STUDY - Technical - New Dacian's Medicine
Physiology
and Pharmacology of the Vegetative Nervous System (4)
Translation Draft
So, today we're talking about the pharmacology of the sympathoadrenergic system.
Numerous therapeutic agents influence the functioning of the sympathetic nervous system or interact with adrenergic receptors, thus making it possible to stimulate or suppress the effects mediated by catecholamines, with some degree of specificity.
Sympathomimetic amines can directly activate adrenergic receptors (direct action) or release NE from sympathetic nerve endings (indirect action). Many agents have both types of effects (direct and indirect).
Let's start with epinephrine and norepinephrine. Natural catecholamines work predominantly by directly stimulating adrenergic receptors. NE is used to support circulation and increase blood pressure in hypotensive states. The main effect is peripheral vasoconstriction, although cardiac stimulation occurs at the same time. It is also used as a presser, has a special use in the treatment of allergic reactions, especially those associated with anaphylaxis. E antagonizes the effects of histamine and other mediators on the smooth vascular and visceral muscle and is useful in the treatment of bronchospasm.
Dopamine is used to treat hypotension, shock and certain forms of heart failure. At low doses injected IV exerts a positive inotropic effect, both through direct interaction on beta1 cardiac receptors and through indirect release of NE from sympathetic nerve endings in the heart. At low doses, direct stimulation of dopamine receptors in renal and mesenteric vessels causes vasodilation at the renal and intestinal levels and facilitates sodium excretion. at high doses injected IV, interaction with alpha-adrenergic receptors results in vasoconstriction, increased peripheral resistance and blood pressure.
We've reached the beta-adrenergic receptor agonists. Isoproterenol, a direct-acting agonist on the beta receptor, stimulates the heart, decreases peripheral resistance and relaxes smooth bronchial muscles. It increases cardiac output and accelerates atrioventricular conduction, in parallel with the increase in ventricular pacemaker automatism. Isoprotenerol is used in the treatment of cardiac block and bronchoconstriction. Dobutamine, a dopamine-like compound with relative selectivity for the beta1 receptor and with a greater effect on myocardial contractility than on heart rate, is also used in the treatment of congestive heart failure, often in association with vasodilators.
Dobutamine, like other related compounds used in investigations and which have a relatively greater effect on heart rate, is used in the diagnosis of myocardial ischemia caused, along with radioisotopic imaging or echocardiographic evaluation of cardiac wall motility. In the case of selective beta2 receptor agonists, cardiac stimulation caused by non-selective beta agonists such as isoproterenol or epinephrine is sometimes dangerous when these agents are used in the treatment of bronchoconstriction. Beta2 selective agonists, administered inhaler for the treatment of bronchospasm, include medium-acting agents (metaproteinol, albuterol, terbutaline, pyrbuterol, isoletarin and bitosterol) and the newer long-acting agent (salmeterol and formoterol) (these drugs have a superior therapeutic index because they achieve bronchodilation with a weaker activation of the cardiovascular system).
Although the selectivity of these agents is relative and at higher doses cardiac stimulation may occur, the inhaler agonists used in the usual doses produce a relatively small cardiac stimulation. Oral administration, which is no longer preferred at present, is associated with several beta-agonist systemic effects. Ritodrine, a kind of selective beta2 agonist, is used as a tocolytic agent (as well as terbutalin), to relax the uterus and prevent premature birth.
As for alpha-adrenergic agonists, phenylephrine and methoxamine are direct-acting alpha agonists that increase blood pressure by increasing peripheral vasoconstriction. They are mainly used in the treatment of hypotension and supraventricular paroxysmal tachycardia, in the latter case increasing the vagal cardiac tone by stimulating the baroreceptor reflex. Phenylephrine and a compound with similar properties, phenylpropanolamine, are the common constituents of decongested medication (often combinations with antihistamines) used in the treatment of allergic rhinitis and upper respiratory tract infections.
The various sympathomimetic amines with mixed actions are represented in particular by ephedrine, which has agonist properties directly on the beta receptor, as well as an indirect effect on sympathetic nerve endings, from which NE is released, and is used mainly as a bronchodilator. Sufedredrine, akin to ephedrine, has a lower bronchodilator effect and is used as a nasal decongestant. Meparaminol has both a direct and indirect effect on sympathetic nerve endings and is used in the treatment of hypotension. Dopamine agonists, such as bromocriptin, the Agonist of the D2 receptor, are used to suppress prolactin secretion. Apomorphine, another Agonist D2, is used to induce vomiting.
Let's see, now, what's with antiadrenergic or sympatholytic agents, starting with central-acting sympathetic inhibitors. Antihypertensive agents methyldopa, clonidine, guanabenz and guanfacin diminish central sympathetic influences by stimulating a central alpha-adrenergic pathway (alpha2 receptors), which decreasevasomotor effects. Adverse reactions in the central nervous system, such as sedation, are common. When clonidine suddenly stops, a withdrawal syndrome, characterized by hyperactivity of the sympathetic nervous system, can produce a crisis-like condition of patients with pheochromocytoma. And opiates can exert a central sympatholytic effect (sympathetic excitation in the case of morphine withdrawal responds to clonidine and vice versa).
Propanolol and reserpine may exert some sympatolytic effects on the central nervous system. In the case of blocking agents of the vegetative ganglia (ganglioplegic agents), transmission to the vegetative ganglia can be antagonized by drugs that block the cholinergic (nicotinic) synapse between the preganglionary and postganglionary vegetative nerves. These agents inhibit both the parasympathetic and sympathetic nervous systems. Only trimetafan has a general clinical use (its major application is in the treatment of hypertensive seizures, especially in the dissection of the aorta, when it is desired to obtain controllable hypotension and decrease myocardial contractility).
Agents acting on sympathetic peripheral nerve endings (especially the blocking agents of adrenergic neurons) depress the function of peripheral sympathetic nerves by decreasing the amount of neurotransmitter released. Guanetidine, the prototype of this class of drugs, is concentrated at the level of sympathetic nerve endings, through the mechanism of amine capture. In these nerve endings, it blocks the release of NE in response to nerve stimulation and eventually decreases the neural reserves of NE by dislocated NE from the intraneuronal deposit granules. This medicine is occasionally used to control severe hypertension, although orthostatic hypotension is a side effect that limits its use.
Bretilium, an agent whose side effects are similar to guanetidine, is used in the treatment of ventricular fibrillation. Both guanetidine and bretillium are antagonized by agents that affect the process of reuptake amines, such as sympathomimetic amines, tricyclic antidepressants, phenoxibenzamine and phenothiazides. The antihypertensive action of guanetidine can be quickly undone by these drugs. Reserpine depletes catecholamines from peripheral, brain and adrenal sympathetic nerve endings. In humans, its antihypertensive effect is usually attributed to the depletion of peripheral NE reserves in sympathetic nerve endings. The occasional sedation and morbid depression accompanying its use occur through NE deplation inside the central nervous system.
Let's move on to adrenergic receptor blockers that antagonize the effects of catecholamines on peripheral tissue. Among the blocking agents of alpha-adrenergic receptors, phenoxypetrol and fentolamine are used mainly in the treatment of pheochromocytoma. Fenoxibenzamine produces a prolonged non-competitive alpha receptor lock, while fentolamine causes a reversible competitive lock. Due to its rapid action and short duration of action, fentolamine is commonly used in the treatment of acute paroxysmal hypertension, secondary to excess catecholamines, as happens in pheochromocytoma.
Both fentolamine and phenoxibenzamine antagonize alpha1 and alpha2 receptors, although phenoxibenzamine is more active on the alpha1 receptor. Prazosin, an alpha-adrenergic blocker with selectivity for alpha1 receptors, has properties similar to those of direct vasodilators and is used to treat essential hypertension and as a post-pregnancy reduction agent in congestive heart failure. Dexazosin and therazosin, long-acting selective alpha1 blockers, are more useful in the treatment of essential hypertension because the regimen is more advantageous and orthostatic hypotension is less severe.
In addition, these agents decrease the level of triglycerides and increase that of high-density lipoproteins (HDL). Selective alpha1 blockers are potentially useful in the symptomatic treatment of urinary tract obstruction and prostatism, as they antagonize sphincter contractions in the bladder trigon. Beta-adrenergic receptor blockers are our next benchmark. These drugs antagonize the effects of catecholamines on the heart and are useful in the treatment of angina, hypertension and cardiac arrhythmias. The benefit of beta-blocking in angina comes from decreased myocardial oxygen consumption as a result of decreased heart rate and myocardial contractility.
The hypotensive effect of beta-blocking is not very well understood. The following mechanisms are possible: decreased cardiac output, decreased NE release from postganglionary sympathetic nerve endings, reduction of renin secretion and suppression of central sympathetic influences. The effectiveness of beta-blockers in the treatment of arrhythmias depends on the reduction of the rate of spontaneous depolarization of pacemaker cells in the synoatrial and junctional nodules, as well as the decrease in conduction in the atria and atrioventricular node.
Beta-blocking is also effective for controlling tachycardia and arrhythmias in patients with pheochromocytoma. Beta-adrenal blockers are also useful in the treatment of migraine, essential tremor, idiopathic hypertrophy subaortic stenosis and aorta dissection. Several studies have shown that long-term beta-blockers reduce mortality after acute myocardial infarction. The mechanism of this cardioprotective effect may involve anti-arrhythmic action, prevention of reinfarction and reduction of the size of the infarction.
I will complete this post "next time" along with the presentation of some elements about the parasympathetic nervous system. Then there's a post about the nitrous oxide and... ready!!! I was able to complete the "class" notes represented by all these posts... There will be a period (very long, probably 2 years) in which I will refine the elements "conspected in class" realizing what might be called "home theme"... And, my great work will very possibly start on January 1, 2015 on dorinm.ro... Thank you, in advance, for understanding all those who accessed these posts!!! And now, a message that I will repeat
in all future posts: Love, Gratitude and Understanding!!! In the face of the Supreme Divinity (Godhead, Holy Power, Holy Spirit, etc.) we have asked for fulfillment. And then, before us came a Road, asked by us, to which we can cope, and thus different from man to man (from soul to soul). At the end of this Road is the great exam, the one before the leap to the higher worlds. And as we go through this Road, we have only two goals: "To accumulate knowledge" (and to understand it) and "To do good" (whatever we "touch" to leave it better, better, than we found giving Love and Gratitude "square")...
So, today we're talking about the pharmacology of the sympathoadrenergic system.
Numerous therapeutic agents influence the functioning of the sympathetic nervous system or interact with adrenergic receptors, thus making it possible to stimulate or suppress the effects mediated by catecholamines, with some degree of specificity.
Sympathomimetic amines can directly activate adrenergic receptors (direct action) or release NE from sympathetic nerve endings (indirect action). Many agents have both types of effects (direct and indirect).
Let's start with epinephrine and norepinephrine. Natural catecholamines work predominantly by directly stimulating adrenergic receptors. NE is used to support circulation and increase blood pressure in hypotensive states. The main effect is peripheral vasoconstriction, although cardiac stimulation occurs at the same time. It is also used as a presser, has a special use in the treatment of allergic reactions, especially those associated with anaphylaxis. E antagonizes the effects of histamine and other mediators on the smooth vascular and visceral muscle and is useful in the treatment of bronchospasm.
Dopamine is used to treat hypotension, shock and certain forms of heart failure. At low doses injected IV exerts a positive inotropic effect, both through direct interaction on beta1 cardiac receptors and through indirect release of NE from sympathetic nerve endings in the heart. At low doses, direct stimulation of dopamine receptors in renal and mesenteric vessels causes vasodilation at the renal and intestinal levels and facilitates sodium excretion. at high doses injected IV, interaction with alpha-adrenergic receptors results in vasoconstriction, increased peripheral resistance and blood pressure.
We've reached the beta-adrenergic receptor agonists. Isoproterenol, a direct-acting agonist on the beta receptor, stimulates the heart, decreases peripheral resistance and relaxes smooth bronchial muscles. It increases cardiac output and accelerates atrioventricular conduction, in parallel with the increase in ventricular pacemaker automatism. Isoprotenerol is used in the treatment of cardiac block and bronchoconstriction. Dobutamine, a dopamine-like compound with relative selectivity for the beta1 receptor and with a greater effect on myocardial contractility than on heart rate, is also used in the treatment of congestive heart failure, often in association with vasodilators.
Dobutamine, like other related compounds used in investigations and which have a relatively greater effect on heart rate, is used in the diagnosis of myocardial ischemia caused, along with radioisotopic imaging or echocardiographic evaluation of cardiac wall motility. In the case of selective beta2 receptor agonists, cardiac stimulation caused by non-selective beta agonists such as isoproterenol or epinephrine is sometimes dangerous when these agents are used in the treatment of bronchoconstriction. Beta2 selective agonists, administered inhaler for the treatment of bronchospasm, include medium-acting agents (metaproteinol, albuterol, terbutaline, pyrbuterol, isoletarin and bitosterol) and the newer long-acting agent (salmeterol and formoterol) (these drugs have a superior therapeutic index because they achieve bronchodilation with a weaker activation of the cardiovascular system).
Although the selectivity of these agents is relative and at higher doses cardiac stimulation may occur, the inhaler agonists used in the usual doses produce a relatively small cardiac stimulation. Oral administration, which is no longer preferred at present, is associated with several beta-agonist systemic effects. Ritodrine, a kind of selective beta2 agonist, is used as a tocolytic agent (as well as terbutalin), to relax the uterus and prevent premature birth.
As for alpha-adrenergic agonists, phenylephrine and methoxamine are direct-acting alpha agonists that increase blood pressure by increasing peripheral vasoconstriction. They are mainly used in the treatment of hypotension and supraventricular paroxysmal tachycardia, in the latter case increasing the vagal cardiac tone by stimulating the baroreceptor reflex. Phenylephrine and a compound with similar properties, phenylpropanolamine, are the common constituents of decongested medication (often combinations with antihistamines) used in the treatment of allergic rhinitis and upper respiratory tract infections.
The various sympathomimetic amines with mixed actions are represented in particular by ephedrine, which has agonist properties directly on the beta receptor, as well as an indirect effect on sympathetic nerve endings, from which NE is released, and is used mainly as a bronchodilator. Sufedredrine, akin to ephedrine, has a lower bronchodilator effect and is used as a nasal decongestant. Meparaminol has both a direct and indirect effect on sympathetic nerve endings and is used in the treatment of hypotension. Dopamine agonists, such as bromocriptin, the Agonist of the D2 receptor, are used to suppress prolactin secretion. Apomorphine, another Agonist D2, is used to induce vomiting.
Let's see, now, what's with antiadrenergic or sympatholytic agents, starting with central-acting sympathetic inhibitors. Antihypertensive agents methyldopa, clonidine, guanabenz and guanfacin diminish central sympathetic influences by stimulating a central alpha-adrenergic pathway (alpha2 receptors), which decreasevasomotor effects. Adverse reactions in the central nervous system, such as sedation, are common. When clonidine suddenly stops, a withdrawal syndrome, characterized by hyperactivity of the sympathetic nervous system, can produce a crisis-like condition of patients with pheochromocytoma. And opiates can exert a central sympatholytic effect (sympathetic excitation in the case of morphine withdrawal responds to clonidine and vice versa).
Propanolol and reserpine may exert some sympatolytic effects on the central nervous system. In the case of blocking agents of the vegetative ganglia (ganglioplegic agents), transmission to the vegetative ganglia can be antagonized by drugs that block the cholinergic (nicotinic) synapse between the preganglionary and postganglionary vegetative nerves. These agents inhibit both the parasympathetic and sympathetic nervous systems. Only trimetafan has a general clinical use (its major application is in the treatment of hypertensive seizures, especially in the dissection of the aorta, when it is desired to obtain controllable hypotension and decrease myocardial contractility).
Agents acting on sympathetic peripheral nerve endings (especially the blocking agents of adrenergic neurons) depress the function of peripheral sympathetic nerves by decreasing the amount of neurotransmitter released. Guanetidine, the prototype of this class of drugs, is concentrated at the level of sympathetic nerve endings, through the mechanism of amine capture. In these nerve endings, it blocks the release of NE in response to nerve stimulation and eventually decreases the neural reserves of NE by dislocated NE from the intraneuronal deposit granules. This medicine is occasionally used to control severe hypertension, although orthostatic hypotension is a side effect that limits its use.
Bretilium, an agent whose side effects are similar to guanetidine, is used in the treatment of ventricular fibrillation. Both guanetidine and bretillium are antagonized by agents that affect the process of reuptake amines, such as sympathomimetic amines, tricyclic antidepressants, phenoxibenzamine and phenothiazides. The antihypertensive action of guanetidine can be quickly undone by these drugs. Reserpine depletes catecholamines from peripheral, brain and adrenal sympathetic nerve endings. In humans, its antihypertensive effect is usually attributed to the depletion of peripheral NE reserves in sympathetic nerve endings. The occasional sedation and morbid depression accompanying its use occur through NE deplation inside the central nervous system.
Let's move on to adrenergic receptor blockers that antagonize the effects of catecholamines on peripheral tissue. Among the blocking agents of alpha-adrenergic receptors, phenoxypetrol and fentolamine are used mainly in the treatment of pheochromocytoma. Fenoxibenzamine produces a prolonged non-competitive alpha receptor lock, while fentolamine causes a reversible competitive lock. Due to its rapid action and short duration of action, fentolamine is commonly used in the treatment of acute paroxysmal hypertension, secondary to excess catecholamines, as happens in pheochromocytoma.
Both fentolamine and phenoxibenzamine antagonize alpha1 and alpha2 receptors, although phenoxibenzamine is more active on the alpha1 receptor. Prazosin, an alpha-adrenergic blocker with selectivity for alpha1 receptors, has properties similar to those of direct vasodilators and is used to treat essential hypertension and as a post-pregnancy reduction agent in congestive heart failure. Dexazosin and therazosin, long-acting selective alpha1 blockers, are more useful in the treatment of essential hypertension because the regimen is more advantageous and orthostatic hypotension is less severe.
In addition, these agents decrease the level of triglycerides and increase that of high-density lipoproteins (HDL). Selective alpha1 blockers are potentially useful in the symptomatic treatment of urinary tract obstruction and prostatism, as they antagonize sphincter contractions in the bladder trigon. Beta-adrenergic receptor blockers are our next benchmark. These drugs antagonize the effects of catecholamines on the heart and are useful in the treatment of angina, hypertension and cardiac arrhythmias. The benefit of beta-blocking in angina comes from decreased myocardial oxygen consumption as a result of decreased heart rate and myocardial contractility.
The hypotensive effect of beta-blocking is not very well understood. The following mechanisms are possible: decreased cardiac output, decreased NE release from postganglionary sympathetic nerve endings, reduction of renin secretion and suppression of central sympathetic influences. The effectiveness of beta-blockers in the treatment of arrhythmias depends on the reduction of the rate of spontaneous depolarization of pacemaker cells in the synoatrial and junctional nodules, as well as the decrease in conduction in the atria and atrioventricular node.
Beta-blocking is also effective for controlling tachycardia and arrhythmias in patients with pheochromocytoma. Beta-adrenal blockers are also useful in the treatment of migraine, essential tremor, idiopathic hypertrophy subaortic stenosis and aorta dissection. Several studies have shown that long-term beta-blockers reduce mortality after acute myocardial infarction. The mechanism of this cardioprotective effect may involve anti-arrhythmic action, prevention of reinfarction and reduction of the size of the infarction.
I will complete this post "next time" along with the presentation of some elements about the parasympathetic nervous system. Then there's a post about the nitrous oxide and... ready!!! I was able to complete the "class" notes represented by all these posts... There will be a period (very long, probably 2 years) in which I will refine the elements "conspected in class" realizing what might be called "home theme"... And, my great work will very possibly start on January 1, 2015 on dorinm.ro... Thank you, in advance, for understanding all those who accessed these posts!!! And now, a message that I will repeat
in all future posts: Love, Gratitude and Understanding!!! In the face of the Supreme Divinity (Godhead, Holy Power, Holy Spirit, etc.) we have asked for fulfillment. And then, before us came a Road, asked by us, to which we can cope, and thus different from man to man (from soul to soul). At the end of this Road is the great exam, the one before the leap to the higher worlds. And as we go through this Road, we have only two goals: "To accumulate knowledge" (and to understand it) and "To do good" (whatever we "touch" to leave it better, better, than we found giving Love and Gratitude "square")...
Dorin, Merticaru