NRSG 305 Flashcards

The Parasympathetic Nervous System, Cholinergic Agonists, and Anticholinergic Agents

Key Terms

• Acetylcholinesterase: An enzyme that rapidly breaks down acetylcholine to prevent overstimulation of cholinergic receptor sites.
• Alzheimer's Disease: A degenerative brain disease characterized by the loss of acetylcholine-producing cells and cholinergic receptors, leading to progressive dementia.
• Cholinergic Agonist: A substance that mimics the action of acetylcholine, stimulating receptor sites and neurons that release acetylcholine.
• Miosis: Pupil constriction, which can relieve intraocular pressure in some types of glaucoma.
• Myasthenia Gravis: An autoimmune disease where antibodies destroy cholinergic receptor sites, decreasing response at the neuromuscular junction and leading to paralysis.
• Nerve Gas: An irreversible acetylcholinesterase inhibitor used in warfare that causes paralysis and death due to prolonged muscle contraction and parasympathetic crisis.
• Parasympathomimetic: A substance that mimics the effects of the parasympathetic nervous system, leading to:
  • Bradycardia
  • Hypotension
  • Pupil constriction
  • Increased gastrointestinal secretions and activity
  • Increased bladder tone
  • Relaxation of sphincters
  • Bronchoconstriction

Overview of the Parasympathetic Nervous System (PSNS)

• Cholinergic nerves produce acetyltransferase, which uses choline from our diet to synthesize acetylcholine (ACh).
• ACh is the primary neurotransmitter in the PSNS.
• The main goal of the PSNS is energy conservation, often referred to as "rest and digest."

Effects of PSNS Activation

• Increased GI motility and secretions
• Increased defecation
• Increased urination
• Decreased heart rate
• Dilation of blood vessels
• Decreased cardiac contractility
• Bronchoconstriction
• Increased pulmonary secretions
• Pupil constriction

Pharmacodynamics of Cholinergic Drugs

• Acetylcholine (ACh) Synthesis:
  • Acetyl CoA + Choline (from diet) \rightarrow ACh
• ACh Action:
  • ACh stimulates muscarinic or nicotinic cholinergic receptors.
• ACh Breakdown:
  • Acetylcholinesterase breaks down ACh into choline and acetic acid, terminating its action.
• Direct-Acting Cholinergic Drugs:
  • Stimulate receptors directly.
• Indirect-Acting Cholinergic Drugs:
  • Block acetylcholinesterase, leading to increased ACh in the synapse.
• CNS Origins:
  • Parasympathetic impulses originate from cranial nerves (e.g., vagus nerve) and sacral nerves.

Acetylcholine (ACh) as a Neurotransmitter

• ACh facilitates communication between nerves and muscles.
• Triggers muscle contraction.
• Involved in cognitive processes, including thought, learning, and memory.
• Associated with awakening.

Termination of Acetylcholine Action

• ACh must be deactivated rapidly to prevent convulsions.
• Acetylcholinesterase (AChE):
  • Breaks down ACh.
  • Prevents overstimulation of cholinergic receptor sites.
  • Responds in approximately 80 seconds.

Cholinergic Receptor Subtypes

• Two primary receptor subtypes:
  • Nicotinic (N, M)
  • Muscarinic (M1, M2, M3)
• Muscarinic Receptors:
  • Activated by muscarine.
  • Located in visceral effector organs (GI tract, bladder, heart, sweat glands, vascular smooth muscle).
  • Stimulation causes:
    • Pupil constriction
    • Increased GI motility/secretions
    • Increased saliva
    • Increased bladder contraction
    • Decreased heart rate
• Nicotinic Receptors:
  • Located in the CNS, adrenal medulla, autonomic ganglia, and neuromuscular junction.
  • Stimulation causes:
    • Skeletal muscle contraction
    • Autonomic responses (stress reaction symptoms)
    • Release of norepinephrine and epinephrine from the adrenal medulla

ACh Stimulation: High vs. Low Doses

• ACh acts on muscarinic (mAChR) and nicotinic (nAChR) receptors.
• Muscarinic Effects (Low Dose):
  • Bradycardia
  • Bronchoconstriction
  • Increased GI motility
  • Bladder constriction
  • Fall in blood pressure
  • Salivation
  • Lacrimation
• Nicotinic Effects (High Dose):
  • CNS stimulation
  • Ganglionic stimulation
  • Release of adrenaline
  • Rise in blood pressure

Muscarinic Receptor Subtypes (M1-M5)

• M1 Receptors:
  • Location: CNS, salivary glands, parietal cells
  • Effects: CNS excitation, memory, locomotor activity, gastric acid secretion
• M2 Receptors:
  • Location: Heart, smooth muscle
  • Effects: Decreased heart rate, decreased AV conduction
• M3 Receptors:
  • Location: Smooth muscle, exocrine glands
  • Effects: Smooth muscle contraction (except vasodilation), glandular secretion
• M4 and M5 Receptors:
  • Location: Mainly in the CNS; exact roles are still being researched.

Nicotinic Receptor Subtypes (NN, NG, NM)

• NN Receptors:
  • Location: CNS
  • Effects: CNS excitation
• NG Receptors:
  • Location: Adrenal medulla, autonomic ganglia
  • Effects: Ganglionic transmission, release of adrenaline
• NM Receptors:
  • Location: Skeletal muscle
  • Effects: Skeletal muscle contraction
• All nicotinic receptors are ionotropic and fast-acting.

Cholinergic Agonists

• Act at the same site as acetylcholine (ACh).
• Increase activity of ACh receptors throughout the body.
• Effects are widespread due to systemic distribution; often causes undesirable systemic effects.
• Increase secretions throughout the body

PSNS Drugs

• Direct-Acting Cholinergic Agonists (Muscarinic):
  • acetylcholine chloride
  • bethanechol
  • carbachol
  • cevimeline
  • pilocarpine
• Direct-Acting Cholinergic Agonists (Nicotinic) and Agents for Nicotine Withdrawal/Abstinence:
  • bupropion
  • nicotine
  • varenicline
• Indirect-Acting Cholinergic Agonists:
  • echothiophate iodide
  • neostigmine
  • pyridostigmine
• Agents for Alzheimer's Disease:
  • donepezil
  • galantamine
  • rivastigmine

Cholinergic Agonists: Direct vs. Indirect

• Cholinergic agonists are parasympathomimetic:
  • Act on ACh receptors throughout the body either directly or indirectly.
  • Not specific; can cause widespread undesirable results.
• Direct-Acting:
  • Act at cholinergic receptors in the peripheral nervous system.
  • Mimic effects of ACh and parasympathetic stimulation.
  • Occupy receptor sites for ACh on effector cells of postganglionic cholinergic nerves.
  • Infrequently used now due to better, less toxic options.
• Indirect-Acting:
  • Cause increased stimulation of ACh receptor sites by reacting with AChE.
  • Prevent AChE from breaking down ACh, thus increasing ACh levels.

Direct-Acting Cholinergic Agonists (Muscarinic)

• Effects:
  • Slowed heart rate
  • Decreased myocardial contractility
  • Vasodilation
  • Bronchoconstriction
  • Increased bronchial mucus secretion
  • Increased GI activity/secretions
  • Increased bladder tone
  • Relaxation of GI and bladder sphincters
  • Pupil constriction
• Therapeutic Uses:
  • Bethanechol/Duvoid: For nonobstructive post-op and postpartum urinary retention and neurogenic bladder (PO or SQ).
  • Acetylcholine chloride/Miochol-E: Ophthalmic agent for eye procedures requiring rapid miosis or to reduce intraocular pressure in glaucoma.
  • Cevimeline/pilocarpine: Systemic muscarinic agonists to increase secretions in the mouth and GI tract for dry mouth in Sjogren’s syndrome.
• Pharmacokinetics:
  • Well absorbed after PO administration.
  • Relatively short half-life (1-6 hours).
  • Metabolism/excretion not well-defined.
  • Topical application typically does not result in systemic absorption.

Direct-Acting Cholinergic Agonists (Muscarinic) - Adverse Effects and Contraindications

• Adverse Effects:
  • Bradycardia, heart block, hypotension (due to cardiac suppressing effects of PSNS)
  • N/V/D, increased salivation, choking, involuntary defecation, dehydration (due to increased GI secretions)
  • Flushing, sweating (due to cholinergic receptors in the SNS)
• Contraindications:
  • Bradycardia
  • Hypotension
  • Vasomotor instability
  • CAD
  • PUD
  • Intestinal obstruction
  • Recent GI surgery
  • Recent bladder surgery
  • Asthma
• Caution: Epilepsy, Parkinson’s, pregnancy, lactation

Direct-Acting Cholinergic Agonists (Nicotinic)

• Key points:
  • Nicotine binds to nicotinic cholinergic receptors in the peripheral and central nervous systems.
  • Increases neuronal activity in the prefrontal cortex, thalamus, and visual system.
  • Releases dopamine, creating a "reward feeling" that causes dependence.
  • Also releases norepinephrine, acetylcholine, serotonin, GABA, glutamate, and endorphins.
• Therapeutic Uses:
  • Nicotine/Nicorette: Nicotine replacement therapy for smoking cessation.
  • Bupropion: Aid in smoking cessation.
  • Varenicline/Chantix: Aid in smoking cessation.
• Pharmacokinetics:
  • Rates of absorption and half-life vary by delivery method.

Direct-Acting Cholinergic Agonists (Nicotinic) - Contraindications and Adverse Effects

• Contraindications/Cautions:
  • Allergy
  • Bupropion: Contraindicated in patients with seizure disorder (lowers seizure threshold).
  • Pregnancy and lactation: Weigh risks and benefits, as smoking is harmful.
• Adverse Effects:
  • Tachycardia
  • Hypertension
  • Airway irritant (avoid inhaled forms for airway disease)
  • Bupropion & varenicline: Increase risk of seizures and neuropsychiatric events like depression, mania, agitation, anxiety, paranoia, hallucinations, and delusions.
  • Nausea, dry mouth, dizziness, skin rash, strange dreams, hypertension

Important Considerations for Nicotine Replacement and Cessation

• Smoking cessation, with or without nicotine replacement, may require dose adjustments for other medications:
  • Insulin
  • Propranolol
  • Acetaminophen
  • Caffeine

Indirect-Acting Cholinergic Agonists

• Also known as:
  • Indirect-acting parasympathomimetics
  • Acetylcholinesterase inhibitors
• Mechanism:
  • Prevent the breakdown of acetylcholinesterase at the synapse, resulting in ACh accumulation
  • Inhibit metabolism of ACh, causing an increase in ACh levels
• Location of action:
  • Works at all ACh receptors (parasympathetic, CNS, and neuromuscular junction)
• Binding:
  • Reversible (therapeutic)
  • Irreversible (nontherapeutic)

Examples of Indirect-Acting Cholinergic Agonists

• Reversible:
  • Pyridostigmine/Mestinon
  • Neostigmine/Bloxiverz
  • Donepezil/Aricept
  • Galantamine/Razadyne
  • Rivastigmine/Exelon
• Irreversible:
  • Organophosphate/Nerve Gas/Mustard Gas
  • Echothiophate

Myasthenia Gravis

• Autoimmune destruction of nicotinic ACh receptors, causing decreased muscle activity and control.
• Neostigmine/Bloxiverz:
  • A reversible cholinesterase inhibitor.
  • Improves muscle strength by preventing the breakdown of ACh.
  • Therapeutic use: Myasthenia gravis.
  • Therapeutic use: Reversal of nondepolarizing neuromuscular blocking agents (paralytics).
• Pyridostigmine/Mestinon:
  • A reversible cholinesterase inhibitor used to improve muscle strength by preventing the breakdown of ACh.
  • Therapeutic use: Myasthenia gravis.
  • Therapeutic use: Antidote for neuromuscular junction blockers and approved for military use after exposure to nerve gas.

Alzheimer’s Disease

• Progressive loss of ACh-producing neurons in the brain cortex.
• Treatment: Reversible indirect-acting cholinergic agonists.
  • Donepezil/Aricept
  • Galantamine/Razadyne
  • Rivastigmine/Exelon
• Pharmacokinetics:
  • Metabolized in the liver and excreted in urine (caution in patients with existing liver or kidney impairment).

Medications for Myasthenia Gravis and Alzheimer’s Disease - Adverse Effects and Overdose

• Adverse Effects:
  • Bradycardia, hypotension, blurred vision, chest pain, confusion, difficulty breathing/SOB, palpitations, sweating, fasciculations, fatigue
• Drug-Drug: Increased risk of GI bleeding when taken with NSAIDs
• Overdose: Cholinergic crisis
  • Withdrawal of all cholinergic drugs and administration of ATROPINE
  • Diarrhea, abdominal cramps, increased salivation and lacrimation, increased bronchial secretions, miosis, diaphoresis, muscle cramps, fasciculations, muscle weakness, paralysis, respiratory depression

Indirect Acting Cholinergic Agonists - Irreversible (Toxicology)

• ACETYLCHOLINESTERASE INHIBITOR
  • WEAPONIZED - NERVE GAS
  • PESTICIDE - ORGANOPHOSPHATES
  • INHALED - RAPID SYSTEMIC EFFECT
• ACH BUILDS UP CREATING A CHOLINERGIC TOXICITY / CRISIS
  • HR SLOWS TILL INEFFECTIVE
  • PUPILS CONSTRICT
  • LUNGS CONSTRICT PREVENTING AIR FLOW
  • MUSCLES CONTINUOUSLY CONTRACT
  • DIAPHRAGM BECOMES IMMOBILE CAUSING RESPIRATORY ARREST
  • DEATH
• ANTIDOTE: ATROPINE (TEMPORARY BLOCK OF CHOLINERGIC ACTIVITY) FOLLOWED BY PRALIDOXIME (PROTOPAM CHLORIDE) TO FREE ACETYLCHOLINESTERASE

Cholinergic Toxicity

• Cholinergic Poisoning (SLUDGE):
  • S - Salivation
  • L - Lacrimation
  • U - Urinary incontinence
  • D - Diarrhea
  • G - GI cramps
  • E - Emesis
• Cholinergic Crisis:
  • Shortness of breath, hypotension, cardiac arrest, bradycardia
• Antidote:
  • ATROPINE (a muscarinic-blocking agent), then PRALIDOXIME (repeated every 15 minutes)

Organophosphate Poisoning

• Organophosphates are AchE inhibitors found in insecticides or pesticides/industrial chemicals.
• Increases Acetylcholine in the Synaptic cleft --> Overstimulation of Ach receptors --> Causing Sign and Symptoms of Occupational Exposure or Accident exposure.

Drug-Drug Interactions with Cholinergic Agonists

• These antagonize cholinergic drugs, resulting in decreased responses:
  • Anticholinergics
  • Adrenergic antihistamines
  • Sympathomimetics
  • Other cholinergic drugs (additive effects)

Cholinergic Agonists Across the Lifespan

• Children:
  • More susceptible to adverse effects, including GI upset, diarrhea, increased salivation (enough to cause choking), bowel/bladder incontinence
• Adults:
  • Flushing, increased sweating, salivation and GI upset, urinary urgency. Possible dizziness, drowsiness, blurred vision. Possible pregnancy risk
• Older adults:
  • More likely to experience CNS, CV, GI, respiratory, and urinary effects due to renal or hepatic impairment. More likely to have toxic levels. If GI issues develop may lead to dehydration. Increased possibility of dizziness/drowsiness

Nursing Considerations for Cholinergic Agonist Administration

• Assess for allergies, presence of GI or GU obstructions, hypotension, peptic ulcer disease, or coronary artery disease
• Perform baseline assessment of vital signs and labs
• Doses should be spread evenly apart to optimize the effects of the medication
• Atropine is the antidote for cholinergics and should be available in the patient’s room for immediate use if needed

Patient Education for Cholinergic Agonist Therapy

• Overdosing can cause life-threatening problems. Patients should not adjust dosages unless directed by their physician.
• Patients should notify their MD if they experience weakness, abdominal cramps, diarrhea, or difficulty breathing
• When to take the medications- Time of day and same time every day
• Encourage patients with myasthenia gravis to take medication 30 minutes before eating to help improve chewing and swallowing

Anticholinergic Agents

• AKA Parasympatholytic
• AKA Cholinergic Antagonist

Examples of Anticholinergics

• Atropine
• Tolterodine/Detrol
• Oxybutynin chloride/Ditropan XL
• Scopolamine
• Benztropine/Cogentin
• Ipratropium/Atrovent HFA
• Dicyclomine/Bentyl

Pharmacodynamics of Anticholinergic Drugs

• Acetyl CoA + Choline (from diet) \rightarrow ACh
• Acetylcholinesterase breaks down ACh
• Anticholinergic drugs block the receptor site

Cholinergic-Blocking Drugs

• Competitively block acetylcholine receptors at the muscarinic cholinergic receptor sites responsible for mediating the effects of parasympathetic postganglionic impulses
• Cholinergic-blocking drugs are also known as Anticholinergics or Parasympatholytics

Therapeutic Actions of Anticholinergic Drugs

• Competitive antagonists…ACh is unable to bind to receptor sites and cause cholinergic effect
• When the parasympathetic system is blocked, the effects of the sympathetic system are more prominent
• May be specific to particular receptors in respiratory/GU/GI tracts
• May block acetylcholine in the CNS, explaining effectiveness in treating N/V and motion sickness

Expected Drug Effects of Anticholinergics

• Eye:
  • Dilated pupils (mydriasis)
  • Decreased accommodation caused by paralysis of ciliary muscles (cycloplegia)
• Gastrointestinal:
  • Decrease intestinal and gastric secretions
  • Relax smooth muscle tone of GI tract
  • Decrease motility and peristalsis
• Genitourinary:
  • Relaxed detrusor muscle
  • Increased constriction of internal sphincter
• Glandular:
  • Decreased bronchial secretions, salivation, sweating
• Cardiovascular:
  • Large doses: Increase heart rate, increase contractility, increase conduction
• Respiratory:
  • Decreased bronchial secretions
  • Dilated bronchial airways
• CNS:
  • Large doses: drowsiness, disorientation, hallucinations

Adverse Effects of Anticholinergic Drugs

• Cardiovascular:
  • Tachycardia, dysrhythmias
• CNS:
  • CNS excitation, disorientation, hallucinations, delirium
• Eye:
  • Dilated pupils, decreased visual accommodation, increased intraocular pressure
• Respiratory:
  • Thickening and drying of respiratory secretions
• Gastrointestinal:
  • Decreased salivation, dry mouth, constipation
• Urinary:
  • Urinary retention
• Other:
  • Decreased sweating (increased risk of hyperthermia)

Atropine

• Derived from the plant belladonna
• Blocks only muscarinic effectors in the parasympathetic nervous system and those in the SNS (sweating)
• Does not block the nicotinic receptors
• Therapeutic use: advanced life support treatment of bradycardia or inhibiting vagal responses
• Therapeutic use: depress salivation and bronchial secretions and dilate bronchi
• At high dose, blocks the parasympathetic/cholinergic effects on pacemaker cells of the SA and AV node = Result is increased heart rate

Scopolamine / Transderm Scop

• Blocks only muscarinic effectors in the parasympathetic nervous system and those in the SNS (sweating)
• Does not block the nicotinic receptors
• Therapeutic use: Decrease N/V and motion sickness, decrease GI secretions, relieve urinary problems, dilate pupils

Ditropan XL / Oxybutynin

• Therapeutic Use: Overactive bladder: Abnormal spasm of the detrusor muscle that results in incontinence
• Relaxes detrusor muscles of the bladder and increase constriction of internal sphincter

Nursing Considerations for Anticholinergic Drug Administration

• Perform baseline assessment of vital signs and physical exam
• Assess for allergies and presence of possible contraindications/cautions such as BPH, glaucoma, tachycardia, heart disease, etc.
• Patients receiving anticholinergics must be monitored for: dry mouth, difficulty swallowing, constipation, urinary retention, tachycardia, pupil dilation, photophobia, cycloplegia, blurred vision, heat intolerance d/t lack of sweating
• REMEMBER!!!!!
  • Antidote for atropine overdose is PHYSOSTIGMINE (a cholinesterase inhibitor) . This has been D/C in the U.S.
  • Antidote for cholinesterase inhibitors is ATROPINE (a anticholinergic)

Patient Education for Anticholinergic Drug Therapy

• Dry mouth may occur; can be handled by chewing gum, frequent mouth care, and hard candy
• Anticholinergics taken by the elderly patient may lead to a higher risk for heatstroke because of the effects on heat-regulating mechanisms
• Check with the physician before taking any other medication, including over-the-counter medications

Clinical Reasoning

• A 55-year-old patient has been admitted to the telemetry unit. Suddenly, the heart monitor shows that he has a heart rate of 35 beats per minute. The nurse checks the patient and finds him groggy, with an apical pulse of 38 beats/min and a blood pressure of 98/32 mm Hg. Atropine is ordered as a standby treatment for symptomatic bradycardia of less than 40. How will it be given?
• A 78-year-old woman has a new prescription for tolterodine (Detrol) as part of the treatment for urinary urgency and frequency. What adverse effects should she be aware of before she takes this medication?