Anesthesia Pharmacology: Autonomic Nervous System Pharmacology

Anesthesia Pharmacology Chapter 4: Autonomic (ANS) Pharmacology: Introduction

Predominant Sympathetic or Parasympathetic Tone
Antatomical Site	Predominant Autonomic Tone
Arterioles	Sympathetic-adrenergic
Veins	Sympathetic-adrenergic
Heart	Parasympathetic-cholinergic
Ciliary Muscle	Parasympathetic-cholinergic
Gastrointestinal Tract	Parasympathetic-cholinergic
Salivary Glands	Parasympathetic-cholinergic
Sweat Glands	Sympathetic-cholinergic

Taylor, P. Agents Acting at the Neuromuscular Junction and Autonomic Ganglia 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.193-195. Adapted from Table 9-3

Baroreceptor Reflexes
A principal mechanism for arterial blood pressure control is the baroreceptor reflex. The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck. A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch. As pressure rises and especially for rapid increases in pressure: Baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in: Vsodilatation of the veins and arterioles in the peripheral vascular beds. Negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction)

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
  - Α-methyltyrosine inhibits tyrosine hydroxylase thus preventing synthesis of norepinephrine.
  - Methyldopa inhibits aromatic amino acid decarboxylase and is itself decarboxylated and hydroxylated to form the "false transmitter" α-methyl norepinephrine.
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 α₁ receptor agonist.
  - Clonidine (Catapres): an α₂ receptor agonist.
  - Prazosin (Minipress): an example of an α₁ receptor antagonist.
  - Yohimbine (Yocon): an example of an α₂ receptor antagonist.
  - Isoproterenol (Isuprel): β₁and β₂receptor agonist.
  - Dobutamine (Dobutrex): a relatively selective myocardial β₁ receptor agonist.
  - Terbutaline (Brethine): relatively selective β₂ receptor agonist.
  - Propranolol (Inderal): an example of a non-selective beta-adrenergic receptor blocker.
  - Metoprolol (Lopressor): an example of a relatively selective β₁ 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 and 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.