Cholinergics Flashcards
What are the direct-acting Ach agonists?
- Ach (not useful as a drug)
- carbachol
- bethanechol
- nicotine
- varenicline
What are the indirect-acting Ach agonists?
- neostigmine
- physostigmine
- doenpezil
- sarin (no therapeutic value)
What chemicals and enzyme synthesize Ach in cholinergic nerve terminals?
choline + acetyl-CoA
choline acetyltransferase (ChAT)
What enzyme rapidly breaks Ach down in the synaptic cleft?
Acetylcholinesterase
What are the two major types of cholinergic receptors?
nicotinic
muscarinic
What kind of Ach receptor are all G-protein-coupled metabotropic receptors?
Muscarinic
What are the two types of muscarinic receptors and what do they do?
- Evens (M2 and M4) - inhibition of cAMP production (stimulates smooth muscle) or activation of voltage-gated K+ channels (inhibits smooth muscle)
- M1, M3, and M5 - activate IP3, diacylglycerol cascase to increase intracellular Ca2+ (stimulates smooth muscle)
What specific muscle do the M2 and M4 cAMP inhibiting receptors act on?
contracts GI muscle
What specific muscle do the M2 and M4 K+ GTP receptors act on?
SA node cells (hyperpolarizes and slows HR)
What specific muscle does the M1, M3 and M5 receptors act on?
Ciliary muscle - increased Ca2+ contracts
Skeletal muscle postsynaptic receptors are what type?
Nicotinic
Postsynaptic autonomic ganglia and adrenal medulla receptors are what type?
nictonic
Presynaptic receptors in the CNS are what type?
mostly nicotinic
Postsynaptic receptors on parasympathetic end organs and sweat glands are what type?
muscarinic
What type of Ach receptor is on the postsynaptic receptors of the CNS?
Mostly muscarinic
What is an important effect of direct acting muscarinic agents on small blood vessels?
causes release of NO which dilates vessels and decreases BP
What are the direct-acting muscarinic agonists?
- carbachol
- bethanechol
what type of drug is carbachol?
direct-acting muscarnic agonist
*also a nicotinic agonist at high doses
what type of drug is bethanechol?
direct-acting muscarinic agonist
Which muscarnic agonists are not broken down by Achesterase?
carbachol and bethanechol
What are the indications for the direct-acting muscarinic agonists?
- paralytic ileus (post-operative)
- urinary retention
- carbachol eyedrops in wide (open) angle glaucoma
What are the adverse effects of the direct-acting muscarinic agonists?
- hypotension
- diarrhea
- vomiting
- bronchial constriction
- sweating
Who is contraindicated from receiving direct acting muscarinic agonists?
- asthma
- heart conditions
- peptic ulcer
- GI or urinary obstruction
- hyperthyroidism (a fib)
What are the effects of the muscarinic antagonists?
- tachycardia
- blunted reflexes
- mydriasis
- inability to sweat
- constipation
- urinary retention
- GI antispasmodic
- possible hallucinations
What kind of drug is atropine and what does it do?
muscarinic antagonist
- preanesthetic medication (reduce secretions, relax bronchi)
- antispasmodic
- antidiarrheal
*crosses the BBB
What kind of drug is ipratropium and what does it do?
muscarinic antagonist
- bronchodilation in COPD
*stays in lungs, limited Vd
What kind of receptors are nicotinic?
excitatory ligand gated ion channels
permeable to Na+ and K+
*Nicotinic neuronal also permable to Ca2+
What is the role of postsynaptic nicotinic receptors?
produce depolarization and excitation of neurons and skeletal muscle
Where does Ach bind to nicotinic receptors?
The alpha subunit
What is the function of presynaptic nicotinic receptors?
enhance release of many other neurotransmitters in the CNS
vecuronium is highly specific for which receptor subtype?
NM
(Muscular)
What drug is a potent nicotinic receptor agonist?
nicotine
*uncharged and readily passes into the BBB
What does nicotine do in the brain?
Binds to presynaptic nicotinic Ach receptors, which causes Ca2+ to enter and excitatory NTs to be released
How does nictoine become addictive?
increases the release of dopamine in the midbrain reward pathway, particularly in the nucleus accumbens
leads to pleasurable feeling
*same circuit as compulsive gambling
What is the midbrain reward circuit for nicotine?
alpha 7 Ach presynaptic receptors on glutamate neurons–> ventral tegmental dopaminergic neurons –>dopmaine nucleus accumbens –>prefrontal cortex
Note that nicotine also binds to alpha4beta2 Ach presynaptic receptors in the ventral tegmental and nucleus accumbens to enhance dopamine release
What are withdrawal symptoms from nicotine?
headache
irritability
inability to concentrate
weight gain
What receptors in the brain are double in amount in smokers, leading to tolerance?
alpha4 beta 2 nicotinic
What are some CNS effects of nicotine in naive users?
nausea and emesis
excitation, increased arousal
increased attention
What are some CNS effects of nicotine in experienced users?
excitation, increased arousal
increased attention
relaxation
addiction
craving
What are the peripheral effects of nicotine?
increased BP
increased HR
stimulation of all autonomic ganglia and adrenal medulla
GI: increased tone and activity
What is a clinical use of nicotine?
smoking cessation (nicorette)
Is vaping a good alternative to cigarette smoking?
Yes and No
fewer carcinogens in vapor
we don’t know the safety of flavors/propylene glycol/glycerin in vaping products
What are some of the smoking cessation drugs?
nicotine replacement
buproprion (antidepressant)
varenicline (chantix)
What is the mechanism of action of varenicline?
partial agonist at alpha4 beta2 nicotinic receptors
binds with 30-60% efficacy, competes with nicotine for access to these receptors
BLACK BOX: for neuropsychiatric symptoms, including depression, suicidal ideation
