1. HuBio 543 September 24, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Muscarinic Antagonists

2. 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

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

6. 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

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

11. 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

12. 80 60 40 20 0 2 1 0.5 Salivary Secretion (-) Micturition Speed (-) Heart Rate (+) Accomodation (-) Increase or Decrease (%) Atropine (mg/70 kg) Sensitivity of Target Organs to Atropine

13. 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

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

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

16. 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

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

18. N-methylatropine does not cross membranes as well as atropine

19. 80 60 40 20 0 100 Cumulative Adsorption (%) Atropine N-methylatropine Distance From the Nose (cm.) 100 200 150 50

20. 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

23. 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

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

25. Rates of Hospitalization in Control and Ipratropium Groups 0 10 20 30 40 50 60 Control Ipratropium Patients Hospitalized (%) All Patients Moderate Asthma Severe Asthma

26. Patient compliance is a big problem Patients prescribed ipratropium inhalers: -Self- reported compliance was 60- 70% -This was confirmed by canister weight BUT: Compliance was also determined by electronic monitoring and found to be much poorer

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

28. 14% of patients actuated inhaler more than 100 times on the day of a visit. Patients want to be liked by their physicians

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

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

31. 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

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

33. 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

34. 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

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