Ganglionic Blockers

Autonomic Ganglia

There are several types of autonomic ganglia. In the sketch of the autonomic reflex arc, two are shown.

The first is labeled "sympathetic trunk ganglion." The sympathetic trunk (or sympathetic chain, as some references call it) is a string of autonomic ganglia lying alongside the spinal cord from the base of the skull to the coccyx (there are two, of course, one on either side). They are connected to the spinal nerves by rami and receive motor fibers of the first ganglion in the motor chain. They contain the somata of the second neurons.

The second type shown in the sketch is a "collateral" ganglion. These are the large ones that usually have their own anatomic names (e.g., the cervicothoracic ganglion). They are located near the organs they serve.

Not shown is the terminal ganglion. These are analogous to the collateral ganglia, but they are usually located within the substance of the organs they serve.

One final special case should be mentioned. The adrenal medulla is formed from neural crest cells in embryonic life. Consequently, since it comes from the neural cell rudiments, its cells have some of the characteristics of neurons. They are secretory, for one thing; more importantly, the materials they secrete (adrenaline and noradrenalin) are known to be neurotransmitters, and in keeping with their neuron-like nature, these cells are capable of responding to a neuronal signal: i.e., they are "excitable" cells. That's exactly what happens. The preganglionic nerve fiber from the CNS enters the adrenal medulla and there it synapses not with another neuron, but with one of the secretory cells. The secretory cell responds to the firing of this preganglionic neuron by secreting its product into the bloodstream. In other words, the secretory cell is the postganglionic "neuron" in this particular situation. It puts out a hormone for which all cells have receptors. Here we see an exquisite interconnection between the nervous system and the endocrine system, the body's two means for responding to changes in the environment.

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The autonomic nervous system plays a major role in the regulation of cardiac and vascular function. Parasympathetic (vagal) nerves leave the vagal nuclei within the medulla as preganglionic efferent vagal fibers. These preganglionic efferent fibers are relatively long and do not synapse until they reach their target organ (e.g., the heart). The preganglionic fibers synapse within small ganglia located near the target tissue (e.g., the sinoatrial node) and release the neurotransmitter acetylcholine (ACh), which binds to nicotinic receptors causing depolarization and action potential generation in the short postganglionic vagal fibers that synapse at the target cells (see the following figure). The neurotransmitter released by these postganglionic fibers at the target tissue is also ACh. In contrast, the sympathetic nerves that originate within the medulla travel down the spinal cord where they synapse with preganglionic cell bodies within the spinal cord. These cell bodies give off preganglionic fibers that are relatively short (compared to the long preganglionic vagal efferents). These preganglionic fibers enter the paravertebral ganglia (sympathetic chain ganglia) that are found on either side of the spinal column.  Either at the same level they enter the chain ganglia, or after traveling up or down the chain, these preganglionic neurons synapse with the cell bodies of postganglionic sympathetic fibers. ACh is the neurotransmitter within these ganglia, and the ACh binds to nicotinic receptors on postganglionic neurons (see the following figure). From these neurons arise relatively long postganglionic fibers that travel to their target organ and release norepinephrine as the primary neurotransmitter. Some of the preganglionic sympathetic fibers, instead of synapsing within paravertebral ganglia, synapse in prevertebral ganglia located within the abdomen (celiac, superior mesenteric, and inferior mesenteric ganglia). ACh, which binds to nicotinic receptors, is the neurotransmitter at these sites as found in the other autonomic ganglia. Postganglionic sympathetic fibers then travel from the prevertebral ganglia to innervate tissues such as blood vessels where they release norepinephrine as the primary neurotransmitter. Therefore, sympathetic postganglionic fibers can originate in either paravertebral or prevertebral ganglia.
The figure below-right summarizes the concepts described above. Additionally, this figure shows the existence of postganglionic sympathetic cholinergic fibers that innervate sweat glands and vessels. These sympathetic cholinergic postganglionic nerves release ACh instead of norepinephrine that is released by the sympathetic adrenergic postganglionic nerves. Sympathetic cholinergic nerves also innervate skeletal muscle arteries. There are also postganglionic sympathetic dopaminergic nerves that release dopamine in the kidneys. Finally, there are preganglionic sympathetic nerves that synapse in the adrenal medulla glands to stimulate the production and release of catecholamines (epinephrine primarily, norepinephrine secondarily).

Physiology

Activation of sympathetic adrenergic nerves to the heart releases norepinephrine that binds to adrenergic receptors (primarily beta-adrenoceptors), which increases heart rate (positive chronotropy), contractility (positive inotropy) and velocity of electrical impulse conduction (positive dromotropy). Together, these changes increase cardiac output and arterial blood pressure. Sympathetic adrenergic activation also constricts blood vessels, through the actions of norepinephrine binding to alpha-adrenoceptors. This increases arterial blood pressure. In contrast, activation of vagal efferent nerves depress heart function through the effects of ACh binding to muscarinic receptors. Except for a few specific organs, there is little or no vagal innervation of blood vessels. Therefore, the cardiovascular effects of vagal activation are primarily mediated through the heart, whereas sympathetic activation affects both the heart and vasculature. Sympathetic cholinergic activation releases ACh that binds to muscarinic receptors, which stimulates sweating and dilates arteries in some tissues, most notably in the skin and skeletal muscle. Sympathetic dopaminergic activation to the kidneys dilates renal vessels through dopamine binding to dopaminergic receptors. This increases renal blood flow and renal glomerular filtration. Finally, the preganglionic sympathetic nerves that synapse in the adrenal glands stimulate catecholamine release that circulates in the blood to affect the heart, blood vessels and other organs by binding to adrenergic receptors.
It is important to note that under basal, resting conditions, vagal and sympathetic adrenergic nerves are tonically active. In the heart, because vagal influences override sympathetic effects, there is resting vagal tone that is responsible for maintaining a low resting heart rate. In contrast, most blood vessels, which have little or no vagal innervation, are dominated by sympathetic adrenergic influences at rest giving rise to what is termed " sympathetic vascular tone." Therefore, blocking ganglionic neurotransmission by a ganglionic blocker removes vagal tone on the heart and sympathetic vascular tone.

 

Sympathetic autonomic ganglia are comprised of the paravertebral ganglia (sympathetic chain ganglia) and the prevertebral ganglia. Preganglionic sympathetic fibers that exit the spinal cord synapse within these ganglia and release the neurotransmitter acetylcholine (ACh), which binds to nicotinic receptors. Activation of the nicotinic receptors depolarizes the cell body of the postganglionic neuron and generates action potentials that travel to the target organ to elicit a response.
Parasympathetic autonomic ganglia are found within the target organ. In the case of the vagal nerves that exit the brainstem, their long preganglionic fibers enter the target organ (e.g., heart) where they synapse with postganglionic neurons within small ganglia. Like the sympathetic ganglia, the neurotransmitter is ACh and it binds to nicotinic receptors to activate the short postganglionic fibers that lie near the target tissue (e.g., sinoatrial node).

General Pharmacology

Sympatholytic drugs can block the sympathetic adrenergic system are three different levels. First, peripheral sympatholytic drugs such as alpha receptor antagonists and beta receptor antagonists block the influence of norepinephrine at the effector organ (heart or blood vessel). Second, there are ganglionic blockers that block impulse transmission at the sympathetic ganglia. Third, there are drugs that block sympathetic activity within the brain. These are called centrally acting sympatholytic drugs.
Neurotransmission within the sympathetic and parasympathetic ganglia involves the release of acetylcholine from preganglionic efferent nerves, which binds to nicotinic receptors on the cell bodies of postganglionic efferent nerves. Ganglionic blockers inhibit autonomic activity by interfering with neurotransmission within autonomic ganglia. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility. Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure. Parasympathetic outflow is also reduced by ganglionic blockers.

Therapeutic Indications

Ganglionic blockers are not used in the treatment of chronic hypertension in large part because of their side effects and because there are numerous, more effective, and safer antihypertensive drugs that can be used. They are, however, occasionally used for hypertensive emergencies.

Specific Drugs

Several different ganglionic blockers are available for clinical use; however, only one (trimethaphan camsylate) is very occasionally used in hypertensive emergencies or for producing controlled hypotension during surgery.

Side Effects and Contraindications

Side effects of trimethaphan include prolonged neuromuscular blockade and potentiation of neuromuscular blocking agents. It can produce excessive hypotension and impotence due to its sympatholytic effect, and constipation, urinary retention, dry mouth due to it parasympatholytic effect. It also stimulates histamine release.