tablets (USP) for oral use are natural preparations derived from porcine thyroid
glands (T3 liotllyronine is approximately four times as potent as T4 levothyroxine
on a micro- gram for microgram basis). They provide 38-mcg levothyroxine (T4)
and 9-mcg liothyronine (T3) per grain of thyroid. The inactive ingredient is microcystalline
CLINICAL PHARMACOLOGY :
The steps in the synthesis
of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone.
TSH) Secreted by the anterior pituitary. This hormone's Secretion is in turn controlled
by a feedback mechanism affected by the thyroid hormones themselves and by thyrotropin
releasing hormone (TRH), a tripeptide of hypothalamic origin Endogenous thyroid
hormone secretion is suppressed when exogenous thyroid hormones are administered
to euthyroid individuals in excess of the normal gland's secretion. The mechanisms
by which thyroid hormones exert their physiologic action are not well understood.
These hormones enhance oxygen consumption by most tissues of the body, increase
the basal metabolic rate, and the metabolism of carbohydrates lipids, and proteins.
Thus, they exert a profound influence on every organ system in the body and are
of particular importance in the development of the central nervous system. The
normal thyroid gland contains approximately 200mcg of levothyroxine (T4) per gram
of gland and 15 mcg of liothyronine (T3) per gram. The ratio of these two hormones
in the circulation does not represent the ratio in the thyroid gland, since about
80 percent of peripheral liothyronine (T3) comes from monodeiodination of levothyroxine
(T4). Peripheral monodeidination (T4) at the 5th position (inner ring) also results
in the formation of reverse (T3), which is calorigenically inactive. Liothyronine
(T3) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation,
hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing
what has been called the (T3) thyronine syndrome.
Animal studies have shown that levothyroxine (T4) is only partia11y absorbed from
the gastrointestinal tract. The degree of absorption is dependent on the vehicle
used for its administration and by the character of the intestinal contents, the
intestinal flora, including plasma protein, and soluble dietary factors, all of
which bind thyroid and thereby makes it unavailable for diffusion. Only 41 percent
is absorbed when given in a gelatin capsu1e as opposed to 74 percent absorption
when given with an albumin carrier. Depending on other factors, absorption has
varied from 48 to 79 percent of the administered dose. Fasting increases absorption
Malabsorption syndromes, as well as dietary factors, (children's soybean formula,
concomitant use of anionic exchange resins such as cholestyramine) cause excessive
fecal loss. Liothyronine (T3) is almost totally absorbed, 95 percent in 4 hours.
The hormones contained in the natural preparations are absorbed in a manner similar
to the synthetic hormones. More than 99 percent of circulating hormones are bound
10 Serum proteins, including thyroid-binding globulin (TBg), thyroid-binding prealbumin
(TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones.
The higher affinity levothyroxine (T4) for both TBg and TBPA as compared to liothyronine
(T3) partially explains the higher serum levels and longer half-life of the former
hormone, Both protein-bound hormones exist in reverse equilibrium with minute
amounts of free hormone, the latter accounting for the metabolic activity. Deiodination
of levothyroxine (T4) occurs at a number of sites, including liver kidney, and
other tissues. The conjugated hormone, in the form of glucuronide or sulfate,
is found in the bile and gut where it may complete an enterohepatic circulation.
Eighty-five percent of levothyroxine (T4) metabolized daily is deiodinated.
INDICATIONS AND USAGE:
1. As replacement or supplemental therapy
in patients with hypothyroidism of any etiology, except transient hypothyroidism
during the recovery phase of subacute thyroiditis. This category includes cretinism,
myxedema and ordinary hypothyroidism in patients of any age (children, adults,
and elderly), or state (including pregnancy); primary hypothyroidism resulting
from functional deficiency, primary atrophy, partial or total absence of thyroid
gland, or the effects of surgery, radiation, or drugs, with or without the presence
of goiter; and secondary (pituitary), or tertiary (hypothalamic) hypothyroidism
2. As pituitary TSH suppressants, in the treatment or prevention
of various types of euthyroid goiters, including thyroid nodules, subacute or
chronic lymphocytic thyroiditis (Hashimoto's), multinodular goiter and in the
management of thyroid cancer.
3. As diagnostic agents in suppression tests
to differentiate suspected mild hyperthyroidism or thyroid gland autonomy.
Drugs with thyroid hormone activity, alone or together
with other therapeutic agents have been used for the treatment of obesity. In
euthyroid patients, doses within the range of daily hormonal requirements are
ineffective for weight reduction. Larger doses may produce serious or even life
threatening manifestations of toxicity, particularly when given in association
with sympathomimetic amines such as those used for their anorectic effects. The
use of thyroid hormones in the therapy of obesity, alone or combined with other
drugs, is unjustified and has been shown to be ineffective. Neither is their use
justified for the treatment of male or female infertility unless this condition
is accompanied by hypothyroidism.
for the patients:- Patients on thyroid hormone preparations and parents of children
on thyroid therapy should be informed that:
1. Replacement therapy is to be
taken essentially for life, with the exception of cases of transient hypothyroidism,
usually associated with thyroiditis, and in those patients receiving a therapeutic
trial of the drug.
2. They should immediately report during the course of
therapy any signs or symptoms of thyroid hormone toxicity, e.g. chest pain, increased
pulse rate, palpitations, excessive sweating, heal intolerance, nervousness, or
any other unusual event.
3. In case of concomitant diabetes mellitus, the
daily dosage of anti diabetic medication may need re-adjustment as thyroid hormone
replacement is achieved. If thyroid medication is stopped, a downward re-adjustment
of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid
hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory
in such patients.
4. In case of concomitant oral anticoagulant therapy, the
prothrombin time should be measured frequently to determine if the dosage of oral
anticoagulants is to be readjusted.
5. Partial loss of hair may be experienced
by children in the first few months of thyroid therapy, but this is usually a
transient phenomenon and later recovery is usually the rule.
Adverse reactions other than those indicative of hyperthyroidism
because of therapeutic overdose, either initially or during the maintenance period
are rare (See OVER DOSAGE)
Sign and symptoms-
Excessive doses of thyroid result in a hypermetabolic state resembling in every
respect the condition of endogenous origin. The condition may be self-induced.
Treatment of over dosage- Dosage should be reduced or therapy temporarily discontinued
if signs and symptoms of over dosage appear. Treatment may be re-instituted at
a lower dosage. In normal individuals, normal hypothalamic pituitary thyroid axis
functions is restored in 6 to 8 weeks after thyroid suppression. Treatment of
acute massive thyroid hormone over dosage is aimed at reducing gastro intestinal
absorption of the drugs and counteracting central and peripheral effects, mainly
those of increased sympathetic activity. Vomiting may be induced initially if
further gastro intestinal absorption can reasonably be prevented and barring contraindications
such as coma, convulsions. Or loss of the gagging reflex. Treatment is symptomatic
and supportive. Oxygen may be administered and ventilation maintained. Cardiac
glycosides may be indicated of congestive heart failure develops. Measures to
control fever, hypoglycemia or fluid loss should be instituted if needed. Anti
adrenergic agents, particularly propranolol, have been used advantageously in
the treatment of increased sympathetic activity. Propranolol may be administered
intravenously at a dosage of 1 to 3 mg over a 10 minute period or orally, 80 to
160 mg per day, initially especially when no contraindications exits for its use.
Other adjunctive measure may include administration of cholestyramine to interfere
with thyroxine absorption, and glucocorticoids to inhibit conversion of T4 or
DOSAGE AND ADMINISTRATION:
The dosage of thyroid hormones
is determined by the indication and must in every case be individualized according
to patient response and laboratory findings.
Thyroid hormones are given orally.
In acute, emergency conditions, injectable levothyroxine sodium (T4) may be given
intravenously when oral administration is not feasible or desirable, as in the
treatment of myxedema coma or during total parenteral nutrition. Intramuscular
administration is not advisable because of reported poor absorption.
Therapy is usually instituted using low doses the increments that depend on the
cardiovascular status of the patient. The usual starting dose is 30 mg with increments
of 15 mg every 2 to 3 weeks. A lower starting dosage, 15 mg per day is recommended
in patients with long standing myxedema, particularly if cardiovascular impairment
is suspected, in which case extreme caution is recommended. The appearance of
angina is an indication for a reduction in dosage. Most patients require 60 to
120 mg per day. Failure to respond to doses of 180 mg suggests lack of compliance
or malabsorption. Maintenance dosages 60 to 120 mg per day usually result in normal
serum T4 and T3 levels. Adequate therapy usually results in normal TSH and T4
levels after 2 to 3 weeks of therapy. Readjustment of thyroid hormone dosage should
be made within the first four weeks of therapy, after proper clinical and laboratory
evaluations, including serum levels of T4, bound and free and TSH. Liothyronine
may be used in preference to levothyroxine during radioisotope scanning procedures,
since induction of hypothyroidism in those cases is more abrupt and can be of
shorter duration. It may also be preferred when impairment of peripheral conversion
of levothyroxine and liothyronine is suspected.
Myxedema Coma: Myxedema coma
is usually precipitated in the hypothyroid patient of long standing by intercurrent
illness or drugs such as sedatives and anesthetics and should be considered a
medical emergency. Therapy should be directed at the correction of electrolyte
disturbances and possible infection besides the administration of thyroid hormones.
Corticosteroids should be administered routinely. (T4) and (T3) may be administered
via a nasogastric tube but the preferred route of administration of both hormones
is intravenous. Levothyroxine sodium (T4) is given at a starting dose of 400 mcg
(100 mcg / ml) given rapidly, and is usually well tolerated, even in the elderly.
This initial dose is followed by daily supplements of 100 to 200 mcg given IV.
Normal T4 levels are achieved in 24 hours followed in 3 days by threefold elevation
of T3. Oral therapy with thyroid hormone would be resumed as soon as the clinical
situation has been stabilized and the patient is able to take oral medication.
Thyroid Cancer: Exogenous thyroid hormone may produce regression of metastases
from follicular and papillary carcinoma of the thyroid and is used as ancillary
therapy of these conditions with radioactive iodine. TSH should be suppressed
to low or undetectable levels. Therefore, larger amounts of thyroid hormone that
those used for replacement therapy are required. Medullary carcinoma of the thyroid
is usually unresponsive to this therapy.
Pediatric Dosage: Pediatric dosage
should follow the recommendations. In infants with congenital hypothyroidism,
therapy with full doses should be instituted as soon as the diagnosis has been
Keep this and all
other medicines safely out of the reach of children.
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