Physiology-Cholinesterase

Question 1

What reaction does acetylcholinesterase catalyze?

Answer 1

Acetylcholine -> Choline + Acetate

Question 2

What types of cholinesterases do humans have?

Answer 2

Acetylcholinesterase at synapses (one of the fastest enzymes ever studied) and Plasma Cholinesterase (Pseudocholinesterase/Butyrylcholinesterase) which is present in the blood.

Question 3

What shuts down circulating ACh-like drugs?

Answer 3

Plasma cholinesterase (pseudocholinesterase/butyrylcholinesterase) which circulates in the blood.

Question 4

What part of the AChE is the functional part?

Answer 4

Serine. The enzyme is a serine hydrolase.

Question 5

How does the AChE reaction take place?

Answer 5

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.

Question 6

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?

Answer 6

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.

Question 7

ACh tends to stimulate the autonomic nervous system. Knowing this, what side effects come with prescribing AChE inhibitors?

Answer 7

Decreased cardiac function, vasodilation, increased smooth muscle tone in the gut, uterus and bronchi, increased secretions, decreased iris diameter (miosis), and increased muscular contraction.

Question 8

How do the pharmacokinetics of the AChE enzyme differ between ACh, Carbamate and Organophosphates and substrates?

Answer 8

ACh turn over is microseconds, Carbamoyl acyl intermediate lasts about 20 minutes and organophosphates’ acyl intermediate lasts hours to days

Question 9

What are the different AChE inhibitors?

Answer 9

*

Question 10

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?

Answer 10

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.

Question 11

What drug might you use for reversing the effects of a patient just coming out of anesthesia?

Answer 11

Edrophonium. It only lasts 10-30 minutes and has very few side effects.

Question 12

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?

Answer 12

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.

Question 13

Symptoms of Cholinergic Crisis

Answer 13

Nausea, vomiting, diarrhea, sweating, flushing, salivation, tearing and constricted pupils and bronchial secretions.

Question 14

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?

Answer 14

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.

Question 15

When prescribing donezipil, rivastigmine, and galantimine, you must look out for drug-drug interactions. Why?

Answer 15

They are metabolized in the kidney where many other drugs are metabolized. They induce 2D6 and 3A4.

Question 16

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?

Answer 16

Irreversible AChE inhibitors are desirable because they will increase ACh at synapses controlling the ocular sphincter and allow for drainage of ocular fluid.

Question 17

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?

Answer 17

Physostigmine. It is metabolized in the liver and eliminated in the kidney. Side effects are consistent with the cholinergic crisis.

Question 18

How do hypocholinergic conditions differ from hypercholinergic conditions?

Answer 18

Hypocholinergic: Myasthenia gravis -> Atropine/Scopolamine/Belladonna/Jimson weed -> BZ Hypercholinergic: Quaternary alcohols -> Carbamates -> Organophophates -> Nerve gas

Question 19

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?

Answer 19

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).

Question 20

How do you treat the farmer that got poisoned by insecticides?

Answer 20

Remove contaminants (clothes), shut down muscarinic receptors with atropine, regenerate AChE with pralidoxime, reduce convulsions with diazepam and maintain respiration.

Question 21

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?

Answer 21

Pralidoxime. It binds to the organophosphate and takes it out of the AChE active site. This is not useful against carbamate.

Question 22

You are being deployed to Syria. How does Uncle Sam make sure you are prepared for contact with nerve gas?

Answer 22

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.

Question 23

What direction is the insecticide taking in drug development.

Answer 23

Prodrugs such as malathion that becomes active once metabolized and they use drugs that are not metabolized by humans.