) a decrease in the secretion of hydrochloric acid

c) Normalization of microcirculation and lymph flow

d) acceleration of regeneration

e) increased mucus secretion

f) a decrease in the concentration of adrenocorticotropic hormone and glycocorticoids in the blood

Side effect - hypotension

3 Calcium channel blockers - lesser effect, but used for forms resistant to histamine and acetylcholine

4 Carbonic anhydrase inhibitors. Diacarb decrease in the formation and secretion of hydrogen protons

DRUGS AFFECTING THE FUNCTIONS OF THE GASTROINTESTINAL TRACT

(continued)

The epithelial protection system consists of several stages:

1 Mucous-bicarbonate barrier

2 Surface phospholipid barrier

3 Secretion of prostaglandins

4 Cell migration

5 Well-developed blood supply

The drugs are divided into gastroprotective (they themselves protect the gastric mucosa) and increase the protective properties of the mucous membrane.

Carbenoxolone_. (biogastron, duogastron)

It is based on Licorice root, similar in structure to aldosterone. Effects:

the main

1 Increased activity of mucocytes

2 Increasing the cover

3 Increase in viscosity of mucus and its ability to adhere

additional

4 Decrease in pepsinogen activity

5 Improvement of microcirculation

6 Reducing the destruction of prostaglandins

Effects of prostaglandins

1 Increased mucus secretion

2 Stabilization of the mucous barrier

3 Increased secretion of bicarbonate

4 Improvement of microcirculation (most important)

5 Reduction of membrane permeability

The drugs have the following effects:

1 Cytoprotective effect (cannot protect all cells, but contribute to the preservation of tissue structure - histoprotective effect)

2 Decrease in secretion: hydrochloric acid, gastrin, pepsin.

Misoprostal_. (Cytotec)

Synthetic analogue of prostaglandin E1. It is used for the treatment of gastric ulcer and duodenal ulcer, the prevention of ulceration when taking substances that irritate the mucous membrane (Aspirin, etc.).

The drugs are divided into:

1 Antiaggressive group (antacid and antisecretory action)

2 Protective

3 Reparants (promotes healing processes)

Drugs directly protecting the mucous membrane

Bismuth subnitrate_. (basic bismuth nitrate)

Astringent, antimicrobial action. It is used to treat: gastric ulcer and duodenal ulcer, enteritis, colitis, inflammation of the skin and mucous membranes.

Bismuth subsalicylate_. (Desmol)

Film-forming action, astringent, increased mucus production, non-specific antidiarrheal action. It is used for gastric ulcer and duodenal ulcer, exacerbation of chronic gastritis, diarrhea of \u200b\u200bvarious origins.

Colloidal bismuth subcitrate_. (Denol, Tribimol, Ventrisol)

Film-forming action only in an acidic environment (gastroselectivity), adsorption of pepsin, hydrochloric acid, an increase in mucosal resistance, an increase in mucus production (and an increase in its protective properties), bicarbonates, prostaglandins. Bactericidal action against Helicobacter pylori.

Sucralfate

1 In an acidic environment - polymerization and binding to erosive areas of the mucous membrane (affinity for the affected epithelium is 8-10 times greater than for healthy tissue).

2 Adsorption of pepsin, bile acids

3 Increased synthesis of prostaglandins in the mucosa.

Release form: tablets of 0.5 - 1 g, apply 4 times before meals and at night.

Reparants

Vitamin preparations: multivitamins, B1, C. Hormonal preparations: sex hormones

Sea buckthorn and rosehip oil. Alanton (Divesil). Trichopolum (Metronidazole) + additional activity against Helicobacter pylori

Vinylin, Aloe juice, Callanchoe extract

Oxyferriscorbon sodium

Pyrimiline bases.

Drugs depressing neurovegetative reactions

Psychotropic

Tranquilizers and sedatives, antipsychotics (Sulpiride, Metoclopramide (Cerucal)), antidepressants

2 Means regulating motor skills. Anticholinergics, myotropic antispasmodics (Papaverin, No-shpa, Galidor, Fenikaberan)

3 Pain relievers. Analgesics, local anesthetics

DRUGS AFFECTING MOTOR FUNCTIONS OF THE GIT

Secretion is a process that depends on the concentration of cAMP. Stimulate secretion: prostaglandins, cholinomimetics, cholera toxin (pathological effect). Suppress secretion: somatostatin, opioids, dopamine and adrenomimetics.

Isoosmotic reabsorption occurs in the intestine due to:

1 Potassium sodium ATPase (electrogenic pump)

2 Sodium chloride transport (electrically neutral pump)

Motor skills are affected by:

1 Food composition (fiber - activates motor skills)

2 Human motor activity (abdominal muscles - massage the intestines and promote the activation of motility)

3 Nervous-humoral regulation

For hypomotoric disorders, the following are used: laxatives, prokinetics, antiparetic agents.

Laxatives

Laxatives are drugs that reduce the time it takes for intestinal contents to pass through the gastrointestinal tract, which leads to the appearance or increased frequency of stools and changes in its consistency.

Hypomotor reasons

1 Diet (fiber deficiency, fresh, refined foods)

2 Hypo- or hypersecretion

3 Hypokinesia: age, profession, bed rest

4 Dysregulatory disorders: operations on the gastrointestinal tract, spine, small pelvis.

5 "Psychogenic" causes (change of scenery)

Classification of laxatives

By mechanism:

1 Irritant (stimulating, contact) Chemically stimulating mucosal receptors

3 Increasing the volume of intestinal contents. They increase the volume and liquefy, due to:

a) increased secretion (and decreased reabsorption)

b) an increase in osmotic pressure in the intestinal lumen

c) water binding

4 Emollient Changes in consistency due to emulsification, detergent properties, surfactant properties

By the strength of the action:

1 Aperitifs (Aperitiva) - normal to soft stools

2 Laxative (Laxativa, Purgentiva) - soft or mushy stools, depending on the dose

3 Drastiva - loose stools

By localization:

1 Small (or whole) 2 Large intestine

By origin:

Vegetable, mineral, synthetic.

Indications:

1 Chronic constipation (with ineffective diet therapy, with prolonged bed rest)

2 Stool regulation in diseases of the anorectal region (hemorrhoids, proctitis, rectal fissures)

3 Preparation for instrumental examinations, operations.

4 Deworming

5 Treatment of poisoning (prevention of absorption of poisons)

Typical Side Effects_ .:

1 Intestinal colic, diarrhea

2 Loss of water and electrolytes

3 Irritation and damage to mucous membranes

4 Addiction, addiction syndrome ("purgentism")

When stopping the intake, the intestines do not cope well with the load

5 Nephro- and hepatotoxicity

Annoying

Plant origin

Preparations from Cassia_. (Alexandrovsky leaf). Leaves, fruits in the form of oil, infusion and extract are used.

Preparations: Senade, Klasksena, Senadexin. Complex preparations: Caliphite (contains extracts of Senna and figs, senna oils, cloves, mint), Depuran (contains Senna extract and oils of anise and cumin)

Preparations from Buckthorn brittle_. Used: bark, zhoster-fruits in the form of decoctions, extracts, compotes and just raw berries. Preparations: Cofranil, Ramnil.

Rhubarb preparations_. - tablets from rhubarb root. Absorbed - degraded - secreted again in the large intestine and acts. Because of these features, the onset of action is 6-12 hours after ingestion (prescribed at night, the effect is in the morning).

Pharmacodynamics:

1 Chemically irritates mucosal receptors

2 Inhibits potassium-sodium ATP-ase, which leads to a decrease in the reabsorption of water and electrolytes.

3 Increases secretion

5 Increases mucosal permeability

Strength: Aperitiva, Laxativa. Depending on individual sensitivity, the dose can fluctuate up to 4 - 8 average. Course: 7-10 days.

Fesyunova // Safety of drugs: from development to medical use: the first scientific and practical. conf. K., May 31 – June 1, 2007 - K., 2007. - P. 51–52. ANOTATION Fesyunova G.S. The main pharmacological effects of coumarinum vasobu - an aqueous extract from herb burkunu.– Manuscript. Dissertation on the scientific level of the candidate of biological sciences for specialties 03/14/05 - pharmacology. - ...

Dozi, as a rule, turn down. The dosage of liquids should be carried out on 1 kg of sickly oil or on one surface of the soil. The pediatric pharmacology is involved in the development of the peculiarities of the child's organisms on the organism of the child. The general rule is to take into account, that mensha child, tim mensh thoroughly at the new mechanisms of nervous and humoral regulation, systems of foreign relations, immunity and type of food is influencing ...

Inotropic drugs. Chronotropic and inotropic effect Features of the influence of nerves

Discovery history

Innervation of the heart

Efferent innervation

Intramural neurons

Features of the influence of nerves

The vagus nerve and its influence

Selecting a mediator

Electrical stimulation of fibers

Inotropic drugs

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