What reaction does acetylcholinesterase catalyze?
Acetylcholine -> Choline + Acetate
What types of cholinesterases do humans have?
Acetylcholinesterase at synapses (one of the fastest enzymes ever studied) and Plasma Cholinesterase (Pseudocholinesterase/Butyrylcholinesterase) which is present in the blood.
What shuts down circulating ACh-like drugs?
Plasma cholinesterase (pseudocholinesterase/butyrylcholinesterase) which circulates in the blood.
What part of the AChE is the functional part?
Serine. The enzyme is a serine hydrolase.
How does the AChE reaction take place?
ACh binds to the serine in the active site, choline floats away and the acyl portion remains bound to the serene. Water removes the acetyl group from the serine and the enzyme is good to go again.
You see a patient with nerve damage and you want to increase function of that nerve. What drugs could you prescribe to increase nerve function?
AChE Inhibitors. These are molecules that look like ACh but stay bound to the active site. They include quaternary alcohols, carbamates, and atypical drugs like donezepil and galantamine.
ACh tends to stimulate the autonomic nervous system. Knowing this, what side effects come with prescribing AChE inhibitors?
Decreased cardiac function, vasodilation, increased smooth muscle tone in the gut, uterus and bronchi, increased secretions, decreased iris diameter (miosis), and increased muscular contraction.
How do the pharmacokinetics of the AChE enzyme differ between ACh, Carbamate and Organophosphates and substrates?
ACh turn over is microseconds, Carbamoyl acyl intermediate lasts about 20 minutes and organophosphates' acyl intermediate lasts hours to days
What are the different AChE inhibitors?
A young man comes to see you with drooping eyelids, double vision and muscle weakness in the extremities. What might be his condition and how can you confirm your diagnosis?
Myasthenia Gravis: the body generates autoantibodies against the nicotinic ACh receptors which results in decreased neurotransmission. You can apply Edrophonium to see if the patient perks up.
What drug might you use for reversing the effects of a patient just coming out of anesthesia?
Edrophonium. It only lasts 10-30 minutes and has very few side effects.
After you confirm a positive Tensilon test, you come to the conclusion that your patient has myasthenia gravis. What prescription do you send him home with to take daily and what side effects to you tell him to look out for?
Pyridostigmine. Its peak concentration is about 30 minutes and is active for about 4 hours. He needs to look out for Cholinergic Crisis: Nausea, vomiting, diarrhea, sweating, flushing, salivation, tearing and constricted pupils and bronchial secretions.
Symptoms of Cholinergic Crisis
Nausea, vomiting, diarrhea, sweating, flushing, salivation, tearing and constricted pupils and bronchial secretions.
You find that a patient has a deficiency of cholinergic neurons and thus decreased neurotransmission. After confirming the patient's diagnosis, what could you prescribe and what are the side effects?
Donezipil, Rivastigmine, Galantimine all act in the forebrain. These drugs have cholinergic crisis effects and require a ramification of dosing as you watch for side effects. These drugs are effective for 80 hours.
When prescribing donezipil, rivastigmine, and galantimine, you must look out for drug-drug interactions. Why?
They are metabolized in the kidney where many other drugs are metabolized. They induce 2D6 and 3A4.
A patient comes to your clinic and you find that they have increased intra-ocular pressure due to optic neuropathy. What drugs are ideal in treating this condition?
Irreversible AChE inhibitors are desirable because they will increase ACh at synapses controlling the ocular sphincter and allow for drainage of ocular fluid.
Some stupid teenagers show up to the ER because they overdosed on Coricidin. What do you give these kids to reverse the effects of antihistamines/anticholinergic drugs? How is this drug metabolized and what are the side effects?
Physostigmine. It is metabolized in the liver and eliminated in the kidney. Side effects are consistent with the cholinergic crisis.
How do hypocholinergic conditions differ from hypercholinergic conditions?
Hypocholinergic: Myasthenia gravis -> Atropine/Scopolamine/Belladonna/Jimson weed -> BZ Hypercholinergic: Quaternary alcohols -> Carbamates -> Organophophates -> Nerve gas
A patient comes to see you weeks after crop-dusting his field with muscle weakness, headaches, memory problems and psych problems. You suspect insecticide poisoning. Why do organophosphates continue to have effects on neurotransmission for weeks?
They modify the function of nicotinic receptors and thus cannot be resolved by atropine, resulting in intermediate syndrome. They also cause AChE-like serine esterase inhibition, resulting in OPIDP (organophosphate-induced delayed polyneuropathy).
How do you treat the farmer that got poisoned by insecticides?
Remove contaminants (clothes), shut down muscarinic receptors with atropine, regenerate AChE with pralidoxime, reduce convulsions with diazepam and maintain respiration.
How do you get the farmer's AChE back to normal after organophosphate poisoning? What type of poisoning can't you use this therapy for?
Pralidoxime. It binds to the organophosphate and takes it out of the AChE active site. This is not useful against carbamate.
You are being deployed to Syria. How does Uncle Sam make sure you are prepared for contact with nerve gas?
Aging with soman poisoning happens within 7 minutes. Thus, you must prophylact with a spontaneously reversible anti cholinesterase (pyridostigmine) before the expected soman exposure so soman does not irreversible bind to AChE. After exposure is over you administer atropine to block extra ACh that built up.
What direction is the insecticide taking in drug development.
Prodrugs such as malathion that becomes active once metabolized and they use drugs that are not metabolized by humans.