Healthcare in India

Anthicholinergic Drugs and Drugs Acting on Autonomic Ganglia

Anticholinergic Drugs
(Muscarinic receptor antagonists, Atropinic, Parasympatholytic)

Conventionally, anticholinergic drugs are those which block actions of Ach on autonomic effectors and in the CNS exerted through muscarinic receptors. Though nicotinic antagonists also block certain actions of Ach, they are generally referred to as ‘ganglion blockers’ and ‘neuromuscular blockers’.

Atropine, the prototype drug of this class, is highly selective for muscarinic receptors, but some of its synthetic substitutes do possess significant nicotinic blocking property in addition. The selective action of atropine can easily be demonstrated on a piece of guinea pig ileum where Ach induced contractions are blocked without affecting those evoked by histamine, 5-HT or other spasmogens. The selectivity is, hoever, lost at very high doses. All anticholinergics are competitive antagonists.

Classification

• Natural alkaloids Atropine, Hyoscince (Scopolamine).
• Somisynthetic derivatives Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide.
• Synthetic Compounds
• Mydriatics: Cyclopentolate, Tropicamide.
• Antisecretory-antispasmodice;
• Quaternary compound; Propantheline, Oxyphenonium, Clidinium, Pipenzolate methylbromide, Isopropamide, Glycopyrolate.
• Tertiary amines: Dicyclomine, Valethamae, Pirenzepine.
• Antiparkinsonian: Trihexyphenidyl (Benzhexol) Procyclidine, Biperiden.
• Vasicoselective: Oxybutynin, Flavoxate, Tolterodine.
• Antiparkinsonian; Trihexyphenidyl (Benzhexol) Procyclidine, Biperiden.

In addition, many other classes of drugs, i.e. tricyclic antidepressants, phenothiazines, antihistamines and disopyramide possess significant antimuscarinic actions.

The natural alkaloids are found in plants of the solanaceae family. The levo-isomers are much moe active than the dextroisomers, Atropine is racemic while scopolamine is l-hyoscine.

Pharmacological actions (Atropine as prototype)

The actions of atropine can be largely predicted from knowledge of parasympathetic responses. Prominent effect are seen in organs which normally receive strong parasympathetic tone. It blocks all subtypes of muscarinic receptors.

1.       CNS
Atropine has an overall CNS stimulant action. However, these effects are not appreciable at low doses which produce only peripheral effects because of restricted entry into the brain. Hyoscine produces central effects (depressant) even at low doses.

• Atropine stimulates many medullary centers-vagal, respiratory, vasomotor.
• It depresses vestibular excitation and has antimotion sickness property. The site of this action is not clear-probably there is a cholinergic link in the vestibular pathway, or it is exerted at the cortical level.
• By blocking the relative cholinergic over activity in basal ganglia, it suppresses tremor and rigidity of parkinsonism.
• High doses cause cortical excitation, restlessness, disorientation, hallucinations and delirium followed by respiratory depression and coma.

Majority of the central actions are due to blockade of muscarnic receptors in the brain, but some actions may have a different basis.

• CVS

Heart The most prominent effect of atropine is to cause tachycardia. It is due to blockade of M2 receptors on SA node through which vagal tone decreases HR. Higher the existing vagal tone more marked is the tachycardia (maximum in young adults, less in children and elderly). On i.m/s.c. injection transient initial bradycardia often occurs. Earlier believed to be due to stimulation of vagal center, it is now throught to be caused by blockade of muscarinic autoreceptors (M1) on vagal nerve endings augmenting Ach release. This is suggested by the finding that selective M1 antagonist pirenzepine is equipotent to atropine in causing bradycardia as are atropine substitutes which do not cross blood-brain barrier. Atropine abbreviates refractory period of A-V node and facilitates A-V conduction, especially if it has been depressed by high vagal tone. P-R interval is shortened.

BP Since cholinergic impulses are not involved in maintenance of vascular tone, atropine does not have any consistent or marked effect on BP. Tachycardia and vasomotor center stimulation tend to raise BP, while histamine release and direct vasodilator action (at high doses) tend to lower BP.

Atropine blocks vasodepressor action of cholinergic agonists.

3. Eye
The autonomic control of iris muscles and the action of mydriatic as well as miotics is illustrated in Fig. 8.1 topical instillation of atropine causes mydriasis, abolition of light reflex and cycloplegia lasting 7-10 days. This results in photophobia and blurring of near vision. The ciliary muscles recover somewhat earlier than sphincter pupillae. The intraocular tension tends to rise, especially in narrow angle glaucoma; conventional systemic doses produce minor ocular effects.

4.  Smooth muscles
All visceral smooth muscles that receive parasympathetic motor innervation are relaxed by atropine (M3 blockade). Tone and amplitude of contractions of stomach and intestine are reduced; the passage of chyme is slowed-constipation may occur, spasm may be relieved. However, peristalsis is only incompletely suppressed because it is primarily regulated by local reflexes and other neurotransmitters (5-HT, enkephalin, etc.) as well as hormones are involved. Enhanced motility due to injected cholinergic drugs is more completely antagonized than that due to vagal stimulation.

Atropine causes bronchodilatation and reduces airway resistance, especially in COPD and asthma patients. Inflammatory mediators like histamine, PGs and kinins increase vagal activity in addition to their direct action on bronchial muscle and glands. Atropine attenuates their action by antagonizing the reflex vagal compounent.

Atropine has relaxant action on ureter and urinary bladder; urinary retention can occur in older males with prostatic hypertrophy. However, the same can be beneficial for increasing bladder capacity and controlling detrusor hyperreflexia in neurogenic bladder/enuresis. Relaxation of biliary tract is less marked and effect on uterus is minimal.

5.  Glands
Atropine markedly decreases weat, salivary, tracheobronchial and lacrimal secretion (M3 blockade). Skin and eyes become dry, talking and swallowing may be difficult.

Atropine decreases secretion of acid, pepsin and musus in the stomach, but the primary action is on volume of secretion so that pH of gastric contents may not be elevated unless diluted by food. Since bicarbonate secretion is also reduced, rise in pH of fasting gastric jice is only modest. Relatively higher doses are needed and atropine  is less efficacious than H2 blockers in reducing acid secretion. Intestinal and pancreatic secretions are not significantly reduced. Bile production is not under cholinergic control, so not affected.

6.  Body temperature
Rise is body temperature occurs at higher doses. It is due to both inhibition of sweating as well as stimulation of temperature regulating center in the hypothalamus. Children are highly susceptible to atropine fever.

7.  Local anaesthetic
Atropine has a mild anaesthetic action on the cornea.
Atropine has been found to enhance Ach (also NA) release from certain postanglionic parasympathetic and sympathetic nerve endings, and thus produce paradoxical responses. This is due to blockade of release inhibitory muscarinic autoreceptors present on these nerve terminals.

The sensitivity of different organs and tissues to atropine varies and can be graded as –
Saliva, sweat, bronchial secretion > eye, bronchial muscle, heart > smooth muscle of intestine, bladder > gastric glands and smooth muscle.

The above differences probably reflect the relative dependence of the function on cholinergic tone vis a vis other influences, and variation in synaptic gaps in different organs. The pattern of relative activity is nearly the same for other atropine substitutes except pirenzepine which inhibits gastric secretion at doses that have little effect on other secretions, heart and eye. This is probably because  atropine equally blocks M1, M2 and M3 receptors whereas pirenzepine is a selective M1 angagonist.

Atropine more effectively blocks responses to exogenously administered cholinergic drugs that those to parasympathetic nerve activity. This may be due to release of Ach very close to the receptors by nerves and involvement of cotransmitter

Hyoscine The other natural anticholinergic alkaloid differs from atropine in many respects, these are tabulated in Table 8.1

Pharmacokinetics

Atropine and hyoscine are rapidly absorbed from g.i.t. Applied to eyes they freely penetrated cornea. Passage across blood-brain barrier is somewhat restricted. About 50 % of atropine is metabolized in liver and rest is excreted unchanged in urine. It has a t ? of 3-4 hours. Hyoscine is more completely metabolized and has better blood-brain barrier penetration.

Atropine sulfate; 0.6-2 mg i.m., i.v. (children 10 ug/kg), 1-2 % topically in eye. Atropine Sulphate; 0.6 mg/ml inj., 1 % eye drop/ointment; ATROSU LPH 1 % eye drop, 5 % eye oint.

Hyoscine hydrobromide; 0.3-0.5 mg oral, i.m.; also as transdermal patch.
Combinations of atropine with analgesics and antipyretics are banned in India.

Atropine Substitutes

Many semisynthetic derivatives of belladonna alkaloids and a large number of synthetic compounds have been introduced with the aim of producing more selective action on certain functions. Most of these differ only marginally from the natural alkaloids, but some recent ones are promising.

Quaternary compounds

These have certain common features –

• Incomplete oral absorption.
• Poor penetration in brain and eye; central and ocular effects are not  seen after parenteral/oral administration.
• Elimination is generally slower; majority are longer acting than atropine.
• Have higher nicotinic blocking property. Some ganglionic blockade may occur at clinical doses ® postural hypotension, impotence are additional side effects.
• At high doses some degree of neuromuscular blockade may also occur.

Drugs in this category are ---
1.  Hyoscine butyl bromide : 20-40 mg oral i.m., s.c., i.v.; less potent and longer acting than atropine; used for esophageal and gastrointestinal spastic conditions.
BUSCOPAN 10 mg tab., 20 mg/ml amp.

2.  Atropine methonitrate : 2.5-10 mg oral, i.m.; for abdominal colics and hyperacidity.
MYDRINDON 1 mg (adult)., 0.1 mg (child) tabl; in SPASMOLYSIN 0.32 mg tab;

3.  Ipratropium bromide : 40-80 ug by inhalation; it acts selectively on bronchial muscle without altering volume or consistency of respiratory secretions. Another desirable feature is that in contrast to atropine, it does not depress mucociliary clearance by bronchial epithelium. It has a gradual onset and late peak (at 60-90 min) of bronchodilator effect in comparison to inhaled sympathomimetics – more suitable for regular prophylactic use rather than for rapid symptomatic relief during an attack. Action lasts 4-6 hours. It acts on receptors located mainly in the larger central airways (contrast sympathomimetrics whose primary site of action is peripheral bronchioles). The parasympathetic tone is the major reversible factor in chronic obstructive pulmonary diseases (COPD). There fore, ipratropium is more effective in COPD than in bronchial asthma. Transient local side effects like dryness of mouth, scratching in trachea, cough, bad taste and nervousness are reported in 20-30 % patients, but systemic effects are rare because of poor absorption from the lungs and g.i.t. (major fraction of inhaled rugs is swalloed).

IPRAVENT 20 mg and 40 mg/puff metered dose inhaler, 2 puffs 3-4 times daily; 250mg/ml respirator soln., 0.4-2 ml nebulized in conjunction with a B2 agonist 2-4 times daily.
Also used to control rhinorrhoea in perennial rhinitis and common cold; IPRANSE-AQ 0.084 % nasal spray (42 mg per actuation), 1-2 sprays in each nostril 3-4 times a day.

4.  Tiotropium bromide : A recently developed congener of ipratropium bromide which binds very tightly to bronchial M1/M3 muscarinic receptors producing long lasting bronchodilation. Binding to M2 receptors is less tight conferring relative M1/M2 selectivity. Like ipratropium, it is not absorbed from respiratory and g.i. mucosa and has exhibited high bronchial selectivity of action.

5. Propantheline : 15-30 mg oral; it has been the most popular anticholinergic used for peptic ulcer and gastritis. It has some ganglion blocking activity as well and is claimed to reduce gastric secretion at doses which produce only mild side effects. Gastric emptying is delayed and action lasts for 6-8 hours. Use has declined due to availability of H2 blockers which are more efficacious.

6.  Oxphenonium : 5-10 mg (children 3-5 mg) oral; similar to propantheline, recommended for peptic ulcer and gastrointestinal hypermotility
ANTRENYL 5, 10 mg tab.

7.  Clidinium : 2.5 – 5 mg oral; used in combination with benzodiazepines for nervous dyspepsia, gastritis, irritable bowel syndrome, colit, peptic ulcer, etc.
In SPASRIL, EQUIREX 2.5 mg tab with chlordiazepoxide 5 mg. NORMAXIN 2.5 mg with dicyclomine 10 mg and chlordiazepoxide 5 mg.

8.  Pipenzolate methyl bromide : 5-10 mg (children 2-3 mg) oral; used for flatulent dyspepsia, infantile colics and other gastrointestinal spasm. In PIPTAL, PIPEN 4 mg + dimethylpolysiloxane 40 mg/ml drops.

9.  Isopropamide : 5 mg oral; indiated in hyperacidity, nervous dyspepsia, irritable bowel and other gastrointestinal problems, specially when associated with emotional / mental disorder.
In STELABID, GASTABID 5 mg tab, with trifluoperazine 1 mg.

10.          Glycopyrrolate : 0.1-0.3 mg i.m., 1-2 mg oral; potent and rapidly acting antimuscarinic lacking central effects. Almost exclusively used for preanaesthetic medication and during anaesthesia. GLYCO-P 0.2 mg/ml amp., 1 mg in 5 ml vial, PYROLATE 0.2 mg/ml., 1 ml amp, 10 ml vial.

Tertiary amines

1.  Dicyclomine : 20 mg oral/i.m. children 5-10 mg; has direct smooth muscle relaxant action in addition to weak anticholinergic; exerts antispasmodic action at doses which produce few atropinic side effects. However, infants have exhibited atropinic toxicity symptoms and it is not recommended below 6 months of age. It also has antiemetic property; has been used in morning sickness and motion sickness. Dysmenorrhoea and irritable bowel are other indications.

CYCLOMINOL, 20 mg tab, 10 mg/ml liuid; DIOSPAS 10 mg, 20 mg tabs, CYCLOPAM INJ. 10 mg/ml in 2 ml, 10 ml, 30 ml amp/vial, also 20 mg tab with paracetamol 500 mg; in COLIMEX 20 mg with paracetamol 500 mg tab, 10 mg/ml drops with dimethicone.

2.  Valethamate: The primary indication of this anticholinergic smooth muscle relaxant is to hasten dilatation of cervix when the same is delayed during labour, and as visceral antispasmodic.
Dose: 8 mg i.m., 10 mg oral repeated as required.
VALAMATE 8 mg in 1 ml inj. EPIDOSIN 8 mg in., 10 mg tab.

3.  Pirenzepine: 100-150 mg/day oral; it selecltively blocks M1 muscarinic receptors and inhibits gastric secretion without producing typical atropinic side effects (these are due to blockade of M2 and M3 receptors). The more  likely site of action of pirenzepine in stomach is intramural plexuses and ganglionic cells rather than the parietal cells themselves. It is nearly equally effective as cimetidine in relieving peptic ulcer pain and promoting ulcer healing, but has been overshadowed by H2 blockers and proton pump inhibitors.

Vasicosellective drugs

1.  Oxybutynin : This recently introduced antimuscarinic has high affinity for receptors in urinary bladder and salivary glands with additional smooth muscle relaxant and local anaesthetic properties. It is relatively selective for M1/M3 subtypes than for M2. Because of vasicoselective action it is used for detrusor instability resulting in urinary frequency and urge incontinence. Beneficial effects have been demonstrated in neurogenic bladder, spina bifida and nocturnal enuresis. Anticholinergic side effects are common after oral dosing, but intravasical instillation increases bladder capacity with few side effects.
Dose : 5 mg BD/TDS oral; children above 5 yr 2.5 mg BD>
OXYBUTIN, CYSTRAN, OXYSPAs 2.5 mg and 5 mg tabs.

2.  Tolterodie : This relatively M3 selective muscarinic antagonist has preferential action on urinary bladder; less likely to cause dryness of mouth and other anticholinergic side effects. It is indicated in overactive bladder with urinary frequency and urgency. Since it is metabolized by CYP3A4, dose should be halved in patients receiving CYP3A4 inhibitors (erythromycin, ketoconazole, etc.)
Dose : 2 mg BD oral; ROLITEN, TORQ 1, 2 mg tabs

3.  Flavoxate has properties similar to oxybutynin and is indicated in urinary frequency, urgency and dysuria associated with lower urinary tract infection.
URISPAS, FLAVATE 200 mg tab, 1 tab TDS

Drotaverine : It is a novel non-anticholinergic smooth muscle antispasmodic which acts by inhibiting phosphodiesterase-4 (PDE-4) selective for smooth muscle. Elevation of intracellular camp/cGMP attends smooth muscle relaxation. Changes in membrane ionic fluxes and membrane potential have also been shown. It has been used orally as well as parenterally in intestinal, biliary and renal colics, irritable bowel syndrome, uterine spasms, etc. without anticholinergic side effects. Adverse effects reported are headache, dizziness, constipation and flushing. Fall in BP can occur on i.v. injection.
Dose: 40-80 mg TDS; DROTIN, DOTARIN, DOVERIN 40, 80 mg tabs, 40 mg/2 ml inj.

Mydriatics
Atropine is a potent mydriatic but its slow and long lasting action is undersirable for refraction testing. Though the pupil dilates in 30-40 min, cycloplegia takes 1-3 hours, and the subject is visually handicapped for about a week. The substitutes attempt to overcome these difficulties.

1.  Homatropine : It is 10 times less potent than atropine. Instilled in eye, it acts in 45-60 min, mydriasis lasts 1-3 days while accommodation recovers in 1-2 days. It often produces unsatisfactory cycloplegia in children who have high ciliary muscle tone.
HOMATROPINE EYE, HOMIDE 1 %, 2 % eye drops.

2.  Cyclopentolate : It is potent and   rapidly acting; mydriasis and cycloplegia occur in 30-60 min and last about a day. It is preferred for cycloplegic refraction, but children may show transient behavioural abnormalities due to absorption of the drug after passage into the nasolacrimal duct. It is also used in iritis and uveitis.
CYCLOMID EYE 0.5 %, 1 %, CYCLOGYL 1 %   eye drops.

3.  Tropicamide : It has the quickest (20-40 min) and briefest (3-6 hours) action, but is relatively unreliable cycloplegic. However, it is satisfactory for refraction testing in adults and as a short acting mydriatic for fundoscopy.
OPTIMIDE, TROPICAMET, TROMIDE 0.5 %, 1.0 % eye drops. TROPAC-P, TROPICAMET PLUS 0.8 % with phenylephrine 5 % drops.

Antiparkinsonian drugs
Uses

I.       As antisecretory
1.       Preanaesthetic Medication : When irritant general anaesthetics (ether) are used, prior administration of anticholinergics (atropine, hyoscine, glycopyrrolate) is imperative to check increased salivary and tracheobronchial secretions. However, with increasing use of nonirritating anaesthetics (halothane) the requirement has decreased, though atropine may still be employed because halothane sensitizes the heart to NA mediated ventricular arrhythmias which are specially prone to occur during vagal slowing. Atropinic drugs also prevent laryngospasm, not by an action on laryngeal muscles, which are sketetal muscles, but by reducing respiratory secretions that reflexly predispose to laryngospasm. Vasovagal attack during anaesthesia may also be prevented.

2.       Peptic Ulcer : Atropinic drugs decrease gastric secretion (fasting and neurogenic phase, but little effect on gastric phase) and afford symptomatic relief in peptic ulcer, though effective doses always produce side effects. They have now been superseded by H2 blockers.

3.       Pulmonary embolism : These drugs benefit by reducing reflex secretions.
4.       To check excessive sweating or salivation, e.g. in parkinsonism.

II.      As antispasmodic
1.       Intestinal and renal colic, abdominal cramps: symptomatic relief is afforded if there is no mechanical obstruction. Atropine is less effective in biliary colic and is not able to completely counteract biliary spasm due to opiates (nitrates are more effective).
2.       Nervous and durg induced diarrhoea, functional diarrhoea, but not effective in infective diarrhoea.
3.       Spastic constipation, irritable bowel syndrome.
4.       Pylorospasm, gastric hypermotility, gastritis, nervous dyspepsia.
5.       To relieve urinary frequency and urgency, enuresis in children. Oxybutynin, tolterodine and flavoxate have demonstrated good efficacy, but dry mouth and other anticholinergic effects are dose limiting.
6.       Dysmenorrhoea: These drugs are not very effective.

III.     Bronchial asthma, asthmatic bronchitis, COPD

Relfex vagal activity is an important factor in causing bronchoconstriction and increased secretion in chronic bronchitis and COPD, but to a lesser extent in bronchial asthma. Orally administered atropinic drugs are broanchodilators, but less effective than adrenergic drugs. They dry up secretion in the respiratory tract, may lead to its inspissation and plugging of bronchioles resulting in alveolar collapse and predisposition to infection. The mucociliary clearance is also impaired. Inhaled ipratropium bromide has been found to be specially effective in asthmatic bronchitis and COPD, though less so in bronchial asthma. Given by aerosol, it has been shown not to decrease respiratory secretions or to impair mucociliary clearance, and there are few systemic side effects. Thus, it has a place in the management of COPD. Its time course of action makes it more suitable for regular prophylactic use rather than for control of acute attacks. The additive bronchodilator action with adrenergic drugs is utilized to afford relief in acute exacerbation of asthma/COPD by administering a combination of nebulized ipratropium and B2 agonist through a mask.

IV.     As mydriatic and cycloplegic
(i)      Diagnostic : For testing error of refraction, both mydriasis and cycloplegia are needed. Tropicamide having briefer action has now largely replaced homatropine for this purpose. These drugs do not cause sufficient cycloplegia in children: more potent agents like atropine or hyoscine have to be used. Atropine ointment (1 %) applied 24 hours and 2 hours before is often preferred for children below 5 years. Cyclopentolate is an alternative.

To facilitate fundoscopy only mydriasis is needed; a short acting antimuscarinic may be used, but phenylephrine is preferred, especially in the elderly, for fear of precipitating or aggravating glaucoma.

(ii)      Therapeutic : Atropine, because of its long lasting mydriatic-cycloplegic and local anodyne action on cornea, is very valuable in the treatment of iritis, iridocyclitis, choroiditis, keratitis and corneal ulcer. It gives rest to the intraocular muscles and cuts down their painful spasm. Atropinic drugs alternated with a miotic prevent adhesions between iris and lens or iris and cornea and may even break them if already formed.

V.      As cardiac vagolytic
Atropine is useful in counteracting bradycardia and partial heart block in selected patients where increased vagal tone is responsible, e.g. in some cases of myocardial infarction, digitalis toxicity. However, cardiac arrhythmias or ischaemia many be precipitated in some cases.

VI.     For central action
1.       Parkinsonism : Central anticholinergics are less effective than levodopa; They are used in mild cases, in drug induced extrapyramidal syndromes and as adjuvant to levodopa.

2.       Motion sickness : Hyoscine is the most effective drug for motion sickness. It is particularly valuable in highly susceptible individuals and for vigorous motions. The drug should be given prophylactically (0.2 mg oral), because administration after symptoms have setin is less effective; action lasts 4-6 hours. A transdermal preparation applied behind the pinna 4 hours before journey has been shown to protect for 3 days. Side effects with low oral doses and transdermal medication are few, but sedation and dry mouth may occur. Hyoscine and other anticholinergics are not  effective in other types of vomiting.

3.       Hyoscine has been used to produce sedation and amnesia during labour (twilight sleep) and to control maniacal states. It had earned a reputation as a ‘lie detector’ during world war II: its amnesic and depressant action was believed to put the subject ‘off guard’ in the face of sustained interrogation and sleep deprivation, so that he came out with the truth.

VII.    To antagonize muscarinic effects of drugs and poisons

Atropine is the specific antidote for anti ChE and early mushroom poisoning. It is also given to block muscarinic actions of neostigmine used for myasthenia gravis, decurarization or cobra envenomation.

SIDE EFFECTS AND TOXICITY

Side effects are quite common with the use of atropine and its congeners; are due to facets of its action other than for which it is being used. They cause inconvenience but are rarely serious.

Belladonna poisoning may occur due to drug overdose or consumption of seeds and berries of belladonna/datura plant. Children are highly susceptible. Manifestations are due to exaggerated pharmacological actions.

Dry mouth, difficulty in swallowing and talking. Dry, flushed and hot skin (especially over face and neck), fever, difficulty in micturition, decreased bowel sounds, a scarlet rash may appear. Dilated pupil, photophobia, blurring of near vision, palpitation.

Excitement, psychotic behaviour, ataxia, delirium, dreadful visual hallucinations.
Hypotension, weak and rapid pulse, cardiovascular collapse with respiratory depression. Convulsions and coma occur only in severe poisoning.

Diagnosis : Methacholine 5 mg or neostigmine 1 mg s.c. fails to induce typical muscarinic effects.

Treatment : If position has been ingested, gastric lavage should be done with tannic acid (KnnO4 is ineffective in oxidizing atropine). The patient should be kept in a dark quiet room. Cold sponging or ice bags are applied for reducing body temperature. Physostigmine 1-3 mg s.c. or i.v. antagonieses both central and peripheral effects, but has been found to produce hypotension and arrhythmias in some cases. As such, its utility is controversial. Neostigmine does not antagonize the central effects.

Other general measures (maintenance of blood volume, assisted respiration, diazepam to control convulsions) should be taken as appropriate.

Contraindications : Atropinic durgs are absolutely contraindicated in individuals with a narrow irrdocorneal angle – may precipitate acute congestive glaucoma. However, marked rise in intraocular tension is rare in patients with wide angle glaucoma.

Caution is advocated in elderly males with prostatic hypertrophy-urinary retention can occur.

Interactions :

• Absorption of most drugs is slowed because atropine delays gastric emptying. This results in slower absorption and greater peripheral degradation of levodopa-less of it reaches the brain. This does not occur when a peripheral decarboxylase inhibitor is combined.

On the other hand, extent of digoxin and tetracycline absorption may be increased due to longer transit time in the g.i.t.

• Antacids interfere with absorption of anticholinergics.
• Antihistaminics, tricyclic antidepressants, phenothiazines, disopyramide, pethidine have anticholinergic property – additive side effects occur with atropinic drugs.
• MAO inhibitors interfere with metabolism of anticholinergic antiparkinsoniam drugs – delirium may occur.

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 NN 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 memberance 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.

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.

NICOINELL-TTS 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 ischemic heart disease are the contraindications.

Varenicilne : This NN subtype nicotinic receptor partial agonist is under clinical development for smoking cessation. Controlled trials have found it to reduce craving as well as nicotine withdraal symptoms in those who stop smoking. Abstinence rates after one year were higher than placebo and comparable to bupropion.

Rimonabant : A selective cannabinoid receptor-1 (CB-1) antagonist which is being tried as antismoking and antiobesity 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/teritiary)
Mecamylamine, Pempidine

          Monosulfonium compound

                   Trimethaphan camforsulfonate
B.      Persistent depolarizing 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 intolerlable side effects. 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.