1. choline come into presyn cell via Na cotransport
2. acetyl CoA made in mit.
3. acetyl Coa and choline make Ach
4. VAT brings ACH into vesicle via H antiport
5. ACh released via Ca release
6. ACh can act on post syn cell or ACh autoreceptor on presyn cell

ALL are G couple metabotropic receptors.

• M2, M4- inh. cAMP production and/or activation of voltage gated potassium channels
  • inh. cAMP- smooth musc.
  • activate potassium channel- hyperpolarization at SA node and atrial muscle
• M1, M3, M5- activate IP3 and DAG cascade to increase intracellular calcium

ALL are pentameric, ligand gated cationic channels permeable to Na, K, and neuronal receptors also permeable to calcium.

• skel musc. R (N_m) subunits-alpha1alpha1 beta1gammaepsilon
• neuronal R (N_n)- various subunits
• postsyn. effects
  • produce depol. and excitation of neurons and skel. muscle
• presyn. effects
  • enhance release of many NT's in CNS
    • dopamine
    • GABA
    • Glu
    • ACh

• alpha 4-beta 2
• alpha 7

• alpha bungarotoxin
• kappa bungarotoxin
• tubocurarine

• post syn.- all parasymp. end organs and sweat glands
• post syn.- bv's (but no cholinergic innervation)
• mostly post synaptic- many CNS neurons

• post syn.- skeletal muscle
• post syn.- all autonomic ganglia and adrenal medulla (alpha 3 beta 2)
• mostly presyn. in CNS (alpha 4-beta 2 and alpha 7)

• ACh (hit nicotinic R at high doses)
• carbachol (hit nicotonic R at high doses)
• bethanechol (only one that does not hit nicotinic R under any dose)

• heart- negative chronotropy and inotropy (SA node, atrial muscl)
• small bv's- release NO, dilate bvs, decrease bp
• eye- miosis, constrict ciliary musc.
• lung- bronchoconstriction, secretion
• glands- increase secretion (sweat, salivary)
• GI- increase motility and secretion
• bladder- relax sphincter

• hypotension
• diarrhea
• vomitting
• bronchial constriction
• sweating

• overcome post op paralytic ileus
• urinary retention
• open angle glaucoma

• asthma
• heart condition
• peptic ulcer
• GI or UT obstruction
• hyperthyroidism (cause atrial fibrillation)

• excessive and damaging orbital pressure due to blockage of aqueous humor drainage into Canal of Schlemm

• carbachol (eyedrops)- miotics (constrict iris and ciliary muscle) allowing for drainiage in trabecular meshwork to improve
• timolol (beta blocker)- reduce prod. of aqueous humor by cells in ciliary body

• nicotine signals ventral tegumental area which stimulates nucleus accumbens to release dopamine
• nicotine increases dopamine release in nucleus acumbens
  • alpha 4 beta 2 R's important for increased dopamine release in mesolimbic reward system (produce pleasurable sensation)
  • smoking doubles amount of alpha 4 beta 2 nicotinic R's in brain
• prolonged nicotine use cause desensitization
  • first cigarrete activate most R's and less get activated throughout the day
  • nicotinic levels cleared each night
• also involves:
  • amygdala
  • insula
  • thalmus
  • cerebral cortex
  • hippocampus

• nausea, emesis to naive uses (CTZ stim)
• excitation, increased arousal in experienced users (amygdala, thalamus)
• some enhancement of short term learning and memory, especially due to increased attention to task at hand
  • cortex, hippocampus, thalmus
• relaxation in experienced users
• addiction
  • drug seeking behavior even in face of known risk to health due to increase release in dopamine from NA
• craving

• all autonomic ganglia and adrenal medulla are stimulate
• incerase bp and HR due to comb of symp. and adrenal medulla stimulation (cause of CV disease)
• less effect on skel. muscle
• GI- increase tone and activity

• smoking cessation
  • reduce withdrawal symptoms
    • irritability
    • headaches
    • no concentration
    • craving cigarrettes
• reduce symptoms of:
  • ulcerative colitis
  • Tourette's syndrome

• Buproprion
• Varenicline

• antidepressant drug
• effects on DA and NE systems CNS help in smoking cessation

• partial agonist at alpha 4 beta 2 nicotinic R
• activate nicotinic R, but not as much as nicotine would
• allows for aiding in smoking cessation
• take twice daily beginning one week prior to quit attempt (start blocking nicotine effects while still smoking)

• neuropsyc symptoms
  • depression
  • suicidal ideation
  • attempted suicide

• ACh
• carbachol
• bethanechol
• nicotinic
• varenicline

• edrophonium
• neostigmine
• phyostigmine
• donepezine
• rivastigmine
• galantamine
• sarin

atropine

ipratroprium

hexamethonium

tubocurarine

vecuronium

succinylcholine