cholinergicsVT.doc - I Cholinergic Agonists a Including...

I. Cholinergic Agonists
a. Including both direct acting agonists and indirect acting drugs that inhibit ACHE
b. Learning Objectives for Cholinergic Agonists
i. Describe/explain the processes of ACH synthesis, release and inactivation
ii. Identify sites and effects of muscarinic and nicotinic receptor activation including
receptor subtype locations and effects when activated
iii. Identify intracellular signaling pathways for M1, M2, M3, Nn and Nm receptors
iv. Compare/contrast direct and indirect cholinergic agonists
v. Describe the therapeutic uses, mechanisms of action, and adverse effects of cholinergic
agonists
c. Autonomic Nervous System Dominance
i. Sympathetic: Arterioles (adrenergic), veins (adrenergic) and sweat glands (cholinergic)
ii. Parasympathetic: Everything else!!!
iii. Why is autonomic dominance therapeutically important? Hint: think about what would
happen when you give a drug that blocks either sympathetic or parasympathetic
transmission.
d. Therapeutic Uses of Drugs Affecting Cholinergic Transmission
(as a review exercise, list one drug for each use below)
i. Modulation of GI tone
ii. Xerostomia (dry mouth)
iii. Glaucoma
iv. Motion sickness and antiemesis
v. Neuromuscular disease (e.g., myasthenia)
vi. Neuromuscular block during surgery
vii. Ganglionic block during aortic dissection
viii. Dystonia (abnormal muscle tone, movement)
ix. Vagally-mediated bradycardia
x. Mydriasis
xi. Bronchodilation in COPD/asthma
xii. Bladder spasm/urinary incontinence
xiii. Cosmetic (decrease skin lines and wrinkles)
xiv. Alzheimer’s Disease, dementia
e. Muscarinic Receptor Subtypes
i. M1
1. “neural”, located in cortex, hippocampus, and striatum
2. Involved with learning and memory, implicated in Alzheimer's
ii. M2
1. Heart, negative inotropic (slight) and chronotropic
2. Decreased SA node firing rate, decreased AV node conduction velocity
iii. M3
1. Smooth muscle (contraction) and glands (secretion)
2. Selective M3 antagonists developed for overactive bladder
3. Synthesis of nitric oxide (NO), EDRF; important for vascular relaxation
iv. Ignore M4 and M5
f. Some terms to review
i. Cholinomimetic – a drug that results in the stimulation of ACH receptors, can be either
direct or indirect
ii. Cholinergic – involving the synthesis, release or action of ACH
iii. Anticholinesterase – inhibits ACHE, an acetylcholinesterase inhibitor or ACHEI
iv. Anticholinergic – a drug that blocks ACH receptors, either N or M
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v. Antimuscarinic – a drug that blocks M receptors
vi. Antinicotinic – a drug that blocks N receptors
vii. Miosis – small pupil (constriction of iris sphincter muscle)
viii. Mydriasis – large pupil (relaxation of iris sphincter muscle)
ix. Bradycardia – slow heart rate, decreased SA node firing rate
x. Tachycardia – rapid heart rate, increased SA node firing rate
g. Binding of ACH to M2 receptor
Binds to subunits 3 and 5 (ionic bonding to 3 and hydrogen bonding of carbonyl and ester O to
subunit 5)
h. Classic SAR for Muscarinic Cholinergic Agonists
i. Nitrogen atom capable of bearing a positive charge, preferably a quaternary ammonium
salt
ii.