B.17 Flashcards
Thyroid and antithyroid drugs. Pituitary hormones. Hypothalamic hormones, hormonanalogs and antagonists
Levothyroxin,
Thiamazole,
Propylthiouracil,
Iodine,
Octreotide,
Bromocriptine,
Desmopressin,
Oxytocin
Biosynthesis of thyroid hormones
In the presence of H2O2, TPO catalyzes the incorporation of I- into tyrosyl residues of TG to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) and the coupling of these iodotyrosyl residues to form T3 and T4
Effects of thyroid hormones
- have influence of the metabolism and utilization of carbohydrates, proteins, lipids and nucleic acids
- Increase the consumption of energy and oxygen, caloricity, synthesis of Na/K ATPase
- Increase the breakdown of glycogen in the liver, blood sugar ↑
- Increase the basal metabolism
- Lipid metabolism: FFA↑, Cholesterol and TAG ↓
- Inhibit in higher quantities the protein synthesis and enhance the proteolysis
- Catecholamine sensitivity ↑→ β receptor expression increases
Hyperthyroidism- Potential causes:
Basedow-Graves disease (autoimmune disease→TSH-R- antibodies stimulate the thyroid gland)
Autonomus adenoma (TSH-R mutation, independent parts of the thyroid gland are activated in absence of TSH constitutively
Multinodular goiter
Iodine induced goiter
Gestational
Increased TSH secretion (hypophysis/hypothalamic disorder)
Treatment of hyperthyroidism
- Thyrostatics:
Thioamides (hormone synthesis inhibitors)
Non-thioamides (iodine, Li etc)
Symptomatic therapy - Radioiodine treatment
- Surgical-thyroidectomy
Hypothyroidism
Total deficiency in childhood: the mental and physical development stops→ cretinism
Deficiency in adulthood: myxedema→ can lead to myxedema coma
Hypothyroidism Potential causes
Hashimoto thyroiditis,
Iatrogenic,
Operation of the thyroid gland,
Iodine deficiency,
Congenital,
Secondary/tertiary (hypophysis, hypothalamic abnormalities)
Hypothyroidism Treatment
substitution therapy: levothyroxine
myxedema
in the connective tissues under the skin there is accumulation of myxoid (mucus) substance
myxedema coma: life threatening state
Thyroid hormone binding
TBG
substances can increase the binding of it: Estrogens, opioids
Some substances can decrease the binding of it: GC, androgens, salicylate, furosemids
Kinetics of thyroid horomones
- Biological T1/2:
T4: 7 days
T3: 1 day - Per os absorption:
T4: 80%
T3: 95% - Onset of action:
T4: slow
T3: fast
Potassium iodide, low dose
Daily phisiological iodine need: 0.1 mg
Dose: p.o → 0.1-0.2mg
IND: Goiter prophylaxis (Normofunctional or hypofunctional goiter)
Levothyroxin
MOA: hormone replacement (T4 analog);
Dose: p.o 50-200μg, on empty stomach, must be titrated according to TSH levels;
IND: substitutional therapy in hypothyroidism, Suppression therapy in tumor of the thyroid gland (to suppress TSH-production), Supplement therapy in hyperthyroidism (additional to thioamide), Euthyroid benign goiter, diagnostic purposes (thyroid suppression test), Non-official utilization (athletes, primaily body-builders as reductant), Liothyronine (T3 analog) p.o/i.v inj. - rarely, (e.g. T4→T3 conversion disorder) or in severe hypothyroidism (myxedemic coma) is applied;
SEs: mainly at the beginning of the therapy or in case of myxedema→ Cardiac (palpitations, tachycardia, rarely arrhythmias, angina pectoris), Untreated hypophyseal-insufficiency (if it causes treatment-requiring adrenocortical insufficiency), Osteoporosis (especially in case of women in menopause), Subclinical hyperthyroidism development (↑sweating, ↑BP); Contra-IND: Untreated adrenocortical insufficiency (well tolerated hypadrenia in case of low TSH levels, higher hormone levels can provoke severe symptoms), Untreated hypophysis insufficiency, Acute MI, acute myocarditis;
Important interactions:
-Efficacy ↓: estrogens, contraceptives, methadone (affects protein binding), Cholestyramine, Iron, Aluminum salts, Soy, Amiodarone (MUST follow up co-administration!), BBLs (→peripheral T4→T3 conversion ↓), Lithium (MUST follow up co-adm.), Enzyme inducers (e.g. phenytoin, carbamazepine, rifampicin), Antiviral protease inhibitors.
-Efficacy ↑: Androgens, NSAIDs, Furosemide, TCA, Coumarines (→TBG binding↓)
Thiamazole (methimazole), Propylthiouracil
MOA: TPO-inhibition (inhibition of iodine incorporation to tyrosine residue), T4→T3 conversion inhibition (only propylthiouracil), the effects begin after 3-4 weeks (after the decrease in stored Tg);
IND: Treatment of Basedow-Graves disease, To reach the euthyroidism before thyroidectomy, before and after 131I-treatment (until effects of the treatment with radioiodine starts), Thyrotoxic crisis (Propythiouracil); Kinetics: Good absorption (propylthiouracil only 50-70%BA), Propylthiouracil binds plasma proteins in 75% (thiamazol binding is insignificant), Thiamzaole get through the placenta→ accumulates in fetal thyroid gland and can also get into breast milk;
SEs: Bone marrow dysfunction (agranulocystosis-rare, aplastic anemia-common), Graves-disease treatment SEs (→Skin symptoms, Vasculitis, Rash, Arthralgia, Myalgia), Paresthesia, dysgeusia (strange taste), Hepatotoxic effect (Propythiouracil), Teratogenic (Thiamazole);
First line treatment: Thiamazole (more effective, faster effect-onset, lower risk of hepatotoxicity);
Treatment during pregnancy: in the first trimester (→propylthiouracil is 1st lne), in the 2nd-3rd trimester (→thiamazole is indicated if necessary→ if the thyroid dysfunction has more negative effect on the fetus); Interactions: Effects of coumarins↑ (INR follow-up!), should be CAREFULLY administered with hepatotoxic and hemopoetic products
Iodine
MOA: I131 uptake by the thyroid gland, primarily emits γ-radiation (the penetrancy of the radiation is approx. 0.5mm, no harmful effect outside the thyroid gland); Kinetics: solution, good p.o abs.;
IND: Graves-Basedow disease (mainly after unsuccessful treatment with thioamide/in older patients), Nodular goiter and malignant thyroid tumors with metastasis, Additional therapy (→Thioamide to avoide the production of radioactive thyroxine with BBLs);
SEs: hypothyroidism (levothyroxine administration is necessary);
Contra-IND: pregnancy, breastfeeding, childhood; Duration-of-therapy: 5-14 days, onset of effects 10-12weeks
