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Summary The evidence which has accumulated on phenytoin's basic mechanisms of action, from the earliest studies to the present, is extensive and consistent. PHT has been shown to have a modulatory effect on bioelectrical activity in single cells, groups of cells and physiological systems. This ability to regulate and/or to correct abnormal membrane function has been demonstrated in brain, spinal cord, autonomic ganglia, peripheral nerve, skeletal muscle, cardiac muscle and conduction systems, and intestinal and vascular smooth muscle. In the nerve and muscle cell, PHT reduces or eliminates excessive potentiation and hyperexcitability, as in post-tetanic potentiation and afterdischarge. If the cell is depolarized and firing rapidly, PHT normalizes it, reducing the firing. The more rapid the firing, the greater the effect. PHT has little or no effect on normal bioelectrical function at therapeutic levels. In the nerve cell, neither the resting potential nor single impulse transmission is altered.1 The basis for PHT's selective effects in neurons and muscle cells is found in its action on the cell membrane-its ability to regulate transmembrane ionic fluxes and also intracellular distribution of sodium, potassium, and calcium. Recent work in neurons suggests that PHT binds to active sodium channels and delays their return from the inactivated, unusable state. This results in a decrease of sodium in-flux and correlates with PHT's frequency-dependent effects on the sodium-dependent action potential. Similar effects on calcium flux have also been reported. At the synapse PHT influences both calcium-dependent neurotransmitter release and postsynaptic response. Ace-tylcholine, norepinephrine, dopamine, GABA, and serotonin release, uptake and/or binding may all be regulated, dependent on the state of the neuron or circuit.3 The functions of other cell types such as glial, endocrine cells and fibroblasts are also modulated by PHT. Examples of PHT's actions include stimulation of glial cell potassium uptake; 2 modulation of hypothalamic-pituitary adrenal function, including ACTH release and cortisol metabolism; and modulation of thyroid stimulating hormone, thyroxine, insulin, vasopressin, oxytocin, calcitonin and other hormone release and metabolism.. PHT stimulates hepatic enzyme metabolizing systems (cytochrome P-450); increases high-density lipoprotein levels; and stimulates healing processes (formation of granulation tissue and neovascularity).PHT has protective effects on cells. It preserves energy compounds and decreases "downhill movement" of ions, characteristic of energy depletion in neurons, whether such depletion is induced by physiological hyperactivity or chemical, electrical, or anoxic/ischemic injury.9 PHT has been reported to diminish or counteract, in animals or in man, the toxic effects of over thirty therapeutic and poisonous substances, as diverse as steroids, cyanide, DDT, digitalis, methaqualone, morphine, ouabain, reserpine and strychnine, and of radiation. The broad range of clinical use of PHT is best understood in the light of its ability to maintain normal bioelectrical activity. A rational basis for the clinical use of PHT takes into account its basic mechanisms of action, which indicate that it may be useful wherever stabilization or modulation of bioelectrical activity can have a therapeutic effect.
1.
See Stabilization of Bioelectrical Activity, and Sodium, Potassium and
Calcium Regulation. 296.
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See Lipid Metabolism-HDL. | |||
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