Endocrine Pharmacology: Thyroid Hormone Analogs & Inhibitors PDF

ENDOCRINE PHARMACOLOGY: THYROID HORMONE ANALOGS & INHIBITORS Chapter 38: Basic & Clinical Pharmacology, Katzung, 14th ed. (pgs. 711-726) Chapter 22: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 867-884) Chapter 43: Goodman & Gilman’s Pharmacological...

ENDOCRINE PHARMACOLOGY: THYROID HORMONE ANALOGS & INHIBITORS Chapter 38: Basic & Clinical Pharmacology, Katzung, 14th ed. (pgs. 711-726) Chapter 22: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 867-884) Chapter 43: Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th ed.  LECTURE OBJECTIVES - 1 1. Explain process for hypothalamic-pituitary stimulation of thyroid hormones 2. Describe biosynthesis of triiodothyronine & thyroxine 3. Explain biological targets for drug therapy 4. Explain drug structure & relationship to thyroid function 5. Describe mechanism of action (MOA) and pharmacokinetics for different thyroid drugs 6. List indications, contraindications, and adverse effects for these thyroid drugs  LECTURE OBJECTIVES - 2 7. List biological targets for drug therapy to treat hyperthyroidism 8. Describe structure and relationship of anti- thyroid drugs to thyroid function 9. Describe mechanism of action (MOA) and pharmacokinetics for anti-thyroid drugs 10. List the indications, contraindications, interactions, and adverse effects 11. List drugs used as adjuvant agents during ‘thyroid storm’; and, describe the purpose for their use  PHARMACOLOGICAL AGENTS COVERED IN THIS LECTURE Hypothyroidism  dessicated thyroid (Armour® Thyroid; Westhroid®)  levothyroxine (Levoxyl®; Synthroid®)  liothyronine (Cytomel®; Triostat®)  liotrix (Thyrolar®) Adjuvants  propranolol Hyperthyroidism (Inderal®)  propylthiouracil (generic; PTU)  atenolol  methimazole (Tapazole®) (Tenormin®)  Sodium iodine (Iodopen®)  esmolol  Sodium iodine (Na131I; Hicon®) (Brevibloc®)  nadolol  HYPOTHALAMUS- PITUITARY - ENDOCRINE AXES 1. Hypothalamus produces (releasing) hormones / biomolecules to stimulate (+) or inhibits (-) the pituitary 2. Pituitary responds  synthesizes and releases specific hormones that enter the circulation 3. Circulating hormones act on specific endocrine glands/ tissues that respond by producing a biological effect HPT: hypothalamus – pituitary – thyroid Harrison’s Principles of Internal Medicine, 18 th ed.  HYPOTHALAMUS- PITUITARY-THYROID (HPT) - AXIS Dopamine TRH from Glucocorticoi ds hypothalamus Retinoids Somatostati n stimulate synthesis/ release of TSH  anterior pituitary Release of TSH inhibited by T3/ T4, Thyroid hormones, T3 / T4 act as negative SST, dopamine, ↑ feedback  inhibit glucocorticoids synthesis & release or of both: TRH & TSH retinoids Iodide is necessary for thyroid hormone Goodman & Gilman; 13 ed. th  Diagram courtesy of ThyroidPharmacist.com SIGNS & SYMPTOMS Notes:  THYROID HORMONES T3 / T4 AND PHYSIOLOGICAL EFFECTS  MECHANISM OF ACTION OF THYROID HORMONES The actions of T3 on several T3, via its nuclear organ systems are shown receptor, induces new 9 Increases BMR proteins generation which produce effects Potentiates brain development Potentiates the beta effects of catecholamines  MAJOR CLINICAL EFFECTS OF THYROID HORMONES (TH) Cretinis Growth & Development m  Critical construction of brain structures  Irreversible mental retardation w/ severe hypothyroidism  Treatment essential during pregnancy  Physical development of nearly entire body Thermogenesis (TH stimulates heat generation) Cardiovascular Effects Result of TH  TRa1 - cardiomyocyte  Effects on Na/K-ATPase and Ca2+ channels REGULATION OF THYROID HORMONE SECRETION  THYROID HORMONES Derived from MIT & DIT condensation  Iodinated tyrosine residues  Tri- and tetra-iodinated thyronines (T3 / T4) Iodination state  De-iodination of outer ring increases activity  T3 is 5X more potent than T4  De-iodination of the inner ring  inactivity  rT3 or reverse T3  CONFORMATIONAL EFFE CTS OF THYROID MOLEC Substituents on inner ring change ULES conformation  Thyronine is free to rotate (torsion ~ 120 degrees)  Iodination restricts rotation around ether bond  Conformation affects receptor binding affinity  THYROTROPIN ALPHA (THYROGEN®)  Recombinant human TSH (rhTSH)  Clinical use  diagnostic tool; test ability of iodine uptake by thyroid tissue, and release thyroglobulin (Tg)  Dose: 0.9 mg IM, followed by 2nd dose 24 hrs later  MOA: agonist at TSH receptors; (Gs) in thyroid follicular cells  Stimulates synthesis and release of T4 and T3 hormones  Pharmacokinetics: t1/2 = 25 hours  Adverse effects: nausea  THYROXINE (T4) / TRIIODOTHYRONINE (T3) FUNCTION THROUGH NUCLEAR RECEPTORS Type II nuclear receptors 1. TR binds DNA (TRE via TR-DBD) before binding ligand (fT3 or fT4) 2. Free T3 / T4 transported inside cell; then, translocates  nucleus 3. Ligand binds TR via TR-LBD; T3 has higher binding affinity than T4 4. Co-repressor bound to TR-DNA complex is ‘kicked off’ Multiple receptor subtypes  TRα1 (cardiovascular and skeletal)  TRα2 (expression is unclear)  TRβ1 (liver >> kidney ≈ heart Monocarboxylic > brain) acid Intracellula transporter; MCT r  REGULATION OF THYROID FUNCTION Activation  Hormones (TRH and TSH)  Physical stimuli Inhibition  Hormones & NT (SST, DA, corticosteroids)  T3 and T4 Transport  T3 & T4 both highly bind to plasma proteins  Thyroxine-binding globulin (TBG) binds both  CLINICAL EFFECTS T3 / T4 – METABOLISM Metabolism  lipids & carbohydrates via TRb1  TH induces hepatic expression  LDL receptors ( LDL)  Hyperthyroidism  lower plasma LDL & T-chol  Hypothyroidism  higher plasma LDL & T-chol  TH have complex effects on carbohydrate metabolism  Thyrotoxicosis is insulin-resistant state  impaired glucose tolerance or clinical diabetes may result  Most hyperthyroid pts usually euglycemic;  Diabetics may require  insulin  Hypothyroidism  decreased insulin & glucose absorption;  Diabetics may require  insulin  MAJOR STEPS IN BIOSYNTHESIS OF THYROID HORMONES A. uptake of iodide ion (I–) by the gland via NIS (Na+/I- symporter) B. oxidation of iodide; iodination of tyrosyl groups on thyroglobulin C. coupling of iodotyrosine residues by ether linkage  iodothyronines D. resorption of thyroglobulin colloid from lumen into the cell E. recycling & reuse of I– in thyroid cells via de-iodination  SUMMARY OF BIOLOGICAL TARGETS Thyroidal biosynthetic reactions  Stimulation by TRH and TSH  Inhibition by SST, DA, and elevated glucocorticoids  Iodide transport and oxidation  Iodination and peripheral metabolism Activity of thyroid molecules  Transport to the target tissue via circulation (TBG)  Transport into the cell (transporters may be tissue specific)  Monocarboxylic acid transporter (MCT); T3/T4, bidirectional, diverse  Action at Type II nuclear receptors (thyroid response elements)  Additionally activates PI3K (endothelial NO production; vasodilation) DRUGS TO TREAT THYROID HORMONE DEFICIENCY  THYROID REPLACEMENT THERAPY Synthetic T3 and T4  levothyroxine (Levothyroid, Synthroid, others)  liothyronine (Cytomel)  liotrix (Thyrolar) Mammalian T3 and T4  Thyroid desiccated (Armour Thyroid)  THYROID DRUGS: INDICATIONS AND INTERACTIONS Indications  Hypothyroidism - severe form is myxedema  Pituitary TSH suppression (2° pituitary)  Post-surgical or radiation thyroidectomy (i.e., thyroid cancer)  Autoimmune (Hashimoto’s thyroiditis)  Drug-induced hypothyroidism Impact of thyroid hormones /analogs on medications  Increased clotting factor catabolism affects anticoagulants  monitor protime / INR for pts on warfarin & thyroid disorder  hyperthyroidism; warfarin dose may need to be adjusted down  hypothyroidism; warfarin dose may need to be adjusted upward  THYROID DRUGS: SIDE EFFECTS/ CONCERNS Side Effects  Similar to hyperthyroidism symptoms  Fatigue, heat intolerance, palpitations, increased bp  Chronic use: headache, GI upset, and osteoporosis Concerns  Narrow therapeutic index – titration necessary  Not recommended to change preparations Contraindications  LEVOTHYROXINE (UNITHROID®, LEVOXYL® SYNTHYROID®)  Synthetic, 100% T (L-tetraiodothyronine) 4  Dose: 100 – 200 mcg PO once daily, take on empty stomach  MOA: precursor to T that is ligand; agonist for TR 3  Pharmacokinetics:  Oral administration varying bioavailability; high protein binding  t - same as endogenous (6-8 days in euthyroid) 1/2 I O  Side effects: see earlier slide HO I OH  Drug-drug interactions: (refer to earlier slides) NH2  Increases anti-coagulant response I O I  Insulin & oral hypoglycemics; decreases effectiveness Levothyroxine  Digoxin; T stimulates Na+/K+-ATPase expression 4  Foods/supplements reduce absorption; take on empty stomach  LIOTHYRONINE (CYTOMEL®, TRIOSTAT®)  Synthetic, 100% T3 (L-triiodothyronine)  Dose: 25 – 100 mcg PO once daily, on empty stomach  MOA: agonist at nuclear T3 receptors (higher binding affinity >> T4)  Pharmacokinetics:  Oral administration, well absorbed; high protein binding  t1/2 is same as endogenous (< 2 days in euthyroid) I O HO I  Side effects: see earlier slide OH NH2  Drug-drug interactions: (refer to earlier slides)H O I  Increases anti-coagulant (warfarin) response Liothyronine  Insulin & oral hypoglycemics; decreases effectiveness  Digoxin; T4 stimulates expression of Na+/K+-ATPase  Potential for food to reduce absorption of drug  LIOTRIX (THYROLAR®) Synthetic; 20% T3 & 80% T4  Combination provides T  slowly metabolized: T & rT ; and 4 3 3 T3  Dose: levothyroxine 50-100 mcg/ liothyronine 12.5 – 25 mcg PO, daily  MOA: agonist at T3 receptors; Transcription / translation genes  Pharmacokinetics:  Oral Absorption: T is 40 – 80%; T is 95% 4 3  T has greater affinity for TBG (affects PK) 4  t : T is 6 – 7 days; T < 2 days ½ 4 3  Side effects: see earlier slide  Drug-drug interactions: (same as earlier slides)  Amiodarone inhibits metabolism of T to T (and rT ) 4 3 3  Anti-coagulants, hypoglycemics, digoxin, bile acid sequestrants  DRUGS / OTHER FACTORS AFFECTING THYROID HORMONE MEDICATIONS Inhibits levothyroxine GI absorption:  food, iron salts, Al-antacids, PPIs, BAS (colestipol),  CaCO3, raloxifene, PO4- binders Increases levothyroxine metabolism: (CYP3A4 inducer)  phenytoin, carbamazepine, rifampin, sertraline Impaired peripheral deiodinase (activation):  Thiouracil derivatives (thioamides)  amiodarone Decrease pharmacodynamic (PD) effect:  estrogen derivatives, pregnancy DRUGS TO TREAT THYROID HORMONE EXCESS  ANTITHYROID DRUGS Drugs used for the treatment of hyperthyroidism : Inhibition of hormone synthesis :  Propylthiouracil, Methimazole & carbimazole Blockade of hormone release :  Iodides: KI, NaI , Iodinated contrast media. Radioactive Iodine 131 Anion Inhibitors :  Perchlorates, Thiocynates. Beta blocking drugs : Propranolol.  HYPERTHYROIDISM & THYROTOXICOSIS Elevated thyroid hormone levels / stimulators  Graves’ disease: thyroid stimulating Igs  TSH-R  Subclinical hyperthyroidism: reduced TSH & normal T3/ T4  Toxic (nodular) goiter: elevated total and free T3  Thyroid storm: life-threatening thyrotoxicosis exacerbation Symptoms of excess thyroid hormones  Elevated metabolism, temperature, heart  IONIC INHIBITORS & IODIDE Iodide  Potassium iodide (ThyroSafe, Iosat, Lugol’s solution)  OTC solutions Glandular destruction  Radioactive iodine (Iodotope) Ionic inhibitors  Fluoroborate  Perchlorate  Pertechnetate  Thiocyanate  NON-PRESCRIPTION IONIC INHIBITORS Structure / mechanism of action  Similar charge and size as iodine  Fluoroborate, perchlorate, pertechnetate, and thiocyanate  MOA: Competitive inhibition of iodide transport by NIS  Prevents iodide “concentration” by the thyroid Adverse effects  Fluoroborate is equally as active at perchlorate  Perchlorate seldom used because of fatal aplastic anemia  POTASSIUM IODIDE (OTC) (THYROSAFE, IOSAT, LUGOL’S SOLUTION) Clinical Uses:  Pre-operative preparation for surgical treatment  Thyroid storm; > 1 hr after anti-thyroid drugs; and w/ propranolol  Pre-treatment  prior to radiation exposure Structure & mechanism of action  Inhibits multiple biosynthetic steps via negative- feedback  Inhibits synthesis if [I-]intracellular is above critical concentration  Decreases vascularity & size of thyroid gland Contraindications:  POTASSIUM IODIDE (THYROSAFE, IOSAT, LUGOL’S SOLUTION) Pharmacokinetics  Rapid onset of action useful in thyroid storm  Inhibition of hormone synthesis is transient (escape 2 – 8 wks)  Inhibition of hormone release lasts 10 – 14 days  Formulation does not affect activity Side effects: uncommon  Acneiform rash, metallic taste, swollen salivary glands Interactions:  ↑ hormone storage reduces thioamide effect; PTU  RADIOACTIVE NA131I Care must be (IODOTOPE) taken by everyone Structure & mechanism of action handling 131I  Concentrates in thyroid and emits b- & g- radiation  DNA damage resulting in cell apoptosis & gland destruction  Localized radiation typically spares surrounding tissue Pharmacokinetics  Concentration by thyroid results in 25x plasma concentration  Renal elimination is 35 – 75% Contraindications  Pregnancy (and nursing mothers)  Patients with vomiting and diarrhea  Anti-thyroid medications must be discontinued 3-4 days prior  RADIOACTIVE 131I (IODOTOPE) Adverse effect  Typical radiation adverse events  Bone marrow depression, leukopenia, acute leukemia, death  High incidence of delayed hypothyroidism Interactions  Intake of stable iodide (KI) will reduce 131 I uptake by thyroid  Still can have toxic effects in other body tissues  Anti-thyroid and thyroid drugs will affect uptake;  Discontinue anti-thyroid drugs within 1 week prior  ANTI-THYROID DRUGS: THIOAMIDES Thioamides Thiouracil derivatives  Propylthiouracil (PTU)  Methimazole (Tapazole)  Carbimazole* (Approved Outside USA) propylthiouracil methimazole carbimazole  PROPYLTHIOURACIL (PTU) BLOCKS BIOSYNTHESIS OF T4 AND T3 Clinical Uses:  Hyperthyroidism and thyroid storm Thioamide (thiocarbamide necessary for inhibitory activity) Mechanisms of action (MOA):  Inhibits thyroidal peroxidase (iodide activation step)  Inhibition of 5’ deiodination activity (methimazole does not)  C thioketone / unsubstituted N essential for inhibitory 2 1 action  C enol and C / C alkyl groups enhance activity 4 5 6 Pharmacokinetics  PTU is 1/10th potency of Methimazole  Highly protein bound (~80-85%); Readily absorbed  Short t (75 mins) requires frequent dosing (50-100 mg; 3- ½ 4X/day)  PROPYLTHIOURACI L (PTU)  Side effects:  Hepatitis / acute liver failure (blackbox warning)  Leukopenia and nephritis/glomerulonephritis  Minor: skin rash, urticaria, nausea & vomiting  Drug-drug interactions:  Radioactive iodine (I131); discontinue PTU ~ 1 week in advance  Amiodarone and iodide reduce effect of PTU  Decreases warfarin effects due ↓ T4/T3 levels; requires dose adj.  nd rd  METHIMAZOLE (TAPAZOLE®) S BLOCKS BIOSYNTHESIS OF T4 HN N AND T3 Clinical uses: Hyperthyroidism Methimazole  Monitor thyroid levels frequently (FT4 and total / free T3) Thioamide Dose: 15 mg (mild), 30-40mg (mod), 60 mg (severe) PO, 3X/day Mechanism of action (MOA):  Inhibits thyroidal peroxidase, TPO; (10X more potent than PTU)  Lacks 5’ de-iodinase inhibitory activity  N1 methyl group prevents 5’ deiodination inhibition activity Pharmacokinetics:  METHIMAZOLE (TAPAZOLE®)  Side effects:  More frequent/ mild: skin rash, urticaria, nausea & vomiting  Rare/ more severe: agranulocytosis, thrombocytopenia, anemia  Liver impairment is possible (less so than PTU)  Drug-drug interactions:  Radioactive iodine (I131); d/c drug ~ 1 week in advance  Inhibition of Vit. K activity will increase anticoagulant activity  Dose adjustment (↓) of concomitant β-blockers or  ADJUNCT THERAPY IN THYROTOXICOSIS: THYROID STORM  Symptomatic control due to elevated thyroid hormone levels  Does not reduce thyroid hormone levels  Verapamil/ diltiazem - Alternatives for patient intolerant to -blockers Structure and mechanism of action MOA: Antagonize sympathetic stimulation at b-1 / b-2 receptors  Propranolol (Inderal®); dose: 10-40 mg PO, 3- 4x/day  Atenolol (Tenormin®); dose: 25 – 100 mg PO, 1- 2x/day   SUMMARY – PART 1  Biosynthesis of thyroid hormones has many targets  TRH, TSH, NIS, TPO, and 5’-deiodinase  TR subtype distribution determines tissue effects  Thyroid hormones serve many metabolic roles  Reduced function results in lethargy, high serum lipid levels  Significant impact on cardiac function  T4 is 100 times more prevalent in the plasma  SUMMARY – PART 2  Elevated thyroid levels have significant consequences  Increased function  excitation, low serum lipid levels  Inability to produce TH  non-toxic goiter from TSH release  Toxic goiter results from increased TSH and TH release  Thyroid storm is life threatening  Drugs available to reduce thyroid function / destroy gland  Inhibitors target iodine transport, oxidation, and TH synthesis  Radioactive iodide accumulates in thyroid and destroys tissue  Overtreatment is a concern  SUMMARY OF THYROID HORMONE -RELATED DRUGS  Thyrotropin alpha (Thyrogen) – TSH; diagnostic tool Thyroid Hormone Replacements  Levothyroxine (Levothyorid, Synthroid; T4)  Liothyronine (Cytomel; T3)  Liotrix (Thyrolar; T3 : T4)  Dessicated thyroid (Armour thyroid; T3 : T4) Anti-thyroid Drugs  Propylthiouracil (PTU)  Methimazole (Tapazole)  Potassium iodide (ThyroSafe, Iosat, Lugol’s solution)  131I (Iodotope) – radioactive iodine Top 200 Drugs  Levothyroxine  Thyroid (desiccated)  PEARLS: THYROID ENDOCRINE SYSTEM 1. Replacement therapy for hypothyroidism typically uses oral thyroxine; 1X/day 2. Therapeutic goals for hypothyroidism: restore serum TSH concentration to normal range; and relieve the signs & symptoms of hypothyroidism 3. In pregnancy, standard dose of thyroid hormone is usually ↑ 4. Options for treating hyperthyroid patients include antithyroid drugs (eg, PTU and methimazole), radioactive iodine, and surgery. 5. Medical therapy with antithyroid drugs to reduce the concentration of thyroid hormone is the preferred approach in younger patients with hyperthyroidism. 6. In older patients or those w/ cardiac disease, 131I is usually recommended after the patient has been rendered euthyroid with antithyroid medication 7. Initial Tx for thyroid cancer is surgical; radioactive iodine is used to ablate remnant thyroid tissue  REFERENCES 1. Basic & Clinical Pharmacology, 15th ed. (2021) by BG Katzung and TW Vanderah. McGraw-Hill Medical (accessed via AccessPharmacy) 2. Foye’s Principles of Medicinal Chemistry, 8th ed. (2019) by Victoria F. Roche, S. William Zito, Thomas L. Lemke, and David A. Williams. Lippincott Williams & Wilkins 3. Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. (2018) by L.L. Brunton, J.S. Lazo, and K.L. Parker. McGraw-Hill (accessed via AccessPharmacy)  THYROID ENDOCRINE CASES A 69-year-old man goes to his family doctor because he has been feeling fatigued and lethargic. His doctor does a complete evaluation. This patient had a myocardial infarction and has a recurrent ventricular arrhythmia. The patient’s TSH is elevated and his T 4 is slightly decreased. The doctor suspects hypothyroidism and begins replacement therapy with levothyroxine. Q1: Why is the TSH elevated in this patient? Q2: What factors might affect the thyroxine dose in this patient? Q3: What commonly prescribed drugs are associated with iodine-induced hypothyroidism? Q4: What is the goal of levothyroxine replacement therapy? Q5: What are adverse effects associated with levothyroxine therapy?  QUESTIONS 1. Levothyroxine is preferred over liothyronine in management of hypothyroidism. Give reason. 2. State the mechanism of action and two indications of levothyroxine. 3. How levothyroxine therapy is monitored? 4. State the rationale of using levothyroxine in small doses in elderly patients? 5. State the rationale of using levothyroxine in higher doses in patients during pregnancy? 6. State the mechanism of action and two ADRs of thioamide group of antithyroid drugs 7. How methimazole (thioamide) therapy is monitored? 8. List two indications of methimazole (thioamide) 9. Prophylthiouracil is preferred thiomide during pregnancy and lactation. Give reason. 10. State the rationale of using iodides in preoperative preparation of hyperthyroidism patient. 11. State the rationale of using iodides in treatment of thyroid storm. 12. State the rationale of using iodinated contrast media in treatment of thyroid storm. 13. List drugs that inhibit the conversion of T4 to T3. 14. State the mechanism of action of radioactive iodine. 15. Radioactive iodine is contraindicated in pregnancy, lactation and in young children. Give reason. 16. List two advantages and two disadvantages of radioactive iodine.