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
Potassium iodide
MOA: in high doses inhibits ALL steps of thyroid hormones biosynthesis (it’s own uptake, T3 and T4 formation, inhibits the endocytosis of Tg and the proteolysis), the thyroid gland gets smaller and less vascularized;
Kinetics: good p.o abs., the excess amount (not taken by the thyroid gland) is excreted by urine, can cross the placenta (→fetal goiter can develop), max. antithyroid effects are reached in 8-10 days (→then the effect decrease, even hyperthyroidism can develop);
IND: Thyrotoxic crisis (3-4x200mg/day), Preparation for thyroidectomy (doses can be continuosly increased for max. 6-10 days (50→200mg)), After nuclear catastrophies (to avoid accumulation of iodine isotopes (100mg iodine));
SEs: Acute allergic reaction, Iodism (rash, eczema, swollen salivary glands, mucosa irritation, fever, sense of taste disorders), Antithyroid effect can develop into hyperthyroidism
Bromocriptine
Ergot derivative;
MOA: Dopamine-agonist, works in the pituitary level; IND: Hyperprolactinemia, infertility, prolactinoma, After delivery to stop milk secretion (if needed), Acromegaly (→inhibition of GH secretion, adjunctive therapy), Parkinson’s disease;
Kinetics: Good abs., metabolized in the liver (CYP3A4), peak effect in 5-10h (80% reduction on prolactin level); SEs: Nausea, vomiting, constipation, Headache, dizziness, somnolence, nasal congestion, Neuropsychiatric symptoms, Pleural infiltrate (fibrosis), hypotonia, syncope
Desmopressin
MOA: ADH-R agonist;
IND: central diabetes insipidus, enuresis nocturna, management of spontaneous bleeding or prevention of bleeding in mild Hemophilia A and in von Wilebrand disease;
Kinetics: injection, nasal spray, p.o
Oxytocin
MOA: Released from posterior pituitary, Oxytocin-R agonist (induces milk ejection and uterine SMC contraction);
IND: induction of lactation. induction+augmentation of labor, prevent post-partum bleeding;
Kinetics: injection
Octreotide
MOA: (Octapeptide analog) Somatostatin (GHIH) analogs (→inhibit GHRH release from the hypothalamus), also affects α and β cells in the pancreas (α-cells→inhibition of glucagon secretion, ↓of glucose-induced insulin secretion; β-cells→ inhibition of insulin secretion);
IND: acromegaly, Neuroendocrine tumors of the GIT (carcinoid syndrome→increased 5-HT metabolism→the effect of octreotide is primarily the decrease of severe diarrhea, it’s not an antineoplastic agent!), In cirrhotic patients for acute GI bleeding (ulcers, esophageal varicies, hemorrhagic gastritis→I.V infusion), TSH-secreting pituitary adenomas, To prevent the complications after pancreatic surgery;
SEs: GI symptoms, steatorrhea, cholelithiasis, Cardiac effects (→sinus bradycardia, conduction problems, QT↑), Hyperglycemia (sometimes hypo), other pituitary hormones can also be inhibited (→ACTH leading to cortison deficiency; TSH leading to hypothyroidism); Kinetics: adm. i.m/s.c 4-5X/week (varicies hemorrhage i.v. infusion);
Drug-interactions: the doses of- BBLs, CCBs or drugs acting on fluid and electrolyte balance, insulin and antidiabetic drugs may need to be adjusted;
Other effects: can potentially restore the fertility
Lanreotide
IND: Acromegaly(only if surgery/irradiation is not possible), GI neuroendocrine tumors;
Kinetics: i.m 4x/week
Pasireotide
IND: acromegally, Cushing’s disease (NOT Cushing’s syndrome!)- ONLY if surgery/irradiation is not possible (for both IND);
Kinetics: deep s.c. injection 4x/week
Thiamazole+Propylthiouracil interaction with coumarins
Effects of coumarins increase. Partially competition for binding to proteins, partially the anti-vitamin K effect of these drugs. The thyroid hormones facilitate the synthesis of vitamin K dependent coagulation factors
Thyroid hormone metabolism
- T3 is 3-4x more potent than T4
- rT3 is inactive
- 5’-deiodinase converts T4→T3 in the blood
- Amiodarone, iodinated contrast media, BBLs and corticosteroids and severe illness or starvation inhibit 5’deiodinase, which results in low T3 and high rT3 levels in the serum
The free:bound ratio of thyroid hormones
T4- 4:10000 (only the free form inhibits TSH release)
T3- :5:1000 (only the free form inhibits TSH release)
Treatment of hyperthyroidism - symptomatic treatment
Propranolol: until the onset of effects of radioiodine; preparation for thyroidectomy
Esmolol: Thyrotoxic crisis (i.v.)
Diltiazem: in case of BBL contra-IND
Most effective: Propranolol (in higher doses inhibits the T4→T3 conversion)
Treatment of hyperthyroidism- Non-thioamides
Lithium
Perchlorate
Glucocorticoids
Rituximab
a silent receptor
A receptor that binds an agonist without initiating biological effect. This is a binding site which has nothing to do with the biological effect.
release of Thyroid hormones
stimulation by TSH
TSH binds TSH-R (Gs / Gq coupled receptor) leading to T3/T4 release
