Pharmacology 2 Finals: Thyroid & Antithyroid Drugs PDF

PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr FINALS:...

PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr FINALS: THYROID & ANTITHYROID DRUGS Endocrine Drugs Hypothalamic & Pituitary Hormones Thyroid & Antithyroid Drugs Calorigenesis - production of heat in Adrenocorticoids & Adrenocortical the body. Antagonists Thyroid hormones decrease hepatic The Gonadal Hormones & Inhibitors LDL receptors, which in turn decreases Pancreatic Hormones & Antidiabetic the total cholesterol in the body. Drugs Thyroid hormones have an inotropic Agents that Affect Bone Mineral effect in the cardiovascular system Homeostasis since they upregulate beta receptors. ○ More beta receptors = Thyroid Hormones increases heart rate and cardiac output. This also Triiodothyronine (T3) and Thyroxine increases blood pressure. (T4) Thyroid hormones promote fluid ○ to normalize growth and retention. development, body temperature, and energy levels Biosynthesis of Thyroid Hormones ○ contain 59% (for T3) and 65% Site: follicular cells in thyroid gland (for T4) of iodine (parafollicular cells or C-cells for ○ Main thyroid hormone calcitonin) Calcitonin ○ Biosynthesis of T3 and T4 ○ second type of thyroid hormone happens in the follicular cells in ○ important in the regulation of the thyroid gland. calcium metabolism ○ Biosynthesis of calcitonin occurs in the parafollicular cells or Functions of Thyroid Hormone C-cells. J.A, L.C. 1 7 4 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr SCN- is also known as thiocyanate TcO4- is also known as sodium pertechnetate. ClO4- is also known as perchlorate. ○ Summary: Iodide goes through the sodium/iodide symporter(NIS) → Iodide enters the follicular cells 1.Uptake of iodide into the follicular cells ○ Transporter: sodium/iodide symporter (NIS) ○ The uptake of iodide into the follicular cells via the sodium/iodide symporter (NIS) Note: iodide is different from iodine. Iodide is the Peroxidase-mediated Steps (2 to 4) ion of iodine ○ Enzyme: Thyroid peroxidase ○ can be inhibited by large doses (TPO) of I− as well as anions (e.g. SCN−, ○ Gene expression of TPO is TcO4− and CIO4−) stimulated by thyroid- Iodide is needed to stimulating hormone (TSH) produce thyroid TSH - is released by hormones, but if iodine anterior pituitary levels are too high in the hormone to signal thyroid body, it inhibits step 1. gland to release thyroid Hence, the production of hormone. thyroid hormones TSH - increases decreases. production of TPO to Iodine concentration signal the thyroid to must be within the range release thyroid hormones. to prevent inhibition. J.A, L.C. 1 7 5 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr ○ Peroxidation is blocked by high levels of intrathyroidal iodide and and thioamide drugs This also applies to any step that requires thyroid peroxidase. ○ Steps 2 to 4 are called peroxidase-mediated steps because it needs thyroid peroxidase for these three steps 3. Organification – iodination of to occur. tyrosine residues within the thyroglobulin molecule ○ Is one of the Peroxidase-mediated Steps (2 to 4) ○ 2 iodine binds to tyrosine = diiodotyrosine (DIT) ○ 1 iodine binds to tyrosine = monoiodotyrosine (MIT) ○ Step where iodine is incorporated into the tyrosine residues (iodination) within the 2. Peroxidation of iodide into iodine thyroglobulin molecule ○ Is one of the ○ Summary: iodide that is Peroxidase-mediated Steps (2 converted into iodine inside the to 4) follicular cells → iodine is ○ Summary: Iodide is oxidized by incorporated into the tyrosine thyroid peroxidase → iodide residues in the thyroglobulin turns into iodine → the charge of molecule → Hence, iodine is now iodine is now 0 since it is combined with the thyroglobulin elemental molecule ○ Note: Thyroglobulin is a protein which has amino acids. One of the amino acids of thyroglobulin is tyrosine J.A, L.C. 1 7 6 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr thyroxine is still bound to thyroglobulin and is not a hormone yet since it is still bound to thyroglobulin. 4. Coupling ○ Is one of the Peroxidase-mediated Steps (2 to 4) ○ Step where either the MIT and 5. Proteolysis–T4, T3, MIT, and DIT are DIT combine or the DIT and DIT released from thyroglobulin combine. ○ T3–thyroglobulin → T3 & ○ MIT + DIT = T3–thyroglobulin thyroglobulin MIT has one iodine while ○ T4–thyroglobulin → T4 & DIT has two iodine. Hence, thyroglobulin T3 (triiodothyronine) is ○ Step where MIT and DIT are formed since there are detached from the now three iodine. The thyroglobulin, now forming the triiodothyronine is still T3 and T4. bound to thyroglobulin ○ Note: MIT and DIT deiodinated and is not a hormone yet and the iodine is since it is still bound to reutilized/recycled to form more thyroglobulin. thyroxine and triiodothyronine ○ DIT + DIT = T4–thyroglobulin ○ Proteolysis is blocked by high DIT has two iodine. Hence, levels of intrathyroidal iodide. when these two DIT are combined, T4 (thyroxine) is formed since there are now four iodine. The J.A, L.C. 1 7 7 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr ○ Only about 0.04% T4 and 0.4% T3 exist in free form (FT4 & FT3) ○ Summary: T3 and T4 are released from the thyroglobulin → T3 and T4 are now in the thyroid gland → T3 and T4 must be released into the different tissues of the body → the blood receives T3 and T4 before it is 6. Exocytosis/release of thyroid distributed into the different hormones into the blood tissues of the body. ○ most of the hormone released is thyroxine – 5:1(T4:T3) For every 5 T4 that is released, only 1 T3 is released along with it. ○ T4 and T3 is reversibly bound to thyroxine-binding globulin (TBG) Once T4 and T3 is released, it is not usually free since it is bound to 7. Deiodination – peripheral thyroxine-binding metabolism of T4 into 3,5,3′- globulin(TBG). triiodothyronine (T3) TBG is different from ○ Enzyme: 5′deiodinase (D1, D2, thyroglobulin. D3) Thyroglobulin is in the ○ 3,5,3′- triiodothyronine is the thyroid gland to produce complete name of T3. thyroid hormones while ○ T3 is 3-4x more potent/active TBG are found in the than T4. plasma. If T3 is high, an individual Thyroxine-binding is more prone to globulin is a plasma hyperthyroidism or binding protein specific thyrotoxicosis. for thyroid hormones. ○ D1 – 24% of the circulating T3. J.A, L.C. 1 7 8 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr D1 - position of iodine in the structure ○ D2 – 64% of the circulating T3; also regulates T3 levels in the brain and pituitary. D2 - position of iodine in the structure Responsible for sending negative feedback and initiating negative feedback mechanism Peripheral Metabolism of Thyroxine when T3 levels are too high, which signals the hypothalamus and pituitary gland to stop producing TRH and TSH, respectively. ○ D3 – produces inactive 3,3′,5′- triiodothyronine (reverse T3 Activation of Thyroxine: D1 and D2 of [rT3]). the thyroxine(T4) undergo deactivation D3 - position of iodine in by removing iodine → it becomes T3 the structure Inactivation of Thyroxine: D3 of D3 is for the deactivation thyroxine undergoes inactivation by of T4 into reverse T3 removing iodine → thyroxine becomes ○ Summary: T4 and T3 is inactive → thyroxine is now reverse T3 released into the blood → Peripheral metabolism of thyroxine - peripheral occurs in the blood metabolism/conversion of T4 Thyroid Hormone Kinetics into T3 occurs → T4, which has a higher ratio, is converted into T3 with the involvement of the enzyme 5′deiodinase (D1, D2, D3) → T4 loses 1 iodine during the deiodination ○ J.A, L.C. 1 7 9 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr Significant Thyroid Hormone Kinetics: Hypothalamus produces TRH → TRH T3 is more active/potent but its signals anterior pituitary to release TSH half-life is shorter (easily degrades) → TSH signals thyroid gland to release Oral absorption of T3 is higher than T4 thyroid hormones In terms of volume of distribution, T3 is Just enough iodine - stimulatory for more distributed in different tissues the thyroid to produce thyroid and organs of the body than T4 due to hormones its potency Too much iodine - inhibitory Thyroid Function Tests Factors that increase the thyroid hormone production: cold temperatures, psychosis, circadian rhythm, exposure to extreme stress Extreme stress, GHIH (somatostatin), corticoids - inhibits production of thyroid hormones High levels of T4 and T3 - signals anterior pituitary glands and hypothalamus to stop release of TRH Nice to know information and TSH Hypothalamic-Pituitary-Thyroid Axis: Thyroid Regulation Thyroid Disorders J.A, L.C. 1 8 0 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr Primary Hyperthyroidism - T3 and T4 is high even without the signal from the anterior pituitary gland. ○ Low TSH but thyroid gland keeps producing hormones Secondary Hyperthyroidism - the Levels of T3 and T4 for types of hyper continuous signal of the TSH from or hypothyroidism - Board exam anterior pituitary gland causes the question continuous production of T3 and T4. Low thyroid hormone(T3 and T4) level - hypothyroidism High thyroid hormone(T3 and T4) level - hyperthyroidism Primary – pathology(problem) is within the thyroid gland ○ The problem is T4 and T3 since the thyroid gland releases them. Secondary – pathology is within the pituitary gland Manifestations of Thyrotoxicosis and ○ The problem is TSH since the Hypothyroidism pituitary gland releases them. Tertiary hypothyroidism – low TRH (hypothalamus); rare Primary Hypothyroidism - the problem is the thyroid → T4 and T3 are low even if the anterior pituitary gland releases TSH → Hence, even if TSH signals thyroid to release T3 and T4, it is still low Secondary Hypothyroidism - the thyroid does not produce T3 and T4 because anterior pituitary doesn’t signal it to release these hormones Hypothyroidism - low T4 and T3 Thyrotoxicosis - high T4 and T3 J.A, L.C. 1 8 1 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr Thyrotoxicosis = increased appetite; attack thyroid gland, Hypothyroidism = decreased apetite which causes scarring or destruction of thyroid Hypothyroidism gland. Common Causes: ○ Drug-induced – e.g. ○ Iodine deficiency – e.g. cretinism amiodarone or congenital hypothyroidism Amiodarone - has high ↓ iodine = cannot iodine in its structure. produce thyroid Signs & Symptoms: hypometabolic hormones and hyposympathetic (e.g. weight Cretinism - occurs when gain, slow movement, ↑sleeping time, mother’s iodine is very constipation) low, which compromises ○ Hyposympathetic - the development of the parasympathetic effects baby(stunted growth, dominate mental retardation, short ○ Hypometabolic - slow lifespan). metabolism ○ Post-procedural (iatrogenic) – e.g. thyroidectomy (removal of Drugs for Hypothyroidism thyroid or a part of it), Requires replacement therapy of T4 radioactive iodine therapy and T3 Hint: Levothyroxine Na Post-procedural/iatrogen ○ Synthetic sodium salt of T4 ic is caused by Synthetic thyroxine ○ Preparation of choice for thyroid compromisation or replacement and suppression destruction of thyroid therapy (maintenance gland. treatment) ○ Autoimmune disease – e.g. ○ DOC and maintenance Hashimoto’s thyroiditis treatment for hypothyroidism Hashimoto’s thyroiditis - Liothyronine Na produces antibodies that ○ Synthetic sodium salt of T3 J.A, L.C. 1 8 2 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr ○ Used for emergency states Thyrotoxicosis – high levels of (myxedema coma) circulating T3 and/or T4 For emergency states ○ Proper term for high T3 and/or only since T3 has a short T4 half-life, not used for Hyperthyroidism – form of maintenance. Used in end-state thyrotoxicosis caused by untreated hyperfunctioning thyroid gland hypothyroidism ○ Very active thyroid (myxedema coma). Myxedema coma - Thyrotoxicosis medical emergency; may Causes: require intubation; ○ Solitary thyroid nodules – are extremely low hyperfunctioning/hypersecretin metabolism; g life-threatening Goiter - hypothyroidism. hyperplasia/enlargement Liotrix of the thyroid; different ○ A 4:1 mixture of T4 and T3 from solitary thyroid 4 - T4; 1 - T3 nodules ○ Board exam question Solitary thyroid nodules - Thyroid, USP (Desiccated thyroid) cyst within the thyroid ○ Prepared from dried and gland defatted animal thyroid glands ○ Autoimmune disease – e.g. and contains a mixture of T4, T3, Grave’s disease (caused by MIT, and DIT thyrotropin receptor antibody or ○ Not used clinically due to TRAb) protein antigenicity Autoimmune disease - ○ Disadvantage: protein produces TRAb which antigenicity, product instability, acts as the TSH by variable hormone stimulating the concentrations, difficulty in thyrotropin receptor to laboratory monitoring signal the thyroid gland to release T3 and T4. Thyroid Hormone Excess J.A, L.C. 1 8 3 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr TRAb in autoimmune ○ Carbimazole - metabolized in disease - binds to vivo into methimazole thyrotropin receptor ○ Carbimazole - prodrug of instead of the TSH. methimazole Hashimoto - hypo; ○ Propylthiouracil (PTU) - Grave’s Disease - hyper Signs & Symptoms: hypermetabolic DOC/antithyroid drug for and hypersympathetic (e.g. weight pregnant women. loss, tremors, palpitations, diaphoresis, ○ Propylthiouracil (PTU) - used easy fatiguability, diarrhea, irritability) for emergency states ○ Methimazole - used for Antithyroid Drugs maintenance treatment Inhibits production of thyroid MOA: inhibits thyroid peroxidase = hormones in hyperthyroidism inhibits peroxidation, organification 1. Thioamides 2. Anion Inhibitors and coupling 3. Iodides Inhibits Step 2 to 4 (Peroxidation, 4. Radioactive Iodine Organification, and Coupling) 5. Adrenoceptor-blocking Agents PTU additional MOA :inhibits peripheral 6. Miscellaneous Agents: Radiocontrast conversion of T4 to T3 dyes, Glucocorticoids ○ Inhibits 5’ deiodinase Also used to control hyperthyroidism prior to thyroid surgery DOC for hyperthyroidism or thyrotoxicosis Thioamides Propylthiouracil (PTU), Methimazole, Carbimazole J.A, L.C. 1 8 4 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr Thiocarbamide moiety - activity Clinical use: iodide-induced hyperthyroidism(amiodarone-induced hyperthyroidism) Adverse Effects: aplastic anemia(perchlorate), goitrogenic ○ Thiocyanate, Perchlorate, Pertechnetate can promote goiter. Thyroid Storm/Thyrotoxic Crisis - T4 ○ Note: Both hypothyroidism and and T3 is too high hyperthyroidism can have Aplasia cutis - no skin in scalp area goiter, but it is more common in (for infants) hypothyroidism because the Black box warning of propylthiouracil TSH is high. - Hepatitis ○ Board exam question Iodides Strong iodine solution (Lugol’s Anion Inhibitors solution), Potassium iodide (KI), Thiocyanate, Perchlorate, Iodine Pertechnetate Can cross the placenta. MOA: competitively inhibits uptake of High iodine content inhibits production iodide into the thyroid gland of thyroid hormone, which is beneficial Monovalent anions with a hydrated for thyrotoxicosis radius similar in size to that of iodide MOA: inhibits organification and ○ Thiocyanate, Perchlorate, hormone release Pertechnetate inhibit iodide by ○ Organification - iodination of entering the thyroid gland tyrosine residues of the instead of iodide. thyroglobulin. Effects can be overcome by large Other effects: decrease the size and doses of iodides = unpredictable vascularity of the hyperplastic gland effects of anion inhibitors J.A, L.C. 1 8 5 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr ○ Applicable for hyperplasia of MOA: emits β particles and x-rays that thyroid gland. cause destruction of the thyroid gland, ○ Vascularity - release of T3 and which stops the thyroid gland from T4 producing T4 and T3. Usually combined with a thioamide, Administered orally rarely used as sole therapy Dose: 1 take (Specific for 131I) Clinical use: used before thyroid Patient is quarantined for 48-72 hours surgery or radiation exposure, after treatment treatment of spirotrichosis (potassium Adverse effect: hypothyroidism iodide/KI) Contraindicated in pregnancy and ○ Spirotrichosis - fungal infection lactation caused by sporothrix. ○ Can cause death of fetus or Gardener’s disease. infant. Adverse Effects: Adrenoceptor-blocking Agents ○ Iodism – acneiform rash, Propranolol, Metoprolol, Atenolol swollen salivary glands, mucous ○ Propranolol - most used. membrane ulcerations, Beta blockers conjunctivitis, rhinorrhea, drug MOA: inhibits peripheral conversion of fever, metallic taste, bleeding T4 to T3 and blocks peripheral effects disorders, and rarely, of thyroid hormones anaphylactoid reactions. ○ Counters sympathetic effects ○ Fetal goiter (CI in pregnancy since they block beta and lactation). adrenoceptors. Radioactive Iodine Causes clinical improvement of 131I - – therapeutic (only isotope used hyperthyroid symptoms but do not for treatment of thyrotoxicosis). typically alter thyroid hormone levels = 123I – diagnostic for hyperthyroidism or symptomatic treatment ONLY thyrotoxicosis. ○ This definition is also applicable Miscellaneous Agents for 125I (rare). J.A, L.C. 1 8 6 Extra note:  PHARMACOLOGY 2 ❁ SEMESTER 1 LEC | 30101 | PROF. CHARINA GAIL B. ISIDORO SY. 2024-2025 rr Radiocontrast dyes (Ipodate, Iopanoic acid) and Glucocorticoids (Dexamethasone) ○ Radiocontrast dyes - Contains iodine MOA: inhibits peripheral conversion of T4 to T3 ○ Retains T4 ○ Important Note: The inhibition of the peripheral conversion of T4 to T3 is important since T3 is more active. J.A, L.C. 1 8 7 Extra note: