Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia

  Chapter -8 

Anticholinergic Drugs and Drugs Acting on Autonomic Ganglia

ANTICHOLINERGIC DRUGS
(Muscarinic receptor antagonists, Atropine, 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 spas Mogens. The selectivity is, however, lost at very high doses. All anticholinergics are competitive antagonists.

CLASSIFICATION

Natural alkaloids Atropine, Hyoscine (Scopolamine).

Semisynthetic derivatives Homatropine, Atropine meth nitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide.

Synthetic compounds

• Mydriatics: Cyclopentolate, Tropicamide

• Antisecretory-antispasmodics:

• Quaternary compounds: Propantheline, Ox phenonium, Aclidinium, Pipenzolate methyl bromide, Isoprenaline, Glycopyrrolate.

• Tertiary amines: Dicyclomine, Valet hamate, Pirenzepine.

• Vasic selective: 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 more 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 effects are seen in organs which normally receive strong parasympathetic tone. It blocks all subtypes of muscarinic receptors.

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 animation 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 overactivity 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 muscarinic 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 centre, it is now thought 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 centre 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.

• Eye The autonomic control of iris muscles and the action of mydriatics 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.

• 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 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.

• Glands Atropine markedly decreases sweat, 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 mucus 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 juice 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. 

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

• Local anesthetic Atropine has a mild anesthetic action on the cornea.

• Atropine has been found to enhance Ach (also NA) release from certain postganglionic parasympathetic and sympathetic nerve endings, and thus produce paradoxical responses. This is due to blockade of release inhibitory muscarinic auto receptors present on these nerve terminals.

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

PHARMACOKINETICS

Atropine and hyoscine are rapidly absorbed from g.i.t. Applied to eyes they freely penetrate 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 t½ of 3–4 hours. Hyoscine is more completely metabolized and has better blood-brain barrier penetration.

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 occ

Drugs in this category are—

• Hyoscine butyl bromide 20–40 mg oral, a.m., sic, i.e., less potent and longer acting than atropine; used for esophageal and gastrointestinal spastic conditions.

• Atropine meth nitrate 2.5–10 mg oral, a.m.; for abdominal colic's and hyperacidity.

• Ipratropium bromide 40–80 μg 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 conciliary 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 sympathomimetics whose primary site of action is peripheral bronchioles, see Fig. 16.2). The parasympathetic tone is the major reversible factor in chronic obstructive pulmonary disease (COPD). Therefore, 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 drug is swallowed).

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

• 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.

• Ox phenonium 5–10 mg (children 3–5 mg) oral; similar to propantheline, recommended for peptic ulcer and gastrointestinal hypermotility.

• Aclidinium 2.5–5 mg oral; used in combination with benzodiazepines for nervous dyspepsia, gastritis, irritable bowel syndrome, colic, peptic ulcer, etc.

• Pipenzolate methyl bromide 5–10 mg (children 2–3 mg) oral; used for flatulent dyspepsia, infantile Colics and other gastrointestinal spasm.

• Isoprenaline 5 mg oral; indicated in hyperacidity, nervous dyspepsia, irritable bowel and other gastrointestinal problems, especially when associated with emotional/mental disorders.

• Glycopyrrolate 0.1–0.3 mg a.m., 1–2 mg oral; potent and rapidly acting antimuscarinic lacking central effects. Almost exclusively used for preanesthetic medication and during anesthesia.

Tertiary amines

• Dicyclomine 20 mg oral/a.m., children 5–10 mg; has direct smooth muscle relaxant action in addition to weak anticholinergic; exerts antispasmodic action at doses which produce few atropines side effects. However, infants have exhibited atropines 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. Dysmenorrhea and irritable bowel are other indicate

• Valet hamate: The primary indication of this anticholinergic-smooth muscle relaxant is to hasten dilatation of cervix when the same is delayed during lab our, and as visceral antispasmodic.

• Pirenzepine 100–150 mg/day oral; it selectively blocks M1 muscarinic receptors (see p. 95) and inhibits gastric secretion without producing typical atropine 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.

Vasicoselective drugs 

• Oxybutynin This recently introduced antimuscarinic has high affinity for receptors in urinary bladder and salivary glands with additional smooth muscle relaxant and local anesthetic properties. It is relatively selective for M1/M3 subtypes than for M2. Because of Vasic selective 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 intravesical instillation increases bladder capacity with few side effects. Dose: 5 mg BD/TDS oral; children above 5 yr. 2.5 mg BD.

• Tolterodine: 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.)

• Flavoxate has properties similar to oxybutynin and is indicated in urinary frequency, urgency and dysuria associated with lower urinary tract infection.

Mydriatics

Atropine is a potent mydriatic but its slow and long lasting action is undesirable 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.

• 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.

• 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 behavioral abnormalities due to absorption of the drug after passage into the nasolacrimal duct. It is also used in iritis and uveitis.

• Tropicamide, It has the quickest (20–40 min) and briefest (3–6 hours) action but is a relatively unreliable cycloplegic. However, it is satisfactory for refraction testing in adults and as a short acting mydriatic for fundoscopy

Antiparkinsonian drugs

I. As antisecretory

• Preana esthetic medication When irritant general an aesthetics (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 an aesthetics (halothane) the requirement has decreased, though atropine may still be employed because halothane sensitizes the heart to NA mediated ventricular arrhythmias which are especially prone to occur during vagal slowing. Atropine drugs also prevent laryngospasm, not by an action on laryngeal muscles, which are skeletal muscles, but by reducing respiratory secretions that reflex Ly predispose to laryngospasm. Vasovagal attack during an aesthesia may also be prevented.

• Peptic ulcer Atropines 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.

• Pulmonary embolism These drugs benefit by reducing reflex secretions.

• To check excessive sweating or salivation, e.g., in parkinsonism

II. As antispasmodic

• 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).

• Nervous and drug induced diarrhea, functional diarrhea, but not effective in infective diarrhea.

• Spastic constipation, irritable bowel syndrome.

• Piroplasm, gastric hypermotility, gastritis, nervous dyspepsia

• 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.

• Dysmenorrhea: These drugs are not very effective.

III. Bronchial asthma, asthmatic bronchitis, COPD

Reflex 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 bronchodilators, 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 β2 agonist through a mask.

IV. As mydriatic and cycloplegic

• 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.

• 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 may be precipitated in some cases.

VI. For central action

• Parkinsonism (see Ch. 31) Central anticholinergics are less effective than levodopa; They are used in mild cases, in drug induced extrapyramidal syndromes and as adjuvant to levodopa.

• 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.

• 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 antagonise muscarinic effects of drugs and poisons

Atropine is the specific antidote for anti ChE and early mushroom poisoning (see Ch. 7). 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 depressio

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 poison has been ingested, gastric lavage should be done with tannic acid (KMnO4 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. antagonises 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 antagonise the central effects.

• Contraindications Atropines drugs are absolutely contraindicated in individuals with a narrow iridocorneal angle—may precipitate acute congestive glaucoma. However, marked rise in intraocular tension is rare in patients with wide angle glaucoma.

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 anticholinergic

•  Antihistamines, tricyclic antidepressants, phenothiazines, disopyramide, pethidine have anticholinergic property—additive side effects occur with atropine drugs.

• MAO inhibitors interfere with metabolism of anticholinergic antiparkinsonian 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 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.

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 Disse

• 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.