(1)α adrenergic receptor agonist:
①α 1α2 receptor agonist, norepinephrine;
②α 1 receptor agonist, phenylephrine;
③α2 receptor agonist, clonidine.
(2)α, β receptor agonist: epinephrine.
(3)β receptor agonist:
①β 1β2 receptor agonist, isoproterenol;
②β 1 receptor agonist, dobutamine;
③β2 receptor agonist, salbutamol.
Norepinephrine (Na; Norepinephrine (ne) is the main transmitter released by noradrenergic nerve endings and can also be secreted by adrenal medulla.
Pharmaceutical products are synthetic products, and its bitartrate is commonly used. The chemical properties are unstable, and it is easy to be oxidized and discolored under neutral and alkaline conditions. It is forbidden to be compatible with alkaline drugs. 1, absorption: oral administration cannot produce absorption; When injected subcutaneously, local tissue necrosis is easy to occur due to the severe contraction of blood vessels and small absorption; Intravenous drip is generally used for administration.
2. Distribution: mostly distributed in the heart, adrenal medulla and other organs innervated by noradrenergic nerves; Exogenous NA rarely reaches brain tissue, probably because it is not easy to penetrate the blood-brain barrier.
3. Metabolism and excretion: Like endogenous NA, it loses its activity after ingesting 1 and 2, and is excreted with urine after MAO and metabolism. It mainly excites α receptor, but NA has a weak effect on cardiac β 1 receptor and almost no effect on β2 receptor.
1, vascular
Stimulate α 1 receptor, and make blood vessels such as skin mucosa and kidney contract.
Coronary vasodilation is mainly due to the excitement of the heart and the increase of myocardial metabolites (such as adenosine), which makes the blood vessels relax. At the same time, due to the increase of blood pressure, the coronary perfusion pressure increases, so the coronary flow increases.
2. Heart
The β 1 of the heart is excited by weakness, which makes the myocardial contractility strengthen, the heart rate accelerate, the conduction accelerate and the cardiac output increase.
Generally speaking, due to the increase of blood pressure, the heart rate can be slowed down reflexively. If the dose is too large, the automatic rhythm of the heart will increase and arrhythmia will occur, but it is not as common as adrenaline.
3. Elevated blood pressure
4. Others
It has a weak influence on the metabolism of the body, and blood sugar will rise only when the dose is large.
Its influence on the central nervous system is also weaker than adrenaline. 1. Early stage of shock: It is mainly used to maintain the systolic blood pressure at about 12kPa(90mmHg) by intravenous drip of small dose of NA for a short time when the blood pressure suddenly drops in the early stage of nervous shock, so as to ensure the blood supply of important organs such as heart and brain.
The key to shock is insufficient microcirculation blood perfusion and reduced effective blood volume, so the key to its treatment should be to improve microcirculation and replenish blood volume. The application of NA is only a temporary measure. If it is used for a long time or in large doses, it will aggravate microcirculation disorder.
2. Drug-induced hypotension: If hypotension is caused by central depressant poisoning, especially chlorpromazine poisoning, NA should be used instead of adrenaline.
3. Upper gastrointestinal bleeding: Take this product 1 ~ 3 mg, take it orally after proper dilution, and contract mucosal blood vessels due to local action in esophagus or stomach to produce hemostasis. 1, ischemic ring death of local tissue: too long intravenous drip of NA, too high concentration or leakage of liquid medicine from blood vessels can cause ischemic necrosis. If leakage or pale skin is found at the injection site, the injection site should be changed, hot compress should be carried out, and procaine or α receptor blocker such as phentolamine should be used for local infiltration injection to dilate blood vessels.
2. Acute renal failure: If the drip time is too long or the dose is too large, the renal blood vessels will contract violently, resulting in oliguria, anuria and renal parenchyma damage, so the urine volume should be kept at least 25ml per hour during the medication. NA disabled in
hypertension
atherosclerosis
Organic heart disease
Oliguria and anuria patients
Patients with severe microcirculatory disturbance 1, m-hydroxylamine, also known as alamin.
In addition to directly acting on α receptor, it can also promote the release of NA in vesicles through substitution, which plays an indirect role.
Continuous application in a short time can gradually weaken the effect and produce rapid tolerance due to the decrease of n a in vesicles.
The effect of raising blood pressure is weaker than that of NA, and the action time is longer.
M-hydroxylamine is a reliable enhancer, which lasts for a long time and causes less adverse reactions such as palpitation and oliguria than NA, and can also be injected intramuscularly. Therefore, it can be used as a substitute for NA in the early stage of various shocks, after surgery or after spinal anesthesia.
2.α 1 receptor agonist
Both phenylephrine (also known as phenylephrine, neofolin) and methoxyamine are synthetic products. Mainly excites α 1 receptor. It is used for anti-shock, but it has no obvious advantage compared with NA.
It can slow down the heart rate through vagus nerve reflex, so it can also be used for paroxysmal supraventricular tachycardia.
Phenylephrine can also excite mydriatic muscles, and generally does not cause an increase in intraocular pressure (the elderly with narrow anterior chamber angle may cause an increase in intraocular pressure). Its 1% ~ 2.5% solution is used as a quick and short-acting mydriatic agent for fundus examination.
3.α2 receptor agonists
clonidine
Adrenaline (AD) is an example of α, β receptor agonist and the main hormone in adrenal medulla. Its biosynthesis is mainly to form NA in medullary chromium cells first, and then methylate NA to form adrenaline through the action of phenylethylamine -N- methyltransferase.
Medicinal adrenaline can be extracted from the adrenal glands of domestic animals or synthesized artificially. Physical and chemical properties are similar to those of sodium. Adrenaline is destroyed in alkaline intestinal juice, intestinal mucosa and liver after oral administration, and its absorption is very small, which can not reach the effective blood concentration.
Subcutaneous injection can constrict blood vessels, so it is absorbed slowly, and the duration of action is about1h.
The absorption of intramuscular injection is much faster than subcutaneous injection, and the duration of action is 10-30min. Adrenaline can stimulate α and β receptors, resulting in strong α and β effects.
1, heart: β 1 receptor acts on myocardium, conduction system and sinoatrial node, strengthening myocardial contractility, accelerating conduction, accelerating heart rate and increasing cardiac output. Adrenaline can relax coronary vessels and improve myocardial blood supply, which is a cardiotonic stimulant. On the negative side, the cardiac work is obviously increased, which increases the myocardial oxygen consumption. If the dose is large or the intravenous injection is too fast, it can cause arrhythmia, premature beat (premature beat) and even ventricular fibrillation.
2. Blood vessels: The types and densities of adrenoceptors (α 1 and β2) in blood vessels in different parts of human body are different, so the effects of adrenaline on blood vessels in different parts are different.
The vasoconstriction of skin mucosa is the strongest; Visceral blood vessels, especially renal blood vessels, also contracted obviously;
It has a weak contraction effect on brain and lung blood vessels, and sometimes passively relaxes due to the increase of blood pressure;
The β2 receptor of skeletal muscle blood vessels is dominant, so it plays a relaxing role; It can also relax coronary vessels.
3. Blood pressure:
During treatment, due to the excitement of the heart, the cardiac output increased and the systolic blood pressure increased; Because the effect of skeletal muscle vasodilation on blood pressure counteracts or exceeds the effect of skin mucosal vasoconstriction, diastolic blood pressure remains unchanged or decreases; At this time, the blood in all parts of the body is redistributed, which is more suitable for the need of energy supply in an emergency.
When a large dose of intravenous injection, systolic blood pressure and diastolic blood pressure increased.
One-time intravenous injection 1μg /kg can make the blood pressure curve show biphasic reaction.
It acts on β 1 receptor of adjacent glomerular cells to promote renin secretion.
4, smooth muscle:
Adrenaline excites β2 receptor of bronchial smooth muscle, strongly relaxes bronchi, inhibits mast cells from releasing allergic active substances, contracts bronchial mucosal blood vessels, reduces capillary permeability and eliminates bronchial mucosal edema, all of which are beneficial to relieve bronchial asthma.
5, metabolism:
It can improve the metabolism of the body and increase the oxygen consumption by 20% ~ 30% at the therapeutic dose.
In human body, the excitement of α receptor and β2 receptor may lead to the decomposition of hepatic glycogen, and adrenaline has both α and β effects, so its hypoglycemic effect is more significant than that of norepinephrine. In addition, epinephrine can also reduce the intake of glucose by peripheral tissues.
Adrenaline can also activate triglycerides to accelerate fat decomposition and increase free fatty acids in the blood. 1. Cardiac arrest is used for cardiac arrest caused by drowning, accidents during anesthesia and operation, drug poisoning, infectious diseases and cardiac block. Cardiac arrest caused by electric shock can also be defibrillated by adrenaline combined with cardiac defibrillator or lidocaine. Generally, it is intravenous injection, and effective artificial respiration and cardiac compression must be carried out at the same time.
2. Anaphylactic shock is the first choice, which can quickly relieve shock symptoms. Generally, intramuscular injection or subcutaneous injection is used, and slow intravenous injection can also be used after dilution with normal saline in case of emergency. Such as anaphylactic shock caused by penicillin.
3, acute attack of bronchial asthma can be effective by subcutaneous or intramuscular injection for a few minutes.
4. The main adverse reactions of compatibility with anesthetics and local hemostasis are palpitation, irritability, headache and insomnia. There is a risk of cerebral hemorrhage when blood pressure rises sharply, so the elderly should use it with caution. It can also cause arrhythmia and even ventricular fibrillation, so the dose should be strictly controlled.
Hypertension, cerebral arteriosclerosis, organic heart disease, diabetes and hyperthyroidism are prohibited.
Adrenaline analogue
1, dopamine
It is the precursor of norepinephrine biosynthesis and the synthetic product of drugs.
① It mainly excites α, β receptors and dopamine receptors. The effect of dopamine on cardiovascular system is related to drug concentration.
② At low concentration, acting on D 1 receptor can relax renal blood vessels, increase renal blood flow and improve glomerular filtration rate. At the same time, it has the effect of sodium excretion and diuresis. At high dose, renal blood vessels contract obviously.
clinical application
Used for anti-shock, it has a good effect on shock patients with decreased myocardial contractility and decreased urine volume, but their blood volume has been supplemented.
In addition, this product can be used in combination with diuretics for acute renal failure. It can also be used for acute cardiac insufficiency. Pay attention to the dosage when daubing.
counteraction
Generally mild, with occasional nausea and vomiting.
If the dose is too large or the drip is too fast, tachycardia, arrhythmia, renal vasoconstriction and decreased renal function may occur. Once this happens, you should slow down the dripping speed or stop taking the medicine.
2. ephedrine
It is an alkaloid extracted from ephedra. Two thousand years ago, there was a record in Shennong Herbal Classic that ephedrine could "relieve cough and resist qi". Ephedrine has been artificially synthesized and used as its levorotatory or racemic form.
pharmacological action
Ephedrine can stimulate adrenoceptors, which has both direct and indirect effects (by promoting NA release). Compared with adrenaline, it has the following characteristics:
① stable chemical properties and effective oral administration;
② Adrenomimetic effect is weak and persistent;
③ The central function is significant;
④ It is easy to produce rapid drug resistance.
clinical application
Bronchial asthma: it is used to prevent attacks and treat mild diseases, but it has poor effect on acute severe attacks.
Nasal congestion caused by congestion of nasal mucosa: nasal drops of 0.5% ~ 1% solution can eliminate mucosal swelling.
Prevention and treatment of some hypotensive States: for example, it is used to prevent and treat hypotension caused by epidural and subarachnoid anesthesia.
Relieve skin and mucosal symptoms of urticaria and angioneurotic edema.
Adverse reactions and contraindications
Sometimes there will be anxiety and insomnia caused by central excitement. It is suggested to add sedative and hypnotic drugs at night to prevent insomnia. Contraindications are the same as adrenaline.
An example of β-agonists-isoproterenol
Isoproterenol is a synthetic product, and its chemical structure is that a hydrogen atom on the amino group of norepinephrine is replaced by isopropyl. It is a classical β 1 β2 receptor agonist. Oral administration is easy to combine with sulfuric acid in intestinal mucosa and fail. Aerosol is inhaled and quickly absorbed. Because sublingual medication can relax local blood vessels, a small amount can be quickly absorbed from submucosal hypoglossal venous plexus.
After absorption, it is mainly metabolized by COMT in liver and other tissues. Isoproterenol is less metabolized by MAO and less absorbed by noradrenergic nerves, so its action lasts a little longer than adrenaline. It has a strong excitatory effect on β receptor, and its selectivity to β 1 and β2 receptor is very low.
1, the heart has typical β 1 receptor excitement, which shows positive muscle strength, positive contraction rate and shortened systolic and diastolic periods. Compared with epinephrine, isoproterenol has a stronger function of accelerating heart rate and conduction, has a significant exciting effect on sinoatrial node, and can also cause arrhythmia, but has less ventricular fibrillation.
2, blood vessels and blood pressure
It has relaxing effect on blood vessels, mainly by stimulating β2 receptor to relax skeletal muscle blood vessels, but it has weak relaxing effect on renal blood vessels and mesenteric blood vessels, and also has relaxing effect on coronary blood vessels.
When intravenous infusion is 2 ~ 10μ g per minute, due to cardiac excitement and peripheral vasodilation, systolic blood pressure increases and diastolic blood pressure decreases slightly, and coronary flow increases at this time;
However, if administered intravenously, it can cause a significant decrease in diastolic blood pressure, reduce coronary perfusion pressure and not increase effective coronary flow.
3. Bronchial smooth muscle excites β2 receptor, relaxes bronchial smooth muscle slightly more than adrenaline, and also inhibits the release of allergic substances such as histamine. But it has no contraction effect on the blood vessels of bronchial mucosa, so the effect of eliminating mucosal edema is not as good as adrenaline. Long-term use can produce tolerance.
4. Others will increase the oxygen consumption of tissues. Compared with epinephrine, it has a similar effect on raising blood free fatty acids, but it has a weak effect on raising blood sugar. It is not easy to penetrate the blood-brain barrier and the central excitability is weak. 1, sublingual or spray administration of bronchial asthma, used to control the acute attack of bronchial asthma, has a rapid and powerful effect.
2, atrioventricular block treatment of ⅱ, ⅲ degree atrioventricular block, using sublingual medication, or intravenous drip.
3. Cardiac arrest is suitable for cardiac arrest complicated with ventricular slow rhythm, high atrioventricular block or sinus node failure, and is often used for intraventricular injection of norepinephrine or m-hydroxylamine.
4, septic shock is common palpitations, dizziness. Pay attention to control the heart rate during medication. Patients with bronchial asthma are already in a state of hypoxia, so it is difficult to master the dose of aerosol. If the dose is too large, it can increase myocardial oxygen consumption, easily lead to arrhythmia and even dangerous tachycardia and ventricular fibrillation.
Coronary heart disease, myocarditis and hyperthyroidism are prohibited.
Isoproterenol-like drug
1, dobutamine: mainly excites β 1 receptor. Compared with isoproterenol, its positive inotropic effect is more significant than its positive contractile effect. It rarely increases myocardial oxygen consumption, causing tachycardia. Clinically, it is mainly used to treat shock with low cardiac output or myocardial infarction complicated with heart failure after cardiac surgery.
2. Salbutamol: it selectively excites β2 receptor and is mainly used to treat asthma in clinic.