Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

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Thyroid gland secretes 2 hormones :Thyroxine (tetraiodothyronine or T4)Triiodothyronine (T3)Secretion ratio T4 to T3 is 15:1Iodine is attached to tyrosine amino acid residuesof thyroglobulin in the gland (organification)Coupling of these residues then produces T4 & T3

Thyroid Physiology

Thyroid Physiology

T4 & T3 released by the gland are bound & transportedby serum proteins :

Thyroxine-Binding Globulin (TBG) : 75 %Thyroxine-Binding Prealbumin (TBPA)Albumin

The free (or unbound) hormone levels are the levelswhich are maintained constant by feedback & regulatethyroid functionTotal measured serum T4 includes bound & unbound

Thyroxine Binding Proteins

Causes of increased TBG levels :Pregnancy, estrogens, cirrhosis, hepatitis,porphyrias

Causes of decreased TBG levels :Protein malnutrition, nephrotic syndrome, hepaticfailure, androgenic steroids, high doseglucocorticoids

Free T4 (FT4) usually constant in the above conditions

Thyroid Hormone

T4 deiodonated in periphery to T3This is 80 % of T3 produced

Other metabolite of T4 is reverse T3 (rT3) which ismetabolically inactiveT3 enters cells & binds to group of nuclear receptors,then affects wide range of cellular metabolic functionsThyroid hormone required for normal cell metabolism

Step 1-Iodide trappingStep 2-Oxidation of iodide to iodineStep -3 Iodide OrganificationStep -4 Formation of T4 and T3Step -5 Release of T4 and T3

Peripheral metabolism of thyroid hormones

The primary pathway for the peripheral metabolism of thyroxine (T4) isdeiodination deiodination of T4 may occur by monodeiodination of the outerring, producing 3,5,3'-triiodothyronine (T3), which is three to four times morepotent than T4

Free form of T3 and T4 enter cell by diffusion /activetransport . T4 is converted to T3 and enters nucleus and bindsto T3 receptors, this leads to increased formation of mRNAand subsequent protein synthesis.

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T4, best absorbed in duodenum and ileum, this can be alteredby food and drugs, such as calcium preparations and antacidscontaining aluminum, intestinal flora .Absorption of T4 is 80% and of T3 is 95%.

Absorption is not affected by mild hypothyroidism but impairedin myxedema with illeus, in this condition parental route ispreferred.

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T4 production is more than T3T4 is converted to T3 in peripheryT3 is more potent than T4T3 acts faster thanT4T3 enters cell easily than T4T3 binds to receptors in nucleus.

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Regulation of Thyroid Hormone

Normal regulation requires intact hypothalamic-pituitary systemHypothalamus secretes Thyrotropin-ReleasingHormone (TRH)TRH then stimulates synthesis & release of thyrotropin(Thyroid Stimulating Hormone or TSH) by the anteriorpituitaryTSH then stimulates the thyroid gland to uptake iodine,synthesize & release T4 & T3T4 & T3 levels feedback to both hypothalamus &pituitary affecting TRH & TSH release

Regulation of Thyroid Hormone

Normal regulation requires intact hypothalamic-pituitary systemHypothalamus secretes Thyrotropin-ReleasingHormone (TRH)TRH then stimulates synthesis & release of thyrotropin(Thyroid Stimulating Hormone or TSH) by the anteriorpituitaryTSH then stimulates the thyroid gland to uptake iodine,synthesize & release T4 & T3T4 & T3 levels feedback to both hypothalamus &pituitary affecting TRH & TSH release

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Hypothalamic –pitutary – thyroid axixThyroid regulation

Hypothyroidism

Cold intoleranceDyspneaAnorexiaConstipationMenorrhagia or amenorrheaArthralgias, myalgiasFatigueDepressionIrritabilityDecreased attention & memoryParesthesias

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Hypothyroidism

SignsDry, yellow (carotenemic ) skinWeight gain (41 % of cases)Thinning, coarse hairMyxedema signs (mucopolysaccharidedeposition in tissues) :

Puffy eyelidsHoarse voiceDependent edemaCarpal tunnel syndrome

Anemia

Primary Hypothyroidism

Autoimmune : most commonSome have lymphocytic infiltration variant

Post surgical thyroidectomyExternal radiationIodine 131 Rx for hyperthyroidismSevere prolonged iodine deficiencyAntithyroid medications (such as lithium)Inherited enzymatic defectsTrue idiopathic

Hypothyroidism and Myxedema Coma

HypotensionBradycardiaPericardial effusionLow voltage EKGProlonged QT intervalInverted / flattened T waves

Thyroid Function Tests

Free T4 Index (FT4I)Correlates with level of Free T4

T3 radioimmunoassay (less useful)Normal 75 to 195 ng / dl

Serum TSHNormal is 0.3 to 5.0 mcU / ml

TRH Stimulation TestMeasures TSH response to TRH IV injectionNormal is increase in TSH to 30 mcU / ml

LEVOTHYROXINE:(T4)

This is the preparation of choice for thyroid replacement andsuppression therapy, because it is stable and has a long (7 days) halflife, to be administered once daily.

Oral preparations available are from 0.025 to 0.3 mg tablets

For parentral use 200-500µg (100µg/ml when reconstituted) forinjection.

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LIOTHYRONINE(T3):

This is more potent (3-4 times) and rapid acting than levothyroxinebut has a short half life (24 hours) compared to levo, is notrecommended for routine replacement therapy, it requires multipledosing in a day.

It should be avoided in cardiac patients.

Oral preparation available are 5-50µg tablets

For parentral use 10µg/ml

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Thyroid hormone preparations

Treatment of Myxedema Coma

O2 +/- intubation / ventilation if resp. failureRapid blood glucose check +/- IV D50 +/-Hydrocortisone 100 to 250 mg IVCautious slow rewarming (warm O2, scalp, groin, & axillawarm packs, +/- NG lavage)Thyroxine (T4) 500 mcg IV, then 50 mcg IV q dayAdd 25 mcg T3 PO or by NG q 12 h (if T4 to T3 peripheralconversion possibly impaired)Careful IV fluid rehydration (watch for CHF)

Disorders of Thyroid HormoneExcess

"Thyrotoxicosis" is the term for all disorders withincreased levels of circulating thyroid hormones"Hyperthyroidism" refers to disorders in which thethyroid gland secretes too much hormoneRadioactive iodine uptake test (RAUI) distinguisheshyperthyroidism from other forms of thyrotoxicosis

Thyrotoxicosis with Elevated RAUI

Graves' DiseasePituitary tumor secreting excess TSHPituitary insensitivity to feedbackHydatidiform moleChoriocarcinomaTestis embryonal carcinomaToxic multinodular goiterToxic uninodular goiterDrugs inducing hyperthyroidism

IodineAmiodaroneLithium

Features of Graves' Disease(Toxic Diffuse Goiter)Most common cause of hyperthyroidism (70 to 85 % of all cases)Caused by thyroid stimulating immunoglobulinsMainly in young adults ages 20 to 505 times more frequent in womenHalf of cases have infiltrative ophthalmopathy with exopthalmos (notseen with other causes of hyperthyroidism)5 % have pretibial myxedemaToxic multinodular goiter-Second most common cause ofhyperthyroidismMost cases in women in 5th to 7th decadesOften have long standing goiterSymptoms usually develop slowly

Symptoms of Thyrotoxicosis

Nervousness, restlessness, shortened attention span,emotional liability, difficulty sleepingIncreased appetiteWeight lossHeat intolerance, feverDiaphoresis,WeaknessMenstrual irregularities

Signs of Thyrotoxicosis

Sinus tachycardia, Atrial fibrillationTremor, hyper-reflexia, muscle wastingWarm, erythematous, moist skinAlopecia, nail friability & separation from bedHyperventilationEyelid retraction, lid lag, persistent stareHyperactive bowel soundsWith Graves' : may have exopthalmos, tender enlargedthyroid, & pretibial myxedema

ThioamidesMETHIMAZOLECARBIMAZOLEPROPYLTHIOURACIL

Radioactive iodine131IODINE

Iodidesaqueous potassium iodide solution- LUGOL’S IODINE

Iodinated contrast mediaORAL IPODATE AND IPANOIC ACID-DIATRIAZOATE

MechanismAgents which interfere production of thyroid hormoneAgents which modify tissue response to thyroid hormonesGlandular destruction with radiation or surgery.

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Methimazole, Carbimazole, Propylthiouracil

Methimazole is 10 times more active thanPropyl thiouracil.

They act by:Inhibiting thyroid peroxidase –catalysed reaction to block

iodine organification.

They block coupling of iodotyrosineThey inhibit peripheral Deiodination of T4 to T3.

Onset of drug is slow requiring 3-4 weeksbefore stores of T4 are depleted.

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Propylthiouracil Methimazole

Absorption Rapid but incomplete At variable rates butcomplete

Vol.of Dist. Approximates body waters Similar

Protein binding more less

accumulation In thyroid Similar

Excretion Kidneys as inactiveGlucuronide in 24 hrs

Excretion slow,60-70%of drug is recovered inurine in 48 hrs

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Propylthiouracil Methimazole

Half life 1.5 hrs 6 hrs

Administration Every 6-8 hrs As a single dose in 24hrs

Duration of activity 100 mg inhibits iodineorganification for 7 hrs

30 mg exertsAntithyroid effect forlonger than 24 hrs

Pregnancy Preferred, though crossplacenta and is conc .infetal thyroid but is highlyprotein bound ,crossplacenta less readily

Cross placenta andconcentrated by fetalthyroid

Nursing mothers Less secreted in breastmilk

secreted

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It occurs in 3-12 % of treated patients

Maculopapular rash and fever are earlier effects.

Urticarial rash, vasculitis, arthralgia, cholestatic jaundice,lymphadenopathy, and hypoprothrombinemia.

Most dangerous complication is agranulocytosis this is infrequent butmay be fatal.

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Well and rapidly absorbed from intestinesRapidly taken by thyroid gland and concentrated thereModerate increase leads to hormone secretion but substantial excessinhibits hormone release and promotes its storage, making the organless vascular and firmer.

Iodides stores in thyroid delays response to thioamidesThey inhibit organification and hormone release.With a dose of > 6 mg /day.

They should be initiated after onset of thioamides therapy.

It also decreases the vascularity of hyperplastic gland

Improvement is rapid within 2-7 days (valuable in thyroid storm)

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Should not be used as a single therapyShould not be used in pregnancyMay produce iodism causing acneform rash, swelling of salivaryglands, mucous membrane ulceration, metallic taste bleedingdisorders and rarely anaphylaxis.

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131 I isotope, administered orallyIt is rapidly absorbed, concentrated in thyroid gland and stored infollicles. It has a half life of 8 days and emits gamma rays and betaparticles. The beta particles get accumulated in gland and destroyparenchyma.It is easy to administer, effective, painless and less expensiveIt causes destruction of parenchyma, necrosis and follicular disruption

Therapeutic effect is due to emission of β-rays.Patients with age above 40 years only can be treated with thisIt crosses placenta and excreted in breast milkIt may cause genetic damage and leukemia and neoplasia, it may becarcinogenic

Iodinated constrast mediasOral ipodate and ipanoic acid andIV diastrizoateThese are richly iodinated compounds which inhibit 5-deiodinase enzymes and prevent conversion of t4 to t3 in liver,kidney, pituitary gland and brain

Drugs causing EuthyroidHyperthyroxinemia

Oral contraceptivesNarcotics (methadone, heroin)PerphenazineClofibrate5-flurouracilHeparinAmiodaroneIodine contrast agents

Thyroid Storm(hyperthyroidism crisis)

"Exaggerated or florid state of thyrotoxicosis""Life threatening, sudden onset of thyroidhyperactivity"May represent end stage of a continuum :

Thyroid hyperactivity to thyrotoxicosis to thyrotoxiccrisis to thyroid storm

"Probably reflects the addition of adrenergichyperactivity, induced by a nonspecific stress, into thesetting of untreated or undertreated hyperthyroidism"

Thyroid Storm

Most cases secondary to Graves' diseaseSome due to toxic multinodular goiterRare causes :

Acute thyroiditisFactitiousMalignancies (most do not efficiently producethyroid hormones)

Thyroid Storm

Important features :High fever (usually over 40 degrees C)Significantly abnormal mental status

Agitation, confusion, psychosis, comaMarked tachycardiaVomiting, diarrheaJaundice (in 20 %)Associated signs of Graves' disease

Thyroid Storm treatment

High flow O2Rapid cooling if markedly hyperthermic

Ice packs, cooling blanket, mist / fans, nasogastric tubelavage, acetominophen (Salicylates contraindicatedbecause cause peripheral deiodination to T3)

IV fluid bolus if dehydratedMay need inotropes instead if in CHF

Propranolol 1 mg doses or labetolol 10 to 20 mg doses IV &repeat doses as needed

IV diltiazem +/- digoxin for rate control for atrial fibIV diuretics if in CHFIV hydrocortisone (or equivalent) 100 mgPropylthiouracil (PTU) 600 to 1200 mg PO or by NGSodium iodide 1 gram IV one hour after the PTUFind and treat the precipitating cause

Thyroid Storm treatment

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