Cholinergic pharmacology intro

Question 1

Why is it relevant whether a drug is a tertiary or quaternary amine?

Answer 1

Tertiary - Uncharged and easily diffuse across biological membranes
Quaternary - Charged and will stay at the site of action

Question 2

What is the primary difference between how skeletal muscles and smooth muscles / glands respond to denervation?

Answer 2

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

Question 3

At what effector junctions of the sympathetic nervous system is the neurotransmitter acetylcholine?

Answer 3

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

Question 4

What are the primary neurotransmitters of the enteric nervous system?

Answer 4

VIP (vasoactive intestinal peptide)
ATP
NO
Ach
Norepinephrine

Question 5

How can acetylcholine cause vascular smooth muscle relaxation?

Answer 5

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

Question 6

What type of acetylcholine receptor is found on postganglionic autonomic neurons?

Answer 6

Primarily nicotinic -> always fast-acting conduction. Includes the receptors on the chromaffin cells in the adrenal medulla

Question 7

What type of Ach receptors are on skeletal muscle cells? Adrenal medulla?

Answer 7

All nicotinic

Question 8

How is acetylcholine synthesized and where? What is rate-limiting?

Answer 8

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

Question 9

Where are choline and acetyl-CoA synthesized?

Answer 9

Choline - quaternary amine synthesized outside the cell

Acetyl-CoA - from glucose metabolism of mitochondria at the nerve terminal

Question 10

Is Ach only released to NMJ during action potentials? Why?

Answer 10

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

Question 11

What is the primary difference between the amount of Ach needed for NMJ transmission and autonomic transmission?

Answer 11

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

Question 12

What is the function of ACh presynaptic receptors?

Answer 12

They play a role in regulation of neurotransmission -> feedback inhibition of the neuron

Question 13

Why can ACh bind many different receptors, but agonists tend to be more selective?

Answer 13

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

Question 14

What are the primary sites of muscarinic Ach receptors?

Answer 14

Autonomic end-organ receptors, also some contribution to autonomic ganglia (though primary cholinoceptor here is nicotinic)

Question 15

What is muscarine?

Answer 15

An alkaloid isolated from a mushroom which is an M-Ach agonist

Question 16

What is nicotine?

Answer 16

A liquid alkaloid that is isolated from tobacco leaf, N-Ach agonist

Question 17

What are the three main muscarinic Ach receptors and where do they tend to be found?

Answer 17

M1 - Neuronal
M2 - Predominant in heart
M3 - Predominant in secretory glands

Question 18

What are the main prototype antagonists blocking the muscarinic and nicotinic Ach receptors?

Answer 18

Muscarinic - atropine

Nicotinic - d-tubocurarine

Question 19

Where are M4 and M5 receptors found?

Answer 19

Brain, function not well understood

Question 20

When is a GPCR active (with respect to Galpha subunit)? How does the amplification occur?

Answer 20

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

Question 21

What types of Galpha subunits are activated by M1, M2, and M3, receptors?

Answer 21

M2 (heart) - Gi

M1, M3 (neuronal, secretory) - Gq

Question 22

How does the Gi functioning of the heart work?

Answer 22

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)

Question 23

How does the Gq function in smooth muscle and acinar glands?

Answer 23

IP3 stimulates release of Ca+2, which directly causes smooth muscle contraction

Question 24

How does the nicotinic Ach receptor function?

Answer 24

Binds the ligand, allows Na+, K+ and Ca+2 to move down their concentration gradients and depolarize the membrane

Question 25

Why does acetylcholine tend not to persist in serum?

Answer 25

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

Question 26

How does the acetylcholinesterase enzyme work? How does this relate to ACh inhibitors?

Answer 26

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)

Question 27

Why can low doses of atropine actually cause bradycardia?

Answer 27

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

Question 28

How do muscarinic agonists affect the release of ACh?

Answer 28

They reduce it, by binding and activating presynaptic ACh receptors

Question 29

What type of receptors are the presynaptic receptors at the neuromuscular junction?

Answer 29

Actually nicotinic ACh -> and they increase ACh release to promote tetanus.

Question 30

How do presynaptic receptors modulate ACh release in the GI tract?

Answer 30

There are presynaptic alpha-2 receptors which, when stimulated (because there is SANS stimulation nearby), will inhibit ACh release

Question 31

What type of ACh receptors are found in the CNS?

Answer 31

Primarily muscarinic, with some nicotinic in the brain. Higher concentration of nicotinic occurs in spinal cord