1. Overview - Indirect cholinergic agonism (AchE inhibition)
- Muscarinic antagonism (emphasis on drugs and organ effects)
- Nicotine-Ach receptor (emphasis on drugs and therapeutics)

2. Indirect cholinergic agonists
Inhibitors of acetylcholinesterase
Increase acetylcholine concentration and lifetime by
inhibiting degradation
Act by binding to AchE active site causing reversible
(non covalent) or long lasting (covalent modification)

3. Mechanisms of indirect agonism
- Quaternary alcohols (ephodronium) – reversible binding (limit acetylcholine access)
Non covalent – enzyme-inhibitor complex lifetime ( minutes)
Carbamate esters – neostigmine, physostigmine – reaction with AchE active site
Covalent carbamoylation – enzyme-inhibitor complex lifetime ( h)
Organophosphates – Parathion, Sarin, Soman - phophorylates AchE active site
Covalent phosphorylation – very stable enzyme-inhibitor complex, days (especially after aging)

4. AchE Inhibitors (quaternary alcohols and carbamates)

5. Organophosphates

6. Aging

7. Organ effects/therapeutic uses
- Effects are due to acetylcholine accumulation and are both sympathetic and parasympathetic
USES Approx Duration
ALCOHOLS
Edrophonium Myasthenia gravis 5 – 15 minutes
arrythmias
CARBAMATES
Neostigmine Myasthenia gravis 0.5 – 2h
Pyridostigmine Myasthenia gravis 3 – 6h
Physostigmine Glaucoma 0.5 – 2h
Demecarium Glaucoma 4 – 6h
Organophosphates
Echotiophate Glaucoma 100 h (> 4 days)

8. Treatment of organophosphate poisoning
1 - maintenance of vital signs (respiration particularly important)
2 - Decontamination (to avoid further absorption)
3 - Atropine parenterally (to minimize muscarinic effects) as required
4 - Rescue of AchE activity with Hydroxylamines (Pralidoxime, Diacetylmonoxime)

9. Muscarinic antagonism
Attropa belladona

10. Muscarinic Antagonists
ATROPINE
SCOPOLAMINE

11. Muscarinic Antagonists
ATROPINE
Attropa belladona
SCOPOLAMINE
Atropine and Scopolamine are belladona alkaloids (competitive inhibitors)
Drugs differ in their CNS effects, scopolamine permeates the blood-brain barrier
At therapeutic doses atropine has negligible effects upon the CNS, scopolamine even at low doses has prominent CNS effects.

12. Mechanism of drug action
Competitively block muscarinic receptors
- Salivary, bronchial, and sweat glands are
most sensitive to atropine
- Smooth muscle and heart are intermediate
in responsiveness
In the eye, causes pupil dilation and difficulty for far vision accomodation
Relaxation of the GI, slows peristalsis

13. History/sources Atropa belladona - used in the renaissance
Deadly nightshade - used in the middle ages to produce prolonged poisoning
Jimson plant leaves burned in India to treat Asthma (1800) purification of atropine (1831)

14. Effect of muscarinic inhibitor in the eye
Pupil dilation vs accomodation

15. Effect of muscarinic inhibition in the heart and salivary glands
Increases the heart rate after a transient bradychardia at the low dose
Diminishes gland excretory function

16. Graphic summary of atropine effects

17. Organ effect – drug review Antidotes
ORGAN DRUG APPLICATION
CNS Benztropine Treat Parkinson’s disease
Scopolamine Prevent/Reduce motion sickness
Eye Atropine Pupil dilation
Bronchi Ipatropium Bronchodilate in Asthma, COPD
GI Methscopolamine Reduce motility/cramps
GU Oxybutinin Treat transient cystitis
Postoperative bladder spasms

18. Toxicity of muscarinic antagonists
“DRY AS BONE, RED AS A BEET, MAD AS HATTER.”
Dry is a consequence of decreased sweating, salivation and lacrimation
Red is a result of reflex peripheral (cutaneous) vasodilation to dissipate heat (hyperthermia)
Mad is a result of the CNS effects of muscarinic inhibition which can lead to sedation, amnesia (hypersensitivity), or hallucination

19. Nicotinic – Acetylcholine Receptor
polarized
Relaxation
depolarized
contraction

20. Signaling through Ach-nicotinic receptor (competitive and depolarizing blockers)

21. Competitive/depolarizing
Binds and locks the receptor
open
Competitive
Physically blocks
Ach binding
INHIBITOR

22. Examples of competitive/depolarizing drugs
Mivacurium
Tubocurarine
Depolarizing
AchE
Butyrylcholinesterase
Sensitive sites
Succinylcholine

23. Clinical uses
Adjuvant use in surgical anesthesia (muscular relaxation)
Advantage – much lighter levels of anesthesia required
Other uses: muscular relaxation for orthopedics (correction of dislocation/alignment of fractures)
(short duration) – facilitate intubation, laryngoscopy, bronchoscopy, esophagoscopy
Control of muscular spasms, strabism, hemifacial spasms, oromandibular and cervical dystonia, spasms of the lower esophageal sphincter
Cosmetic – Bottox (Botulinum toxin A)
Paralytic action on skeletal muscle

24. Agents/Features/Duration
AGENT CLASS PROPERTY ONSET DURATION
Succinylcholine Dicholine ester Depolarization min – 8 min
Tubocurarine Alkaloid Competitive min – 120 min
Atracurium Benzylisoquinoline Competitive min – 60 min
Mivacurium Benzylisoquinoline Competitive min – 18 min
Pancuronium Ammonio Steroid Competitive min – 180 min
Vecuronium Ammonio Steroid Competitive min – 90 min
Hydrolysis by esterases
Liver clearance/renal elimination
Both

25. Precautions/Toxicity
- Prolonged apnea, cardiovascular collapse
Sequence of paralysis : Eye muscles, Jaw, Larynx, limbs and trunk, intercostal muscles and the dyaphragm
Generally caused by diminished esterase activity, renal malfunction, liver insufficiency, poor circulatory function.
Special caution in patients with electrolyte imbalance (K+)
Antidote : Neostigmine/Ephodronium to increase Ach, and atropine to block Ach muscarinic stimulation.
Malignant hyperthermia – results from a discharge of Ca2+, exacerbated muscular action – tachycardia, hyperthermia, acidosis and rigidity (mutations of RYR1, central core disease) treated with Dantrolene, preservation of respiration

26. Summary Ach pilocarpine Muscarine Bethanechol Neostigmine**
Edrophonium**
Atropine
Scopolamine
Tubocurarine
Mivacurium
Tetrodoxin
Batrachotoxin X X
Hemicholinium
Botulinum toxin X
Curare alkaloids
Snake venom α X
Dantrolene X
AchE inhibitors X
Hydrolysis
Ach
** Indirect

27. Movie
Nicotine in the brain