Week 2 parasympathomimetics and cholinesterase inhibitors, cholinergic synaptic communication

Question 1

How is acetylcholine synthesized and broken down?

Answer 1

• synthesis: starts with phosphatidyl-ethanolamide at membrane in neurons–>phosphatidyl-choline. choline cleaved and reacted with acetyl-CoA by choline acetyltransferase (CAT) ( marker for cholinergic neurons)
• breakdown: by acetylchoilnesterase to choline and acetate. choline is recycled

Question 2

Describe the two types of acetylcholine receptors.

Answer 2

1. nicotinic receptors: chemically gated Na+ ion channels. Fine tuning by phosphorylation. Nicotine is agonist and curare is an antagonist.
2. muscarinic receptors: slower actions, longer lasting changes. associated with G proteins. Muscarine is agonist, atropine is antagonist.

Question 3

What are opportunities to pharmacologically manipulate the cholinergic neuronal communication?

Answer 3

Can manipulate

1. Ach synthesis
2. Ach transport into vesicles
3. Release from presynaptic vesicles
4. post synaptic receptor modulation
5. presynpatic muscarinic receptor mediates feedback mechanism
6. acetylcholinesterase inhibition
7. choline uptake inhibition

Question 4

How does the tetanus and botulism toxin work?

Answer 4

• botulism: toxin destroys neuroexocytosis that prevents release of acetylcholine
• tetanus: toxin binds to peripheral neuron terminals, transported to cell body. Blocks release of inhibitory NTs like glycine and GABA

Question 5

What are possible future developments in pharmacological manipulation of cholinergic synapses?

Answer 5

• nicotine for alzheimers and ADHD, parkinson’s
• mapping of nicotinic receptors
• nicotine for treatment for chronic pain

Question 6

What is the mechanism of action of a cholinesterase inhibitor?

Answer 6

• cholinesterase metabolizes acetylcholine and some other direct acting parasympathomimetics
• an inhibitor would prevent the above

Question 7

What are the differences between cholinesterase inhibitors and parasympathomimetic drug?

Answer 7

• Everything is the same except ChE inhibitors don’t cause hypotension and do cause skeletal muscle fasciculations
• hypotension: with direct acting parasympathomimetic, nerve doesn’t need to be present since no Ach releasing nerves associated with arterioles, only receptors. Giving cholinesterase doesn’t stop anything since no Ach is released and there’s no cholinesterase
• Skeletal muscles: direct acting parasympathomimetics bind to muscarinic cholinergic receptors, so won’t bind to nicotinic receptors in muscle. Cholinesterase inhibitors allows Ach accumulation bc it isn’t metabolized, stimulates muscle without voluntary action to trigger

Question 8

What are 2 different types of cholinesterase inhibitors and how do their actions compare?

Answer 8

1. Reversible cholinesterase inhibitors:
   - tertiary amines cross BBB: donepezil, galantamine. CNS effects to treat Alzheimers. Also physotigmine.
   - don’t cross BBB: edrophonium( useful for Myasthenia Gravis diagnosis), neostigmine, pyridositmine. To treat bladder or gut atonia
2. Irreversible cholinesterase inhibitors: organophosphates
   - slow metabolism, massive parasympathetic action and lead to death
   - no longer used

Question 9

List the effects of organophosphate poisoning.

Answer 9

• broncho constriction
• diarrhea
• increased frequency of urination
• urination
• sweating, salivation, tearing
• bradycardia
• miosis
• erection
• skeletal muscle fasciculations
• abdominal cramps

Question 10

Describe the treatment for organophosphate poisoning.

Answer 10

• organophosphates work by phosphorylating cholinesterase so that it can’t break down acetylcholine
• A drug called pralidoximine (PAM or Protopam) can remove the phosphate group

Question 11

List the effects of parasympathetics on organs that contain acetylcholine receptors

Answer 11

1. contracts eye: miosis
2. lacrimal glands: increases tearing
3. Salivary glands: increases salivation
4. Heart: supraventricular-decelerates SA, AV node and decreases atrial contractility
   * 5. Blood vessels: no nerve endings
5. bronchiolar SM: contracts-wheezing
6. GI: contracts walls, relaxes sphincters, increases secretions, activates myenteric plexus
7. GU: contracts bladder wall, relaxes sphincter, causes erection (release of NO)
   * 9. Sweat Glands: Secretion, is stimulated (only have sympathetic innervation but release Ach)
8. Sympathetic nerve endings: decreases Norepi release

Question 12

Describe how direct acting parasympathomimetics mimic the actions of parasympathetic nerve stimulation and why drugs in this class are effective in parasympathetic denervated organs

Answer 12

• Bind to acetycholine receptors, both muscarinic and nicotinic
• only need Ach receptors and not nerves
• are Ach structural analogs

Question 13

Compare the action of direct acting parasympathomimetic drugs with parasympathetic nerve stimulation of target tissues

Answer 13

1. methacholine: more specific for the heart
2. Bethanechol: more specific for GI tract and bladder, minimal binding to heart and more to arterioles
3. Pilocarpine and carbachol used mainly topically to eye

Question 14

Where in the nervous system do you find acetylcholine released?

Answer 14

• Parasympathetics: pre ganglionic and post ganglionic
• Sympathetic: pre ganglionic
• somatic: released in striated muscle

Question 15

Where in the nervous system do you find acetylcholine released?

Answer 15

• Parasympathetics: pre ganglionic and post ganglionic
• Sympathetic: pre ganglionic
• somatic: released in striated muscle

Question 16

List the adverse reactions after treatment with direct acting parasympathomimetics

Answer 16

• Excessive sweating, tearing
• urinary frequency
• diarrhea
• fall in blood pressure
• cardiac standstill
• wheezing

Question 17

Lists the parasympathomimetics and compare the drugs that are hydrolyzed by cholinesterase and those that are not

Answer 17

• specific cholinesterase is near Ach receptor, non specific is in plasma
• The parasympathomimetics are: acetylcholine, methacholine, bethanechol, carbachol, pilocarpine
  1. Hydrolyzed by specific cholinesterase: AcH, methacholine
  2. Hydrolyzed by nonspecific cholinesterase: acetycholine
  3. Non hydrolyzed by either: bethanechol, carbachol, pilocarpine (have longer half lives and more potent effect)

Question 18

Describe the cardiovascular feedback system.

Answer 18

1. High Blood pressure detected via increased firing of baroreceptors and sensed by cardiovascular center
2. cardiovascular center sends out increased signals through PNS to SA node to decrease heart rate (increase parasympathetic output)
3. Ach is released:
   parasymp output increased–>heart rate decreased, contractility of heart decreased
   -sympathetic output inhibited–>vasodilation leading to decreased peripheral resistance and cardiac output
4. blood pressure drops
5. baroreceptors sense decreased bp, the slowing of their firing–>cardiovascular center–>stimulates sympathetic output and inhibit parasympathetic output
   =REFLEX

Question 19

Compare the sites of action of a ganglionic blocker with a direct acting parasympathomimetic and a cholinesterase inhibitor

Answer 19

• Ganglionic blockers bind to Ach receptors to prevent binding of Ach. Won’t fit in muscle nicotinic receptors (4 carbons wider) and only in ganglionic nicotinic receptors
• blocks both sympathetic and parasympathetic stimulation
• parasympathomimetics activate parasympathetic stimulation
• cholinesterase blocks breakdown of Ach and stimulates parasympathetics

Question 20

Compare and contrast the actions of ganglionic inhibitors on nicotinic receptors in ganglia and nicotinic receptors on muscle end plates

Answer 20

-ganglionic inhibitors have no effect on nicotinic receptors in skeletal muscle because it doesn’t fit in the receptor

Question 21

List the overall effect of ganglionic blockers on each of the target organs that are sympathetically or parasympathetic ally innervated after treatment with a ganglionic blocker

Answer 21

• sympathetic efect is expressed except in the heart, over more effectively blocks parasympathetic actions
  1. eye: expansion, blinded by light, cycloplegia, loss of ability to accommodate focus
  2. Lacrimal gland: dry eye
  3. Salivary gland: dry mouth-lack of salivation
  4. sweat glands: lack of sweating
  5. bronchioles: dilation
  6. GI: atonic gut, constipation
  7. Urinary: difficulty to urinate with possible urinary retention
  8. male genital tract: impotence, neither erection or ejaculation can occur
  9. Cardiovascular: decreased atrial contractility, relaxed arterioles, postural hypotension

Question 22

Describe the effect of a low verses high end diastolic volume and the effect of ventricular muscle stretching on cardiac output

Answer 22

• Stroke volume=End diastolic volume-end systolic volume =the amount of blood pumped out of the heart in one contraction of the ventricle
• cardiac output=stroke volume x heart rate
• If there is a higher EDV, there is more blood in heart and more blood ejected from the heart. The cardiac muscle fiber is stretched, and there is an increase in force of contraction. Blood i ejected under greater force due to increased EV

Question 23

Describe the effect of a low verses high end diastolic volume and the effect of ventricular muscle stretching on cardiac output

Answer 23

-

Question 24

Why are parasympathetics blocked more effectively than sympathetic actions by ganglionic blockers?

Answer 24

• Normally, Ach from parasympathetic system blocks sympathetic system from releasing norepinephrine
• with ganglionic blocker, that block from above is removed

Question 25

What happens in a healthy individual when they are treated with a vasoconstrictor? What happens if they were pre treated with a ganglionic blocker?

Answer 25

1. With vasoconstrictor, bp increases. Reflex causes drop in heart rate.
2. pre treated with ganglionic blocker: bp increases, no reflex and heart rate stays the same (ganglionic blocker prevents sympathetic output to heart

Question 26

What happens in a healthy individual when they are treated with a vasoconstrictor? What happens if they were pre treated with a ganglionic blocker?

Answer 26

1. With vasoconstrictor, bp increases. Reflex causes drop in heart rate.
2. pre treated with ganglionic blocker: bp increases, no reflex and heart rate stays the same (ganglionic blocker prevents sympathetic output to heart

Question 27

What happens in a healthy individual when they are treated with a vasodilator? What happens if they were pre treated with a ganglionic blocker?

Answer 27

1. with vasodilator, bp decreases. Reflex causes increase in heart rate.
2. with ganglionic blocker: bp decreases, no reflex and heart rate stays the same.

Question 28

What are the effects of low dose nicotine (ganglionic agonist)?

Answer 28

Nicotine has agonist actions on nicotinic receptors

• sympathetic nerve stimulation: tachycardia, vasoconstriction of skin and kidney vessels
• stimulation of adrenal gland: increase circulating epinephrine and norepineprhine
• parasympathetic nerve stimulation: increased peristalsis of the GI tract, may stimulate gastric, salivary, and bronchial glands
• skeletal muscle: fasciculations
• CNS: stimulates ADH release, vomiting center

Question 29

List the name of parasympathomimetics

Answer 29

acetycholine
methacholine
bethanechol
pilocarpine
carbachol

Question 30

List the names of cholinesterase inhibitors

Answer 30

physostigmine
neostigmine
pyridostigmine
edrophonium
donezepil
galantimine

Question 31

List the names of ganglionic blockers

Answer 31

hexamethonium
trimethaphan
ceamylamine

Question 32

list the name of ganglionic agonists

Answer 32

nicotine