What is an Agonist?

An agonist is also called a stimulant. Molecules such as drugs, enzyme agonists, and hormones that can enhance the activity of another molecule and promote a response. An agonist is a molecule such as a drug, an enzyme agonist, and a hormone that enhances the activity of another molecule and promotes a response. It has both high affinity and high intrinsic activity with the receptor, and can bind to the receptor to produce the maximum effect (E _max ), also known as a full agonist ^[1] .

Chinese name: Agonist

Foreign name: agonist

Agonist classification

Generally divided into selective and non-selective two. Selective promotes only one type of response, non-selective promotes one type of response.

Beta receptor agonist

(1) Selective ₁ receptor agonists, such as dobutamine; Selective ₂ receptor agonists, such as salbutamol, tert-butyl, and asthma. ₂ receptor agonist activates excitatory G protein and activates adenylate cyclase by binding with ₂ receptor on airway target cell membrane, catalyzes the conversion of intracellular ATP to cAMP, and increases the level of cAMP in the cell. By activating cAMP-dependent protein kinase (PKA), smooth muscle is eventually relaxed through the decrease of intracellular free calcium concentration, inactivation of myosin light chain kinase (MCLK), and open potassium channels. In addition, -receptor agonism can also inhibit mast cells and neutrophils from releasing inflammatory mediators, enhance airway ciliary movement, promote airway secretion, reduce vascular permeability, and reduce submucosal edema, etc. These effects are beneficial Relieves or eliminates asthma.

(2) Non-selective receptor agonists, such as isoproterenol, act on the bronchial ₂ adrenaline receptor, relax the bronchial smooth muscle, and inhibit the release of histamine and other mediators; excite the ₁ adrenergic receptor, Increase heart rate, increase myocardial contractility, increase the conduction speed of the cardiac conduction system, and shorten the refractory period of the sinoatrial node; expand peripheral blood vessels and reduce the load on the heart (left heart) to correct low blood output and severe vasoconstriction State of shock.

M Agonist M receptor agonist

For example, pilocarpine has been used as an ophthalmic antihypertensive drug for more than a century. In order to prolong the efficacy and reduce side effects, ophthalmologists have done a lot of research work. As a slow-release drug-carrying system of pilocarpine used in the treatment of glaucoma, liposomes will have good development prospects due to its good efficacy, small side effects, and convenient use ^[2] .

N Agonist N receptor agonist

Such as nicotine, which is the main alkaloid of tobacco, accounting for about 90% of the total alkaloid content, is closely related to resistance to insect pests, and is also an important indicator of the quality of tobacco and cigarettes. The accumulation of nicotine is the result of the cooperative expression of structural genes encoding the nicotine biosynthetic pathway, and structural genes are usually controlled by regulatory genes such as COI1, JAZ, and MYC-2. At present, most genes involved in the biosynthesis, regulation and transport of nicotine and nornicotine have been identified ^[3] .

Agonist cases

1 Agonist selective 1 receptor agonist

Dobutamine

It is a synthetic product with similar chemical structure to dopamine and optical rotation. It is used as a racemate in clinical practice.

[Pharmacokinetics] Similar to dopamine, it is easily destroyed by the intestine and liver after oral administration, and is eliminated quickly. The t _{1/2 is} about 2 minutes. Therefore, it is generally administered by intravenous drip, and the time to reach the steady-state plasma concentration is about 10 -12 minutes.

[Pharmacological effects] Dobutamine L-body excites the ₁ receptor, and D-body antagonizes the ₁ receptor, so the effect of the racemate on the -receptor is canceled out. Both L- and D-body can stimulate the receptor. Body, and the intensity of the latter is 10 times that of the former. Dobutamine has little effect on ₂ receptors on blood vessels. Therefore, the comprehensive result of the effect of racemic dobutamine is mainly manifested by the activation of ₁ receptor. Compared with isoprenaline, dobutamine enhances myocardial contractility more significantly than speeding up the heart rate, and less causes tachycardia, but when the intravenous drip is too fast or the concentration is too high, it causes the heart rate to increase. Accelerating atrioventricular and ventricular conduction is similar to isoproterenol.

[Clinical application] For the treatment of heart failure with weakened myocardial contractility caused by various reasons, such as heart failure complicated by acute myocardial infarction, dilated cardiomyopathy, heart failure caused by rheumatic valvular disease, after open heart surgery The low blood volume syndrome caused by it is clinically used as short-term supportive treatment. Can increase myocardial contractility, increase cardiac output and reduce pulmonary capillary wedge pressure, significantly reduce left ventricular filling pressure, while not increasing heart rate, is conducive to improving heart function, but also can promote sodium drainage and diuresis, which is beneficial to Eliminate edema. It is superior to dopamine in improving left ventricular function in patients with heart failure with low blood output and slow heart rate.

[Adverse reactions and precautions] Symptoms such as palpitations, nausea, headache, chest pain, and shortness of breath. If there is an increase in systolic blood pressure (mostly increased by 10-20mmHg, a few increased by 50mmHg or more), and the heart rate is increased (mostly increased by 5-10 times per minute on the original basis. A few can be increased more than 30 times), which is related to the dose , Medication should be reduced or suspended. Because it can accelerate atrioventricular conduction, patients with atrial fibrillation may have a faster ventricular rate after taking the drug. Therefore, digoxin should be used before this medicine to avoid rapid ventricular rate response.

[Contraindications] Patients with obstructive hypertrophic cardiomyopathy are contraindicated.

Non-selective beta agonist

Isoprenaline

It is a synthetic product, and the hydrogen atom on the NA amino group is replaced by an isopropyl group.

[Pharmacokinetics] When taken orally, intestinal mucosal cells can destroy and fail; sublingual bladder can relax local blood vessels, and a small amount can be quickly absorbed from the sublingual vein plexus; aerosols are inhaled for rapid absorption. After absorption, it is mainly metabolized by COMT in the liver and other tissues, less metabolized by MAO, and less absorbed by noradrenergic nerve endings, so the action time is slightly longer than that of adrenaline, and t _1/2 is about 2 hours. Prototype and its metabolites are mainly excreted by the kidneys.

[Pharmacological action] It has almost no effect on receptors, and has strong agonistic effects on ₁ and ₂ receptors.

(1) Heart: Activating beta ₁ receptors, which produces a strong cardiac excitatory effect, enhances myocardial contractility, increases cardiac output, accelerates conduction, accelerates heart rate, and shortens both systolic and diastolic periods. Isoproterenol excites the heart stronger than epinephrine, but mainly excites the sinoatrial node and has a weaker effect on the ectopic pacemaker, so it rarely causes arrhythmias such as ventricular fibrillation.

(2) Blood vessels and blood pressure: ₂ receptors on excited blood vessels significantly relax skeletal muscle blood vessels, have a relaxing effect on coronary vessels, and have a weaker relaxing effect on renal and mesenteric vessels. Due to cardiac excitement and peripheral vasodilation, the systolic blood pressure is increased and the diastolic blood pressure is slightly decreased. Large-volume intravenous injections can cause a significant drop in blood pressure.

(3) Bronchus: Activates the 2 receptors of bronchial smooth muscle, relaxes the bronchial smooth muscle, and can also inhibit the release of allergens such as histamine, relieve the spasm of bronchial smooth muscle, and expand the bronchi. Because the metabolism of isoproterenol has -receptor antagonism, repeated use over a long period of time may reduce the efficacy.

(4) Metabolism: increase tissue oxygen consumption; promote liver glycogen breakdown and increase blood glucose are weaker than epinephrine; promote lipolysis and increase free fatty acid in blood are similar to epinephrine.

Clinical application

(1) Acute exacerbation of bronchial asthma: the effect of aerosol inhalation is 2-5 minutes, the effect is maintained for 0.5-2 hours, and the effect of sublingual administration is 15-30 minutes, the effect is maintained for about 1 hour.

(2) Atrioventricular block: administered sublingually or intravenously to treat and degree atrioventricular block.

(3) Cardiac arrest: It is suitable for cardiac arrest with slow ventricular rhythm, high atrioventricular block or sinoatrial node failure. To prevent diastolic blood pressure from decreasing coronary perfusion pressure, it is often associated with NA or Intravenous injection of m-hydroxylamine.

(4) Shock: On the basis of supplementing blood volume, it can be used for the treatment of septic shock with high central venous pressure and low cardiac output, but the microcirculation is not improved, and isoproterenol increases myocardial oxygen consumption and The effect of heart rate is not good for shock, and it has been rarely used clinically.

[Adverse Reactions and Precautions] Common adverse reactions include palpitations, dizziness, and headaches. Patients in hypoxia who inhale isoproterenol in large doses are prone to arrhythmias, induce and aggravate angina pectoris due to increased myocardial oxygen consumption; long-term abuse of asthma patients Isoprenaline may cause sudden death. Care should be taken to control heart rate during medication.

[Contraindications] It is contraindicated in patients with coronary heart disease, myocarditis and hyperthyroidism.

M Agonist M receptor agonist

Pilocarpine

The medicine, also known as pilocarpine, is an alkaloid that is proposed from the genus Rutica.

[Pharmacological effect] M choline receptors that can directly affect the effector organs dominated by the parasympathetic ganglion fibers (including the sympathetic nerves that control sweat glands), especially have significant effects on the eyes and glands.

(1) Eyes: Eye drops can cause contraction, reduce intraocular pressure, and regulate spasms. Reduction of pupils: There are two kinds of smooth muscles in the iris, one is the pupil sphincter, which is innervated by the parasympathetic fiber cholinergic nerves of the optic nerve. The pupil sphincter contracts when excited, and the pupil shrinks. Adrenergic innervation, the pupils of the pupil dilatation during the excitement contract to the periphery, so that the pupils dilate. This product can stimulate the M-choline receptors of the pupil sphincter, which manifests as pupil dilation, and the effect can last for several hours to one day after topical application. Reduction of intraocular pressure: aqueous humor is produced by the secretion of ciliary body epithelial cells and vascular exudation, and flows into the anterior chamber through the pupil, reaches the anterior chamber angle gap, mainly flows into the scleral sinus through the filter curtain, and finally enters the blood circulation. This product can pull the iris toward the center through the reduction of the pupil, and the root of the iris becomes thinner, so that the anterior chamber angle gap around the iris is enlarged, and the aqueous humor easily enters the scleral sinus through the filter curtain, which reduces the intraocular pressure. Regulating spasm: When the eye sees near objects, it changes the unevenness of the lens through the lens, so that the object can be imaged on the optic nerve omentum, so that the object can be seen clearly. The accommodative effect of the eye is mainly dependent on changes in the curvature of the lens. The lens capsule is full of elasticity, which promotes the lens to have a slightly spherical tendency. However, the lens can be maintained in a relatively flat state due to the outward pulling of the ligament. Suspensory ligaments are controlled by ciliary muscles. Ciliary muscles are composed of circular and radial smooth muscle fibers. When the oculomotor nerve is excited or pilocarpine acts, the ring muscles are contracted toward the pupil center, causing the suspension ligament to relax, and the lens becomes more convex due to its elasticity. At this time, it is only suitable for near objects and difficult to see distant objects. This effect of the drug is called regulating spasm, and this effect can disappear within 2 hours. The ciliary muscle is also innervated by noradrenergic nerves, but it does not occupy an important position in the regulation of the eye. Therefore, pseudoadrenaline drugs generally do not affect the regulation of the eye.

(2) Glands: Higher doses of pilocarpine (10-15mg subcutaneously injected) can significantly increase the secretion of sweat glands, salivary glands, and lacrimal glands, gastric glands, pancreas, small intestinal glands, and respiratory mucosa.

(3) Smooth muscle: In addition to the intraocular smooth muscles mentioned above, pilocarpine can excite the intestinal smooth muscles, increasing their tension and peristalsis; bronchial smooth muscle excitement (inducing asthma) can also excite the uterus, bladder, gallbladder, and biliary tract smooth muscle.

(4) Cardiovascular system: When pilocarpine 0.1mg / kg is injected intravenously, the heart rate and blood pressure can be temporarily reduced. If N-blockers are used first, it can produce a significant boosting effect. Both of the above effects can be cancelled by atropine, but the mechanism of antagonism of pilocarpine caused by it is not clear, and may be related to the excitement of ganglia and adrenal medulla.

Clinical application

(1) Glaucoma: Glaucoma is a common clinical ophthalmic disease. Patients are mainly characterized by progressive optic nerve nipple depression and vision loss, accompanied by symptoms of increased intraocular pressure, and severe cases can cause blindness. Trichocarpine (less than 2%) eye drops can be used to treat angle-closure glaucoma (also known as congestive glaucoma). After medication, the patient's pupils can be reduced, the anterior chamber angle gap can be enlarged, and the intraocular pressure can be reduced. However, high-concentration drugs can cause symptoms to worsen, so it should not be used. This product also has a certain effect on the early stage of open-angle glaucoma, also known as simple glaucoma. The drug easily enters the eye chamber through the cornea, and the intraocular pressure can be reduced within a few minutes after administration, and it can last for 4-8 hours. The mechanism is unknown. Eye drops are usually used in 1% -2% solutions. Intraocular pressure should be oppressed during eye drops to avoid side effects after absorption.

(2) Iriditis: used interchangeably with pupil dilatation to prevent the iris from adhering to the lens.

(3) Others: This medicine can be used orally for dry mouth after neck radiation, but at the same time as increasing saliva secretion, sweat secretion is also significantly increased. Can also be used for rescue of atropine poisoning.

[Adverse reactions] The overdose of this drug may show symptoms similar to muscarinic poisoning, manifested as symptoms of excessive excitability of M choline receptors, and can be treated symptomatically with atropine, maintaining blood pressure and artificial respiration, etc. ^[4] .

Agonistic dose- effect relationship

The dose-response relationship of the agonist is shown in Figure A, which indicates that the drug concentration [D] mol / L and the effect E are hyperbolic. If the ordinate is changed to the maximum response percentage and the abscissa is log [D], a left-right symmetric S-shaped curve is obtained, as shown in Figure B. If the ordinate is changed to the reciprocal of the effect percentage and the abscissa is changed to the reciprocal of the drug concentration, then a straight line ^[1] is obtained.