STUDY - Technical - New Dacian's Medicine
Physiology
and Pharmacology of the Vegetative Nervous System (5)
Translation Draft
We continue the previous post with the presentation of some elements about the pharmacological properties of beta receptor blockers.
We continue the previous post with the presentation of some elements about the pharmacological properties of beta receptor blockers.
In general, there are
available for use (at this time) 13 beta-blockers (atenolil,
acebutolol, betaxolol, bisoprolol, carteolol, esmolol,
metoprolol, nadolol, pindolol, penbutolol, propanolol, sotalol
and timolol). Other agents (alprenolol, bevantolol, didevalol,
oxprenolol, etc.) are used less often. The usefulness of these
drugs derives mainly from blocking beta-adrenergic receptors.
In general, they have similar clinical efficacy. Although much has been written about other pharmacological properties, including cardioselectivity, membrane stabilisation effects (local anesthetics), sympathomimetic intrinsic activity (partial agonist) and liposolubility, the clinical significance of these additional properties is small. The local anesthetic properties are more evident in propanolol (however, membrane stabilization probably does not contribute substantially to clinical usefulness). Various beta-blockers differ in their liposolubility and hydrosolubility.
Lipophilic agents (propanolol, metoprolol, oxprenolol, bisoprolol) are easily absorbed from the gastrointestinal tract, metabolized in the liver, have a high volume of distribution and penetrate well into the central nervous system (hydrophilic agents such as acebutolol, atenolol, betaxolol, carteolol, nadolol and sotalol are absorbed more heavily, are not fully metabolized and have a relatively long plasma half-life). As a result, hydrophilic agents can be administered once a day. Liver failure may prolong the plasma half-life of lipophilic agents while renal failure may prolong the duration of action of hydrophilic agents.
So the degree of liposolubility provides a basis for choosing a specific agent in patients with hepatic or renal impairment. Although hydrophilic agents penetrate harder into the central nervous system, side effects are described at this level (sedation, depression, hallucinations) for both hydrophilic and lipophilic compounds. Some beta-adrenergic blockers exhibit beta-agonist activity. This has been referred to as "intrinsic sympathomimetic activity" (ASI). Agents with such partial agonistactivity (pindolol, alprenolol, acebutolol, carteolol, dilevalol, oxprenolol) decrease the resting heart rate slightly or not at all (partial agonist effect), but block tachycardia that occurs in response to physical exertion or to the administration of an isoproteinol beta-agonist. The presence of partially agonistic activity may be useful when bradycardia limits the use of treatment in patients with low resting heart rate.
Pindolol also produces mild vasodilation, possibly partially related to peripheral stimulation of beta2 receptors. Agents with partial agonist activity appear to cause smaller changes in blood lipid levels than agents without agonistproperties. Theoretically, intrinsic sympathomimetic activity would not be desirable in the treatment of thyrotoxicosis, idiopathic hypertrophic subaortic stenosis, aorta dissections and tachyarrhythmias.
We have reached cardioselective agents blocking adrenergic receptors (beta1-adrenergic blockers). Propanolol, the prototype of non-selective beta-blockers, produces a competitive lock of both beta1 and beta2 receptors. Other non-selective beta blockers are: alprenolol, carteolol, nadolol, dilevalolol, oxprenolol, penbutolol, pindolol, sotanol and thymolol. Metoprolol, esmolol, acebutolol, atenolol and betaxolol exhibit relative selectivity for the beta1 receptor. Although beta1-(cardio)-selective agents have the theoretical advantage of producing less bronchoconstriction and peripheral vasoconstriction, a very clear clinical advantage of cardioselective agents has not yet been demonstrated, since beta1 selectivity is only relative. Bronhoconstriction may occur when beta1-selective agents are administered in high therapeutic doses.
Now, about the adverse effects of beta receptor blockers. In addition to the effects on the central nervous system, most adverse reactions that occur when taking beta-blockers are the consequence of beta-adrenergic blockage. These effects include precipitation of heart failure in patients whose cardiac compensation depends on increased sympathetic tone, worsening of bronchospasm in asthma patients, predisposition for hypoglycaemia in insulin-dependent diabetics (by blocking the counterglation mediated by catecholamines and antagonization of adrenergic warning signals for hypoglycaemia), development of hyperpotassium in diabetic or uremic patients with impaired potassium tolerance , favouring coronary vasospasm or peripheral arteries, increasing triglyceride levels and lowering the level of high-density lipoproteins (HDL). The effects on lipids (and probably peripheral circulation) are lower (or absent) for agents with partial agonistic activity (beta2).
Various adrenergic blockers, such as labetalol, used as an antihypertensive agent, is a competitive antagonist of both alpha and beta-adrenergic receptors. Although labetalol produces a relatively higher blockage of beta receptors than alpha-adrenergic receptors, the decrease in peripheral resistance may be marked after acute administration of the drug. Vasodilation may be mediated, in part, by the partial agonist effect on the beta2-adrenergic receptor (labetalol does not exhibit partially agonistic activity for the beta1-cardiac receptor).
Metoclopramide is a dopaminergic antagonist with cholinergic agonist properties. It accelerates the emptying of the stomach, increases the tone of the lower esophageal sphincter, increases the secretion of prolactin and aldosterone and antagonizes the emetic effect produced by apomorphine. It is clinically useful for hastening the emptying of the stomach (in the absence of organic obstruction), for example, in diabetic gastroparesis, for preventing gastroesophageal reflux and as an antiemetic during chemotherapy for neoplasm.
And just like that, we got to the parasympathetic nervous system.
In this case, acetylcholine (AC) acts as a neurotransmitter for all vegetative ganglia, at the level of postganglionary parasympathetic nerve endings, in the postganglionary sympathetic endings that irritate the ecrine sweat glands and in the neuromuscular plaque. The cholinetilel enzyme transfers the AC synthesis of acetyl coenzyme A (CoA), produced in nerve endings, and from choline, actively captured from extracellular fluid. AC is stored inside cholinergic nerve endings in tiny synaptic vesicles and is released from them in response to nerve impulses that depolarize nerve endings and increase calcium influx. There are different receptors (cholinergics) for AC on postganglionary neurons in the vegetative ganglia and at the level of postjunctional vegetative effector situses.
Receptors in the vegetative ganglia and medulloadrenal are predominantly stimulated by nicotine (nicotinic receptors), and those in the vegetative effector cells of muscarin alkaloid (muscarinic receptors). Ganglioplegic agents antagonize nicotinic receptors, while atropine blocks muscarinic receptors. The muscarinic receptor (M) has recently been classified into several subtypes. The M1 receptor is located in the central nervous system and probably in the parasympathetic ganglia, the M2 receptor is the non-neuronal muscarinic receptor in the smooth muscle, heart muscle and glandular epithelium.
Betanecol is a selective agonist of the M2 receptor, pirenzepine is a selective antagonist of the M1 receptor], which profoundly reduces gastric acid secretion. The M2 receptor inhibits adenylate-cyclase and uses the Gi regulating protein (the M1 receptor interacts with Gi and stimulates phospholipase C). The M3 receptor, present in the smooth muscle and secretory glands, is antagonized by atropine and uses phospholipase C, IP3 and DAG as second messengers. They have been identified, through molecular biology techniques, and other subtypes, but they have not yet been fully characterized.
There's still something to be done about acetylcholinesterase. AC hydrolysis, under the action of acetylcholinesterase, inactivates the neurotransmitter in cholinergic synapses. This enzyme (also known as specific or true cholinesterase) is present in neurons and is different from butylcolinesterase (serum cholinesterase or pseudocolinesterase). The last enzyme is present in plasma and non-nervous tissues and is not primarily involved in stopping the effects of AC in vegetative effectors. The pharmacological effects of anticholinesterase agents are due to the inhibition of neural (true) acetylcholinesterase.
Now, some more "stuff" about the physiology of the parasympathetic nervous system. The parasympathetic nervous system participates in the regulation of the cardiovascular system, the gastrointestinal tract and the genitourinary system. The liver, kidneys, pancreas and thyroid are also parasympathetic lyverate in metabolic control, although the cholinergic effects on metabolism are not well known.
In the case of the cardiovascular system, the parasympathetic effects on the heart are mediated by the vagus nerve. AC reduces the frequency of spontaneous depolarization of the synoatrial node and decreases heart rate. AC also delays impulse conduction in the atrial musculature, while shortening the absolute refractory period, a combination of factors that can initiate or maintain atrial arrhythmias. At the atrioventricular node, AC decreases the driving speed, increases the absolute refractory period and thus decreases the ventricular response during atrial fibrillation or flutter. The decrease in inotropism under the action of AC is linked to a prejunctional inhibitory effect on sympathetic nerve endings, as well as a direct inhibitory effect on the atrial myocardium. The ventricular myocardium is not too much affected, because its cholinergic innervation is minimal. The direct cholinergic contribution to the regulation of peripheral resistance seems unlikely, since parasympathetic innervation can directly influence peripheral resistance by inhibiting the release of NE from sympathetic nerves.
In the case of the gastrointestinal tract, the parasympathetic innervation of the digestive tract is achieved through the vagus nerve and sacral nerves. The parasympathetic nervous system increases the tone of the gastrointestinal smooth muscles and peristaltic activity and relaxes the gastrointestinal sphincters. AC stimulates exocrine secretion of the glandular epithelium and increases the secretion of gastrine, secretin and insulin.
For the genitourinary system, the sacral parasympathetic nerves irritate the bladder and genitals. AC increases ureteral peristalsis, contracts the bladder detrusor muscle and relaxes the trigon and sphincter, thus playing an essential role in coordinating shrinkage. The respiratory tract is inervated by parasympathetic fibers from the vagus nerve. AC increases tracheobronsic secretion and stimulates bronchoconstriction.
I've reached the pharmacology of the parasympathetic nervous system, and I'm going to start with the cholinergic agonists. AC itself has no therapeutic importance due to its nonspecific effects and short duration of action. Compounds related to AC are less susceptible to hydrolysis under the action of cholinesterase and have a narrower spectrum of physiological effects. Betanecol, the only systemic cholinergic agonist used, stimulates the smooth gastrointestinal and genitourinary muscles, with minimal effects on the cardiovascular system. It is used for the treatment of urinary retention, in the absence of obstruction and, less often, in gastrointestinal disorders such as can-vagotomy gastric atone.
Pilocarpine and carbacol are topical cholinergic agonists used in the treatment of glaucoma. Now, about acetylcholinesterase inhibitors. Cholinesterase inhibitors increase the effects of parasympathetic stimulation by reducing AC inactivation. Therapeutic administration of reversible cholinesterase inhibitors is based on the role of AC as a neurotransmitter in the neuro-effector junction of the striated muscle fiber and in the central nervous system. These drugs are used for the treatment of severe myasthenia, for the removal of neuromuscular blockage after general anesthesia and as an antidote to intoxication with central anticholinergic substances.
Physostigmine, a tertiary amine, penetrates well into the central nervous system, while related quaternary amines (neostigmine, pyridostigmine, ambenoon and edrophonia) do not pass through the blood-brain barrier. Organophosphoric compounds inhibitors of cholinesterase produce irreversible cholinesterase blockage (these agents are mainly used as insecticides and have especially toxicological interest). As for the vegetative nervous system, cholinesterase inhibitors have limited use in the treatment of smooth intestinal and bladder muscle dysfunction, such as those that occur during the paralytic ileus and atoneal bladder. Cholinesterase inhibitors induce a vagoton response at the heart level and may be useful in stopping bouts of supra ventricular paroxysmal tachycardia. It's the "turn" of cholinergic receptor blockers.
Atropine blocks muscarinic cholinergic receptors, with a weak effect on cholinergic transmission in the vegetative ganglia and neuromuscular junctions. Many of the actions of atropine and atropine-like agents on the central nervous system are attributed to blocking the central muscarinic synapses. The related alkaloid, scopolamine, is similar to atropine, but causes sedation, euphoria and amnesia, effects that make it suitable in pre-anesthetic medication. Atropine increases heart rate and atrioventricular conduction, actions that may be useful in combating bradycardia or heart disease associated with increased vagal tone. In addition, atropine cancels cholinergic mediated bronchoconstriction and reduces respiratory tract secretions. These effects contribute to its use as a preanesthetic medication.
Atropine also decreases the motility and secretion of the gastrointestinal tract. Although many agents derived and related to atropine (e.g. propantelin, isopropamide and glycopirolate) have been recommended for patients with peptic ulcers or diarrheal syndromes, their prolonged use is limited by other manifestations of parasympathetic inhibition, such as dry mouth and urinary retention. Pirenzepin, a selective M1 inhibitor used in investigations, inhibits gastric secretion at doses that have other minimal anticholinergic effects (this agent may be useful in the treatment of peptic ulcers). Atropine and the related compound, ipratropium, administered inhaled, causes bronchodilation. The latter is used experimentally for the treatment of asthma.
Here we have completed this post...
In general, they have similar clinical efficacy. Although much has been written about other pharmacological properties, including cardioselectivity, membrane stabilisation effects (local anesthetics), sympathomimetic intrinsic activity (partial agonist) and liposolubility, the clinical significance of these additional properties is small. The local anesthetic properties are more evident in propanolol (however, membrane stabilization probably does not contribute substantially to clinical usefulness). Various beta-blockers differ in their liposolubility and hydrosolubility.
Lipophilic agents (propanolol, metoprolol, oxprenolol, bisoprolol) are easily absorbed from the gastrointestinal tract, metabolized in the liver, have a high volume of distribution and penetrate well into the central nervous system (hydrophilic agents such as acebutolol, atenolol, betaxolol, carteolol, nadolol and sotalol are absorbed more heavily, are not fully metabolized and have a relatively long plasma half-life). As a result, hydrophilic agents can be administered once a day. Liver failure may prolong the plasma half-life of lipophilic agents while renal failure may prolong the duration of action of hydrophilic agents.
So the degree of liposolubility provides a basis for choosing a specific agent in patients with hepatic or renal impairment. Although hydrophilic agents penetrate harder into the central nervous system, side effects are described at this level (sedation, depression, hallucinations) for both hydrophilic and lipophilic compounds. Some beta-adrenergic blockers exhibit beta-agonist activity. This has been referred to as "intrinsic sympathomimetic activity" (ASI). Agents with such partial agonistactivity (pindolol, alprenolol, acebutolol, carteolol, dilevalol, oxprenolol) decrease the resting heart rate slightly or not at all (partial agonist effect), but block tachycardia that occurs in response to physical exertion or to the administration of an isoproteinol beta-agonist. The presence of partially agonistic activity may be useful when bradycardia limits the use of treatment in patients with low resting heart rate.
Pindolol also produces mild vasodilation, possibly partially related to peripheral stimulation of beta2 receptors. Agents with partial agonist activity appear to cause smaller changes in blood lipid levels than agents without agonistproperties. Theoretically, intrinsic sympathomimetic activity would not be desirable in the treatment of thyrotoxicosis, idiopathic hypertrophic subaortic stenosis, aorta dissections and tachyarrhythmias.
We have reached cardioselective agents blocking adrenergic receptors (beta1-adrenergic blockers). Propanolol, the prototype of non-selective beta-blockers, produces a competitive lock of both beta1 and beta2 receptors. Other non-selective beta blockers are: alprenolol, carteolol, nadolol, dilevalolol, oxprenolol, penbutolol, pindolol, sotanol and thymolol. Metoprolol, esmolol, acebutolol, atenolol and betaxolol exhibit relative selectivity for the beta1 receptor. Although beta1-(cardio)-selective agents have the theoretical advantage of producing less bronchoconstriction and peripheral vasoconstriction, a very clear clinical advantage of cardioselective agents has not yet been demonstrated, since beta1 selectivity is only relative. Bronhoconstriction may occur when beta1-selective agents are administered in high therapeutic doses.
Now, about the adverse effects of beta receptor blockers. In addition to the effects on the central nervous system, most adverse reactions that occur when taking beta-blockers are the consequence of beta-adrenergic blockage. These effects include precipitation of heart failure in patients whose cardiac compensation depends on increased sympathetic tone, worsening of bronchospasm in asthma patients, predisposition for hypoglycaemia in insulin-dependent diabetics (by blocking the counterglation mediated by catecholamines and antagonization of adrenergic warning signals for hypoglycaemia), development of hyperpotassium in diabetic or uremic patients with impaired potassium tolerance , favouring coronary vasospasm or peripheral arteries, increasing triglyceride levels and lowering the level of high-density lipoproteins (HDL). The effects on lipids (and probably peripheral circulation) are lower (or absent) for agents with partial agonistic activity (beta2).
Various adrenergic blockers, such as labetalol, used as an antihypertensive agent, is a competitive antagonist of both alpha and beta-adrenergic receptors. Although labetalol produces a relatively higher blockage of beta receptors than alpha-adrenergic receptors, the decrease in peripheral resistance may be marked after acute administration of the drug. Vasodilation may be mediated, in part, by the partial agonist effect on the beta2-adrenergic receptor (labetalol does not exhibit partially agonistic activity for the beta1-cardiac receptor).
Metoclopramide is a dopaminergic antagonist with cholinergic agonist properties. It accelerates the emptying of the stomach, increases the tone of the lower esophageal sphincter, increases the secretion of prolactin and aldosterone and antagonizes the emetic effect produced by apomorphine. It is clinically useful for hastening the emptying of the stomach (in the absence of organic obstruction), for example, in diabetic gastroparesis, for preventing gastroesophageal reflux and as an antiemetic during chemotherapy for neoplasm.
And just like that, we got to the parasympathetic nervous system.
In this case, acetylcholine (AC) acts as a neurotransmitter for all vegetative ganglia, at the level of postganglionary parasympathetic nerve endings, in the postganglionary sympathetic endings that irritate the ecrine sweat glands and in the neuromuscular plaque. The cholinetilel enzyme transfers the AC synthesis of acetyl coenzyme A (CoA), produced in nerve endings, and from choline, actively captured from extracellular fluid. AC is stored inside cholinergic nerve endings in tiny synaptic vesicles and is released from them in response to nerve impulses that depolarize nerve endings and increase calcium influx. There are different receptors (cholinergics) for AC on postganglionary neurons in the vegetative ganglia and at the level of postjunctional vegetative effector situses.
Receptors in the vegetative ganglia and medulloadrenal are predominantly stimulated by nicotine (nicotinic receptors), and those in the vegetative effector cells of muscarin alkaloid (muscarinic receptors). Ganglioplegic agents antagonize nicotinic receptors, while atropine blocks muscarinic receptors. The muscarinic receptor (M) has recently been classified into several subtypes. The M1 receptor is located in the central nervous system and probably in the parasympathetic ganglia, the M2 receptor is the non-neuronal muscarinic receptor in the smooth muscle, heart muscle and glandular epithelium.
Betanecol is a selective agonist of the M2 receptor, pirenzepine is a selective antagonist of the M1 receptor], which profoundly reduces gastric acid secretion. The M2 receptor inhibits adenylate-cyclase and uses the Gi regulating protein (the M1 receptor interacts with Gi and stimulates phospholipase C). The M3 receptor, present in the smooth muscle and secretory glands, is antagonized by atropine and uses phospholipase C, IP3 and DAG as second messengers. They have been identified, through molecular biology techniques, and other subtypes, but they have not yet been fully characterized.
There's still something to be done about acetylcholinesterase. AC hydrolysis, under the action of acetylcholinesterase, inactivates the neurotransmitter in cholinergic synapses. This enzyme (also known as specific or true cholinesterase) is present in neurons and is different from butylcolinesterase (serum cholinesterase or pseudocolinesterase). The last enzyme is present in plasma and non-nervous tissues and is not primarily involved in stopping the effects of AC in vegetative effectors. The pharmacological effects of anticholinesterase agents are due to the inhibition of neural (true) acetylcholinesterase.
Now, some more "stuff" about the physiology of the parasympathetic nervous system. The parasympathetic nervous system participates in the regulation of the cardiovascular system, the gastrointestinal tract and the genitourinary system. The liver, kidneys, pancreas and thyroid are also parasympathetic lyverate in metabolic control, although the cholinergic effects on metabolism are not well known.
In the case of the cardiovascular system, the parasympathetic effects on the heart are mediated by the vagus nerve. AC reduces the frequency of spontaneous depolarization of the synoatrial node and decreases heart rate. AC also delays impulse conduction in the atrial musculature, while shortening the absolute refractory period, a combination of factors that can initiate or maintain atrial arrhythmias. At the atrioventricular node, AC decreases the driving speed, increases the absolute refractory period and thus decreases the ventricular response during atrial fibrillation or flutter. The decrease in inotropism under the action of AC is linked to a prejunctional inhibitory effect on sympathetic nerve endings, as well as a direct inhibitory effect on the atrial myocardium. The ventricular myocardium is not too much affected, because its cholinergic innervation is minimal. The direct cholinergic contribution to the regulation of peripheral resistance seems unlikely, since parasympathetic innervation can directly influence peripheral resistance by inhibiting the release of NE from sympathetic nerves.
In the case of the gastrointestinal tract, the parasympathetic innervation of the digestive tract is achieved through the vagus nerve and sacral nerves. The parasympathetic nervous system increases the tone of the gastrointestinal smooth muscles and peristaltic activity and relaxes the gastrointestinal sphincters. AC stimulates exocrine secretion of the glandular epithelium and increases the secretion of gastrine, secretin and insulin.
For the genitourinary system, the sacral parasympathetic nerves irritate the bladder and genitals. AC increases ureteral peristalsis, contracts the bladder detrusor muscle and relaxes the trigon and sphincter, thus playing an essential role in coordinating shrinkage. The respiratory tract is inervated by parasympathetic fibers from the vagus nerve. AC increases tracheobronsic secretion and stimulates bronchoconstriction.
I've reached the pharmacology of the parasympathetic nervous system, and I'm going to start with the cholinergic agonists. AC itself has no therapeutic importance due to its nonspecific effects and short duration of action. Compounds related to AC are less susceptible to hydrolysis under the action of cholinesterase and have a narrower spectrum of physiological effects. Betanecol, the only systemic cholinergic agonist used, stimulates the smooth gastrointestinal and genitourinary muscles, with minimal effects on the cardiovascular system. It is used for the treatment of urinary retention, in the absence of obstruction and, less often, in gastrointestinal disorders such as can-vagotomy gastric atone.
Pilocarpine and carbacol are topical cholinergic agonists used in the treatment of glaucoma. Now, about acetylcholinesterase inhibitors. Cholinesterase inhibitors increase the effects of parasympathetic stimulation by reducing AC inactivation. Therapeutic administration of reversible cholinesterase inhibitors is based on the role of AC as a neurotransmitter in the neuro-effector junction of the striated muscle fiber and in the central nervous system. These drugs are used for the treatment of severe myasthenia, for the removal of neuromuscular blockage after general anesthesia and as an antidote to intoxication with central anticholinergic substances.
Physostigmine, a tertiary amine, penetrates well into the central nervous system, while related quaternary amines (neostigmine, pyridostigmine, ambenoon and edrophonia) do not pass through the blood-brain barrier. Organophosphoric compounds inhibitors of cholinesterase produce irreversible cholinesterase blockage (these agents are mainly used as insecticides and have especially toxicological interest). As for the vegetative nervous system, cholinesterase inhibitors have limited use in the treatment of smooth intestinal and bladder muscle dysfunction, such as those that occur during the paralytic ileus and atoneal bladder. Cholinesterase inhibitors induce a vagoton response at the heart level and may be useful in stopping bouts of supra ventricular paroxysmal tachycardia. It's the "turn" of cholinergic receptor blockers.
Atropine blocks muscarinic cholinergic receptors, with a weak effect on cholinergic transmission in the vegetative ganglia and neuromuscular junctions. Many of the actions of atropine and atropine-like agents on the central nervous system are attributed to blocking the central muscarinic synapses. The related alkaloid, scopolamine, is similar to atropine, but causes sedation, euphoria and amnesia, effects that make it suitable in pre-anesthetic medication. Atropine increases heart rate and atrioventricular conduction, actions that may be useful in combating bradycardia or heart disease associated with increased vagal tone. In addition, atropine cancels cholinergic mediated bronchoconstriction and reduces respiratory tract secretions. These effects contribute to its use as a preanesthetic medication.
Atropine also decreases the motility and secretion of the gastrointestinal tract. Although many agents derived and related to atropine (e.g. propantelin, isopropamide and glycopirolate) have been recommended for patients with peptic ulcers or diarrheal syndromes, their prolonged use is limited by other manifestations of parasympathetic inhibition, such as dry mouth and urinary retention. Pirenzepin, a selective M1 inhibitor used in investigations, inhibits gastric secretion at doses that have other minimal anticholinergic effects (this agent may be useful in the treatment of peptic ulcers). Atropine and the related compound, ipratropium, administered inhaled, causes bronchodilation. The latter is used experimentally for the treatment of asthma.
Here we have completed this post...
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 (objectives): "To accumulate knowledge" (and to understand it) and "To do good" (whatever we "achieve" to leave it better, better, than we found giving Love and Gratitude "squared").
The first "obligation" cannot be fulfilled in a single life (passing through the material cycle), as in a school class. How we graduate from these classes (accumulating the knowledge necessary for graduation) depends only on us, as it all depends on the number of "returns" in other later lives, in terms of "doing good". In all these passages, our paths are innumerable, and each of us has well defined the path before us.
The problem is to find the way (the road) before us, proposed by ourselves and thus put by Him in our path. We are somehow put in the situation of a driver (driver, moto, stake, etc.) who searches the entrance to a highway where he has a lane of his own (only and only his), to an unknown city and without having any idea (or map) how to get there. In addition, in order not to cheat, this road is like a road in the night when there is no way to see further than the headlights. And so, from 100 to 100 meters (depends on the "light of each") we must go forward in our search to reach the city that is constituted to be our destination (from where, of course, will begin a new, superior road, which will be "started" only and only with our will, following our choice).
And as we go through this Road, we have only two goals (objectives): "To accumulate knowledge" (and to understand it) and "To do good" (whatever we "achieve" to leave it better, better, than we found giving Love and Gratitude "squared").
The first "obligation" cannot be fulfilled in a single life (passing through the material cycle), as in a school class. How we graduate from these classes (accumulating the knowledge necessary for graduation) depends only on us, as it all depends on the number of "returns" in other later lives, in terms of "doing good". In all these passages, our paths are innumerable, and each of us has well defined the path before us.
The problem is to find the way (the road) before us, proposed by ourselves and thus put by Him in our path. We are somehow put in the situation of a driver (driver, moto, stake, etc.) who searches the entrance to a highway where he has a lane of his own (only and only his), to an unknown city and without having any idea (or map) how to get there. In addition, in order not to cheat, this road is like a road in the night when there is no way to see further than the headlights. And so, from 100 to 100 meters (depends on the "light of each") we must go forward in our search to reach the city that is constituted to be our destination (from where, of course, will begin a new, superior road, which will be "started" only and only with our will, following our choice).
Dorin, Merticaru