ANTICHOLINERGIC DRUGS

Introduction
• Drugs which block Cholinoreceptors have
important clinical effects, some of which are
of great clinical value
• What are the Cholinoreceptors learned so far?
- RECALL !

• Muscarinic and Nicotinic

– M1, M2, M3, M4 and M5
– NN and NM
 Cholinergic Receptors
• Conventionally – Anticholinergic drugs are those
which block actions of Ach autonomic effectors and I
the CNS exerted through Muscarinic receptors
• Nicotinic (NN) antagonists – ganglion blockers
• NM Blockers – neuromuscular blockers
• Atropine is the prototype – many synthetic and semi
synthetics are available now
• All are competitive antagonists
 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
• Atropos is the name of one of the Fates, mythical beings who
controlled the destinies of humans (Clotho, Lachesis, and
Atropos)

Datura stramonium Atropa belladona

 Atropine – Mechanism of Action
• Atropine causes reversible blockade of
cholinomimetic actions at muscarinic
receptors
– 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 conjunctiva – some even over the skin (scopolamine)
– Penetrates cornea freely
– Quaternary ones – only upto 30%
• Distribution:
– Atropine and the other tertiary agents are widely distributed in the body
– Scopolamine is rapidly and fully distributed into the central nervous system
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 60% excretes unchanged in
urine
– Effects disappear quickly within 2 Hrs except eye
– Hyoscine is more completely metabolized
• Preparations: Atropine IM or IV; Hyoscine – Oral/IM/transdermal
 Pharmacological actions of Atropine -
CVS
• Heart: Moderate and high doses: TACHYCARDIA (Blockade of
M2 receptor on SA node - vagal tone decreases HR)
– IM/SC injection initially – transient BRADYCARDIA – may be due to
inhibition of prejunctional postsynaptic M autoreceptor inhibition (not
due to stimulation of vagal centre)
• BP: No consistent effect – tachycardia and VMC stimulation – raises
BP; but histamine release and direct vasodilator action counteract
• Vascular
• no (direct) effect
• except, dilate cutaneous vessels (red as a beet)
• block hypotensive effect of muscarinic agonists
 Pharmacological actions - CNS
• At normal doses atropine stimulates medullary centers,
However, at higher doses produce excitement, agitation,
hallucinations and coma.
• Depresses vestibular excitation and has anti motion sickness
properties
• Supresses tremor and rigidity of parkinsonism by blocking
cholinergic overactivity in basal ganglia.
• Scopolamine has more marked central effects (depressant) –
amnesia and drowsiness
 Pharmacological actions, Atropine-Eye
• MYDRIASIS
• Topical atropine and other
antimuscarinic drugs - results in
unopposed sympathetic dilator
activity and mydriasis
• Cycloplegia and abolition of light
reflex - desirable in Ophthalmology
• Photophobia and blurring of near
vision
• IOP rises: hazardous in narrow angle
glaucoma
• Dry Eye: Not desirable
 Atropine on Smooth Muscle
• Respiratory: Bronchodilatation and reduction in airway
resistance – COPD and asthma patients
– Also antagonizes vagal mediated over activity due to Histamine, PG,
leucotrienes etc.
• Urinary: Relaxation of ureter & bladder – urinary
retention in older males with BHP
– Sometimes useful in increasing bladder capacity and controlling
detrussor hyperreflexia - neurogenic bladder/enuresis
• Visceral SM: Relaxation – mediated by M3 blockade
– Tone and amplitude of contraction of Stomach and Intestine reduced
• Passage of chyme reduced – CONSTIPATON and relieve of SPASM
 Atropine on Glands
• Decreases salivary, sweat, tracheobronchial and lachrymal
secretions (M3 blockade)
– dryness of mouth, dry skin and conjunctiva and difficulty in talking and
swallowing
• Stomach (M1): decreases acid, pepsin and mucus secretions –
Atropine is less efficacious than H2 blockers
• No effect on intestinal and pancreatic secretion
• No effect on bile production
 Therapeutic Uses
Central Nervous System Disorders-
• Parkinson’s disease – Benztropine,
Trihexyphenidyl
• Those who cannot take Levodopa
• Helpful in decreasing salivation, spasticity and
tremors
• Motion Sickness (Scopolamine)
• Drug-induced extrapyramidal reactions(due to
antipsychotics)
 Therapeutic Uses
CVS –
• Atropine is used to increase heart rate in
symptomatic bradycardias.
• Sinus node dysfunction
• Symptomatic second-degree heart block
• Sinus or nodal bradycardia (due to myocardial
infarction)
 Therapeutic Uses
Respiratory system-
• Decreased secretions from nose, mouth,
pharynx, bronchi so can be used as a pre-anesthetic agent.
• Relaxed smooth muscles in bronchi
and bronchioles
• Decreased airway resistance
• Bronchodilation
Respiratory agents are used to treat:
• Exercise-induced bronchospasms
• Chronic bronchitis
• Asthma
• Chronic obstructive pulmonary disease
• Ipratropium as inhalation (or Tiotropium)
 Therapeutic Uses
Gastrointestinal:
• Decreased secretions
• Relaxation of smooth muscle
• Decreased GI motility and peristalsis
Gastrointestinal agents are used to treat:
• Peptic Ulcer: Pirenzepine
• As antispasmodic :Butylscopolamine
• Irritable bowel disease: Propantheline
• GI hypersecretory states
 Therapeutic Uses
Urologic disorders-
• Antispasmodic effects seen in overactive
bladder and in urinary incontinence -
Oxybutynin
• Detrusor hyper-reflexia,
• Enuresis( repeated inability to control
urination)
-Increase bladder capacity
-Decrease bladder pressure
 Therapeutic Uses
Opthalmological Disorders-
• Homatropine,tropicamide
• Accurate measurement of refractive error in
uncooperative patients (e.g, children)
• Examination of retina (Mydriasis)
• Other use:
It is used in the treatment of poisoning by
anticholinesterase agents because it
antagonizes the actions of Ach.
 Side Effects of anticholinergics
Body System Side/Adverse Effects
Cardiovascular Increased heart rate,
dysrhythmias

CNS CNS excitation, restlessness,

irritability, disorientation,
hallucinations,delirium
 Side Effects of anticholinergics
Body System Side/Adverse Effects
Eye Dilated pupils, decreased
visual accommodation,
increased intraocular pressure

Gastrointestinal Decreased salivation,

decreased gastric secretions,
decreased motility
 Side Effects of anticholinergics
Body System Side/Adverse Effects
Genitourinary Urinary retention

Glandular Decreased sweating

Respiratory Decreased bronchial secretions

 Toxicity of Anticholinergics
• Anticholinergic overdose syndrome (Belladona
poisoning- consumption of seeds or berries of
belladona or dhatura plant) is characterized by:
Hyperthermia, delirium, dry mouth, tacycardia,
ileus, urinary retention. Seizures, coma and
respiratory arrest may occur.
• Treatment – Gastric lavage with tannic acid,
cold sponging or ice bags, Physostigmine s.c. or
i.v., diazepam to control convulsions.
 Contraindications
• Glaucoma
• Urinary tract obstruction
• Gastrointestinal tract obstruction
• Infectious diarrhea
• Reflux esophagitis
• Tachyarrhythmias
• Angina
• Hyperthyroidism
• Pregnancy
Drugs acting on Ganglions
Drugs acting on Autonomic ganglia
• ACh is excitatory neurotransmitter - parasympathetic
and sympathetic
• Drugs which inhibit synthesis or release – interfere
with ganglionic transmission
• NN mediate rapid depolarization of ganglion cells
– also present are M1 & M2, adrenergic, dopaminergic,
amino acid, peptidergic receptors - slow – mediate slowly
developing and longer lasting effects
– Released from preganglionic cholinergic terminals – but by
themselves
– One transmitter – one cell junction ... Over simplification
 Ganglion stimulants and blockers
• Ganglion stimulants:
– Selective agonists: Nicotine (small dose), Lobeline, DMPP, TMA and
Varenicline
– Non-selective: Acetylcholine, carbachol, Pilocarpine,
Anticholinesterases
• Ganglion Blockers:
– Competitive blockers:
• Quaternary compounds: Hexamethonium, Pentolinium
• Secondary/tertiary: Mecamylamine, Pempidine
• Monosulfonium compound: Trimethaphancamforsulfonate
– Persistent depolarizers: Nicotine (large dose) and Anticholinesterases
(large doses)
Nicotine

• Source – alkaloid in Nicotiana tabacum

• Action – stimulation of Para symp and symp
ganglia via NN and NM receptors at low dose
– Large doses – persistent depolarization
• Only Indication – short term nicotine
replacement in tobacco abstinent Subjects
 Pharmacotherapy of smoking
cessation
• Difficult to quit - Nicotine dependence – counseling and motivation
• Aim of treatment:
– To reduce the craving for satisfying (reward) effects of nicotine
– To suppress the physical withdrawal symptoms
• Drugs: Nicotine replacement, Partial agonists of α4β2 Nicotinic receptors
(Varenicline) and antidepressants (Bupropion)
• Nicotine transdermal: once daily on the hip/abdomen/chest/upper arm –
supresses nicotine withdrawal but craving only partially (10, 20, 30 cm2
patches)
– Also nicotine chewing gum - alternative of patches (NULIFE 1, 2, 4 mg
chewing gums)
– ADRs of nicotine replacement: headache, dyspepsia, abdominal cramps, loose
motion, flu like symptoms etc
Ganglionic Blockers

These are drugs that competitively block Ach receptors in

autonomic ganglia (pharmacologic antagonists).

Not selective in action (block both sympathetic and

parasympathetic ganglia), so, they are no longer used in the
routine therapy of hypertension.

e.g. hexamethonium, mecamylamine

Trimethaphan

• It is a ganglion blocker with short duration of action,

poorly lipid soluble, inactive orally.

• The drug was used to produce hypotension during

surgery and in the treatment of malignant hypertension.

• Because ganglionic blockers interrupt control of

venous tone, they cause marked venous pooling;
postural hypotension is a major manifestation of this
effect.

• Other toxicities include dry mouth, blurred vision,

constipation, sever sexual dysfunction.
Neuromuscular blockers

1. Competitive NMB
• Competitive block at the end plate nicotinic receptors, causing
flaccid paralysis.
• e.g. tubocurarine, pancuronium, gallamine

2. Depolarizing NMB
• Nicotinic agonists, causing spastic paralysis.
• e.g. succinylcholine; hydrolysed by pseudocholinesterase .
Cholinesterase regenerators

• They are chemical antagonists.

• e.g. Pralidoxime: it contains an oxime group,
which has an extremely high affinity for the
phosphorous atom in organophosphate
insecticides.
• They are able to bind the inhibitor and displace
the enzyme (if aging has not occurred). The active
enzyme is thus regenerated.
• Pralidoxime is used to treat patients exposed to
insecticides such as parathion.