Chapter 15: Cholinesterase Inhibitors and Their Use in Myasthenia Gravis

Excessive muscarinic stimulation of neostigmine

Bradycardia Diaphoresis Increase GI motility Urinary urgency

Asthma

Broncho restriction Any time of obstructive lung disease

Hyperthyroidism

CNS stimulation at high dose of cholinesterase inhibitors

Cholinergic Crisis

Characterized by extreme muscle weakness or frank paralysis and signs of excessive muscarinic stimulation Treatment with respiratory support and atropine to increase heart rate

Neuromuscular blockade of neostigmine

Excessive dose • Initially have nicotinic receptor activation • Myochondic movements jerking • Ticks • Asphyxiation • Eventually decrease in muscular tone or muscle weakness

Signs of overmedication of cholinesterase inhibitors

Excessive salivation and other muscarinic responses Cholinergic like response MUR: Bradycardia, urinary urgency, diarrhea, vomiting

Mechanism of action from Neostigmine: Muscarinic response

Identical to those of the direct-acting muscarinic agonists · Prevents breakdown of Ach · Cholinesterase inhibitors can cause o Bradycardia o Bronchial constriction o Urinary urgency o Increased glandular secretions o Increased tone and motility of gastrointestinal smooth muscle § Diarrhea o Miosis o Focusing of the lens for near vision

Myasthenic Crisis

Inadequate medication Looks like Cholinergic response minus muscinaric response Extreme muscle weakness Caused by insufficient ACh at the neuromuscular junction Left untreated, myasthenic crisis can result in death as a result of paralysis of the muscles of respiration A cholinesterase inhibitor (such as neostigmine) is used to relieve the crisis

Peptic Ulcer Disease

Increase in gastric secretions

Obstruction of gastrointestinal or urinary tract

Increase of urgency and GI motility can present as problem

• Coronary insufficiency

Inhibitors have a direct effect on myocardia and increases myocardium oxygen demand

Distinguishing myasthenic crisis from cholinergic crisis

Myasthenic won't have musinaric response Challenging dose of edrophonium • If patient is having a cholinergic crisis: would worsen the crisis because giving them something that is increasing AcH • Have oxygen or code cart near by History of medication use or signs of excessive muscarinic stimulation assist with differential diagnosis • Known history of taking cholinesterase inhibitors it would make sense if patient has extreme muscle weakness is likely to be cholinergic crisis • Signs of muscular stimulation for cholinergic • Bradycardia • Drooling Identification by the patient

Signs of undermedication of cholinesterase inhibitors

Ptosis and difficulty swallowing

• Seizures higher doses

Stimulate CNS can stimulate seizures

1. A patient is newly diagnosed with myasthenia gravis. The nurse is providing patient teaching. The patient asks the nurse to describe how the disease affects the body. How should the nurse respond?

Myasthenia gravis is an autoimmune disease. Patients with myasthenia gravis have a lack of acetylcholine receptor sites or a decreased response from the acetylcholine receptor sites as a result of an antibody response.

acronym to remember overdose neostigmine can cause cholinergic crisis

Salivation, Lacrimation, Urination, Diaphoresis/Diarrhea, Gastrointestinal cramping, Emesis; Bradycardia, Bronchospasm, Bronchorrhea

What is the only clinical application for irreversible cholinesterase inhibitators

Using echothiophate for glaucoma

myasthenia gravis

autoimmune disease that causes neuromuscular dysfunction due to lack of Ach

Reversible Cholinesterase Inhibitors

bind to cholinesterase for a short period of time

Overdose of neostigmine can cause ___________ crisis

cholinergeric crisis

Neostigme has ____ effects on brain and fetus because it ________________

minimal; cannot cross membrane

What disease is neostigmine used to manage

myasthenia gravis

How to tell if therapeutic dose of neostigmine for neuromuscular effect

o Two ways to tell § Eyelids · Less drooping or do not have droop · Droop stays improved § Give water to sip · Can swallow

Neostigmine is a _________ substrate for ___________

poor; cholinesterase (ChE)

Neostigmine is absorbed ________ with oral adminstration

poorly

Irreversible cholinesterase Inhibitors

takes extremely long time for them to be cleaved from cholinesterase. Not really used clinically not really irreversible. Do have one for glaucoma. Insecticides

Mechanism of action from Neostigmine: Neuromuscular effect for therapeutic dose and toxic levels

· Therapeutic dose: Increases force of contraction in skeletal muscle · Toxic levels: Decrease force of contraction

Mechanism of action from Neostigmine: Central nervous system for therapeutic dose and toxic levels

· Therapeutic levels: Mild stimulation · Toxic levels: Depression of the central nervous system o Respiratory arrest because of depression of respiratory center in the brain

Describe process of myasthenia gravis

Ø Autoimmune process in which antibodies attack nicotinicM receptors on skeletal muscle and interferes with Ach binding to receptors thereby causing muscle weakness

Pathophysiology of Myasthenia Gravis

Ø Characterized by fluctuating muscle weakness and predisposition to rapid fatigue • At worst can cause respiratory arrest due to failure of respiratory muscles

Drugs for Alzheimer's disease

Ø Galantamine Ø Rivastigmine: Exelon • Patch Ø Donepezil • Most common oral drug -Brand name: Aricept

Toxicology

Ø Sources of poisoning: gamma phosphates and insecticides Ø Symptoms • Cholinergic crisis

Other features of cholinesterase inhibitors

• All contain an atom of phosphorus • Almost all are highly lipid soluble • Lack charge • Uncharged phosphate • Readily absorbed from several routes - All membranes including the brain • Potential use in chemical warfare as nerve gas

Edrophonium (Tensilon)

Administration of edrophonium given IV. PRIM FOR M GRAVIS DIAGNOSIS Ø Distribution half-life of 9 to 12 min Ø Elimination half-life of 30 min to 2 hours Ø Increase in the muscular strength has myasthenia gravis Ø Start to breathe better and stop drooling Ø Reversible agent for the competitive neuromuscular nondepolarizing blockade

Mechanism of action from Neostigmine: Pharmacologic effects

By decreasing the breakdown of ACh, neostigmine and the other cholinesterase inhibitors make more ACh available; this can intensify transmission at virtually all junctions where ACh is the transmitter

How is Neostigmine managed?

Can be used to cleave ChE, less Ach Breaking down, more Ach for the neuromuscular junction INDIRECTLY

1. The patient asks the nurse how the medication edrophonium chloride [Tensilon] is used to diagnose complications of the disease. What should the nurse say?

If edrophonium-induced elevation of ACh levels alleviates symptoms, the crisis is myasthenic. Conversely, if edrophonium intensifies symptoms, the crisis is cholinergic. Because the symptoms of cholinergic crisis will be made even worse by edrophonium and could be life-threatening, atropine and oxygen should be immediately available whenever edrophonium is used for this test. For a diagnosis of myasthenia gravis, an improvement should be seen after the administration of edrophonium.

What are irreversible cholinesterase inhibitators primarily used for?

Insecticides

1. The patient asks the nurse how the disease can be treated. How should the nurse reply?

The medications neostigmine [Prostigmine] and pyridostigmine bromide [Mestinon] can be used to treat patients with myasthenia gravis. Avoiding triggers such as infection, emotional stress, pregnancy, surgery, trauma, low potassium levels, extremes of temperature, and alcohol and certain medications is helpful to control the disease.

The nurse cares for a patient with myasthenia gravis. Before administering pyridostigmine [Mestinon], it is most important for the nurse to take which action? A)Assess the patient's ability to swallow a sip of water. B)Cleanse the patient's skin before applying the transdermal patch. C)Ask whether the patient has an allergy to aspirin. D)Give the patient food or milk to prevent stomach upset.

• Answer: A • Rationale: Pyridostigmine may be administered orally or intravenously. A patient with myasthenia gravis may not have sufficient muscle strength to permit swallowing. The nurse should assess the patient's ability to swallow a few sips of water before giving him or her oral medications. If the patient is unable to swallow the water, parenteral medication must be substituted for oral medication. Pyridostigmine may cause stomach upset and should be given with food or milk; however, it is more important to assess the patient's ability to swallow.

Question 4: A patient is prescribed a medication to be taken on an empty stomach. Which statement should the nurse include when providing patient teaching? A. "Take the medication 1 hour before eating." B. "Take the medication with a small glass of water." C. "Take the medication before going to bed at night." D. "Take the medication 1 hour after a meal."

• Answer: A • Rationale: To administer a drug on an empty stomach means to administer it at least 1 hour before or 2 hours after a meal.

A patient who has myasthenia gravis reports extreme muscle weakness. Which of the following medications should the nurse prepare to administer to distinguish myasthenic crisis from cholinergic crisis? A)Echothiophate [Phospholine iodide] B)Edrophonium [Tensilon] C)Atropine [AtroPen] D)Ambenonium [Mytelase]

• Answer: B • Rationale: Edrophonium is used to distinguish cholinergic crisis from myasthenic crisis. If edrophonium administration induces the elevation of ACh levels and symptoms are alleviated, the crisis is myasthenic. Conversely, if edrophonium intensifies symptoms, the crisis is cholinergic. Because the symptoms of cholinergic crisis will be made even worse by edrophonium and could be life-threatening, atropine and oxygen should be immediately available whenever edrophonium is used for this test. Short acting

The nurse instructs a patient with myasthenia gravis who is taking neostigmine [Prostigmin]. Which statement, if made by the patient to the nurse, indicates an understanding of the instructions? A)"The antidote for this medication is norepinephrine." B)"An extra dose should be taken if paralysis occurs." C)"A medical alert bracelet should be worn at all times." D)"The medication will be prescribed for 2 to 3 months."

• Answer: C • Rationale: Medical identification should be worn by the patient to alert medical personnel to the presence the condition, because myasthenic and cholinergic crises can be fatal. Neostigmine [Prostigmin] is a reversible cholinesterase inhibitor; atropine is the antidote for an overdose. Emergency medical assistance should be obtained for symptoms of weakness or muscle paralysis to determine whether the episode is a myasthenic or cholinergic crisis. The condition is not curable, and neostigmine will need to be taken for life.

How does neostigmine (Prostigmin) work as a substrate?

• Binds to ChE and prevents ChE from binding to Ach • Ach is more available at the motor end plate

Neostigmine [Prostigmin] cannot readily cross membranes. Such as? And why can't it cross

• Cannot cross Blood Brain Barrier, placenta, and gi tract due to drug's positive charge

Side effects of cholinesterase inhibitor treatment for myasthenia gravis

• Excessive muscarinic response • Excessive Ach on organs

Adverse effects/ acute toxicity of neostigmine

• Excessive muscarinic stimulation • Neuromuscular blockade

Treatment for irreversible cholinesterase inhibitors

• Mechanical ventilation • Pralidoxime: the antidote for irreversible cholinesterase inhibitors. Work in the neuromuscular junction Break apart Cholinesterase from poison More Cholinesterase to break down Ach Decrease effects of AcH Specific antidote to poisoning Effectiveness affected by early administration • Can cause irreversible breakage between cholinesterase and poison within two minutes • Diazepam: sig CNS stimulation to treat seizures

Drug interactions

• Muscarinic antagonists Will do opposite of the effect of cholinesterase inhibitors • Nondepolarizing neuromuscular blockers -Depolarizing neuromuscular blockers

Example of "Reversible" Cholinesterase Inhibitors

• Neostigmine [Prostigmin] • Physostigmine • Ambenonium • Edrophonium • Pyridostigmine • Drugs for Alzheimer's disease -Galantamine -Rivastigmine: Exelon -Patch - Donepezil -Most common oral drug -Brand name: Aricept

Precautions and contraindications of Neostigme

• Obstruction of gastrointestinal or urinary tract • Peptic ulcer disease • Asthma • Coronary insufficiency • Seizures higher doses • Hyperthyroidism

Mechanisms of action from Neostigmine

• Pharmacologic effects • Muscarinic responses § Neuromuscular effects § Central nervous system

What are common symptoms of Myasthenia Gravis

• Ptosis:eye lid droop • Dysphagia: patient cannot swallow Weakness of skeletal muscles

Therapeutic uses for Neostigmine in Myasthenia Gravis

• Reversal of nondepolarizing neuromuscular blockade Environment to paralyze patients Used postoperatively Treatment of overdose Likely to elicit substantial muscarinic responses May need to administer atropine (muscarinic antagonist) in an overdose of Neostigmine • Immediate increase in heart rate to reverse bradycardia • decrease GI motility • Dry up secretions

Dosage adjustment for myasthenia gravis treatment with cholinesterase inhibitors

• Start small and adjust to patient response • May need to modify dosage in anticipation of exertion If patient knows they are going to go on a jog they know to increase dosage

How to treat overdose of neostigmine

• Treatment with antagonist [Atropine] for overdose • Would need mechanical ventilation due to paralysis of the respiratory muscles as well as oxygen

How do you treat myasthenia gravis

• Treatment with cholinesterase inhibitors b/c they prevent breakdown of Ach. More Ach greater strength of patient

Physostigmine

• generic intramuscular or intravenous used as an antidote to poisoning by muscarinic antagonist