Cholinergic Pharmacology

Chapter 6:  Autonomic Pharmacology: Cholinergic Drugs

 

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Spectrum of Action of Choline Esters

Choline Ester

Sensitivity to ACHE

Cardiovascular

Gastrointestinal

Urinary Bladder

Eye (Topical)

Atropine Sensitive

Activity at Nicotinic Sites

Acetylcholine

Methacholine

Carbachol

No

Bethanechol

No

??

No

  1. Modified from Table 7-1: Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, 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, p 143

  2. Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, 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) TheMcGraw-Hill Companies, Inc.,1996, p 142-143.

Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms

Muscarinic Receptor Coupling Mechanisms

Nicotinic Muscle Receptor

Antagonists

Tissue

Responses

Molecular Aspects

Tubocurarine

alpha-bungarotoxin

Neuromuscular Junction

Membrane Depolarization leading to muscle contraction

Nicotinic (muscle) receptor's cation ion channel opening

 

Nicotinic Neuronal Receptor

Antagonists

Tissue

Responses

Molecular Aspects

Mecamylamine (Inversine)

Autonomic Ganglia

Depolarization: postsynaptic cell activation

Nicotinic (muscle) receptor's cation ion channel opening

Adrenal Medulla

Catecholamine secretion

CNS

unknown

 

Muscarinic Type M1

Antagonist

Tissue

Responses

Molecular Aspects

Atropine

Pirenzepine (more selective)

Autonomic Ganglia

Depolarization (late EPSP)

Stimulation of Phospholipase C (PLC): activation of inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol (DAG) leading to increased cytosolic Ca2+

CNS

Unknown

 

Muscarinic Type M2

Tissue (Heart)

Responses

Molecular Aspects

SA node

decreased phase 4 depolarization; hyperpolarization

K+ channel activation through -gamma Gi subunits;

Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels.

(Gi can inhibit directly Ca2+ channel opening)

Atrium

decreased contractility; decreased AP duration

AV node

decreased conduction velocity

Ventricle

decreased contractility

 

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) TheMcGraw-Hill Companies, Inc.,1996, p119.

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, pp.112-137.

 

Choline esters: Comparisons and Contrasts

Choline Ester

Sensitivity to ACHE

Cardiovascular

Gastrointestinal

Urinary Bladder

Atropine Sensitive

Activity at Nicotinic Sites

Acetylcholine

 Methacholine

Carbachol

No 

Bethanechol (Urecholine)

No 

??

No

 

Potentiation by Acetylcholinesterases

Choline Ester Agent

Sensitivity to ACHE

Acetylcholine (potentiated by AchE inhibitors)

Methacholine (potentiated by AchE inhibitors)

Carbachol (AchE inhibitors have no effect)

No 

Bethanechol (Urecholine) (AchE inhibitiors have no effect)

No

Pharmacological Effects of Cholinomimetics

Cardiovascular: Four major effects

Vasodilation:  

This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines.

  1.  The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptors.

  2.  Increased NO activates guanylate cyclase which increases cyclic GMP concentrations.

  3.  Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+.

  4.  Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation.

  5.  Ca2+ complexes with calmodulin activating light-chain myosin kinase

    •  Increased cGMP promotes dephosphorylation of myosin light-chains.

    •  Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction.

 

 

 

Cellular Events following Cholinergic Receptor Activation

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

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

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 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, pp.136-137

Clinical Uses

 

 Indirect-acting Cholinomimetic Drugs

Stoelting, R.K., "Anticholinesterase Drugs and Cholinergic Agonists", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, 224-237;  Taylor, P. Anticholinesterase Agents, 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) TheMcGraw-Hill Companies, Inc.,1996, pp.161-174.

Taylor, P. Anticholinesterase Agents, 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, p. 167.

 

Sites of Drug Intervention in Management of Myasthenia Gravis

 

Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472.: Figure adapted from Figure 382-2, p. 2471

 

  1. Taylor, P. Anticholinesterase Agents, 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) TheMcGraw-Hill Companies, Inc.,1996, pp. 172-173.;

  2. Moroi, S.E. and Lichter, P.R. Ocular Pharmacology 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, p. 1634;

  3. Drachman, D.B. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction , In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, p. 2469-2472

 

 

Indirect Cholinomimetic Agents

Acetylcholinesterase Inhibitors ("Reversible")

Acetylcholinesterase Inhibitors ("Irreversible")

  • Neostigmine (Prostigmin)

  • Physostigmine (Antilirium)

  • Edrophonium (Tensilon)

  • Soman

  • Parathion

  • Malathion

  • Isoflurophate

  • (Diisopropylflurorphosphate DFP)

  • Echothiophate

 

 

 

 Cholinoceptor-Blocking Drugs

Brown, J.H. and Taylor, P. Muscarinic Receptor Agonists and Antagonists, 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) TheMcGraw-Hill Companies, Inc.,1996, pp.149-150

 

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