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Pharmacology

August 24, 2000

9:00 A.M.

Dr. P. Carroll

Jughead/Archie: Rishi Kapila/Zee Khan

Cholinergics III: Drugs Which Inhibit Acetylcholinesterase (AchE)

A. Physiology of AchE

1.Acetylcholine's action at nicotinic and muscarinic receptor sites is terminated by the enzyme acetylcholinesterase (AChE), in the synaptic cleft.

2. Following the binding of a single molecule of ACh to its receptor only once, AChE breaks it down into

choline and acetate.

3.AChE will break down ACh very quickly (~100 microseconds). Ach only has time to interact with one receptor at one time. By inhibiting AchE, builds up Ach in synaptic cleft; reacts multiple times with receptors

a. Also found on the surface of RBCs. The function of this location is unknown.

4. . In the plasma, pseudocholinesterase is the active enzyme that breaks down ACh. There is no therapeutic benefit to be achieved to inhibiting only pseudocholinesterase. The true substrate for pseudocholinesterase is butyrocholine. There is not any known butyrocholine in the body for pseudocholinesterase to break down.

5.RBC’s AchE receptors can be used as indicators of organophosphate intoxication

anophosphate are irreversible AchE inhibitors, causing sky high levels of Ach resulting in bronchial secretions, salivation, sweating, gastric distress, respiratory problem

a. Act at nicotinic Ach junction, Ach builds up due to desensitization of Ach receptors

b. act also at muscarinic receptors leading to bronchioconstriction compromising breathing

7. A blood sample in a patient with organophosphate intoxication will have a decreased activity of acetylcholinesterase and pseudocholinesterase. Pseudocholinesterase is more sensitive to organophosphate intoxication and may reach 100% inhibition while AChE is less sensitive and may reach 50% inhibition.

8. We will discuss, acetylcholine mimic that looks like two Ach molecules attached together, called succinylcholine, tomorrow

9. Pseudocholinesterase found on glial cells, again nobody knows why

B.Two different types of AchE inhibitors: reversible and irreversible

1. Some of these reversible inhibitors have a charge (neostigmine, pyridostigmine, edrophonium). Charged inhibitors act directly on nicotinic Ach receptor, causing slight muscular contractions.

2.They have dual action in improving Myasthenia Gravis by building up Ach and activating Ach receptors.

3. Edrophonium’s action, some believe, due more to charge than ability to inactivate AchE

4. Physostigmine is uncharged reversible AchE inhibitor. It’ll cross BBB, causing Ach build up centrally and peripherally. Charged inhibitors won’t cross BBB, no central side effects.

5. DFP is an uncharged irreversible AchE inhibitor. Echothiophate is a charged irreversible AchE inhibitors.

C.Process of Achetylcholine Breakdown

1. ACh can bind to two sites on AChE.

2. The choline portion of ACh is positively charged binding to anionic site of AchE

3. Esteratic Site - This is the active site on the enzyme that will hydrolyze the ester to choline and acetic acid. Covalent bond is formed here.

4. Inhibitors can bind to either the anionic site, esteratic site, or both sites.

5. Even Choline can act as inhibitor of AchE at high levels

D. Drugs/binding locations

1. ACh

a. Acetylates the esteratic site.

b. Hydrolyzed in microseconds.

2. Edrophonium +

a. Competitively binds to both the esteratic and anionic site.

b. Not hydrolyzed by AChE.

c. Rapidly cleared by the kidneys

d. Short duration of action (5 min)

3.Carbamylate Inhibitors (Neostigmine, Physostigmine, Pyridostigmine)

a. Carbamylates the esteratic site on AChE to form a stronger bond (covalent) and bind to anionic site.

b.These three look like ACh chemically

c.Neostigmine + is hydrolyzed to edrophonium by AchE

d. Hydrolysis may take from 60 to 180 minutes, so while AchE is bound by carbamylate, Ach builds up

E. Irreversible AchE inhibitors phosphorylate esteratic site, forming stronger bond than carbamylates. Hydrolysis may take up to two weeks. So, these inhibitors aren’t technically irreversible but two weeks is a heck of a long time!

1.Esterase is one of the slowest turning over enzymes in the body. It takes a long time to replace itself. So, it can’t return to its normal level in two weeks’ time.

F. Antidotes

1. Atropine

a. Not charged and thus will pass the blood-brain barrier.

b. Blocks the muscarinic effects caused by the buildup of ACh at muscarinic receptor sites.

c.The effect of this drug at nicotinic receptor sites is questionable.

2. Pralidoxime +

a. Positively charged and thus will not pass the blood-brain barrier.

b. Must be given within 20 to 30 minutes of organophosphate exposure to prevent the "aging" of AChE.

c. Pulls the organophosphate off the esteratic site of AChE.

d. Works especially well at the NMJ.

e. If mistakenly given to a non-organophosphate intoxicated patient (i.e. one that overdosed on a reversible AChE inhibitor), death may occur. Be careful when administering this drug!

G. Therapeutic uses of AChE inhibitors

1.Treats gastric atony

2. Treats bladder atony

3. Narrow and wide angle glaucoma

4. Myasthenia gravis (AChE inhibitors are the major drugs for treating this disease)

5. Termination of an overdose of a curare like competitive blocker (d-tubocurare or vecuronium).

6.Reversal of the photophobia and mydriasis induced by atropine during retinal exams.

H. Reversible AChE inhibitors

1. Neostigmine +

a. Positively charged, therefore it will not readily cross the blood-brain barrier.

b. Duration of action is only 2-4 hours.

c. It will stimulate GI motility and is a good drug to treat gastric atony. Two Mechanisms: 1) inhibiting esterase 2) ganglionic stimulation will increase parasympathetic tone.

d. Can be used to restore bladder function, but bethanechol is a better drug to treat this condition due to its better absorption.

e. Can be used for both wide and narrow angle glaucoma, but the positive charge will limit the penetration into the eye.

f. At one time, this agent was the drug of choice in treating patient with myasthenia gravis. Due to its poor oral absorption, little of this drug actually will reach the NMJ. The short duration of action of this drug further limits its use.

g. Can be used in d-tubocurare (muscle relaxant) overdoses. . Side Effects: GI distress

2. Pyridostigmine +

a. Positively charged, therefore it will not have any central effects.

b. Duration of action is 3-6 hours and is available in time release portions.

c. Considered a better drug than neostigmine in the treatment of myasthenia gravis due to its better oral absorption and longer duration of action.

d. In comparison to neostigmine, this drug will have fewer GI tract effects.

e. Muscarinic effects of pyridostigmine/neostigmine wane after few weeks’ treatment. Atropine can be used to block these side effects.

3. Physostigmine

a. Is not charged, therefore it will cross the blood-brain barrier and will penetrate the membranes of the eye. Can act centrally and peripherally.

b. Combined with pilocarpine in the treatment of narrow angle glaucoma. Pilocarpine will act directly on the muscarinic receptors to lower intraocular pressure. Physostigmine is indirectly acting in that it will inhibit AChE to increase ACh activity at muscarinic receptors.

c. Used as an antidote for atropine intoxication.

d. Shouldn’t use for myasthenia gravis ‘cause will cause central side effects.

4. Edrophonium +

a. A very short duration of action (five minutes).

b. Used to diagnose myasthenia gravis. When given by IV, it will give a rapid improvement (five minutes) in muscle strength.

c. Is a competitive agonist that is not broken down by AChE.

d. Used in control of pyridostigmine dosing levels. The muscle weakness in a patient with too low a dose of pyridostigmine will decrease with edrophonium treatment. If the muscle weakness increases with edrophonium administration, the patient's pyridostigmine dose is too high.

e. Can be used for supraventricular tachycardia

5. Additional noncharged AchE inhibitors: Tacrine and Donepezil

a. Both will cross the blood-brain barrier (not charged).

b. Used in the treatment of Alzheimer's disease. These drugs can improve conditions by increasing the ACh levels in the hippocampus of the brain. Unfortunately, these drugs are only effective in 20-25% of the patients.

I. ACh related autoimmune diseases

1. Myasthenia Gravis

a. Mainly considered a postjunctional autoimmune disease.

b. The body produces antibodies directed against nicotinic receptors at the motor endplate of the NMJ.

c. As high as 80% of the nicotinic receptors may be inactivated by the binding of antibodies.

d. The antibodies do not recognize nicotinic receptors at autonomic ganglia or adrenal medulla.

e. Muscle strength is not normal due to the rapid fatigability of patients with this disease.

f. Nightly breathing difficulties may occur and eventually, this disease will kill due to respiratory arrest.

g. Some people are helped by removal of thymus gland (since it is producing T-cells).

h. Neostigmine will work well to alleviate Myasthenia Gravis but will cause initial gastric distress, lasting 2 – 4 hours. Have to get up in the middle of the night to redose.

1. (-bungarotoxin

a. A drug used to identify patients with myasthenia gravis.

b. This drug has a high affinity for nicotinic receptors at the NMJ.

c. A muscle biopsy will exhibit a decreased binding of this drug due to the antibodies blocking the nicotinic receptors (up to 80% decreased binding).

2. Myasthenic Syndrome (Lambert Eaton)

a. A very rare disease in comparison to myasthenia gravis.

b. A prejunctional defect in ACh release where antibodies block the calcium channels that mediate the release of ACh.

c. Like myasthenia gravis, this disease involves a similar muscle weakness.

d. Through α-bungarotoxin binding studies, the two diseases can be differentiated. For the myasthenic syndrome, there will be normal binding of α-bungarotoxin to nicotinic receptors.

e. Guanidine is used to treat this disease because it will increase ACh release.

J. Side Effects of Reversible AChE Inhibitors

1. Can be muscarinic or nicotinic (muscle fasciculations) in nature.

2. Due to bronchial constriction and increased bronchial secretions, this class of drugs is contraindicated in asthmatics.

3. Can cause increased urinary frequency, GI cramping, sweating and diarrhea. Gastric effects seem to disappear after about two weeks.

4. Physostigmine has been known to cause dysphoria, and restlessness.

K (as in Khan and Kapila, baby!). Irreversible AChE inhibitors

1. Echothiophate +

a. Shouldn’t be taken parenterally, only can be used in the eye.

b. DFP used to be used, but is not anymore

c. Won’t penetrate membranes of eye, won’t get to site of action

d. Can be used for wide angle glaucoma, yet is not the first drug of choice. The adrenergic drug, timolol, is a better treatment, followed by the cholinergic drugs pilocarpine and physostigmine.

e. The advantage to this drug is its long duration of action (two weeks) and is stable in solution for six months.

f. Extended use (more than six months) can cause cataracts.

2. Organophosphates (Mipafox)

a. Used as an insecticide.

b. Delayed Neurotoxicity (associated with some, but not all organophosphates)

1. Approximately 7 to 10 days following exposure, individuals will begin to show signs of irreversible neurotoxicity.

2. Delayed neurotoxicity has nothing to do with inhibition of AchE or pseudocholinesterase

3. It is believed that the compounds that cause this condition bind to some form of neurotoxic esterase and cause the regression and demyelination of motor nerve terminals.

4. Start out with ataxia and can lead to paralysis. There is currently no drug antidote for delayed neurotoxicity.

5. There is a screening procedure that can determine which organophosphates cause it and which ones do not. It involves determining which organophosphates compete with DFP for binding to a neurotoxic esterase, then they will very likely cause delayed neurotoxicity.

6. afflicted suffer from ataxia

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