Anticholinergic Drugs

Introduction
Parasympathetic Nervous System plays an
important role in physiologic and
pathophysiologic responses -Rest and Digest
Drugs that block Cholinoceptors have
important applications, some of which are of
great clinical value.
Cholinoceptor antagonists are, like agonists -
Muscarinic and Nicotinic
Antinicotinic ganglion blockers(eg.
trimethoprim) and NM junction blockers eg
,tubocurarine.
Muscarinic receptors
M1 receptors are located on CNS,neurons,
sympathetic postganglionic cell bodies and many
presynaptic sites.
M2 receptors are located in heart, smooth muscle,
some neuronal sites
M3 receptors are located on effector cell membranes
of smooth muscles & glands
M4 and M5 are less important and play a role in the
CNS rather than periphery
Recall - Muscarinic (M) and
Nicotinic (N) Receptors:
Muscarinic blockers
Natural compounds used as medicines ,
poisons and cosmotics include:
Atropine( hyoscyamine) from Atropa belladona
and Datura stramoinum is the prototype.
Scopolamine(hyoscine) from Hyoscymus niger
Many synthetic and semisynthetic analoges
are available
Tertiary amines such as pirenzepine,
dicyclomine, used for peptic ulcers;
tropicamide used as a mydriatic
Benztropine and trihexyphenydyl are
tertiary amines used in parkinsonism.
Quaternary amines such as ipratropium
(used for asthma), propantheline,
glycopyrolate (used for GIT diseases).
All are competitive blockers of muscarinic
receptors.
Many antihistamines, antipsychotics and
antidepressants have significant
antimuscarinic activity
 Muscarinic Receptor Subtypes: M1, M2, M3,
M4 and M5(muscarinic actions are those that can be
reproduced by muscarine & blocked by atropine and
scopolamine) M1 M2 M3
Location Autonomic ganglia, Heart and CNS SMs of Viscera,
Gastric glands and CNS Eye, exocrine
glands and
endothelium
Functions EPSP & Histamine release Less impulse Visceral SM
& acid secretion, with generation, less contraction,
CNS learning and motor velocity of Constriction of
functions conduction, pupil, contraction
decreased of Cilliary muscle
contractility, less and vasodilatation
Ach release
Agonists Ach, Oxotremorine Ach,Methacholi- Ach,Bethanechol
ne
Antagonist- Atropine, Pirenzepine Atropine,Metho- Atropine,Darifen-
s ctramine & acin,ipratropium
Triptramine
Nicotinic (N) Receptors
Nicotinic receptors: nicotinic actions of ACh
are those that can be reproduced by the
injection of alkaloid nicotine from Nicotiana
tobacum
Can be blocked by trimethophan,
hexamethonium and tubocurarine.
Are ligand-gated ion channels
activation results in a rapid increase in
cellular permeability to Na+ and Ca++
resulting in depolarization and initiation of
action potential
Sites of Cholinergic transmission
and types of Receptors
Site Types Selective Selective
agonist antagonist

All Postganglionic
Parasympathetic
Muscarinic Muscarine Atropine &
Postganglionic scopolamine
sympathetic to
sweat gland & BV

Ganglia (Both Para- NN DMPP Hexamethoniu-

and sympathetic, and m&
also Adrenal Medulla trimethophan

Skeletal Muscle(NMJ) NM PTMA tubocurarine

CNS Muscarinic Muscarine Atropine

Oxotremorine
Classification - Anticholinergics
Natural: Atropine and Hyoscine (scopolamine).
Semisynthetic derivtives: Homatropine, Atropine
methonitrate, Hyoscine butylbromide, Ipratropium
bromide, Tiotropium bromide
Synthetic Compounds:

Mydriatics: Cyclopentolate and Tropicamide

Vasicoselective: Oxybutynin, Flvoxate, Tolterodine
Antiparkinsonism: Trihexyphenidyl,benztropine,
Procyclidine, Biperiden
Antisecretory:
Quartenary ammonium compounds:
Propantheline, Oxyphenonium, Clidinium,
Glycopyrrolate, Isopropamide
Tertiary amines: Dicyclomine, Valethamate,
Pirenzepine
Atropine as Prototype
Atropine (hyoscyamine) is found in the plant
Atropa belladonna, or deadly nightshade
Also in Datura stramonium, also known as
jimsonweed (Jamestown weed) or thorn apple
Scopolamine (hyoscine) occurs in Hyoscyamus
niger
Many compounds with similar structures:
Histamine H1-blockers, Serotonin antagonists, &
Ergots alkaloids, Antipsychotic Agents & Lithium
and antidepressant drugs have similar structures
and, predictably, significant antimuscarinic
effects
Datura stramonium
Atropa belladona
Atropine - Chemically
Atropine: Ester of tropic acid (aromatic acid) +
tropine
Scopolamine: Ester of tropic acid (aromatic acid) +
scopine
Chemically tropine and scopine are closely similar
Most of the actions of both are similar
 Atropine - Mechanism
Atropine causes reversible (surmountable)
blockade of cholinomimetic actions at muscarinic
receptor
blockade by a small dose of atropine can be
overcome by a larger concentration of
acetylcholine or equivalent muscarinic agonist

Atropine is highly selective for muscarinic

receptors
Does not distinguish between the M1, M2, and M3
Some quaternary amine antimuscarinic agents
have significant ganglion-blocking actions
Atropine - Pharmacokinetics
Absorption:
The natural alkaloids and most tertiary antimuscarinic drugs are well
absorbed from the gut and conjunctival membranes some even over
the skin (scopolamine)
Quaternary amines are only upto 30% orally absorbed due to less lipid
solubility.

Distribution:
Atropine and the other tertiary agents are widely distributed in the
body including CNS,which may limit dose tolerated.
Scopolamine is rapidly and fully distributed into the CNS where it has
greater effects than most other antimuscarinic drugs
Quaternary derivatives are poorly taken up by the brain

Metabolism:
Atropine is metabolized in liver by conjugation and 50% excretes
unchanged in urine.Elimination occurs in two phases, T1/2 of rapid
phase is 2 hrs and that of slow phase is 13 hrs
About 50% is excreted unchanged and the rest as conjugates
Effect in the eye persists for more than 72hrs
Pharmacological Effects - Atropine
Atrpoine reversibly blocks muscarinic receptors, ie high dose of Ach
reverses the blockade.
Atropine blocks release of IP3,DAG and inhibition of adenylylcyclase
caused by muscarinic agonists.
Central Nervous System: Overall CNS stimulant
Atropine has only peripheral effects and minimal stimulant effect on CNS
low entry
Atropine stimulates many medullary centres vagal, respiratory and
vasomotor
Depresses vestibular excitation antimotion sickness property.
Scopolamine has more marked central effects amnesia and drowsiness .
Parkinson's disease is reduced by centrally acting antimuscarinic drugs
acting on basal ganglia (atropine,benztropine, trihexyphendyl)
Eye:
Topical atropine and other tertiary antimuscarinic drug - results in
unopposed sympathetic dilator activity and mydriasis
Cycloplegia: desirable in Ophthalmology
but hazardous in narrow angle glaucoma
Dry sandy eye: Not desirable
Paralysis of accommodations -
Atropine
Effect of Scopolamine
Pharmacological Effects of
Atropine contd.
CVS:
Moderate and high doses: Tachycardia.
More in young adults due to vagotonia
MOA: SA-node & AV-node are richly
supplied by parasympathetic nerves
Atropine produces PS blockade in SA-
node causing tachycardia.
AV node: Atropine produces PS blockade
leading to higher AV nodal conduction
rate (reduced PR interval in ECG)
 IM/SC injection initially transient
BRADYCARDIA may be due to inhibition
of presynaptic M1 autoreceptor inhibition
(not due to stimulation of vagal centre).
The ventricles are affected by
antimuscarinics due to less ps innervation
BP: Parasympathetic nerve stimulation
dilates coronary arteries, and sympathetic
cholinergic nerves (predominant) cause
vasodilatation in the skeletal muscle vascular
bed - Atropine can block this vasodilatation
But, histamine release cause direct
vasodilatation
However, No marked effect on BP
Heart rate and salivary secretion
after Atropine
Pharmacological Effects of Atropine
contd.
Respiratory System:
Smooth muscles and secretor glands receive
innervations from parasympathetic system
Bronchodilatation and reduction in secretion in
asthma
Particularly used in COPD and prior to initiation of
inhalation therapy in asthma
Sweat glands:
Suppresses thermoregulatory sweating
peripheral and central action
May cause "atropine fever in children
Urinary:
Slows voiding
Useful in spasm conditions inflammation
Danger in Elderly (BHP)
Pharmacological Effects of
Atropine contd.
GIT:
Decrease in GI motility
Gastric emptying time is prolonged, and
intestinal transit time is lengthened
Dry mouth occurs frequently in patients
taking antimuscarinic drugs
Gastric secretion is blocked with larger
doses blocks acid, pepsin and mucus
secretion
Pirenzepine is more effective
Various Effects of Atropine
Anticholinergics - Ophthalmic uses
Mydriatic and Cycloplegic
Used as eye drop or ointment:
Diagnostic:
Atropine 1% ointment is used
Measurement of refractive error
Ophthalmic examination of retina - fundoscopy
Preferred ones: Homatropine, Tropicamide and
cyclopentolate shorter action
Therapeutic Uses:
For resting eye: Iritis, iridocyclitis, keratitis,
corneal ulcer etc.
Alternating with miotics (prevention of synechia)
Therapeutic Uses
Anticholinergics
Antisecretory:
1. Preanaesthetic medication:
To reduce secretions
To prevent laryngospasm
2. Peptic ulcers
3. Pulmonary embolism
4. Hyperhidrosis
Antispasmodic:
Intestinal and renal colics not in biliary colic
Diarrhoea (nervous and drug induced)
(diphenoxylate) Lomotil, loperamide(lyspafen).
Pylorospasm, gastric hypermotility, gastritis,
nervous dyspepsia etc.
Uses Anticholinergics contd.
Parkinsonism: Mild cases of parkinsonism
(early cases), drug induced Parkinsonism
as an adjunct to
Levodopa.Beztropine,biperidin &
trihexyphenydyl are the agents in use.
Motion sickness:
Hyoscine (scopolamine) is the drug used Orally,
by injection and transdermal patch
0.2 mg orally given as prophylaxis before journey
Not effective in other type of vomiting
Twilight sleep: sedation and amnesia.
To antagonize muscarinic effects of drugs and poisons: Anti-
ChE, Mushroom poisoning, and to block Muscarinic effects of
Neostigmine, Cobra venom
 Anticholinergics uses
CVS:
Vagolytic - Marked reflex vagal discharge in
myocardial infarction - depression of SA or AV
node function to impair cardiac output -
Parenteral atropine or a similar antimuscarinic
Hyperactive carotid sinus reflexes
Respiratory:
Ipratropium Bromide in COPD and chronic
bronchitis
Improves mucociliary clearance and
bronchodilatation
Useful in bronchial asthma
 Anticholinergic - ADRs
Commonly occurring but of non serious type
Mydriasis and cycloplegia when used to reduce GIT
motility, antisecretory or preanaesthetic medication
Poisoning:
Causes:
Drug overdose
Consumption of Belladona and Datura seeds
Symptoms:
Dry mouth,mydriasis, tachycardia,difficulty in
swallowing and talking
Dry, flushed and hot skin, fever, decreased bowel
sound, photophobia, agitation
Excitement, psychotic behavior, delirium and
hallucinations
Hypotension and cardiovascular collapse
Atropine Poisoning contd.
Diagnosis: Methacholine 5 mg or
Neostigmine 1 mg SC no muscarinic
effects
Treatment:
Gastric lavage in case of ingestion
KMNO4
Dark Room
Cold sponging and ice bags
Physostigmine 13 mg SC or IV
Maintenance of blood volume, assisted
respiration and Diazepam to control convulsions
Anticholinergic - Contraindications
Glaucoma Narrow angle (Precipitation
of angle closure)
BPH urinary retention in elderly men
Acid peptic ulcer diseases (Non-
selective ones) precipitation of
symptoms due to slowing of gastric
emptying
Atropine Substitutes - Quarternary
compounds
Incomplete Oral absorption, Poor penetration in Eye and CNS,
Longer acting than Atropine, Higher Nicotinic Blocking Property,
NM Blockade
Drugs:
Hyoscine Butylbromide: Oesophageal and GIT spastic
conditions Buscopan
Atropine methonitrate: Abdominal colics and hypercidity
Ipratropium Bromide: Selective action on Bronchial SM
Enhanced mucocilliary clearance (contrast to Atropine)
Slowly acting Bronchodilator - 1-2 Hrs (prophylactic use)
Acts mainly on larger Central airways (contrast to
sympoathomimetics)
More effective in COPD than Asthma
Other Drugs Tiotropium bromide, Propantheline,
Oxyphenonium, Clidinium and Glycopyrrolate
Tertiary Amines
Dicyclomine and valethamate
Dicyclomine: Direct SM relaxant and weak antispasmodic
Lesser side effects than Atropine
Atropine toxicity in infants (not recommended below 6
months)
Valethmate: Dilatation of Cervix in delayed labour
Individual Drugs
Vasicoselective
Oxybutynin:
Specific selectivity for receptors in Urinary bladder and salivary gland (M1/M3)
Additional smooth muscle relaxation property
Uses:
Bladder surgery after urologic surgery
Spina bifida and nocturnal enuresis
Involuntary voiding in patients with neurologic disease - children with
meningomyelocele
Dose: 5 mg BD/tds or local instillation
Tolterodine M3 selective
Flavoxate similar to Oxybutynin
Drotaverine: Newer Drug - Non anticholinergic smooth muscle relaxant
elevation of cAMP/cGMP
Renal colic, biliary colic, IBS, uterine spasms etc.
Dose: 40 80 mg tds
Mydriatics
Homatropine,
Cyclopentolate and
Tropicamide
various
ophthalmological
procedures as
substitutes of
Atropine
Drugs acting in Autonomic ganglia
Ganglion stimulants:
Selective agonists: Nicotine, Lobeline, DMPP and TMA
Non-selective: Acetylcholine, carbachol, Pilocarpine,
Anticholinesterases
Ganglion Blockers:
Competitive blockers:
Quaternary compounds: Hexamethonium,
Pentolinium
Secondary/tertiary: Mecamylamine, Pempidine
Persistent depolarizers: Nicotine (large dose) and
Anticholinesterases
Remember !!!
Atropine and its Pharmacological Effects
Therapeutic uses of Atropine
Mechanism of Mydriasis and Cycloplegia
Names of Atropine Substitutes with their
Uses
Details of Atropine Substitutes Ipratropium
bromide
Treatment of Atropine Poisoning
Ganglion Stimulants and Blockers Drugs
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