Term
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Definition
a. Synthesis of ACh in cholinergic nerve terminals from choline and acetyl-CoA by choline acetyltransferase
b. ACh collected in synaptic vesicles
c. Releases of ACh-containing vesicles released from presynaptic terminals after Ca signaling
d. Bind to receptor (nicotinic and muscarinic)
e. Rapid hydrolysis of ACh by acetylcholinesterase |
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Term
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Definition
i. rapidly hydrolyzes (ms) any released ACh
ii. Anticholinesterases block the enzyme and increase ACh levels
1. are indirect agonists |
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Term
| Indirect cholinergic agonists |
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Definition
i. at low or moderate doses: enhance action of ACh at muscarinic receptors
ii. little effect on vascular smooth muscle and BP (unlike direct agonists)
iii. high concentrations: activation of nicotinic receptors including increased muscular contractions and fasciculations, and CNS effects including convulsions |
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Term
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Definition
i. All are G-protein-coupled metabotropic receptors
1. M2 and M4: inhibition of cAMP (alpha i) production and/or activation of voltage-gated K+ channels
a. smooth muscle (decreased cAMP), SA node, atrial muscle (hyperpolarization via K-channel)
2. M1, M2, and M5: activate IP3, diacylglycerol cascade to increase intracellular Ca
a. ciliary muscle |
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Term
| Direct-acting muscarinic agonists (ACh, Carbachol, Bethanechol): Effects |
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Definition
a. Heart: negative chronotropy and inotropy (SA node, atrial muscle)
b. Small blood vessels: cause release of NO
c. Eye: miosis, ciliary muscle
d. Lung: brochoconstriction, secretion
e. Glands: increased secretion (sweat, salivary)
f. GI: increased motility and secretion
g. Bladder: relaxation of sphincter |
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Term
| Direct-acting muscarinic agonists: Rx considerations |
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Definition
a. Adverse effects: hypoTN, diarrhea, vomiting, bronchial constriction, sweating
b. indications for use: overcoming postoperative paralytic ileus, urinary retention, open angle glaucoma
i. Glaucoma
1. most common form is primary open angle closure glaucoma (POAG): have excessive and damaging orbital pressure due to blockage of Canal of Schlemm (aqueous humor)
a. carbachol are used in eyedrops: constrict the iris and ciliary muscle with improves drainage through the trabecular meshwork
b. Timolol (beta-adrenergic antagonist): reduces the productionof aqueous humor by cells in the ciliary body
2. Angle closure glaucoma (narrow angle glaucoma) is much rarer , and usually requires surgery to remove some iris tissue that is blocking the drainage system
c. Contraindications
i. asthma, heart condition, peptic ulcer, GI or urinary tract obstruction, hyperthyroidism (AF) |
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Term
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Definition
i. pentameric, ligand-gated cationic channels permeable to Na+ and K+ and neuronal receptors (NN) also permeable to Ca
ii. skeletal muscle receptor (NM): α1α1β1γε
iii. Neuronal receptors: various subunits
iv. Postsynaptic: Produce depolarization and excitation of neurons and skeletal muscle
v. Presynaptic: enhance release of many NTs (including DA, GABA, glutamate, ACh) in the CNS
vi. Neuronal (NN) Nicotinic Receptors
1. Many subtyupes p[resent in brain and autonomic ganglia and are made up of combinations of nicotinic subunits α2-α10 and β2-β4
2. Major subtype in autonomic ganglia: α3β2
3. Two major subtypes in CNS: α4β2 and α7
4. some agonists and antagonists distinguish between subtypes
vii. Selectivity of Nicotinic Antagonists
1. hexamethonium: α3β2
2. tubocuranine: NM (some α3β2)
3. vecuronium: NM |
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Term
| Muscarinic receptor locations |
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Definition
Postsynaptic: All parasympathetic end organs and the sweat glands
Postsynaptic: Blood vessels (but no cholinergic innervation)
Mostly postsynaptic: many CNS neurons |
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Term
| Nicotinic receptor locations |
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Definition
Postsynaptic: Skeletal muscle (NM)
Postsynaptic: All autonomic ganglia and adrenal medulla (α3β2)
Mostly presynaptic: In CNS (α4β2 and α7) |
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Term
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Definition
a. Loss of cholinergic function (both muscarinic and nicotinic) due to cholinergic neuron damage and death, thus leading to impairments in cognition and memory
b. FDA approved treatments include several anticholinesterases: mechanism of action is to increase ACh levels at CNS synapses
i. Donepezil: crosses BBB, once a day pill, dosing decreases enzyme activity levels about 40%
ii. Rivastigmine: pill or patch (reduced GI upset with once a day patch)
iii. Galantamine: similar to above except also enhances ACh activation of nicotinic receptors by binding to an allosteric site on the nicotinic receptor
c. Improvements in cognition and memory following anticholinesterase Rx are modest. Does not prevent progression of dx
i. Adverse effects: nausea, diarrhea, insomnia |
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Term
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Definition
1. uncharged and readily passes into the brain from the bloodstream
2. potent nicotinic receptor agonist with major effects in CNS and PNS |
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Term
| Nicotine and dopamine release |
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Definition
i. α4β2 receptors important for increased DA release in mesolimbic reward system which produces a pleasurable sensation
1. cigarette smoking double the amount of receptors
ii. α7 in ventral tegmental area
iii. areas involved in craving for cigarettes among smokers: insula, amygdala, thalamus, cerebral cortex, hippocampus |
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Term
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Definition
i. nausea, emesis in naïve users (CTZ stimulation – chemoreceptor trigger zone)
ii. excitation, increased arousal in experienced users (amygdala, thalamus)
iii. some enhancements of short-term learning and memory, especially due to increased attention to task at hand (cortex, hippocampus, thalamus)
iv. relaxation in experienced users
v. Addiction: DA in the nucleus accumbens
vi. Craving |
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Term
| Nicotine and peripheral effects |
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Definition
i. all autonomic ganglia and the adrenal medulla are stimulated
ii. increased blood pressure and heart rate : sympathetic and adrenal medulla stimulation (CV dx)
iii. less effect on skeletal muscle
iv. GI: increased tone and activity |
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Term
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Definition
a. aid in smoking cessation: 75% fail
b. ulcerative colitis
c. Tourette’s syndrome |
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Term
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Definition
1. partial agonist of α4β2 nicotinic receptors (~30-60% efficacy)
2. take one week before quitting attempt
3. Potential adverse effects: neuropsychiatric sx, |
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Term
| Indirect acting antagonists |
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Definition
| edrophonium, neostigmine, physostigmine, donepezil, rivastigmine, galantmine, sarin |
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Term
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Definition
1. myasthenia gravis, paralytic ileus
2. 5-10 min |
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Term
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Definition
1. myasthenia gravis, gut and bladder atony, paralytic ileus after abdominal surgery
2. .5-2h
3. does not cross BBB
4. give with atropine to reduce unwanted muscarinic receptor activation
5. can reverse paralysis caused by skeletal muscle blockers such as vecuronium |
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Term
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Definition
1. Glaucoma (miotic)
2. 0.5-2h
3. lipid soluble so can cross BBB |
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Term
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Definition
1. Alzheimer’s
2. 24 h
3. once a day pill, decreases enzyme activity levels about 40% |
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Term
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Definition
1. Alzheimer’s
2. 12 h
3. pill or patch (reduced GI upset with once a day patch) |
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Term
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Definition
1. Alzheimer’s
2. 12 h
3. similar to donepezil and rivastigmine, also enhances ACh activation of nicotinic receptors by binding to an allosteric site on the nicotinic receptor |
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Term
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Definition
1. >4 h
2. Effects
a. irreversible anticolinesterases: organophosphorus nerve gases, which are volatile liquids that are readily aerosolized and extremely toxic – lipid soluble so any exposure to skin will allow the toxin into the body
b. Progressive symptoms include:
i. SLUD: salivation, lacrimation, urination, defecation
ii. bronchoconstriction, miosis, sweating, Bradycardia, hypotension, pulmonary edema (muscarinic)
iii. respiratory paralysis (desensitized muscle nAChRs), twitching (nicotinic)
iv. ataxia, confusion, convulsions, coma
3. Treatment:
a. Atropine (block excess mucarinic activation)
b. Pralidoxime (can reactivate acetylcholinesterase) |
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Term
| Botulinum (ACh release inhibitor) |
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Definition
1. reduces wrinkles – inject locally into muscle to produce relaxation
2. FDA approved local IM injection in blepharospasm, hemifacial spasm, spasms in muscular dx, and cosmetic
3. Effect
a. potent protein neurotoxin that blocks release of ACh from cholinergic nerve terminals by cleaving SNAP-25, a protein required for release of synaptic vesicles (lasts several months but does wear off)
b. Adverse: excessive muscle paralysis |
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Term
| Muscarinic antagonist effects |
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Definition
1. Heart: tachycardia (may see brady cardia at subtherapeutic doses due to central effect), blunted reflexes
2. Eye: prolonged mydriasis – dangerous in acute angle glaucoma
3. Glands: secretion inhibited
4. GI and urinary: antispasmodic, constipation, urinary retention
5. CNS: excitement, possible hallucinations
6. Blood vessels: little or no effect because there is no ACh innervation of vessels |
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Term
| Types of muscarinic antagonists |
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Definition
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Term
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Definition
a. Crosses BBB
b. Used in preanesthetic medication (reduces secretions, relax bronchi), antispasmodic, antidiarrheal |
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Term
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Definition
a. Quaternary amine – does not enter CNS
b. Use: bronchodilation in COPD
i. prepared as a suspended inhalational aerosol, limited systemic absorption
ii. marked reduction of symptoms such as wheezing |
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Term
| Hexamethonium (nicotinic antagonist) |
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Definition
1. Effects (site-predominant tone-effect of ganglionic blockade)
a. Arterioles – sym (adrenergic) – vasodilation, increased peripheral blood flow, hypotension
b. Veins – sym (adrenergic) – dilation, peripheral pooling of blood, decreased venous return, decreased cardiac output
c. Heart – para (cholinergic) – tachycardia
d. Iris – para (cholinergic) – mydriasis
e. ciliary muscle – para (cholinergic) – cycloplegia (focus on far vision)
f. GI tract – para (cholinergic) – reduced tone and motility, constipation, decreased gastric and pancreatic secretions
g. Urinary bladder – para (cholinergic) – urinary retention
h. salivary glands – para (cholinergic) – xerostomia
i. sweat glands – sympathetic (cholinergic) – anhidrosis
j. genital tract – sym and para – decreased stimulation |
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Term
| Trimethaphan (nicotinic antagonist) |
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Definition
| currently the only clinically available ganglionic blocker – used in acute aortic aneurysm to rapidly control BP and block reflexes) |
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Term
| Non-depolarizing skeletal muscle blockers |
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Definition
can be reversed by neostigmine and atropine by overcoming blockade at NMJ, Drug interactions: inhalation anesthetics and aminoglycoside antibiotics; both will augment the blockade by nondepolarizing blocker
tubocurarine, vecuronium |
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Term
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Definition
i. long-acting (2 hr) muscle paralysis s muscle analgesia
ii. used to eliminate muscle movements during surgery, produces hypotension due to both direct action on mast cells to release histamine and to some blockade of neuronal nicotinic receptors in autonomic ganglia
iii. does not cross BBB |
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Term
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Definition
i. similar to tubocurarine, except shorter duration of action (1-1.5 hr) and much less hypotension and histamine release
ii. used in surgery |
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Term
| succinylcholine (depolarizing skeletal muscle blocker) |
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Definition
i. very rapid onset (<1min) and short-acting (5-10 min), metabolized by cholinesterase (do not use neostigmine to reverse)
ii. Use: rapid sequence induction endotracheal intubation, often under emergency conditions (rapid procedures reduce risks of gastric aspiration and does not increase intracranial pressure)
iii. adverse:
1. unpleasant muscle fasciculations may occur during Phase 1 (activation)
2. Caution: with atypical cholinesterase, the enzyme does not readily metabolize succinylcholine and the effects will be pronounce and prolonged
3. can produce malignant hyperthermia (treated with dantrolene – blocks Ca relaease from SR in skeletal muscle)
4. will increase K+ release from musclehyperkalemia and cardiac arrhythmias so contraindicated in renal failure, burn patients, multiple trauma or when have large areas of denervated muscle |
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Term
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Definition
| cholinesterase reactivator, used in sarin poisoning |
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