Innervation of the heart. Chronotropic effect
Inotropic drugs are drugs that increase myocardial contractility. The best known inotropic drugs include cardiac glycosides. At the beginning of the XX century, almost all cardiology "kept" on cardiac glycosides. And even in the early 80s. glycosides remained the main drugs in cardiology.
The mechanism of action of cardiac glycosides is the blockade of the sodium-potassium "pump". As a result, the flow of sodium ions into cells increases, the exchange of sodium ions for calcium ions increases, which, in turn, causes an increase in the content of calcium ions in myocardial cells and a positive inotropic effect. In addition, glycosides slow down AV conduction and reduce heart rate (especially in atrial fibrillation) due to vagomimetic and antiadrenergic action.
The effectiveness of glycosides in circulatory insufficiency in patients without atrial fibrillation was not very high and was even questioned. However, specially conducted studies have shown that glycosides have a positive inotropic effect and are clinically effective in patients with impaired left ventricular systolic function. Predictors of glycoside efficacy are: an increase in heart size, a decrease in ejection fraction, and the presence of a third heart sound. In patients without these signs, the likelihood of the effect of the appointment of glycosides is low. Currently, digitalization is no longer used. As it turned out, the main effect of glycosides is precisely the neurovegetative effect, which is manifested when small doses are prescribed.
In our time, the indications for the appointment of cardiac glycosides are clearly defined. Glycosides are indicated in the treatment of severe chronic heart failure, especially if the patient has atrial fibrillation. And not just atrial fibrillation, but a tachysystolic form of atrial fibrillation. In this case, glycosides are the first choice. Digoxin is the main cardiac glycoside. Other cardiac glycosides are currently hardly used. With the tachysystolic form of atrial fibrillation, digoxin is prescribed under the control of the ventricular rate: the goal is a heart rate of about 70 per minute. If, while taking 1.5 tablets of digoxin (0.375 mg), it is not possible to reduce the heart rate to 70 per minute, P-blockers or amiodarone are added. In patients with sinus rhythm, digoxin is prescribed if there is severe heart failure (stage II B or III-IV FC) and the effect of taking an ACE inhibitor and a diuretic is insufficient. In patients with sinus rhythm with heart failure, digoxin is prescribed in a dose of 1 tablet (0.25 mg) per day. At the same time, for the elderly or patients who have had myocardial infarction, as a rule, half or even a quarter of a digoxin tablet (0.125-0.0625 mg) per day is sufficient. Intravenous glycosides are prescribed extremely rarely: only in acute heart failure or decompensation of chronic heart failure in patients with a tachysystolic form of atrial fibrillation.
Even in such doses: from 1/4 to 1 tablet of digoxin per day, cardiac glycosides can improve the well-being and condition of severe patients with severe heart failure. With higher doses of digoxin, there is an increase in mortality in patients with heart failure. In mild heart failure (stage II A), glycosides are useless.
The criteria for the effectiveness of glycosides are the improvement of well-being, a decrease in heart rate (especially with atrial fibrillation), an increase in urine output, and an increase in efficiency.
The main signs of intoxication: the occurrence of arrhythmias, loss of appetite, nausea, vomiting, weight loss. When using small doses of glycosides, intoxication develops extremely rarely, mainly when digoxin is combined with amiodarone or verapamil, which increase the concentration of digoxin in the blood. With the timely detection of intoxication, a temporary discontinuation of the drug with a subsequent dose reduction is usually sufficient. If necessary, additionally use potassium chloride 2% -200.0 and / or magnesium sulfate 25% -10.0 (if there is no AV block), with tachyarrhythmias - lidocaine, with bradyarrhythmias - atropine.
In addition to cardiac glycosides, there are non-glycoside inotropic drugs. These drugs are used only in cases of acute heart failure or in severe decompensation of patients with chronic heart failure. The main non-glycoside inotropic drugs include dopamine, dobutamine, adrenaline, and norepinephrine. These drugs are administered only by intravenous drip in order to stabilize the patient's condition, to bring him out of decompensation. After that, they switch to taking other medicines.
The main groups of non-glycoside inotropic drugs:
1. Catecholamines and their derivatives: adrenaline, norepinephrine, dopamine.
2. Synthetic sympathomimetics: dobutamine, isoproterenol.
3. Phosphodiesterase inhibitors: amrinone, milrinone, enoximone (drugs such as iimobendan or springrinone, in addition to inhibiting phosphodiesterase, directly affect sodium and / or calcium flow through the membrane).
Table 8
Non-glycoside inotropic drugs
|
A drug |
Initial infusion rate, μg / min |
Approximate maximum infusion rate |
|
Adrenalin |
10 μg / min |
|
|
Norepinephrine |
15 μg / min |
|
|
Dobutamine |
||
|
Isoproterenol |
||
|
700 μg / min |
||
|
Vasopressin |
Norepinephrine.Stimulation of 1- and α-receptors causes increased contractility and vasoconstriction (but the coronary and cerebral arteries dilate). Reflex bradycardia is often noted.
Dopamine... The precursor of norepinephrine and promotes the release of norepinephrine from nerve endings. Dopamine receptors are located in the vessels of the kidneys, mesentery, coronary and cerebral arteries. Their stimulation causes vasodilation in the vital organs. When infused at a rate of up to about 200 mcg / min (up to 3 mcg / kg / min), vasodilation ("renal" dose) is provided. With an increase in the rate of dopamine infusion over 750 μg / min, stimulation of α-receptors and a vasoconstrictor effect ("pressor" dose) begin to prevail. Therefore, it is rational to administer dopamine at a relatively low rate - approximately in the range from 200 to 700 μg / min. If a higher rate of dopamine administration is required, try connecting a dobutamine infusion or switch to a norepinephrine infusion.
Dobutamine.Selective stimulator of 1-receptors (however, there is also a slight stimulation of 2- and α-receptors). With the introduction of dobutamine, a positive inotropic effect and moderate vasodilation are noted.
In refractory heart failure, dobutamine infusion is used for a duration of several hours to 3 days (by the end of 3 days, tolerance usually develops). The positive effect of intermittent infusion of dobutamine in patients with severe heart failure can persist for quite a long time - up to 1 month or more.
Inotropic drugs are a group of drugs that increase the force of myocardial contraction.
CLASSIFICATION
Cardiac glycosides (see section "Cardiac glycosides").
Non-glycoside inotropic drugs.
✧ Stimulants β 1-adrenergic receptors (dobutamine, dopamine).
✧
Phosphodiesterase inhibitors (amrinone℘ and milrinon ℘; they are not registered in the Russian Federation; allowed only for short courses with circulatory decompensation).
✧
Calcium sensitizers (levosimendan).
MECHANISM OF ACTION AND PHARMACOLOGICAL EFFECTS
Stimulantsβ
1
-adrenoreceptors
The drugs of this group, administered intravenously, affect the following receptors:
β 1-adrenoreptors (positive inotropic and chronotropic action);
β 2-adrenergic receptors (bronchodilation, expansion of peripheral vessels);
dopamine receptors (increased renal blood flow and filtration, dilatation of the mesenteric and coronary arteries).
A positive inotropic effect is always combined with other clinical manifestations, which can have both positive and negative effects on the clinical picture of AHF. Dobutamine - selectiveβ 1-adrenomimetic, however, it also has a weak effect onβ 2 - and α 1-adrenergic receptors. With the introduction of usual doses, an inotropic effect develops, sinceβ 1-stimulating effect on the myocardium prevails. A drug
regardless of the dose, it does not stimulate dopamine receptors, therefore, renal blood flow increases only due to an increase in stroke volume.
Phosphodiesterase inhibitors.
The drugs of this subgroup, increasing myocardial contractility, also lead to a decrease in the systemic vascular resistance, which makes it possible to simultaneously influence the preload and afterload in AHF.
Calcium sensitizers.
The drug of this group (levosimendan) increases the affinity of Ca2+
to troponin C, which enhances myocardial contraction. It also has a vasodilating effect (reducing the tone of the veins and arteries). Levosimendan has an active metabolite with a similar mechanism of action and a half-life of 80 hours, which causes a hemodynamic effect within 3 days after a single administration of the drug.
Clinical significance
Phosphodiesterase inhibitors can increase mortality.
In acute left ventricular failure against the background of acute MI, the administration of levosimendan was accompanied by a decrease in mortality achieved in the first 2 weeks after the start of treatment, which remained in the future (for 6 months of follow-up).
Levosimendan has advantages over dobutamine in relation toeffect on blood circulation parameters in patients with severe CHF decompensation and low cardiac output.
INDICATIONS
Acute heart failure. Their purpose does not depend on the presence of venous congestion or pulmonary edema. There are several algorithms for prescribing inotropic drugs.
Shock against the background of an overdose of vasodilators, blood loss, dehydration.
Inotropic drugs should be prescribed strictly individually, it is imperative to evaluate the indicators of central hemodynamics, and also to change the dose of inotropic drugs in accordance with
with a clinical picture.
Dosing
Dobutamine.
The initial infusion rate is 2-3 micrograms per kg of body weight per minute. When dobutamine is administered in combination with vasodilators, control of the pulmonary artery occlusion pressure is necessary. If the patient received beta-adrenergic blockers, then the effect of dobutamine will develop only after the elimination of beta-adreno blocker.
Algorithm for the use of inotropic drugs (national recommendations).
Algorithm for the use of inotropic drugs (American Heart Association).
Dopamine.
The clinical effects of dopamine are dose-dependent.
In low doses (2 μg per 1 kg of body weight per minute or less in terms of lean body weight), the drug stimulates D1 - and D 2-receptors, which is accompanied by vasodilatation of the mesentery and kidneys and makes it possible to increase GFR when refractory to the action of diuretics.
In medium doses (2–5 μg per 1 kg of body weight per minute), the drug stimulatesβ 1- adrenergic receptors of the myocardium with an increase in cardiac output.
In high doses (5-10 mcg per 1 kg of body weight per minute), dopamine activatesα 1- adrenergic receptors, which leads to an increase in OPSS, LV filling pressure, tachycardia. Typically, high doses are given in urgent cases to rapidly increase SBP.
Clinical features:
tachycardia is always more pronounced with the introduction of dopamine compared with dobutamine;
the dose is calculated only for lean, and not for total body weight;
persistent tachycardia and / or arrhythmia arising from the introduction of a "renal dose" indicate a too high rate of drug administration.
Levosimendan.
The introduction of the drug begins with a loading dose (12-24 mcg per 1 kg of body weight for 10 minutes), and then switch to long-term infusion (0.05-0.1 mcg per 1 kg of body weight). Increase in stroke volume, decrease in pulmonary artery wedge pressure are dose-dependent. In some cases, it is possibleincreasing the dose of the drug to 0.2 μg per 1 kg of body weight. The drug is effective only in the absence of hypovolemia. Levosimendan is compatible withβ
-adrenergic blockers and does not lead to an increase in the number of rhythm disturbances.
Features of prescribing inotropic drugs for patients with decompensated chronic heart failure
Due to a pronounced adverse effect on the prognosis, non-glycoside inotropic drugs can be prescribed only in the form of short courses (up to 10-14 days) with a clinical picture of persistent arterial hypotension in patients with severe CHF decompensation and reflex kidney.
SIDE EFFECTS
Tachycardia.
Supraventricular and ventricular rhythm disturbances.
Subsequent increase in left ventricular dysfunction (due to increased energy consumption to ensure the increasing work of the myocardium).
Nausea and vomiting (dopamine in high doses).
General Provisions
- The goal of inotropic support is to maximize tissue oxygenation (assessed by plasma lactate concentration and mixed venous oxygenation), rather than increasing cardiac output.
- In clinical practice, catecholamines and their derivatives are used as inotropes. They have a complex hemodynamic effect due to α- and β-adrenergic effects and are distinguished by a predominant effect on certain receptors. Below is a description of the hemodynamic effects of the main catecholamines.
Isoprenaline
Pharmacology
Isoprenaline is a synthetic agonist of β-adrenergic receptors (β 1 and β 2) and has no effect on α-adrenergic receptors. The drug expands the bronchi, with blockade acts as a pacemaker, affecting the sinus node, increases conductivity and reduces the refractory period of the atrioventricular node. It has a positive inotropic effect. It has an effect on skeletal muscles and blood vessels. The half-life is 5 minutes.
Drug interactions
- The effect is increased when administered together with tricyclic antidepressants.
- β-blockers are isoprenaline antagonists.
- Sympathomimetics can potentiate the action of isoprenaline.
- Gaseous anesthetics, increasing the sensitivity of the myocardium, can cause arrhythmias.
- Digoxin increases the risk of tachyarrhythmias.
Epinephrine
Pharmacology
- Epinephrine is a selective β 2 -adrenergic agonist (the effect on β 2 -adrenergic receptors is 10 times greater than the effect on β 1 -adrenergic receptors), but also acts on α-adrenergic receptors, without exerting a differential effect on α 1 - and α 2 -adrenoceptors.
- Usually insignificantly affects the level of mean blood pressure, with the exception of cases of administration of the drug against the background of non-selective blockade of β-adrenergic receptors, in which the vasodilation effect of epinephrine mediated by the effect on β 2 -adrenergic receptors is lost and its vasopressor effect sharply increases (α 1 -selective blockade does not cause such an effect ).
Application area
- Anaphylactic shock, angioedema and allergic reactions.
- The field of use of epinephrine as an inotropic drug is limited only to septic shock, in which it has advantages over dobutamine. However, the drug causes a significant decrease in renal blood flow (up to 40%) and can only be administered together with dopamine in a renal dose.
- Heart failure.
- Open-angle glaucoma.
- As an adjunct to local anesthetics.
Doses
- 0.2-1 mg intramuscularly for acute allergic reactions and anaphylaxis.
- 1 mg for cardiac arrest.
- In case of shock, 1-10 mcg / min is administered drip.
Pharmacokinetics
Due to the rapid metabolism in the liver and nervous tissue and 50% binding to plasma proteins, the half-life of epinephrine is 3 minutes.
Side effects
- Arrhythmias.
- Intracerebral hemorrhage (in case of overdose).
- Pulmonary edema (in case of overdose).
- Ischemic necrosis at the injection site.
- Anxiety, dyspnea, palpitations, tremors, weakness, cold extremities.
Drug interactions
- Tricyclic immunosuppressants.
- Anesthetics.
- β-blockers.
- Quinidine and digoxin (arrhythmias often occur).
- α-Adrenomimetics block the α-effects of epinephrine.
Contraindications
- Hyperthyroidism.
- Hypertension.
- Angle-closure glaucoma.
Dopamine
Pharmacology
Dopamine affects several types of receptors. In small doses it activates α 1 - and α 2 -dopamine receptors. α 1 -dopamine receptors are localized in vascular smooth muscle and are responsible for vasodilation in the renal, mesenteric, cerebral and coronary blood flow. α 1 -dopamine receptors are located in the postganglionic endings of the sympathetic nerves and ganglia of the autonomic nervous system. In an average dose, dopamine activates β 1 -adrenergic receptors, having positive chronotropic and inotropic effects, and in high doses, it additionally activates α 1 - and α 2 -adrenergic receptors, eliminating the vasodilating effect on the renal vessels.
Application area
Used to improve renal blood flow in patients with impaired renal perfusion, usually with multiple organ failure. There is little evidence regarding the effect of Dopamine on clinical outcome.
Pharmacokinetics
Dopamine is captured by sympathetic nerves and is rapidly distributed throughout the body. The half-life is 9 minutes and the volume of distribution is 0.9 L / kg, but equilibrium is reached within 10 minutes (i.e., faster than expected). Metabolized in the liver.
Side effects
- Arrhythmias are rare.
- Hypertension with very high doses.
- Extravasation can cause skin necrosis. In this case, phentolamine is introduced into the ischemic zone as an antidote.
- Headache, nausea, vomiting, palpitations, mydriasis.
- Increased catabolism.
Drug interactions
- MAO inhibitors.
- α-blockers can enhance the vasodilating effect.
- β-blockers can enhance the hypertensive effect.
- Ergotamine enhances peripheral vasodilation.
Contraindications
- Pheochromocytoma.
- Tachyarrhythmia (without treatment).
Dobutamine
Pharmacology
Dobutamine is an isoprenaline derivative. In practice, a racemic mixture of a dextrorotatory isomer selective for β 1 and β 2 adrenergic receptors and a levorotatory isomer having an α 1 selective effect is used. The effects on p2-adrenergic receptors (vasodilation of the mesentarial and musculoskeletal vessels) and α 1 -adrenergic receptors (vasoconstriction) suppress each other, therefore, dobutamine has little effect on blood pressure if not prescribed in a high dose. Has less arrhythmogenic effect in comparison with dopamine.
Application area
- Inotropic support for heart failure.
- In septic shock and liver failure, it can cause vasodilation, therefore it is not the most preferred inotropic drug.
- Used in functional diagnostics for cardiac stress tests.
Pharmacokinetics
It is rapidly metabolized in the liver. It has a half-life of 2.5 minutes and a volume of distribution of 0.21 l / kg.
Side effects
- Arrhythmias.
- With an increase in cardiac output, myocardial ischemia may occur.
- The hypotensive effect can be minimized by the simultaneous administration of dopamine in a vasoconstrictor dose. This combination of drugs may be required to treat patients with sepsis or liver failure.
- Allergic reactions are extremely rare.
- Skin necrosis may occur at the injection site.
Drug interactions
α-adrenomimetics increase vasodilation and cause hypotension.
Contraindications
- Low filling pressure.
- Arrhythmias.
- Cardiac tamponade.
- Valvular heart disease (aortic and mitral stenosis, hypertrophic obstructive cardiomyopathy).
- Established hypersensitivity to the drug.
Norepinephrine
Pharmacology
Norepinephrine, like epinephrine, has an α-adrenergic effect, but to a lesser extent affects most β 1 -adrenergic receptors and has a very low β 2 -adrenergic activity. The weakness of β 2 -adrenergic effect leads to a predominance of the vasoconstrictor effect, which is more pronounced than that of epinephrine. Norepinephrine is prescribed for acute hypotension, but due to its slight effect on cardiac output and its ability to cause severe vasospasm, this drug can significantly increase tissue ischemia (especially in the kidneys, skin, liver and skeletal muscles). The norepinephrine infusion should not be interrupted suddenly, as it is dangerous with a sharp drop in blood pressure.
Drug interactions
Tricyclic antidepressants (blocking the re-entry of catecholamines into the nerve endings) increase the sensitivity of receptors to epinephrine and norepinephrine by 2-4 times. MAO inhibitors (for example, tranylcyprominr and pargyline) significantly potentiate the effect of dopamine, therefore, its administration should be started with a dose equal to 1/10 of the usual starting dose, i.e. 0.2 μg / (kgxmin).
Dobutamine is not a substrate for MAO.
Milrinon
Milrinone belongs to the group of phosphodiesterase (type III) inhibitors. Its cardiac effects are possibly due to its influence on calcium and fast sodium channels. β-Adrenomimetics enhance the positive inotropic effect of a million.
Side effects
Enoximonr
Enoximone is a phosphodiesterase (type IV) inhibitor. The drug is 20 times more active than aminophylline, its half-life is approximately 1.5 hours. It is broken down to active metabolites with 10% activity of enoximonar with a half-life of 15 hours. It is used for the treatment of congestive heart failure, it can be prescribed in tablet form, and intravenously.
Side effects
Patients with hypovolemia may develop hypotension and / or cardiovascular collapse.
Bicarbonate of soda
Pharmacology
Sodium bicarbonate plays an important role in the body as a buffer. Its effect is short-lived. The administration of sodium bicarbonate leads to sodium overload and the formation of carbon dioxide, which leads to intracellular acidosis and reduces the force of myocardial contraction. Therefore, the drug should be administered with great caution. Along with this, sodium bicarbonate shifts the oxyhemoglobin dissociation curve to the left and reduces the effective delivery of oxygen to tissues. Moderate acidosis causes vasodilation in the brain, so correcting it may impair cerebral blood flow in patients with cerebral edema.
Application area
- Severe metabolic acidosis (conflicting data exist regarding use in diabetic ketoacidosis).
- Severe hyperkalemia.
- The use of sodium bicarbonate in cardiopulmonary resuscitation is best avoided, since cardiac massage and artificial respiration are sufficient.
Dose
Produced in the form of an 8.4% solution (hypertonic, 1 ml contains 1 mmol of bicarbonate ion) and 1.26% solution (isotonic). Usually, a bolus of 50-100 ml is administered under the control of arterial blood pH and hemodynamic monitoring. According to the recommendations of the British Council for Resuscitation, the approximate dose of 8.4% sodium bicarbonate solution can be calculated as follows:
Dose in ml (mol) \u003d [VExt (kg)] / 3, where BE is the base deficit.
Thus, a patient weighing 60 kg with a base deficit of -20 requires 400 ml of 8.4% sodium bicarbonate solution to normalize the pH. This volume contains 400 mmol of sodium. From our point of view, this is a lot, so it is advisable to adjust the pH to a level of 7.0-7.1 by prescribing 50-100 ml of sodium bicarbonate, followed by an assessment of arterial blood gases and re-administration of the drug, if necessary. This allows you to gain enough time for more effective and safe medical and diagnostic measures and treatment of the disease that led to the development of acidosis.
Side effects
- With extravasation, tissue necrosis occurs. If possible, the drug is administered through a central catheter.
- When administered simultaneously with calcium preparations, calcifications are formed in the catheter, which can lead to microembolism.
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 - the 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.
In addition, 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 a slowdown in 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 tissues - edema disappears.
(fraction of elimination) Polar does not bind to proteins - fast and strong effect and rapid elimination through the kidneys
CED - 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 effect).
If the dose is still increased, the batmotropic effect appears.
1. Increase in 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 stimulation of respiration), is a surfactant that displaces toxins.
Disadvantages:
The oil solution - therefore it is 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 consumption of oxygen by 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 a cell, changes in myocardial activity, conduction disturbances with a 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), an increase in the destruction of quinidine in the liver occurs.
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, may be an exacerbation of glaucoma The course of treatment is not 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 glycoside 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 injected into the blood, which leads to an increase in the volume of hyperosmotic tubular urine and an increase in the rate of urine flow - an increase in water and electrolyte losses.
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), delayed excretion of calcium (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, as 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 fruit, 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 adrenomimetics
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
It 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 for the treatment of bronchial asthma, it is used 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 in 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 drug 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 "Recoil" syndrome: First, a tachyphylaxis reaction occurs and the drug stops acting, 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 Decrease in pressure in the pulmonary artery
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, suffering from cor pulmonale 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 attacks of suffocation.
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 for 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 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 acidity)
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 (diet errors, 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 preparations - 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, therefore, 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 turns 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
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, which is 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 Improving 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 Decrease in 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.
In the intestine, isoosmotic reabsorption occurs 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 - means that reduce the time of passage of intestinal contents through the gastrointestinal tract, which leads to the appearance or increased frequency of stools and changes in its consistency.
Hypomotoric 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, 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, oils of senna, cloves, mint), Depuran (contains extract of Senna 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 6-12 hours after ingestion (prescribed at night, the effect 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. - pp. 51–52. ANOTATION Fesyunova G.S. Basic pharmacological efficacy of coumarinum asoba - 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 ...
Table of contents of the subject "Excitability of the heart muscle. Cardiac cycle and its phase structure. Heart sounds. Innervation of the heart.":1. Excitability of the heart muscle. Myocardial action potential. Contraction of the myocardium.
2. Excitation of the myocardium. Contraction of the myocardium. Conjugation of excitation and contraction of the myocardium.
3. Cardiac cycle and its phase structure. Systole. Diastole. Asynchronous pruning phase. Isometric contraction phase.
4. Diastolic period of the ventricles of the heart. Relaxation period. Filling period. Heart preload. Frank-Starling law.
5. Heart activity. Cardiogram. Mechanocardiogram. Electrocardiogram (ECG). ECG electrodes.
6. Heart sounds. First (systolic) heart sound. Second (diastolic) heart tone. Phonocardiogram.
7. Sphygmography. Phlebography. Anacrot. Catacroth. Phlebogram.
8. Cardiac output. Regulation of the cardiac cycle. Myogenic mechanisms of regulation of the heart. Frank - Starling effect.
10. Parasympathetic effects on the heart. Effect on the heart of the vagus nerve. Vagus effects on the heart.
Heart is abundant innervated organ... Among the sensitive formations of the heart, two populations of mechanoreceptors are of primary importance, concentrated mainly in the atria and the left ventricle: A receptors respond to changes in the tension of the heart wall, and B receptors are excited during its passive stretching. Afferent fibers associated with these receptors are part of the vagus nerves. Free sensory nerve endings, located directly under the endocardium, are the terminals of afferent fibers passing through the sympathetic nerves.
Efferent innervation of the heart carried out with the participation of both divisions of the autonomic nervous system. The bodies of sympathetic preganglionic neurons involved in the innervation of the heart are located in the gray matter of the lateral horns of the three upper thoracic segments of the spinal cord. Preganglionic fibers are directed to the neurons of the superior thoracic (stellate) sympathetic ganglion. The postganglionic fibers of these neurons, together with the parasympathetic fibers of the vagus nerve, form the upper, middle and lower cardiac nerves. Sympathetic fibers penetrate the entire organ and innervate not only the myocardium, but also the elements of the conducting system.
The bodies of parasympathetic preganglionic neurons involved in innervation of the heart, are located in the medulla oblongata. Their axons are part of the vagus nerves. After the vagus nerve enters the chest cavity, branches depart from it, which are included in the heart nerves.
The processes of the vagus nerve, which are part of the heart nerves, are parasympathetic preganglionic fibers... From them, excitation is transmitted to intramural neurons and then - mainly to the elements of the conducting system. The influences mediated by the right vagus nerve are mainly addressed to the cells of the sinoatrial, and the left ones - to the cells of the atrioventricular node. The vagus nerves do not have a direct effect on the ventricles of the heart.
Innervating the fabric of pacemakers, autonomic nerves are able to change their excitability, thereby causing changes in the frequency of generation of action potentials and heart contractions ( chronotropic effect). Nervous influences change the rate of electrotonic transmission of excitation and, consequently, the duration of the phases of the cardiac cycle. Such effects are called dromotropic.
Since the action of mediators of the autonomic nervous system is to change the level of cyclic nucleotides and energy metabolism, autonomic nerves in general are able to influence the strength of heart contractions ( inotropic effect). Under laboratory conditions, the effect of changing the value of the excitation threshold of cardiomyocytes under the action of neurotransmitters was obtained; it is designated as batmotropic.
The listed pathways of the nervous system on the contractile activity of the myocardium and the pumping function of the heart are, although extremely important, but secondary to myogenic mechanisms, modulating influences.