What would happen in an individual received:

1. a small dose of acetylcholine.

2. a large dose of acetylcholine.

Acetylcholine is a neurotransmitter of the parasympathetic nervous system and can act on at the muscarinic or the nicotinic receptors.

Its effects in the heart mimic vagal stimulation; decreasing heart rate and stroke volume. It also decreases blood pressure by activating M3 receptors of the smooth muscles of blood vessels. It would act in the GI tract by increasing gastric and intestinal secretions as well as increasing motility. It causes an urgency to urinate as well as pupil constriction. Thus, in small doses these effects would be observed.

In large doses its effects would be deadly due to cardiac failure, asystole, and muscle paralysis unless it was reversed.

How do neostigmine, phridostigmine, edrophonium, and physostigmine work?

What might be the indicationsfor each of these medications?

All of these drugs act as indirect-acting cholinergic agonists by inhibiting acetylcholinesterase.

Neostigmine is used as an antidote to neuromuscular blocking agents. It is also used in treatment of Myasthenia Gravis

Pyridostigmine is another cholinesterase inhibiter, also used to treat MG because it has a longer duration of action than neostigmine and it can be given orally.

Edrophonium acts similar to neostigmine but has a rapid onset and very short duration. Used to diagnose myasthenia gravis. Injection IV would render a rapid increase in muscle strength in someone with MG.

Physostigmine is a substrate for acetylcholinesterase. It forms a carbamoylated intermediate with the enzyme, thus inactivating it. It is used to increase bladder and intestinal motility. It can be used topically to cause miosis (pilocarpine works better). Used in tx of overdose of anticholinergic drugs (atropine, phenothiazines, and tricyclic antidepressants).

Neostigmine is used to reverse the effects of NDNMB's (non-depolarizing neuromuscular blockers), specifically through the inhibition of acetylcholinesterase. Neostigmine is a parasympathomimetic acetylcholinesterase inhibitor. Reversal of NDNMB's occurs during preparation for emergence from anesthesia. Glycopyrrolate is coadministered to protect against bradycardia from the muscarinic effects of neostigmine. Glycopyrrolate will also decrease salivary, tracheobronchial, and pharyngeal secretions.

Neostigmine causes ACh levels to increase everywhere (nicotinic and muscarinic receptors). Since your goal when reversing muscle relaxants is to affect only nicotinic receptors, the muscarinic effects of neostigmine (especially severe bradycardia) can be blocked by coadministering glycopyrrolate or atropine.

Beta-blockers, Cholinergics, Alpha Agonists, Carbonic Anhydrase Inhibitors. Timolol (beta-blocker) will decrease intraocular fluid levels.

Alpha agonist such as Apraclonidine decreases intraocular fluid and increases fluid drainage.

Pilocarpine (cholinergic agonist) produces miosis, thus increasing drainage.

Carbonic Anhydrase Inhibitor (acetazolamide) also decreases production of intraocular fluid.

Atropine (cholinergic antagonist) will block all cholinergic action through the inhibition of muscarinic receptors. This action will dilate the pupil, thus possibly increasing IOP.

Glycopyrrolate (cholinergic antagonist)

Scopolamine (cholinergic antagonist)...although review of literature is unclear

Succinylcholine (Depolarizing NMB)...again, controversial in the literature

Ketamine may increase IOP...literature is controversial

Bethanechol stimulates muscarinic receptors located on smooth muscle of the gastrointestinal and urinary tracts. Therefore the drug can be used urologically and gastrologically. In the genitourinary tract, it increases muscle tone in the detrusor urinae muscle in the bladder and stimulation of urethral peristalsis causing the expulsion of urine. In addition, the trigone and external sphincter are relaxed. Bethanechol also increases GI peristalsis. Uses include relief of gastric atony after bilateral vagotomy. It can also be used in combating urinary retention in postoperatively and postpartum period in certain cases of neurogenic bladder. Adverse effects of bethanchol include generalized cholinergic stimulation which include sweating, salivation, flushing, decreased blood pressure, abdominal pain, bronchospasm, and nausea.

What are organophosphate compounds?

When are these agents used and how would you treat the toxic side-effects of these agents?

Chemically, organophosphate (OP) compounds are degradable organic compounds containing carbon-phosphorous bonds. They are a diverse group of chemicals used in both industrial and domestic settings. Examples of OP compounds include insecticides, nerve gas agents, ophthalmic agents, and antihelmintics (drugs that expel parasitic worms from the body). Toxic side effects of these agents include muscarinic, nicotinic, and CNS effects due to acetylcholine accumulation.

Treatment of OP are as listed:
1. Airway maintenance for respiratory distress due to 

    larangospasm, bronchospasm, seizures, and copious

    secretions.

2. Use of Anticholinergic Agents:
    a. Atropine as a competitive inhibitor at autonomic 

        postganglionic cholinergic receptors.

        Administration will compete with acetycholine at

        muscarinic receptor sites. The end point of

        atropinization is dried pulmonary secretions and

        oxygenation. Tachycardia and mydriasis should

        not stop atropine administration because

        respiratory failure secondary to excessive airway 

        secretions is the main concern with OP toxicity.
    b. Glycopyyrolate is another antimuscarinic agent

        used to reduce excessive secretions. It is usually

        used after atropine with recurrent symptoms. It

        does not cross the blood brain barrier, so it does

        not treat a central cholinergic toxicity

3. Pralidoxime (2-PAM) is the antidote for OP poisoning.

    It is a nucleophillic agent that reactivates the

    phophorylated acetylcholinsterase by binding to the

    OP molecule. The mechanism of action of OP is the

    inactivation of AChE by phosphorylation of the AChE

    hydroxyl group. OP then attaches to the AChE. Once

    OP and AChE are attached, the enzyme can undergo

    one of the following:
    a. Hydrolysis

    b. Reactivation by a strong nucleophile such as        

        2-PAM

    c. Irreversible binding and permanent enzyme

        inactivation (aging)

Treatment is not as effective once AChE is aged. Pralidoxime will reverse muscle paralysis. Should be administered with atropine since Pralidoxime does not relieve depression of the respiratory center or muscarinic effects.

Make sure you know organophosphates block ACh (acetylcholine) metabolism by blocking AChE (acetylcholinesterase). Organophosphates can cause death by causing ACh levels to go dangerously high. The treatment is atropine (for muscarinic effects), mechanical ventilation (for nicotinic effects) and 2-PAM, pralidoxime (reactivate the AChE enzyme).

Pilocarpine can abort an acute attack of glacoma, because it caused pupillary constriction to lower intraoccular pressure. It binds mainly to muscarinic receptors and can enter the brain. It is not effective in inhibiting secretions.

Organophospates exert their effect by irreversibly binding to acetylcholinesterase and, thus, can cause a cholinergic crisis. Administation of atropine will block the muscarinic sites; however, it will not reactivate the enzyme, which will remain blocked for a long period of time. Therefore, it is essential to also administer 2-PAM as soon as possible to reactivate the enzyme before aging occurs. Administering 2-PAM alone will not protect the patient against the effects of acetylcholine resulting from acetylcholine inhibition.

Edrophonium is a short-acting inhibitor of acetylcholinesterase that is used to diagnose myasthenia gravis. It is a quaternary compound and odes not enter the CNS.

Neostigmine is used in the treatment of myasthenia gravis but is not employed in its diagnosis.