Anesthesia Pharmacology: Antianginal Drugs

• Nitric Oxide

  • Overview: nitric oxide

    • Chemical messenger- homeostatic activities

      • Cardiovascular tone

      • Platelet regulation

      • Immune regulation

      • CNS signaling

      • Gastrointestinal smooth muscle relaxation

      • Possible effector for volatile anesthetics

  • Synthesis/Transport

    • Precursor: amino acid L-arginine; synthetic enzyme: NO synthases

    • Target: (NO, a gas,diffuses from producing cells) , guanylate cyclase activation leading to  increase cGMP concentration leading to vasodilatation

    • Half-life: < 5 seconds

    • NO binds to iron of heme proteins (inactivated by hemoglobin)

    • Metabolic transformation:

      • Interaction with hemoglobin yields nitrate

      • Interaction with oxygen yields nitrogen dioxide (NO₂) -- pulmonary toxicant ("silo filler's disease")

  • Mechanisms: Regulation of Myosin-light chain kinase activity and control of vascular smooth muscle tone: Modulation by nitric oxide and sympathomimetic amines

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      Regulation of Myosin-light chain kinase activity and control of vascular smooth muscle tone

      Increases in NO activate guanylyl cyclase causing increased formation of cGMP and vasodilation. The precise mechanisms by which cGMP relaxes vascular smooth muscle is unclear; however, cGMP can activate a cGMP-dependent protein kinase, activate K+ channels, decrease IP3, and inhibit calcium entry into the vascular smooth muscle Attribution:  http://www.cvphysiology.com/; original material, © 1999 Richard E. Klabunde, used with permission and since updated.

• Increases in NO activate guanylyl cyclase causing increased formation of cGMP and vasodilation. 

  • The precise mechanisms by which cGMP relaxes vascular smooth muscle is unclear; however, cGMP can activate a cGMP-dependent protein kinase, activate K⁺ channels, decrease IP₃, and inhibit calcium entry into the vascular smooth muscle (see above figure legend).

• Cardiovascular System

  • Regulation of systemic vascular resistance/pulmonary vascular resistance is associated with:

    • Flow-induced shear stress involving continual NO release.

    • Pulsatile arterial flow involvingcontinual NO release.

  • Endothelial NO production determines cardiac output distribution, in particular pulmonary and cerebral blood distribution.

  • Endothelial NO release is based upon autoregulation with decreased oxygenation resulting in increased NO production.

  • NO opposes pulmonary hypertensive response to arterial hypoxemia

  • NO causes:

    •  Negative inotropism

    •  Negative chronotropism

  • Arteries generate more NO than veins (possible explanation why internal mammary artery bypass grafts associated with increased patency (compared to venous grafts))

• Pulmonary

  • Nitric oxide may contribute to bronchodilation.

  • Nitric oxide may be important in mediating ventilation-to-perfusion matching.

• Platelets

  • Nitric oxide inhibits platelet aggregation and adhesion.

  • The mechanism of this inhibition involves:

    1. Guanylate cyclase enzyme activation.

    2. A reduction in intracellular calcium.

    3. Nitric oxide effects may act in a manner synergistic with prostacyclin.

• Nervous System:

  • Nitric oxide is a neurotransmitter/neuromodulator in the brain, spinal cord and periphery.

    • Brain

    • Spinal cord

    • Periphery

  • Peripheral Nervous System: Nonadrenergic and noncholinergic systems release NO as a neurotransmitter withpossible innervation sites including:

    • Peripheral nerves generating the myenteric plexus and GI tract smooth muscle relaxation

    • Innervation of the corpora cavernosa (responsible for penile erection)

• Immune Function:

  • Nitric oxide:

    • Macrophage activation by cytokines, an effect secondary to NO synthase induction.

      •  This process results in high NO concentrations which damage fungi, bacteria, and protozoa.

    • Nitric oxide appears also to be an inflammation modulation

• Abnormal NO:   Possible Pathophysiological consequences

  • Essential hypertension may involve reduced NO release.

  • Septic shock hypotension may involve excess NO release.

  • Defective NO production: possible prior role in atherosclerosis by inducing:

    • Platelet aggregation

    • Platelet-induced vasoconstriction

    • Leukocyte adhesion

  • Vasospastic reactions after subarachnoid hemorrhage (possibly secondary to reduced NO which inactivated by exposure to  hemoglobin)

  •  Possibly defective NO production:

    • may cause or contribute to pulmonary hypertension.

  •  Gastrointestinal:

    • A reduction in NO activity may occur in pyloric stenosis in achalasia

    • NO- modulation of morphine-induced constipation

  •  CNS: nitric oxide may be involved in epilepsy pathogenesis.

• Anesthesia:

  • Suppression of NO synthesis by anesthetics could:

    • Dcrease excitatory neurotransmission:

      • Reduce glutamate and cholinergic excitatory systems

    • Increase inhibitory neurotransmission

      • Increased GABA function

• Clinical Uses:

  • I-NO vent delivery system:

    • Adds NO to ventilator breathing system (inspired NO concentration = constant)

  • Therapy of pulmonary disease (NO rapidly inactivated by hemoglobin)

    • NO diffusion from alveoli to pulmonary vascular smooth muscle: rapid

  • Selective pulmonary vasodilator -- maybe useful in pulmonary hypertension (may follow cardiopulmonary bypass; endothelial dysfunction induced by bypass)

  • NO: treatment may be useful in cases of persistent pulmonary hypertension in the newborn and such treatment reduces need for extracorporeal membrane oxygen therapy.

  • Adult Respiratory Distress Syndrome

    •  Findings: pulmonary hypertension and arterial hypoxemia

    •  Management: IV pulmonary vasodilators including:

      • Nitroprusside, nitroglycerin, prostaglandin E1, prostacyclin, nefedipine result modest decrease in pulmonary artery pressure (large decreases in systemic BP/arterial oxygenation)

      • Inhaled NO: decrease pulmonary resistance and enhanced arterial oxygenation

        • Oxygenation improvement dependent on initial pulmonary vascular resistance prior to treatment

        • Improvement in arterial oxygenation: rationale --

          • Inhaled NO distributed based on ventilation resulting in associated vasodilation which improves blood flow to well- ventilated regions which improves ventilation/perfusion matching.

    • Associated with NO-mediated decreased pulmonary hypertension and improved arterial oxygenation which results in increased time for pulmonary healing.

    • Potential for NO-mediated pulmonary toxicity

Stoelting, R.K., "Peripheral Vasodilators", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp. 313-315.

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