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Hypothyroidism
CURRENT THERAPEUTIC CONCEPTS
Hypothyroidism by Eric T. Herfindal and Joseph L. Hirschman
F
rom the point of view of the pharmacist, it would appear that a great proportion of the American public is suffering from hypothyroidism. Sometimes it seems as if every other slightly overweight, middle-aged female who appears at our counter has a prescription for one of the thyroid preparations. The only proven therapeutic indications for thyroid hormones are for diagnosable thyroid deficiencies and as suppressants of TSH production by the anterior pituitary. Even so, these drugs continue to be prescribed for a number of conditions such as the "tired housewife syndrome," obesity, metabolic insufficiency and a number of gynecologic conditions. There is no convincing evidence that thyroid hormones have a clear indication in these cases. Because of the extensive use of these medications, it behooves the pharmacist to review this disease and become familiar with the proper use of thyroid hormones. Thyroid deficiency may range in severity from a mild hypothyroid state that is difficult to diagnose to a severe emergency state called myxedema coma. The severity of the disease depends upon the ability of the thyroid gland to produce and secrete the thyroid hormone and the age of the patient. The treatment of hypothyroidism is generally very satisfactory, especially if started early enough.
for thyroid synthesis. After ingestion, iodine is converted to iodide and absorbed. In the gland iodide is rapidly oxidized to iodine and bound to tyrosine to form monoiodotyrosine (MIT) which is next iodinated to form diiodotyrosine (DIT). Two DIT molecules then condensed to form T 4 • T 3 is formed by the condensation of MIT and DIT (Figure 1, see below). The two hormones are bound to a glycoprotein called thyroglobin. When they are secreted, the peptide bounds are hydrolysed and free hormone is released. However, neither the secretory process, nor the hormone synthesis can function without the cooperation of the pituitary. The anterior pituitary releases a hormone, thyrotropin (TSH) that stimulates the activity of the thyroid gland. When the anterior pituitary secretes TSH, iodine uptake is increased, hormone synthesis is increased and more hormone is secreted. Thyroglobulin synthesis is also increased. The pituitary responds to elevated thyroxine levels by decreasing the secretions of TSH. The dayto-day maintenance of thyroid secretion depends on a feed-back interplay between TSH and thyroxine. Prolonged TSH stimulation results in an enlargement of the thyroid (goiter). Thyrotropin releasing factor (TRF) mediates the release of TSH in the hypothalamus. The free thyroxine liberated by
the thyroid is bound to protein in the plasma. Normally about nine micrograms of thyroxine per hundred milliters of plasma is found bound to protein. This is in equilibrium with free thyroxine (0.004 micrograms per 100 ml) . Free thyroxine is the fraction that is physiologically active and also suppresses pituitary secretion of TSH. T 3 is bound to protein, but less strongly. The biological half life of T 4 is six to seven days, T 3 has a shorter half life, about two and a half days. The thyroid hormones are not essential to life, but in their absence there is poor resistance to cold, mental and physical slowing and, in children, mental retardation and dwarfism. Thyroid hormones stimulate the oxygen consumption of most cells of the body, help regulate lipid and carbohydrate metabolism and are necessary for normal growth and maturation. Most of the effects of T 3 and T 4 are related to their calorigenic action; in other words, the ability to increase oxygen consumption. This is reflected in the metabolic rate. When the metabolic rate is increased, weight is lost if food intake is not increased. This weight loss is due to breakdown of fat and protein stores. The thyroid hormones also effect1. Heat production. Thyroid secretion is increased in a cold environment. Large doses of thyroid can cause an increase in body tempera-
Normal Function
The thyroid gland is a highly vascular organ weighing 20-25 grams in the average adult. It has one of the highest rates of blood flow of any organ in the body. The gland consists of two lobes connected by the thyroid isthmus and is made up of follicles containing a proteinaceous material called colloid. The two principle hormones secreted by the thyroid, thyroxine (T4 ) and triiodothyronine (T3 ) are synthesized in the colloid. Iodine is an essential raw material
FIGURE
1
Biosynthesis of Thyroid Hormones Tyrosine Iodine
.j. Monoiodotyrosine (MIT)
+ Diiodotyrosine (DIT) --+Triiodothyronine (T,)
Iodine
.j. Diiodotyrosine (DIT)
+ Diiodotyrosine (DIT) --+Thyronine (T,) Vol. NS11, No. 9, September 1971
493
ture. Hypothyroid patients tend to have subnormal body temperatures. 2. Cardiac output. Pulse pressure and cardiac output is increased due to the effects of thyroid and catecholamines on the heart. 3. Vitamin absorption and requirements. In the absence of thyroid, Vitamin B12 absorption is reduced which may lead to an anemia associated with decreased bone marrow metabolism. In thyrotoxicosis, vitamin requirements are increased due to higher metabolic rate. Thyroid is required for the liver conversion of carotenes to vitamin A. Carotenemia with yellowing of the skin may be seen in hypothyroidism. 4. Milk secretion. Milk secretion is decreased in hypothyroidism. 5. Nervous system. Lack of thyroid hormone produces slowing of mentation. The effect of thyroid may be due to the increased sensitivity of the brain to catecholamines. In infants, lack of thyroid seriously retards the development of the nervous system. The peripheral nervous system is also affected by thyroid hormone. Reaction time of reflexes is faster in hyperthyroid and slower in hypothyroid patients. 6. Carbohydrate metabolism. Thyroid increases carbohydrate absorption from the GI tract resulting in a transient hyperglycemia and glycosuria after meals. 7. Cholesterol metabolism. Thyroid stimulates cholesterol synthesis but it also stimulates removal of cholesterol from the circulation by the liver. The rate of removal is greater than the increase in synthesis, so a net reduction in serum cholesterol is seen. The d-form of T 4 has little "thyroid" effect but still retains the ability to reduce cholesterol. 8. Action of catecholamines. Thyroid potentiates the effect of norepinephrine and epinephrine by an unknown mechanism. Catecholamine secretion is usually normal in hyperthyroidism, but the increased cardiovascular effects, tremulousness and sweating can be blocked by catecholamine depleters such as reserpine or guanethidine. 9. Growth and development. Thyroid hormone potentiates the effect of growth hormone. In the absence of thyroid, the secretion of growth hormone by the pituitary is decreased.
Etiology A lack of the appropriate amounts of thyroid hormone may be due to a number of causes. The Committee on N~menclature of the American Thyr~Id Association lists the following ?Iseases as being primarily characterIzed by hypothyroidism!. Idiopathic myxedema 2. Cretinism (a) endemic (b) congenital goitrous 494
Eric T. Herfindal, PharmD, has been assistant clinical professor of pharmacy at the University of California school of pharmacy at San Francisco since 1968 and this year was also appointed assistant director of pharmaceutical services there. After earning his PharmD in 1965 from the University of California school of pharmacy, San Francisco, Dr. Herfindal practiced community pharmacy for two years until he became a member of the clinical pharmacy staff at the University of California Hospitals, San Francisco. He is a member of APhA, ASHP and the California Pharmaceutical Association.
Joseph L. Hirschman, PharmD, is an assistant clinic_al professor of pharmacy at the school of pharmacy, University of California at San Francisco. He has also served as supervisor of the Drug Information Analysis Service since 1968. Dr. Hirschman earned his PharmD in 1965 from the University of California school of pharmacy and has had experience as a community pharmacist. From 1966 to 1968 he served on the clinical pharmacy staff of the U niversity of California Hospitals in San Francisco. Among his memberships are APhA, ASHP, California Pharmaceutical Association and Peninsula Pharmaceutical Society.
3. Thyrotropin (TSH) deficiency (a) isolated (b) panhypopituitary 4. Thyrotropin releasing factor (TRF) deficiency due to hypothalamic injury or disease 5. Thyroid destruction (a) post-operative (b) post-radioiodine (c) post X-ray 6. Congenital aplasia
No matter what the etiology of the deficiency, the manifestations of the disease are relatively constant depending on the age of the patient and degree of deficiency. Thyroid deficiency in fetal or neonatal life is manifested in the condition of cretinism. The cause of the lack of hormone may be1. Endemic-lack of iodine in the diet 2. Congenital (a) failure of the gland to develop (b) defective hormone secretion (c) failure of gland to synthesize hormone (d) maternal ingestion of goitrogenic substances
In a majority of cases the cause of primary myxedema, (not due to pituitary insufficiency), is not known. There is some reason to believe that in most cases, the destruction of the thyroid is due to auto-immune mechanisms. However, hypothyroidism may result as a complication of thyroidectomy, the use of radioactive iodine or the exposure of the patient to goitrogenic substances. The thiocarbamides (methimazole and propylthiouracil) block the oxidation of iodide to iodine and are used
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Beclinically in hyperthyroidism. cause they block thyroid activity, they are referred to as goitrogens (Table I, A number of other see below). substances also block thyroid activity by different mechanisms. Anions such as sodium and potassium perchlorate are potent goitrogens but are too toxic to use therapeutically. Administration of agents such as paraaminobenzoic acid and sulfonamides have also been reported to produce decreased thyroid activity in rare cases. In addition to the antithyroid drugs, certain vegetables such as rutabagas, cabbage and turnips have antithyroid activity. Large amounts ingested daily over a long period of time are necessary to produce any significant degree of hypothyroidism. Secondary hypothyroidism is due to a disorder of the pituitary gland. As such, concomitant disorders of the adrenals and gonads are also seen. TABLE I
Goitrogenic Substances Thiocar bamides Methimazole Propylthiouracil Iodides Radioiodine Anions Thiocyanates (SCN-) Perchlorates (ClQ4-) Nitrates (NOa-) Vegetables Turnips Rutabagas Cabbage Miscellaneous Agents Para-aminobenzoic acid Sulfonamides
Signs and Symptoms, Cretinism The failure to feed properly may be the first sign of cretinism. This may be observed as early as four weeks after birth. In addition, a swollen tongue, dry, yellow, cold skin, a "pot belly" with umbilical hernia, hyporeflexia and constipation may be seen. Later, delayed skeletal maturation, mental retardation, hoarseness, a round face and dark brittle hair may also be observed. If thyroid therapy is not initiated immediately upon diagnosis, irreversible mental retardation may result.
Signs and Symptoms, Myxedema Early in the course of adult myxedema, signs and symptoms may be few or absent. If symptoms are present, they are likely to be lethargy, menstrual disturbances, weakness, fatigue, headache, cold intolerance, nervousness, thinning, course hair, brittle nails and delayed deep tendon reflexes. Later, slow speech, weight gain, constipation, anginal pain, absence of sweating and deafness may be seen. The pulse is slow and regular and elevated blood pressure may be seen in elderly patients. The circulation time is slow and anemia may be present. Myxedema coma is an emergency condition that must be treated vigorously. This is a condition that is mostly seen in elderly patients, characterized by a sudden onset of coma associated with seizures. Normally these are patients with a long history of myxedema. The emergency can be precipitated by a number of factors such as infection, drug overdose, myocardial infarction, hypoglycemia and congestive heart failure (CHF).
Laboratory Findings There are a number of laboratory tests available with which to measure thyroid activity. These tests are based on the physiologic and chemical characteristics of the thyroid hormone. Basal Metabolic Rate (BMR). This test is based on the ability of the thyroid to stimulate oxygen consumption. The basal metabolic rate is the lowest level of energy production compatible with life. In clinical practice, this is measured by the oxygen consumption of the patient for a certain period of time under basal conditions. The value obtained is corrected to standard conditions of temperature and barometric pressure. The normal BMR for an individual of the patient's age and sex is obtained from standard tables. The patient's actual rate is expressed as a plus or minus percentage of the normal. A number of factors will elevate the BMR-fever, congestive failure, emphysema, asthma, pheochromocytoma, malig-
GLOSSARY Aplasia-Congenital absence of an organ Autoii!Jmune-A disordered immune reaction directed against a constituent of a pat1ent's own body Catecho_lamines-Amines (n_orepinephrine, epinephrine and isoproterenol) that act directly on sy:mpathetlc effectors Colloid-The proteinaceous material found in the thyroid follicle that contains the thyroid hormones Cretinism-Myxedema due to congenital thyroid deficiency or thyroid lack in early childhood Endemic-The continuing prevalence of a disease in a certain geographical area Euthyroid-A condition of having a thyroid gland with normal function Goiter-Chronic enlargement of the thyroid gland Goitrogenic-Causing goiter Hyporeflexia-A condition in which the reflexes are weakened Idiopathic-Denoting a disease of unknown cause Myxedema-Advanced deficiency of thyroid hormone Panhypopituitary-A universal deficiency of function of the pituitary gland Pheochromocytoma-A tumor characterized by the secretion of adrenal medullary hormones such as norepinephrine Thyroglobulin-The glycoprotein found in thyroid colloid that binds the thyroid hormones Thyrotoxicosis-Poisoning by an excess of thyroid hormone from the gland or exogenous sources Thyrotropin-Thyroid-stimulating hormone (TSH) produced by the anterior pituitary
nant lymphoma, infections and thyroid hormone. A BMR of -15 to +10 percent is considered normal. In hypothyroidism, the BMR may be -30 to -60 percent. Malnutrition and Addison's disease may also cause a lowering of the BMR. Protein Bound Iodine (PBI). This test is based on the measurement of total iodine bound to serum protein. It measures mainly T 4 since T 3 is poorly bound to plasma protein. In normal (euthyroid) patients, the concentration is between four and eight micrograms per 100 mi. In hyperthyroidism, the value is elevated and in hypothyroidism it is lowered. The total amount of protein bound iodine depends on the concentration of thyroxin binding globulin (TBG) and any conditions that elevate the TBG would tend to interfere with the PBI. A number of drugs may displace the iodine on the TBG and thus interfere with this test (Table II, see page 496). Butanol Extractable Iodine (BEl). This test parallels the PBI but is not effected by inorganic iodides bound to the protein. However, it is raised by organic iodides such as radio-opaque dyes. Euthyroid levels range from 2.9 to 6.4 micrograms per 100 mi. Radioactive Iodine Uptake (RAIU). An oral dose of J131 is taken and the uptake by the thyroid gland is measured. Euthyroid levels are 15-45 percent uptake in 24 hours. Higher levels of uptake indicate hyperthyroidism and lowering of the RAIU is indicative of myxedema. Triiodothyronine Uptake (TB Uptake). These tests measure the satura-
tion of protein binding sites. Radioactive T 3 is added to serum in the presence of a standard quantity of resin (or red blood cells) capable of binding T 3 . If the thyroid hormone binding sites on TBG are saturated with endogenous T 3 and T 4 , the radioactive T 3 added to the serum will be bound preferentially by the resin and the uptake will be higher indicating hyperthyroidism. Conversely, when the TBG sites are unsaturated the uptake will be low indicating myxedema. This test is not affected by exogenous organic or inorganic iodides. However, any condition that alters the TBG in the serum will modify the results. Conditions such as pregnancy, hepatitis, acidosis, renal disease and pulmonary insufficiency will alter the amount of binding sites available. Serum Thyroxin (Serum T 4). This test measures the displacement of radioactive T 4 by serum T 4 from a protein mixture containing TBG. It is not influenced by iodine but it is atlered by changes in serum TBG. Serum Free Thyroxine (Free T 4 ). This measures only the metabolically active (free) hormone using dialysis techniques. Thyroid Suppression Test. This test is based upon the feed-back mechanism of thyroid homeostasis described earlier. When daily oral doses of T 3 (100 micrograms) are given for a period of seven days, the thyroid activity as measured by Jl3 1 uptake should be suppressed in a normal patient. This test is mainly used in the diagnosis of hyperthyroid states, where suppression is not achieved. Vol. NSll. No. 9, September 1971
495
TABLE II
Effects of Various Conditions and Drugs on Thyroid Function Tests
AntiInorganic Organic thyroid Iodides , Iodides Drugs
t
PBI -
BEl
~
RAIU -
Ta Uptake
t t
~
~
~
Androgens, DiphenylPreg- hydannancy, to in, Estro- Salicylgens ates
t t
~
~
t t
t t
-
-
-
~
~
~
t t t
t t t
t
~
~
t
~
t
~
~
t
-
-
FreeT,
-
-
~
Thyrotropin Stimulation Test (TSH stimulation). Five to ten units of thyrotropin, USP is given intramuscularly and the thyroid activity as measured by PBI or pa1 uptake is determined. This test can differentiate primary thyroid deficiency from secondary pituitary dysfunction. Nonspecific tests such as serum cholesterol, glucose tolerance, 17-ketosteroids and serum triglycerides are also useful in diagnosing hypothyroidism.
Treatment The treatment of hypothyroidism (Table III, see below) is generally effectively carried out by the careful
Thyroid Sodium Sodium lioUSP, levothyroThyrothyrnine globulin oxine (T,) (Ta) Liotrix
~
-
Serum T,
Hormone replacement therapy with
-
-
administration of thyroid hormone. All of the commercially available preparations of thyroid hormone are effective. However, there are a number of qualities of each drug that should be considered before a selection is made. Thyroid USP. Dessicated thyroid is made from the dried and defatted thyroid glands of slaughtered cows and pigs. This preparation is standardized only with respect to iodine content. Since no requirements are made as to thyroxine or triiodothyronine, the ratio of hormones and the total amount of hormones may vary. However, with very few exceptions, this preparation has been shown to be satisfactorily uni-
form in potency. However, the preparation may deteriorate under poor storage conditions and produce unsatisfactory results. Absorption of thyroid hormone is generally good, although variations in totaL amounts absorbed have been reported. Entericcoated preparations produce more variation in response than compressed tablets. Because thyroid USP contains both T 4 and T 3 , the PBI can be monitored and produce euthyroid levels when the patient has achieved a normal metabolic rate. The other laboratory tests also produce predictable levels. Because of its low price, thyroid USP remains the most heavily prescribed thyroid preparation. Thyroglobulin (Proloid). This drug consists of the partly purified, denatured thyroglobulin derived from slaughtered pigs. In addition to being standardized by iodine content, thyroglobulin is also bioassayed. Thyroglobulin has no apparent advantages over thyroid, USP, and is slightly more expensive. Sodium levothyroxine, USP (Synthroid, Letter) . Sodium levothyroxine is the sodium salt of synthetic Lthyroxine (T4 ). As such, the amount of hormone present is certain. Because it contains no T 3 , this preparation has the tendency of producing higher than normal euthyroid PBI levels when normal metabolic activity is estabLished. This is no real disadvantage if the physician is cognizant
TABLE III
Available Thyroid Preparations Dose to maintain norm BMR (euthyroid)
Drug
Route
Preparation
t '/•
(bioi)
Peak
Euthyroid PBI meg/ Dura- 100 Standardtion ml ized
Advantages
Disadvantages
Thyroid, USP
6D-240 mg P.O. av = 120 mg
Ta+ T, (cow and pig)
Thyroglobulin (Proloid)
6Q-240 mg P.O. av = 120 mg
Purified 1-3 6-7 thyroglob days weeks ulin (Pig)
Sodium Levothyroxine USP (Synthroid) (Letter)
0.1-0.4 mg P.O. Synthetic T, av=0.2mg I.V
1-3 6-7 days weeks
7- 10 Chroma to3 graphic weeks assay
Long-acting Can monitor T , Known potency
Slow excretion: disadvantage in toxicity Expensive
Sodium Liothyronine USP (Cytomel)
0.025-0.1 mg P.O. av = 0.05 mg
Synthetic Ta
24-72 2.5 days hours
5-6 days
1- 2 Chroma tographic assay
Good absorption Rapid onset Known potency
Difficult to monitor by lab tests Expensive Short duration: divided dosage
Liotrix (Euthroid) (Thyrolar)
"l"-''4" av = "2"
Synthetic 6-7 1-3 T, and Ta days weeks ratio 4 : I
Chromatographic assay
Known potency Known ratio of T, to Ta Can monitor T,
Expensive
496
Journal of
P.O.
6-7 1-3 days weeks
the AMERICAN PHARMACEUTICAL ASSOCIATION
3 4- 8 Iodine content weeks (0.170 . 23 %) 3 4-8 weeks
3 4-8 weeks
Inexpensive Can monitor T, Has T a + T,
Variations in lots Poorly standardized What is T,fTa ratio? Deterioration on storage
Relatively inexpensive Variable TafT , Iodine ratio Can monitor T , content, bioassay, Has Ta and T, chroma tographic assay
of this fact. The absorption of the drug is varied, and 4D-50 percent has been recovered from the stool. The preparation is also available for intravenous administration. Sodium liothyronine ( Cytomel). Sodium Iiothyronine is the sodium salt of synthetic L-triiodothyronine (T3 ). It is thus a pure form of T 3 that has been chromatographically assayed. The major advantage and disadvantage of this drug is its relatively short half life and rapid onset of activity. In emergency conditions (myxedema coma) where a rapid onset is mandatory, sodium liothyronine is the drug of choice. It is not commercially avaiLable in intravenous form, but many physicians consider it the drug of choice in myxedema coma. There are few indications for the use of this drug on a chronic basis. Because of its short half life it should be given three times a day. In rare cases where relatively rapid abatement of action (severe angina, CHF) may be desired, this drug could be used for maintenance. Because T 3 is poorly bound to serum protein, the PBI levels are barely raised from hypothyroid levels. Liotrix (Euthroid, Thyrolar). Liotrix is a four to one mixture of the sodium salts of T 4 and T 3 • Even though the two commercialLy available preparations vary slightly in composition, they are clinically equivalent. The major advantage of liotrix is that the two hormones are present in a uniform ratio and of known strength. As with thyroid, USP and thyroglobulin, PBI levels are in the euthyroid range when a normal metabolic rate has been achieved. Because of its higher cost this preparation should generalLy be reserved until the less expensive natural preparations have been shown to produce erratic results in a particular patient. Toxicity. The toxicity of thyroid hormones mimics hyperthyroidism. One can expect to see hyperirritability, nervousness, insomnia, tachycardia, cardiac arrhythmias, angina pectoris, intolerance to heat, increased pulse and blood pressures, diarrhea, cramps, weight loss, vomiting and tremors. In children, accelerated rate of bone maturation is an early manifestation of toxicity. At the earliest sign of toxicity, the drug should be discontinued for two to six days in the case of thyroid, thyroglobulin and sodium levothyroxine and two to three days in the case of sodium liothyronine. The drug should be restarted at a lower dose following abatement of toxicity. Therapy, Cretinism Immediately upon diagnosis of hypothyroidism, thyroid replacement therapy should be initiated. The drug
of choice is either thyroid, USP or equivalent doses of liotrix. Sodium levothyroxine and sodium liothyronine will give unpredictable PBI levels, making monitoring difficult. The more myxedematous infants are more sensitive to the action of thyroid hormone, necessitating the initiation of treatment with very small doses and followed by gradual dose increases. An initial dose of 30 mg per day is the starting dose, increased by 15 mg a day every three weeks. The maintenance dose should not be less than 60 mg a day of thyroid or equivalent. (Table IV, see at right). A one-year old usually will require 90 mg a day. Three-year old children will require 90 to 120 mg per day; five-year-old children, 120 to 150 mg, ten-year old children 150 to 180 mg. Older patients require proportionally higher doses, up to 240 mg per day of thyroid or equivalent. Treatment must be continued for life. Therapy, Myxedema The drug of choice in myxedema depends on a number of factors1. Patient's age 2. Severity and duration of disease 3. Presence of other disease such as congestive heart failure, angina or diabetes. Generally, older patients with severe myxedema and concomitant heart disease must be started with small doses of thyroid-8--'15 mg for one week and increased by 15 mg every week up to 120 to 180 mg. The dose is increased until the clinical signs of the disease have disappeared or signs of toxicity appear. The laboratory findings should reflect a euthyroid state. Younger patients can generally tolerate higher initial doses; 30 mg for one week, then increased by 30 mg every week until euthyroid levels are reached. In post-radio-iodine, postthyroidectomy and post x-ray hypothyroidism maintenance levels can be reached sooner than in long-standing myxedema. The more severe the deficiency, the more sensitive is the patient to the effect of thyroid hormone. Although some patients may require more than 300 mg of thyroid or equivalent per day, most patients become euthyroid below this level. Because of this, the diagnosis of hypothyroidism is questionable in patients receiving massive doses of thyroid. In patients with severe angina or congestive heart failure, the use of sodium liothyronine should be considered. If toxicity symptoms appear, the effect can be terminated relatively rapidly due to the drug's short half life. Increments of five meg are generally employed. As stated before,
TABLE IV
Equivalent Doses of Thyroid Preparations Thyroid, USP Thyroglobulin Sodium levothyroxine, USP Sodium liothyronine, USP Liotrix
60mg 60 mg 0.1 mg 25 meg "1"
PBI is not a reliable indicator with this drug. Myxedema coma is an emergency condition requiring the use of intravenous sodium levothyroxine 20D-500 meg. This dose may be repeated in 24 hours. Some physicians prefer sodium liothyronine 1D-20 meg intravenously every eight hours (not available commercially). Prolonged hypothyroidism leads to adrenocortical depression, so hydrocortisone should be given in doses of 100 mg intravenously every eight hours until the crisis is over. In addition, precipitating factors such as infection, drug overdose, myocardial infarction, hyponatremia, hypoglycemia and congestive heart failure should be treated immediately. Care must be taken to avoid overhydration, which can worsen the hyponatremia. The patient should be warmed, but too rapid correction of the hypothermia may lead to peripheral vasodilatation and worsening of the shock. Myxedematous patients metabolize drugs very slowly and are thus very sensitive to overdosages. Sedatives and opiates must be used with caution since normal doses may produce signs of overdosage. Signs of Cushing's syndrome have been produced in hypothyroid patients with relatively low doses of corticosteroids. Patients requiring digitalis may require lower maintenance doses than euthyroid patients. Thyroid hormones may potentiate the action of oral anticoagulants, and the dose may have to be adjusted when thyroid therapy is initiated. The initiation of thyroid therapy in diabetic patients is usually accompanied by an increased requirement of insulin or oral hypoglycemics. This is due to the enhanced carbohydrate absorption produced by thyroid hormones. Prognosis, Cretinism Even with early treatment, the chances of a congenital cretin reaching full mental development is poor. However, full skeletal and sexual maturation may be achieved with optimal thyroid therapy. Prognosis, Myxedema Hypothyroidism of later onset generally responds excellently to thyroid (continued on page 508) Vol. NSll. No. 9, September 1971
497
Women's Auxiliary
Attracting and Keeping Members "Consider yourself at home, consider yourself one of the family . . .. consider yourself one of us .. ." sings the Artful Dodger in the Broadway musical "Oliver." This is just exactly what we would like to say to each of you who has an interest in pharmacy. In September, many auxiliaries start up again after a summer hiatus. The problem of how to attract new members, and then how to keep these members, is much discussed. The following suggestions for growing were compiled by Mrs. John Foley for the Auxiliary Handbook.
I. Growing in numbers. A. Develop a membership campaign each year. 1. Study the potential in your area. 2. Enlist the cooperation of your local pharmaceutical association in supplying the names of its members. 3. Put on your own "thinking cap" and suggest the names of women eligible for membership. 4. Plan a membership event (tea, luncheon) at which you entertain prospective members-with strictly ulterior motives. · Do follow the written invitation with a personal invitation, or 5. Use the individual approach in an organized way by inviting personally one or more prospective members as your guests at each meeting. Do follow this with a personal invitation from the membership chairman to join the auxiliary (and a letter of welcome from the president when she does). B. Give some thought to the care and treatment of prospective members. 1. Introduce them to as many members as possible. 2. Make them feel welcome and special. 3. Tell them something about the Auxiliary, its purposes and accomplishments. 4. Give them something tangible to take home (besides the
Hypothyroidism (continued from page 497)
therapy. Improvement can be very striking with early treatment and can be maintained indefinitely with continued therapy. Relapses will occur if treatment is interrupted. Myxedema coma has a high mortality rate, but with prompt recognition of the cause and the immediate initiation of appropriate therapy a significant number of patients survive. Conclusion Hypothyroidism is a relatively easy 508
door prize! )-a copy of your news bulletin, a reprint of the Auxiliary news in the APhA Journal. C . Make that new member into a real member. 1. 1, 2, 3 under B. 2. Include her in the group-and let her get a word in edgewise. 3. Have an orientation meeting at which you tell (as ingeniously as possible) about the history and the work of the Auxiliary. 4. Honor new members and tell something about their background and special interests. . 5. Bring your new member into active participation by letting her work with someone else on some job, however tiny. Recognize what she does! 6. Make sure that new members are called between meetings and make sure that she is called before the next four or five meetings. Give her a chance to establish the "attendance habit." D. Examine your conscience when a member "drops out." 1. Did you make the effort to find out why? 2. Did she really feel that she "belonged"? 3. What happened at the meetings she attended? Was she bored? Ignored? Given a chance to participate? 4. Did she really feel that she was important to the Auxiliary and the Auxiliary important to pharmacy? 5. Did she have special problems related to attendance? Try to keep her an interested, if inactive member. II. Growing in interest and enthusiasm. A . Be sure "everybody knows everybody." B. Remember "it pays to adverti~e"-even your own meetings. C. Heed the adage, "Variety is the mother of enjoyment." D. Beware of the comment, "I thought the business meeting would never end." Helen I. Lowe 3105 Silverleaf Dr. Austin, TX 78757
disease to diagnose. A large number of specific laboratory tests are available to substantiate cLinical findings. However, these tests may be altered by a number of disease states and drugs. Subtle differences between the available thyroid preparations make the selection of the proper drug important. Myxedematous patients have altered metabolism of drugs such as digitalis, narcotics, hypnotics and corticosteroids. The initiation of thyroid therapy may alter the patient's requirements of oral hypoglycemics, insulin and anticoagulants. By being aware of all these factors and conveying his knowledge to the physician
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
and the patient, the pharmacist can play an important role in the rational therapy of hypothyroidism. • Recommended Reading 1. Bakke, J. L., and Klotz, L. J,, "Treatment of Hypothyroidism With Synthetic Thyroid Hormones," Northwest. Med. 68, 651 (July 1969) . 2. Alley, R. A.; Danowski, T. S.; Robbins, T. J. L.; Weir, T. F.: Sebeh, G., and Moses, C. L ., "Indices During Administration of T • and T a to Euthyroid Adults," Metabolism, 17, 97 (Feh. 1968) ·· 3. Levy, P. L., and Marshall, J. S., "ShortTerm Drug Effects on Thyroid Function Tests," Arch. Int. Med. 114, 413 (Sept. 1964) 4 Davis, P. J, "Factors Affecting the Determination of the Serum Protein-Bound Iodine," Amer. ]. of Med., 40, 918 (June 1966)
Hypothyroidism by Eric T. Herfindal and Joseph L. Hirschman
F
rom the point of view of the pharmacist, it would appear that a great proportion of the American public is suffering from hypothyroidism. Sometimes it seems as if every other slightly overweight, middle-aged female who appears at our counter has a prescription for one of the thyroid preparations. The only proven therapeutic indications for thyroid hormones are for diagnosable thyroid deficiencies and as suppressants of TSH production by the anterior pituitary. Even so, these drugs continue to be prescribed for a number of conditions such as the "tired housewife syndrome," obesity, metabolic insufficiency and a number of gynecologic conditions. There is no convincing evidence that thyroid hormones have a clear indication in these cases. Because of the extensive use of these medications, it behooves the pharmacist to review this disease and become familiar with the proper use of thyroid hormones. Thyroid deficiency may range in severity from a mild hypothyroid state that is difficult to diagnose to a severe emergency state called myxedema coma. The severity of the disease depends upon the ability of the thyroid gland to produce and secrete the thyroid hormone and the age of the patient. The treatment of hypothyroidism is generally very satisfactory, especially if started early enough.
for thyroid synthesis. After ingestion, iodine is converted to iodide and absorbed. In the gland iodide is rapidly oxidized to iodine and bound to tyrosine to form monoiodotyrosine (MIT) which is next iodinated to form diiodotyrosine (DIT). Two DIT molecules then condensed to form T 4 • T 3 is formed by the condensation of MIT and DIT (Figure 1, see below). The two hormones are bound to a glycoprotein called thyroglobin. When they are secreted, the peptide bounds are hydrolysed and free hormone is released. However, neither the secretory process, nor the hormone synthesis can function without the cooperation of the pituitary. The anterior pituitary releases a hormone, thyrotropin (TSH) that stimulates the activity of the thyroid gland. When the anterior pituitary secretes TSH, iodine uptake is increased, hormone synthesis is increased and more hormone is secreted. Thyroglobulin synthesis is also increased. The pituitary responds to elevated thyroxine levels by decreasing the secretions of TSH. The dayto-day maintenance of thyroid secretion depends on a feed-back interplay between TSH and thyroxine. Prolonged TSH stimulation results in an enlargement of the thyroid (goiter). Thyrotropin releasing factor (TRF) mediates the release of TSH in the hypothalamus. The free thyroxine liberated by
the thyroid is bound to protein in the plasma. Normally about nine micrograms of thyroxine per hundred milliters of plasma is found bound to protein. This is in equilibrium with free thyroxine (0.004 micrograms per 100 ml) . Free thyroxine is the fraction that is physiologically active and also suppresses pituitary secretion of TSH. T 3 is bound to protein, but less strongly. The biological half life of T 4 is six to seven days, T 3 has a shorter half life, about two and a half days. The thyroid hormones are not essential to life, but in their absence there is poor resistance to cold, mental and physical slowing and, in children, mental retardation and dwarfism. Thyroid hormones stimulate the oxygen consumption of most cells of the body, help regulate lipid and carbohydrate metabolism and are necessary for normal growth and maturation. Most of the effects of T 3 and T 4 are related to their calorigenic action; in other words, the ability to increase oxygen consumption. This is reflected in the metabolic rate. When the metabolic rate is increased, weight is lost if food intake is not increased. This weight loss is due to breakdown of fat and protein stores. The thyroid hormones also effect1. Heat production. Thyroid secretion is increased in a cold environment. Large doses of thyroid can cause an increase in body tempera-
Normal Function
The thyroid gland is a highly vascular organ weighing 20-25 grams in the average adult. It has one of the highest rates of blood flow of any organ in the body. The gland consists of two lobes connected by the thyroid isthmus and is made up of follicles containing a proteinaceous material called colloid. The two principle hormones secreted by the thyroid, thyroxine (T4 ) and triiodothyronine (T3 ) are synthesized in the colloid. Iodine is an essential raw material
FIGURE
1
Biosynthesis of Thyroid Hormones Tyrosine Iodine
.j. Monoiodotyrosine (MIT)
+ Diiodotyrosine (DIT) --+Triiodothyronine (T,)
Iodine
.j. Diiodotyrosine (DIT)
+ Diiodotyrosine (DIT) --+Thyronine (T,) Vol. NS11, No. 9, September 1971
493
ture. Hypothyroid patients tend to have subnormal body temperatures. 2. Cardiac output. Pulse pressure and cardiac output is increased due to the effects of thyroid and catecholamines on the heart. 3. Vitamin absorption and requirements. In the absence of thyroid, Vitamin B12 absorption is reduced which may lead to an anemia associated with decreased bone marrow metabolism. In thyrotoxicosis, vitamin requirements are increased due to higher metabolic rate. Thyroid is required for the liver conversion of carotenes to vitamin A. Carotenemia with yellowing of the skin may be seen in hypothyroidism. 4. Milk secretion. Milk secretion is decreased in hypothyroidism. 5. Nervous system. Lack of thyroid hormone produces slowing of mentation. The effect of thyroid may be due to the increased sensitivity of the brain to catecholamines. In infants, lack of thyroid seriously retards the development of the nervous system. The peripheral nervous system is also affected by thyroid hormone. Reaction time of reflexes is faster in hyperthyroid and slower in hypothyroid patients. 6. Carbohydrate metabolism. Thyroid increases carbohydrate absorption from the GI tract resulting in a transient hyperglycemia and glycosuria after meals. 7. Cholesterol metabolism. Thyroid stimulates cholesterol synthesis but it also stimulates removal of cholesterol from the circulation by the liver. The rate of removal is greater than the increase in synthesis, so a net reduction in serum cholesterol is seen. The d-form of T 4 has little "thyroid" effect but still retains the ability to reduce cholesterol. 8. Action of catecholamines. Thyroid potentiates the effect of norepinephrine and epinephrine by an unknown mechanism. Catecholamine secretion is usually normal in hyperthyroidism, but the increased cardiovascular effects, tremulousness and sweating can be blocked by catecholamine depleters such as reserpine or guanethidine. 9. Growth and development. Thyroid hormone potentiates the effect of growth hormone. In the absence of thyroid, the secretion of growth hormone by the pituitary is decreased.
Etiology A lack of the appropriate amounts of thyroid hormone may be due to a number of causes. The Committee on N~menclature of the American Thyr~Id Association lists the following ?Iseases as being primarily characterIzed by hypothyroidism!. Idiopathic myxedema 2. Cretinism (a) endemic (b) congenital goitrous 494
Eric T. Herfindal, PharmD, has been assistant clinical professor of pharmacy at the University of California school of pharmacy at San Francisco since 1968 and this year was also appointed assistant director of pharmaceutical services there. After earning his PharmD in 1965 from the University of California school of pharmacy, San Francisco, Dr. Herfindal practiced community pharmacy for two years until he became a member of the clinical pharmacy staff at the University of California Hospitals, San Francisco. He is a member of APhA, ASHP and the California Pharmaceutical Association.
Joseph L. Hirschman, PharmD, is an assistant clinic_al professor of pharmacy at the school of pharmacy, University of California at San Francisco. He has also served as supervisor of the Drug Information Analysis Service since 1968. Dr. Hirschman earned his PharmD in 1965 from the University of California school of pharmacy and has had experience as a community pharmacist. From 1966 to 1968 he served on the clinical pharmacy staff of the U niversity of California Hospitals in San Francisco. Among his memberships are APhA, ASHP, California Pharmaceutical Association and Peninsula Pharmaceutical Society.
3. Thyrotropin (TSH) deficiency (a) isolated (b) panhypopituitary 4. Thyrotropin releasing factor (TRF) deficiency due to hypothalamic injury or disease 5. Thyroid destruction (a) post-operative (b) post-radioiodine (c) post X-ray 6. Congenital aplasia
No matter what the etiology of the deficiency, the manifestations of the disease are relatively constant depending on the age of the patient and degree of deficiency. Thyroid deficiency in fetal or neonatal life is manifested in the condition of cretinism. The cause of the lack of hormone may be1. Endemic-lack of iodine in the diet 2. Congenital (a) failure of the gland to develop (b) defective hormone secretion (c) failure of gland to synthesize hormone (d) maternal ingestion of goitrogenic substances
In a majority of cases the cause of primary myxedema, (not due to pituitary insufficiency), is not known. There is some reason to believe that in most cases, the destruction of the thyroid is due to auto-immune mechanisms. However, hypothyroidism may result as a complication of thyroidectomy, the use of radioactive iodine or the exposure of the patient to goitrogenic substances. The thiocarbamides (methimazole and propylthiouracil) block the oxidation of iodide to iodine and are used
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
Beclinically in hyperthyroidism. cause they block thyroid activity, they are referred to as goitrogens (Table I, A number of other see below). substances also block thyroid activity by different mechanisms. Anions such as sodium and potassium perchlorate are potent goitrogens but are too toxic to use therapeutically. Administration of agents such as paraaminobenzoic acid and sulfonamides have also been reported to produce decreased thyroid activity in rare cases. In addition to the antithyroid drugs, certain vegetables such as rutabagas, cabbage and turnips have antithyroid activity. Large amounts ingested daily over a long period of time are necessary to produce any significant degree of hypothyroidism. Secondary hypothyroidism is due to a disorder of the pituitary gland. As such, concomitant disorders of the adrenals and gonads are also seen. TABLE I
Goitrogenic Substances Thiocar bamides Methimazole Propylthiouracil Iodides Radioiodine Anions Thiocyanates (SCN-) Perchlorates (ClQ4-) Nitrates (NOa-) Vegetables Turnips Rutabagas Cabbage Miscellaneous Agents Para-aminobenzoic acid Sulfonamides
Signs and Symptoms, Cretinism The failure to feed properly may be the first sign of cretinism. This may be observed as early as four weeks after birth. In addition, a swollen tongue, dry, yellow, cold skin, a "pot belly" with umbilical hernia, hyporeflexia and constipation may be seen. Later, delayed skeletal maturation, mental retardation, hoarseness, a round face and dark brittle hair may also be observed. If thyroid therapy is not initiated immediately upon diagnosis, irreversible mental retardation may result.
Signs and Symptoms, Myxedema Early in the course of adult myxedema, signs and symptoms may be few or absent. If symptoms are present, they are likely to be lethargy, menstrual disturbances, weakness, fatigue, headache, cold intolerance, nervousness, thinning, course hair, brittle nails and delayed deep tendon reflexes. Later, slow speech, weight gain, constipation, anginal pain, absence of sweating and deafness may be seen. The pulse is slow and regular and elevated blood pressure may be seen in elderly patients. The circulation time is slow and anemia may be present. Myxedema coma is an emergency condition that must be treated vigorously. This is a condition that is mostly seen in elderly patients, characterized by a sudden onset of coma associated with seizures. Normally these are patients with a long history of myxedema. The emergency can be precipitated by a number of factors such as infection, drug overdose, myocardial infarction, hypoglycemia and congestive heart failure (CHF).
Laboratory Findings There are a number of laboratory tests available with which to measure thyroid activity. These tests are based on the physiologic and chemical characteristics of the thyroid hormone. Basal Metabolic Rate (BMR). This test is based on the ability of the thyroid to stimulate oxygen consumption. The basal metabolic rate is the lowest level of energy production compatible with life. In clinical practice, this is measured by the oxygen consumption of the patient for a certain period of time under basal conditions. The value obtained is corrected to standard conditions of temperature and barometric pressure. The normal BMR for an individual of the patient's age and sex is obtained from standard tables. The patient's actual rate is expressed as a plus or minus percentage of the normal. A number of factors will elevate the BMR-fever, congestive failure, emphysema, asthma, pheochromocytoma, malig-
GLOSSARY Aplasia-Congenital absence of an organ Autoii!Jmune-A disordered immune reaction directed against a constituent of a pat1ent's own body Catecho_lamines-Amines (n_orepinephrine, epinephrine and isoproterenol) that act directly on sy:mpathetlc effectors Colloid-The proteinaceous material found in the thyroid follicle that contains the thyroid hormones Cretinism-Myxedema due to congenital thyroid deficiency or thyroid lack in early childhood Endemic-The continuing prevalence of a disease in a certain geographical area Euthyroid-A condition of having a thyroid gland with normal function Goiter-Chronic enlargement of the thyroid gland Goitrogenic-Causing goiter Hyporeflexia-A condition in which the reflexes are weakened Idiopathic-Denoting a disease of unknown cause Myxedema-Advanced deficiency of thyroid hormone Panhypopituitary-A universal deficiency of function of the pituitary gland Pheochromocytoma-A tumor characterized by the secretion of adrenal medullary hormones such as norepinephrine Thyroglobulin-The glycoprotein found in thyroid colloid that binds the thyroid hormones Thyrotoxicosis-Poisoning by an excess of thyroid hormone from the gland or exogenous sources Thyrotropin-Thyroid-stimulating hormone (TSH) produced by the anterior pituitary
nant lymphoma, infections and thyroid hormone. A BMR of -15 to +10 percent is considered normal. In hypothyroidism, the BMR may be -30 to -60 percent. Malnutrition and Addison's disease may also cause a lowering of the BMR. Protein Bound Iodine (PBI). This test is based on the measurement of total iodine bound to serum protein. It measures mainly T 4 since T 3 is poorly bound to plasma protein. In normal (euthyroid) patients, the concentration is between four and eight micrograms per 100 mi. In hyperthyroidism, the value is elevated and in hypothyroidism it is lowered. The total amount of protein bound iodine depends on the concentration of thyroxin binding globulin (TBG) and any conditions that elevate the TBG would tend to interfere with the PBI. A number of drugs may displace the iodine on the TBG and thus interfere with this test (Table II, see page 496). Butanol Extractable Iodine (BEl). This test parallels the PBI but is not effected by inorganic iodides bound to the protein. However, it is raised by organic iodides such as radio-opaque dyes. Euthyroid levels range from 2.9 to 6.4 micrograms per 100 mi. Radioactive Iodine Uptake (RAIU). An oral dose of J131 is taken and the uptake by the thyroid gland is measured. Euthyroid levels are 15-45 percent uptake in 24 hours. Higher levels of uptake indicate hyperthyroidism and lowering of the RAIU is indicative of myxedema. Triiodothyronine Uptake (TB Uptake). These tests measure the satura-
tion of protein binding sites. Radioactive T 3 is added to serum in the presence of a standard quantity of resin (or red blood cells) capable of binding T 3 . If the thyroid hormone binding sites on TBG are saturated with endogenous T 3 and T 4 , the radioactive T 3 added to the serum will be bound preferentially by the resin and the uptake will be higher indicating hyperthyroidism. Conversely, when the TBG sites are unsaturated the uptake will be low indicating myxedema. This test is not affected by exogenous organic or inorganic iodides. However, any condition that alters the TBG in the serum will modify the results. Conditions such as pregnancy, hepatitis, acidosis, renal disease and pulmonary insufficiency will alter the amount of binding sites available. Serum Thyroxin (Serum T 4). This test measures the displacement of radioactive T 4 by serum T 4 from a protein mixture containing TBG. It is not influenced by iodine but it is atlered by changes in serum TBG. Serum Free Thyroxine (Free T 4 ). This measures only the metabolically active (free) hormone using dialysis techniques. Thyroid Suppression Test. This test is based upon the feed-back mechanism of thyroid homeostasis described earlier. When daily oral doses of T 3 (100 micrograms) are given for a period of seven days, the thyroid activity as measured by Jl3 1 uptake should be suppressed in a normal patient. This test is mainly used in the diagnosis of hyperthyroid states, where suppression is not achieved. Vol. NSll. No. 9, September 1971
495
TABLE II
Effects of Various Conditions and Drugs on Thyroid Function Tests
AntiInorganic Organic thyroid Iodides , Iodides Drugs
t
PBI -
BEl
~
RAIU -
Ta Uptake
t t
~
~
~
Androgens, DiphenylPreg- hydannancy, to in, Estro- Salicylgens ates
t t
~
~
t t
t t
-
-
-
~
~
~
t t t
t t t
t
~
~
t
~
t
~
~
t
-
-
FreeT,
-
-
~
Thyrotropin Stimulation Test (TSH stimulation). Five to ten units of thyrotropin, USP is given intramuscularly and the thyroid activity as measured by PBI or pa1 uptake is determined. This test can differentiate primary thyroid deficiency from secondary pituitary dysfunction. Nonspecific tests such as serum cholesterol, glucose tolerance, 17-ketosteroids and serum triglycerides are also useful in diagnosing hypothyroidism.
Treatment The treatment of hypothyroidism (Table III, see below) is generally effectively carried out by the careful
Thyroid Sodium Sodium lioUSP, levothyroThyrothyrnine globulin oxine (T,) (Ta) Liotrix
~
-
Serum T,
Hormone replacement therapy with
-
-
administration of thyroid hormone. All of the commercially available preparations of thyroid hormone are effective. However, there are a number of qualities of each drug that should be considered before a selection is made. Thyroid USP. Dessicated thyroid is made from the dried and defatted thyroid glands of slaughtered cows and pigs. This preparation is standardized only with respect to iodine content. Since no requirements are made as to thyroxine or triiodothyronine, the ratio of hormones and the total amount of hormones may vary. However, with very few exceptions, this preparation has been shown to be satisfactorily uni-
form in potency. However, the preparation may deteriorate under poor storage conditions and produce unsatisfactory results. Absorption of thyroid hormone is generally good, although variations in totaL amounts absorbed have been reported. Entericcoated preparations produce more variation in response than compressed tablets. Because thyroid USP contains both T 4 and T 3 , the PBI can be monitored and produce euthyroid levels when the patient has achieved a normal metabolic rate. The other laboratory tests also produce predictable levels. Because of its low price, thyroid USP remains the most heavily prescribed thyroid preparation. Thyroglobulin (Proloid). This drug consists of the partly purified, denatured thyroglobulin derived from slaughtered pigs. In addition to being standardized by iodine content, thyroglobulin is also bioassayed. Thyroglobulin has no apparent advantages over thyroid, USP, and is slightly more expensive. Sodium levothyroxine, USP (Synthroid, Letter) . Sodium levothyroxine is the sodium salt of synthetic Lthyroxine (T4 ). As such, the amount of hormone present is certain. Because it contains no T 3 , this preparation has the tendency of producing higher than normal euthyroid PBI levels when normal metabolic activity is estabLished. This is no real disadvantage if the physician is cognizant
TABLE III
Available Thyroid Preparations Dose to maintain norm BMR (euthyroid)
Drug
Route
Preparation
t '/•
(bioi)
Peak
Euthyroid PBI meg/ Dura- 100 Standardtion ml ized
Advantages
Disadvantages
Thyroid, USP
6D-240 mg P.O. av = 120 mg
Ta+ T, (cow and pig)
Thyroglobulin (Proloid)
6Q-240 mg P.O. av = 120 mg
Purified 1-3 6-7 thyroglob days weeks ulin (Pig)
Sodium Levothyroxine USP (Synthroid) (Letter)
0.1-0.4 mg P.O. Synthetic T, av=0.2mg I.V
1-3 6-7 days weeks
7- 10 Chroma to3 graphic weeks assay
Long-acting Can monitor T , Known potency
Slow excretion: disadvantage in toxicity Expensive
Sodium Liothyronine USP (Cytomel)
0.025-0.1 mg P.O. av = 0.05 mg
Synthetic Ta
24-72 2.5 days hours
5-6 days
1- 2 Chroma tographic assay
Good absorption Rapid onset Known potency
Difficult to monitor by lab tests Expensive Short duration: divided dosage
Liotrix (Euthroid) (Thyrolar)
"l"-''4" av = "2"
Synthetic 6-7 1-3 T, and Ta days weeks ratio 4 : I
Chromatographic assay
Known potency Known ratio of T, to Ta Can monitor T,
Expensive
496
Journal of
P.O.
6-7 1-3 days weeks
the AMERICAN PHARMACEUTICAL ASSOCIATION
3 4- 8 Iodine content weeks (0.170 . 23 %) 3 4-8 weeks
3 4-8 weeks
Inexpensive Can monitor T, Has T a + T,
Variations in lots Poorly standardized What is T,fTa ratio? Deterioration on storage
Relatively inexpensive Variable TafT , Iodine ratio Can monitor T , content, bioassay, Has Ta and T, chroma tographic assay
of this fact. The absorption of the drug is varied, and 4D-50 percent has been recovered from the stool. The preparation is also available for intravenous administration. Sodium liothyronine ( Cytomel). Sodium Iiothyronine is the sodium salt of synthetic L-triiodothyronine (T3 ). It is thus a pure form of T 3 that has been chromatographically assayed. The major advantage and disadvantage of this drug is its relatively short half life and rapid onset of activity. In emergency conditions (myxedema coma) where a rapid onset is mandatory, sodium liothyronine is the drug of choice. It is not commercially avaiLable in intravenous form, but many physicians consider it the drug of choice in myxedema coma. There are few indications for the use of this drug on a chronic basis. Because of its short half life it should be given three times a day. In rare cases where relatively rapid abatement of action (severe angina, CHF) may be desired, this drug could be used for maintenance. Because T 3 is poorly bound to serum protein, the PBI levels are barely raised from hypothyroid levels. Liotrix (Euthroid, Thyrolar). Liotrix is a four to one mixture of the sodium salts of T 4 and T 3 • Even though the two commercialLy available preparations vary slightly in composition, they are clinically equivalent. The major advantage of liotrix is that the two hormones are present in a uniform ratio and of known strength. As with thyroid, USP and thyroglobulin, PBI levels are in the euthyroid range when a normal metabolic rate has been achieved. Because of its higher cost this preparation should generalLy be reserved until the less expensive natural preparations have been shown to produce erratic results in a particular patient. Toxicity. The toxicity of thyroid hormones mimics hyperthyroidism. One can expect to see hyperirritability, nervousness, insomnia, tachycardia, cardiac arrhythmias, angina pectoris, intolerance to heat, increased pulse and blood pressures, diarrhea, cramps, weight loss, vomiting and tremors. In children, accelerated rate of bone maturation is an early manifestation of toxicity. At the earliest sign of toxicity, the drug should be discontinued for two to six days in the case of thyroid, thyroglobulin and sodium levothyroxine and two to three days in the case of sodium liothyronine. The drug should be restarted at a lower dose following abatement of toxicity. Therapy, Cretinism Immediately upon diagnosis of hypothyroidism, thyroid replacement therapy should be initiated. The drug
of choice is either thyroid, USP or equivalent doses of liotrix. Sodium levothyroxine and sodium liothyronine will give unpredictable PBI levels, making monitoring difficult. The more myxedematous infants are more sensitive to the action of thyroid hormone, necessitating the initiation of treatment with very small doses and followed by gradual dose increases. An initial dose of 30 mg per day is the starting dose, increased by 15 mg a day every three weeks. The maintenance dose should not be less than 60 mg a day of thyroid or equivalent. (Table IV, see at right). A one-year old usually will require 90 mg a day. Three-year old children will require 90 to 120 mg per day; five-year-old children, 120 to 150 mg, ten-year old children 150 to 180 mg. Older patients require proportionally higher doses, up to 240 mg per day of thyroid or equivalent. Treatment must be continued for life. Therapy, Myxedema The drug of choice in myxedema depends on a number of factors1. Patient's age 2. Severity and duration of disease 3. Presence of other disease such as congestive heart failure, angina or diabetes. Generally, older patients with severe myxedema and concomitant heart disease must be started with small doses of thyroid-8--'15 mg for one week and increased by 15 mg every week up to 120 to 180 mg. The dose is increased until the clinical signs of the disease have disappeared or signs of toxicity appear. The laboratory findings should reflect a euthyroid state. Younger patients can generally tolerate higher initial doses; 30 mg for one week, then increased by 30 mg every week until euthyroid levels are reached. In post-radio-iodine, postthyroidectomy and post x-ray hypothyroidism maintenance levels can be reached sooner than in long-standing myxedema. The more severe the deficiency, the more sensitive is the patient to the effect of thyroid hormone. Although some patients may require more than 300 mg of thyroid or equivalent per day, most patients become euthyroid below this level. Because of this, the diagnosis of hypothyroidism is questionable in patients receiving massive doses of thyroid. In patients with severe angina or congestive heart failure, the use of sodium liothyronine should be considered. If toxicity symptoms appear, the effect can be terminated relatively rapidly due to the drug's short half life. Increments of five meg are generally employed. As stated before,
TABLE IV
Equivalent Doses of Thyroid Preparations Thyroid, USP Thyroglobulin Sodium levothyroxine, USP Sodium liothyronine, USP Liotrix
60mg 60 mg 0.1 mg 25 meg "1"
PBI is not a reliable indicator with this drug. Myxedema coma is an emergency condition requiring the use of intravenous sodium levothyroxine 20D-500 meg. This dose may be repeated in 24 hours. Some physicians prefer sodium liothyronine 1D-20 meg intravenously every eight hours (not available commercially). Prolonged hypothyroidism leads to adrenocortical depression, so hydrocortisone should be given in doses of 100 mg intravenously every eight hours until the crisis is over. In addition, precipitating factors such as infection, drug overdose, myocardial infarction, hyponatremia, hypoglycemia and congestive heart failure should be treated immediately. Care must be taken to avoid overhydration, which can worsen the hyponatremia. The patient should be warmed, but too rapid correction of the hypothermia may lead to peripheral vasodilatation and worsening of the shock. Myxedematous patients metabolize drugs very slowly and are thus very sensitive to overdosages. Sedatives and opiates must be used with caution since normal doses may produce signs of overdosage. Signs of Cushing's syndrome have been produced in hypothyroid patients with relatively low doses of corticosteroids. Patients requiring digitalis may require lower maintenance doses than euthyroid patients. Thyroid hormones may potentiate the action of oral anticoagulants, and the dose may have to be adjusted when thyroid therapy is initiated. The initiation of thyroid therapy in diabetic patients is usually accompanied by an increased requirement of insulin or oral hypoglycemics. This is due to the enhanced carbohydrate absorption produced by thyroid hormones. Prognosis, Cretinism Even with early treatment, the chances of a congenital cretin reaching full mental development is poor. However, full skeletal and sexual maturation may be achieved with optimal thyroid therapy. Prognosis, Myxedema Hypothyroidism of later onset generally responds excellently to thyroid (continued on page 508) Vol. NSll. No. 9, September 1971
497
Women's Auxiliary
Attracting and Keeping Members "Consider yourself at home, consider yourself one of the family . . .. consider yourself one of us .. ." sings the Artful Dodger in the Broadway musical "Oliver." This is just exactly what we would like to say to each of you who has an interest in pharmacy. In September, many auxiliaries start up again after a summer hiatus. The problem of how to attract new members, and then how to keep these members, is much discussed. The following suggestions for growing were compiled by Mrs. John Foley for the Auxiliary Handbook.
I. Growing in numbers. A. Develop a membership campaign each year. 1. Study the potential in your area. 2. Enlist the cooperation of your local pharmaceutical association in supplying the names of its members. 3. Put on your own "thinking cap" and suggest the names of women eligible for membership. 4. Plan a membership event (tea, luncheon) at which you entertain prospective members-with strictly ulterior motives. · Do follow the written invitation with a personal invitation, or 5. Use the individual approach in an organized way by inviting personally one or more prospective members as your guests at each meeting. Do follow this with a personal invitation from the membership chairman to join the auxiliary (and a letter of welcome from the president when she does). B. Give some thought to the care and treatment of prospective members. 1. Introduce them to as many members as possible. 2. Make them feel welcome and special. 3. Tell them something about the Auxiliary, its purposes and accomplishments. 4. Give them something tangible to take home (besides the
Hypothyroidism (continued from page 497)
therapy. Improvement can be very striking with early treatment and can be maintained indefinitely with continued therapy. Relapses will occur if treatment is interrupted. Myxedema coma has a high mortality rate, but with prompt recognition of the cause and the immediate initiation of appropriate therapy a significant number of patients survive. Conclusion Hypothyroidism is a relatively easy 508
door prize! )-a copy of your news bulletin, a reprint of the Auxiliary news in the APhA Journal. C . Make that new member into a real member. 1. 1, 2, 3 under B. 2. Include her in the group-and let her get a word in edgewise. 3. Have an orientation meeting at which you tell (as ingeniously as possible) about the history and the work of the Auxiliary. 4. Honor new members and tell something about their background and special interests. . 5. Bring your new member into active participation by letting her work with someone else on some job, however tiny. Recognize what she does! 6. Make sure that new members are called between meetings and make sure that she is called before the next four or five meetings. Give her a chance to establish the "attendance habit." D. Examine your conscience when a member "drops out." 1. Did you make the effort to find out why? 2. Did she really feel that she "belonged"? 3. What happened at the meetings she attended? Was she bored? Ignored? Given a chance to participate? 4. Did she really feel that she was important to the Auxiliary and the Auxiliary important to pharmacy? 5. Did she have special problems related to attendance? Try to keep her an interested, if inactive member. II. Growing in interest and enthusiasm. A . Be sure "everybody knows everybody." B. Remember "it pays to adverti~e"-even your own meetings. C. Heed the adage, "Variety is the mother of enjoyment." D. Beware of the comment, "I thought the business meeting would never end." Helen I. Lowe 3105 Silverleaf Dr. Austin, TX 78757
disease to diagnose. A large number of specific laboratory tests are available to substantiate cLinical findings. However, these tests may be altered by a number of disease states and drugs. Subtle differences between the available thyroid preparations make the selection of the proper drug important. Myxedematous patients have altered metabolism of drugs such as digitalis, narcotics, hypnotics and corticosteroids. The initiation of thyroid therapy may alter the patient's requirements of oral hypoglycemics, insulin and anticoagulants. By being aware of all these factors and conveying his knowledge to the physician
Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION
and the patient, the pharmacist can play an important role in the rational therapy of hypothyroidism. • Recommended Reading 1. Bakke, J. L., and Klotz, L. J,, "Treatment of Hypothyroidism With Synthetic Thyroid Hormones," Northwest. Med. 68, 651 (July 1969) . 2. Alley, R. A.; Danowski, T. S.; Robbins, T. J. L.; Weir, T. F.: Sebeh, G., and Moses, C. L ., "Indices During Administration of T • and T a to Euthyroid Adults," Metabolism, 17, 97 (Feh. 1968) ·· 3. Levy, P. L., and Marshall, J. S., "ShortTerm Drug Effects on Thyroid Function Tests," Arch. Int. Med. 114, 413 (Sept. 1964) 4 Davis, P. J, "Factors Affecting the Determination of the Serum Protein-Bound Iodine," Amer. ]. of Med., 40, 918 (June 1966)