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Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents
Part 4: The Cholinergic Toxidrome
Section 3: Muscarinic Acetylcholine Receptors

Course: WB 1098
CE Original Date: October 16, 2007
CE Renewal Date: October 16, 2010
CE Expiration Date: October 16, 2012
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Learning Objectives

Upon completion of this section, you will be able to:

  • Describe the key ways that muscarinic receptors differ from nicotinic receptors.
  • Describe where muscarinic receptors are found.
  • Identify the key physiological effects that result from stimulation of muscarinic receptors by excessive amounts of acetylcholine.

Muscarinic, G-Protein Mediated Receptors

The key response differences between muscarinic and nicotinic receptors is that the response of muscarinic receptors: (Hoffman and Taylor 2001)

  • Is slower.
  • May be excitatory or inhibitory.
  • Do not affect skeletal muscles, but do influence the activity of smooth muscle, exocrine glands, and the cardiac conduction system. In contrast to skeletal muscle and neurons, smooth muscle and the cardiac conduction system normally exhibit intrinsic electrical and mechanical rhythmic activity. This activity is modulated, rather than initiated, by the muscarinic receptors. (Hoffman and Taylor 2001) For those interested in how muscarinic receptors work at the molecular level, the subject is covered in the Optional Reading below.

Molecular Physiology of Muscarinic Receptors (Optional Reading)

Muscarinic acetylcholine receptors --- like nicotinic receptors -- are proteins that extend through the cell membrane from the outside to the inside.

However, they do not contain channels to allow ions inside the cell. Instead, when acetylcholine attaches to the external part of the muscarinic receptor, the internal portion of the receptor releases large guanine nucleotide binding proteins (G-Proteins) (See note below), inside the cell. G-proteins then initiate other activities within the cell, such as smooth muscle contraction, gland excretion, etc. (Hoffman and Taylor 2001; Mailman and Lawler 2001; Guyton and Hall 2006)

Note on G-Proteins: Many functions of the nervous system (e.g., memory) require prolonged changes in neurons after the initial neurotransmitter is gone. Ligand-gated channels (such as those found in nicotinic receptors) are not suitable for this because the channels close in milliseconds. Prolonged changes can be achieved, however by activating G-proteins inside the post-synaptic neuron. It is then the G-proteins that trigger the prolonged effects. (Guyton and Hall 2006)

Molecular Structure and Physiology of Muscarinic Receptors (Optional Reading)

Nicotinic Receptor

Figure 7. The muscarinic (G-protein) receptor. Modified with permission from: Guyton AC, Hall JE: Textbook of Medical Physiology (2006) Elsevier Saunders, Philadelphia. p. 561. Used with permission.

Where Muscarinic Receptors Are Located

Muscarinic receptors are located in the: (See also Figure 5)

  • Parasympathetic nervous system.
    • Cardiac conduction system.
    • Exocrine glands.
    • Smooth muscles.
  • Sympathetic nervous system.
    • Sweat glands.
  • Central nervous system.

Clinical Effects on the Peripheral Nervous System Due to Excessive Stimulation of Muscarinic Receptors

Excessive Stimulation of muscarinic receptors due to cholinesterase inhibitor poisoning results in increased parasympathetic: (Erdman 2004)

  • Cardiac effects.
    • AV blocks, with escape rhythms.
    • Bradycardia.
    • Ventricular dysrhythmias.
  • Exocrine gland activity.
    • Bronchorrhea.
    • Hyperamylasemia.
    • Lacrimation.
    • Rhinorrhea.
    • Salivation.
  • Smooth muscle activity.
    • Bladder stimulation, sphincter relaxation.
    • Bronchospasm.
    • Miosis (pupillary constriction), eye pain due to ciliary spasm.
    • Nausea, vomiting, cramps, diarrhea.

Peripheral Muscarinic Effects

The table below summarizes the peripheral mostly parasympathetic* (muscarinic) effects of cholinesterase inhibitors. (Ecobichon 1996; Sidell 1997; Reigart and Roberts 1999; Tareg, B et al. 2001) (See also Figure 5)

*Sweat glands, which are enervated by the sympathetic nervous system, are activated via muscarinic receptors.

End Organ Effected
Parasympathetic (Muscarinic) Effects

Respiratory tract

  • bronchorrhea (thick, mucoid secretions)
  • bronchospasm
  • chest tightness
  • dyspnea
  • productive cough
  • rhinorrhea

Eyes

  • blurred vision (especially, difficulty focusing on near objects)
  • conjunctival injection
  • dimness of vision
  • miosis (pupillary constriction)

Gastrointestinal tract

  • cramping
  • diarrhea
  • incontinence
  • nausea
  • vomiting

Urinary tract

  • incontinence
  • urination

Cardiovascular system

  • AV block
  • bradycardia
  • hypotension
  • idioventricular rhythm
  • ventricular dysrhythmias (torsades des points)

Exocrine glands

  • hyperamylasemia
  • lacrimation
  • salivation

Note: Reflex nausea and vomiting may occur with isolated eye exposure, even in the absence of systemic toxicity. (Sidell 1997)

Muscarinic Mnemonics

Two mnemonics are helpful to remember the muscarinic (mostly parasympathetic*) peripheral effects of cholinesterase inhibitors. (Clark 2002; Robey and Meggs 2004)

*Sweating/diaphoresis is a muscarinic effect, but is actually mediated via the sympathetic nervous system.

SLUDGE
DUMBELS

Salivation

Defecation/Diaphoresis

Lacrimation

Urination

Urination

Miosis (pupillary constriction)

Defecation

Bronchospasm and Bronchorrhea

GI pain

Emesis

Emesis

Lacrimation

 

Salivation

Key Points

  • Muscarinic receptors respond more slowly than nicotinic receptors.
  • The effects of muscarinic receptors may be excitatory or inhibitory.
  • Muscarinic receptors do not affect skeletal muscles, but do influence the exocrine glands as well as the inherent activity of smooth muscles and the cardiac conduction system.
  • In contrast to skeletal muscle and neurons, smooth muscle and the cardiac conduction system normally exhibit intrinsic electrical and mechanical rhythmic activity. This activity is modulated, rather than initiated, by the muscarinic receptors.
  • With the exception of the sweat glands (enervated by the sympathetic nervous system), the peripheral nervous system effects (on the cardiac conduction system, exocrine glands, and smooth muscle) mediated by muscarinic receptors are parasympathetic.

   

Progress Check

15. When compared with the action of nicotinic receptors, muscarinic receptors: (Choose ALL correct answers)

A. Are faster.
B. Initiate rather than modulate smooth muscle activity.
C. Have primarily parasympathetic effects on the peripheral nervous system.
D. Stimulate sweating via the sympathetic nervous system.
E. None of the above.

Answer:

To review relevant content, see Muscarinic G-Protein Mediated Receptors in this section.

16. Cholinesterase inhibitor toxicity leads to the following clinical findings mediated by muscarinic receptors: (Choose ALL correct answers)

A. Miosis (pupillary constriction).
B. Bronchorrhea.
C. Nausea.
D. Bronchospasm.
E. None of the above.

Answer:

To review relevant content, see Muscarinic Mnemonics in this section.

17. Muscarinic receptors are found in: (Choose ALL correct answers)

A. Skeletal muscle.
B. Smooth muscle.
C. Exocrine glands.
D. Sweat glands.
E. None of the above.

Answer:

To review relevant content, see Where Muscarinic Receptors Are Located in this section.

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