Cholinergic pharmacology intro Flashcards
Why is it relevant whether a drug is a tertiary or quaternary amine?
Tertiary - Uncharged and easily diffuse across biological membranes
Quaternary - Charged and will stay at the site of action
What is the primary difference between how skeletal muscles and smooth muscles / glands respond to denervation?
Skeletal muscles - will atrophy -> require Ach from motor neurons of somatic nervous system to survive
Smooth muscles / glands - exhibit spontaneous activity in the absence of autonomic innervation -> do not require ANS innervation to survive
At what effector junctions of the sympathetic nervous system is the neurotransmitter acetylcholine?
Adrenal medulla -> stimulates chromaffin cells
Sweat glands -> muscarinic receptor
Skeletal muscle arterioles -> muscarinic receptor
Still considered sympathetic because the preganglionic neurons come from T1 to L2
What are the primary neurotransmitters of the enteric nervous system?
VIP (vasoactive intestinal peptide) ATP NO Ach Norepinephrine
How can acetylcholine cause vascular smooth muscle relaxation?
There are M3 receptors which cause the release of NO on the smooth muscle, which has no physiologic relevance unless a muscarinic agonist is applied
What type of acetylcholine receptor is found on postganglionic autonomic neurons?
Primarily nicotinic -> always fast-acting conduction. Includes the receptors on the chromaffin cells in the adrenal medulla
What type of Ach receptors are on skeletal muscle cells? Adrenal medulla?
All nicotinic
How is acetylcholine synthesized and where? What is rate-limiting?
Synthesized at cholinergic nerve terminal from choline and acetyl-CoA via choline acetyltransferase (made in cell body)
Rate-limiting: Reuptake of choline from synaptic cleft
Where are choline and acetyl-CoA synthesized?
Choline - quaternary amine synthesized outside the cell
Acetyl-CoA - from glucose metabolism of mitochondria at the nerve terminal
Is Ach only released to NMJ during action potentials? Why?
No, there is some random release of Ach which is not enough to stimulate muscle contraction. Cause “miniature endplate potentials” - has an influence on the skeletal muscle to know that the nerve is still functional
What is the primary difference between the amount of Ach needed for NMJ transmission and autonomic transmission?
NMJ transmission - saturated at much less Ach than is actually released
Autonomic - Is not saturated by released levels -> can still have graded potentials based on rate of firing
What is the function of ACh presynaptic receptors?
They play a role in regulation of neurotransmission -> feedback inhibition of the neuron
Why can ACh bind many different receptors, but agonists tend to be more selective?
ACh is very floppy -> can easily conform to whatever shape it needs, oriented by negative charge or receptors
Agonists - tend to be more rigid, can have more selectivity for receptor type or subtype
What are the primary sites of muscarinic Ach receptors?
Autonomic end-organ receptors, also some contribution to autonomic ganglia (though primary cholinoceptor here is nicotinic)
What is muscarine?
An alkaloid isolated from a mushroom which is an M-Ach agonist
What is nicotine?
A liquid alkaloid that is isolated from tobacco leaf, N-Ach agonist
What are the three main muscarinic Ach receptors and where do they tend to be found?
M1 - Neuronal
M2 - Predominant in heart
M3 - Predominant in secretory glands
What are the main prototype antagonists blocking the muscarinic and nicotinic Ach receptors?
Muscarinic - atropine
Nicotinic - d-tubocurarine
Where are M4 and M5 receptors found?
Brain, function not well understood
When is a GPCR active (with respect to Galpha subunit)? How does the amplification occur?
Whenever GTP is bound to alpha subunit. When the ligand binds the GPCR, a conformational change occurs which facilitates replacement of GDP to GTP, and subsequent dissociation of G protein. A single receptor can do this to many G proteins -> amplification
What types of Galpha subunits are activated by M1, M2, and M3, receptors?
M2 (heart) - Gi
M1, M3 (neuronal, secretory) - Gq
How does the Gi functioning of the heart work?
Gi lowers cAMP levels in the heart, decreasing contractility.
beta-gamma subunit also associates with a K+ channel, activating it and causing hyperpolarization (especially in the SA node)
How does the Gq function in smooth muscle and acinar glands?
IP3 stimulates release of Ca+2, which directly causes smooth muscle contraction
How does the nicotinic Ach receptor function?
Binds the ligand, allows Na+, K+ and Ca+2 to move down their concentration gradients and depolarize the membrane
Why does acetylcholine tend not to persist in serum?
There is a second group of cholinesterases called pseudocholinesterases in the plasma and liver (act nonspecifically on substrates containing ester linkages)
-> explains why ACh is not that useful as an injected drug
How does the acetylcholinesterase enzyme work? How does this relate to ACh inhibitors?
Enzyme is negatively charged to attract ACh, then uses a serine to do an Acyl transfer reaction. The intermediate is an acetyl group covalently attached to serine. The structure is ultimately resolved via hydrolysis (this step is blocked via acetylcholinesterase inhibitors which remain covalently bound)
Why can low doses of atropine actually cause bradycardia?
If atropine preferentially binds the presynaptic ACh receptors, which are muscarinic (usually M2), the amount of ACh released can be increased 2-8x, actually causing bradycardia post-synaptically
How do muscarinic agonists affect the release of ACh?
They reduce it, by binding and activating presynaptic ACh receptors
What type of receptors are the presynaptic receptors at the neuromuscular junction?
Actually nicotinic ACh -> and they increase ACh release to promote tetanus.
How do presynaptic receptors modulate ACh release in the GI tract?
There are presynaptic alpha-2 receptors which, when stimulated (because there is SANS stimulation nearby), will inhibit ACh release
What type of ACh receptors are found in the CNS?
Primarily muscarinic, with some nicotinic in the brain. Higher concentration of nicotinic occurs in spinal cord
