Autonomic Agents

CHOLINERGIC AGENTS

What are the major subdivisions of the autonomic nervous system?

It is divided into the sympathetic and the parasympathetic nervous systems.

What is the major neurotransmitter of the parasympathetic autonomic nervous system?

Acetylcholine (ACh). ACh is released into the synaptic clefts from the pre-and the postsynaptic neurons of the parasympathetic nervous system.

In the sympathetic nervous system, what neurotransmitter is released from the preganglionic neuron into the synaptic cleft?

ACh. Remember that while the postganglionic neurotransmitters may differ between the sympathetic and parasympathetic branches of the autonomic nervous system, the preganglionic neurotransmitter released into the synaptic cleft is identical—ACh.

Where are sympathetic preganglionic fibers located?

In the paravertebral chains on either side of the spinal column or the prevertebral ganglia on the ventral surface of the aorta. Sympathetic preganglionic fibers are short.

Where are parasympathetic preganglionic fibers located?

In or near the wall of the organ they innervate. Parasympathetic preganglionic fibers are very long.

Where are nicotinic receptors located?

Postsynaptic neurons in ganglia of both the parasympathetic nervous system (PNS) and sympathetic nervous system (SNS); adrenal medulla; neuromuscular junction (NMJ); central nervous system (CNS)

Where are muscarinic receptors located?

Organs innervated by the PNS; thermoregulatory sweat glands innervated by the SNS; CNS (cortex, hippocampus)

What does the PNS do to heart rate?

It decreases the heart rate. Remember that at rest the heart is constantly under parasympathetic tone to slow the heart rate from the intrinsic rate set by the sinoatrial (SA) node at about 80 beats per minute.

What enzyme catalyzes the reaction between choline and acetyl-CoA to form ACh?

Choline acetyltransferase (CAT)

The neuronal release of ACh into the synapse is inhibited by what toxin?

Botulinum toxin

What organism produces botulinum toxin?

Clostridium botulinum (anaerobic, spore forming, gram-positive rod)

The venom of which spiders result in the release of stored ACh into the synapse?

Any spider of the genus Latrodectus (widow spiders) of which the black widow is the most common species found in North America. They produce α-latrotoxin which causes the release of ACh from the preganglionic neuron into the synaptic cleft.

What enzyme degrades ACh?

Acetylcholinesterase (AChE)

What are the breakdown products of ACh?

Choline and acetate

Where is AChE located in the autonomic nervous system?

In the synaptic cleft

What is muscarine?

It is an alkaloid found in various poisonous mushrooms.

Where are each of the following types of muscarinic receptors found in the body?

M ₁

Nerves; gastric parietal cells

M ₂

Nerves; cardiac cells; smooth muscle

M₃

Smooth muscle; exocrine glands; lungs; gastrointestinal (GI) tract; eye; bladder

M₄

CNS

M₅

CNS

For each of the following muscarinic receptor types, name the type of G-protein it is coupled to and the second messenger system responsible for execution of its activity upon stimulation:

M ₁

G_q coupled; inositol triphosphate (IP₃), diacylglycerol (DAG) cascade

M ₂

G_i coupled; inhibition of cyclic AMP (cAMP) production, activation of potassium channels

M ₃

G_q coupled; IP₃, DAG cascade

M ₄

G_i coupled; inhibition of cAMP production

M ₅

G_q coupled; IP₃, DAG cascade

Does the PNS directly innervate the vasculature?

No. Vascular tone is primarily determined by the degree of stimulation of adrenergic receptors of the sympathetic nervous system which directly innervate the vascular smooth muscle cells. However, there are muscarinic receptors located on the vasculature.

How can ACh lower blood pressure?

ACh binds to ACh receptors in the vasculature leading to increased synthesis of nitric oxide (NO) via second messenger pathways. An increase in NO leads to vasodilation.

NO is also known as what?

Endothelial-derived relaxation factor (EDRF)

What amino acid is a precursor to NO synthesis?

Arginine

Does AChE have a high affinity for ACh?

Yes

Does ACh increase or decrease the following (in other words, what is the effect of parasympathetic stimulation of the following)?

Blood pressure

Decreases (both arterial and venous dilation via NO)

Heart rate

Decreases (via M₂ receptors)

Salivation

Increases (via M₃ receptors)

Lacrimation

Increases (via M₃ receptors)

Sweating

Increases (via sympathetic stimulation of muscarinic cholinergic receptors)

GI secretions

Increases (via M₃ receptors)

GI motility

Increases (via M₃ receptors)

Miosis (constriction of pupil)

Increases (via M₃ receptors)

Bladder detrusor muscle tone

Increases (via M₃ receptors)

Bladder sphincter tone

Decreases (in combination with increased detrusor tone this leads to increased urination also via M₃receptors)

Bronchodilation

Decreases (via M₃ receptors)

What does ACh do to the ciliary muscle of the eye?

Increased contraction which leads to increased accommodation

How does ACh cause miosis?

Increased contraction of the circular muscle in the iris

Does bethanechol have muscarinic activity?

Yes (agonist)

Does bethanechol have nicotinic activity?

No

Does AChE have a high affinity for bethanechol?

No (zero affinity). This gives bethanechol a long duration of action.

What is a clinical use for bethanechol?

Nonobstructive urinary retention as can result from denervation of the urinary sphincter in conditions such as diabetes or spinal cord injury. Bethanechol can also be used for gastroesophageal reflux disease (GERD). As a cholinergic drug, it will increase detrusor tone and GI motility.

Does carbachol have muscarinic activity?

Yes, it is a muscarinic agonist.

Does carbachol have nicotinic activity?

Yes, it is also a nicotinic agonist.

Does AChE have a high affinity for carbachol?

No, the enzyme has zero affinity for carbachol.

What is carbachol used for?

It is a miotic agent to reduce intraocular pressure (IOP) in emergency settings of narrow-angle and open-angle glaucoma.

Does pilocarpine have muscarinic activity?

Yes, it is a muscarinic agonist.

Does pilocarpine have nicotinic activity?

No

Does AChE have a high affinity for pilocarpine?

No, the enzyme has zero affinity for pilocarpine.

What is pilocarpine used for?

It is the miotic drug of choice to lower IOP in emergency settings of narrow-angle and open-angle glaucoma.

Can pilocarpine cross the blood-brain barrier (BBB)?

Yes. Because it is a tertiary, uncharged amine.

Give examples of reversible AChE inhibitors:

Neostigmine; pyridostigmine; physostigmine; edrophonium; rivastigmine; donepezil; galantamine; tacrine

What are donepezil, galantamine, rivastigmine, and tacrine used for?

Alzheimer-type dementia. They are AChE inhibitors, thereby increasing the levels of ACh in the brain.

What two AChE inhibitors are quaternary ammonium compounds and therefore cannot cross the BBB?

1. Neostigmine
   
2. Pyridostigmine

As a result, these drugs will not reverse the central nervous system effects of cholinergic toxicity.

What short-acting AChE inhibitor is used to diagnose myasthenia gravis and is also used to differentiate myasthenic from cholinergic crisis?

Edrophonium. The trade name of edrophonium is Tensilon. This test is commonly referred to as the Tensilon test.

Which reversible AChE inhibitor is used as an antidote in atropine overdose?

Physostigmine, a tertiary amine, is able to cross the BBB to act on the CNS.

Give examples of irreversible AChE inhibitors:

Echothiophate; isoflurophate; sarin; malathion; parathion

Name an irreversible AChE inhibitor that is used as nerve gas:

Sarin

Which two AChE inhibitors are used as insecticides?

1. Malathion
   
2. Parathion

What is another name for the irreversible AChE inhibitors?

Organophosphates

How do organophosphates irreversibly inhibit AChE?

The phosphate group covalently binds to serine hydroxyl group in the active site of AChE, thereby rendering the enzyme permanently inactive.

What is used to counteract the muscarinic and CNS effects of organophosphate poisoning?

Atropine via competitive inhibition. Atropine binds the muscarinic receptors, outcompeting the increased levels of ACh thereby preventing overstimulation.

What agent is used to reactivate inhibited AChE during organophosphate poisoning?

Pralidoxime (2-PAM). It is critical to initiate treatment with pralidoxime early along with atropine to prevent the process of aging where AChE is irreversibly inactivated by the organophosphates.

What are the signs and symptoms of organophosphate poisoning?

SLUDGE: salivation; lacrimation; urination; diaphoresis; GI motility (diarrhea); emesis. Basically, parasympathetic overstimulation.

Does atropine block nicotinic receptors, muscarinic receptors, or both?

It blocks muscarinic receptors.

What are the pharmacologic actions of atropine?

Mydriasis; cycloplegia; tachycardia; sedation; urinary retention; constipation; dry mouth; dry eyes; decreased sweating; hallucinations; sedation; hyperthermia; delirium; blurred vision; coma (high doses). Basically, anticholinergic/sympathetic overstimulation.

What class of drugs can be used to counteract atropine overdose?

AChE inhibitors

Name three drug classes that may cause antimuscarinic adverse effects:

1. Sedating/first-generation antihistamines (diphenhydramine)
   
2. Tricyclic antidepressants (TCAs)
   
3. Phenothiazines

Low-dose (<0.5-1 mg) atropine does what to heart rate?

Decreases heart rate (unknown paradoxical vagalmimetic effect)

High-dose (>0.5-1 mg) atropine does what to heart rate?

Increases heart rate (parasympatholytic effect)

What is belladonna?

A perennial plant also known as “deadly nightshade” due to the toxic effects of its foliage and berries from which atropine is derived. Other toxins include scopolamine and hyoscyamine. The name belladonna derives from the cosmetic enhancing effects of dilated pupils, blushing of the cheeks, and reddening of the lips for which the plant was originally used.

How does scopolamine differ from atropine?

Scopolamine has a longer duration of action, more potent CNS effects, and is able to block short-term memory.

What is the main therapeutic indication of scopolamine?

Motion sickness

Giving drugs with anticholinergic activity can precipitate an emergent situation in patients with what medical condition?

Patients with narrow-angle glaucoma

What are the signs and symptoms of acute-angle-closure glaucoma?

General distress; pain; headache; red eye; photophobia; increased IOP; visual changes; malaise; nausea; vomiting

What two anticholinergic agents are quaternary ammonium compounds and used for the treatment of asthma and chronic obstructive pulmonary disease (COPD)?

1. Ipratropium
   
2. Tiotropium

Tiotropium has a longer half-life compared to ipratropium.

Does ipratropium effect airway secretions?

No (unlike atropine, which decreases airway secretions)

Name three ganglionic blocking agents:

1. Hexamethonium
   
2. Mecamylamine
   
3. Trimethaphan

What are ganglionic blocking agents primarily used for?

Lowering blood pressure; blocking autonomic nervous system reflexes; smoking cessation due to blockade of central nicotine receptors

Why can ganglionic blockers cause a marked postural hypotension?

Since sympathetic tone to the blood vessels is blocked, both arterial and venous dilation occur, lowering blood pressure. Moreover, the ganglionic blockers prevent the sympathetically mediated baroreceptor response to a sudden decrease in blood pressure, such as that occurs with a rapid change in position from sitting to standing.

Neuromuscular blocking agents (NMBs) can be grouped into what two general categories?

1. Depolarizing
   
2. Nondepolarizing

Do NMBs work at muscarinic or nicotinic receptors?

Nicotinic receptors (remember the NMJ has nicotinic receptors).

How many subunits is the nicotinic receptor made of?

Five subunits. Two α:- and three β-subunits make up this transmembrane ligand-gated ion channel.

Which subunit of the nicotinic receptor does ACh bind to?

Between the two α-subunits

Binding of ACh to the nicotinic receptor at the NMJ is required to open which type of ion channel?

Sodium channel

What is the most commonly used NMB?

Succinylcholine, the only depolarizing NMB. This is an ideal drug for endotracheal intubation due to its fast onset of action and short duration of action.

How does succinylcholine work at the NMJ?

It behaves as a cholinergic agonist that remains bound to the ACh receptor for a prolonged period.

What happens during each of the following phases of succinylcholine activity at the NMJ?

Phase I

The receptor becomes depolarized and transient fasciculations are observed as various motor units depolarize.

Phase II

The receptor becomes resistant to depolarization and a flaccid paralysis ensues.

What are the two main uses of succinylcholine?

1. It is used for facilitation of endotracheal intubation via relaxation of pharyngeal and laryngeal muscles.
   
2. It is used as an adjunct during electroconvulsive shock therapy to prevent prolonged full body convulsions which would result in muscle breakdown. A tourniquet is placed on a lower extremity to prevent the drug from reaching this location so that the seizure is visible in a localized area and the rest of the body is spared.

Is succinylcholine short or long acting?

It is short acting with a duration of 4-8 minutes because of rapid hydrolysis by plasma cholinesterase.

What are the adverse effects of succinylcholine?

Malignant hyperthermia; apnea; hypertension; hyperkalemia

What are the signs and symptoms of malignant hyperthermia?

Muscular rigidity; increased oxygen consumption; increased carbon dioxide production (usually the first sign detected during surgery); tachycardia; hyperthermia is a late finding

How is malignant hyperthermia treated?

With dantrolene

What is the mechanism of action of dantrolene?

It inhibits calcium release from the sarcoplasmic reticulum of muscle cells, thereby relaxing muscle tone and reducing heat production.

Succinylcholine may have a prolonged half-life in what type of patients?

Patients with a genetic deficiency or altered form of plasma cholinesterase

What is the mechanism of action of nondepolarizing NMBs?

Competitive antagonists of ACh at the NMJ

Which drug is the prototype of the nondepolarizing NMBs?

Tubocurarine

What antidote is used in tubocurarine overdose?

AChE inhibitor (increases ACh concentration which competes with tubocurarine at ACh receptors at the NMJ)

List in order, from first to last, the muscles that are paralyzed by nondepolarizing NMBs:

1. Small muscles of the face and eye
   
2. Fingers
   
3. Limbs, neck, trunk
   
4. Intercostals
   
5. Diaphragm

Which antimicrobial class of drugs may act in synergy with nondepolarizing NMBs by inhibiting release of ACh from nerve endings by competing with calcium ions, thereby increasing neuromuscular blockade?

Aminoglycosides (most likely to occur with high doses; patients with hypocalcemia, hypomagnesemia, or neuromuscular disorders)

Give examples of nondepolarizing NMBs:

Tubocurarine; atracurium; mivacurium; rocuronium; vecuronium; pancuronium; pipercuronium

What is the only nondepolarizing NMB that does not require dosage reduction in patients with renal failure?

Atracurium, which excreted in bile, not in urine

What nondepolarizing NMB has the most rapid onset of action?

Rocuronium. Think: ROcuronium—Rapid Onset

In what situations are nondepolarizing NMBs used?

Adjunct to general anesthesia to facilitate endotracheal intubation and to relax skeletal muscles during surgery; to facilitate mechanical ventilation in ICU patients

ADRENERGIC AGENTS

Stay updated, free articles. Join our Telegram channel

Join