Propylthiouracil dosing

One excellent study [151] employed intravenous and oral dosing at each of several times postsurgery (1-2 weeks, 6 and 12 months). This design permits valid conclusions about the absorption process. There was a significant reduction after surgery in ampicillin absorption but no change in propylthiouracil absorption. 

When 20 mg/kg of methimazole was administered i.p. or orally to rats, urinary methimazole glucuronides accounted for 36-48% of the dose in 24 hours. The only other urinary metabolite accounted for 10-20% and was not characterized. An additional 14-20% of methimazole was excreted unchanged in 24 hour urine. The bile contained methimazole glucuronide and two unidentified metabolites. One of which was the same as the unidentified urinary metabolites. Plasma proteins bound 5% of methimazole which had no affinity for any specific tissue. Methimazole had a much greater CHCI3/H2O partition coefficient and 1 0 solubility than did propylthiouracil. Between 77 and 95% of the methimazole was excreted in the urine and approximately 10% in the bile. Since fecal excretion was neglegible an enter-ohepatic circulation was present. The half life of urinary excretion was 5-7 hours regardless of the route of administration (15). 

PROPYLTHIOURACIL Usually given in 3 equal doses at approximately 8 hour intervals. 

Propylthiouracil [PTU] [Antithyroid Agent/Thyroid Hormone Antagonist] Uses HypCTthyroidism Action X Production of Tg T4 conversion of T4 to Tg Dose Adults. Initial 100 mg PO q8h (may need up... 

The initial dose for carbimazole or methimazole is 20-60 mg/day until the patient is rendered euthyroid with maintenance therapy of 5-15 mg/day. For propylthiouracil the initial dose is 300 50 mg/day with maintenance doses of 50-150 mg/day. Higher doses are sometimes used in severe disease. Two different treatment regimens may be used (1) titration regimen, to try to achieve a euthyroid state by dose tritation and (2) block-replacement regimen, with... 

Propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50-80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Most of an ingested dose of propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours. 

In contrast, methimazole is completely absorbed but at variable rates. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of propylthiouracil. Excretion is slower than with propylthiouracil 65-70% of a dose is recovered in the urine in 48 hours. 

If caused by maternal TSH-R Ab [stim], the disease is usually self-limited and subsides over a period of 4-12 weeks, coinciding with the fall in the infant s TSH-R Ab [stim] level. However, treatment is necessary because of the severe metabolic stress the infant experiences. Therapy includes propylthiouracil in a dose of 5-10 mg/kg/d in divided doses at 8-hour intervals Lugol s solution (8 mg of iodide per drop), 1 drop every 8 hours and propranolol, 2 mg/kg/d in divided doses. Careful supportive therapy is essential. If the infant is very ill, oral prednisone, 2 mg/kg/d in divided doses, will help block conversion of T4 to T3. These medications are gradually reduced as the clinical picture improves and can be discontinued by... 

Antithyroid drugs may also suppress lymphocytic infiltration into the thyroid and thereby directly modulate the basic disorder of autoimmune hyperthyroidism (SEDA-6, 364 SEDA-9, 344). Propylthiouracil, but not the thioimidazoles, also inhibits the conversion of thyroxine to its more active derivative triiodothyronine. This effect is significant during high-dose treatment, and propylthiouracil may therefore be preferred if a more rapid onset of action is desired, for example thyrotoxic crisis, although clear experimental proof of the advantageous effect is still lacking (3). 

In a retrospective review of 497 patients taking propylthiouracil for hyperthyroidism, clinically overt hepatitis developed in six patients at 12-49 days after starting the drug (50). Jaundice and itching were present in five, fever in two, rash in two, and arthralgia in one. Serum bilirubin, alanine transaminase, and alkaline phosphatase were increased in five, four, and six patients respectively. The type of hepatic injury was cholestatic in three, hepatocellular in one, and mixed in two. There were no differences in age, sex, drug dose, or serum thyroid hormone concentrations at time of diagnosis in those with hepatic injury compared with those without. Liver function normalized in all patients at 16-145 days after withdrawal of propylthiouracil. In addition to these cases of overt liver injury, 14% of the cohort had mild asymptomatic liver enzyme rises at a mean of 75 days after the start of treatment. 

Several cases of collagen-like or lupus-like disease have been reported (joint pain, skin rash, and positive antinuclear antibodies) during treatment with either propylthiouracil or thiamazole (SEDA-8, 372) (SEDA-10, 368). Some cases of general vasculitis can be fatal, although high-dose glucocorticoid therapy can be helpful (90). 

Scalp atresia has been described in an infant whose mother had taken carbimazole in a high dose (60 mg/ day) during the first 12 weeks of pregnancy and propylthiouracil thereafter (101). The infant had other dysmorphic features (a flat face, low-set ears, upper lip retraction, and a low-set fifth finger) in addition to transient hypothyroidism. 

He CT, Hsieh AT, Pei D, et al. Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves hyperthyroidism. Clin Endocrinol. 2004 60 676-681. 

Determination of 131-1 in the thyroid of rats at the end of a treatment period is a useful additional test, which can be applied to satellite groups, preferably control and high dose. This is a sensitive test which readily detects inhibition of thyroid hormone synthesis e.g. by propylthiouracil. 

Walker and Levy (1989) used implantable pellets of propylthiouracil to induce thyroid dysfunction in rats. In the modification based on uptake of labelled iodine, as standard dose of radio-iodine 131-1 is injected in each animal, and the amount of radioactivity in the thyroid gland is determined in a gamma counter. 

Blood dyscrasias, mostly dose independent, are among the most important allergic-type adverse reactions to drugs. Aplastic anemia is a serious but rare (presumably) idiosyncratic reaction. It has been reported in association with chloramphenicol, quinacrine, phenylbutazone, mephenytoin, gold compounds, and potassium chlorate. Hemolytic anemia, thrombocytopenia, and agranulocytosis may result from an unusual, acquired sensitivity to a variety of widely used drugs including aminopyrine, phenylbutazone, phenothiazines, propylthiouracil, diphenylhydantoin, penicillins, chloramphenicol, sulfisoxazole, and tolbutamide. 

Carbimazole and methimazole (the chief metabolite of carbimazole) (t) 6h) and propylthiouracil (t) 2 h) are commonly used, but t) matters little since the drugs accumulate in the thyroid and act there for 30-40 h thus a single daily dose suffices. 

Propylthiouracil differs from other members of the group in that it also inhibits peripheral conversion of T to Tj, but only at the high doses used in treatment of thyroid storm (p. 705). 

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