Unit 2 - Autonomics II Flashcards
where are muscarinic M1 cholinoreceptors typically located? what are the results of ligand binding?
- CNS neurons
- sympathetic postganglionic neurons
- some presynaptic sites
form IP3 and DAG –> increased intracellular Ca++ (like M3/5)
where are muscarinic M2 cholinoreceptors typically located? what are the results of ligand binding?
- myocardium
- smooth muscle
- some presynaptic sites
- CNS neurons
open K+ channels –> inhibit AC
where are muscarinic M3 cholinoreceptors typically located? what are the results of ligand binding?
- exocrine glands
- vessels (smooth muscle and endothelium)
- CNS neurons
form IP3 and DAG –> increased intracellular Ca++ (like M1/5)
where are muscarinic M4 cholinoreceptors typically located? what are the results of ligand binding?
- CNS neurons
- possibly vagal nerve endings
open K+ channels –> inhibit AC (like M2)
where are muscarinic M5 cholinoreceptors typically located? what are the results of ligand binding?
- vascular endothelium, especially cerebral vessels
- CNS neurons
form IP3 and DAG –> increased intracellular Ca++ (like M3/5)
where are muscarinic nicotinic Nn cholinoreceptors typically located? what are the results of ligand binding?
- postganglionic neurons
- some presynaptic cholinergic terminals
opening of Na+/K+ channels, depolarization (same as Nm)
where are muscarinic Nm cholinoreceptors typically located? what are the results of ligand binding?
- skeletal muscle
- neuromuscular end plates
opening of Na+/K+ channels, depolarization (same as Nn)
for nicotinic receptors, which are at the NMJ and which are at the ganglia?
Nm are at the NMJ
Nn are at the ganglia
which are GPCRs and which are ion channels? nicotinic or muscarinic?
nicotinic are ion channels
muscarinic are GPCRs
explain the muscarinic receptor mechanism
ACh released from postganglionic parasympathetic terminal causes smooth muscle contraction via M3 receptors, PLC activation, PIP2 hydrolysis, IP3 formation, Ca++ mobilization, and MLCK activation
what is pilocarbine?
a nonselective, direct-acting, non-ester muscarinic agonist
what happened in M2 -/- and M3 -/- mice when exposed to muscarinic agonist methacholine (MCh)
M2 -/- mice displayed no decrease in HR during vagal stimulation, but had enhanced bronchoconstriction due to loss of prejunctional autoinhibitory function of M2 receptors on vagal efferents to airway smooth muscle
M3 -/- mice displayed no bronchoconstrictor responses to vagal stimuation
do muscarinic agonists exhibit selectivity?
no selectivity between the 5 receptor types
-certain antagonists do show selectivity
do muscarinic agonists exhibit selectivity?
yes; some show selectivity towards Nn rather than Nm receptors
what is the mechanism of direct-acting cholinomimetic agents?
directly bind to and activate muscarinic or nicotinic receptors
what is the mechanism of indirect-acting cholinomimetic agents?
produce primary effects by inhibiting action of AChE, to increase the concentration of endogenous ACh in synaptic clefts and neuroeffector junctions
- excess ACh stimultes cholinoceptors to evoke increased responses
- act as amplifiers of endogenous ACh and act where ACh is physiologically released
are cholinesterase inhibitors direct-acting or indirect-acting?
some have modest direct action, especially quaternary carbamates (neostigmine activates neuromuscular nicotinic cholinoreceptors in addition to blocking cholinesterase)
what are the 2 groups of direct-acting cholinomimetrics?
- esters of choline (ACh, MCh)
2. non-esters (muscarine and nicotine)
what does the structure of choline esters do for its job?
poorly absorbed by CNS b/c of quaternary ammonium group
- addition of beta-methyl group reduces potency at nicotinic receptors (MCh and bethanechol)
- substitution of carbamic acid group causes resistance to hydrolysis (carbachol and bethanechol)
what is bethanechol and what is it primarily used for?
it is a carbamic acid ester (direct acting cholinomimetic)
-used for postoperative and neurogenic ileus, and urinary retention
are non-choline-ester direct cholinomimetrics absorbed well?
pilocarpine and nicotine are well-absorbed (nicotine through skin)
- muscarine is less well absorbed, but enough to be toxic
- cevimeline is relatively specific for M3 receptors
what do direct-acting cholinoceptor stimulants do to the eye?
- sphincter muscle of iris: contraction (miosis)
- ciliary muscle: contraction for near vision or to reduce intraocular pressure (facilitates outflow of aqueous humor)
what do direct-acting cholinoceptor stimulants do to the heart?
SA node: decrease in HR (negative chronotropy)
atria: decrease in contractile strength (negative inotopy) and refractory period
AV node: decrease in conduction velocity (negative dromotropy), increase in refractory period
ventricles: small decrease in contractile strength
what do direct-acting cholinoceptor stimulants do to the blood vessels?
arteries: dilation (via EDRF - NO), constriction (high-dose direct effect)
veins: dilation (via EDRF - NO), constriction (high-dose effect)
what do direct-acting cholinoceptor stimulants do to the lung?
bronchial muscle: contraction (bronchoconstriction)
bronchial glands: stimulation
what do direct-acting cholinoceptor stimulants do to the GIT?
motility: increase
sphincters: relaxation
secretion: stimulation
what do direct-acting cholinoceptor stimulants do to the urinary bladder?
detrusor: contraction
trigone/sphincter: relaxation
what do direct-acting cholinoceptor stimulants do to the glands?
sweat, salivary, lacrimal, and nasopharyngeal: secretion
where do indirect-acting cholinomimetics have their primary effect?
at the active site of acetylcholinesterase at cholinergic synapses
what is the difference between different indirect-acting cholinomimetics?
chemical and pharmacokinetic differences
-pharmacodynamic properties are identical
what are important cholinesterase inhibitors and their structure?
- neostigmine - ester of carbamic acid, and phenol with quaternary ammonium group
- pyridostigmine is similar to neostigmine
- physostigmine - naturally occuring carbamate and tertiary amine
- edrophonium and donepezil - bind to active site of enzyme (not an ester)
- donepezil - hydrophobic and readily crosses blood brain barrier
what are organophosphate cholinesterase inhibitors? what are they used for?
insecticides
- isoflurophate
- Sarin (nerve gas)
- echothiophate
- parathion
- paraoxon
compare the rates of:
- normal acetylcholinesterase
- neostigmine and other carbamates (indirect)
- edrophonium (indirect)
- sarin (indirect)
- makes choline and acetic acid, plus regenerated enzyme in 0.15 msec
- total 0.5 - 6 hours
- binding, but no covalent bond, so duration of inhibition depends on metabolism
- total is 100s of hours due to aging and irreversibility
what is pralidoxime and its mechanism?
PAM is strong nucleophile cholinesterase inhibitor that regenerates enzyme (acetylcholinesterase) that has been phosphorylated (aged)
what is the condition and response that cholinomimetics have on the eye? do you use direct or indirect drugs?
use both to treat glaucoma
-ciliary muscle contraction and reduced intraocular pressure
what is the condition and response that cholinomimetics have on the GIT? do you use direct or indirect drugs?
use both to treat postoperative atony and adynamic ileus
-GI smooth muscle contraction and increased motility
what is the condition and response that cholinomimetics have on the urinary tract? do you use direct or indirect drugs?
use both for urinary retention
-bladder smooth muscle contraction and emptying
what is the condition and response that cholinomimetics have on the salivary glands? do you use direct or indirect drugs?
use both for xerostomia due to radiation of Sjogren
-increased salivation
what is the condition and response that cholinomimetics have on the NMJ? do you use direct or indirect drugs?
use indirect acting drugs for myasthenia gravis and paralysis induced by non-depolarizing NMJ blocker
- ACh in NMJ and increased muscle strength (myasthenia gravis)
- increased ACh and reversal of paralysis (nerve gas)
what is the condition and response that cholinomimetics have on the CNS? do you use direct or indirect drugs?
use indirect acting drugs for Alzheimer’s
-increased ACh and possible cognitive enhancement
is bethanechol a direct acting or indirect-acting agonist? what are its clinical applications and actions?
direct-acting agonist
- used in postoperative and neurogenic ileus, and urinary retention
- -activates bowel and bladder smooth muscle
is neostigmine a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting agonist
- used in postoperative and neurogenic ileus and urinary retention (like bethanechol) by amplifying endogenous ACh
- used in myasthenia gravis and reversal of neuromuscular blockade by amplifying endogenous ACh to increase skeletal muscle strength
is pilocarpine a direct acting or indirect-acting agonist? what are its clinical applications and actions?
direct-acting drug
- used in glaucoma
- -activates papillary sphincter and ciliary muscles of the eye
is pyridostigmine a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting
- used in myasthenia gravis and reversal of neuromuscular blockade
- -amplifies endogenous ACh and increases skeletal muscle strength
is cevimeline a direct acting or indirect-acting agonist? what are its clinical applications and actions?
direct-acting
-treats dry mouth (xerostomia) by increasing salivation
is edrophonium a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting
- used in myasthenia gravis and reversal of neuromuscular blockade
- -amplifies endogenous ACh and increases skeletal muscle strength
is nicotine (NRT) a direct acting or indirect-acting agonist? what are its clinical applications and actions?
direct-acting agonist
-used to stop smoking by reducing cravings
is physostigmine a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting agonist
- used in glaucoma (eye has lots of NS and M3 receptors)
- -amplifies effects of ACh
is echothiophate a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting agonist
- used in glaucoma (eye has lots of NS and M3 receptors)
- -amplifies effects of ACh
is donepezil a direct acting or indirect-acting agonist? what are its clinical applications and actions?
indirect-acting agonist
-used in Alzheimer’s by amplifying endogenous ACh in brain
what is the structure, use, and approximate duration of action of edrophonium?
alcohol
- myasthenia gravis and ileus
- takes 5-15 minutes
what is the structure, use, and approximate duration of action of neostigmine?
carbamate-related
- myasthenia gravis and ileus
- takes 0.5 to 2 hours
what is the structure, use, and approximate duration of action of pyridostigmine?
carbamate-related
- myasthenia gravis
- 3-6 hours
what is the structure, use, and approximate duration of action of physostigmine?
carbamate-related
- glaucoma
- 0.5 to 2 hours
what is the structure, use, and approximate duration of action of echothiophate?
organophosphate
- glaucoma
- 100 hours
what can occur if there is overdose of cholinomimetics?
SLUDGE Salivation Lacrimation Urination Defecation GI distress Emesis
what can occur if there is toxicity of cholinesterase inhibitors?
SLUDGE + respiratory collapse from CNS effects + skeletal muscle paralysis + bronchospasm
what is therapy for cholinesterase inhibitor toxicity?
atropine and pralidoxime
