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----- Original Message -----
From: Jansy Berndt de Souza Mello
To: don barton johnson
Sent: Wednesday, December 08, 2004 2:14 PM
Subject: melancholie/colline/ anticholinergic Belladonna sounds...by Googling
Description
The anticholinergics/antispasmodics are a group of medicines that include the natural belladonna alkaloids (atropine, belladonna, hyoscyamine, and scopolamine) and related products.
The anticholinergics/antispasmodics are used to relieve cramps or spasms of the stomach, intestines, and bladder. Some are used together with antacids or other medicine in the treatment of peptic ulcer. Others are used to prevent nausea, vomiting, and motion sickness.
Anticholinergics/antispasmodics are also used in certain surgical and emergency procedures. In surgery, some are given by injection before anesthesia to help relax you and to decrease secretions, such as saliva. During anesthesia and surgery, atropine, glycopyrrolate, hyoscyamine, and scopolamine are used to help keep the heartbeat normal. Scopolomine is also used to prevent nausea and vomiting after anesthesia and surgery. Atropine is also given by injection to help relax the stomach and intestines for certain types of examinations. Some anticholinergics are also used to treat poisoning caused by medicines such as neostigmine and physostigmine, certain types of mushrooms, and poisoning by ?nerve?' gases or organic phosphorous pesticides (for example, demeton [Systox], diazinon, malathion, parathion, and ronnel [Trolene]). Also, anticholinergics can be used for painful menstruation, runny nose, and to prevent urination during sleep.
What You Should Know About Acetyl Choline, Anti-Cholinergic Drugs, the Autonomic Nervous System, and Botox
By Dr. Abraham Lieberman, 4/26/2004
Atropine, Belladonna, Charcot and Parkinson
Atropine, a component of belladonna, was the first drug used to treat PD. In the 1870's the French neurologist Jean-Martin Charcot noted that women who used belladonna to dilate their pupils and make them into "bedroom eyes" complained of a dry mouth. Belladonna, it's noted, means beautiful woman. As Charcot's PD patients often complained of drooling, the opposite of a dry mouth, Charcot thought belladonna might help his PD patients. Belladonna stopped their drooling and, unexpectedly, decreased their tremor. Charcot reasoned that belladonna acted both centrally, inside the brain (to decrease tremor) and peripherally, outside the brain (to dilate the pupils and block the salivary glands). Charcot, didn't know atropine is the active ingredient in belladonna, didn't not know atropine blocked a chemical secreted inside and outside the brain called acetyl-choline (abbreviated Ach), didn't know Ach was a messenger, a neuro-transmitter, that facilitated the movement of impulses from one nerve to another, didn't know there were different receptors for Ach-and didn't know that Ach existed. Given the lack of information on how drugs worked and how the brain was "wired", Charcot's insight is remarkable. Charcot is, correctly, considered one of the great neurologists of the 19 th Century. It was Charcot who recognized James Parkinson's contribution in describing PD and it was Charcot who named the disease for Parkinson. It was Charcot who trained Sigmund Freud.
Acetyl-Choline, Anti-Cholinergic Drugs, Alzheimer Disease
In 1906 Otto Loewi discovered that nerves "talked" to each other by releasing chemicals called neuro-transmitters, and he identified Ach as the first neuro-transmitter. For his work Loewi won the Nobel Prize for Medicine in 1936. Subsequently noradrenalin, adrenalin, dopamine, serotonin, glutamate, GABA, and more than a hundred other neuro-transmitters have been discovered. Because belladonna blocked Ach and relieved PD symptoms, it was thought, at the time, PD resulted from an excess of Ach. Atropine, extracted from belladonna, became the treatment for PD. Atropine, an anti-cholinergic drug (because it blocks acetyl-choline) was followed by anti-cholinergic drugs such as Artane, Akineton, Cogentin and Kemadrin. These drugs had a better effect on some symptoms of PD, and fewer side effects. The anti-cholinergic drugs are little used today because current drugs have a better effect on more symptoms of PD and fewer side effects.
The anti-cholinergic drugs have peripheral and central side effects. The peripheral side effects occur when anti-cholinergic drugs block, excessively, the secretion of Ach from nerves outside the brain (nerves in the periphery) on their target organs. Normally Ach slows the heart, constricts the pupils, increases secretions, increases gut mobility, empties the bladder, and increases sweating. Blocking Ach in the periphery can result in a fast heart rate, dilated pupils ( Charcot's "bedroom eyes"), dry mouth, constipation, difficulty urinating, and dry skin.
Central side effects of Ach include confusion, disorientation, memory loss, hallucinations and paranoia. Older people, 70 years and up, are more likely to have these side-effects. The side effects result from blocking Ach centrally, in the brain, in a region called the Nucleus Basalis. The Nucleus Basalis is at the base of the Frontal Lobes, across the fissure that separates the Frontal from the Temporal Lobes. The Nucleus Basalis is at a level with two structures in the Temporal Lobe: the amygada which orchestrates the brain's response to anxiety and fear, and the hippocampus, which stores the brain's memories. The Nucleus Basalis contains cells, neurons that secrete Ach and through long radiating fibers these cells communicate with major regions of the brain including the hippocampus.
The first changes of Alzheimer disease appear in the Nucleus Basalis, as the first changes of PD appear in the substantia nigra. Twisted and tangled fibers rich in a protein called tau crowd the cytoplasm of Nucleus Basalis neurons in Alzheimer disease, as a Lewy body crowds the cytoplasm of substantia nigra neurons in PD. The twisted fibers of Alzheimer disease are called neurofibrillary tangles. Shapeless, amorphous, plaques rich in a protein called amyloid appear outside Nucleus Basalis neurons. Later, neurofibrillary tangles appear inside and amyloid plaques appear outside neurons in all regions of the brain to which the Nucleus Basalis neurons project. Amyloid plaque also appears in the walls of the arteries that supply blood to these regions. As Alzheimer disease evolves, levels of Ach in the Nucleus of Basalis neurons drop. It's unclear if the first physical evidence of Lewy BodyDementia also appears in the Nucleus Basalis.
Ach is metabolized by an enzyme called Acetyl-choline esterase (abbreviated Ach-E). Drugs such as Aricept and Exelon that block Ach-E and increase Ach levels in the Nucleus Basalis and improve memory. Nicotine may improve memory. This occurs when nicotine binds to nicotine receptors on Ach neurons causing them to release Ach.
The Relationship of Acetyl Choline to Dopamine
Parkinson disease results from a loss of neurons in a region of the brain called the substantia nigra. These neurons secrete dopamine. There are 200,000 substantia nigra dopamine neurons on each side of the brain. When the brain loses 50% of the dopamine neurons in the substantia nigra, the first symptoms of PD appear. The dopamine neurons in the substantia nigra project to a region of the brain called the striatum and to a part of the striatum called the putamen. The putamen on each of the brain contains approximately 10,000,00 neurons. These neurons are of medium size and have spines on their surface hence their name medium spiny neurons. Each dopamine neuron may innervate, or supply dopamine to 50 medium spiny neurons. Some of the medium spiny neurons are inter-neurons, they project to other medium spiny neurons in the putamen. These medium spiny neurons then project to a region of the brain called the globus pallidus (one of the targets for deep brain stimulation). Some inter-neurons "talk to" the neurons that project to the globus pallidus using Ach, some using GABA.
In the putamen Ach acts as a brake on dopamine. Anti-cholinergic drugs such as Artane or Cogentin, lower Ach and, in effect, "raise" dopamine. It's still unclear, from the above, why in some people Ach has a specific effect on tremor. Perhaps the inter-neurons that use Ach and "talk to" the neurons that project to the globus pallidus are more specific for tremor
Acetyl Choline, Choline Acetyl- Transferase, and Acetyl Choline Esterase
Ach is produced by a reversible reaction in which the enzyme cholineacetyl transferase (abbreviated ChA-T) transfers an acetyl group from acetylcoenzyme A (abbreviated CoA) to choline. Choline is found in the diet. CoA is found in most cells, in a part of the cell called the mitochondria. The mitochondria are the "batteries" or "power plants of each cell." There are scores of mitochondria in each cell. Co A is one of the products of energy production in the mitochondria. The acetyl group from Co A converts an un-reactive compound, choline, into a reactive compound, Ach.
Ach is produced inside one neuron (called the pre-synaptic neuron), transported along the pre-synaptic nerve to the nerve terminal, released into the space between neurons called the synapse, binds, reversibly, to an Ach-receptor on another neuron (called the post-synaptic neuron), stimulates the Ach-receptor, then it's actions are ended by the enzyme acetyl cholinesterase(Ach-E), which "breaks-apart" Ach into acetate and choline. Ach-E can break-apart 1,000 Ach molecules/second/molecule of enzyme. Ach-E is found both in the cell's membrane (near the Ach receptor) and inside the cell, in the cytoplasm.
Anti-cholinesterase Drugs, Aricept and Exelon
Drugs called anti-cholinesterases block Ach-E outside the cell, resulting in an accumulation of Ach.. This results in over-stimulation of Ach receptors. Reversible blockers of Ach-E include drugs such as physostigmine and neostigmine that block Ach-E for up to four hours. Neostigmine does not enter the brain and acts in the periphery (outside the brain). Physostigmine does enter the brain, and acts both in the brain and in the periphery. Both drugs are used to treat myasthenia gravis. In myasthenia gravis (described later), there's a lack of Ach in the junction, called the neuromuscular junction, between a peripheral nerve and it's target organ, one of the voluntary, or skeletal muscles. The voluntary muscles are also called striated or stripped muscles because of their stripped appearance. The voluntary or striated muscles include the muscles of the eyes, the face, the limbs, the trunk and the belly. The lack of Ach results in weakness. Physostigmine and neostigmine by blocking Ach-E increase Ach in the neuromuscular junction and reverse the weakness. Aricept and Exelon enter the brain and, reversibly, block Ach-E in cells in the Nucleus Basalis. Aricept and Exelon improve memory by increasing Ach in the brains of people with Alzheimer disease and Parkinson dementia.
Compounds called organo-phosphates irreversibly bind to Ach-E in the periphery and in the brain. Some of organo-phosphates are used as insecticides and some are used as nerve gases. Organo-phosphates result in an increase of Ach in the brain, in the synapses between pre-synaptic and post-synaptic nerves in the Autonomic Nervous System (abbreviated ANS), and in the junctions between nerves and muscles. The symptoms of nerve gas poisoning include drooling, choking, constricted pupils, a slow heart rate (initially), loss of bowel and bladder control, and weakness. Treatment consists of injecting atropine and a drug that can displace the poison from the Ach receptor. Paradoxically, too little Ach, as in myasthenia gravis, and too much Ach, as in nerve gas poisoning, result in weakness
Botulinum Toxin (Botox)
Botulinum toxin (Botox), tetanus toxin , and curare blockthe release of Ach from nerves to muscles resulting in paralysis. Black widow spider venom, acts in an opposite way, and releases, massively, Ach from nerves. This too results in paralysis. Botox, tetanus toxin and curare block the release of Ach differently. Botox binds to a specific protein on the surface of the nerve terminal forming a Botox-protein complex. This steps takes 30 minutes. Next, the membrane of the nerve folds around the complex, forms a vesicle, and "absorbs" the complex. Inside the nerve terminal, the complex is split, Botox is released, and binds to and inactivates a second protein, one that's essential to releasing Ach. The effects of a Botox injection lasts 2-6 months, depending on the muscle injected and the amount of Botox used.
Botox, tetanus toxin, and curare when injected into a vein or artery gain access to all neuromuscular junctions and result in generalized paralysis. The paralysis of b otulism starts in the muscles of the eyes and face and then involves the muscles of the arms and legs and the muscles of breathing. Clostridia are anaerobic bacteria, they grow in the absence oxygen, in dark, airless places. If Clostridia contaminate food and if the food is canned, without being heated, Clostridia grow and release a toxin--botulinum toxin. The toxin is sensitive to heat and is destroyed by cooking. If improperly canned food is eaten without being heated the toxin is swallowed, absorbed from the gut, enters the blood stream and causes botulism. If Clostridia contaminate a wound, if the wound's not properly dressed, Clostridia can grow and produce botulinum toxin. If the toxin enters the blood stream it causes botulism.
Botox, which is prepared under sterile conditions from Clostridia is used to treat strabismus ( eye muscle spasm), hemi-facial spasm, and focal dystonia including blepharospasm (inability to open the eyes), torticollis (wry neck), spasmodic dysphonia (squeaky voice), and writer's cramp. Botox in addition to blocking the release of Ach from nerves to muscles, blocks the release of Ach to the salivary glands. This is why Botox is used to treat drooling.
Nicotine and Muscarine Receptors
Ach is active in the Autonomic Nervous System (ANS), the part of the nervous system that regulates automatic activity, Ach is active in the peripheral nervous system, the part of the nervous system that regulates the voluntary or striated muscles, and Ach is active in the brain. Ach, a simple molecule, is able to act, simultaneously, in many different parts of the nervous system, and result in actions that are specific for that part, because it binds to and interacts with protein molecules--Ach-receptors that are specific for the different parts of the nervous system.
Ach receptors, commonly called cholinergic receptors, are divided into nicotine and muscarine receptors because, originally, they were distinguished by their selectivity for the drugs muscarine and nicotine.
The N icotinic Receptors are called ligand-gated channel receptors. Such receptors are responsible for regulating the flow of charged particles (ions) through a channel between the space outside and inside he cell. The ions can be positively charged such as sodium, potassium, calcium, and magnesium, or they can be negatively charged such as chloride. Nicotine receptors regulate positively charged ions. When a ligand, such as nicotine, binds to such a receptor, the "gate" opens and ions flow from one direction to another. The flow of ions, from either outside to inside the cell or vice versa (the direction of flow depends upon the receptor and the ligand) changes the electrical charge on the cell and either makes it more likely or less likely to conduct a nerve impulse.
A ligand that is an agonist, a stimulant, an excitatory drug, is more likely to change the electrical charge on the cell so that it does conduct a nerve impulse. Nicotine is an agonist, a stimulant at the nicotine receptor. A ligand that is an antagonist, an inhibitor, a blocker, is more likely to change the electrical charge on the cell so that it doesn't conducts a nerve impulse. A drug, a ligand, can be an agonist at one receptor and an antagonist at another receptor. Stimulation of ligand-gated receptors such as nicotinic receptors results in a rapid onset of action, but one that's of short duration. Ligand-gated receptors are more likely to respond to repetitive stimulation.
Nicotine receptors are on the nerve endings to skeletal muscles, they're the ideal receptors for rapidly, and repetitively, conducting impulses to muscles . Nicotinic receptors have a low affinity, a low ability to bind Ach, in the resting state. The affinity for Ach is increased during activation. But at high concentrations of Ach the receptor becomes desensitized. This may explain why low concentrations of Ach in the neuromuscular junction after Botox injections and high concentrations of Ach after spider venom injections both result in paralysis.
Nicotinic receptors are in tissues other than nerve endings to skeletal muscle, including the ANS and the brain. The chemical composition of nicotinic receptors differs in these different parts of the nervous system.
The muscarinic receptor are G-protein coupled receptors. Such receptors are responsible for translating a message from outside the cell to inside the cell and causing the cell to make a specific chemical or a protein in response to the "outside message or stimulus." The receptors consist of a protein, called the G-protein, that straddles the outside and inside of the cell, binds to a ligand (such as Ach or muscarine), undergoes a structural or conformational changes, and through a series of secondary messengers transmits the message to the cell's nucleus where a part of the cell's DNA is activated and, through messenger RNA, causes the cell to make the new chemical or protein. A ligand that is an agonist is more likely to increase energy generation of the cell. A ligand that is an antagonist is more likely to increase energy generation of cell. Stimulation of ligand-G-protein coupled receptors such as muscarinic receptors results in a slow onset of action, but one that's of long duration. Ligand-G-coupled receptors are less likely to respond to repetitive stimulation.
In the late 1980's, molecular cloning identified five types of muscarinic receptors. Each receptor shares common features including specificity of binding for the agonist Ach and the antagonist atropine. Each receptor type couples to a second messenger system through a G-protein. The M 1,M 3 and M 5 muscarine receptors stimulate a G-protein that's linked to a particular chemical that's linked to energy generation. The M 2 and M 4 muscarine receptors block a protein (adenylate cyclase) that's linked to energy generation. M 1 receptors are in the hippocampus and cerebral cortex. M 2 receptors are in the heart and brainstem. M 3 receptors are in smooth (or involuntary) muscles. Smooth muscles, unlike voluntary muscles do not have stripes, smooth muscles surround the airways of the lung, the stomach, intestines, rectum and bladder. M 3 receptors are in salivary glands. M 4 receptors are in the putamen. M 5 receptors are in the substantia nigra. M 5 receptors may regulate, in part, the release of dopamine.
Muscarine antagonists such as scopolamine and atropine are among the oldest known drugs. Muscarine antagonists (called anti-cholinergic drugs) help control drooling. They help control gastric acidity. They help control diarrhea. They help control vomiting. The patch that's placed behind the ear to control the vomiting of sea-sickness is scopolamine, an anti- cholinergic drug. Anti-cholinergic drugs help, in a limited way, in PD, especially with tremor. In large doses, or in people with dementia, anti-cholinergic drugs can cause delusions, hallucinations, and memory loss.
The Autonomic Nervous System
The Autonomic Nervous System (ANS) as its name implies, regulates the body's internal environment. Shortly after a person arrives in a doctor's office, or an emergency room, his vital signs are checked: temperature, pulse rate, blood pressure, and rate of respiration. The vital signs mirror the body's internal environment. They must be maintained for each organ: brain, heart, gut, kidneys, liver, lung, skin to work efficiently. Ach is used as a neuro-transmitter in the Parasympathic part of the ANS (abbreviated P-ANS) and, in regions of the Sympathetic part of the ANS (abbreviated S-ANS). Ach in the S-ANS and the P-ANS acts largely on muscarinic receptors. In the S-ANS the actions of Ach are often opposed by noradrenalin and anti-cholinergic (atropine-like) drugs. In the P-ANS are opposed by anti-cholinergic drugs. The ANS, the P-ANS and S-ANS acting together or, paradoxically, against each other, regulate the body's internal environment. The ANS maintains:
Body temperature at 98.6 Fahrenheit . If the temperature rises because, from among other things an infection, an inflammation of a joint, a muscle, or a vein, a hot bath, or a sun burn, the ANS rids the body of heat by shuttling blood from the internal organs to the skin. From here it radiates or evaporates as sweat. Ach, released by the S-ANS on sweat glands is responsible. As a result a person, in addition to sweating, may feel flushed or feverish. If a person's anxious, the ANS can be subconsciously "tricked" into thinking the temperature's up (when it's not) and a person may feel flushed, feverish, or sweat.
If body temperature drops because of an under-active thyroid gland, a dip in a cold bath, The ANS warms the body by shuttling blood away from the skin to the internal organs. As a result a person may feel cold or turn blue. If a person's anxious, fearful, or panicked the ANS can be "tricked" into thinking the temperature's down (when it's not) and a person may feel cold (when no one else does).
Maintains the pulse or heart rate between 60 to 90 beats/minute. If the temperature, or need for oxygen, or metabolism increases, or if the body loses fluids (by dehydration or bleeding), or if a person's in pain, then the ANS through a "direct line" to the heart, can make it beat faster. The S-ANS secretes noradrenalin onto conducting fibers in the heart which makes the heart beat faster. Blocking the actions of the S-ANS with a drug such as propranolol ( brand name Inderal) slows the heart rate. The P-ANS secretes Ach onto conducting fibers in the heart which makes the heart beat slower. Blocking the actions of the P-ANS with a drug such as atropine increases the heart rate. If a person's anxious, the ANS can be "tricked" into making the heart beat faster and a person may feel his heart pounding (or think it's pounding).
Maintains the blood pressure between 95-140/50-90. To maintain a stabile internal environment, blood flow to critical organs must be adequate. Because flow cannot be easily measured, blood pressure is measured instead. The relationship is: (Blood Pressure) = (Blood Flow) x (Resistance-of-the-Blood Vessels). If the blood pressure falls because a persons You stands up quickly, because he's dehydrated, because he's lost blood, for blood flow to remain unchanged, the resistance of the blood vessels (arteries and veins) must increase. This is done by the S-ANS which releases noradrenalin from nerve endings on arteries and vein which increases resistance by narrowing the arteries. Propanolol by blocking the actions of noradrenalin, decreases the resistance of arteries and lowers blood pressure.
The role of Ach in regulating blood pressure is complex. S-ANS nerves that originate from neurons in the hypothalamus, and P-ANS nerves that originate from neurons in the brainstem (the part of the nervous system between the cerebral cortex, commonly referred to as the brain, and the spinal cord) secrete Ach onto neurons in ganglia (clusters of neurons outside the spinal cord). The ganglia can be S-ANS ganglia. These cluster around the spinal cord. The ganglia can be P-ANS ganglia. These cluster around the organs they innervate. Nerves from the S-ANS, and the P-ANS ganglia in turn innervate different organs including the arteries and veins. Blocking the actions of Ach in the S-ANS and P-ANS has a varying effect on different organs. The effect depends on whether the organ is mainly innervated by the S-ANS or the P-ANS or a combination of the two, and whether the final neuro-transmitter, the one between the nerve and the organ is Ach or noradrenalin. If despite the narrowing, blood pressure continues to drop, flow to critical organs such as the brain, the heart, the lungs, is maintained by shunting blood away from less critical organs such as the gut, the kidneys, the liver, or the skin. In this case the ANS changes the resistance of the veins because 70% of circulating blood is in the veins. If a person's anxious, or fearful, or panicked his ANS can be "tricked" into decreasing the resistance of his arteries, or veins, dropping his blood pressure, making him feel dizzy, or lightheaded, or faint.
Maintains a person's respiratory rate below 18 breaths/minute, preventing hyperventilation. If a person's need for oxygen, or his temperature, or his metabolism rises, the ANS responds by making the person breath faster. As he does so, each breath is shallower and he spend more energy on the mechanics of breathing. This fatigues his chest muscles, the "bellows" for the lungs-making him gasp for air. The S-ANS plays a major role in regulating breathing. Nerves from the S-ANS secretes noradrenalin on the bronchi (the tubes of the airway). This results in dilation of the bronchi. This is different from the actions of noradrenalin on the arteries where nerves from the S-ANS cause the arteries to constrict. From the point of view of the body, as a whole, this makes sense. If a person's in danger he activates the S-ANS which uses noradrenalin to increase the heart rate, constrict the blood vessels in the periphery of the body so more blood is pumped to the heart and brain, and to dilate the bronchi so breathing is more efficient.
From the point of view of treating high blood pressure the ANS is confusing because drugs such as propanolol that lower blood pressure by dilating blood vessels, narrow bronchi, and in some people, bring-on an attack of asthma. If a person's anxious, or fearful, or panicked, his ANS can be "tricked" into making him breath faster or hyperventilate. When a person hyperventilates, he "blow-off" carbon dioxide. This, in turn, can make his heart pound, his vision blur, his ears ring or can make him feel dizzy, or lightheaded, or faint.
The Sympathetic and Para-Sympathetic ANS.
The ANS has two parts: the S-ANS and the P-ANS. Most organs are regulated mainly by the S-ANS through it's control of the organ's blood supply. Some organs, the eye, the salivary glands, the heart, and the lungs are regulated by the S-ANS and the P-ANS. The S-ANS, using noradrenalin or adrenalin widens the pupil. The P-SNS constricts the pupil. The S-ANS using noradrenalin decreases saliva. The P-ANS using Ach increases saliva. Blocking the Ach from the P-ANS with atropine DECREASES saliva. The ANS mobilizes the body's defenses against fever, dehydration, pain, shock-anxiety, fear, terror, or panic. To prepare the body, in the words of Walter B Cannon the great 20th Century physiologist, for "flight, fright, or fight."
Although the ANS is programmed to react to physical emergencies such as fever, dehydration, pain, or shock-appropriately, it isn't programmed to react to emotional emergencies such as fear, terror or panic. Confronted by fear, the mind, unable to distinguish fear from fact activates the ANS which then mobilizes the same defenses as in a physical emergency.
Anxiety-related symptoms that can be activated by the ANS include:
Feeling hungry (when a person shouldn't). Or over-eating. Anxiety or fear activates the S-ANS causing the pancreas to release insulin, dropping the blood sugar-making a person hungry, and causing him to drool. Although the S-ANS normally causes a person's mouth to become dry, when a person's hungry, both the S-ANS and the P-ANS are activated, and drooling, rather than a dry mouth results. Anxiety activates the ANS resulting in forced contraction of the gut which can lead to a hasty or an inappropriate bowel movement. The bowels are controlled by their own nervous system, called the Enteric Nervous System. The bowels, through the Enteric Nervous System, respond in a complex way to activation by the S-ANS and the P-ANS. Anxiety activates the ANS resulting in forced contraction of the bladder which can lead to hasty or inappropriate urination. The ANS regulates blood flow to the penis. Over-activation of the ANS as in times of anxiety, or guilt, can result in impotence.
The S-ANS starts in the hypothalamus, deep inside the brain . The hypothalamus is below the thalamus and above the pituitary or master gland. The hypothalamus regulates the pituitary gland that in turn governs: the thyroid gland which regulates metabolism. The adrenal glands which regulate, in part, blood pressure and fluid balance. Part of the adrenalin gland secretes noradrenalin and adrenalin, which are also secreted by nerves from the S-ANS. Part of the adrenal gland secretes steroid hormones. The pancreas which regulates blood sugar. The ovaries and testes.
The thalamus is the brain's main relay center . And through the eyes, the ears, the nose, and from nerve endings in the skin, the thalamus receives information about the outside world. Every sense, except that of smell, first goes to the thalamus. It's thought the thalamus helps coordinate the flow of sensory information to the brain-so that they arrive simultaneously. The thalamus receives information about the body's internal organs from: Pressure sensors on the heart and large arteries Stretch sensors on medium and small arteries and veins. Pressure sensors on the major airways. Sensors in the heart, small arteries and veins, liver, kidney, and pancreas that monitor oxygen levels, blood acidity (pH), sugar, and salt concentration. Stretch sensors on the walls of the stomach, intestines, rectum, and bladder. Information about the outside world and the internal organs after being "decoded" is sent to a region of the brain called the amygdala and the hypothalamus.
In the hypothalamus groups of nerve cells, called primary S-ANS cells reanalyze the information and send it to secondary S-ANS cells in the brainstem and spinal cord.
Groups of secondary S-ANS cells extend along the spinal cord from the neck to the lower back. The secondary S-ANS send information to third-order S-ANS cells located in chains that parallel the spinal cord. Flow of information from primary to secondary to third-order cells to their target organs, is aided by the chemicals nor-adrenalin and adrenalin. On blood vessels these chemicals interact with specialized receptors. The S-ANS can activate all the body's organs, a few organs, or part of an organ. The "fine-tuning" is accomplished by activating: specific number, or sequence, or group of S-ANS cells. A specific number, or sequence, or type of receptors on an organ. Selective release of hormones from the pituitary, thyroid, adrenal, pancreas, ovaries or testes.
The P-ANS starts in the brainstem, below the hypothalamus. Primary P-ANS cells receive information from the outside world and the internal organs. But, compared to the sympathetic cells, the amount and quality of information is limited. Most of it after being analyzed is sent via the Vagus Nerve (vagus means wandering and the Vagus Nerve is a large and wandering nerve) to secondary P-ANS cells located in chains near the organs they serve. Information is relayed from these cells to receptors on their target organs by Ach. Vagus serves almost every organ except the rectum, bladder, uterus, and testis. These are served, via sacral nerves, by primary P-ANS cells in the lower spinal cord.
As the ANS is hard to understand an analogy is offered. Think of the S-ANS as the Federal Government. The Federal Government's central offices are in Washington. Similarly, the S-ANS "central offices" are in the hypothalamus. The Federal Government has regional offices throughout the nation. Similarly, the S-ANS "regional offices," are on secondary cells throughout the spinal cord. The Federal Government has local offices in cities, counties, and towns. Similarly, the S-ANS "local offices" are on third-order cells near their target organs. The Federal Government receives feedback, from it's Washington, regional, local, and overseas offices, from the people and their Representatives. Similarly the S-ANS receives information from sensors on its target organs, secondary, and third-order cells, and the thalamus. The Federal government has executive, legislative, and judicial functions. These effect people in discrete, overlapping, or, even contradictory ways. Similarly the S-ANS alone or with help from one or multiple glands can effect an organ in different or contradictory ways. Thus, a person with a diseased heart will respond to anxiety differently from a person with a healthy heart.
Think of the P-ANS as a state government. There are large populous states: California, Texas, New York, Florida. And less populous states: Rhode Island , Delaware , North and South Dakota . Each has it's own capital. Similarly, the P-ANS "large populous"(capital) offices are in the brainstem. And the "less populous" (capital) offices are in the lower spinal cord. Each state has local offices in it's cities, counties, and towns. There are no regional offices. Similarly, the P-ANS "local offices" are on secondary cells near their target organs. There are no third order cells. Each state government receives feedback from its local offices, from its people and their representatives. Similarly the P-ANS receives feedback from sensors on it's target organs and their secondary cells and the thalamus Each state has executive, legislative, and judicial functions. These effect their people in discrete, overlapping, or, even contradictory ways. Similarly the P-ANS can effect an organ in different or contradictory ways.
The Federal Government and the states also effect people in overlapping or even contradictory ways. Similarly the S-ANS and P-ANS can effect an organ, or multiple organs in different or contradictory ways. Just as outside danger, disease, or pain can activate the ANS anxiety, fear, anger and panic can also activate the ANS.
Myasthenia gravis (MG )
MG is less common than PD. It's estimated there are 3,000 new cases in the United States , versus 50,000 for PD. Mean age of onset is 28 years in women, 42 years in mean. Mean age of onset of PD is 60 years in women and men. MG, because it affects the nicotine Ach receptor (abbreviated N Ach-R), has helped in understanding all Ach-Rs.
Myasthenia gravis (MG) is a disease in which the body's immune system, mistakes part of the body, part of the proteins that are the N Ach-Rs in the neuro-muscular junctions, as foreign substances or antigens and-attacks them. The immune system does this by making a protein, an antibody, against part of the N Ach-Rs. The N Ach-R is a protein that sits in the neuro-muscular junction, the space or synapse between the pre-synaptic nerve terminal of a peripheral nerve and the post-synaptic muscle membrane of a voluntary or stripped muscle. The N Ach-R sits on the post-synaptic muscle membrane. The antibody "coats" the N Ach-R and makes it less responsive or unresponsive to Ach. At the same time other parts of the immune system try to destroy the antibody coated N Ach-R. This sets-up an inflammatory response around the N Ach-Rs on the post-synaptic membranes of striated muscles.
The decreased response of N Ach-Rs to Ach results in fatigue and weakness of the voluntary muscles. The fatigue and weakness may, initially, be confined to a few voluntary muscles (the muscles of the eyes, or of the neck, or of swallowing). Later the fatigue and weakness may affect most of the voluntary muscles. As activity of the voluntary muscles increases, as more Ach is needed, the fatigue and weakness increases. In MG, the first movements of a muscle may be normal, but as the muscle's activity increases, fatigue and weakness increases. In the morning, people with MG appear normal, but in the evening complain of double-vision, difficulty holding-up their necks, and difficulty swallowing.
MG, a disease in which the body's immune system destroys part of itself, is called auto-immune diseases. Lupus and multiple sclerosis (MS) are also examples of auto-immune diseases. Anti-bodies to the N-Ach R are found in 80-90% of people with MG. The anti-bodies are made by B-cells. B-cells are a type of circulating white blood cell (called lymphocytes) made in the bone-marrow. B-cells are called "B" cells because they're made in bone marrow. The T-cells, a type of circulating white blood cell made in the thymus gland play a secondary role. T-cells are called "T" cells because they're made in the thymus. Normally, in response to invasion by a foreign substance, bacteria or viruses, B-cells and T-cells work together to identify or "tag" the invader, "coat" the invader with an antibody, and then destroy the antibody coated invader by "turning" on the body's complement system. The complement system is the body's way of digesting and destroying foreign substances. Sometimes, however, the body's immune and complement systems are tricked into destroying part of itself--an auto-immune disease.
The nerve terminal of the peripheral nerve to a particular muscle enlarges at its end, this is called the bouton terminale or terminal bulb. The bulb lies in a groove or indentation along the voluntary muscle fiber. The pre-synaptic membrane (part of the peripheral nerve's membrane) the post-synaptic membrane (part of the muscle's membrane), and the synaptic cleft (the space between the both membranes) make-up the neuro-muscular junction.
The pre-synaptic terminal contains vesicles filled with Ach. On arrival of a nerve impulse or action potential, the contents of these vesicles are released into the synaptic cleft or space. The release requires the presence of calcium. The released Ach molecules diffuse across the synapse or space and bind to the N Ach-Rs on the post-synaptic muscle membrane. The N Ach-R is a ligand-gated sodium channel that opens briefly upon binding to Ach. This allows entry of sodium ions into the inside of the muscle, which results in partial depolarization (discharge) of the post-synaptic muscle membrane. This generates an electrical potential called an excitatory post-synaptic potential ( abbreviated EPSP). If the number of open sodium channels reaches threshold, a self-propagating action potential is generated on the post-synaptic muscle membrane, spreads along the muscle fiber and causes the muscle to contract.
Ach molecules are hydrolyzed, broken-apart, by the enzyme Ach-E, which is abundantly present at the neuro-muscular junction. The surface area of the post-synaptic muscle membrane is increased by in-folding of the membrane next to the nerve terminal. This allows the neuro-muscular junction to more fully capture, bind, and utilize the released Ach. N Ach-Rs consist of 5 subunits, each of which is a protein, and each of which is partly inside and partly outside the muscle membrane. The subunits are arranged in a circular fashion, forming a central opening that functions as an ion channel. In the case of the N Ach-R, the ion is sodium, a positively charged ion, called a cation.
When Ach binds to the N Ach-R, the receptor undergoes a 3-dimensional change that opens the sodium channel, resulting in an increased flow of sodium into the muscle. In MG, the binding of Ach to N Ach-Rs can be altered and impair nerve conduction and muscle contraction in several ways:
(1) An anti-body can cross-link two adjacent N Ach-Rs and decrease their response to Ach. (2) An anti-body can accelerate the "normal" degradation of aging N Ach-Rs, making fewer N Ach-Rs available for binding to Ach. (3) An anti-body can block the binding of Ach to the N Ach-R. (4) An anti-body to the post-synaptic membrane can decrease the number of sites available for newly made N Ach-Rs, making fewer sites available for binding with Ach.
MG is characterized by fluctuating weakness and fatigue that increases with activity. . Weakness and fatigue increase during the day and improve with rest. Weakness of the eye muscles (extra-ocular muscles) and the eye-lids is present, initially, in 50 % of people with MG and is present, sometimes in the disease, in 90 % of people. Weakness of the extra-ocular muscles shows itself as double vision. Weakness of the eye-lids shows itself as ptosis, or drooping of the lids. Weakness of the facial muscles, the neck muscles, and the muscles of swallowing are also common. These muscles are, preferentially involved, because there is a smaller ratio of pre-synaptic nerve terminals to muscle fibers, as few as 1:3 in the eye ocular muscles. As there are fewer nerve terminals to muscle fibers, there are fewer neuro-muscular junctions, fewer N Ach-Rs. Thus the loss of just a few N Ach-Rs has more consequences.
Weakness can also involve the muscles of the limbs. Usually limb weakness follows weakness of eye or neck muscles. Sometimes limb weakness precedes weakness of eye or neck muscles. The proximal muscles of the limbs are involved more than the distal muscles: the shoulder muscles are involved more than the hands, the hip muscles are involved more than the feet. The weakness of all muscles progress from mild to moderate to marked over weeks or months.
The symptoms of MG, the muscle weakness, is treated with drugs that block the enzyme, Ach-E, the enzyme that "breaks-apart" Ach. Drugs such as neostigmine, an anti-cholinesterase ( anti-Ach-E), by blocking the actions of Ach-E in the neuro-muscular junction, increase the availability of Ach. The more Ach that's available to the N Ach-R, the less muscle weakness. The cause of MG, the auto-antibodies produced by the body's immune system, is treated by drugs that block the production of anti-bodies by B-cells, and by removing the thymus gland, the source of the T-cells.
Some drugs can worsen MG. These drugs include antibiotics such as gentamycin, cipro, erythromycin and ampicillin. They include beta-blockers such as propranolol (Inderal) and timolol (an eye-drop used for glaucoma). They include calcium channel blockers such as verapamil. They include lithium and magnesium. They include curare and curare-like muscle relaxants such as succinyl choline used in anesthesia. They include anti-cholinergic drugs such as Artane and Cogentin.
