Pharmacology Jan and Kristina
9/1/00 1:00 pm Friday Dr. Syapin
Thyroid Pharmacology
· Thyroid produces thyroid hormone which is important in the development of the body and in the body of an adult.
· How thyroid synthesizes thyroid hormone
- Key ingredient is Iodine
- Thyroid cells have an active transport mechinism to transport Iodine into the cytoplasm, actually all the way across the cell into the luminal area of the thyroid, an open area full of protein, predominantly thyroglobulin.
- An enzyme, thyroid peroxidase, in the lumen changes the Iodine to Iodide (I2). That same enzyme will iodinate the tyrosine residues on the thyroglobulin.
- The thyroid peroxidase will put one or two Iodine residues on to the tyrosine of the thyroglobulin and form molecules called Monoiodotyrosine (MIT) and Diiodotyrosine (DIT).
- If two DIT couple it will form T4, thyroxine, and if DIT and MIT couple they form T3, triiodothyronine. T4 can also go onto form reverse T3, which is an inactive molecule.
- These molecules are in storage as thyroglobulin until signaled.
- Most of the active hormone is in the form of T4 and has the majority of the iodine in its molecule, 35%. Only 5% of the total iodine is bound in the form of T3, which is actually the more active form of the active hormones. The rest of the iodine is in the form of DIT, 30%, and MIT, 20%.
- Only small amounts of the hormones are released at a time in normal people. Therefor, if one were to stop the iodination of the thyroglobulin it would take a couple of months to deplete the store of the thyroid’s T3 and T4.
· Enzymatic degradation of the thyroglobulin causes the release of T3 and T4.
· Bodies normal regulation of the release of thyroid hormone is a negative feedback loop involving the hypothalamus, anterior pituitary, thyroid, and various hormones.
· Stimuli cause the hypothalamus to release TRH, which then acts upon the anterior pituitary. The anterior pituitary then release TSH, and it causes stimulation of the thyroid.
- The thyroid hormone can go through the negative feedback loop and inhibit TSH from being secreted from the anterior pituitary. ( However, he said it also goes back to the hypothalamus to inhibit TRH, but we look in two other sources which disagreed).
- Iodine has both stimulating and inhibiting effects, at low dietary levels it will stimulated the production of T3 and T4, and at high levels it will inhibit the production. This forms the basis of using iodine to treat thyroid conditions.
- Somatostatin, cortisol, and dopamine all have negative effects on the release of TSH.
· TSH is a trophic hormone that stimulates the growth of thyroid cells, and increases the vascularity. It also stimulates the synthesis, breakdown, and secretion of thyroid hormone.
- If circulating blood levels of T3 and T4 are low, there is not as much negative feedback, and the anterior pituitary keeps on releasing TSH. The constant stimulation of the thyroid by the TSH can cause it to enlarge. This is called endemic goiter.
- TSH acts on a 7 transmembrane G protein coupled receptor on the plasma membrane of a thyroid cell.
- When TSH acts upon the receptor, it stimulates the G protein to activate a lysosomal system, thus breaking down the thyroglobulin. The remnance, MIT and DIT, are then recycled back into the thyroglobulin.
- When T4 and T3 are released go into bloodstream their primary effects are calorigenesis, and increases your basal metabolic rate. Secondary effects develop from this increase in BMR, example vitamin deficiency, and CNS effects. This is due to the increase in energy utilization.
- Heart is particularly sensitive to thyroid hormone, in fact, oxygen consumption increases in all tissues except spleen, brain, and testis.
· Although more T4 is released than T3, the active form is T3. T4 gets deiodinated in the peripheral tissue to T3.
· Two best characterized effects of T3 are in the mitochondria, and in the nuclease. In the mitochondria T3 causes effects on oxidative phosphorylation, and in the nucleus T3 causes the receptor it binds to act as a transcription factor. The genes that it activates are mainly the ones involved in metabolic activity.
· There is evidence amino acid and glucose entry into the cell is elicited by T3 on the plasma membrane.
· Hypothyroidism
- possible causes are: block of uptake of the iodine into the thyroid. An example is use of lithium in psychiatric disorders.
- People who work around jets get hypothyroidism, due to the perchlorate in the jet fuel.
- Genetic enzyme deficiency, and dietary iodine deficiency are some other causes of hypothyroidism.
- In a pregnant woman, a deficiency in iodine, can give the child congenital hypothyroidism (cretinism).
- The body can produce antibody that blocks the TSH receptor, which also causes hypothyroidism.
- Hashimoto’s thyroiditis, an autoimmune disorder, in which the immune system will attack the thyroid and cause hypothyroidism.
- Hypopituitarism can cause hypothyroidism with lack of TSH.
- Radiation, accidental exposure to X-Rays can cause it.
· What would you do in the case of hypothyroidism?
- In the case of drug induced hypothyroidism, as in lithium or percholorate, remove the drug if you can.
- Dietary deficiency of Iodine, take in more Iodine.
- For all other conditions, replacement therapy to replace what is missing in the system.
- T4, levothyroxine, is the drug of choice for thyroid replacement, due to longer half life. You only have to take this guy once a day. T3, lithothyronine, can be used also, but you take it several times a day. There is also a T4/T3 combo, liotrix, the ratio of T4:T3 is 4:1. There is no clinical advantage to taking liotrix as opposed to levothyroxine.
- Can also give desiccated thyroid powder, prepared from thyroid gland of animals, yum. The active ingredient to the powder is thyroglobulin.
· Student question: “How would you differentiate what the cause of hypothyroidism is with the blood TSH levels”?
- If drug induced, the TSH is probably high because T3 and T4 is low.
- If not producing T3 and T4 again TSH will be high.
- Iodine deficiency, and all other reasons the TSH is low.
· Hyperthyroidism
- The most common cause is Grave’s disease, an autoimmune disorder. Half the patients examined produce an antibody that stimulate the TSH receptor. This causes the hyperthyroidism.
- Can treat hyperthyroid with drugs or surgery.
- With hyperthyroid, lots of metabolism is going on, therefor, are deficient in vitamin. Therefore, give vitamins. The heart is working harder, therefor, give beta-blockers glucocorticoids can also be given. Among many of the actions of the glucocorticoid is the reduction of the amount of T3. This is due to the blocking of the enzyme that is primarily in the liver that converts T4 to T3.
- If things get really bad you can have a thyrotoxic crisis, also called a THYROID STORM. This is where George Clooney and Marky-Mark invade your thyroid to catch some fish. Just kidding. The symptoms are hypermetabolism and an excess of adrenergic activity. This is where beta-blockers are used. Fever and tachycardia can also occur. Patients can go into coma or die of heart failure and pulmonary edema.
- The way to treat this is to give an antithyroid drug to block the synthesis of T4 and T3 by inhibiting the thyroid peroxidase, and then giving high levels of iodine which will quickly shut off the release of T4 and T3 from the thyroid. And then propranolol to block adrenergic activity. Dexamethosone, a glucocorticoid, to manage other symptoms and block the conversion of T4 to T3.
- Potassium iodide and its use in thyroid disorder: low dosage found in the microgram range stimulate thyroid function if there is a iodine deficiency. However, higher concentrations in the mg range, will inhibit the release of T3 and T4. It is also used to block organification, and does it more quickly than thyoamides (exp propylthiouracil). Potassium iodide works in 2-7 days. A negative effect of potassium iodide is that you saturate the body with iodide and that causes a delay in thioamide effect. It will also delay the use of radiation with I-131 for a thyroidectomy. Potassium iodide is not used by itself for long periods of time because the body will adapt. It is used initially to stop release, but then use other drugs for the long run. Potassium iodide decreases the vascularity and size of the thyroid in preparation for surgery on the thyroid.
· Thyroamides
- There are two drugs in this category used in the United States, propylthiouracis and methimazole. These drugs act by inhibiting the thyroid peroxidase. They do not effect the uptake of the iodine or the release of thyroid hormones.
- These drugs do not have a fast onset of action.
- One difference between the two drugs is that the proplythiouracil blocks the iodothyronine-5 deiodinase-1. Therefor, in addition to blocking production of new thyroglobulin ( the iodinated form), it will also block the peripheral conversion of T4 to T3. Methimazole does not do this.
- Both are oral-active and their plasma half lives are short. They accumulate in the thyroid, therefor, have a long duration and you can do a daily single dosing.
- These drugs are used to block the synthesis or thyroid hormones in hyperthyroid. In thyroid crisis you give these drugs before you begin treatment with high level of potassium iodide. That way you allow the thioamides to get into the thyroid. After some time you can stop the administration of the iodide, and just use one of the thioamide drugs.
- Toxicity of thioamides are low, but when they occur they manifest themselves as pruritic rash, sometimes accompanied by fever. The most serious complication is potentially fatal agranulocytosis.
Thioamides / Oxidation of iodine to iodide, coupling of iodotyrosinePropylthiouracil / Thioamide effect plus the deiodination of T4 and T3 in peripheral tissue
Iodine in high doses / T4/T3 release, organification of I, coupling to iodotyrosine
Glucocorticoids and Beta blockers / Deiodination of T4 to T3 at symptomatic sites.