Nursing Pharmacology Chapter 5:  Autonomic Pharmacology: Cholinergic Drugs

 

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 Indirect-acting Cholinomimetic Drugs

Nursing Implications:  Cholinergic Drugs: Reversible Acetylcholinesterase Inhibitors
  • Clinically important reversible acetylcholinesterase inhibitors include the following agents:

    • Ambenonium (Mytelase, discontinued in U.S.)

    • Donepezil (Aricept)

    • Edrophonium (Tensilon)

    • Galantamine (Nivalin, Razadyne, Reminyl, Lycoremine)

    • Neostigmine (Prostigmin, Vasostigmin)

    • Physostigmine (Eserine)

    • Pyridostigmine (Mestinon)

    • Rivastigmine (Exelon),

    • and Tacrine (Cognex, discontinued in the U.S.).

  • These agents are used to address a number of therapeutic challenges.

    • For example: acetylcholinesterase inhibitors are used:

      • To reverse the action of nondepolarizing neuromuscular antagonist drugs

      • To reduce the effect of poisoning by muscarinic blockers

      • To provide modest benefit in management of Alzheimer's disease

      • To treat glaucoma and

      • To treat myasthenia gravis.

        • In the case of myasthenia gravis, typically fast-acting reversible acetylcholinesterase inhibitors help with assessing the extent of neuromuscular dysfunction of the disease.

          • Assessment criteria include fatigue, ptosis, ability to swallow and muscle strength.

            • Ptosis of the left eyelid (unilateral ptosis)

              • Ptosis may occur when muscles that raise the eyelid are not strong enough to do so.  Myasthesia gravis is one of several possible causes.

              • This image is of an unidentified male presenting with eyelid ptosis in 1852.

              • Attribution:  William Bell

              • http://en.wikipedia.org/wiki/Ptosis_(eyelid)

          • Certain patients are identified as "High-Risk" with respect to taking these medications.

            • Acetylcholinesterase inhibitors are contraindicated for those patients who have intestinal or urinary tract mechanical obstruction.

            • Cautious use should be exercised when administering these agents to those patients with hyperthyroidism, low heart rate (bradycardia), peptic ulcer disease or asthma.

              • The underlying rationale for these concerns is that when acetylcholinesterase inhibitors are administered, the effect is to increase acetylcholine concentration enhancing cholinergic tone or cholinergic effect.

              • For example, acetylcholinesterase inhibitors because they increase local acetylcholine concentration in the heart would be expected to reduce heart rate, just as the physiological transmitter, acetylcholine, would normally cause.

  • These drugs may be given topically, orally, and parenterally, (i.e. intramuscular, IV, and subcutaneously).

  • In management of myasthenia gravis the patient might be administered medication orally; however, if swallowing is compromised by the disease, the parenteral route of administration would be preferable.

    • The dosage would typically be adjusted while monitoring therapeutic responses and it is important that patients learn to distinguish between either insufficient or excessive dosing.

      • It is especially important for patients to participate in dosage adjustment.

        • To facilitate patient participation, patients should be informed that myasthenia gravis, not typically curable, requires lifelong treatment.

        • Furthermore, myasthenic patients are at risk for complications due to either too much acetylcholine accumulation (cholinergic crisis) or not enough acetylcholine (myasthenic crisis, perhaps due to insufficient medication).

          • Accordingly, the patient should be encouraged to carry appropriate identification such that emergency personnel,  responding to a serious complication take into account the patient's myasthenic condition.

           

  • With respect to the use of these drugs for reversing nondepolarizing neuromuscular blockade, pyridostigmine or edrophonium IV may be effective in counteracting the effect of nondepolarizing agents, such as tubocurarine.

    • The basic idea here is again that the acetylcholinesterase inhibitor allows local accumulation of acetylcholine, which in this instance competes with the nondepolarizing blocker at the receptor, thus helping to overcome the blockade.

    • If such a reversal is needed, respiration must be supported, perhaps by the use of a ventilator, until muscle strength is sufficiently recovered to support physiological respiration.

     

  • For management of muscarinic antagonist poisoning, physostigmine, the drug of choice, would be administered by either intramuscularly or by slow IV.

 

  • Reversible acetylcholinesterase inhibitors play a role also in evaluating therapeutic effectiveness in myasthenia gravis.

    • In this application the following four steps are helpful in deciding to increase or decrease acetylcholinesterase inhibitor medication.

      • (1) monitor and record the times of drug administration

      • (2) monitor and record time when fatigue occurs

      • (3) monitor and record indicators of muscle strength, ptosis, and swallowing ability and

      • (4) monitor and record indications of excessive muscarinic receptor stimulation.

    • As suggested earlier myasthenic crisis which manifests as substantial muscle weakness,  including respiratory muscle paralysis may occur when acetylcholinesterase inhibitor dosage is inadequate.

      • Should this event occur, respiratory assistance along with increasing medication dosage are appropriate.

      • A particular, very short acting reversible acetylcholinesterase inhibitor, edrophonium (Tensilon) is helpful in distinguishing between a presentation of myasthenic crisis from a presentation of cholinergic crisis.

        • Following edrophonium administration, myasthenic crisis symptoms should be reduced; whereas, symptoms of cholinergic crisis become more pronounced.

         

  • Excessive dosage of acetylcholinesterase inhibitors results in a number of predictable physiological effects.

    • All these effects may be explained by an excessively high acetylcholine level, which occurs as a result of inhibiting acetylcholinesterase.

      • Acetylcholine hydrolysis by acetylcholinesterase is the principal way by which the biological effects of acetylcholine is terminated.

    • Adverse effects associated with excessively elevated acetylcholine are mediated by muscarinic receptor stimulation and include:

      • increased tone and gut motility

      • urinary urgency

      • significance salivation

      • sweating

      • miosis

      • difficulty in visual accommodation

      • bradycardia, and

      • bronchoconstriction.

    • Patient should typically be advised of these possible side effects and associate them with possible excessive muscarinic receptor stimulation.

      • Furthermore, should such presentations occur, the patient should be advised to notify a physician.

        • These excessive muscarinic responses may be treated with an anticholinergic drug, such as atropine.

      • With acetylcholinesterase inhibitor overdose, skeletal muscle paralysis as a result of depolarizing neuromuscular blockade may occur, along with the effects noted above due to excessive muscarinic receptor stimulation.

      • This effect, cholinergic crisis, may be managed with a combination of an anti-cholinergic drug, such as atropine and ventilatory support.

Lehne RA Pharmacology for Nursing Care, Sixth Edition, Chapter 14:  Muscarinic Agonists and Antagonists, Saunders/Elsevier, 2007, pp138-139.

 

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237;  Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.161-174.

Taylor, P. Anticholinesterase Agents, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 167.

Sites of Drug Intervention in Management of Myasthenia Gravis

 

Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472.: Figure adapted from Figure 382-2, p. 2471

 

  1. Taylor, P. Anticholinesterase Agents, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp. 172-173.;

  2. Moroi, S.E. and Lichter, P.R. Ocular Pharmacology In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p. 1634;

  3. Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472

 

 

Indirect Cholinomimetic Agents

Acetylcholinesterase Inhibitors ("Reversible")

Acetylcholinesterase Inhibitors ("Irreversible")

Neostigmine (Prostigmin)

Physostigmine (Antilirium)

Edrophonium (Tensilon)

Soman

Parathion

Malathion

Isoflurophate

Diisopropylflurorphosphate, DFP

Echothiophate

 

Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, In, Goodman and Gillman's The Pharmacological Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.149-150

 
 
 
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