Pharmacology 3rd stage
Thyroid hormones and anti-thyroid drugs.
The thyroid gland is responsible for the normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function ,the two major thyroid hormones are Tri iodo thyronine (T3, the most active form .), and Thyroxin (T4) .
Inadequate secretion of thyroid hormones (hypothyroidism), results in bradycardia with mental and physical slowing (in children this can cause mental retardation and dwarfism).
An excess of thyroid hormones secretion (hyperthyroidism) lead tachycardia, cardiac arrhythmias', body wasting, nervousness, tremor and excess heat production can occur.
The thyroid gland secrets another hormone which regulate calcium ions concentration in blood and bone called Calcitonin.
Synthesis of T3 and T4:-
Thyroid function is controlled by thyroid stimulating hormone (TSH )by anterior pituitary gland ,TSH is under control hypothalamic thyrotropin releasing hormone (TRH ) ,TSH action is stimulate of iodide uptake in what is called (iodine trapping mechanism )where iodine is transferred from GIT to be concentrated in thyroid gland (concentration is about 20-25 time more than that in blood ) ,then oxidation of 2 iodide ions to form iodine ; by peroxidase which will bind iodine to essential amino acid called Tyrosine to form mono iodo tyrosine in a process called (orgnification) , and last step combination of di iodo tyrosine with mono iodo tyrosine to form T3 ,while combination of 2 molecules of di iodo tyrosine will lead to form T4, in process called condensation ; these hormones are store in the lumen of thyroid follicles in colloid (thyroglobulin),then by enzymatic hydrolysis or cleavage ,they are release into circulation under influence of TSH, in the blood most of both T3 and T4 are bond extensively with plasma protein called thyroxin- binding globulin (TBG) , in about 99.9% .Mechanism of action :-
Both T3 and T4 must dissociated from TBG prior to entry into cells either by diffusion or by active transport ;T4 is enzymatically deiodinated to T3 which enters the nucleus and attach to specific receptors that promote formation RNA and subsequent protein synthesis which responsible for the metabolic changes of thyroid hormones .
Pharmacokinetic :-
Both T3 and T4 are well absorbed from GIT ,food ,antacids reduce the absorption ,the hormones are metabolized by the cytochrom P450 system ,drugs induce this system such as Phenytoin ,Rifampicin and Phenobarbital accelerate metabolism of the thyroid hormones ,the absorption is decrease in hypothyroidism and the parentral therapy is required .
Indications of thyroid hormones :-
1- Failure function of thyroid gland (hypothyroidism ).2- In non toxic nodular goiter ; when giving T4 lead to decrease TSH and lead to decrease the
hypertrophy .
3- Where there is no secretion in Hashimoto҆s disease and after resection .
Treatment of hypothyroidism
1-Levothyroxine (T4):-
a single dose reaches its maximum effect in 10 days ,its binding to plasma protein is strong ,half life is 7 days in euthyroid ,14 days in hypothyroidism, and 3 days in hyperthyroidism ;the main indication of Levothyroxine (T4) is treatment of deficiency (wither neonatal hypothyroidism –cretinism- or adult hypothyroidism .), also used for non toxic nodular goiter through suppresses secretion .2- Liothyronine (T3 ) :-
Is about 5 times as biologically potent as T4 ,a single dose reaches its maximum effect in about 24 hours ;its binding to plasma protein is weak ;half life is 2 days in euthyroid subject ;it is not used in routine treatment of hypothyroidism ,because of its rapid onset of effect where can induce tachycardia and heart failure ; its main indication in myxodema coma .Adverse effects of thyroid hormones :-
Give symptoms and signs of hyperthyroidism from tremor of hands ,weight loss, insomnia, exophthalmus ,muscle weakness, nervousness , excessive sweating ,palpitation, ,atrial fibrillation or heart failure in patient with pre existing IHD .Anti thyroid drugs and hyperthyroidism :-
Drugs used in treatment hyperthyroidism include :-
1-Thionamides ; which block the synthesis of thyroid hormones .
2- Iodine ; radio iodine destroys the cells making thyroid hormones ;an excess of iodide reduces the production of thyroid hormones temporarily by an unknown mechanism ,both excess and deficiency can cause goiter .
Thionamides include the following drugs
1-Carbimazole and Methimazole .
2- Propylthiouracil .
The major action of Thionamides is to reduce the formation of thyroid hormones by inhibiting oxidation , orgnification and condensation processes ,the maximum effect is delayed until existing hormones stores are exhausted (takes weeks ).
Carbimazole and Methimazole (active metabolite of Carbimazole ),half life is 6 h. and for Propylthiouracil is 2 h. the drugs are accumulate in thyroid and act in thyroid gland for 30-40 hours ;thus a single daily dose is sufficient ;the Propylthiouracil differs from other members of the group in that it also inhibits peripheral conversion of T4 to T3 in peripheral tissues ;but only at a high doses used in treatment of thyroid storm .
The drugs are used in hyperthyroidism as ;
1-Pernciple therapy .
2- adjuvant to radioiodine to control the disease until the radiation achieves its effects .
3- To prepare the patients for surgery .
The clinical improvement is noticeable in 2-4 weeks , and patients be euthyroid in 4-6 weeks .
Adverse effects of Thionamides :-
Minor side effects are ; rash ,urticaria, arthralgia, fever ,anorexia, nausea, abnormal taste and smell . Major side effects are ; agranulocytosis ,thrombocytopenia ,acute hepatic necrosis ,cholestatic hepatitis , lupus-like syndrome ,vasculitis ,the blood disorder are the most common in the first two months of treatment ; routine leukocyte count have been advocated in order to detect blood dyscrasia before symptoms develop .
Potassium iodide and radioactive iodine I131 :-
Iodide is well absorbed from intestine, it distributed like chloride in the body and rapidly excreted by the kidney, and it is selectively taken up and concentrated by the thyroid gland.
Clinical uses:-
Iodide (large dose) is used for thyroid storm (crisis) and in preparation for thyroidectomy; because it is rapidly benefit the patients by reducing hormones release.
Side effects:-
Relatively minor and include sore mouth and throat, rash, ulceration of mucous membrane and metallic taste in the mouth.