Thyroid Diseases Dr SIVA

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Pharmacotherapeutics of Thyroid diseases : 

Pharmacotherapeutics of Thyroid diseases

Anatomy and Physiology of the Thyroid Gland : 

Anatomy and Physiology of the Thyroid Gland Member of the Endocrine System Secretes thyroid hormones, thyroxine and calcitonin, which regulate metabolism and growth. Located in neck adjacent to the 5th cervical vertebra (C5). Composed of epithelial cells which specialize in the absorption of iodine and, of course, secretion of thyroid hormones. Follicles surround a protein core, the colloid, where thyroglobulin, a substrate in thyroid hormone synthesis, and thyroid hormones are stored.

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TSH is released from anterior pituitary in 1-2 hrs cycle → thyroxin (T4) & triiodothyronin (T3). 75% of T4 & T3 are bound to thyroid-binding globulin (TBG), the rest bound to albumin and transthyretin. Free T4=0.04% and free T3=0.05%. Iodine is trapped by the gland and converted to iodide to synthesize thyroglobulin. Each molecule carries 3-4 molecules of T4. T3 is produced by peripheral deiodination of T4 and it is 3 times more potent than T4. Anatomy and Physiology of the Thyroid Gland

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T4 – inactive (prohormone) 3,5,3’,5’-tetraiodothyronine (thyroxine) t1/2 - 6 days metabolized by deiodinases to T3 or rT3 T3 - active 5’-deiodinase -> 3,5,3’-triiodothryonine t1/2 - 0.05 days rT3 - inactive 5-deiodinase -> 3,3’,5’-triiodothyronine THYROID HORMONES

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In pregnancy: TBG ↑ in first 2 wks to reach a plateau at 20 wks due to ↑ Oestrogen level . ↑ TBG → ↑ serum T4 & T3 with no change in free T4 & T3. Iodine deficiency (↑GFR + fetal thyroid uptake) → ↑ thyroid gland uptake & enlargement (goitre). hCG occupies TSH receptors → ↓TSH but it stimulates the gland → ↑ T4. Placental conversion of T4 to T3 to prevent excess T4 & even low T4 level in late pregnancy.

Fetal thyroid function : 

Fetal thyroid function First trimester: fetus needs maternal T4 for brain development. Small amount of maternal T4 crosses placenta before 12 wks. Maternal T3,T4 & TSH does not cross the placenta after 12 wks. Fetal thyroid produces T3 & T4 after 10 wk’s gestation & reaches the adult levels at 36 wks. Thyrotropin-releasing hormone (TRH) & iodine cross the placenta

Synthesis of Thyroid Hormones : 

Synthesis of Thyroid Hormones Regulation: The hypothalamus in the brain secretes thyroid releasing hormone, TRH, that target the pituitary gland which, in turn, secretes thyroid stimulating hormone, TSH. The pituitary gland’s sensitivity toward TRH varies with the body’s need for thyroid hormones. TSH is absorbed into the thyroid, stimulating the thyroid to absorb iodine and synthesize hormones. Thyroid hormones provide negative feedback for TSH production via a “homeostatic feedback loop.”

Synthesis of Thyroid Hormones : 

Synthesis of Thyroid Hormones TH Synthesis: Thyroid peroxidase (TPO) catalyzes the conversion of iodide (I2) to iodine (I-) using H2O2 as a cofactor. TPO then catalyzes the addition of iodine to the C-3 and C-5 position of a tyrosine residue of thyroglobulin. Two iodinated thyrosine rings condense to form thyroxine, or T4, with four iodine substituents. Triiodothyronine, or T3, with three iodine substituents, accounts for about 10% of thyroid hormone production.

TH Effects on Metabolism : 

TH Effects on Metabolism TH serves as a nuclear transcription factor, regulating gene expression in targeted cells to increase metabolism. Increase size and number of mitochondria in the cell. Synthesizes cytochromes which feed into the electron transfer chain of cellular respiration, stimulating metabolism through increasing ATP production. Increase ATPase concentration, the enzyme which cleaves a phosphate group from ATP forming ADP and inorganic phosphate. Increased K+ and Na+ concentrations in the cell.

TH Effects on Metabolism : 

TH Effects on Metabolism Increase the body’s basal metabolic rate, BMR, to maintain electrochemical gradient in cell. Stimulate carbohydrate metabolism and lipolysis, or the break down of fats. Affects protein synthesis. Increase the body’s sensitivity to cathecholamines, i.e. adrenaline, which is also a derivative of TH.

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Increases metabolism & temperature Sensitizes -adrenergic receptors, magnifies the effect of their stimulation Increases contractility, ejection fraction, heart rate, diastolic relaxation, venous return, cardiac output. Decreases afterload CLINICAL EFFECTS OF T3

Clinical symptoms : 

Clinical symptoms Psychiatric Hyperactivity Emotional lability Anxiety Decreased concentration Insomnia

Clinical symptoms : 

Clinical symptoms Muscle Weakness Proximal muscle weakness in 50% pts. Decreased muscle mass and strength May take up to six months after euthyroid state to gain strength Hypokelemic periodic paralysis especially in Asian men (cause is not known) Myesthenia Gravis, especially in Grave’s disease.

Clinical symptoms : 

Clinical symptoms Endocrine Increased sensitivity of pancreatic beta cells to glucose Increased insulin secretion Antagonism to peripheral action of insulin Latter effects usually predominate leading to intolerance.

Etiology : 

Etiology 1 Grave’s disease Autoimmune disease caused by antibodies to TSH receptors Can be familial and associated with other autoimmune diseases 2 Toxic multi-nodular goiter 5% of all cases 10 times more common in iodine deficient area Typically occurs in older than 40 with long standing goiter

Etiology : 

Etiology 1 Grave’s disease Autoimmune disease caused by antibodies to TSH receptors Can be familial and associated with other autoimmune diseases 2 Toxic multi-nodular goiter 5% of all cases 10 times more common in iodine deficient area Typically occurs in older than 40 with long standing goiter

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Etiology 3 Toxic adenoma More common in young patients Autonomically functioning nodule

Etiology : 

Etiology 4 Thyroiditis Subacute Abrupt onset due to leakage of hormones Follows viral infection Resolves within eight months Can re-occur Lymphatic and postpartum Transient inflammation Postpartum can occur in 5-10% cases in the first 3-6 months Transient hypothyroidism occurs before resolution

Etiology : 

Etiology 5 Treatment Induced Hyperthyroidism Iodine Induced Excess iodine indirect Exposure to radiographic contrast media Medication Excess iodine increases synthesis and release of thyroid hormone in iodine deficient and older patients with pre-existing goiters

Etiology : 

Etiology Amiodarone Induced Thyroiditis Up to 12% of patients, especially in iodine deficient cases Most common cause of iodine excess in US. Two types: *Type I - due to excess iodine Amiodarone contains 37% iodine. *Type II –– occurs in normal thyroid

Etiology : 

Etiology Thyroid Hormone Induced Factitious hyperthyroidism in accidental or intentional ingestion to lose weight Tumors -Metastatic thyroid cancer -Ovarian tumor that produces thyriod hormone (struma ovarii) -Trophoblastic tumor -TSH secreting tumor

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HR, contractility CO O2 consumption, CO2 production Vt, RR / PTH levels bone turnover (i.e. formation/ catabolism) Vasodilation Blood flow

Systems Signs/Sx : 

Systems Signs/Sx Constitutional Sweating, warm/moist skin, muscle weakness, wt loss, appetite CV HR, high-output CHF, cardiomegaly, pulm/periph edema, MVP, Afib, heart block, dysrhythmias Resistant to digitalis/ cardiac glycosides. ‘apathetic’ (i.e. blunted signs/sx) hyperthyroidism in pts age>60, cardiac manifestations predominate, e.g AFib. Pulm RR, min vent

Systems Signs/Sx : 

Systems Signs/Sx Neuro Anxiety, confusion, tremor, seizures GI Secretory diarrhea, alk phos Heme Wbc, Hb, Plts Renal K excretion, Na excretion.

Systems Signs/Sx : 

Systems Signs/Sx Ocular Exophthalmus Derm Vitiligo, hyperpigmentation. Psych Emotional instability, insomnia

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Low TSH Measure Free T4 Level Normal High Measure Free T3 Level Normal High -Subclinical hyperthyroidism -Resolving Hyperthyroidism -Medication -Pregnancy -New thyroid illness T3 Toxicosis Primary hyperthyroidism Thyroid uptake Low High Measure thyroglobulin decreased Increased Exogenous Thyroiditis Iodide exposure Exrtraglandular production DIffuse Nodular hormone Graves disease Multiple areas One “hot” area Toxic multinodular goiter Toxic adenoma

Etiology : 

Etiology Hyperthyroidism with high RIU - Grave’s disease - Toxic adenoma - Toxic multinodular goiter - TSH- producing pituitary adenoma - Hyperemesis gravidarum - Trophoblastic disease

Etiology : 

Etiology Hyperthyroidism with low RIU - Subacute thyroiditis - Exogenous harmone intake - Ectopic ovarii - Metastatic follicular thyroid CA - Radiation thyroiditis - palpation thyroiditis - Amiodarone induced

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THYROID FUNCTIONAL STATES

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THYROID FUNCTIONAL STATES

Conditions that Impair Thyroid Function: Hypothyroidism : 

Conditions that Impair Thyroid Function: Hypothyroidism Insufficient amount of thyroid hormone synthesized causing lethargy and weight gain, among other symptoms. Primary hypothyroidism is typically caused by Hashimoto’s Disease, an auto-immune disorder in which the thyroid is destroyed by antibodies. Impaired hypothalamus and pituitary function, typically due to a tumor, can inhibit the secretion of THS, causing secondary hypothyroidism. A diet insufficient in iodine causes hypothyroidism as well.

Symptoms of Thyroid Disfunction: Goiter : 

Symptoms of Thyroid Disfunction: Goiter Enlarged thyroid, symptom of hypothyroidism. Goiters form for different reasons depending on the cause of hypothyroidism Hashimoto’s disease, also known as chronic lymphocytic thyroiditis, causes goiters due to the accumulation of lymphocytes. The decreased amount of thyroid hormones in the body, due to Hashimoto’s or other thyroid disorders including infection, signals the increased production of TSH which accumulates in the thyroid causing a characteristic goiter. Goiters form due to an insufficient amount of ingested iodine and serve to increase the surface area of the thyroid and aid in its absorption of iodine.

Treatment for Hypothyroidism : 

Treatment for Hypothyroidism Hormone replacement therapy Administered orally with a bioavailability ranging from 48%-80%. Levothyroxine—Synthetic T4 Liothyronine—Synthetic T3 Liotrix—Combination of synthetic T4 and T3 Natural Thyroid Hormones—Thyroid hormones derived from pigs, contains T4 and T3 Armour Thyroid Dosage specific to individual and is determined by their TSH serum levels. Typically 1.5μg T4 per kg body weight. Because thyroid hormones serve to increase heart rate, T4, the inactive form, is typically administered to older patients who have an increased risk for heart attack on account of their age. Synthetic T3 is reserved for younger patients, who do not have a history of heart problems and individuals non-responsive to T4 treatment. Some men are inefficient in the conversion of T4 to T3, making combination drugs like Litrix and Armour Thyroid ideal treatment options. Dosage for individuals suffering from secondary hypothyroidism determined by the amount of free T4 and T3 circulating in their system. Administering too high of a dosage leads to hyperthyroid symptoms.

Hyperthyroidism : 

Hyperthyroidism The over production of thyroid hormones. Symptoms include fatigue, weight lose, rapid heart beat, anxiety, swollen eyes, and sensitivity to hot temperatures. Causes: Grave’s disease, and autoimmune disorder in which antibodies serve as agonists to the THS receptors on the thyroid’s surface, causing thyroid growth and activation of hormone synthesis and secretion. Thyroid tumors which cause the uncontrolled synthesis and secretion of thyroid hormones. Thyroiditis, inflammation of the thyroid typically caused by infection.

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INHIBITION OF T4 SYNTHESIS Propylthiouracil (PTU) or methimazole INHIBITION OF T4 SECRETION Iodide, sodium iopanoate BLOCK CONVERSION OF T4 TO T3 -blockers, PTU, amiodarone BLOCK PERIPHERAL ACTIONS OF T3 -blockers SUPPORTIVE THERAPY TREATMENT OF THYROTOXICOSIS

Beta Blockers : 

Beta Blockers Prompt relief of adrenergic symptoms Propranolol widely used Any beta blocker can be used, but non-selectives have more direct effect on hyper-metabolism Start with 10-20 mg q6h Increase progressively until symptoms are controlled Most cases 80-320 mg qd is sufficient CCB can be used if beta blocker not tolerated or contraindicated

Iodides : 

Iodides Iodide blocks peripheral conversion of T4 to T3 and inhibits hormone release. These are used as adjunct therapy Before emergency non-thyroid surgery Beta blockers cannot curtail symptoms Decrease vascularity before surgery for Grave’s disease

Iodides : 

Iodides Iodides are not used for routine treatment because of paradoxical increase of hormone release with prolonged use Commonly used: Radiograph contrast agents -Iopanoic acid -Ipodate sodium Potassium iodide Dose 1 gram/ 12 weeks

Anti-thyroid Drugs : 

Anti-thyroid Drugs They interfere with organification of iodine—suppress thyroid hormone levels Two agents: -Tapazole (methimazole) -PTU (propylthiauracil)

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Anti-thyroid Drugs Remission rate: 60% when therapy continued for two years Relapse in 50% of cases. Relapse more common in -smokers -elevated TS antibodies at end of therapy

Anti-thyroid Drugs : 

Anti-thyroid Drugs Methimazole Drug of choice for non-pregnant patients because of : Low cost Long half life Lower incidence of side effects Can be given in conjunction with beta-blocker Beta-blockers can be tapered off after 4-8 weeks of therapy Dose 15-30 mg/day

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Anti-thyroid Drugs Methimazole Monthly Free T4 or T3 until euthyroid Maintenance dose 5-10 mg/day TSH levels may remain undetectable for months after euthyroid and not to be used to monitor the therapy

Anti-thyroid Drugs : 

Anti-thyroid Drugs Methimazole At one year if patient is clinically and biochemically euthyroid and TS antibodies are not detectable, therapy can be discontinued Monitor every three months for first year then annually Relapses are more common in the first year but can occur years later If relapse occurs, iodide or surgery although anti-thyroid drugs can be restarted

Anti-thyroid Drugs : 

Anti-thyroid Drugs Propyl Thiouracil (PTU) Prefered for pregnant patients Methimazole is associated with rare genetic abnormalities Dose 100 mg t.i.d Maintenance 100-200 mg/day Goal: Keep Free T4 at upper level of normal

Anti-thyroid Drugs : 

Anti-thyroid Drugs Complications Agranulocytosis up to 0.5% High with PTU Can occur suddenly Mostly reversible with supportive Tx Routine WBC monitoring controversial Some people monitor WBC every two weeks for first month then monthly Advised to stop drug if they develop sudden fever or sore throat

Radioactive Iodine : 

Radioactive Iodine Treatment of choice for Grave’s disease and toxic nodular goiter Inexpensive Highly effective Easy to administer Safe Dose depends on estimated weight of gland Higher dose increases success rate but higher chance of hypothyroidism Some studies have shown increase of hypothyroidism irrespective of dose

Radioactive Iodine : 

Radioactive Iodine Higher dose is favored in older patient Cardiac disease Other group needs prompt control Toxic nodular goiter or toxic adenoma

Radioactive Iodine : 

Radioactive Iodine Side effects 50% of Grave’s ophthalmology can develop or worsen by use of radioactive iodine Use 40-50 mg Prednisone for at least three months can prevent or improve severe eye disease in 2/3 of patients Use lower dose in ophthalmology because post Tx hypothyroidism may be associated with exacerbation of eye disease Smoking makes ophthalmopathy worse.

Radioactive Iodine : 

Radioactive Iodine Use of anti-thyroid drugs with iodine is not recommended in most cases May improve safety for severe or complicated cases Withdraw three days before iodine Tx Beta blockers used to control symptoms before radioactive iodine and can be combined throughout Tx Iodine containing meds need to be stopped several weeks before therapy

Radioactive Iodine : 

Radioactive Iodine Safety Most radioactive iodine is eliminated in the urine, saliva and feces in 4-8 weeks. Have double flushing of toilet and frequent hand washing for several weeks No close contact with children and pregnant patients for 48-72 hours Additional Tx may be needed after three months if indicated

Treatment for Hyperthyroidism : 

Treatment for Hyperthyroidism Anti-thyroid drugs—Inhibits thyroid hormone synthesis by irreversibly binding to TPO inhibiting its ability to break down iodine (I2→I-) and covalently attach it to the tyrosine residue of thyroglobulin. Propylthiouracil Methimazole Carbamizole─Degraded to methimazole in the body. Radioactive Iodine Thyroidectomy β-Blockers used in the treatment of thyroiditis to treat symptoms.

Anti-Thyroid Drugs : 

Anti-Thyroid Drugs Effective in the long-term treatment of hyperthyroidism. 6-8 weeks before maximum effect of the drug achieved. Drug inhibits hormone synthesis, so hormones synthesized prior to drug use will continue to cause hyperthyroid condition. Typical side effects include headache, nausea, vomiting, itchy skin and rash, and muscle aches and pains. Serious liver damage, decreased red and white blood cell synthesis, as well as decreased platelet production have been reported in a few cases. The drug’s interaction with other enzymes responsible for clotting factor synthesis accounts for some of these serious side effects. Administering too high a dosage of anti-thyroid drugs can cause hypothyroidism.

Thyroid Treatment: Potential Drug Interactions : 

Thyroid Treatment: Potential Drug Interactions Drugs that reduce thyroid hormone production Lithium Iodine-containing medications Amiodarone (Cordarone) Drugs that reduce thyroid hormone absorption Sucralfate (Carafate) Ferrous sulfate (Slow Fe) Cholestyramine (Questran) Colestipol (Colestid) Aluminum-containing antacids Calcium products Drugs that increase metabolism of thyroxine Rifampin (Rifadin) Phenobarbital Carbamazepine (Tegretol) Warfarin (Coumadin) Oral hypoglycemic agents Drugs that displace thyroid hormone from protein binding Furosemide (Lasix) Mefenamic acid (Ponstel) Salicylates

TSH Replacement Drugs : 

TSH Replacement Drugs Thyrotrophic alpha—A synthetic form of TSH. Administered intravenously. Used in thyroid cancer treatment. Tumors of the hypothalamus or pituitary gland can cause the uncontrolled release of TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary cancer of the thyroid. Partial or total thyroidectomy typical. Following thyroidectomy, the individual is dependent on exogenous thyroid hormones to regulate metabolism, but thyrotropin alpha is also used to suppress the release of endogenous TSH, which could trigger cancerous growth again. Used as a diagnostic tool to determine the reoccurrence of cancer.

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Drug Interactions

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