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Neuroscience Part 2.1 > ANS - Cholinergic Pharmacology II > Flashcards

ANS - Cholinergic Pharmacology II Flashcards

1
Q

What mediates fast synpatic transmission in autonomic ganglia?

A

Nicotinic Acetylcholine Receptors

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2
Q

What neurotransmitter mediates transmission at both sympathetic and parasympathetic auntonomic ganglia?

A

Acetylcholine

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3
Q

What kind of receptors are nicotinic receptors?

A

Ionotropic receptors (they are ion channels) so transmission is fast (no 2nd messenger coupling)

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4
Q

How is synpatic transmission blocked in autonomic ganglia?

A

Nicotinic antagonists

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5
Q

How is transmission potentiated in autonomic ganglia?

A

Acetylcholinesterase inhibitors

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6
Q

What receptor mediates transmission from somatic nerves to skeletal muscle?

A

Nicotinic receptors

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7
Q

What are the three types of nicontinic receptors?

A

Nm- skeletal, NMJ, Nn- Autonomic Ganglia, Adrenal Meduall, Ncns - Brain and Spinal Cord

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8
Q

What is response of autnomic ganglia nicotinic receptors after being stimulated?

A

Depolarization, firing of post synpatic neuron

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9
Q

What are the spectrum effects of Nicotine?

A

Insert slide (14)

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10
Q

What kind of drug is Hexamethonium?

A

Ganglionic Blocking Drug

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11
Q

What are the effects of ganglionic blockade, on a resting patein in the exam room?

A
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12
Q

What are the therapeutic uses of Hexamethonium?

A

Historically used extensively for chronic hypertension, largely supplanted by adrenergic receptor-selective agents, some limited specific used in CV regulation

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13
Q

What kind of drug is Curare?

A

Comptetive antagonist of nictonic receptors (blocker used at skeletal NMJ)

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14
Q

What is a protoype of curare?

A

d-tubocurarine (active components of curare extracts), effective competitive antagonist, very long duration of action

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15
Q

What kind of drug is succinylcholine?

A

Depolarizing blocker

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16
Q

What is the action of succinylcholine ?

A

Initial action is to open nicotinic channels (like Ach), however persists for longer durations in the synaptic cleft (due to resistance to acetylcholinesterase), leads to longer-lasting depolarizaiton, resulting in a brief period of repeitive excitation that my elicit transient muscle fasiculation. This initial phase is followed by block of neuromuscular transmission and flaccid paralysis. This becasue endogenous ACh binds to receptors on a already-depolarized end plate. (Brief muscle faciculations, followed by muscle relaxation)

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17
Q

What is succinylcholine doing at the NMJ?

A

It depolarizes everything, the receptor will no longer respond to endogenous ACh

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18
Q

What happens once infusion of succinylcholine is terminated?

A

Rapid termination by butyrylcholinesterase in plasma and liver

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19
Q

What are the therapeutic uses of Neuromuscular Junction Blockers?

A

Surgery, relaxation of skeletal muscle to facilitate operative manipulations particularly abdominal, short-duration blockers for intubation, bronchoscopy, esophagoscopy

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20
Q

What can treat focal dystonia?

A

Botulinum Toxin (BOTOX)

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21
Q

What is dystonia?

A

Disorder in which a person’s muscles contract ucontrollably

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22
Q

What is mechanism of action of Botulinum Toxin?

A

degrades SNAP 25 and thus prevents synaptic vesicle fusion with the axon terminal (presynaptic) membrane - inhibitor of ACh release

23
Q

What are adverse effects of Botulinum Toxin?

A

Cardiac arrhythmia, syncope (temporarily loss of consciousness because of insufficient blood flow to the brain), hepatotoxicity, anaphylaxis

24
Q

How is cholinerginc transmission terminated?

A

Termination of cholinergic transmission happens by the enzyme Acetylcholinesterase

25
Q

Where is AChE density high?

A

NMJ, auntomic ganglia

26
Q

Why is it important to limit acetylcholine’s duration of action?

A

In order for acetylcholine to be useful for rapid, repeated neurotransmission a mechanism to limit it’s duration of action is needed. Degredation of ACh is essential not only to prevent unwanted actiavation (high fedility) of neighboring neurons or muscle cells , but also to ensure proper timing of signaling at the postsynaptic cell.

27
Q

What enzyme degrades acetylcholine?

A

Acetylcholinesterase, one of the fast hydrolytic enzymes, and butyrylcholinesterase (BuChE)

28
Q

How is a single receptor molecule capable of distinguishin between two sequential presynaptic release events?

A

Because degradation of ACH in the synaptic cleft occurs faster than the time course of nAChR activation

29
Q

Where is AChE density low?

A

Parasympathetic - Postganglia to Muscarinic receptor at Target organ

30
Q

Where would a AChE inhibitor have the greatest effect and why?

A

Parasympathetic innervation of target organs because density of AChE is already low there, no urgency to clear away the agonist

31
Q

What’s the general mechanism of AChE inhibitors?

A

They stop the binding of Acetylcholine to the enzyme pocket that causes hydrolysis

32
Q

What nicotinic receptors are Neuromusclular drugs selective for?

A

Nm (nicotinic receptors) at neuromuscular junction but not Nn recpetors (autonomic system)

33
Q

What quaternary alcohols are AChE inhibitors?

A

Edrophonium - electrostatic interaction with AChE (short-lived)

34
Q

What carbamate esters are AChE inhibitors?

A

Neostigmine, Physostigmine, Pyridostigmine - covalent interaction with AChE, longer lived (up to 6 hr)

35
Q

What organophosphates are AChE inhibitors?

A

Malathion, Parthion, Echothiophate - extremely stable (100s of hours), Ageing results in irreversible cholinesterase inhibitors)

36
Q

What is cholinergic crisis?

A

Skeletal muscle weakness, due to depolarization of motor endplate by high concentrations of acetylcholine (eg cholinesterase inhibitor overdose)

37
Q

What is myasthenia gravis?

A

Autoimmune disorder, antibodies directed agains nicotinic ACh receptors at motor endplate, skeletal muscle weakness casue by defect in nicotinic receptors

38
Q

If administration of edrophonium cause further weakness…

A

Cholinergic crisis is occruing, because this is a AChE inhibitor so this would inhibit the breakdown of acetylcholine casue more depolarization of motor end plate

39
Q

If administration of edrophonium improves msucle strength….

A

Myasthenia Gravis, an AChE would make more acteylcholine available for functioning receptors

40
Q

What is the treatment for myasthenia gravis?

A

Neostigmine, Pyridostigmine - increase response of myasthenic muscle to repetitive nerve impusle, preservation of endogenous Ach

41
Q

What is the action of low doses of nicotine?

A

ANS ganglia, NMJ, brain - low doses cause stimulation

42
Q

What is the action of large dose of nicotine?

A

Initial stimulation, followed by longer lasting blockade

43
Q

Why are large dose of nicotine harmful?

A

Large doses cause desensitization b/c nicotinic receptors are fast on/fast off, not meant to stay on, high dose would cause blockade or inversion of response

44
Q

What are three ways that Cholinesterase inhibitor poisoning could happen?

A
  1. Side effects of cholinesterase inhibitor therapy 2. Accidental exposure to (insecticide spraying) 3. Warfare agents
45
Q

What effects does low-dose cholinesterase inhibition have on the following targets?

A
46
Q

What are the effects of cholinesterase inhibitor toxicity? (Slide 48)

A

Insert sidle (49) - where there is nicotinic receptors the effect flips

47
Q

What is the prophylaxis/treatment of acetylcholinesterase inhibitor toxicity?

A
  1. Pyridostigmine - binds reversibly to AChE - protects form irreversible bind of nerve gas agents (prophylactic) 2. Heroic doses of atropine - Effective for parasympathetic effects, but ineffect against NMJ effects 3. Pralidoxime - will effectively reverse all symptoms, by “regenerating” acetylcholinesterase, has been used as prophylactic agen for agricultural workers, MUST be applied before agein of organophospahte inhibitors 4. Artificial respiration and anticonvulsants - in cases of severe intoxication
48
Q

Pyridostigmine

A

Cholinesterase inhibitor, Clinical Application - Myasthenia Gravis (long acting), Increases Acetylcholine, Increases Muscle strength - does not penetrate CNS (quaternary amine)

49
Q

Neostigmine

A

Cholinesterase inhibitor, Clinical Application - Postoper and nurogenic ileus and urinary retention, myasthenia gravis, reversal of neuromuscular junction blockate (post operative), Increase Acetylecholine, No CNS penetration (quatenary amine), Neostigmine also has direct cholinergic agonist effect at Nm receptors

50
Q

Physostigmine

A

Cholinesterase inhibitior, Clinical Application - Antidote for anticholinergic toxicity (atropine overdose), non polar structure use fur treating CNS anticholinergic toxicity, tertiary amine so it is able to cross Blood Brain barrier

51
Q

Sarin

A

Organophosphate, AChE inhibitor - extremely potent “nerve gas”

52
Q

What is the ageing of an organophosphate?

A

This process apparently involves the breaking of one of the oxygen-phosphorus bonds of the inhibitor and further strengthens the phosphorus-enzyme bond. The rate of aging varies with the particular organophosphate compound. For example, aging occurs within 10 minutes with the chemical warfare agent soman, but as much as 48 hours later with the drug VX. If given before aging has occurred, strong nucleophiles like pralidoxime are able to break the phosphorus-enzyme bond and can be used as “cholinesterase regenerator” drugs for organophosphate insecticide poisoning

53
Q

Malothion, Parathion

A

Organophospahtes, AChE inhibitor - insecticides

54
Q

What kind of drug is pralidoxime?

A

Cholinesterase regenerator if given early can break phosphorous enzyme bond between organophosphate and AChE

Neuroscience Part 2.1 (5 decks)

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