Nursing Pharmacology Chapter 9:  Antianginal Drugs

• Nitric Oxide

  • Overview: nitric oxide (NO)

    • 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 (nitric oxide synthase enzyme)

    • Target: (NO, a gas, diffuses from producing cells), then interacts with an enzyme, guanylate cyclase, activates it causing an increase cGMP concentration which then causes 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

    • 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.

• Cardiovascular System

  • Regulation of systemic vascular resistance/pulmonary vascular resistance-- secondary to:

    • Flow-induced shear stress: continual NO release

    • Pulsatile arterial flow: continual NO release

  • Endothelial NO production: determines cardiac output distribution, particularly

    1. Pulmonary distribution

    2. Cerebral distribution

  • Endothelial NO release: autoregulation (decreased oxygenation  results in increased NO production)

  • NO opposes pulmonary hypertensive response to arterial hypoxemia

  • NO causes:

    •  Negative inotropism (reduced force of heart contraction; i.e. reduced contractility)

    •  Negative chronotropism (reduced heart rate)

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

• Pulmonary

  • NO: may contribute to bronchodilation

  • may be important in mediating ventilation- to-perfusion matching

• Platelets

  • Inhibit platelet aggregation and adhesion

  • Mechanism:

    1. Activation of guanylate cyclase

    2. Reduced intracellular calcium

    3. NO effects are synergistic with prostacyclin

• Nervous System

  • Nitric oxide is a neurotransmitter in:

    • Brain

    • Spinal cord

    • Periphery

  • Peripheral Nervous System:

    • Both nonadrenergic and noncholinergic systems release NO as a neurotransmitter with the following being possible innervation sites:

      • 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 may be involved with the following immune system responses:

    • Macrophage activation by cytokines (secondary to NO synthase induction)

      •  Resultant high NO concentrations -- damage fungi, bacteria, protozoa

    • Inflammation modulation

• Abnormal NO:   Possible Pathophysiological consequences

  • Essential hypertension: reduced NO release

  • Septic shock hypotension: 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:

    • Cause/contribute to pulmonary hypertension

  •  Gastrointestinal:

    • reduced NO activity in:

      • Pyloric stenosis and achalasia

    • NO- modulation of morphine-induced constipation

  •  CNS: epilepsy pathogenesis

• Anesthesia

  • Suppression of NO synthesis by anesthetics could:

    • Decrease 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

  • As a selective pulmonary vasodilator, nitric oxide maybe useful in pulmonary hypertension (may follow cardiopulmonary bypass; endothelial dysfunction induced by bypass)

  • NO: treatment may be helpful in managing persistent pulmonary hypertension in the newborn and may reduce the need for extracorporeal membrane oxygen therapy.

  • Adult Respiratory Distress Syndrome

    •  Findings: ARDS is associated with 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. This nitric oxide effect improves ventilation/perfusion matching.

    • Nitric oxide administration may decrease 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.