Parasympatholytic drugs/ Anticholinergic drugs

Dr. Kiran Vakade

MD (clinical Pharmacology)
Fellowship in diabetes (Apollo Hospital)
Certificate course in thyroid disorders
Certificate course in evidence based diabetes management (CCEBDM)
Professor and Head
Department of clinical pharmacology
DVVPF’s Medical college
Ahmednagar
Anticholinergic drugs
• Conventially, the term “anticholinergic drugs” is restricted
to those which block actions of ACh exerted through
muscuranic receptors.
• Though nicotinic receptor 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 muscuranic receptors, but some of its synthetic
substitutes do posses significant nicotinic blocking property
in addition.
• All anticholinergics are competitive blockers.
Anticholinergic drugs MOA

•All anticholinergics are competitive

blockers of muscuranic receptors.

•These drugs blocks the muscuranic

receptors  action of ACh on muscuranic
receptor is inhibited.
Pharmacological actions of anticholinergic drugs

Organ Cholinergic action Anticholinergic action

Heart (M2) Decrease impulse generation from SA Node Increase impulse generation from
Decrease conduction through AV node SA Node
Decrease force of contraction of Atria Increase conduction through AV
Decrease force of contraction of ventricles node
Increase force of contraction of
Atria
Increase force of contraction of
ventricles

Blood Vessels: Endogenous ACh: No action Does not have any consistent or
On Smooth muscles M3 Exogenous ACh marked effect on BP
and on endothelium M3 Intact endothelium: Vasodilatation
Damaged Endothelium : Vasoconstriction
Pharmacological actions of anticholinergic drugs
Organ Cholinergic action Anticholinergic action

Smooth muscle Contraction of smooth muscles of Relaxation of smooth muscles of

gastrointestinal tract and relaxation of gastrointestinal tract and
sphincter Evacuation of bowel contraction of sphincter  Spasm
Contraction of detrusor muscle and may relieve ,Constipation may
relaxation of sphincter and bladder  occur
voiding of bladder Relaxation of detrusor muscle and
contraction of sphincter and
Contraction of bronchial smooth muscle bladder  Urinary retention
precipitation of bronchial asthma Relaxation of bronchial smooth
muscle  useful in bronchial
asthma
Pharmacological actions of anticholinergic drugs
Organ Cholinergic action Anticholinergic action

Eyes Contraction of circular muscle: Miosis Relaxation of circular

Contraction of ciliary muscle: spasm of muscle : passive mydriasis.
accommodation. Drainage of aqueous Relaxation of ciliary muscle:
humor is increased (Decrease in IOP) Paralysis of accommodation
Lacrimal gland: increase lacrimation or cycloplegia .
Decreases drainage of
aqueous humor…
Precipitation of glaucoma in
narrow angle glaucoma
patient. (Increase in IOP)
Loss of light reflex
Lacrimal gland: decrease
lacrimation
Pharmacological actions of Anticholinergic drugs
Organ Cholinergic action Anticholinergic action
Glands Increase in secretion from salivary, Decrease Salivary , Lacrimal,
lacrimal, sweat &tracheobronchial Sweat and trachiobronchial
tree secretions = Skin and eyes
become dry , talking and
swallowing may be difficult

Increases secretion of acid, pepsin Atropine decreases secretion of

and mucus in the stomach acid, pepsin and mucus.
However atropine is less
efficacious than H2 antagonists
in reducing acid secretion.

Not significant control on intestinal Intestinal and pancreatic

and pancreatic secretion secretion not significantly
reduced
Bile secretion is not under
cholinergic control Bile secretion is not affected
Anticholinergic drugs
SOFT
CT
bladDER

POP of
Ceiling Is
Good

BP
Pipenzolate
methyl
bromide
PVD
Classification
• Natural: Atropine,
Hyoscine (Scopolamine)
• Semi - synthetic: Homatropine
Atropine methonitrate
Hyoscine butyl bromide
Ipratropium bromide
Tiotropium bromide
• Synthetic:
a)Mydriatics: Cyclopentolate, Tropicamide

b) Antisecretory antispasmodic:
I) Quaternary compounds: Propantheline, Oxyphenonium,
Pipenzolate methyl bromide, Clidinium, Cimetropium
bromide, Isopropamide Glycopyrolate.
II) Tertiary compounds: Pirenzepine, valethamate,
Dicyclomine,
c) Vasicoselective: Oxybutinin, Flavoxate, Tolterodine

d) Antiparkinsonian: Trihexyphenidyl (Benzhexol), Biperidin,

procyclidine.
• Synthetic:

a)Mydriatics: Cyclopentolate, Tropicamide

CT POP of Ceiling is
Good
b) Antisecretory antispasmodic:

I) Quaternary compounds: Propantheline, Oxyphenonium, Pipenzolate methyl

bromide, Clidinium, Isopropamide, Glycopyrolate.
PVD:

II) Tertiary compounds: Pirenzepine, valethamate, Dicyclomine,

c) Vasicoselective: Solifenacin, Oxybutynin, Flavoxate, Tolterodine, Darifenacin

BP: Blood
SOFT bladDER
Pressure
d) Antiparkinsonian: Trihexyphenidyl (Benzhexol), Biperidin, procyclidine.
Source and chemistry
• Atropine is obtained from atropa belladonna and datura
stramonium (jimson weed).

• Hyoscine is obtained from Hyocyamus niger

• Semisynthetic derivatives obtained by modifying natural

compounds.

• Some compounds are quaternary while some are tertiary

amines.
Pharmacokinetics
Absorption:
• Natural alkaloids and most tertiary antimuscuranic
drugs are well absorbed from the gut and conjuctival
membrane.
• When applied in a suitable vehicle, some (e.g.
scopolamine) are even absorbed across the skin
(transdermal route).
• In contrast, only 10-30% of a dose of a quaternary
antimuscarinic drug is absorbed after oral
administration., reflecting the decrease lipid solubility
of the charged molecules.
Pharmacokinetics
Distribution:
• Atropine and other tertiary agents are widely
distributed in the body. Significant level achieved in the
CNS within 30 min to 1 hr.
• Scopalamine has more prominent CNS action than
atropine.
• Quaternary derivatives are poorly taken up by the brain
and therefore are relatively free of CNS effects at
therapeutic doses.
Pharmacokinetics
Metabolism and excretion:

• 50% atropine metabolised in the liver and 50% excreted

unchanged in the urine.

• The drug’s effect on parasympathetic function declines

rapidly in all organs except in the eye. Effect on the iris
and ciliary muscle persist for ≥72 hrs.
Pharmacodynamics
MOA:
Pharmacological actions (Organ system effect):
• CNS:
• Heart:
• BP:
• Eye:
• Smooth muscles:
• Glands:
• Body temperature:
• Local anaesthetics:
Pharmacological actions
(atropine as prototype)
CNS:
• Atropine has an overall stimulant action.
• Hyoscine has CNS depressant action (at low dose).
• At high dose both atropine and hyoscine produces CNS
stimulation.
• Atropine stimulates many medullary centres – vagal, respiratory,
vasomotor.
• Depresses vestibular excitation and has antimotion sickness
property.
• Antiparkinsonian effect by reducing cholinergic overactivity
in basal ganglia
• High doses: cortical excitation, restlessness, hallucination,
delirium, disorientation followed by respiratory depression and
coma
How is hyoscine useful in motion sickness?
Pathophysiology of motion sickness

• During travelling  vestibular apparatus is stimulated

 vestibular apparatus stimulates vomiting centre
through cholinergic link  vomiting occur

• Anticholinergic drugs block cholinergic link and prevent

stimulation of voting centre  prevents vomiting during
travelling.
• Antiparkinsonian effect is produced by
reducing cholinergic overactivity in basal
ganglia.

• Anticholinergic drugs considered as drug of

choice for drug induced parkinsonism.
Pharmacological actions
(atropine as prototype)
Heart:
• M2 Muscuranic receptors present on heart
• Most prominent effect of atropine is tachycardia.
Mechanism ??
• Higher the existing vagal tone  more marked is the
tachycardia (maximum in young adult, less in children and
elderly.)
• It abbreviates refractory period of A-V node and facilitates
A-V conduction , especially if it has been depressed by high
vagal tone. PR interval is shortened.
Pharmacological actions
(atropine as prototype)
Blood vessels:
• Since cholinergic impulses are not involved in the
maintenance of vascular tone, atropine does not have
consistent or marked effect on the 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.
Pharmacological actions
(atropine as prototype)
EYE:
• Topical instillation of atropine causes Mydriasis, Loss of light
reflex, Cycloplegia lasting for 7-10 days results in
photophobia and blurring of near vision.
• The ciliary muscles recover somewhat earlier than sphinctor
pupillae muscle.
• The IOT tends to rise, especially in narrow angle glaucoma.
• Lacrimal gland : decrease lacrimation
Anticholinergic drugs Mydriasis and Action lasts for
cycloplegia occurs
within

Atropine 30-40 min- mydriasis 1week

1-3 hrs cycloplegia
Homatropine 45-60 min 1-3 days

Cyclopentolate 30-60 min 1day

Tropicamide 20-40 min (quickest) 3-6 hours (Brifest)

Quickest acting and

shortest acting
Difference between anticholinergic and
adrenergic drugs on Eye
• Anticholinergic drugs responsible for mydriasis, cycloplegia, loss of light reflex
and increase in IOT.
• Adrenergic drugs responsible for mydriasis, no cycloplegia, No loss of light reflex
and decrease in IOT
• Anticholinergic drugs produce passive mydriasis while adrenergic drugs produce
active mydriasis.
• Anticholinergic drugs are preferred in Refractory testing while Adrenergic drugs
are preferred in Fundoscopy …. Why???
• Anticholinergic drugs responsible for decrease lacrimation while adrenergic drugs
have no effect on lacrimation .
Pharmacological actions
(atropine as prototype)
Smooth muscles:
• All visceral smooth muscles that receive parasympathetic innervation
are relaxed by atropine.
• GIT: tone and amplitude of contractions of stomach and intestines are
reduced; the passage of chyme also slowed. - constipation may
occur.
• However peristalsis is only incompletely suppressed.
• Bronchi: bronchodilatation (especially in COPD and asthmatics).
• Ureter and urinary bladder: relaxant action: beneficial for increasing
bladder capacity and controlling detrusor hyperreflexia in neurogenic
bladder /enuresis.
• Effect on biliary tract and uterus is less marked.
Pharmacological actions
(atropine as prototype)
Glands:
• Atropine markedly decreases sweat, salivary,
tracheobronchial and lacrimal secretions.
• Skin and eyes become dry, talking and swallowing may be
difficult.
• Atropine also decreases secretion of acids, pepsin and
mucus the stomach.
• Bile production is not under cholinergic control, so not
affected.
Pharmacological actions
(atropine as prototype)
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's are highly susceptible for atropine fever.
Local anaesthetic : mild anaestetic action on cornea.
Quaternary compounds
• These have certain common features-
(i) Incomplete oral absorption.
(ii) Poor penetration in brain and eye; central and
ocular effects are not seen after parenteral / oral
administration.
(iii) Elimination is generally slower; majority are longer
acting than atropine.
(iv) Have higher nicotinic blocking property. Some
ganglionic blockade may occur at clinical doses 
postural hypotension, impotence are additional side
effects.
(v) At high doses some degree of neuromuscular
blockade may also occur.
• Hyoscine butyl bromide:
• Ipratropium bromide
• Tiotropium bromide
• Propanthaline:
• Oxyphenonium:
• Dicyclomine:
• Valethamate: cervical dilatation and visceral antispasmodic
• Pirenzepine
• Oxybutynin:
• Tolterodine
• Flavoxate
• Darifenacin and solifenacin:
• Homatropine
• Cyclopentolate
• Tropicamide
• Antiparkinsonian drugs
Salient features of some anticholinergic drugs

• Atropine sulfate: 0.6–2 mg i.m., i.v. (children 10 μg/kg),

1–2% topically in eye.

• ATROPINE SULPHATE: 0.6 mg/ml inj.

• ATROPINE SULPHATE: 1% eye drop/ ointment;

• ATROSULPH 1% eye drop, 5% eye ointment.

Atropine 1% eye drop
0.6 mg/ml
Salient features of some anticholinergic drugs
• Hyoscine hydrobromide: 0.3–0.5 mg oral, i.m.; also
as transdermal patch.
Salient features of some anticholinergic drugs
• Hyoscine Butyl Bromide :
• Dose: 20–40 mg
• Route of administration: oral, i.m., s.c., i.v.
• It is less potent and longer acting than atropine
• Use: used for esophageal and gastrointestinal
spastic conditions.
BUSCOPAN 10 mg tab., 20 mg/ml amp.
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
• Ipratropium Bromide:
Advantages over atropine:
It is used by inhalational route
It acts selectively on bronchial muscle without altering volume
and consistency of respiratory secretions.
It dose not depress mucociliary clearance by bronchial
epithelium.
Gradual onset and late peak as compare to
sympathomimetics more suitable for regular
prophylaxis rather than for rapid symptomatic
relief during an attack.
It acts on receptors located mainly in the larger
central airways (contrast to that
sympathomimetics primarily acts on peripheral
bronchioles)
Salient features of some anticholinergic drugs

Higher parasympathetic tone is mainly involved in pathophysiology of

COPD. Therefore, ipratropium bromide is more effective in COPD than
in bronchial asthma.
Local adverse effects: dryness of mouth, scratching sensation in
trachea, cough, bad taste, nervousness.
Systemic side effects: Rare because of poor absorption from lungs
and git (major fraction of any inhaled drug is swallowed )
Dose : 40- 80 μg by inhalational route.
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs

• Tiotropium bromide:
• A newer congener of ipratropium bromide.
• Binds very tightly to bronchial muscuranic receptors  producing
long lasting bronchodilatation.
• More selectively block M1/ M3 receptors.
• Used by inhalational route.
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
• Propanthaline : 15-30 mg oral . In the past used for
peptic ulcer and gastritis. Its use has been declined
due to availability of H2 blockers and PPIs.
• Oxyphenonium: can be used in peptic ulcer or
gastritis. Rarely used now a days due to availability of
better drugs.
• Clidinium: 2.5 – 5 mg oral .. Used for nervous
dyspepsia, gastritis, IBS, colic, peptic ulcer.
• Cimetropium bromide: Mainly use in IBS. 50 mg 2-3
times a day .
Salient features of some anticholinergic drugs
Salient features of some anticholinergic drugs
• Glycopyrolate:
Potent and rapidly acting
Devoid of central effects
Exclusively used for preanaesthetic medication and
during anaesthesia.
0.2 -0.4 mg i.m.
Salient features of some anticholinergic drugs

• Dicyclomine:
Direct smooth muscle relaxant action in addition to weak M1
selective anticholinergic action.
Exerts antispasmodic action at doses which produce few atropinic
side effects.
Not recommended below 6 month of age
Uses: abdominal colic, morning sickness, motion sickness, IBS,
Dysmenorrhoea.
• Valethamate:
Mainly used for cervical dilatation when it is delayed during labour.
Urinary, biliary , intestinal colic.
Dose 8 mg im or 10 mg tab.
• Pirenzepine: M1 slective blocker
• Oxybutynin:
High affinity for receptors in urinary bladder, salivary glands along
with additional smooth muscle relaxant and local anaesthetic action
It is used for detrusor instability resulting in urinary frequency and
urge incontinence.
Beneficial effects demonstrated in post prostatectomy vasical spasm,
neurogenic bladder, spina bifida and nocturnal enuresis.
• Tolterodine, Flavoxate, Darifenacin, Solifenacin are other
Vasicoselective anticholinergic drugs can be used in overactive
bladder with urinary frequency and urgency.
• Drotaverine:
Non anticholinergic smooth muscle antispasmodic
Acts by inhibiting PDE-4 enzyme.
Used orally or parenterally in intestinal, biliary and renal colics, IBS,
uterine spasms.
Adverse effects: headache, dizziness, constipation flushing, fall in
BP.
Dose : 40-80 mg TDS
Mydriatics
• Atropine is a potent mydriatics but its slow and long lasting action is
undesirable for refractory testing.
Anticholinergic drugs Mydriasis and Action lasts for
cycloplegia occurs
within

Atropine 30-40 min- mydriasis 1week

1-3 hrs cycloplegia

Homatropine 45-60 min 1-3 days

Cyclopentolate 30-60 min 1day
Tropicamide 20-40 min (quickest) 3-6 hours (Brifest)
Uses
• As antiscertory:
Preanaesthetic medication: to decrease secretion, to
prevent laryngeal spasm
Peptic ulcer,
pulmonary embolism,
Parkinsonism
• As antispasmodic:
Intestinal and renal colic, abdominal cramps:
Nervous, functional, drug induced diarrhoea
IBS
Gastritis, Dyspepsia, Gastric hypermotility.
To relieve urinary frequency and urgency, enuresis in
children
Dysmenorrhoea
Uses
• Bronchial asthma, asthmatic bronchitis, COPD:
Role of anticholinergics in chronic bronchitis, COPD and asthma.
Drawbacks of atropine
Advantages of Ipratropium bromide and Tiotropium bromide.
Advantage of anticholinergic and β2 agonist combination
Role in COPD, chronic bronchitis and Asthma
• As mydriatics and cycloplegic:
Diagnostic: For testing error of refraction, both mydriasis and cycloplegia are
needed. Tropicamide is preferred due to its fastest and briefest duration of
action.

Therapeutic: Because of its long lasting mydriatics and cycloplegic and local
anodyne (pain relieving) action on cornea, atropine is very valuable in the
treatment of iritis, iridocyclitis, choroiditis, keratitis and corneal ulcer. It gives rest
to the intraocular muscle and cuts down their painful spasm.
• As cardiac vagolytic:
Atropine is useful in counteracting sinus bradycardia and partial
heart block in selected patients where increased vagal tone is
responsible, e.g. in myocardial infarction and in digitalis toxicity.
• For central actions:
Parkinsonism:
For idiopathic parkinsonism, they are less effective than levodopa. They are
used in mild cases or as adjuvant to levodopa.
For drug induced parkinsonism: they are considered as drug of choice.
Levodopa is not effective in drug induced parkinsonism.
Motion sickness: hyoscine or Dicyclomine
• To antagonise muscuranic effects of drugs and poisons:
Atropine is specific antidote for AntiChE drug (organophosphate and
carbamate) and early mushroom poisoning.
Atropine or Glycopyrrolate can be combine with neostigmine to block
muscuranic effects of neostigmine when used for myasthenia gravis,
decurarisation or cobra bite.
Side effects
• At therapeutic dose: Dry mouth, difficulty in swallowing and talking.
Dry, flushed and hot skin Fever ,Difficulty in micturation, decreased
bowel sounds, dilated pupil, photophobia, blurring of near vision,
palpitation
• High dose: excitation, delirium, hallucination, ataxia, hypotension,
weak and rapid pulse, cardiovascular collapse with respiratory
depression, convulsion, coma
• Treatment of balladona/ datura/ atropine poisoning:
Gastric lavage with tannic acid.
Pt should be kept in a dark quite room.
Cold sponging or ice bags are applied to reduce the temperature.
Physostigmine 1-3 mg sc or iv
Maintenance of blood pressure, respiration
Convulsion-diazepam
• Contraindications: Glaucoma