Pharmacological Modification of Autonomic Function

• Transmitter Synthesis: Site 1

  • Cholinergic

    • Hemicholinium (HC-3) blocks the choline transport system into the nerve ending, thus limiting acetylcholine (ACh) synthesis.

  • Adrenergic

    • Alpha-methyltyrosine inhibits tyrosine hydroxylase thus preventing synthesis of norepinephrine.

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    • Methyldopa inhibits aromatic amino acid decarboxylase and is itself decarboxylated and hydroxylated to form the "false transmitter" alpha-methyl norepinephrine

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• Transmitter Release: Site 2

  • Cholinergic

    • Botulinum toxin can be used clinically to treat ocular muscle spasms, muscle dystonias, and spasms.

    • Botulinus toxin binding at a presynaptic site blocks ACh release.

    • Vesamicol blocks ACh transport into storage vesicles, thus limiting release.

  • Adrenergic

    • Bretylium and guanethidine prevent action-potential mediated norepinephrine release.

    • Transient release may occur with these agents because they displace norepinephrine from storage sites.

    • Tyramine, amphetamine, and ephedrine can produce a brief liberation of transmitter.

    • Reserpine, by inhibiting vesicular uptake, produces a slow, depletion of norepinephrine, ultimately causing adrenergic blockade. Cytoplasmic MAO metabolizes the neurotransmitter.

    • Reserpine similarly depletes dopamine and serotonin. Physiological effects of reserpine are due to depletion of many transmitters.

• Receptor Interactions: Site 3

  • Cholinergic

    • Tetraethylammonium, trimethaphan and hexamethonium are nicotinic ganglionic antagonists.

    • Decamethonium, a depolarizing drug, selectively causes neuromuscular blockade.

    • All classes of muscarinic receptors are blocked by atropine.

  • Adrenergic

    • Phenylephrine (Neo-Synephrine): an alpha₁ receptor agonist.

    • Clonidine (Catapres): an alpha₂ receptor agonist.

    • Prazosin (Minipress): an example of an alpha₁ receptor antagonist.

    • Yohimbine (Yocon): an example of an alpha₂ receptor antagonist.

    • Isoproterenol (Isuprel): ß₁ and ß₂ receptor agonist.

    • Dobutamine (Dobutrex): a relatively selective myocardial ß₁ receptor agonist.

    • Terbutaline (Brethine): relatively selective ß₂ receptor agonist.

    • Propranolol (Inderal): an example of a non-selective beta-adrenergic receptor blocker.

    • Metoprolol (Lopressor): an example of a relatively selective ß₁ receptor antagonist.

• Termination of Transmitter Effects: Site 4

  • Cholinergic

    • Acetylcholinesterase inhibitors prevent breakdown and inactivation of acetylcholine.

      • ACh accumulation at the neuromuscular junction causes flacid paralysis.

      • ACh accumulation at postganglionic muscarinic sites results in either excessive stimulation (contraction & secretion) or inhibition (hyperpolarization), depending on the site.

      • ACh accumulation at autonomic ganglia cause increased transmission.

  • Adrenergic

    • Interference with neurotransmitter reuptake results in potentiation of catecholamine effects.

    • Cocaine and imipramine are examples of drugs that inhibit the reuptake system.

    • Monoamine oxidase (MAO) inhibitors potentiate actions of tyramine; whereas catechol-O-methyl transferase (COMT) inhibitors (pyrogallol and tropolone) only slightly increase catecholamine effects.

Autonomic and Somatic Innervation

• Skeletal muscle is innervated by somatic nerves, controlling voluntary actions

• All other innervated structures are supplied by the autonomic or involuntary system.

• Somatic system: No ganglia present

• Autonomic nervous system (ANS) has ganglia.

  • these ganglia are sites at which preganglionic fibers form synaptic connections with postganglionic neurons

  • these ganglia are located outside the cerebrospinal axis

• Other differences between Somatic and Autonomic Innervation

  • Motor nerves to skeletal muscle: myelinated

  • Postganglionic autonomic nerves are nonmyelinated

  • Denervation of skeletal muscle results in paralysis and atrophy

  • Denervated smooth muscle or glands retain some activity

Category: Pharmacology Notes