Autonomic Pharmacology:

Cholinergic & Anticholinergic

Drugs

Dr Hoda Abolhasani
Pharmacist & medicinal chemist
 Cholinoceptor-
activating &
Cholinesterase-
inhibiting Drugs
SSRRT

1. Ago M &N
2. Anta M & N
3. Cholinesterase-inhibiting Drugs
 Direct-acting Cholinoceptor
Stimulants
1. Four important Choline Esters

2. Cholinomimetic Alkaloids: tertiary amine

(Pilocarpine, Nicotine, Lobeline) & quaternary
amine (Muscarine)
 Indirect-acting Cholinomimetics
3 Chemical groups of cholinesterase inhibitors:
1. Simple alcohols bearing a quaternary ammonium group: Edrophonium
2. Carbamic acid esters of alcohols with quaternary or tertiary ammonium:
carbamates: Neostigmine, Pyridostigmine, Physostigmine but
Carbaryl is insecticide & very high lipid solubility, absorb by insect CNS
3. Organic derivatives of phosphoric acid (organophosphates):
irreversible: Echothiophate, Soman, Parathion, Malathion
Direct-acting Cholinoceptor Stimulants
 Clinical Pharmacology Of The
Cholinomimetics
• The major therapeutic uses are for diseases of:
A. Eye (glaucoma, accommodative esotropia):
B. GI & Urinary tracts (postoperative atony, neurogenic bladder)
C. Neuromuscular junction (myasthenia gravis, curare-induced ptosis
neuromuscular paralysis: inhibition of N)
D. Heart (certain atrial arrhythmias)
E. Cholinesterase inhibitors are occasionally used in the treatment of diplopia
Atropine overdosage
F. Several newer cholinesterase inhibitors are being used to treat patients
with Alzheimer's disease:
Decrease of A.ch in brain
 Cholinomimetics Clinical Uses
A. Glaucoma: direct agonists (Pilocarpine, Methacholine, Carbachol) or
cholinesterase inhibitors (Physostigmine, Demecarium,
Echothiophate, Isoflurophate), [for chronic glaucoma: these drugs have
been largely replaced by topical β-blockers & prostaglandin derivatives]
B. postoperative ileus & congenital megacolon: Bethanechol for GI
problems, urinary retention, Neostigmine for paralytic ileus or atony of
the urinary bladder, Pilocarpine for increase salivary secretion,
Cevimeline (Ago M) for treatment of dry mouth associated with
Shogren's syndrome & radiation damage of the salivary glands
C. Myasthenia gravis: (ptosis, diplopia, difficulty in speaking & swallowing,
weakness): Long-term therapy with Pyridostigmine, Neostigmine,
Ambenonium, diagnostic test for myasthenia with Edrophonium
D. Supraventricular Tachyarrhythmias: short-acting cholinesterase
inhibitor Edrophonium
E. Antimuscarinic Drug (Atropine & TCA) Intoxication: Physostigmine:
enters the CNS & reverses the central & peripheral signs of M blockade
F. Alzheimer's disease: (acetylcholinesterase inhibitors) Tacrine (hepatic
toxicity), Donepezil, Galantamine, Rivastigmine (newer)
 Cholinomimetics Toxicity
A. Direct-acting Muscarinic Stimulants: Pilocarpine & Choline Esters
{mushrooms Inocybe & Amanita muscaria contain muscarinic alkaloids}
overdosage: nausea, vomiting, diarrhea, urinary urgency, salivation, sweating,
cutaneous vasodilation, bronchial constriction (all blocked competitively by
Atropine & Its Congeners)
B. Direct-acting Nicotinic Stimulants: Nicotine is in tobacco products &
insecticides, Acute Nicotine Poisoning: (1) central stimulant actions: cause
convulsions, coma, respiratory arrest; (2) skeletal muscle & plate depolarization:
respiratory paralysis; (3) hypertension & cardiac arrhythmias (Treatment:
symptom-directed, Atropine, Diazepam, mechanical respiration), Chronic
Nicotine Toxicity: increased risk of vascular disease & sudden coronary death,
high incidence of ulcer recurrences in smokers with peptic ulcer (stop smoking:
Nicotine in the form of gum, transdermal patch, nasal spray, inhaler,
Varenicline is more effective than Bupropion {antidepressant})
C. Cholinesterase Inhibitors: Pesticide, Organophosphate Agents, Chemical
Warfare Agents (Soman, Sarin, VX), miosis, salivation, sweating, bronchial
constriction, vomiting, diarrhea (Treatment: (1) maintenance of vital signs
respiration, (2) decontamination to prevent further absorption, wash & clothes,
(3) Atropine, Pralidoxime, Benzodiazepines, Personnel are given
autoinjection syringes containing a Carbamate, Pyridostigmine, Atropine
 Muscarinic &
Nicotinic Receptor-
blocking Drugs
 Muscarinic Receptor-
blocking Drugs

• The structure of Atropine (oxygen

[red] at [1] is missing) or
Scopolamine (Hyoscyn) (oxygen
present), In Homatropine
hydroxymethyl (blue) at [2] is replaced
by a hydroxyl group, and oxygen at [1]
is absent
 Therapeutic Applications Of The
Muscarinic Receptor-blocking Drugs
• CNS Disorders: Parkinson's Disease ( Colinergic & Dopaminergic)
(polypharmacy: antimuscarinic drugs & Levodopa, Motion Sickness:
Scopolamine (injection, mouth, transdermal patch), sedation & dry mouth
• Ophthalmologic Disorders: Accurate measurement of refractive error
(need ciliary paralysis), ophthalmoscopic examination of the retina (need
mydriasis): antimuscarinic agents, Glycopyrrolate, Atropine
• Respiratory Disorders: inhalational drug in asthma & COPD in older
patients, particularly chronic smokers: bronchodilators, especially
antimuscarinic agents: Atropine, Ipratropiumm & Tiotropium (longer
acting bronchodilator)
• GI Disorders: treatment of common traveler's diarrhea, Lomotil (atropine
+ diphenoxylate)
• Urinary Disorders: relieve bladder spasm, improve bladder capacity:
Oxybutynin, Trospium, Darifenacin, Solifenacin, Tolterodine,
Fesoterodine, Imipramine (TCA & anti M), Propiverine
• used in urolithiasis to relieve the painful ureteral smooth muscle spasm
caused by passage of the stone
 Use of Anti M in Cholinergic Poisoning
• Severe cholinergic excess by cholinesterase inhibitors: Insecticides,
Wild Mushrooms, Chemical Warfare "Nerve Gases“ SO treatments:
1. Antimuscarinic Therapy: Atropine to treat the CNS effects as well as
the peripheral effects of the organophosphate inhibitors, Large doses of
atropine may be needed to oppose the muscarinic effects of extremely
potent agents like parathion & chemical warfare nerve gases: 1-2 mg of
atropine sulfate may be given IV every 5-15 minutes until signs of effect
(dry mouth, reversal of miosis) appear, drug may have to be repeated
many times, 1 g of atropine per day may be required for as long as 1
month for full control of muscarinic excess
2. Cholinesterase Regenerator Compounds: capable of regenerating
active enzyme from the organophosphorus-cholinesterase complex,
oxime agents include pralidoxime (PAM) [no CNS],
diacetylmonoxime (DAM) [go to CNS],..
• The oxime group (=NOH) has a very high
affinity for the phosphorus atom, & these drugs
can hydrolyze the phosphorylated enzyme
if the complex has not "aged"
Adverse Effects & Contraindications of the Anti M
• Adverse Effects: mydriasis & cycloplegia are adverse effects when an
antimuscarinic agent is used to reduce GI secretion or motility, even
though they are therapeutic effects when the drug is used in ophthalmology
• Atropine is a remarkably safe drug in adults
• Atropine poisoning: induce hallucinations, dry mouth, mydriasis,
tachycardia, hot & flushed skin, agitation, delirium, body temperature is
frequently elevated [these effects are memorialized: "dry as a bone, blind
as a bat, red as a beet, mad as a hatter“]
• highly dangerous drug when overdose occurs in infants or children
• Symptomatic treatment: temperature control with cooling blankets,
seizure control with Diazepam, antimuscarinic effects, with a
cholinesterase inhibitor: Neostigmine, Control of hypotension with a
sympathomimetic: Phenylephrine
• Contraindications:
• In patients with glaucoma, especially angle-closure glaucoma
• In elderly men with caution & avoided in a history of prostatic hyperplasia
• Increase symptoms in patients with gastric ulcer