They split into direct-acting agents (react with the receptor itself) and indirect-acting agents (block acetylcholinesterase so ACh lingers). The indirect group includes the drugs for myasthenia gravis and the drugs for Alzheimer's disease.
Cholinergic Agonists: Generic and Brand Names
- Direct-acting Cholinergic Agonists
- bethanechol (Duvoid, Urecholine)
- carbachol (Miostat)
- cevimeline (Evoxac)
- pilocarpine (Salagen)
- Indirect-acting Cholinergic Agonists
- Agents for Myasthenia Gravis
- ambenonium (Mytelase)
- edrophonium (Reversal)
- neostigmine (Prostigmin)
- pyridostigmine (Mestinon)
- Agents for Alzheimer's Disease
- donepezil (Aricept)
- galantamine (Razadyne)
- rivastigmine (Exelon)
- tacrine (Cognex)
- Agents for Myasthenia Gravis
Tacrine appears on older drug lists but is no longer available in the United States. It was withdrawn from the market because it caused liver injury (transaminase elevations), and donepezil, galantamine, and rivastigmine, which are effective without that hepatotoxicity, replaced it.
Disease Spotlight: Alzheimer's Disease and Myasthenia Gravis
Direct-acting agonists treat neurogenic bladder atony in children, relieve intraocular pressure in glaucoma, and ease dry mouth in Sjogren's syndrome.
The indirect-acting agents treat myasthenia gravis and Alzheimer's disease. Myasthenia gravis is a chronic muscular disease caused by a defect in neuromuscular transmission, thought to be autoimmune: the body makes antibodies to its own ACh receptors. As receptor sites disappear, the patient develops progressive weakness and loss of muscle control. Alzheimer's disease is a progressive neural degeneration that strips away memory and the ability to manage activities of daily living.
Direct-acting Cholinergic Agonists
Direct-acting agents resemble ACh and bind the receptor directly, producing the same response ACh would. Bethanechol and pilocarpine are the common examples.
Therapeutic Action
They occupy ACh receptor sites on effector cell membranes and increase stimulation. Expect a slowed heart rate and decreased myocardial contractility, vasodilation, bronchoconstriction with increased bronchial mucus, increased GI activity and secretions, increased bladder tone, relaxation of GI and bladder sphincters, and pupil constriction.
Indications
Systemically, these drugs increase bladder tone, urinary excretion, and GI secretions; as ophthalmic agents, they cause miosis to relieve increased intraocular pressure in glaucoma. Bethanechol targets cholinergic receptors in the urinary bladder and treats nonobstructive postoperative and postpartum urinary retention and neurogenic bladder atony, directly increasing detrusor tone and relaxing the sphincters to improve emptying. Carbachol is an ophthalmic agent that induces miosis and relieves the increased intraocular pressure of glaucoma. Cevimeline and pilocarpine bind muscarinic receptors throughout the body to increase mouth and GI secretions and relieve dry mouth; they are approved in adults and given 3 times a day, often with meals.
Across age groups: children are at greater risk for GI upset, diarrhea, increased salivation (a choking hazard), and loss of bowel and bladder control. Bethanechol is approved for neurogenic bladder in children older than 8 years of age. Neostigmine and pyridostigmine control myasthenia gravis and reverse neuromuscular junction blocker effects in children; edrophonium is for diagnosis of myasthenia gravis only. Adults should be warned about dizziness, GI upset, and urinary urgency and kept off machinery. Use in pregnancy and lactation only when benefit clearly outweighs risk. Older adults need dose adjustment and are more prone to toxic drug levels because of renal or hepatic impairment.
Pharmacokinetics
Here are the characteristic interactions of direct-acting cholinergic agonists and the body in terms of absorption, distribution, metabolism, and excretion:
| Route | Onset | Peak | Duration |
|---|---|---|---|
| Oral | 30-90 min | 60-90 min | 1-6 h |
| Half-life (T1/2) | Metabolism | Excretion |
|---|---|---|
| Unknown | Unknown | Unknown |
Contraindications and Cautions
- Allergy to any component of the drug. Prevents hypersensitivity reactions.
- Bradycardia, hypotension, vasomotor instability, coronary artery disease. Worsened by the cardiac- and cardiovascular-suppressing effects of parasympathetic stimulation.
- Peptic ulcer, intestinal obstruction, recent GI surgery. Aggravated by GI stimulation.
- Bladder obstruction. Aggravated by stimulatory effects on the bladder.
- Epilepsy and parkinsonism. Affected by stimulation of ACh receptors in the brain.
- Hepatic or renal dysfunction. Drugs used for Alzheimer's are metabolized in the liver.
- Pregnancy and lactation. Potential adverse effects on the fetus or neonate.
Adverse Effects
- CV: bradycardia, heart block, hypotension, cardiac arrest
- GI: nausea, vomiting, cramps, diarrhea, increased salivation
- GU: urinary urgency
- Other: flushing, increased sweating
- WARNING: pilocarpine and cevimeline may cause swallowing difficulties.
Interactions
- Acetylcholinesterase inhibitors. Increased risk of cholinergic effects.
- NSAIDs. Increased risk of GI bleeding.
Indirect-acting Cholinergic Agonists
Indirect-acting agents do not bind the ACh receptor. They react with acetylcholinesterase in the synaptic cleft and stop it from breaking down ACh. The binding is reversible or irreversible. The irreversible binders are not used therapeutically; they are developed as nerve gas weapons, and the antidote is pralidoxime. The reversible indirect-acting agents fall into two groups: agents for myasthenia gravis and agents for Alzheimer's disease.
Therapeutic Action
By blocking acetylcholinesterase, ACh accumulates and keeps stimulating its receptors longer than normal. In myasthenia gravis, the higher ACh levels improve transmission at the neuromuscular junction. In Alzheimer's disease, elevated cortical ACh slows the neuronal degradation that drives the disease.
Indications
Treatment of myasthenia gravis, antidote for nondepolarizing neuromuscular junction blockers, and increased survival after nerve gas exposure; treatment of mild to moderate Alzheimer's disease.
Pharmacokinetics
Here are the characteristic interactions of agents for myasthenia gravis and the body in terms of absorption, distribution, metabolism, and excretion:
| Route | Onset | Peak | Duration |
|---|---|---|---|
| Oral | 35-45 min | N/A | 3-6 h |
| IM | 15 min | N/A | 3-6 h |
| IV | 5 min | N/A | 3-6 h |
| Half-life (T1/2) | Metabolism | Excretion |
|---|---|---|
| 1.9-3.7 h | Liver | Urine |
Here are the characteristic interactions of agents for Alzheimer’s disease and the body in terms of absorption, distribution, metabolism, and excretion:
| Route | Onset | Peak | Duration |
|---|---|---|---|
| Oral | Varies | 2-4 h | N/A |
| Half-life (T1/2) | Metabolism | Excretion |
|---|---|---|
| 70 h | Liver | Urine |
Contraindications and Cautions
- Allergy to any component of the drug. Prevents hypersensitivity reactions.
- Bradycardia, intestinal or urinary tract obstruction. Exacerbated by cholinergic receptor stimulation.
- Pregnancy. The uterus could be stimulated and labor induced.
- Asthma, coronary disease, peptic ulcer, arrhythmias, epilepsy, parkinsonism. Exacerbated by parasympathetic stimulation.
- Hepatic or renal dysfunction. Interferes with metabolism and excretion.
Adverse Effects
- CNS: miosis, blurred vision, headaches, dizziness, drowsiness
- CV: bradycardia, heart block, hypotension, cardiac arrest
- GI: nausea, vomiting, cramps, diarrhea, increased salivation, involuntary defecation
- GU: urinary urgency
- Other: flushing, increased sweating
Interactions
- NSAIDs. Increased risk of GI bleeding.
- Theophylline. Increased levels when combined with tacrine.
Nursing Considerations for Cholinergic Agonists
Nursing Assessment
Screen for contraindications and cautions: drug allergy, GI obstruction, pregnancy or lactation status. Establish a baseline physical assessment. Check orientation, affect, and reflexes for CNS effects. Take vital signs, especially pulse and blood pressure, to catch excess cardiac stimulation. Auscultate the abdomen for bowel sounds and palpate for distention. Monitor intake and output and note any urinary urgency.
Nursing Diagnosis and Care Planning
- Acute pain related to GI effects
- Decreased cardiac output related to CV effects
- Impaired urinary elimination related to effects on the bladder
Implementation with Rationale
Give oral drugs on an empty stomach to cut nausea and vomiting. Give IV doses slowly to avoid severe cholinergic effects. Monitor response closely (blood pressure, ECG, urine output) and adjust the dose accordingly. Keep atropine on standby as the antidote for excessive cholinergic dosing. Discontinue the drug if excessive salivation, diarrhea, emesis, or frequent urination becomes a problem. Provide safety precautions if visual acuity is poor in dim light. Offer comfort measures (quiet room, support, relaxation) and patient education on drug effects and warning signs to report.
Evaluation
Monitor the response to therapy (improvement in the treated condition) and for adverse effects (GI upset, CNS changes, CV changes). Confirm the patient can name the drug, its indication, and the adverse effects to watch for, and monitor compliance.
Frequently Asked Questions
What does a cholinergic agonist do in the body? It raises acetylcholine activity, mimicking parasympathetic stimulation. Expect a slower heart rate, more secretions, increased GI activity, greater bladder tone, and pupil constriction, which is why these drugs are also called parasympathomimetics.
What is the difference between direct and indirect-acting agents? Direct-acting agents bind the acetylcholine receptor itself and trigger the response. Indirect-acting agents block acetylcholinesterase so the body's own acetylcholine lingers longer at the receptor.
What is the antidote for excessive cholinergic effects? Atropine, an anticholinergic that competitively blocks muscarinic receptors. Keep it on standby and use it for signs of overdose such as bradycardia, heavy salivation, and bronchospasm.
Why is tacrine no longer used for Alzheimer's disease? Tacrine (Cognex) was withdrawn from the US market because it caused liver injury. Donepezil, galantamine, and rivastigmine treat mild to moderate Alzheimer's disease effectively without that hepatotoxicity.
Which cholinergic drugs treat myasthenia gravis? The indirect-acting agents neostigmine and pyridostigmine improve neuromuscular transmission and are used for ongoing treatment. Edrophonium is used only to help diagnose the condition.
Why give oral cholinergic drugs on an empty stomach? Taking them on an empty stomach reduces the nausea and vomiting these drugs commonly cause. Give intravenous doses slowly for the same reason, to avoid a sudden surge of cholinergic effects.