Chapter 8 Anticholinergic Drugs and

Drugs Acting on Autonomic

Ganglia

ANTICHOLINERGIC DRUGS (c)Vasicoselective: Oxybutynin, Flavoxate,

(Muscarinic receptor antagonists, Tolterodine.
Atropinic, Parasympatholytic) (d)Antiparkinsonian: Trihexyphenidyl (Benzhe-
xol), Procyclidine, Biperiden.
Conventionally, the term ‘anticholinergic drugs’
is restricted to those which block actions of ACh In addition, many other classes of drugs, i.e.
on autonomic effectors and in the CNS exerted tricyclic antidepressants, phenothiazines, anti-
through muscarinic receptors. Though nicotinic histamines and disopyramide possess significant
receptor antagonists also block certain actions of antimuscarinic actions.
ACh, they are generally referred to as ‘ganglion The natural alkaloids are found in plants of
blockers’ and ‘neuromuscular blockers’. the solanaceae family. The levo-isomers are much
Atropine, the prototype drug of this class, is more active than the dextroisomers. Atropine is
highly selective for muscarinic receptors, but some racemic while scopolamine is l-hyoscine.
of its synthetic substitutes do possess significant
nicotinic blocking property in addition. The PHARMACOLOGICAL ACTIONS
selective action of atropine can easily be demon- (Atropine as prototype)
strated on a piece of guinea pig ileum where
ACh induced contractions are blocked without The actions of atropine can be largely predicted
affecting those evoked by histamine, 5-HT or other from knowledge of parasympathetic responses.
spasmogens. The selectivity is, however, lost at Prominent effects are seen in organs which
very high doses. All anticholinergics are compe- normally receive strong parasympathetic tone.
titive antagonists. Atropine blocks all subtypes of muscarinic
receptors.
CLASSIFICATION 1. CNS Atropine has an overall CNS stimu-
1. Natural alkaloids Atropine, Hyoscine lant action. However, these effects are not appre-
(Scopolamine). ciable at low doses which produce only peripheral
2. Semisynthetic derivatives Homatropine, effects because of restricted entry into the brain.
Atropine methonitrate, Hyoscine butyl Hyoscine produces central effects (depressant)
bromide, Ipratropium bromide, Tiotropium even at low doses.
bromide. • Atropine stimulates many medullary centres
3. Synthetic compounds —vagal, respiratory, vasomotor.
(a) Mydriatics: Cyclopentolate, Tropicamide. • It depresses vestibular excitation and has
(b) Antisecretory-antispasmodics: antimotion sickness property. The site of this
(i) Quaternary compounds: Propantheline, action is not clear—probably there is a
Oxyphenonium, Clidinium, Pipenzolate cholinergic link in the vestibular pathway, or
methyl bromide, Isopropamide, Glycopyr- it may be exerted at the cortical level.
rolate. • By blocking the relative cholinergic over-
(ii) Tertiary amines: Dicyclomine, Valetha- activity in basal ganglia, it suppresses tremor
mate, Pirenzepine. and rigidity of parkinsonism.
114 DRUGS ACTING ON ANS

• High doses cause cortical excitation, restless-

ness, 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.

2. CVS
Heart The most prominent effect of atropine
is tachycardia. It is due to blockade of M2
receptors on the SA node through which vagal
SECTION 2

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, thereby augmenting ACh
release. This is suggested by the finding that
selective M1 antagonist pirenzepine is equipotent
to atropine in causing bradycardia. Moreover,
atropine substitutes which do not cross blood-
brain barrier also produce initial bradycardia.
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 the 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 Fig. 8.1: Autonomic control of pupil (A); and site of
BP. action of mydriatics (B) and miotics (C)
Atropine blocks vasodepressor action of choli-
nergic agonists. However, conventional systemic doses of atropine
produce minor ocular effects.
3. Eye The autonomic control of iris muscles
and the action of mydriatics as well as miotics 4. Smooth muscles All visceral smooth
is illustrated in Fig. 8.1. Topical instillation of muscles that receive parasympathetic motor
atropine causes mydriasis, abolition of light reflex innervation are relaxed by atropine (M3 blockade).
and cycloplegia lasting 7–10 days. This results Tone and amplitude of contractions of
in photophobia and blurring of near vision. stomach and intestine are reduced; the passage
The ciliary muscles recover somewhat earlier than of chyme is slowed—constipation may occur,
sphincter pupillae. The intraocular tension tends spasm may be relieved. However, peristalsis is
to rise, especially in narrow angle glaucoma. only incompletely suppressed because it is
 ANTICHOLINERGIC DRUGS AND DRUGS ACTING ON AUTONOMIC GANGLIA 115

primarily regulated by local reflexes in the enteric 7. Local anaesthetic Atropine has a mild
plexus, and other neurotransmitters (5-HT, anaesthetic action on the cornea.
enkephalin, etc.) are involved. Enhanced motility Atropine has been found to enhance ACh (also NA) release
due to injected cholinergic drugs is more from certain postganglionic parasympathetic and sympathetic
completely antagonised than that due to vagal nerve endings, and thus produce paradoxical responses. This
stimulation, because intramural neurones which is due to blockade of release inhibitory muscarinic autorecep-
tors present on these nerve terminals.
are activated by vagus utilize a number of
noncholinergic transmitters as well. The sensitivity of different organs and tissues to
Atropine causes bronchodilatation and atropine varies and can be graded as—
reduces airway resistance, especially in COPD and Saliva, sweat, bronchial secretion > eye, bron-

CHAPTER 8
asthma patients. Inflammatory mediators like chial muscle, heart > smooth muscle of
histamine, PGs, leucotrienes and kinins which intestine, bladder > gastric glands and smooth
participate in asthma increase vagal activity in muscle.
addition to their direct stimulant action on bronchial The above differences probably reflect the relative dependence
muscle and glands. Atropine attenuates their action of the function on cholinergic tone vis a vis other influences,
and variation in synaptic gaps in different organs. The pattern
by antagonizing the reflex vagal component. of relative activity is nearly the same for other atropine
Atropine has relaxant action on ureter and substitutes except pirenzepine which inhibits gastric secretion
urinary bladder; urinary retention can occur in at doses that have little effect on other secretions, heart and
older males with prostatic hypertrophy. However, eye. This is probably because atropine equally blocks M1,
M2 and M3 receptors whereas pirenzepine is a selective M1
this relaxant action can be beneficial for increasing antagonist.
bladder capacity and controlling detrusor Atropine more effectively blocks responses
hyperreflexia in neurogenic bladder/enuresis. to exogenously administered cholinergic drugs
Relaxation of biliary tract is less marked and effect than those to parasympathetic nerve activity. This
on uterus is minimal. may be due to release of ACh very close to the
5. Glands Atropine markedly decreases sweat, receptors by nerves and involvement of cotrans-
salivary, tracheobronchial and lacrimal secretion mitters (see p. 97).
(M3 blockade). Skin and eyes become dry, talking Hyoscine This natural anticholinergic alkaloid
and swallowing may be difficult. differs from atropine in many respects, these are
Atropine decreases secretion of acid, pepsin tabulated in Table 8.1.
and mucus in the stomach, but the primary action
is on volume of secretion so that pH of gastric PHARMACOKINETICS
contents may not be elevated unless diluted by
Atropine and hyoscine are rapidly absorbed from
food. Since bicarbonate secretion is also reduced,
g.i.t. Applied to eyes they freely penetrate cornea.
rise in pH of fasting gastric juice is only modest.
Passage across blood-brain barrier is somewhat
Relatively higher doses are needed and atropine
restricted. About 50% of atropine is metabolized
is less efficacious than H2 blockers in reducing
in liver and rest is excreted unchanged in urine.
acid secretion. Intestinal and pancreatic secretions
It has a t½ of 3–4 hours. Hyoscine is more
are not significantly reduced. Bile production is
completely metabolized and has better blood-brain
not under cholinergic control, so not affected.
barrier penetration.
6. Body temperature Rise in body tempera- Atropine sulfate: 0.6–2 mg i.m., i.v. (children 10 µg/kg), 1–2%
ture occurs at higher doses. It is due to both topically in eye. ATROPINE SULPHATE: 0.6 mg/ml inj., 1%
inhibition of sweating as well as stimulation of eye drop/ointment; ATROSULPH 1% eye drop, 5% eye oint.
Hyoscine hydrobromide: 0.3–0.5 mg oral, i.m.; also as
temperature regulating centre in the hypothala-
transdermal patch.
mus. Children are highly susceptible to atropine Combinations of atropine with analgesics and antipyretics are
fever. banned in India.
116 DRUGS ACTING ON ANS

TABLE 8.1 Comparative features of atropine and hyoscine

Atropine Hyoscine
1. Chief source Atropa belladonna, Datura stramonium Hyoscyamys niger
2. Alkaloidal ester Tropine (base) Scopine (base)
of tropic acid with
3. CNS effect Excitatory Depressant (amnesia, fatigue,
low dose Excitation (mild) drowsiness, N-REM sleep)
high dose Excitation (strong) Excitation
4. Anticholinergic property More potent on heart, bronchial More potent on eye and
SECTION 2

muscle and intestines secretory glands

5. Duration of action Longer Shorter
6. Anti-motion sickness ++ +++

ATROPINE SUBSTITUTES 2. Atropine methonitrate 2.5–10 mg oral,

i.m.; for abdominal colics and hyperacidity.
Many semisynthetic derivatives of belladonna
MYDRINDON 1 mg (adult), 0.1 mg (child) tab; in
alkaloids and a large number of synthetic com- SPASMOLYSIN 0.32 mg tab;
pounds have been introduced with the aim of
producing more selective action on certain 3. Ipratropium bromide 40–80 µg by
functions. Most of these differ only marginally inhalation; it acts selectively on bronchial muscle
from the natural alkaloids, but some recent ones without altering volume or consistency of
appear promising. respiratory secretions. Another desirable feature is
that in contrast to atropine, it does not depress muco-
Quaternary compounds ciliary clearance by bronchial epithelium. It has
a gradual onset and late peak (at 40–60 min) of
These have certain common features— bronchodilator effect in comparison to inhaled
• Incomplete oral absorption. sympathomimetics. Thus, it is more suitable for
• Poor penetration in brain and eye; central and regular prophylactic use rather than for rapid
ocular effects are not seen after parenteral/ symptomatic relief during an attack. Action lasts
oral administration. 4–6 hours. It acts on receptors located mainly in
• Elimination is generally slower; majority are the larger central airways (contrast sympathomi-
longer acting than atropine. metics whose primary site of action is peripheral
• Have higher nicotinic blocking property. Some bronchioles, see Fig. 16.2). The parasympathetic
ganglionic blockade may occur at clinical doses tone is the major reversible factor in chronic
→ postural hypotension, impotence are obstructive pulmonary disease (COPD). Therefore,
additional side effects. ipratropium is more effective in COPD than in
• At high doses some degree of neuromuscular bronchial asthma. Transient local side effects like
blockade may also occur. dryness of mouth, scratching sensation in trachea,
Drugs in this category are— cough, bad taste and nervousness are reported in
20–30% patients, but systemic effects are rare
1. Hyoscine butyl bromide 20–40 mg oral, because of poor absorption from the lungs and g.i.t.
i.m., s.c., i.v.; less potent and longer acting than (major fraction of any inhaled drug is swallowed).
atropine; used for esophageal and gastrointestinal
IPRAVENT 20 µg and 40 µg/puff metered dose inhaler, 2 puffs
spastic conditions. 3–4 times daily; 250 µg/ml respirator soln., 0.4–2 ml nebulized
BUSCOPAN 10 mg tab., 20 mg/ml amp. in conjunction with a β2 agonist 2–4 times daily.
 ANTICHOLINERGIC DRUGS AND DRUGS ACTING ON AUTONOMIC GANGLIA 117

Also used to control rhinorrhoea in perennial rhinitis and lacking central effects. Almost exclusively used
common cold; IPRANASE-AQ 0.084% nasal spray (42 µg per for preanaesthetic medication and during
actuation), 1–2 sprays in each nostril 3–4 times a day.
anaesthesia. GLYCO-P 0.2 mg/ml amp., 1 mg in 5 ml
4. Tiotropium bromide A newer congener of vial, PYROLATE 0.2 mg/ml, 1 ml amp, 10 ml vial.
ipratropium bromide which binds very tightly to
bronchial M1/M3 muscarinic receptors producing Tertiary amines
long lasting bronchodilatation. Binding to M2 1. Dicyclomine 20 mg oral/i.m., children
receptors is less tight confering relative M1/M3 5–10 mg; has direct smooth muscle relaxant
selectivity (less likely to enhance ACh release from action in addition to weak anticholinergic. It exerts
vagal nerve endings in lungs due to M2 receptor antispasmodic action at doses which produce few

CHAPTER 8
blockade). Like ipratropium, it is not absorbed from atropinic side effects. However, infants have
respiratory and g.i. mucosa and has exhibited high exhibited atropinic toxicity symptoms and it is
bronchial selectivity of action. not recommended below 6 months of age. It also
TIOVA 18 μg rotacaps; 1 rotacap by inhalation OD. has antiemetic property: has been used in morn-
5. Propantheline 15–30 mg oral; it was a ing sickness and motion sickness. Dysmenorrhoea
popular anticholinergic drug used for peptic ulcer and irritable bowel are other indications.
and gastritis. It has some ganglion blocking activity CYCLOSPAS-D, 20 mg with dimethicone 40 mg tab;
CYCLOPAM INJ. 10 mg/ml in 2 ml, 10 ml, 30 ml amp/vial,
as well and is claimed to reduce gastric secretion also 20 mg tab with paracetamol 500 mg; in COLIMEX,
at doses which produce only mild side effects. COLIRID 20 mg with paracetamol 500 mg tab, 10 mg/ml drops
Gastric emptying is delayed and action lasts for with dimethicone.
6–8 hours. Use has declined due to availability 2. Valethamate: The primary indication of this
of H2 blockers and proton pump inhibitors. anticholinergic-smooth muscle relaxant is to hasten
PROBANTHINE 15 mg tab.
dilatation of cervix when the same is delayed
6. Oxyphenonium 5–10 mg (children 3–5 mg) during labour, and as visceral antispasmodic,
oral; similar to propantheline, recommended for urinary, biliary, intestinal colic.
peptic ulcer and gastrointestinal hypermotility. Dose: 8 mg i.m., 10 mg oral repeated as required.
ANTRENYL 5, 10 mg tab. VALAMATE 8 mg in 1 ml inj, EPIDOSIN 8 mg inj., 10
mg tab.
7. Clidinium 2.5–5 mg oral; This antisecretory-
3. Pirenzepine 100–150 mg/day oral; it selectively blocks
antispasmodic has been used in combination with
M1 muscarinic receptors (see p. 101) and inhibits gastric
benzodiazepines for nervous dyspepsia, gastritis, secretion without producing typical atropinic side effects
irritable bowel syndrome, colic, peptic ulcer, etc. (these are due to blockade of M2 and M3 receptors). The
In SPASRIL, ARWIN 2.5 mg tab with chlordiazepoxide 5 mg. more likely site of action of pirenzepine in stomach is intramu-
NORMAXIN, CIBIS 2.5 mg with dicyclomine 10 mg and ral plexuses and ganglionic cells rather than the parietal cells
chlordiazepoxide 5 mg. themselves. It is nearly equally effective as cimetidine in
relieving peptic ulcer pain and promoting ulcer healing, but
8. Pipenzolate methyl bromide 5–10 mg has been overshadowed by H2 blockers and proton pump
(children 2–3 mg) oral; It has been promoted inhibitors.
especially for flatulent dyspepsia, infantile colics
and abdominal cramps. Vasicoselective drugs
In PIPEN 4 mg + dimethylpolysiloxane 40 mg/ml drops.
1. Oxybutynin This newer antimuscarinic has
9. Isopropamide 5 mg oral; indicated in high affinity for receptors in urinary bladder and
hyperacidity, nervous dyspepsia, irritable bowel salivary glands alongwith additional smooth
and other gastrointestinal problems, specially muscle relaxant and local anaesthetic properties.
when associated with emotional/mental disorders. It is relatively selective for M1/M3 subtypes
In STELABID, GASTABID 5 mg tab. with trifluoperazine 1 mg. with less action on the M2 subtype. Because of
10. Glycopyrrolate 0.1–0.3 mg i.m. (5–10 vasicoselective action, it is used for detrusor
μg/kg), potent and rapidly acting antimuscarinic instability resulting in urinary frequency and urge
118 DRUGS ACTING ON ANS

incontinence. Beneficial effects have been Mydriatics

demonstrated in post-prostatectomy vasical spasm,
Atropine is a potent mydriatic but its slow and
neurogenic bladder, spina bifida and nocturnal
long-lasting action is undesirable for refrac-
enuresis. Anticholinergic side effects are common tion testing. Though the pupil dilates in 30–40
after oral dosing, but intravasical instillation min, cycloplegia takes 1–3 hours, and the subject
increases bladder capacity with few side effects. is visually handicapped for about a week. The
Oxybutynin is metabolized by CYP3A4; its dose substitutes attempt to overcome these difficulties.
should be reduced in patients being treated with
inhibitors of this isoenzyme. 1. Homatropine It is 10 times less potent than
Dose: 5 mg BD/TDS oral; children above 5 yr 2.5 mg BD. atropine. Instilled in the eye, it acts in 45–60 min,
SECTION 2

OXYBUTIN, CYSTRAN, OXYSPAS 2.5 mg and 5 mg tabs. mydriasis lasts 1–3 days while accommodation
2. Tolterodine: This relatively M3 selective recovers in 1–2 days. It often produces unsatisfac-
muscarinic antagonist has preferential action on tory cycloplegia in children who have high ciliary
urinary bladder; less likely to cause dryness of muscle tone.
HOMATROPINE EYE, HOMIDE 1%, 2% eye drops.
mouth and other anticholinergic side effects. It
is indicated in overactive bladder with urinary 2. Cyclopentolate It is potent and rapidly
frequency and urgency. Since it is metabolized acting; mydriasis and cycloplegia occur in 30–
by CYP3A4, dose should be halved in patients 60 min and last about a day. It is preferred for
receiving CYP3A4 inhibitors (erythromycin, cycloplegic refraction, but children may show
ketoconazole, etc.) transient behavioural abnormalities due to
Dose: 1–2 mg BD or 2–4 mg OD of sustained release tab. oral. absorption of the drug after passage into the
ROLITEN, TOLTER 1, 2 mg tabs, TORQ 2, 4 mg SR tab. nasolacrimal duct. It is also used in iritis and
3. Flavoxate has properties similar to oxybuty- uveitis.
CYCLOMID EYE 0.5%, 1%; CYCLOGYL, CYCLOPENT
nin and is indicated in urinary frequency, urgency 1% eye drops.
and dysuria associated with lower urinary tract
infection. 3. Tropicamide It has the quickest (20–40
URISPAS, FLAVATE, FLAVOSPAS 200 mg tab, 1 tab min) and briefest (3–6 hours) action, but is a
TDS. relatively unreliable cycloplegic. However, it is
Darifenacin and Solifenacin are other relatively M 3 satisfactory for refraction testing in adults and
subtype selective antimuscarinics useful in bladder
disorders. as a short acting mydriatic for fundoscopy. The
mydriatic action can be augmented by combining
Drotaverine It is a novel non-anticholinergic with phenylephrine.
smooth muscle antispasmodic which acts by OPTIMIDE, TROPICAMET, TROMIDE 0.5%, 1.0% eye
inhibiting phosphodiesterase-4 (PDE-4) selective drops. TROPAC-P, TROPICAMET PLUS 0.8% with
for smooth muscle. Elevation of intracellular phenylephrine 5% eye drops.
cAMP/cGMP attends smooth muscle relaxation.
Changes in membrane ionic fluxes and membrane Antiparkinsonian drugs (see Ch. 31)
potential have also been shown. It has been used USES
orally as well as parenterally in intestinal, biliary
and renal colics, irritable bowel syndrome, uterine I. As antisecretory
spasms, etc. without anticholinergic side effects. 1. Preanaesthetic medication When irritant
Adverse effects reported are headache, dizziness, general anaesthetics (ether) were used, prior
constipation and flushing. Fall in BP can occur administration of anticholinergics (atropine,
on i.v. injection. hyoscine, glycopyrrolate) was imperative to check
Dose: 40–80 mg TDS; DROTIN, DOTARIN, DOVERIN 40, increased salivary and tracheobronchial secretions.
80 mg tabs, 40 mg/2 ml inj. However, with current use of nonirritating
 ANTICHOLINERGIC DRUGS AND DRUGS ACTING ON AUTONOMIC GANGLIA 119

anaesthetics (halothane, etc.) the requirement has 6. Dysmenorrhoea: These drugs are not very
decreased, though atropine may still be employed effective; NSAIDs are superior.
because halothane sensitizes the heart to NA
mediated ventricular arrhythmias which are III. Bronchial asthma, asthmatic
specially prone to occur during vagal slow- bronchitis, COPD
ing. Atropinic drugs also prevent laryngospasm, Reflex vagal activity is an important factor in
not by an action on laryngeal muscles, which are causing bronchoconstriction and increased secretion
skeletal muscles, but by reducing respiratory in chronic bronchitis and COPD, but to a lesser
secretions that reflexly predispose to laryngo- extent in bronchial asthma. Orally administered
spasm. Vasovagal attack during anaesthesia can

CHAPTER 8
atropinic drugs are bronchodilators, but less
also be prevented. effective than adrenergic drugs; not clinically used.
2. Peptic ulcer Atropinic drugs decrease gastric secretion They dry up secretion in the respiratory tract,
(fasting and neurogenic phase, but little effect on gastric may lead to its inspissation and plugging of
phase) and afford symptomatic relief in peptic ulcer,
bronchioles resulting in alveolar collapse and
though effective doses always produce side effects. They have
now been superseded by H2 blockers/proton pump inhibitors. predisposition to infection. The mucociliary
clearance is also impaired. Inhaled ipratropium
3. Pulmonary embolism These drugs benefit bromide has been found to be specially effective
by reducing pulmonary secretions evoked reflexly in asthmatic bronchitis and COPD, though less
by embolism. so in bronchial asthma. Given by aerosol, it neither
4. To check excessive sweating or salivation, e.g. decreases respiratory secretions nor impairs
in parkinsonism. 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
II. As antispasmodic
suitable for regular prophylactic use rather than
1. Intestinal and renal colic, abdominal cramps: for control of acute attacks. The additive broncho-
symptomatic relief is afforded if there is no dilator action with adrenergic drugs is utilized
mechanical obstruction. However, parenteral to afford relief in acute exacerbation of asthma/
opioids and NSAIDs provide greater pain relief COPD by administering a combination of nebulized
in renal colic than atropine. Atropine is less ipratropium and β2 agonist through a mask.
effective in biliary colic and is not able to Tiotropium bromide is an equally effective and
completely counteract biliary spasm due to longer acting alternative to ipratropium bromide.
opiates (nitrates are more effective).
2. Nervous, functional and drug induced diarrhoea IV. As mydriatic and cycloplegic
may be controlled to some extent, but (i) Diagnostic For testing error of refraction,
anticholinergics are not useful in infective both mydriasis and cycloplegia are needed.
diarrhoea. Tropicamide having briefer action has now largely
3. Spastic constipation, irritable bowel syndrome: replaced homatropine for this purpose. These
modest symptomatic relief may be afforded. drugs do not cause sufficient cycloplegia in
4. Pylorospasm, gastric hypermotility, gastritis, children: more potent agents like atropine or
nervous dyspepsia may be partially suppressed. hyoscine have to be used. Atropine ointment (1%)
5. To relieve urinary frequency and urgency, enu- applied 24 hours and 2 hours before is often
resis in children. Oxybutynin, tolterodine and preferred for children below 5 years. Cyclopen-
flavoxate have demonstrated good efficacy, but tolate drops are an alternative.
dry mouth and other anticholinergic effects are To facilitate fundoscopy only mydriasis is
dose limiting. needed; a short acting antimuscarinic may be used,
120 DRUGS ACTING ON ANS

but phenylephrine is preferred, especially in the 3. Hyoscine was used to produce sedation and amnesia
elderly, for fear of precipitating or aggravating during labour (twilight sleep) and to control maniacal states.
It had earned a reputation as a ‘lie detector’ during world
glaucoma. A combination of phenylephrine + war II: its amnesic and depressant action was believed to
tropicamide drops is frequently used. put the subject ‘off guard’ in the face of sustained interrogation
and sleep deprivation, so that he came out with the truth.
(ii) Therapeutic Because of its long lasting
mydriatic-cycloplegic and local anodyne (pain VII. To antagonise muscarinic effects of
relieving) action on cornea, atropine is very drugs and poisons
valuable in the treatment of iritis, iridocyclitis,
Atropine is the specific antidote for anti ChE and
choroiditis, keratitis and corneal ulcer. It gives
early mushroom poisoning (see Ch. 7). Atropine
rest to the intraocular muscles and cuts down their
SECTION 2

or glycopyrrolate is also given to block muscarinic

painful spasm. Atropinic drugs alternated with
actions of neostigmine used for myasthenia gravis,
a miotic prevent adhesions between iris and lens
decurarization or cobra envenomation.
or iris and cornea and may even break them if
already formed.
SIDE EFFECTS AND TOXICITY
V. As cardiac vagolytic
Side effects are quite common with the use of
Atropine is useful in counteracting sinus atropine and its congeners; are due to facets of
bradycardia and partial heart block in selected its action other than for which it is being used.
patients where increased vagal tone is responsible, They cause inconvenience but are rarely serious.
e.g. in some cases of myocardial infarction and Belladonna poisoning may occur due to drug
in digitalis toxicity. However, cardiac arrhythmias overdose or consumption of seeds and berries of
or ischaemia may be precipitated in some cases. belladonna/datura plant. Children are highly
susceptible. Manifestations are due to exaggerated
VI. For central action pharmacological actions.
Dry mouth, difficulty in swallowing and talking.
1. Parkinsonism (see Ch. 31) Central Dry, flushed and hot skin (especially over face
anticholinergics are less effective than levodopa; and neck), fever, difficulty in micturition, dec-
They are used in mild cases, in drug induced reased bowel sounds. A scarlet rash may appear.
extrapyramidal syndromes and as adjuvant to Dilated pupil, photophobia, blurring of near vision,
levodopa. palpitation.
2. Motion sickness Hyoscine is the most Excitement, psychotic behaviour, ataxia, delirium,
dreadful visual hallucinations.
effective drug for motion sickness. It is particularly
Hypotension, weak and rapid pulse, cardiovas-
valuable in highly susceptible individuals and for
cular collapse with respiratory depression. Con-
vigorous motions. The drug should be given
vulsions and coma occur only in severe poisoning.
prophylactically (0.2 mg oral), because admi-
nistration after symptoms have setin is less Diagnosis Methacholine 5 mg or neostigmine
effective; action lasts 4–6 hours. A transdermal 1 mg s.c. fails to induce typical muscarinic
preparation applied behind the pinna 4 hours effects.
before journey has been shown to protect for 3 Treatment If poison has been ingested, gastric
days. Side effects with low oral doses and lavage should be done with tannic acid (KMnO4
transdermal medication are few, but dry mouth is ineffective in oxidizing atropine). The patient
and sedation can occur: driving is risky. should be kept in a dark quiet room. Cold spon-
Dicyclomine is another anticholinergic used for ging or ice bags are applied to reduce body
motion sickness. These drugs are not effective temperature. Physostigmine 1–3 mg s.c. or i.v.
in other types of vomiting. antagonises both central and peripheral effects,
 ANTICHOLINERGIC DRUGS AND DRUGS ACTING ON AUTONOMIC GANGLIA 121

but has been found to produce hypotension and In addition to the dominant nicotinic NN
arrhythmias in some cases. As such, its utility receptors, which mediate the primary rapid
is controversial. Neostigmine does not antagonise depolarization of ganglionic cells, there are
the central effects. subsidiary muscarinic M1, M2, adrenergic, dopa-
Other general measures (maintenance of blood minergic, amino acid and peptidergic receptors
volume, assisted respiration, diazepam to control which bring about secondary, slowly developing
convulsions) should be taken as appropriate. but longer lasting changes in membrane potential,
Contraindications Atropinic drugs are absolu- both positive and negative, that modulate the
tely contraindicated in individuals with a narrow primary response. Separate catecholamine (NA,
DA) and amino acid transmitter containing cells

CHAPTER 8
iridocorneal angle—may precipitate acute con-
gestive glaucoma. However, marked rise in are present in ganglia, but peptides are released
intraocular tension is rare in patients with wide from the preganglionic cholinergic terminals
angle glaucoma. themselves. Thus, autonomic ganglion is not
Caution is advocated in elderly males with merely a one transmitter—one cell junction, but
prostatic hypertrophy—urinary retention can occur. a complex system capable of local adjustments
in the level of excitability.
Interactions
Drugs can either stimulate or block the ganglia.
1. Absorption of most drugs is slowed because
atropine delays gastric emptying. This results GANGLIONIC STIMULANTS
in slower absorption and greater peripheral
degradation of levodopa—less of it reaches Selective nicotinic Nonselective/
the brain. This does not occur when a peripheral agonists muscarinic agonists
decarboxylase inhibitor is combined. Nicotine (small dose) Acetylcholine
On the other hand, extent of digoxin and Lobeline Carbachol
tetracycline absorption may be increased due Dimethyl phenyl Pilocarpine
to longer transit time in the g.i.t. piperazinium (DMPP) Anticholinesterases
2. Antacids interfere with absorption of anti- Tetramethyl ammonium MCN 343-A
cholinergics. (TMA)
3. Antihistaminics, tricyclic antidepressants, Varenicline
phenothiazines, disopyramide, pethidine have
anticholinergic property—additive side effects
occur with atropinic drugs. Nicotine
4. MAO inhibitors interfere with metabolism of It is the principal alkaloid in tobacco (Nicotiana
anticholinergic antiparkinsonian drugs — tabacum); acts as an agonist on both NN and NM
delirium may occur. subtypes of nicotinic cholinergic receptors (NRs).
Sympathetic as well as parasympathetic ganglia
DRUGS ACTING ON AUTONOMIC are stimulated, but larger doses cause persistent
GANGLIA depolarization and ganglionic blockade. Nicotine
Acetylcholine is the primary excitatory neuro- is important in the context of smoking and tobacco
transmitter in both sympathetic and parasym- chewing; its only clinical indication is short-term
pathetic ganglia. Drugs which inhibit synthesis nicotine replacement in tobacco abstinent subjects.
(hemicholinium) or release (botulinum toxin, There is no therapeutic application of ganglionic
procaine) of ACh can interfere with ganglionic stimulants, because no useful purpose can be
transmission, but drugs which act on cholinergic served by stimulating both sympathetic and
receptors in the ganglia are more selective. parasympathetic ganglia concurrently.
122 DRUGS ACTING ON ANS

Treatment of smoking cessation/quiting Side effects of nicotine replacement therapy are

tobacco chewing headache, dyspepsia, abdominal cramps, loose
Majority of smokers (and tobacco chewers) wish motions, insomnia, flu-like symptoms and local
to quit smoking/chewing, but fail to do so because irritation. Vasospastic angina may be precipitated.
of nicotine dependence. The most important Cardiac arrhythmias and ischaemic heart disease
measure to help smokers quit is counselling and are the contraindications.
motivation. This may be supplemented by phar- Varenicline This α4β2 subtype NR selective
macotherapy. The goals of such pharmacotherapy partial agonist has been marketed as oral tablets
are: in many countries (UK, USA, Europe, etc) to
• To reduce the craving for the satisfying
SECTION 2

help smoking cessation. Recent evidence has

(reward) effects of nicotine. shown that the reward (reinforcing) action of
• To suppress the physical withdrawal symptoms nicotine is exerted through the α4β2 subtype of
of nicotine. neuronal NRs which are mainly localized in
The drugs currently utilized for the above goals nucleus accumbens and other mesolimbic areas.
are: Activation of these NRs by nicotine induces DA
• Nicotine replacement release which produces feelings of satisfaction/
• Partial agonists of α4β2 NRs (Varenicline) reward and has reinforcing effect. Since
• Antidepressants (Bupropion) varenicline is a partial agonist at these receptors,
it provides some level of nicotine substitution,
Nicotine transdermal This patch formulation but blocks the reward effect of smoking. Clinically
of nicotine is applied once daily on the hip/
it has been found to reduce craving as well as
abdomen/chest/upper arm as an aid to smoking
nicotine withdrawal symptoms in those who stop
cessation. It ameliorates the symptoms of nicotine
smoking. Abstinence rates at one year of cessation
withdrawal, but only partially suppresses the
are comparable to those of nicotine replacement
craving, because the intermittent peak nicotine
and of bupropion. However, varenicline is not
blood levels that occur during smoking are not
entirely safe. Side effects noted are mood changes,
reproduced by the patch.
irrational behaviour, appetite and taste distur-
NICOTINELL-TTS 10, 20, 30 cm2 patches releasing 7, 14, bances, sleep disorder and agitation. Warning has
21 mg nicotine per 24 hr respectively. in those smoking been issued that it may promote suicidal thoughts.
> 20 cigarettes every day-start with 30 cm2 patch, shift to
smaller patches every 5–8 days, treat for 3–4 weeks (max. Dose: Initially 0.5 mg OD, gradually increase upto 1 mg
12 weeks). BD according to need, for not more than 12 weeks; then
taper off.
Nicotine chewing gum Developed as an
alternative to nicotine transdermal, this Bupropion This atypical antidepressant inhibits
formulation is found more satisfying by some reuptake of DA and NA, and has been marketed
dependent subjects. The number of gum pieces as a sustained release tablet specifically for
chewed daily can be adjusted according to the smoking cessation. Clinical efficacy has been rated
need felt. equivalent to nicotine replacement, and it has
NULIFE 1, 2, 4 mg chewing gum; for those smoking >20 produced fewer side effects (see Ch. 33).
cigarettes/day—start with 4 mg gum chewed and retained
in mouth for 30 min when urge to smoke is felt. After a
few days change over to 2 mg gum and then to 1 mg gum.
GANGLION BLOCKING AGENTS
Not more than 15 pieces to be used in a day. Treatment
A. Competitive blockers
can be started at lower doses for less heavy smokers.
A nasal spray delivering 0.5 mg per activation, and an inhaler Quaternary ammonium compounds
with nicotine cartridge are also available in some countries. Hexamethonium, Pentolinium
 ANTICHOLINERGIC DRUGS AND DRUGS ACTING ON AUTONOMIC GANGLIA 123

TABLE 8.2 Relative autonomic tone and effects of ganglionic blockade on organ function

Organ Dominant tone Effect of ganglionic blockade (Side effect)

1. Heart Para-symp. Tachycardia (palpitation)
2. Blood vessels Symp. Vasodilatation, abolition of reflexes (postural and
exercise hypotension, syncope)
3. Iris Para-symp. Mydriasis (photophobia)
4. Ciliary muscle Para-symp. Cycloplegia (blurring of near vision)
5. Intestines Para-symp. Decreased motility (distension, constipation)

CHAPTER 8
6. Bladder Para-symp. Decreased tone (difficulty in micturition)
7. Male sexual function Para-symp. Inhibition of erection ⎫
(impotence)
Symp. Inhibition of ejaculation ⎬
⎭
8. Salivary glands Para-symp. Inhibition of salivation (dryness of mouth, difficulty
in swallowing and talking)
9. Sweat glands Symp. (cholinergic) Inhibition of sweating (anhydrosis)

Amines (secondary/tertiary) understanding the relative roles of sympathetic

Mecamylamine, Pempidine and parasympathetic divisions in regulating the
various organ functions.
Monosulfonium compound
Trimethaphan camforsulfonate Trimethaphan It is an ultrashort acting ganglion blocker;
has been occasionally infused i.v. to produce controlled
B. Persistent depolarising blockers hypotension and in hypertensive emergency due to aortic
Nicotine (large dose) dissection.
Anticholinesterases (large dose) Mecamylamine Either alone or in combination with nico-
tine patch, it has been tried for smoking cessation. It appears
The competitive ganglion blockers were used in
to block the reward effect of nicotine and improve abstinence
the 1950s for hypertension and peptic ulcer, rate compared to placebo. Constipation occurred in many
but have been totally replaced now because they subjects, and it is not an approved drug.
produce a number of intolerable side effects (see There is at present no clinical relevance of
Table 8.2). In fact, these side effects help in ganglion blockers.

) PROBLEM DIRECTED STUDY

8.1 An elderly male aged 74 years was brought to the hospital since he had not passed urine
for the past 24 hours and had severe pain in lower abdomen. On examination there was a bulge
in the pubic region due to full urinary bladder. On catheterization, he passed 1.5L urine and
the pain was relieved.
He gave the history of having difficulty in passing urine, poor stream, frequent urge to urinate
and post-void dribbling for the last 3 years. Over the past few days he had been experiencing
episodes of vertigo for which he was prescribed a medicine that he was taking for 2 days. Examination
of the prescription revealed that he was taking tab. Dimenhydrinate 50 mg 3 times daily.
(a) Could there be any relationship between the anti-vertigo medication and the episode of acute
urinary retention?
(see Appendix-1 for solution)