HuBio 543 September 24, 2007 Neil M. Nathanson K-536A, HSB Muscarinic Antagonists

Atropine H2CH2C H2CH2C CH NCH 3 CH CH 2 CHO O C C CH 2 OH H C C CH NCH 3 CH CH 2 CHO O C C CH 2 OH H O H H Scopolamine Tertiary Muscarinic Antagonists

Tertiary Antagonists Atropine * Scopolamine * Homatropine Tropicamine Tolterodine Oxybutynin Quaternary Antagonists N- methyl atropine * N- methyl scopolamine Ipratropium * Propantheline Tiotropium*

Why the biphasic dose-response curve to atropine? 1. CNS- Low doses of atropine may act preferentially in the CNS to increase parasympathetic outflow 2. Presynaptic effect- Low doses of atropine may act preferentially on presynaptic mAChR on parasympathetic terminals, resulting in increased ACh release onto the heart

Therefore: Less ACh is released, Heart Rate is not slowed as much

Biphasic Effect of Atropine on Human Heart Rate Low doses preferentially: 1. Act in CNS to increase parasympathetic outflow- decreases HR 2. Blocks presynaptic receptor on parasympathetic nerve terminal-increases ACh release, decreases HR Parasymp. Ganglion MR High doses: Block mAChR on heart- Block effects of ACh, increases HR

Salivary Secretion (-) Micturition Speed (-) Heart Rate (+) Accomodation (-) Increase or Decrease (%) Atropine (mg/70 kg) Sensitivity of Target Organs to Atropine

Toxic Effects of 3 o mAChR Antagonists Visual problems Constipation and urinary retention Glaucoma in predisposed individuals Hallucinations and delirium Decreased sweating and salivation Erectile problems/impaired vaginal lubrication Can use AChE inhibitors as an antidote

Tricyclic anti-depressants can act as mAChR antagonists (of smooth muscle)

Physostigmine reverses anti- muscarinic CNS effects of tricyclic anti-depressants

Ipratropium N-methylatropine H2CH2C H2CH2C CH NCH 3 CH CH 2 CHO O C C CH 2 OH H (H 3 C) 2 HC + H2CH2C H2CH2C CH NCH 3 CH CH 2 CHO O C C CH 2 OH H H3CH3C + Quaternary Muscarinic Antagonists

Tertiary Antagonists Atropine * Scopolamine * Homatropine Tropicamine Tolterodine Oxybutynin Quaternary Antagonists N- methyl atropine * N- methyl scopolamine Ipratropium * Propantheline Tiotropium*

N-methylatropine does not cross membranes as well as atropine

Cumulative Adsorption (%) Atropine N-methylatropine Distance From the Nose (cm.)

Therapeutic uses of mAChR Antagonists (Preanesthetic medication) Ophthalmological- mydriasis and cylcoplegia GI and Urinary Tract- decrease tone & motility Decrease excessive sweating CV- block vagally-mediated bradycardia CNS- motion sickness Respiratory tract- bronchodilation

Therapeutic uses of mAChR Antagonists (Preanesthetic medication) Ophthalmological- mydriasis and cylcoplegia GI and Urinary Tract- decrease tone & motility Decrease excessive sweating CV- block vagally-mediated bradycardia CNS- motion sickness Respiratory tract- bronchodilation

Lumen Gland SMOOTH MUSCLE Cholinergic Innervation Lumen Cholinergic Innervation of the Airways

Rates of Hospitalization in Control and Ipratropium Groups Control Ipratropium Patients Hospitalized (%) All Patients Moderate Asthma Severe Asthma

Patient compliance is a big problem Patients prescribed ipratropium inhalers: -Self- reported compliance was % -This was confirmed by canister weight BUT: Compliance was also determined by electronic monitoring and found to be much poorer

Medilog: electronic inhaler monitor Monitoring showed that only 15% of subjects actually used the inhaler as prescribed.

14% of patients actuated inhaler more than 100 times on the day of a visit. Patients want to be liked by their physicians

From CNS ACh N Synaptic Transmission Through a Sympathetic Ganglion: To Target M Main Pathway Modulatory Pathway

Effect of Ganglionic Stimulants + Hexamethonium: + DMPP BP HR + McN-A-343

Muscarinic Receptors in Sympathetic Ganglia Excitatory (normally modulate transmission through the nicotinic pathway) Selectively activated by McN-A-343 (McN-A-343 therefore causes increased BP) Selectively blocked by pirenzepine

% Receptors Blocked DRUG CONCENTRATION Atropine (atria or ganglia) Pirenzepine (ganglion) Pirenzepine (atria) Pirenzepine Selectively Blocks mAChR in Sympathetic Ganglia

Subtypes of mAChR Five different mAChR in humans (all in CNS) M 1 - in sympathetic ganglia (and adrenal medulla), activated by McN-A-343, blocked by pirenzepine M 2 - cardiac mAChR; can contribute to contraction of some smooth muscles; a presynaptic receptor on some nerve terminals M 3 - mediates contraction of smooth muscle, relaxation of vasculature, and secretion from many glands

Cevimeline Selective M 3 agonist Used for treatment of xerostomia and Sjorgren’s syndrome Long-lasting sialogogic agent May have fewer side effects than pilocarpine Tiotropium Selective M 3 antagonist –Very slow dissociation from M 3 mAChR –4° antagonist –like ipratropium, is an inhaled bronchodilator Used for treatment of COPD

Effect of Ganglionic Stimulants + Hexamethonium: + DMPP BP HR + McN-A-343