2.2.4. Cholinesterase Flashcards Preview

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Flashcards in 2.2.4. Cholinesterase Deck (53)
1

Distinguishing Characteristics of the Somatic Nervous System

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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Distinguishing Characteristics of the AutonomicNervous System

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

3

Two types of cholinesterases

1. Acetylcholinesterase
2. Plasma Cholinesterase

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AChE

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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Plasma Cholinesterase

(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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Two examples of ACh-like drugs?

1. Succinylcholine: a neuromuscular blocker

2. Procaine: ester-type anesthetic

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What is the active site "gorge" of AChE?

Serine Hydrolase (critical serine in esteric site)

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

Regeneration by nucleophilic attack of water

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Therapeutic Goal of AChE inhibitors

To increase ACh neurotransmission at specific sites

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Clinically used AChE inhibitors

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

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Organophosphates

Clinically used: DFP (diisopropyl fluorophosphate), echothiphate

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

Nerve gas: sarin, soman

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Effects of Increased ACh on the Heart

-Decreased heart rate
-Decreased conduction and contraction
-Slower cardiac rhythm (due to cardiac muscle hyperpolarization)

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Vascular effects of increased ACh

Arteriolar vasodilation

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Smooth muscle effects of increased ACh

-Increased intestinal tone with peristaltic contraction
-Increased ureter tone
-Bronchoconstriction

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Results of Increased ACh on secretions

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

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Ocular Effects of Increased ACh

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

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Increased ACh at the neuromuscular junction

-low concentration = muscle contraction
-high concentration = inhibition

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Anticholinesterases that treat Myasthenia gravis

Target: NMJ

Edrophonium (diagnosis)

Pyridostigmine, Neostigmine, and Ambemonium (treatment)

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Anticholinesterases that treat Anesthesia

Target: NMJ (after medical procedure is completed)

Edrophonium and Pyridostigmine

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Anticholinesterases that treat Alzheimer's disease

Target: basal forebrain (cognition enhancement)

Donepezil, Rivastigmine, Galantamine

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Anticholinesterases that treat Glaucoma

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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Anticholinesterases used in Emergency Medicine

Physostigmine

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

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Anticholinesterases that help with bladder control

Neostigmine

Localized reversal of atony of the bladder

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Anticholinesterases that treat Dry Mouth

Physostigmine gel

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Chemistry behind Anticholinesterases

Acyl intermediate is LONG LIVED

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AChE + ACh

Half-life of the intermediate is several microseconds

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AChE + Carbamate

Half-life of the intermediate is 15 to 20 minutes

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AChE + Organophosphate

Half-life of the intermediate is several hours or days

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Carbamates vs. Organophosphates

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

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Edrophonium

Used to diagnosis Myasthenia Gravis

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Myasthenia Gravis

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

Drooping eyelids, double vision, and muscle weakness

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Pyridostigmine

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

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Alzheimer's Disease

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

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Administration of Donezipil, Rivastigmine, and Galantimine

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)

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Echothiphate, DFP, Physostigimine, Demecarium

Glaucoma Treatment

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

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Scopolamine and Atropine

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

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Benadryl and Dramamine

AKA diphenhydramine and dimethylhydrinate

Anti-cholinergic activity at high doses

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Hypocholinergic symptoms

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

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Hypercholinergic symptoms

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

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Chemically, why are organophosphates so toxic?

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

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Cholinergic Syndrome/Crisis

Poisoning by anti-AChE agents

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What are the 2 chronic effects of organophosphate poisoning?

1. Intermediate syndrome
2. OPIDP (OrganoPhosphate-Induced Delayed Polyneuropathy)

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Intermediate Syndrome

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.

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ODIDP

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

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Goal of treatments for organophosphate poisoning

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

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Atropine

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

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Pralidoxime (2-PAM)

Used immediately to regenerate the enzyme (used before "aging")

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Diazepam

Used to reduce convulsions by inhibiting neurotransmissions

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

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

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How do you protect someone from nerve gas poisoning?

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

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Agents similar to 2-PAM

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)

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Why do we use Malathion to kill bugs?

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

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Soman (GD)

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