2.2.4. Cholinesterase Flashcards
Distinguishing Characteristics of the Somatic Nervous System
- One neuron in the efferent pathway
- Excitatory effects
- Releases ACh (nicotinic receptor) OR Norepinephrine (alpha or beta receptor)
- Targets skeletal muscle
Distinguishing Characteristics of the AutonomicNervous System
- Two neurons in the efferent pathway
- Excitatory/inhibitory effects
- Releases ACh (muscarinic receptor)
- Targets smooth or cardiac muscle, some exocrine/endocrine glands, and some adipose tissue
Two types of cholinesterases
- Acetylcholinesterase
2. Plasma Cholinesterase
AChE
- Present at synapses
- Predominant form is anchored to the extracellular matrix, near ACh receptors
- One of the fastest enzymes
- DOES NOT hydrolyze butyrylcholine
- One gene product
Plasma Cholinesterase
(pseudocholinesterase, butyrylcholinesterase)
- Made in the liver and secreted into the blood
- Hydrolyzes butyrylcholine as well as it hydrolyzes ACh
- Relevant if ACh or ACh-like drugs pass through the bloodstream
- Considerable polymorphism in humans
Two examples of ACh-like drugs?
- Succinylcholine: a neuromuscular blocker
2. Procaine: ester-type anesthetic
What is the active site “gorge” of AChE?
Serine Hydrolase (critical serine in esteric site)
Why is the acyl intermediate (formed after the enzymatic reaction with ACh) short lived?
Regeneration by nucleophilic attack of water
Therapeutic Goal of AChE inhibitors
To increase ACh neurotransmission at specific sites
Clinically used AChE inhibitors
- Edrophonium (quaternary alcohols)
- Neostigmine, Pyridostigmine, Physostigmine, Ambenonium, Demecarium (carbamates)
- Donezepil, Galantamine (atypicals)
Organophosphates
Clinically used: DFP (diisopropyl fluorophosphate), echothiphate
Insecticides: paraoxon, malaoxon, parathion, malathion, etc.
Nerve gas: sarin, soman
Effects of Increased ACh on the Heart
- Decreased heart rate
- Decreased conduction and contraction
- Slower cardiac rhythm (due to cardiac muscle hyperpolarization)
Vascular effects of increased ACh
Arteriolar vasodilation
Smooth muscle effects of increased ACh
- Increased intestinal tone with peristaltic contraction
- Increased ureter tone
- Bronchoconstriction
Results of Increased ACh on secretions
-increased saliva, sweat and lacrimal secretions (lubricates the surface of the eye)
Ocular Effects of Increased ACh
Decrease of iris diameter (miosis) and lower intra-ocular pressure
Increased ACh at the neuromuscular junction
- low concentration = muscle contraction
- high concentration = inhibition
Anticholinesterases that treat Myasthenia gravis
Target: NMJ
Edrophonium (diagnosis)
Pyridostigmine, Neostigmine, and Ambemonium (treatment)
Anticholinesterases that treat Anesthesia
Target: NMJ (after medical procedure is completed)
Edrophonium and Pyridostigmine
Anticholinesterases that treat Alzheimer’s disease
Target: basal forebrain (cognition enhancement)
Donepezil, Rivastigmine, Galantamine
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)
Anticholinesterases used in Emergency Medicine
Physostigmine
Used to reverse the psychosis caused by an overdose of anti-cholinergics or antihistamines
Anticholinesterases that help with bladder control
Neostigmine
Localized reversal of atony of the bladder
Anticholinesterases that treat Dry Mouth
Physostigmine gel
Chemistry behind Anticholinesterases
Acyl intermediate is LONG LIVED
AChE + ACh
Half-life of the intermediate is several microseconds
AChE + Carbamate
Half-life of the intermediate is 15 to 20 minutes
AChE + Organophosphate
Half-life of the intermediate is several hours or days
Carbamates vs. Organophosphates
Carbamates typically do not have adverse effects. Organophosphates (like Donezepil which is used to treat Alzheimer’s) have multiple adverse effects
Edrophonium
Used to diagnosis Myasthenia Gravis
Myasthenia Gravis
Patients have autoantibodies against nicotinic ACh receptors, resulting in reduced neurotransmission
Drooping eyelids, double vision, and muscle weakness
Pyridostigmine
Used to treat Myasthenia Gravis. Unlike Edrophonium, this drug is active for much longer and has adverse affects associated with the GI tract
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
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)
Echothiphate, DFP, Physostigimine, Demecarium
Glaucoma Treatment
These drugs are no longer the first-line treatment, due to potential toxic side effect
Scopolamine and Atropine
Block binding of ACh to nicotinic receptors. Physostigmine is used to reverse their effect.
Benadryl and Dramamine
AKA diphenhydramine and dimethylhydrinate
Anti-cholinergic activity at high doses
Hypocholinergic symptoms
Dry, hot, mydriasis (dilation of the pupil), hallucination, and muscle weakness
Hypercholinergic symptoms
Secretion, miosis (contraction of the pupil), cramps, muscle twitches
Chemically, why are organophosphates so toxic?
De-alkylation of the phosphate (aka “aging”) leads to irreversible intermediate that can never be cleaved by water
Cholinergic Syndrome/Crisis
Poisoning by anti-AChE agents
What are the 2 chronic effects of organophosphate poisoning?
- Intermediate syndrome
2. OPIDP (OrganoPhosphate-Induced Delayed Polyneuropathy)
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.
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
Goal of treatments for organophosphate poisoning
- Decontamination
- Stop secretion
- Release AChE enzymes from inhibition
- Stop convulsions; supportive care
Atropine
Muscarinic receptor inhibitor, used immediately to treat OP in order to stop secretions
Pralidoxime (2-PAM)
Used immediately to regenerate the enzyme (used before “aging”)
Diazepam
Used to reduce convulsions by inhibiting neurotransmissions
Why is it hard to protect someone from nerve gas poisoning?
- Some OPs undergo rapid aging, making pralidoxime (2-PAM) ineffective
- The symptoms of AChE poisoning does not appear until more than 50% of the activity of AChE has been inhibited
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
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)
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
Soman (GD)
Poisoning is extremely difficult to reverse because the cholinesterase rapidly develops a stable monoalkyl bond that resists regeneration (it undergoes rapid aging)
