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.
2. See Sodium, Potassium and Calcium Regulation.
3. See Neurotransmitter Regulatory Effects of PHT.
4. See Pituitary-Adrenal Hormones.
5. See Pituitary-Thyroid Function and Other Hormones.
6. Enzyme regulation: see Refs. 296, 442, 450, 451, 771, 772, 896, 915, 998, 1003, 1004, 1128, 1130, 1208, 1251, 1573, 1740, 2128, 2129, 2334, 2335, 2336, 2564, 2587, 2732, 2735, 2739, 2740, 2742, 2873, 2891.

296. Remmer, H., Estabrook, R. W., Schenkman, J., and Greim, H., Reaction of drugs with microsomal liver hydroxylase: its influence on drug action, Naunyn-Schmiedeberg Arch. Pharm., 259: 98-116, 1968.

442. Burns, J. J. and Conney, A. H., Enzyme stimulation and inhibition in the metabolism of drugs, Proc. Roy. Soc. Med., 58: 955-960, 1965.

450. Sholiton, L. J., Werk, E. E., and MacGee, J., The effect of diphenylhydantoin in vitro on the metabolism of testosterone by rat liver slices, Acta Endocr., 56: 490-498, 1967.

451. Sholiton, L., Werk, E. E., Jr., and MacGee, J., The in vitro effect of 5,5-diphenylhydantoin on the catabolism of cortisol by rat liver, Metabolism, 13: 1382-1392, 1964.

771. Ariyoshi, T. and Takabatake, E., Effect of diphenylhydantoin on the drug metabolism and the fatty acid composition of phospholipids in hepatic microsomes, Chem. Pharm. Bull., 20: 180-184, 1972.

772. Ariyoshi, T., Zange, M., and Remmer, H., Effects of diphenylhydantoin on the liver constituents and the microsomal drug metabolism enzyme systems in the partially hepatectomized rats, J. Pharm. Soc. Jap., 94: 526-530, 1974.

896. Choi, Y., Thrasher, K., Werk, E. E., Sholiton, L. J., and Olinger, C., Effect of diphenylhydantoin on cortisol kinetics in humans, J. Pharmacol. Exp. Ther., 176: 27-34, 1971.

915. Conney, A. H., Jacobson, M., Schneidman, K., and Kuntzman, R., Induction of liver microsomal cortisol 6 .²-hydroxylase by diphenylhydantoin or phenobarbital: an explanation for the increased excretion of 6-hydroxycortisol in humans treated with these drugs, Life Sci., 4: 1091-1098, 1965.

998. Edmundson, W. F., Davies, J. E., Maceo, A., and Morgade, C., Drug and environmental effects on DDT residues in human blood, Southern Med. J., 63: 1440-1441, 1970.

1003. Eling, T. E., Harbison, R. D., Becker, B. A., and Fouts, J. R., Diphenylhydantoin effect on neonatal and adult rat hepatic drug metabolism, J. Pharmacol. Exp. Ther., 171: 127-134, 1970.

1004. Eling, T. E., Harbison, R. D., Becker, B. A., and Fouts, J. R., Kinetic changes in microsomal drug metabolism with age and diphenylhydantoin treatment, Europ. J. Pharmacol., 11: 101-108, 1970.

1128. Hague, N., Thrasher, K., Werk, E. E., Jr., Knowles, H. C., J r., and Sholiton, L. J., Studies on dexamethasone metabolism in man: effect of diphenylhydantoin, J. Clin. Endocr., 34: 44-50, 1972.

1130. Harbison, R. D., Eling, T. E., and Becker, B. A., Effects of diphenylhydantoin on neonatal rat liver drug metabolizing enzymes, Fed. Proc., 28(2): 1969.

1208. Kato, R., Chiesara, E., and Vassanelli, P., Increased activity of microsomal strychnine-metabolizing enzyme induced by phenobarbital and other drugs, Biochem. Pharmacol., 11: 913-922, 1962.

1251. Kutt, H., Waters, L., and Fouts, J. R., Diphenylhydantoin-induced difference spectra with rat-liver microsomes, Chem. Biol. Interactions, 2: 195-202, 1970.

1573. Sotaniemi, E. A., Arvela, P., Hakkarainen, H. K., and Huhti, E., The clinical significance of microsomal enzyme induction in the therapy of epileptic patients, Ann. Clin. Res., 2: 223-227, 1970.

1740. Bechtel, P., Delafin, C. and Bechtel, Y., Induction of hepatic cytochrome P-450 and b5 in mice by phenytoin during chronic hypoxia, C. R. Soc. Biol. (Paris), 170(2): 325-30, 1976.

2128. Workman, P., Effects of pretreatment with phenobarbitone and phenytoin on the pharmacokinetics and toxicity of misonidazole in mice, Br. J. Cancer, 40; 335-53, 1979.

2129. Workman, P., Bleehen, N. M. and Wiltshire, C. R., Phenytoin shortens the half-life of the hypoxic cell radiosensitizer misonidazole in man: implications for possible reduced toxicity, Br. J. Cancer, 41: 302-4, 1980.

2334. Billings, R. E., Interactions between folate metabolism, phenytoin metabolism and liver microsomal cytoebrome P450, Drug. Nutr. Interact., 3(l); 21-32, 1984.

2335. Billings, R. E., Fischer, L. J., Oxygen-18 incorporation studies of the metabolism of phenytoin to the catechol, Drug Metab. Dispos., 13(3): 312-17, 1985.

2336. Billings, R. E., Hansen, D. K., Species differences in phenytoin induction of cytochrome P450 due to pharmacokinetic differences, Proc. West Phartnaeol. Soc., 27: 539-42, 1984.

2564. Gut, I., Becker, B. A., Diphenylhydantoin stimulation of various pathways of hepatic microsomal drug metabolism in rabbits, Acta Univ. Carol. Med., 26(1-2): 105-14, 1980.

2587. Heinicke, R. J., Stobs, S. J., Al-Turk, W., Lemon, H. M., Chronic phenytoin administration and the hepatic mixed function oxidase system in female rats, Gen. Pharmacot., 15(2): 85-9, 1984.

2732. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Arranto, A., Ehnholm, C., Plasma high-density lipoproteins and hepatic microsomal enzyme induction: relation to histological changes in the liver, Eur. J. Clin. Pharmacol., 23: 275-82, 1982.

2735. Luoma, P. V., Pelkonen, R. O., Sotaniemi, E. A., Plasma high-density lipoprotein cholesterol and hepatic drug metabolizing enzyme activity in man, Acta Physiol. Scand., 226: 71, 1979.

2739. Luoma, P. V., Sotaniemi, E. A., Arranto, A. J., Serum LDL cholesterol, the LDL/HDL cholesterol ratio and liver microsomal enzyme induction evaluated by antipyrine kinetics, Scand. J. Clin. Lab. Invest., 43; 671-75, 1983.

2740. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Myllyla, V. V., Plasma high-density lipoprotein cholesterol and hepatic cytochrome P-450 concentrations in epileptics undergoing anticonvulsant treatment, Scand. J. Clin. Lab. Invest., 40: 163-67, 1980.

2742. Luoma, P. V., Sotaniemi, E. A., Pelkonen, R. O., Inverse relationship of serum LDL cholesterol and the LDL/HDL cholesterol ratio to liver microsomal enzyme induction in man, Res. Commun. Chem. Pathol. Pharmacol., 42(l): 1736, 1983.

2873. Pirttiaho, H. I., Sotaniemi, E. A., Pelkonen, R. O., Pitkanen, U., Hepatic blood flow and drug metabolism in patients on enzyme-inducing anticonvulsants, Eur. J. Clin. Pharmacol., 22:441-5, 1982.

2891. Rane, A., Peng, D., Phenytoin enhances epoxide metabolism in human fetal liver cultures, Drug Metab. Dispos., 13(3): 382-5, 1985.

7. See Lipid Metabolism-HDL.
8. See Healing.
9. See Anti-Anoxic Effects of PHT.
10. See Anti-Toxic Effects of PHT.

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