Nursing Pharmacology Chapter 5:  Autonomic Pharmacology: Cholinergic Drugs

Cellular Events following Cholinergic Receptor Activation

• Nicotinic Muscle Receptor

  • Response:

    • Membrane Depolarization leading to muscle contraction

  • Molecular Aspects:

    • Nicotinic (muscle) receptor's cation ion channel opening

• Nicotinic Neuronal Receptor

  • Responses:

    • Depolarization: postsynaptic cell activation

    • Catecholamine secretion

  • Molecular Aspects

    • Nicotinic (muscle) receptor's cation ion channel opening

• Muscarinic Type M₁

  • Response:

    • Depolarization (late EPSP)

  • Molecular Aspects

    • Stimulation of Phospholipase C (PLC) with formation of inositol-1,4,5 triphosphate (IP₃ ) and diacylglycerol (DAG)resulting in increased cytosolic Ca²⁺

• Muscarinic Type M₂

  • SA node

    • Responses: decreased phase 4 depolarization; hyperpolarization

    • Molecular Aspects: K⁺ channel activation through ß-gamma G_i subunits.

  • Atrium 

    • Responses: decreased contractility; decreased AP duration

    • Molecular Aspects: G_i -mediated inhibition of adenylyl cyclase which decreases intracellular Ca²⁺ levels (reduces contractility);(G_i can inhibit directly Ca²⁺ channel opening)

  • AV node

    • Responses: decreased conduction velocity

  • Ventricle:

    • Responses: decreased contractility

    • Molecular Aspects: G_i -mediated inhibition of adenylyl cyclase which decreases intracellular Ca²⁺ levels (reduces contractility);(G_i can inhibit directly Ca²⁺ channel opening)

Adapted from Table 6-2: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, p119

Muscarinic Receptors: Second Messenger Systems

• Activation of IP₃, DAG cascade

  • DAG may activate smooth muscle Ca²⁺ channels

  • IP₃ releases Ca²⁺ from endoplasmic and sarcoplasmic reticulum

• Increase in cGMP

• Increase in intracellular K⁺ by cGMP-K⁺ channel binding

• Inhibition of adenylyl cyclase activity (heart)

Pappano, A.J. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs, In Basic and Clinical Pharmacology, 7th Edition, (Katzung, B.G.,ed) Appleton & Lange, 1998, p. 93-94

• Nitric Oxide and Muscarinic Receptor Activation

  • Activation of salivary gland and intestinal parasympathetic systems produce significant vasodilation.

  • This effect depends on nitric oxide (EDRF) release and subsequent guanylate cyclase activation. (NO binding to the heme group of guanylate cyclase).

  • Increased levels of cGMP results in stimulation of ion pumps which lower intracellular Ca²⁺ promoting relaxation.

  • Increased nitric oxide production may be mediated by:

    • Acetylcholine

    • Substance P

    • Bradykinin

    • Direct mechanical (shear forces) on endothelial membranes.

• Nitric oxide synthase²

  • Nitric oxide synthase catalyzes the conversion of L-arginine and molecular oxygen to nitric oxide.

  • Three forms of nitric oxide synthase

    • form 1 (constitutive): release nitric oxide over short time periods in response to increase in intracellular Ca²⁺ .

    • form 2: responsible for Ca²⁺ - dependent nitric oxide neuronal release.

    • form 3: induced following cytokine or endotoxin cellular activation. This form catalyzes nitric oxide synthesis for an extended time. This form is Ca²⁺ - independent and is responsible for some pathophysiological responses to endotoxin (hypotension, e.g.).

¹Granger,D.N., Regulation of Regional Blood Flow, In Essential Physiology,(Johnson, L.,ed) Lippincott-Ravin,1998, p. 231.

²Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacological Basis of Therapeutics, (Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.136-137