Dr. V. John Massari©
I. Ganglionic Neurotransmission
A. The primary event at autonomic ganglia is the rapid depolarization of postsynaptic Nn receptors by ACh. The duration of this event is on the order of milliseconds. This effect is blocked by hexamethonium.
B. The next event seen is the development of an IPSP which also lasts only milliseconds. The IPSP is blocked by both atropine, and by alpha adrenergic blockers. This evidence suggests that a preganglionic cholinergic nerve terminal in the ganglion acts on M2 receptors to activate a catecholaminergic interneuron (probably containing dopamine) which then synapses on the postganglionic neuron.
C. The next event is the development of the late EPSP. This event lasts on the order of 30-60 seconds. It is blocked by atropine and appears to be due to the activation of M1 receptors.
D. Finally one sees the late slow EPSP, which persists for several minutes. This appears to be due to the action of multiple peptides including VIP, SP, NPY, Enkephalin, etc etc.
E. It should be emphasized that the secondary events of ganglionic transmission
modulate the primary depolarization, by making it more or less likely to occur. This is so
because these secondary events either facilitate or inhibit the processes of spatial and
temporal summation of subthreshold depolarizing stimuli. The relative importance of
secondary pathways and receptors also appear to differ between different parasympathetic
and sympathetic ganglia. Remember that conventional Nn receptor antagonists can inhibit
ganglionic transmission completely, but muscarinic antagonists, alpha adrenergic
antagonists, and peptidergic antagonists can not do so.
II. Ganglionic Stimulating Drugs
A. Nicotine is an alkaloid isolated from the leaves of tobacco, Nicotiana tabacum in 1828. Its pharmacological actions are complex and often unpredictable because 1) its effects are on both sympathetic and parasympathetic ganglia, and 2) because stimulation is frequently followed by depolarization blockade. The drug also can stimulate and desensitize receptors. The ultimate response of any one system thus represents the summation of several different and opposing effects of nicotine. For example, heart rate can be increased by excitation of sympathetic or inhibition of parasympathetic ganglia. Conversely, heart rate can be decreased by excitation of parasympathetic or inhibition of sympathetic ganglia. Nicotine also 1) stimulates release of Epi from the adrenal medulla, 2) excites cardiorespiratory reflexes by a direct effect on the chemoreceptors of the carotid and aortic bodies, 3) excites cardiovascular responses secondary to evoked blood pressure changes mediated by baroreceptors, and 4) stimulates and blocks CNS cholinergic pathways in the medulla influencing heart rate.
1. In autonomic ganglia,the major action of nicotine consists initially in transient stimulation and subsequently in a more persistent depression. In larger doses, stimulation is followed very rapidly by blockade of transmission.
2. Nicotine also stimulates the nicotinic receptors of muscle (Nm), and this is followed rapidly by depolarization blockade.
3. Nicotine stimulates sensory receptors including mechanoreceptors, thermoreceptors, and pain receptors.
4. In the CNS, nicotine can cause tremors which proceed to convulsions as the dose is increased. Excitation of respiration which is a prominent effect seen after nicotine is due to both activation of medullary sites, and activation of chemoreceptors of carotid body. Stimulation is followed by depression and death occurs from respiratory paralysis of both central origin and due to paralysis of muscles of respiration. Another CNS effect of nicotine is stimulation of the area postrema ie the chemoreceptor trigger zone to induce vomiting.
5. Nicotine is readily absorbed from the respiratory tract, oral membranes, and skin. Since nicotine is a strong base it is highly ionized in the stomach and hence poorly absorbed from the stomach. It is metabolized primarily in the liver, but also in the lung and kidney. Both nicotine and its metabolites are rapidly excreted by the kidney. Nicotine is excreted in the milk of lactating mothers who smoke.
6. Poisoning occurs from exposure to insecticides containing nicotine, or in children
by accidental ingestion of tobacco products. Death may result within a few minutes from
respiratory failure. For therapy, vomiting should be induced with syrup of ipecac, or
gastric lavage performed. Activated charcoal is then passed into the stomach to bind free
B. Other ganglionic stimulants
1. Tetramethyl ammonium (TMA) and dimethylphenyl piperazinium
(DMPP) are also ganglionic stimulants. They differ from nicotine primarily in the
fact that stimulation is not followed by ganglionic depolarization blockade.
III. Ganglionic blocking drugs
A. The available ganglionic blockers in the U.S.A. are trimethaphan and mecamylamine. They are competitive antagonists. Trimethaphan has a positive charge, while mecamylamine does not, therefore trimethaphan is given intravenously and acts peripherally, while mecamylamine can be given orally, but crosses the blood-brain barrier. Trimethaphan is rapidly excreted in unchanged form by the kidney. Mecamylamine is excreted by kidney much more slowly. Other ganglionic blockers that you may hear about include hexamethonium and pentolinium, but they are no longer in clinical use in the U.S.
B. Pharmacological properties of ganglionic blockers can often be predicted by knowing which division of the ANS exerts dominant control of various organs ieSITE PREDOMINANT TONE EFFECT OF GANGLIONIC BLOCKADE
|Blood vessels Sympathetic Vasodilation, hypotension|
|Sweat glands Sympathetic Anhidrosis|
|Heart Parasympathetic Tachycardia|
|Iris Parasympathetic Mydriasis|
|GI tract Parasympathetic Reduced tone and motility|
|Bladder Parasympathetic Urinary retention|
|Salivary Gland Parasympathetic Xerostomia (reduced secretions) |
1. The importance of existing sympathetic tone in determining the extent to which blood pressure is reduced by ganglionic blockers is illustrated by the fact that they may have little or no effect when the patient is recumbent, but cause orthostatic hypotension when shifting to the standing state, because standing activates sympathetic reflexes to prevent pooling of blood in the feet. Since these reflexes are blocked postural hypotension is a major problem in ambulatory patients. In the old days, these compounds were in fact used for the treatment of hypertension, but they were abandoned as more selective treatment became available, which did not cause so many side effects. Some of the more severe side effects include marked hypotension, constipation, fainting, paralytic ileus, and urinary retention. For mecamylamine, which crosses the blood-brain barrier, large doses can cause tremors, mental confusion, seizures, mania or depression. The only remaining use of ganglionic blockers in hypertension is for the initial control of blood pressure in patients with acute dissecting aortic aneurysm. An additional use of these compounds is in the production of controlled hypotension during surgery in order to minimize hemmorhage in the operative field, and to facilitate surgery on blood vessels. Trimethaphan can be used in the treatment of autonomic hyperreflexia. This syndrome is commonly seen in patients with injuries of the spinal cord in whom minimal provocation (ie distended bladder) can elicit profound sympathoadrenal discharge.