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MSK Week 2 > 2.2.4. Cholinesterase > Flashcards

2.2.4. Cholinesterase Flashcards

1
Q

Distinguishing Characteristics of the Somatic Nervous System

A
  1. One neuron in the efferent pathway
  2. Excitatory effects
  3. Releases ACh (nicotinic receptor) OR Norepinephrine (alpha or beta receptor)
  4. Targets skeletal muscle
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2
Q

Distinguishing Characteristics of the AutonomicNervous System

A
  1. Two neurons in the efferent pathway
  2. Excitatory/inhibitory effects
  3. Releases ACh (muscarinic receptor)
  4. Targets smooth or cardiac muscle, some exocrine/endocrine glands, and some adipose tissue
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3
Q

Two types of cholinesterases

A
  1. Acetylcholinesterase

2. Plasma Cholinesterase

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4
Q

AChE

A
  1. Present at synapses
  2. Predominant form is anchored to the extracellular matrix, near ACh receptors
  3. One of the fastest enzymes
  4. DOES NOT hydrolyze butyrylcholine
  5. One gene product
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5
Q

Plasma Cholinesterase

A

(pseudocholinesterase, butyrylcholinesterase)

  1. Made in the liver and secreted into the blood
  2. Hydrolyzes butyrylcholine as well as it hydrolyzes ACh
  3. Relevant if ACh or ACh-like drugs pass through the bloodstream
  4. Considerable polymorphism in humans
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6
Q

Two examples of ACh-like drugs?

A
  1. Succinylcholine: a neuromuscular blocker

2. Procaine: ester-type anesthetic

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7
Q

What is the active site “gorge” of AChE?

A

Serine Hydrolase (critical serine in esteric site)

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8
Q

Why is the acyl intermediate (formed after the enzymatic reaction with ACh) short lived?

A

Regeneration by nucleophilic attack of water

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9
Q

Therapeutic Goal of AChE inhibitors

A

To increase ACh neurotransmission at specific sites

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10
Q

Clinically used AChE inhibitors

A
  1. Edrophonium (quaternary alcohols)
  2. Neostigmine, Pyridostigmine, Physostigmine, Ambenonium, Demecarium (carbamates)
  3. Donezepil, Galantamine (atypicals)
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11
Q

Organophosphates

A

Clinically used: DFP (diisopropyl fluorophosphate), echothiphate

Insecticides: paraoxon, malaoxon, parathion, malathion, etc.

Nerve gas: sarin, soman

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12
Q

Effects of Increased ACh on the Heart

A
  • Decreased heart rate
  • Decreased conduction and contraction
  • Slower cardiac rhythm (due to cardiac muscle hyperpolarization)
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13
Q

Vascular effects of increased ACh

A

Arteriolar vasodilation

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14
Q

Smooth muscle effects of increased ACh

A
  • Increased intestinal tone with peristaltic contraction
  • Increased ureter tone
  • Bronchoconstriction
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15
Q

Results of Increased ACh on secretions

A

-increased saliva, sweat and lacrimal secretions (lubricates the surface of the eye)

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16
Q

Ocular Effects of Increased ACh

A

Decrease of iris diameter (miosis) and lower intra-ocular pressure

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17
Q

Increased ACh at the neuromuscular junction

A
  • low concentration = muscle contraction

- high concentration = inhibition

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18
Q

Anticholinesterases that treat Myasthenia gravis

A

Target: NMJ

Edrophonium (diagnosis)

Pyridostigmine, Neostigmine, and Ambemonium (treatment)

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19
Q

Anticholinesterases that treat Anesthesia

A

Target: NMJ (after medical procedure is completed)

Edrophonium and Pyridostigmine

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20
Q

Anticholinesterases that treat Alzheimer’s disease

A

Target: basal forebrain (cognition enhancement)

Donepezil, Rivastigmine, Galantamine

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21
Q

Anticholinesterases that treat Glaucoma

A

Target: iris sphincter (local activation of muscarinic receptors to trigger constriction, aka miosis, leading to aqueous outflow)

Physostigmine, Echothiophate, Demacarium, Diisoflurophosphate (DFP)

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22
Q

Anticholinesterases used in Emergency Medicine

A

Physostigmine

Used to reverse the psychosis caused by an overdose of anti-cholinergics or antihistamines

23
Q

Anticholinesterases that help with bladder control

A

Neostigmine

Localized reversal of atony of the bladder

24
Q

Anticholinesterases that treat Dry Mouth

A

Physostigmine gel

25
Q

Chemistry behind Anticholinesterases

A

Acyl intermediate is LONG LIVED

26
Q

AChE + ACh

A

Half-life of the intermediate is several microseconds

27
Q

AChE + Carbamate

A

Half-life of the intermediate is 15 to 20 minutes

28
Q

AChE + Organophosphate

A

Half-life of the intermediate is several hours or days

29
Q

Carbamates vs. Organophosphates

A

Carbamates typically do not have adverse effects. Organophosphates (like Donezepil which is used to treat Alzheimer’s) have multiple adverse effects

30
Q

Edrophonium

A

Used to diagnosis Myasthenia Gravis

31
Q

Myasthenia Gravis

A

Patients have autoantibodies against nicotinic ACh receptors, resulting in reduced neurotransmission

Drooping eyelids, double vision, and muscle weakness

32
Q

Pyridostigmine

A

Used to treat Myasthenia Gravis. Unlike Edrophonium, this drug is active for much longer and has adverse affects associated with the GI tract

33
Q

Alzheimer’s Disease

A

Patients have reduced neurotransmission, believed to include deficiency of cholinergic neurons; secondary effects are believed to be due to reduced inflammation in the CNS

34
Q

Administration of Donezipil, Rivastigmine, and Galantimine

A

Alzheimer Treatment

  • therapeutic dosage requires 15 days, including a 1 week titration to avoid adverse effects
  • Donepezil and Galantamine are NOT metabolized by butyrylcholinesterase, but rather by cytochrome P450 (CYP2D6 and CYP3A4)
35
Q

Echothiphate, DFP, Physostigimine, Demecarium

A

Glaucoma Treatment

These drugs are no longer the first-line treatment, due to potential toxic side effect

36
Q

Scopolamine and Atropine

A

Block binding of ACh to nicotinic receptors. Physostigmine is used to reverse their effect.

37
Q

Benadryl and Dramamine

A

AKA diphenhydramine and dimethylhydrinate

Anti-cholinergic activity at high doses

38
Q

Hypocholinergic symptoms

A

Dry, hot, mydriasis (dilation of the pupil), hallucination, and muscle weakness

39
Q

Hypercholinergic symptoms

A

Secretion, miosis (contraction of the pupil), cramps, muscle twitches

40
Q

Chemically, why are organophosphates so toxic?

A

De-alkylation of the phosphate (aka “aging”) leads to irreversible intermediate that can never be cleaved by water

41
Q

Cholinergic Syndrome/Crisis

A

Poisoning by anti-AChE agents

42
Q

What are the 2 chronic effects of organophosphate poisoning?

A
  1. Intermediate syndrome

2. OPIDP (OrganoPhosphate-Induced Delayed Polyneuropathy)

43
Q

Intermediate Syndrome

A

Symptoms occur for up to a week after OP exposure. Modification in the function of nicotinic receptors at the NMJ caused by excess levels of ACh. Symptoms do NOT respond to atropine, and 2-PAM is NOT indicated.

Symptoms resolve on their own after a week or two.

44
Q

ODIDP

A

Muscle weakness, headaches, psychiatric problems, memory problems, etc.

Likely cause is the inhibition of AChE-like serine esterase called “neuropathy target esterase” or NTE

No established pharmaceutical therapy

45
Q

Goal of treatments for organophosphate poisoning

A
  1. Decontamination
  2. Stop secretion
  3. Release AChE enzymes from inhibition
  4. Stop convulsions; supportive care
46
Q

Atropine

A

Muscarinic receptor inhibitor, used immediately to treat OP in order to stop secretions

47
Q

Pralidoxime (2-PAM)

A

Used immediately to regenerate the enzyme (used before “aging”)

48
Q

Diazepam

A

Used to reduce convulsions by inhibiting neurotransmissions

49
Q

Why is it hard to protect someone from nerve gas poisoning?

A
  1. Some OPs undergo rapid aging, making pralidoxime (2-PAM) ineffective
  2. The symptoms of AChE poisoning does not appear until more than 50% of the activity of AChE has been inhibited
50
Q

How do you protect someone from nerve gas poisoning?

A

Inhibit a fraction of AChE with a spontaneously reversible anti-AChE (e.g., pyridostigmine) BEFORE an anticipated soman exposure

51
Q

Agents similar to 2-PAM

A

HI-6 (smaller dose, but ineffective against GA and paraoxon)

HLo-7 (effective against GA and a smaller dose, but higher reactivation after exposure)

MMB4 (smaller dose than 2-PAM)

52
Q

Why do we use Malathion to kill bugs?

A

The “prodrug” activity of malathion (an insecticide) is higher in bugs than it is in people

Parathion, along with malathion, do not persist in the environment very long because the phosphate hydrolyzes rapidly, but acute toxicity is a considerable risk to farm laborers and animals

53
Q

Soman (GD)

A

Poisoning is extremely difficult to reverse because the cholinesterase rapidly develops a stable monoalkyl bond that resists regeneration (it undergoes rapid aging)

MSK Week 2 (28 decks)

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