Thyroid Drugs PDF

Physiological anatomy of the thyroid gland Ismtmus 2 cm (4.4 x 1.5 x 1.3 cm) The thyroid gland is composed of large #’s of closed follicles that are filled w/ a secretory substance called colloid and lined with cuboidal epithelial cells that secrete into the inferior of the folli...

Physiological anatomy of the thyroid gland Ismtmus 2 cm (4.4 x 1.5 x 1.3 cm) The thyroid gland is composed of large #’s of closed follicles that are filled w/ a secretory substance called colloid and lined with cuboidal epithelial cells that secrete into the inferior of the follicles The major constituent of colloid is the large glycoprotein, thyroglobulin, which contains the thyroid hormones Thyroid gland also contains C cells that secrete calcitonin, a hormone that contributes to the regulation of plasma calcium ion concentration ○ Hormone produced by the parafollicular cells (C cells) of the thyroid gland ○ Its primary role is to help regulate calcium levels in the blood by lowering them when they are too high Thyroglobulin and thyroid peroxidase (TPO) - components in the production of thyroid hormones Thyroglobulin Is a glycoprotein produced by the follicular cells of the thyroid gland Precursor for the synthesis of thyroid hormones (thyroxine (T4) and triiodothyronine (T3)) When iodide is taken up from the bloodstream Is then stored in the colloid until it is broken down to release the hormones into the bloodstream as needed Thyroid Peroxidase (TPO) Enzyme crucial It catalyzes the iodination of tyrosine residues in thyroglobulin Forms precursors Additionally, a role in the coupling of iodinated tyrosine to form T3 & T4 Hypothyroidism  Traditionally defined as deficient thyroidal production of thyroid hormone More common in women H-P-T axis ○ Hypothalamic-Pituitary-Thyroid axis, which is a crucial part of the endocrine system that regulates metabolism, growth, and development ○ Hypothalamus (H): The hypothalamus produces thyrotropin-releasing hormone (TRH), which stimulates the pituitary gland. ○ Pituitary Gland (P): In response to TRH, the anterior pituitary releases thyroid-stimulating hormone (TSH). TSH then signals the thyroid gland to produce thyroid hormones (T3 and T4). ○ Thyroid Gland (T): The thyroid gland, located in the neck, produces T3 (triiodothyronine) and T4 (thyroxine), which regulate various metabolic processes in the body. ○ Axis functions through a feedback loop: elevated levels of thyroid hormones signal the hypothalamus and pituitary to decrease TRH and TSH production, maintaining balance in hormone levels ○ Primary ○ Autoimmune disease (Hashimoto thyroiditis)- most common in US ○ Iodine deficiency- most common worldwide ○ Surgery/radiation therapy ○ Medications (eg, Lithium, tyrosine kinase inhibitors) Secondary ○ Tumors (pituitary adenoma, craniopharyngioma, meningioma) ○ Trauma (surgery, irradiation, head injury) ○ Infiltrative (sarcoidosis, histiocytosis, hemochromatosis) ○ Chronic lymphocytic hypophysitis ○ Drugs (dopamine, glucocorticoids) Diagnosis of primary hypothyroidism  Indicates decreased thyroidal secretion of the thyroid hormone by factors affecting thyroid gland itself Fall in serum concentrations of thyroid hormone causes an increased secretion of TSH resulting in elevated serum TSH concentrations Characterized by high TSH and low free T4 Thyroid peroxidase (TPO) antibodies are elevated in the majority of patients with chronic autoimmune thyroiditis Common symptoms: fatigue, cold intolerance, weight gain, constipation, dry skin, myalgia, and menstrual irregularities Physical examination: goiter, bradycardia, diastolic hypertension, and a delayed relaxation phase of the deep tendon reflexes Metabolic abnormalities: hypercholesterolemia, macrocytic anemia, elevated creatine kinase, and hyponatremia T3/T4 Pharmacology Thyroxine (T4) ○ Half life = 7 days ○ Stable/long acting ○ Intestinal absorption of oral T4 is ~80% Triiodothyronine (T3) ○ Half life = 0.75 days ○ Onset of action: 2–4 hours ○ Rapidly absorbed ○ Markedblood level fluctuations ○ May falsely suppress TSH if taken close to bloodwork Treatment of Primary Hypothyroidism Goal to normalize TSH T4 (levothyroxine, Synthroid) drug of choice Generic/brand-name bioequivalent but altered bioavailability reported Full replacement dose usually about 1.6 mcg/kg (body weight) Absorption more complete/ less erratic in fasting state Patients advised to take L-T4 tablets in morning or late evening ○ Advised to take 30 min before breakfast for better absorption Some patients don’t need full replacement at first; never wrong to start low and titrate up Careful in CAD, elderly: start with lower dose~25-50 mcg/day ○ Anything that has cations (calcium, magnesium) might go against the absorption levothyroxine ○ Be careful w/ anemic patients as well Avoid taking with iron/calcium - impairs absorption Dose titrated up to normalize TSH Recheck 6-8 weeks (1 month) after dose changes and 6-12 months thereafter ○ Get them on a level that is normal TSH T3/T4 & combo. Active form has a lesser half form but very rare it’s used alone? Treatment of choice: Levothyroxine (LT4) Evidence does not support use of LT3/LT4 combinations Armour Thyroid/NP Thyroid ○ 1grain = 60 mg–contains T3 9 mcg, T4 38mcg ○ Nature-thyroid and Westhroid ○ 1grain = 65 mg:contains T3 9 mcg, T4 38mcg ○ Pharmacologic equivalence: 74 mcg of T4 T3 is four times more potent than T4 ○ The way it works varies, it is just taking 75 mcg of Synthroid and patients feel fine and are functional 9 x 4 = 36… 36 + 38 = 74 Clinically 90-100 mcg of Levothyroxine Dose adjustment Increased dose ○ Decreased intestinal absorption due to other problems pt may have ○ Dietary fiber supplements ○ Reduced gastric acid secretion: proton-pump inhibitors/H2 blockers ○ Malabsorption: coeliac disease, bariatric surgery ○ Bile-acid sequestrants ○ Agents that bind L-T4: sucralfate, aluminum hydroxide, ferrous sulfate, calcium carbonate, sevelamer (phosphate binding medication) Increased need for T4 ○ Weight gain ○ Estrogens (TGB, increased iodine storage) ○ Pregnancy Increased metabolic clearance of T4 ○ Antiepileptic drugs (phenobarbital, phenytoin, carbamazepine) ○ Tuberculostatic drugs (rifampicin) Decreased dose (start off 50 mcg) ○ 1) Decreased need for T4 Weight loss Androgens ○ 2) Decreased metabolic clearance of T4 Old age Do not have the same metabolism as before so adjust accordingly Hyperthyroidism Elevated levels of T3 and T4 in the blood Causes ○ Adenomas / carcinomas  If you have a overactive thyroid due to thyroid cancer, different story ○ Thyroiditis Inflammation of thyroid and normally see in Grave’s immunity; an immunity response to the thyroid ○ Autoimmune response causes a hyperactivity Hyperthyroidism does not = to Grave’s disease Grave’s Disease #1 common cause of hyperthyroidism 60-80% but not the only cause of hyperthyroidism Autoimmune disorder associated with circulating immunoglobulins (talking about the involvement from plasmatic cells to the formation of antibodies which is called the humoral response) that bind to and stimulate the thyrotropin (TSH) receptor, resulting in sustained thyroid over activity & it can be familial Not equivalent to proptosis ○ Ex: Proptosis being a cause of hyperthyroidism and has eye involvement, we call it a thyroid eye disease (Grave’s ophthalmopathy) ○ You can have proptosis and not have thyroid issues Symptoms ○ Nervousness, irritability ○ Tremors ○ Palpitation ○ Weight loss ○ Sweating ○ Heat intolerance ○ Diarrhea ○ Short breath ○ Itching ○ Exophthalmos (abnormal protrusion of the eyeball from the eye socket) ○ Thyroid enlargement Treatment ○ Thioamides (normally to unless the hyperthyroidism is going out of proportion) Methimazole By inhibiting thyroid peroxidase, methimazole decreases the incorporation of iodine into thyroglobulin, further reducing the production of T3 and T4 Absorption: absorbed from GIT  Protein binding: most of the drug is free Accumulation: thyroid Excretion: slow, 60-70% of drug is recovered in urine in 48 hrs Half-life: 6 hrs (long ½ life) Administration: as a single dose Pregnancy: not recommended Breastfeeding: not recommended Propylthiouracil (PTU) In addition to inhibiting thyroid hormone synthesis, PTU also reduces the conversion of thyroxine (T4) to triiodothyronine (T3) in peripheral tissues Absorption: both are rapidly Protein binding: 80-90% Accumulation: both are accumulated in thyroid Excretion: kidneys are inactive metabolite within 24 hrs Half-life: 1.5 hrs (short ½ life) Administration: q 6-8 hrs Pregnancy: both cross placenta and fetal thyroid as it is highly protein bound ○ Crossing placenta is less readily so recommended in pregnancy Breastfeeding: less secreted in breast milk; recommended ○ Beta-blockers Help symptoms such as palpitations, anxiety ○ Iodides ○ Radioactive iodine ○ Surgery ○ ^ more invasive treatment Mechanism of action Inhibit the synthesis of thyroid hormones ○ By inhibiting thyroid peroxidase (TPO) enzyme that catalyzes iodide oxidation to form iodine atoms which are added onto tyrosine residues on thyroglobulin for the production of thyroxine or triiodothyronine ○ They block the conversion of T4 to T3 within the thyroid & in peripheral tissues (propylthiouracil) ○ PTU converts more peripherally Adverse effects Do a CMP to check liver enzymes and CBC (to check for granulocytes) Cutaneous reactions ( urticaria , maculopapular rash ) Arthralgia GI upset, Hepatotoxicity (mainly with methimazole) Most dangerous complication is agranulocytosis occur within 90 days of treatment  ○ A life-threatening condition that involves having severely low levels of WBCs (neutrophils) Adrenoreceptor Blocking Agents Adjunctive therapy to relieve the adrenergic symptoms of hyperthyroidism such as tremor, palpitation, heat intolerance and nervousness ○ Sometimes used by itself and are somewhat alright but they get palpitations so beta-blocker is given E.g. Propranolol, Atenolol, Metoprolol Propranolol is contraindicated in asthmatic patients ○ Non-selective beta-blocker that causes vasoconstriction so no no for asthamatics Can use benzoth. To treat anxiety symptoms but can be addicting