Anticonvulsants and thyroid function.

Serum total and free thyroid hormone concentrations were estimated in 42 patients with epilepsy taking anticonvulsants (phenytoin, phenobarbitone, and carbamazepine either singly or in combination). There was a significant reduction in total thyroxine (TT4), free thyroxine (FT4), and free triiodothyronine (FT3) in the treated group compared with controls. Free hormone concentrations were lower than total hormone concentrations, suggesting that increased clearance of thyroid hormones occurs in patients receiving anticonvulsants. Detailed analysis indicated that phenytoin had a significant depressant effect on TT4, FT4, FT3, and reverse T3 (rT3). Phenobarbitone and carbamazepine had no significant main effects, but there were significant interactions between phenytoin and carbamazepine for TT4 and FT4. phenobarbitone and carbamazepine for FT3, and phenytoin and phenobarbitone for rT3.     

Incidence of Anticonvulsant Osteomalacia and Effect of Vitamin D: Controlled Therapeutic Trial

The bone mineral content (B.M.C.) in both forearms (related to total body calcium) was measured by photon absorptiometry for a controlled therapeutic trial in a representative sample of epileptic outpatients, comprising 226 patients treated with one or two major anticonvulsant drugs (phenytoin, phenobarbitone, primidone).Initially the mean B.M.C. value for all epileptic patients was 87% of normal. During treatment with 2,000 international units of vitamin D₂ daily for three months an average B.M.C. increase of 4% was found, whereas the B.M.C. values remained unchanged in the placebo group and in the control groups. The incidence of hypocalcaemia and raised serum alkaline phosphatase was 12% and 43% respectively. The biochemical indices of osteomalacia were related to B.M.C. These results indicate that epileptic patients should be closely supervised for the occurrence of anticonvulsant osteomalacia, and, possibly, receive prophylactic treatment with vitamin D.     

Interaction of phenytoin and primidone.

The ratio of derived phenobarbitone to unmetabolized primidone in the serum was significantly higher in 50 epileptic patients on a combination of primidone and phenytoin than in 12 patients on primidone alone, though the dose and serum levels of primidone were similar in the two groups. Out of 253 patients attending a seizure clinic 47% were taking a combination of these two anticonvulsants. The effect of phenytoin on the metabolism of primidone may have clinical implications in view of the frequency of their combined use.     

Treatment of alcoholism; problems arising from the substitution of other drugs in therapy

Of the 139 patients admitted to hospital for chronic alcoholism, 32 had been taking other drugs also, and 17 were addicted to the drugs. Of the 32 patients, 16 used barbiturates, and 8 were addicted. Five took large amounts in suicidal attempt. Ten patients combined still other drugs with alcohol and barbiturates; and seven of them were addicted to barbiturates. Of the six patients combining alcohol with drugs other than barbiturates, two were addicted to the use. Of the 16 patients who used drugs other than barbiturates, eight used one or more opiates such as meperidine, morphine, codeine or dihydromorphinone. Four used stimulants such as benzedrine or dexedrine, alone or in combination. Still other drugs were used in some combination by 32 patients.     

TREATMENT OF ALCOHOLISM—Problems Arising from the Substitution of Other Drugs in Therapy

Of the 139 patients admitted to hospital for chronic alcoholism, 32 had been taking other drugs also, and 17 were addicted to the drugs. Of the 32 patients, 16 used barbiturates, and 8 were addicted. Five took large amounts in suicidal attempt.Ten patients combined still other drugs with alcohol and barbiturates; and seven of them were addicted to barbiturates. Of the six patients combining alcohol with drugs other than barbiturates, two were addicted to the use.Of the 16 patients who used drugs other than barbiturates, eight used one or more opiates such as meperidine, morphine, codeine or dihydromorphinone. Four used stimulants such as benzedrine or dexedrine, alone or in combination. Still other drugs were used in some combination by 32 patients.     

Outbreak of Anticonvulsant Intoxication in an Australian City

An outbreak of anticonvulsant intoxication occurred in epileptic patients in Australia during 1968-9. All affected patients studied in Brisbane were taking one brand of phenytoin. In 87% of them the blood phenytoin levels were above the therapeutic range. Reduction of phenytoin dosage relieved the intoxication in all patients. The excipient in the responsible phenytoin capsules had been changed several months before the outbreak, and this change was probably related causally to the altered blood phenytoin concentrations.     

Associations between Drugs Administered during Pregnancy and Congenital Abnormalities of the Fetus

In a retrospective study to compare the drug consumption during pregnancy of mothers of infants with congenital abnormalities and of those without, over 97% of 1,369 mothers took prescribed drugs and 65% self-administered drugs. Significantly more mothers of infants with congenital abnormalities took aspirin, antacids, dextroamphetamine, phenobarbitone, sodium amytal, other barbiturates, cough medicines, iron, sulphonamides, and nicotinamide than mothers in the control group. However, most mothers taking analgesics, antacids, appetite suppressants, barbiturates, cough medicines, iron, sulphonamides, and vitamins produced normal infants. Any teratogenic effect of these drugs is therefore one of low potency. On the other hand, deficiencies such as those of ascorbic acid and folic acid may have a teratogenic effect. There is need for caution in presuming teratogenic effects on the basis of the associations shown here. During pregnancy, however, it would appear wise to avoid the administration of any drug which carries a suspicion of teratogenicity unless that drug is specifically indicated, and self-medication with common household remedies such as aspirin and antacids should be avoided. These recommendations would also apply to any woman of childbearing age in whom conception is likely.     

Latent Osteomalacia in Epileptic Patients on Anticonvulsants

The bone mineral content was measured in 10 epileptic patients on long-term treatment with phenytoin before and during treatment with vitamin D. None of the patients showed biochemical signs of osteomalacia. Initially subnormal values for bone mineral content were found, which increased significantly during treatment. The results suggest the occurrence of latent osteomalacia in a fairly high proportion of epileptic patients on anticonvulsants.     

25-Hydroxycholecalciferol absorption in steatorrhoea and postgastrectomy osteomalacia.

Post-absorption levels of 25-hydroxy vitamin D (25-OHD) after oral administration of 25-hydroxycholecalciferol (25-OHD3) were measured in 11 subjects. Five had presented with steatorrhoea of various causes while six had post-gastrectomy osteomalacia. Post-absorption levels of 25-OHD were low in four of the patients with steatorrhoea but normal in five of those with post-gastrectomy osteomalacia. There was a significant inverse correlation between peak post-absorption 25-OHD levels and faecal fat excretion. All patients with active post-gastrectomy osteomalacia had subnormal baseline plasma 25-OHD levels, which indicates that the condition is due to a deficiency of vitamin D. Only two of the patients with osteomalacia had estimated dietary vitamin D intakes ofer 1-75 microng/day. These findings suggest that an oral 25-OHD absorption test may be a valuable measure of small intestinal function and that poor dietary vitamin D intake rather than impaired absorption of the vitamin may be the major cause of post-gastrectomy osteomalacia.     

Oxalate excretion in rats injected with xylitol or glycollate: stimulation by phenobarbitone pre-treatment.

The hypothesis that the prior intake of barbiturates may predispose patients to form increased amounts of oxalate following the intravenous infusion of xylitol was investigated in the rat. Phenobarbitone pre-treatment resulted in a 2-3 fold increase in urinary [14C] oxalate concentration following the intraperitoneal injection of [U-14C] xylitol or [l -14C] glycollate. The absence of any marked changes in urine volumes and creatinine excretion implied that this increase in urinary oxalate excretion was due to the enhanced synthesis of oxalate. The activities of key enzymes in hepatic oxalate synthesis, glycollate oxidase, lactate dehydrogenase, catalase and alanine aminotransferase were not altered by phenobarbitone pre-treatment. It is suggested that the increased activity of the microsomal mixed function oxidases, following phenobarbitone treatment, may facilitate the oxidation of glycollate and possibly xylitol. This communication leads experimental support to the concept that the prior intake of drugs, such as barbiturates, may predispose patients to form increased amounts of oxalate.     

Mortality from ischaemic heart disease among patients using anticonvulsive drugs: a case-control study.

Patients who use phenytoin and some other anticonvulsive drugs have been shown to have raised concentrations of plasma high density lipoprotein. As this lipoprotein is known to be inversely associated with the incidence of ischaemic heart disease the causes of death of all patients with epilepsy known to be taking anticonvulsive drugs who died during 1978-80 were studied. Of 1399 deaths of anticonvulsant users, 258 (18.4%) were caused by ischaemic heart disease. This was significantly less (p less than 0.001) than the 382 deaths from ischaemic heart disease (27.3%) observed among paired controls matched for sex, age, and date of death. The total cardiovascular mortality was also lower among patients with epilepsy than among controls (p less than 0.02) despite there being more deaths due to cerebrovascular disease among patients. The difference in mortality from ischaemic heart disease was significant for both sexes and was not accounted for by excess deaths due to any other single cause. Users of phenytoin, carbamazepine, and barbiturates (alone or in combination) showed 29% less mortality due to ischaemic heart disease than respective controls (p less than 0.001).     

Parenteral 1,25-dihydroxycholecalciferol in hepatic osteomalacia.

Despite regular long-term parenteral vitamin D2 treatment, four patients with biliary cirrhosis had multiple symptoms of bone disease and bone biopsy specimens showed osteomalacia without osteoporosis. Three patients also had a proximal myopathy. Plasma calcium values (after correction for albumin), phosphorus, magnesium, and serum 25-hydroxy-vitamin D were within normal limits. Treatment with 1,25-dihydroxy-cholecalciferol (1,25-(OH)2D3) relieved symptoms in three of the four patients and improved those in the fourth. Histological examination of bone showed improvement in all four patients, but serum and urinary biochemical changes were not pronounced. We conclude that 1,25-(0H)2D3 treatment has a beneficial effect on bone and muscle in hepatic osteomalacia, either because vitamin D 1-hydroxylation fails in biliary cirrhosis or because hepatic osteomalacia is resistant to vitamin D2 metabolites.     

Controlled trial of sodium valproate in severe epilepsy.

In a double-blind crossover trial sodium valproate or placebo was added to the existing anticonvulsant treatment of 20 patients with chronic uncontrolled epilepsy. Sodium valproate 1200 mg/day significantly reduced the frequency of both tonic-clonic and minor seizures in these patients. Only mild and transient side effects occurred (drowsiness, ataxia, and nausea), and these may have been due to the effect of adding sodium valproate to existing phenobarbitone or phenytoin treatment. Further controlled trials are needed to assess more fully the efficacy of this drug in various types of epilepsy.     

Anticonvulsants and trifluoperazine inhibit the evoked release of GABA from cerebral cortex of rat at different sites

The action of anticonvulsant drugs, phenytoin, diazepam, clonazepam and phenobarbitone, was tested on the release of [¹⁴C]-GABA from tissue slices of rat cerebral cortex. All drugs caused a significant dose-dependent depression of the 33mM-K⁺-evoked release of [¹⁴C]-GABA but had little effect on the resting release of [¹⁴C]-GABA, except at high concentrations. The IC₅₀ values for inhibition of K⁺-evoked release of [¹⁴C]-GABA were 4.7 × 10^?5, 7 × 10^?5, 28 × 10^?5 and 7.9 × 10^?4M for diazepam, clonazepam, phenytoin and phenobarbitone respectively. Trifluoperazine also caused a similar and complete inhibition of [¹⁴C]-GABA release with an IC₅₀ of 1 × 10^?5M. The effect of diazepam and trifluoperazine were additive. The inhibition by trifluoperazine could be overcome by addition of exogenous calmodulin, whereas that of diazepam, phenytoin or phenobarbitone was not overcome. It is proposed that the anticonvulsants tested inhibit calcium-dependent transmitter release at a site distal to the formation of a calcium-calmodulin complex, which is presumably activated by this complex. Trifluoperazine, on the other hand, acts by reducing the availability of calmodulin.     

Secondary Hyperparathyroidism in Osteomalacia

Twenty-one patients with histologically proved osteomalacia from various causes were investigated for biochemical and radiological evidence of osteomalacia and secondary hyperparathyroidism. Among the 15 who maintained a normal serum calcium, seven had a raised phosphate excretion index, seven had a raised serum alkaline phosphatase, and six had phalangeal erosions. On the other hand, six patients had a subnormal serum calcium; of these, none showed a raised phosphate excretion index, one had a raised serum alkaline phosphatase, and one had erosions. The phosphate excretion index and the alkaline phosphatase were strongly correlated (r = +0·84). It is concluded that this absence of manifest secondary hyperparathyroidism in some patients with osteomalacia is due to failure of an increase in the release of parathyroid hormone. Measurement of phosphaturia does not appear to be a useful means of detecting osteomalacia. Subsequently, the 24-hour (stable) strontium space measurement was found to be the most sensitive single biochemical screening test for osteomalacia.     

A comparative evaluation of the clinical x-ray picture of uremic osteodystrophy before and after parathyroidectomy]

The authors present the results of clinical, x-ray, and biochemical studies carried out in 51 patients with uremic osteodystrophy, treated with hemodialysis, before and after parathyroidectomy. The patients were divided into 4 groups with various patterns of x-ray symptoms. Patients with x-ray signs of fibrous osteodystrophy made up group 1, the second group consisted of patients with a combination of fibrous osteodystrophy and osteomalacia with secondary hyperparathyrosis predominance; the third group, like the second one, included patients with the mixed form of uremic osteodystrophy, but with the predominance of the osteomalacic syndrome; Group 4 patients had no x-ray signs of bone changes, and the diagnosis of uremic osteodystrophy was confirmed by clinical laboratory evidence. Analysis of the clinical and x-ray data before and after parathyroidectomy has brought the authors to a conclusion that such an intervention was effective only in cases with manifest clinical and x-ray symptoms of fibrous osteodystrophy. In Group 2 patients with the mixed form of uremic osteodystrophy and less manifest osteomalacia as against fibrous osteodystrophy, subtotal or partial parathyroidectomy is advisable only in cases when conservative therapy is of no avail and fibrous dystrophy is progressing. Surgical treatment is contraindicated to patients in whom x-ray signs of osteomalacia predominate over fibrous osteodystrophy in the total picture of uremic osteodystrophy; it may result in a rapid progress of osteomalacia.     

Disturbance of Calcium Metabolism by Anticonvulsant Drugs

A survey of calcium metabolism in epileptic patients in a residential centre showed a subnormal serum calcium level in 22·5% of patients and a raised alkaline phosphatase in 29%. Hypocalcaemia was related to high dosage of anticonvulsant drugs, to multiple drug therapy, and to the use of individual anticonvulsant drugs in the following order, with decreasing order of importance: pheneturide, primidone, phenytoin, phenobarbitone. Subnormal serum calcium levels occurred more commonly in patients with a raised liver alkaline phosphatase isoenzyme than in those whose phosphatase was mainly of bone origin.Preliminary results of treatment with calciferol suggested that the disturbance of calcium metabolism was the result of vitamin D deficiency. It is possible that anticonvulsant drugs accelerate the breakdown of vitamin D by liver enzyme induction.     

Osteomalacic dialysis osteodystrophy: a trial of phosphate-enriched dialysis fluid.

To assess whether phosphate depletion is an aetiological factor in osteomalacic dialysis osteodystrophy we undertook a prospective trial of phosphate-enriched dialysis fluid, in association with oral 1alpha-hydroxycholecalciferol, for this condition. Thirty patients started the trial; of the 27 who completed more than 6 months'' treatment, 14 had iliac crest bone biopsies at the beginning and end of the treatment period. Side effects included pruritus, stiffness, and increase in corneal and vascular calcification. Only one patient showed histological improvement of osteomalacia, and eight deteriorated; in seven the osteitis fibrosa worsened. Myopathy showed some improvement in four patients, but became worse in four. This treatment does not seem to have a place in the routine management of non-hypophosphataemic patients on dialysis.     

Prevention of alcohol withdrawal seizures with oral diazepam loading

Twenty patients withdrawing from alcohol who had reliable histories of previous alcohol-withdrawal seizures and thus were at high risk for a subsequent seizure were treated in hospital with oral diazepam loading: 20 mg of the drug was given every hour to a minimum total of 60 mg. None of the patients had a seizure during the stay in hospital. We believe that phenytoin prophylaxis is not necessary in these circumstances. However, if the patient is already taking phenytoin, this drug should not be abruptly discontinued in the withdrawal period in favour of diazepam loading.