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HuBio 543 September 24, 2007

HuBio 543 September 24, 2007. Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Muscarinic Antagonists. C. C. H 2 C. CH 2. CH. CH 2 OH. CHO. NCH 3. C. H. CH 2. CH. H 2 C. O. O. C. CH 2. CH. CH 2 OH. CHO. NCH 3. C. O. H. CH 2. C. CH.

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HuBio 543 September 24, 2007

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

  2. C C H2C CH2 CH CH2OH CHO NCH3 C H CH2 CH H2C O O C CH2 CH CH2OH CHO NCH3 C O H CH2 C CH Tertiary Muscarinic Antagonists Atropine H H Scopolamine

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

  4. 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

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

  6. 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 MR High doses: Block mAChR on heart- Block effects of ACh, increases HR

  7. 80 Salivary Secretion (-) 60 Micturition Speed (-) Heart Rate (+) 40 Increase or Decrease (%) 20 Accomodation (-) 0 2 1 0.5 Atropine (mg/70 kg) Sensitivity of Target Organs to Atropine

  8. Toxic Effects of 3o 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

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

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

  11. H2C CH2 CH CH2OH C C + CHO NCH3 C H3C H CH2 CH H2C O O H2C CH2 CH CH2OH + CHO NCH3 C (H3C) 2HC H CH2 CH H2C Quaternary Muscarinic Antagonists N-methylatropine Ipratropium

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

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

  14. 100 80 Cumulative Adsorption (%) Atropine 60 40 20 N-methylatropine 0 200 150 50 100 Distance From the Nose (cm.) N-methylatropine does not cross membranes as well as atropine

  15. 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

  16. 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

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

  18. 60 Control Ipratropium 50 Patients Hospitalized (%) 40 30 20 10 0 Severe Asthma All Patients Moderate Asthma Rates of Hospitalization in Control and Ipratropium Groups

  19. 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

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

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

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

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

  24. 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

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

  26. Subtypes of mAChR • Five different mAChR in humans (all in CNS) • M1- in sympathetic ganglia (and adrenal medulla), activated by McN-A-343, blocked by pirenzepine • M2- cardiac mAChR; can contribute to contraction of some smooth muscles; a presynaptic receptor on some nerve terminals • M3- mediates contraction of smooth muscle, relaxation of vasculature, and secretion from many glands

  27. Cevimeline • Selective M3 agonist • Used for treatment of xerostomia and Sjorgren’s syndrome • Long-lasting sialogogic agent • May have fewer side effects than pilocarpine Tiotropium • Selective M3 antagonist • Very slow dissociation from M3 mAChR • 4° antagonist • like ipratropium, is an inhaled bronchodilator • Used for treatment of COPD

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

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