Muscarinic blockers

Anti-muscarinic drugs Natural

Atropine, scopolamine

Synthetics
Mydriatic Cyclopentolate, Homatropine Anti-parkinsonism Benztropine (tertiary amine) Anti-asthmatic Ipratropium, Tiotropium (quaternary amine) GIT and Genitourinary Tertiary amines Pirenzepine, Telenzepine, Dicyclomine, Darifenacin, Solifenacin, Oxybutynin, Tolterodine quaternary amines Glycopyrrolate, Trospium, Oxyphenonium, Isopropamide

Chemistry and Pharmacokinetics Source and Chemistry

Atropine (Hyoscyamine) Tertiary amine alkaloids ester of tropic acid, Atropa belladonna Datura stramonium, thorn apple. Naturally occurring l(-) hyoscyamine while commercial is racemic d,l hyoscyamine l(-) hyoscyamine is 100 more potent than d(+) hyoscyamine
Scopolamine (Hyoscine) Occurs in Hyoscymus niger Naturally as l(-) hyoscine which 100 more potent as compared to d(+) hyoscine

Absorption
Tertiary amines, well absorbed from gut and membranes In quaternary amines after oral administration only 10-30% of drug absorbed

Distribution
Well distributed, Tertiary amines penetrate CNS Quaternary amines poorly taken up by CNS

Metabolism and excretion

Atropine: Two phases, 2hrs and 13hrs Parasympathetic drugs metabolized rapidly beside eyes (72hrs)

Pharmacodynamic Mechanism of action

Atropine: reversible non-selective antimuscarinic, no potency for nicotinic-R Mutation Experiments: Aspartate in 3rd membrane----N-atom of Ach Inverse agonist, Prevent the release of Ip3 and block Adenylyl Cyclase activity Tissue and drug specific effects Muscarine-R M1 M2 M3 Location Nerves
Antagonist Pirenzepine, Telenzepine, Dicyclomine

Heart, Nerves, Smooth Gallamine, Methoctramine muscles Glands, Smooth muscles, Endothelium
Oxybutynin, Solifenacin, Darifenacin

Organ System effects

Central Nervous System
At therapeutic doses
Prolong sedation, Drowsiness and amnesia (scopolamine) Decrease tremors in PD (Atropine, Benztropine) Prevent vestibular disturbance especially motion sickness

At toxic doses
Excitement, agitation, hallucination and coma

Eye
Mydriasis Loss of accommodation for near vision Decrease lacrimal secretion, dry eyes

CVS
Heart: Initially Bradycardia then tachycardia, decrease PR interval Blood vessels: Blockage of EDRF and skeletal muscle vasodilation.
Cutaneous vasodilation

Respirator tract
Bronchodilation Reduced bronchial secretion

Gastrointestinal tract
Decrease salivary and basal gastric secretions, Pirenzepine & Telenzepine gastric acid secretion, M1 blockage Pancreatic and intestinal secretion are less effected Relax GIT wall, Prolong gastric and intestinal transit time

Genitourinary tract
Relax smooth muscles of ureters and bladders Precipitation urinary retention in old people

Sweat Glands
Suppression of thermoregulatory sweating Increase body temperature (Atropine fever in children)

Therapeutic Applications Parkinson Disease

Antimuscarinic agents (Benztropine) , before Levodopa to treat PD

Motion sickness
Scopolamine: Vestibular disorder, seasickness, injection, oral Sedation and dry mouth

Ophthalmic disorders
Measurement of refractive error and examination of retina (Mydriasis) Ointments, Glycopyrrolate and atropine Alpha receptor agonist, Phenylphrine, short mydriasis Drug Atropine Scopolamine Homatropine Cyclopentolate Tropicamide Duration of action 7-10 3-7 1-3 1 0.25 Concentration % 0.5-1 0.25 2-5 0.5-2 0.5-1

Respiratory disorders
Ether anesthesia, Atropine and scopolamine Ipratropium: aerosol inhalants, asthma, COPD Thiotropium: COPD in elderly and smokers, once a day

CVS disorders
Atropine: Vasovagal attack and syncope Auto-antibodies against 2nd M2 loop and Trypanosoma cruzi

GIT disorders
In past used to treat ulcer Atropine + Diphenoxylate (opioid): diarrhea, motility

Urinary disorders
Oxybutynin: M3 antagonist, Oral & via catheter Relieve bladder spasm after prostatectomy, Involuntary voiding Trospium comparable efficacy and side effect as oxybutynin Dairfenacin, Slifenacin, Tolterodine, Fesoterodine: Anti-M3, urinary complications Imipramine, incontinence in old people, replaced by propiverine