Lecture 8 Flashcards
what kind of receptors are muscarinic receptors
G-protein coupled receptors
what kind of receptors are nicotinic receptors
cation-selective ion channels
muscarinic receptors contain ______ transmembrane domains.
the ____ cytoplasmic loop is coupled to _______ that function as _______
7 transmembrane domains
3rd cytoplasmic loop is coupled to G proteins that function as TRANSDUCERS
true or false
all muscarinic receptors are GPCR’s
true
location of M1
nerves
location of M2
heart
nerves
smooth muscle
location of M3
glands
smooth muscle
endothelium
location of M4
CNS
location of M5
CNS
what is another name for M2
cardiac M2
postreceptor mechanism of M1
IP3, DAG cascade
(Gq!)
postreceptor mechanism of M2
Gi
inhibits cAMP production, activates K+ channels
results in decreased heart rate - good for HTN pts
post receptor mechanism of M3
IP3, DAG cascade
(Gq!)
postreceptor mechanism of M4
inhibits cAMP production
Gi
postreceptor mechanism of M5
IP3, DAG cascade (Gq)
structural features of M1, M3, M5
seven transmembrane segments
Gq/11 protein-linked
structural features of M2, M4
seven transmembrane segments
Gi/o protein-linked
TRUE OR FALSE
NM and NN have the same postreceptor mechanism
TRUE
Na+, K+ depolarizing ion channel
location of Nm
skeletal muscle – neuromuscular junction
location of Nn
CNS -
postganglionic cell body, dendrites
structural features of Nn, Nm
pentamer
early studies on the effects of muscarine were termed……..
what does this mean?
parasympathomimetic
does not increase the amount of neurotransmitter, but mimics the neurotransmitter
muscarine has action on receptors on effector cells
alkaloid nicotine stimulates _________ but NOT _______
stimulates autonomic ganglia and NMJ at skeletal muscle, but NOT autonomic effector cells
relaxes our muscles and makes us feel good
name 2 types of drugs that can be considered cholinergic agonists, but 1 is direct and 1 is indirect
DIRECT = drugs that activate cholinoreceptors. true agonists
INDIRECT = cholinesterase inhibiting drugs. not a true agonist, but produces the same effect by preventing the degradation of ACh
what can be considered ACh “amplifiers”
cholinesterase inhibiting drugs
true or false
a drug cannot be selective to nicotinic or muscarinic receptors
FALSE - they can
explain how some drugs are selective for certain nicotinic receptors
some drugs stimulate the nicotonic receptors at NMJ and have less effect on the nicotinic receptors in the autonomic ganglia
how can organ selectivity of drugs for nicotonic/muscarinic receptors be achieved?
give an example
by using different routes of administration
muscarinic stimulants can be administered to the eye to modify ocular function while also minimizing systemic side effects
what is “pharmacokinetic selectivity”
achieving organ selectivity by using different routes of administration
which cholinoreceptor is found in the nerves
M1 (also M2 but mainly M1)
which Cholinoreceptor is found in the heart and smooth muscle?
M2
(M3 also smooth muscle)
which cholinoreceptor is found in the glands and endotheloium?
M3
name 2 types of drugs that are DIRECT ACTING cholinergic stimulants
choline and carbamic acid esters
cholinomimetic alkaloids
name 2 types of drugs that are indirect acting cholinergic stimulants
carbamates
organophosphates
true or false
cholinomimetic alkaloids are indirect acting cholinergic stimulants
FALSE - direct acting
true or false
carbamates are indirect acting cholinergic stimulants
true
name 4 cholinomimetic alkaloids
are they direct acting or indirect acting?
DIRECT ACTING
muscarine
pilocarpine
nicotine
lobeline
name 4 carbamates that are cholinergic stimulants
are they direct or indirect acting?
INDIRECT ACTING
neostigmine
carbaryl
physostigmine
edrophonium
name 4 organophosphates
are they direct or indirecting cholinergic stimulants?
INDRECT
parathion
malathion
sarin
echothiophate
pesticides - not used in humans
name 4 choline and carbamic acid esters
are they direct or indirect acting cholinergic stimulants?
direct acting
acetylcholine and methacholine = choline esters
bethanachol
carbachol
both are carbamic acid esters
none of the clinically useful cholinergic stimulants are….
selective for receptor subtypes
just selective for either nicotinic or muscarinic as a group
explain the structure of choline esters and name 2 choline esters
are they direct or indirect acting?
direct acting
acetylcholine
methacholine
have permanently charged quaternary ammonium group and are thus relatively insoluble in lipids
many naturally occuring and synthetic cholinomimetic drugs are……..
alkaloids
the ________ receptor is strongly stereoselective
explain
muscarinic
(S)-bethanechol is almost 1000x more potent than R bethanechol
what is bethanechol
a carbamic acid ester.
direct acting cholinergic stimulant
name a pharmacokinetic property of choline esters
they are poorly absorbed and poorly distributed into the CNS bc they are hydrophilic
all are hydrolyzed in the GI tract and are thus less active by oral route
explain a pharmacokinetic consideration of acetylcholine
it is very rapidly hydrolyzed in the GI tract (it’s a choline ester!), so to achieve desired effects large amounts have to be infused IV
differentiate between the resistance to hydrolysis between the choline and carbamic acid esters
negligible susceptibility to choline esterase: carbachol and bethanacol (the carbamic acid esters)
little susceptibility: methacholine
VERY SUSCEPTIBLE to cholinesterase: ACETYLCHOLINE
The carbamic acid esters have extremely little susceptibility to hydrolysis by cholinesterase
methanachol has a little susceptibility, and acetycholine is EXTREMELY SUSCEPTIBLE
what does this mean for duration of action?
the carbamic acid esters have much longer durations of action (bethanchol, carbachol)
the ______ group on bethanachol and methacholine reduces the potency of these drugs at _______ receptors
beta methyl group
nicotinic
rank the carbamic acid esters and choline esters based on their muscarinic action
most: methacholine
acetylcholine
tied for last: carbachol and bethanchol
rank the carbamic acid and choline esters according to their nicotinic action
acetylcholine and carbachol tied for 1st
methacholine and bethanachol have NO NICOTINIC ACTION (bc of beta methyl group!)
the beta methyl group of ___ and ___ reduces the potency of these drugs at nicotinic receptors
bethanachol and methacholine
explain the absorption of the natural tertiary cholinomimetic alkaloids (also name 3)
well absorbed from most sites of administration
pilocarpine nicotine lobeline
can nicotine be absorbed across the skin?
yes
it is sufficiently lipid soluble
is muscarine a tertiary amine?
what does this mean about it’s absorption?
not a tertiary amine - a quaternary amine
it is less absorbed from the GI tract than the tertiary amines
TOXIC when ingested from certain mushrooms - enters the brain
the tertiary amine natural cholinomimetic alkaloids - pilocarpine, nicotine, and lobeline are excreted mainly be the kidneys
what accelerates their clearance?
acidification of the urine
when acetylcholine binds to M2, what happens?
decreased heart rate
BY complex dissociates
adenylyl cyclase activity is decreased and cAMP production is decreased
PKA is also decreased - required to open calcium channel
where is the nicotinic receptor present in extremely high concentration
in the membranes of electric organs of electric fish
what happens when acetylcholine binds to nicotinic receptors?
in case of a NMJ - will cause depolariazation — OPENING OF LIGAND-GATED SODIUM CHANNEL and EPSP generation and contraction of the muscle
in case of neuron - will cause excitation
what does nicotinic and muscaranic action do?
causes parasympathetic nervous system events - rest and digest
PSNS: what happens to the eye?
the sphincter muscle of the iris contracts (miosis)
the ciliary muscle contracts for near vision
pupil gets smoler
what happens to the sinoatrial node when PSNS is activated
decreased rate
(negative chronotrophy)
what happens to the atria and ventricles of the heart when PSNS is activated
atria - decrease in contractile strength (called negative inotropy) and decrease in refractory period
ventricles - small decrease in contractile strength
what happens to the VA node when PSNS is activated
decrease in conduction velocity (negative dromotropy)
increase in refractory period
what happens to the blood vessels (arteries and veins) when PSNS is activated
dilation via EDRF (endothelial derived relaxation factor)
high dose direct effect - constriction
what happens to bronchial muscle and bronchial glands when PSNS is activated
bronchoconstriction
bronchial glands are stimulated to release their secretions
what happens to:
GI motility
GI sphincters
GI secretion
when PSNS is stimulated
increased GI motility
sphincters relax
secretion is stimulated
true or false
all glands release secretions when PSNS is activated
FALSE - all exc sweat glands
sweat glands are under sympathetic control
what happens to urinary bladder:
detrussor
trigone
sphincter
when PSNS is stimulated
detrusor contracts
trigone and sphincter relax
