Drugs acting on Autonomic Ganglia

Drugs acting on Autonomic Ganglia

•      Autonomic ganglia are clusters of neuronal cell bodies which are located peripherally and essentially form a junction between autonomic nerves originating from the central nervous system  and autonomic nerves innervating their target organs in the periphery.

•      Autonomic ganglia are integral part of autonomic nervous system and are affected by a large number of drugs.

•      The autonomic ganglionic acting drugs act selectively on cholinergic receptors in the ganglia and either stimulate or inhibit the nerve
transmission in both sympathetic and parasympathetic ganglia.

•      Drugs or toxicants which inhibit synthesis (e.g. hemicholinium) or
release (e.g. botulinum toxin and procaine) of acetylcholine can
also interfere with ganglionic transmission, but conventionally
these agents are not taken as autonomic ganglionic acting drugs
because they act on other cholinergic sites as well.

•      Depending on  the type of action, the drugs acting on autonomic ganglia are categorised into two groups:

            autonomic ganglionic stimulants and autonomic ganglionic inhibitors.

AUTONOMIC GANGLIONIC STIMULATING DRUGS

Autonomic ganglionic stimulating drugs (autonomic ganglionic-stimulants) are a group of drugs which stimulate the cholinergic receptors present on both sympathetic and parasympathetic autonomic ganglia and propagate nerve impulses in the autonomic ganglia.

These drugs have no therapeutic applicability due to their non-specific and unpredictable actions, and high incidence of adverse effects.

Classification

•      Depending on their specificity for type of cholinergic receptors, ganglionic stimulant drugs are divided into two groups:

I. Nicotinic receptor stimulants

Natural alkaloids e.g. nicotine (small dose) and lobeline.

Synthetic stimulants  e.g. tetramethylammonium (TEA) and dimethylphenyl piperazinium (DMPP).

II. Muscarinic receptor stimulants

            e.g. acetylcholine, muscarine, methacholine and  anticholinesterase agents.

1. NICOTINIC-RECEPTOR STIMULANTS

•      Nicotinic-receptor stimulants have affinity for N_N nicotinic  receptors present on cell bodies (post-synaptic membrane) of post-ganglionic neurons and include naturally occurring alkaloids nicotine and lobeline, and some synthetic drugs.

•      Their excitatory effects on ganglia are rapid in onset, mimic fast EPSP (primary pathway) and are blocked by non-depolarising ganglionic blocking drugs (e.g. hexamethonium).

•      Naturally occurring drugs like nicotine and lobeline have complex and unpredictable actions in the body because after initial stimulation of autonomic ganglia (both sympathetic and parasympathetic) they produce blockade.

•      Stimulation of autonomic ganglia by synthetic drugs like
tetramethyl ammonium (TMA) or dimethylphenyl piperazinium 
(DMPP) is not followed by depression of autonomic ganglia.

•      These drugs have no therapeutic utility.

•      Nicotine is an important toxicant and DMPP is used as an experimental drug.

II. MUSCARINIC RECEPTORS STIMULANTS

•      These autonomic ganglionic stimulants include various parasympathomimetic agents which have non-selective action on muscarinic receptors present on the post-ganglionic neurons.

•      Their excitatory action on ganglia is slow in onset, blocked by atropine-like drugs and mimics the slow EPSP.

•      The non-selective ganglionic stimulants have also no therapeutic utility and include muscarine, methacholine and anticholinesterase agents.

AUTONOMIC GANGLIONIC BLOCKING DRUGS

•      Autonomic ganglionic blocking (Ganglioplegic) drugs inhibit or block the nerve impulse transmission across both sympathetic and parasympathetic ganglia.

•      These drugs are mainly non-selective in action on autonomic ganglia, although some selectivity has been attained with newer agents.

•      These drugs have no real application in veterinary medicine, but have contributed much to the present understanding on neurotransmission in autonomic ganglia.

Classification

Autonomic ganglionic blocking drugs have been classified  into two groups on

the basis of their mode of action.

I. Persistent depolarising ganglionic blocking drugs
e.g. nicotine (large dose) and lobeline.

ll. Non-depolarising ganglionic blocking drugs

1. Quaternary ammonium compounds

e.g. hexamethonium, pentolinium, pentamethonium, pentamine and chlorisondamine.

2. Monosulphonium compounds

e.g. trimetaphan.

3. Tertiary/Secondary amines

e.g. mecamylamine and pempidine.

I. PERSISTENT DEPOLARISING GANGLIONIC BLOCKING DRUGS

•      Persistent depolarising ganglionic blocking drugs act on post-synaptic N_N nicotinic receptors on autonomic ganglia to cause
depolarisation and initiation of fast EPSP, but they have persistent depolarising action resulting in blockade later on.

            Accordingly, these agents initially cause autonomic ganglionic stimulation followed by dominant ganglionic blockade.

Nicotine

•      Nicotine is a liquid alkaloid obtained from the leaves of tobacco plant Nicotiana tabacuum.

•      It is a hygroscopic, oily liquid that is miscible with water in its base form.

•      As a nitrogenous base, nicotine forms salts with acids which are usually solid and water soluble.

•      Nicotine is a potent poison and is occasionally used as an insecticide.

•      It has no therapeutic use, but is of considerable interest in human medicine because of its wide use in tobacco smoking and chewing, and as an experimental tool in pharmacology.

Mechanism of action

•      Nicotine acts on the N_N nicotinic acetylcholine receptors present in the autonomic ganglia (mainly), adrenal medulla and CNS.

•      In small concentrations or in initial stages of high concentrations, nicotine increases the activity of these receptors, but in later stages of high concentrations, it blocks these nicotinic receptors due to persistent depolarisation of post-synaptic membranes.

•      Initial stimulation of nicotinic receptors in autonomic ganglia facilitates ganglionic nerve transmission, in adrenal medulla causes release of catecholamines and in CNS increases concentration of several neurotransmission (e.g. norepinephrine, vasopressin, dopamine and beta-endorphin).

•      Blockade of N_N receptors in higher nicotine concentration reverses the said effects in ganglia, adrenal medulla and CNS.

Pharmacological effects

•      Nicotine first stimulates and then depresses both the sympathetic and parasympathetic autonomic ganglia.

•      Similarly, nicotine possesses a biphasic action on adrenal medulla, neuromuscular junction and CNS causing their initial stimulation in small doses to be followed by persistent depression in large  doses.

•      Nicotine is also known to stimulate a number of sensory receptors like mechanoreceptors which respond to stretch or pressure, chemoreceptors of the carotid body, thermal receptors of skin and pain receptors.

•      Due to these reasons, the pharmacological actions of nicotine are complex and depend on the dosage and site of action.

•      In general, the ultimate response of anyone structure or system represents summation of several different and opposite effects of nicotine and the predominance of sympathetic and parasympathetic tone in a particular structure.

Peripheral nervous system:

Cardiovascular system:

•      When administered intravenously to dog, nicotine produces an increase in blood pressure due to stimulation of the predominating sympathetic ganglia and adrenal medulla. Later with higher doses, the blood pressure falls due to ganglion blockade and loss of motor tone.

•      Effect of nicotine on heart is variable. Since the cardio-inhibitor vagus nerve is predominant in heart, the response to a small dose is decreased pulse rate (tachycardia may occur after IV dose due to rapid release of catecholamines from adrenal medulla). However after blockade of autonomic ganglia, a relative tachycardia may occur.

•      Gastrointestinal tract: The effect of nicotine on GI tract is
due largely to parasympathetic stimulation. This results in
increased gastric secretion, vomiting, increased peristalsis and
defecation. Blockade of autonomic ganglia may produce decreased
tone and motility of Gl tract and constipation.

•      Exocrine glands: Nicotine causes initial stimulation of salivary
and bronchial secretions which is followed by predominant inhibition.

•      Central nervous system: Nicotine transiently stimulates and then depresses the central nervous system. In humans, initial stimulation by low dose of nicotine produces a psychostimulant effect characterised by enhancement in concentration, memory, arousal and alertness. At slightly higher doses, nicotine may produce sedative, anti-anxiety and analgesic effects. In very high doses nicotine severely depresses CNS, suppressing many essential activities. Death occurs from respiratory paralysis of the diaphragm and chest muscle resulting from descending paralysis and depolarisation block of the neuromuscular junction.

Pharmacokinetics

•      In humans, nicotine is readily absorbed from respiratory tract, buccal mucosa and GI tract (mainly intestine).

•      Clearance of nicotine involves metabolism in the liver (mainly) and also lungs and kidneys.

•      In liver, nicotine is metabolized by cytochrome P450 enzymes (mostly CYP2A6 and CYP2B6) to several metabolites including cotinine (major metabolite), nicotine N'-oxide, nomicotine, nicotine isomethonium ion, 2-hydroxynicotine and nicotine glucuronide.

•      The half life of nicotine in the humans is around two hours. The rate of urinary excretion of nicotine is more in acidic urine pH.

Side effects/Adverse effects

•      High dosage of nicotine results in acute toxicosis
characterised by excitement, irritability, tremors, hyperpnoea, salivation, pulse rate irregularities, intestinal cramps, diarrhoea and emesis.

•      This transient stimulatory phase is followed by a
depression phase characterised primarily by incoordination, dyspnoea, coma and death from respiratory paralysis.

•      Physical dependence on nicotine develops rapidly after chronic use in human beings.

•      Withdrawal is characterised by irritability, anxiety, restlessness, insomnia, etc.

Clinical uses

•      Nicotine is not used therapeutically in veterinary practices.

•      In human medicine, the primary clinical use of nicotine is in smoking cessation therapy. Controlled levels of nicotine are given to patients through gums, dermal patches, lozenges, electronic / substitute cigarettes or nasal sprays in an effort to wean them off their dependence.

•      Nicotine (in the form of chewing gum or a
transdermal patch) is being explored as an experimental treatment for obsessive-compulsive disorder (OCD), a disorder characterized
by intrusive thoughts which produce anxiety.

Lobeline

•      Lobeline is an alkaloid obtained from Lobelia inflata (Indian
tobacco) and Lobelia tupa (Devil's tobacco).

•      Lobeline does not resemble nicotine in structure, but has some resemble in pharmacological actions.

•      It has multiple mechanisms of action in the body including a mixed agonist-antagonist at nicotinic acetylcholine receptors, an antagonist at u-opioid receptors and a ligand for vesicular monoamine transporter-2 (VMA T2), a carrier that transports biogenic amines such as dopamine from cellular cytosol into synaptic vesicles.

•      It stimulates dopamine release to a moderate extent when administered alone, but reduces the dopamine release caused by methamfetamine.

•      Lobeline has been  used as a smoking cessation aid and may have application in the treatment of other drug addictions such as addiction to amfetamines, cocaine or alcohol.

•      It has also a long history of therapeutic usage as an emetic and a respiratory stimulant.

NON-DEPOLARISING/COMPETITIVE GANGLIONIC BLOCKING DRUGS

•      Non-depolarising (Competitive) ganglionic blocking drugs compete with acetylcholine for the nicotinic receptor sites in autonomic ganglia and thereby block the transmission of impulses
from pre-ganglionic to post-ganglionic neurons without causing initial stimulation.

•      Like nicotine, they are non-selective in action and affect both sympathetic and parasympathetic ganglia.

•      The intensity of action depends on the prevailing tone of the organ. These drugs have a small place in therapeutics.

1. Quaternary Ammonium Compounds

•      Quaternary nitrogen containing ganglionic blocking drugs competitively interact with nicotinic receptors at the ganglia with minimal neuromuscular and muscarinic receptor blocking activities.

•      Being charged compounds, they are poorly absorbed from the gut and do not cross the blood-brain barrier.

•      Accordingly they have to be given by IV route for predictable effect.

•      Important quaternary ammonium ganglionic blocking agents include hexamethonium, pentolinium, tetraethyl ammonium (TEA),
chlorisondamine, trimethidinium and azamethonium.

Hexamethonium

•      Hexamethonium bromide was the first autonomic ganglionic  blocker to be used in therapy. It is often referred to as the prototypical ganglionic blocker.

•      It primarily acts on the N_N receptors  located in at autonomic-ganglionic sites in both the sympathetic  and parasympathetic nervous systems and causes the receptor  blockade.

•      Unlike nicotine, hexamethonium produces ganglion blockade without initial stimulation.

•      It does not have any effect on the muscarinic acetylcholine receptors (mAChR) located on target organs of the parasympathetic nervous system; but may act as antagonist at the N_M nicotinic acetylcholine receptors at the neuromuscular junction which are responsible for some skeletal muscle motor response.

•      The pharmacological effects of hexamethonium are due to blockade of both sympathetic and parasympathetic activities in body.

•      Systemic administration of hexamethonium produces decrease in peripheral vascular resistance and fall in systemic blood pressure.

•      The effect of hexamethonium on heart rate depends on the initial vagal tone, but the usual effect is a slight tachycardia due to inhibition of cardiac vagus.

•      Since the compensatory reflexes maintaining blood pressure are interrupted, It produces marked postural hypotension leading to syncope.

•      It is poorly absorbed from the gastrointestinal tract and does not cross the blood-brain barrier.

•      Side-effects include combined antiadrenergic (e.g. vasodilation, orthostatic hypotension and sexual dysfunction) and anticholinergic effects (e.g. xerostomia, constipation, urinary retention, glaucoma, blurred vision and decreased lachrymal secretion).

•      Hexamethonium may precipitate renal failure in patients of renal ischaemia due to diminished renal blood flow. 

•      Hexamethonium has been used for a variety of therapeutic purposes including hypertension but, like the other ganglionic blockers, it has now been replaced by more specific drugs.

•      Presently it is widely used as a research tool.

Pentolinium

•      Pentolinium tartrate is a quaternary ammonium compound with potent ganglionic blocking action.

•      Pentolinium acts as a nicotinic acetylcholine receptor antagonist with pharmacological properties resembling hexamethonium, but it is about 5 times as potent as hexamethonium in lowering blood pressure.

•      It is suggested that pentolinium has some selectivity for the sympathetic ganglia.

•      It is used occasionally as an antihypertensive drug during surgery or to control severe hypertension, particularly when other drugs have failed.

•      Pentolinium can be given orally, injected intramuscularly or administered intravenously.

Other quaternary ammonium ganglionic blocking drugs

•      Some other quaternary ammonium compounds such as pentamethonium, pentamine and chlorisondamine are used to block the nicotinic acetylcholine receptors in both sympathetic and parasympathetic autonomic ganglia.

•      Pentamethonium resembles structurally to hexamethonium and has same antihypertensive use.

•      Pentamine is a ganglionic blocker used occasionally for the treatment of pneumocystis pneumonia.

•      Chlorisondamine diiodide produces antagonistic action at both neuronal and ganglionic nicotinic receptors and has an exceptionally long lasting effect for several weeks.

•      Most of these ganglionic blockers agents are now used only in animal research.

2. Monosulphonium Compounds

Trimetaphan

•      Trimetaphan (Trimethaphan) camsilate is a sulphonium compound and therefore carries a positive charge.

•      It acts as a non-depolarizing competitive antagonist at the N_N nicotinic acetylcholine receptors of the autonomic ganglia and therefore blocks both the sympathetic and parasympathetic nervous systems.

•      Trimetaphan has very strong action on the cardiovascular system.

•      Loss of sympathetic system input to the blood vessels  causes vasodilation and lowering of blood pressure.

•      Besides ganglionic blockade, it also causes direct vasodilation and liberation of histamine, which further lowers blood pressure.

•      Effects on the heart include a decreased force of contraction and an increase in heart rate (tachycardia).

•      Reflexive tachycardia can be  diminished or remain undetected because trimetaphan is also blocking the sympathetic ganglia innervating the heart.

•      Like quaternary ammonium compounds, trimetaphan camsilate is poorly absorbed from the GI tract and does not cross blood-brain barrier.

•      It has short duration of action, therefore is used  mainly by IV infusion to produce controlled hypotension to reduce bleeding during surgery, especially surgery on blood vessels and
orthopaedic procedures.

•      It can also be used in the management  of autonomic hyper-reflexia syndrome seen due to excessive sympathetic discharge because of upper spinal cord injury.

•      For surgical procedures, the infusion of trimetaphan may continue for up to 2 hours, and on stoppage the blood pressure returns to  normal in about 5 to 10 minutes.

•      Postural hypotension, cycloplegia, mydriasis, urinary retention, sexual dysfunctions and constipation are some important side effects of trimetaphan.

3. Tertiary / Secondary amines

Mecamylamine

•      Mecamylamine hydrochloride is a secondary amine that was
introduced in the 1950s as an antihypertensive agent and is one
of very few ganglionic blocking agents which are still being used
in therapy.

•      It is a relatively long acting ganglionic blocking agent with nonselective and noncompetitive blocking action at nicotinic acetylcholine receptors.

•      It is well absorbed after oral administration and widely distributed in body.

•      Mecamylamine is occasionally used in therapeutics to control severe hypertension in patients refractory to other antihypertensive agents.

•      Mecamylamine is also sometimes used as an anti-addictive drug to help people stop smoking tobacco, and is now more widely used for this application than it is for lowering blood pressure.

•      Important side/adverse effects related to mecamylamine include blurred vision, constipation, dry mouth, dilated pupils, decreased sex drive, loss of appetite, nausea, vomiting and urinary retention.

•      Unlike quaternary ammonium compounds, it penetrates into the brain and may cause central side effects like tremors, mental confusion, mania and depression as seen in humans.

•      Overdosage may cause paralytic ileus.

Pempidine

•      Pempidine is a tertiary amine autonomic ganglionic blocker.

•      Similar to mecamylamine, pempidine is readily and completely absorbed after oral administration and widely distributed in body.

•      Its pharmacological effects are also similar to mecamylamine, only  that pempidine has shorter duration of action.

•      Adverse effects of  the overdosage last shorter than those of mecamylamine because of the rapid elimination of pempidine.

•      Pempidine has been used in the treatment of hypertension, but now has largely been replaced for that purpose by more specific drugs.

•      Presently it is used only as an experimental tool.