Drugs Acting on Autonomic Ganglia

DRUGS ACTING ON AUTONOMIC GANGLIA

Acetylcholine is the primary excitatory neurotransmitter in both sympathetic and parasympathetic ganglia. Drugs which inhibit synthesis (hemicholinium) or release (botulinus toxin, procaine) of ACh can interfere with ganglionic transmission, but drugs which act on cholinergic receptors in the ganglia are more selective.

In addition to the dominant nicotinic N_N receptors, which mediate the primary rapid depolarization of ganglionic cells, there are subsidiary muscarinic M₁, M₂, adrenergic, dopaminergic, amino acid and peptidergic receptors which bring about secondary, slowly developing but longer lasting changes in membrane potential, both positive and negative, that modulate the primary response. Separate catecholamine (NA, DA) and amino acid containing cells are present in ganglia, but peptides are released from the preganglionic cholinergic terminals themselves. Thus, autonomic ganglion is not merely a one transmitter—one cell junction, but a complex system capable of local adjustments in the level of excitability.

Drugs can either stimulate or block the ganglia.

Ganglionic stimulants

Selective nicotinic  Nonselective/muscarinic

agonists                agonists

Nicotine (small dose)      Acetylcholine

Lobeline                Carbachol

Dimethyl phenyl   Pilocarpine

piperazinium (DMPP)    Anticholinesterases

iodide                    MCN 343A

Tetramethyl ammonium

(TMA)

Nicotine (from Nicotiana tabacum) is important in the context of smoking or chewing tobacco, but there is no clinical application of ganglionic stimulants, because no useful purpose can be served by stimulating both sympathetic and parasympathetic ganglia concurrently.

Nicotine transdermal has recently become available for treatment of nicotine dependence and as an aid to smoking cessation. It ameliorates the symptoms of nicotine withdrawal, but does not completely suppress craving, because the peak nicotine blood levels that occur after smoking are not reproduced by the patch.

NICOTINELLTTS 10, 20, 30 cm2 patches releasing 7, 14, 21 mg nicotine per 24 hr respectively.

In those smoking >20 cigarettes every day—start with 30 cm2 patch, shift to smaller patches every 5–8 days, treat for 3–4 weeks (max. 12 weeks). Headache, insomnia, flu like symptoms, dyspepsia, loose motion and local irritation are the side effects. Cardiac arrhythmias and ischaemic heart disease are the contraindications.

Varenicline This N_N subtype nicotinic receptor partial agonist is under clinical development for smoking cessation. Controlled trials have found it to reduce craving as well as nicotine withdrawal symptoms in those who stop smoking. Abstinence rates after one year were higher than placebo and comparable to bupropion (see No. 33).

Rimonabant A selective cannabinoid receptor1 (CB1) antagonist which is being tried as antismoking and anti-obesity drug. It appears to have the potential to help smoking cessation as well as maintain smoking abstinence.

Ganglion blocking agents

          A) Competitive blockers

Quaternary ammonium compounds Hexamethonium,Pentolinium

Amines (secondary/tertiary) Mecamylamine, Pempidine

Monosulfonium compound Trimethaphan camforsulfonate

          B) Persistent depolarising blockers

Nicotine (large dose) Anticholinesterases (large dose)

The competitive ganglion blockers were used in the 1950s for hypertension and peptic ulcer, but have been totally replaced now because they produce a number of intolerable side effects (see Table 8.2). In fact, these side effects help in understanding the relative roles of sympathetic and parasympathetic divisions in regulating the various organ functions.

Trimethaphan It is an ultrashort acting ganglion blocker; has been occasionally used to produce controlled hypotension and in hypertensive emergency due to aortic dissection.

Mecamylamine alone, as well as in combination with nicotine patch, has been tried for smoking cessation. It appears to block the reward effect of nicotine and improve abstinence rate compared to placebo. Constipation occurred in many subjects, and it is not an approved drug.

There is at present no clinical relevance of ganglion blockers.