P&T News: November 1997
Barbara A. Mutnick, R.Ph., M.H.P. and Jacqueline D. Joss,
Pharm.D.
Peer Review Status: Internally Peer Reviewed by Mark
A. Granner, M.D., Assistant Professor, Department of
Neurology.
The incidence of osteomalacia is difficult to establish and varies widely among studies. Many studies were conducted in institutionalized patients; however, the widest variation, ranging from no experience of osteomalacia8 to 75% of patients showing changes in bone morphology upon bone biopsy,9 occurred in outpatient populations. Despite these wide differences in results, a 2 to 8% incidence is the generally recognized range in outpatient populations. The roles of dietary vitamin D intake, exposure to the sun, degree of physical activity, concomitant use of other anticonvulsant drugs (phenobarbital and carbamazepine also cause this effect), and length of therapy still have not been conclusively established.
Mechanism of Phenytoin Interference
A number of mechanisms have been postulated to mediate the
phenytoin-induced interference in calcium and vitamin D metabolism.
Phenytoin has been shown to inhibit intestinal absorption of calcium
and reduce the amount of available mineral necessary to calcify
bone.10
Two equally active forms of vitamin D that humans can utilize are vitamin D2 and vitamin D3, which are generally found in food and vitamin supplements. Both forms are absorbed in the proximal small intestine or produced by a conversion mediated by irradiation in the skin; they are then converted in the liver to 25-hydroxyvitamin D (25- (OH)D). This metabolite is transported to the kidneys for biotransformation to 24,25 dihydroxyvitamin D (24,25- (OH)2D) or 1,25 dihydroxyvitamin D (1,25-(OH)2D), the latter being the most active form (7 to 10 times more potent than the parent compound). The production of 25-(OH)D in the liver is regulated by feedback inhibition; the renal conversion to 1,25-(OH)2D is stimulated by the parathyroid hormone, as well as through regulatory feedback mechanisms due to reduced serum levels of calcium and phosphorus. Under conditions of diminished intake, decreased cutaneous production, or increased metabolism or utilization, this feedback system is inadequate to maintain normal levels of biologically active vitamin D and a clinical state of deficiency occurs. Phenytoin is also capable of inducing the liver microsomal mixed-function oxidase enzyme system which leads to increased catabolism of vitamin D and its active metabolites to inactive metabolites which are excreted in the urine and bile.10
Patients receiving phenytoin have been shown to display low levels of 25-(OH)D, thus lowering the amount available for conversion in the kidneys to the more active metabolites.10 Enhanced excretion of 25-(OH)D and 1,25- (OH)2 D and a drug-induced secondary hyperparathyroidism have also been postulated to mediate this effect.7
Recent UIHC Reports
During a recent nine-month period, five patients were identified
through the hospital s adverse drug reaction reporting program as
experiencing hypocalcemia and elevations in serum alkaline
phosphatase levels and, in some cases, possible osteomalacia. Four of
these patients were receiving phenytoin for eight years or longer;
the fifth patient received phenytoin for at least four years.
Three patients had 25-(OH)D levels drawn; one of these patients, a 70-year-old male who experienced a hip fracture, had normal levels. The two other patients, a 58-year-old women and a 72-year-old male, had low normal or below normal levels. One 65-year-old female, who did not have serum vitamin levels drawn, experienced a fracture of the tibia and a compression fracture of the spine. Her history was compounded by an additional diagnosis of osteoporosis. She has been on hormone replacement therapy and had a course of alendronate therapy during the year previous to her fractures. The final patient, a 44-year-old female, had low serum calcium levels reported since 1988.
Prevention and Treatment
Alterations in calcium and bone metabolism should be monitored in
high-risk patients receiving phenytoin. The high-risk population
includes the elderly, immobile patients, institutionalized patients,
and post-menopausal women. Physical activity, a daily supplement
of a multivitamin, and an adequate dietary calcium intake should be
prescribed for all patients receiving phenytoin. In the high-risk
population, vitamin D 800 IU per day and elemental calcium 1500 mg
per day should be prescribed upon initiation of therapy.7 After six
months of therapy serum calcium, phosphorus, and alkaline phosphatase
levels should be measured in the high-risk group. Rises in alkaline
phosphatase levels, alone, are not definitive for bone disease since
anticonvulsants commonly cause this enzyme to be elevated due to
sources from the liver.10 If abnormalities are discovered in calcium,
phosphorus, and alkaline phosphatase levels, a serum 25-(OH)D level
should be drawn.
If 25-(OH)D levels are low, therapy with 50,000 IU of vitamin D once a week should be started. A new 25-(OH)D level should be redrawn after three months and the dose of vitamin D adjusted periodically to maintain levels in the normal range. When the 25-(OH)D levels return to normal, a 24-hour urinary calcium level should be drawn to determine if calcium absorption is normal. If this level is low, an increase in daily calcium intake should be made. Assessments should be repeated yearly, thereafter.
In high-risk patients who are currently receiving phenytoin therapy, the serum calcium, phosphorus, and alkaline phosphatase levels should be obtained. If values are normal, supplementation of calcium 1500 mg and vitamin D 800 IU daily should be started. If abnormalities are found, a serum 25-(OH)D level should be measured. If serum 25- (OH)D levels are below normal, vitamin D 50,000 IU per week should be prescribed for the patient with subsequent monitoring as described above. These recommendations7 are summarized below in Table 1.
Summary
The diagnosis of osteomalacia, made in the past by bone biopsy and
more recently by measurements of bone mineral density, may be over
looked in some patients. However, prevention of this adverse effect
in high-risk patients who are receiving long-term therapy with
phenytoin can be accomplished by monitoring for early alterations in
bone metabolism. Monitoring can easily be carried out by following
serum calcium, phosphorus, and alkaline phosphatase levels, and serum
25-(OH)D levels, when indicated. Supplementation with calcium and
vitamin D is a key component to the prevention of osteomalacia.
Preventing the development of this potentially serious effect will
decrease patient morbidity.
Initiation of Therapy
After 6 Months or More of Therapy OR Patient Previously Started on Therapy and Not Monitored
Three Months Later (If 25-(OH)D levels are low)
On a Yearly Basis
_______
+The high-risk group includes: the elderly, immobile patients,
institutionalized patients, and post-menopausal women.
*These same alterations have been reported with carbamazepine and phenobarbital therapy. Patients receiving chronic therapy with these agents may also benefit from similar monitoring and supplementation.
Adapted from: Primer of Metabolic Bone Disease and Disorders of Mineral Metabolism, 1993.
PHARMACY AND THERAPEUTICS SUBCOMMITTEE ACTIONS
DRUGS ADDED TO STOCK
DELAVIRDINE Tablets: 100 mg Delavirdine (Rescriptor[R] - Pharmacia & Upjohn), a non- nucleoside reverse transcriptase inhibitor, is indicated for the treatment of HIV-I infection in combination with antiretroviral agents such as didanosine and/or zidovudine.
ROPIVACAINE Injection: 0.5%, 0.75% Ropivacaine is a local anesthetic indicated for the production of local or regional anesthesia for surgery, for postoperative pain management, and for obstetrical procedures. Note: The prescribing of ropivacaine is restricted to Anesthesia.
ADDITIONAL ACTIONS
BACLOFEN 50 mcg per ml INJECTION The 1 ml ampul has been added to stock.
BARIUM SULFATE 70% ORAL PASTE This product (Intropaste[R]) is a replacement for Esophotrast[R].
SODIUM CHLORIDE 1 g TABLETS This commercially available product will replace compounded 600 mg tablets.
DRUGS DELETED FROM STOCK
ATROPINE 0.25% OPHTHALMIC SOLUTION Discontinued due to low use. Atropine 0.5% ophthalmic solution is available.
DIATRIZOATES, MEGLUMINE-SODIUM (GASTROGRAPHIN[R]) 76% ORAL SOLUTION Replaced with MD-Gastroview[R]
DIPHTHERIA, TETANUS, AND WHOLE-CELL PERTUSSIS (DTP) VACCINE Discontinued due to the availability of diphtheria, tetanus, and acellular pertussis (DTaP) vaccine.
TRIMETHAPHAN (ARFONAD[R]) INJECTION Discontinued by all manufacturers. Nitroprusside sodium, hydralazine, labetalol, and enalaprilat injections are available.