FKG3 Tambahan - Hormone Thyroid

8/23/2019 FKG3 Tambahan - Hormone Thyroid

1/21

Thyroid Physiology and Pharmacology

Overview

o

Thyroido Two hormones types released:

thyroxine and triiodothyronine

calcitonin

o Thyroxine and triiodothyronine are important in:

1 1 growth

1 1 development

1 1 maintaining normal body temperature

1 1 energy metabolism regulation

Receptors:

Thyrotropin (TSH, a pituitary hormone) modulates thyroid function by

binding to TSH receptors (TSH-R)

TSH-R: localization and properties:

o basolateral membrane of thyroid follicular cells.

Iodide:

Metabolism:

Iodide intake: gastrointestinal tract absorption from food, water, or

medication.

Iodide:

o rapid absorption

o enters extracellular pool

o thyroid removes amount required for hormone secretion

excess iodide: urinary excretion

Non-Physiological Thyroid Simulation:

o Graves' disease:

Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and Antithyroid Drugs, in Basic

and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 619-633.


2/21

Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine

14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.

and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2012-

2034

Thyroid Hormones

Chemistry of thyroid hormones:

o Active isomer -- levo (L-form) -- thyroxine, triiodothyronine, reverse

iodothyronine (reverse T4)

Pharmacokinetics:

o T4 -- well absorbed from the ileum and duodenum following oral

administration-- about 80% absorbed on average

o Modification of absorption:

food

drugs (e.g., sucralfate, iron, aluminum-containing antacids)

o T3 -- almost completely absorbed (95%) following oral administration

o T4 and T3 absorption may be impaired by myxedema (may require parenteral

administration {IV}, as a result)

o Factors that alter T4 and T3 clearance:

hyperthyroidism: increases

hypothyroidism: decreases

Drugs (hepatic microsomal enzymes inducers): Clearance is enhanced;

Euthyroid state may be maintained because of thyroid hyperfunction.

phenobarbital

carbamazepine (Tegretol)

phenytoin (Dilantin)

rifampin

o Increases in the number of TBG binding sites (due to pregnancy, estrogen use,oral contraceptive use)


3/21

more thyroid hormone is bound; elimination rate declines (only free

hormone can be eliminated); normal hormone concentration

would be eventually restored

Mechanism of Hormone Action:

1. Unbound T4 and T3 diffuse into the cell (passive diffusion, possibly active transport)

2. Inside cell:

3. T4 converted to T3

4. T3 is transported to the cell nucleus where T3 binds to a specific T3

nuclear receptor

Thyroid hormones: metabolic actions

o nuclear receptor activation results in increased RNA and protein synthesis:examples --

increased Na/K ATPase causes increased ATP turnover,

increased oxygen consumption --calorigenic effect

Thyroid Hormone Effects*

Physiological

system

Hyperthyroidism

(thyrotoxicosis)Hypothyroidism

skin --appendages

warm, moist skin;

sweating; fine, thin

hair; Plumber's

nails; pretibialdermopathy

(Graves' disease)

pale, cool, puffy skin; brittle

hair and nails

Eyes, face

Upper lid retraction

(wide stare);

periorbital edema;

exophthalmos,

diplopia (Graves'

disease)

Eyelid drooping; periorbital

edema; puffy, nonpitting

facies; large tongue

Cardiovascular decreased peripheral

resistance, increasedcardiac output,

increased peripheral

resistance, decreasedcardiac output, stroke


4/21

stroke volume, heart

rate, pulse pressure;

congestive heart

failure (high-

output); increased

contractility,.arrhythmogenic;

angina

volume, heart rate, pulse

pressure; congestive heart

failure (low output);

bradycardia (low voltage

ECG with prolonged PRinterval, flat T wave);

pericardial effusion

Respiratorydyspnea; reduced

vital capacity

hypoventilation (CO2

retention) pleural effusions

Gastrointestinal

increased appetite;

increased bowel

movement

frequency;

hypoproteinemia

decreased appetite,

decreased bowel movement

frequency; ascites

CNS

Nervousness,

hyperkinesia,

variable emotional

states

lethargy, neuropathy

Musculoskeletal

Weakness; fatigue;

hypercalcemia,

osteoporosis,

increased deep

tendon reflex

muscle fatigue, reduced

deep tendon reflex,

increased alkaline

phosphatase, LDH, AST

Renal

Increased renal blood

flow; increased GFR;

mild polyuria

Decreased renal blood flow;

decreased GFR; reduced

water excretion

Hematopoietic

anemia (increased

RBC turnover);

increased

erythropoiesis

anemia (decrease

production rate, decreased

iron absorption, decreased

folate acid absorption,

autoimmune pernicious

anemia),decreased

erythropoiesis

Reproductive

decreased fertility;

menstrual

irregularity;

enhanced gonadal

steroid metabolism

infertility;hypermenorrhea,decreased libido; impotence,

decreased gonadal steroid

metabolism

Metabolic increased basal rate;

negative nitrogen

balance,

hyperglycemia;

increased free fatty

acids, decreased

cholesterol andtriglycerides;

decreased basal rate;

delayed insulin degradation,

with increased sensitivity;

enhanced cholesterol and

triglyceride levels;

decreased hormone

degradation; decreasedrequirements for fat-and


5/21

increased hormone

degradation;

increased

requirement for fat-

and water-soluble

vitamins; enhanceddrug detoxification

water-soluble vitamins;

decreased drug

detoxification.

* * Adapted from Table 38-4, Greenspan, F.S., and Dong, B. J.. Histamine, Thyroid and

Antithyroid Drugs, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-

Lange, 1998, p 625.



Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.


2034

Thyroid preparations:

o Synthetic:

levothyroxine

liothyronine

liotrix

o Animal origin:

dessicated thyroid-- never justifiable; many disadvantages {protein

antigenicity; product instability and variable hormone concentration;

difficulty and lab assessment}

o Preparations of choice: synthetic levothyroxine:

Applications:

thyroid replacement suppression therapy


6/21

Rationale:

11 low-cost

11 stability

11 non-allergenic (no foreign protein)

11 serum levels readily obtained

1 1 long half-life (seven days) -- supports once-daily dosing

1 1 since T4 is converted to T3 inside the cell, T4 administration produces both hormones

o Liothyronine -- more active than levothyroxine but not recommended because

of:

11

shorter half-life (multiple dosing)

11 more costly

11 higher hormonal activity enhances cardiotoxicity (T3 -- contraindicated in patients

with cardiac disease)

11 most appropriate use: short-term TSH suppression

Antithyroid Drugs:

Overview

o Purpose:


7/21

reduction of thyroid activity

reduction of hormone effects

o Approach:

use drugs that change tissue response to thyroid hormones

destroy the the thyroid with surgical or radiation interventions

o Definition:

"goitrogens" --

1. compounds that suppress T3 and T4 secretion

2. thereby increasing TSH

3. increased TSH levels produces thyroid gland enlargement(goiter)

o Antithyroid drugs include:

thioamides

iodides

radioactive iodine

Thioamides:

o Major drugs for thyrotoxicosis:

Propylthiouracil

rapidly absorbed

bioavailability: 50 -- 80% (incomplete absorption/large first-

pass effect)

metabolism: glucuronidation by the liver; excreted by the

kidney

short half-life (1.5 hours) but accumulated by the thyroid

crosses placental barrier (increased protein binding compared

to methimazole makes propylthiouracil preferable for use in

pregnancy since less free drug is available to cross into the

fetus)

Methimazole

(about 10 times more active than propylthiouracil)

well absorbed

accumulated by the thyroid


8/21

crosses the placental barrier

Mechanism of Action: thioamides

11 Major action: inhibits thyroidal peroxidase-catalyzed reactions, blocking iodine

organification: -- thus preventing hormone synthesis.

11 Propylthiouracil and methimazole (too a much reduced degree) inhibit peripheral

deiodination of T4 and T3

11 Slow onset of pharmacological effect

Toxicity:

Frequency of adverse effects: 3-12%.

Most common: maculopapular pruritic rash

Most serious potential reaction: agranulocytosis -- risk 0.3% -

0.6 % of patients; reversible upon discontinuation; cross

sensitivity between propylthiouracil and methimazole

possibly increased risk in:

o elderly

o patients receiving high-dose methimazole

Anion Inhibitors

o Competitive inhibition:

Perchlorate

Pertechnetate

Thiocyanate

o Major clinical use -- potassium perchlorate ( not often used because of the

possibility of causing aplastic anemia)

blockade of thyroid gland reuptake of I- in patients with iodide-induced

hyperthyroidism

Iodides

o rarely used now as monotherapy

o Actions on the thyroid:

inhibit organification

inhibit hormone release-- major action

Mechanism: perhaps inhibition of thyroglobulin proteolysis


9/21

decreased thyroidal size and vascularity

may induce hyperthyroidism (jodbasedow)

may precipitate hypothyroidism

o Clinical Considerations:

may be useful in short-term management of thyroid storm

maybe helpful in preoperative preparation for surgery (due to reduction

in gland vascularity, size, and fragility)

Major disadvantages:

11 iodide therapy increases intraglandular iodine concentration

may delay initiation of thioamides treatment

may delay use of radioactive iodine treatment

11 chronic iodide used in pregnancy: avoid -- iodide crosses the placenta and may cause

fetal goiter

11 iodide as monotherapy: not appropriate; iodide block lasts only 2-8 weeks;

withdrawal at this time may exacerbate thyrotoxicosis

Iodide use, if at all, should be initiated only after thioamide treatment

and not used if radioactive iodine therapy is planned

Iodinated Radiographic Contrast Media

o Useful in management of hyperthyroidism (off label use)

o Ipodate and iopanoic acid inhibit T4 to T3conversion in:

kidney

liver

pituitary gland

brain

o additional mechanism: iodine release-mediated inhibition of hormone release

o Clinical Use:

11 adjunctive treatment of thyroid storm

11 alternatives if thioamides and iodides are contraindicated

o Toxicity:similar to iodides; relatively nontoxic.

Radioactive Iodine:


10/21

o131I is the radioactive isotope used for treating thyrotoxicosis.

o Mechanism of Action:

rapidly absorbed, concentrated in the thyroid

incorporated into thyroid follicles

beta emission is the basis for therapeutic efficacy

Thyroid parenchymal destruction occurs within a few weeks.

o Therapeutic Advantages for radioiodine:

11 good efficacy

11 easy to administer

11 low expense

11 pain free treatment

o Contraindication:

131I-- not administered to pregnant women or nursing mother;131I

crosses placental barrier and excreted in breast milk.

Adrenergic receptor blocking drugs:

o

Rationale: reduction of sympathetic manifestations in thyrotoxicosis:

Applicable drugs:

beta adrenoceptor blockers

guanethidine

Agent of choice: propranolol (Inderal, nonselective beta-receptor

antagonist)


11/21

Hypothyroidism

Overview: hypothyroidism1. cause: inadequate thyroid hormone synthesis

2. Cretinism -- when hypothyroidism is present from birth and accompanied by

developmental abnormalities

3. Myxedema: severe hypothyroidism associated with:

deposition of hydrophilic mucopolysaccharides in the dermis (ground

substance) and other tissues-- causing:

facial feature thickening

doughy skin induration

Pretibia myxedema


12/21

Adult hypothyroidism: Pretibial myxedema in the foot and lower extremity skin

1999 KUMC Pathology and the University of Kansas, used with permission;courtesy of Dr. James Fishback, Department of Pathology, University of Kansas

Medical Center.

Hypothyroidism: Causes/Classification

Thyroid

Thyroprivic* Goitrous

Congenital development defect Biosynthesis defect (genetic)

Idiopathic (primary) Transmitted by the mother

(antithyroid drugs)

Postablative {postsurgical,131I} Iodine deficiency

Postradiation {e.g. for lymphoma} Drug-induced {e.g. salicylates,


13/21

lithium,iodides,

phenylbutazone,iodoantipyrine}

chronic thyroiditis (Hashimoto's

disease); interleukin 2

Suprathyroid (Trophoprivic)

Pituitary Hypothalamic

Panhypopituitarism Congenital defect

Isolated low TSH levels Infection (e.g. encephalitis)

Neoplasm; Infiltrative (sarcoidosis)

Hypothyroidism: pathogenesis

1. inadequate thyroid hormone synthesis causes TSH hypersecretion which

results in goiter

2. if this compensatory physiological response is insufficient, goitrous

hypothyroidism occurs

o Causes of goitrous hypothyroidism (North America)

most common cause: Hashimoto's disease

Mechanism:

A. defective binding of iodide

B. abnormal secretion of iodoproteins

Iodide-induced goiter with or without hypothyroidism: intrinsic defect

inorganic binding mechanism

Euthyroid patients with Graves' disease {particularly

following surgery or radioiodine therapy}, patients with

Hashimoto's disease, and normal fetuses are particularlysusceptible to iodide-induced goiter.


14/21

(Right) Struma lymphomatosa in Hashimoto thyroiditis, gross. Note: diffuse,

pale yellow infiltrate affecting the entire thyroid. The yellow infiltrate is caused

by an influx of lymphocytes, which may form follicles. Normal thyroid (Left)

1999 KUMC Pathology and the University of Kansas, used with permission;courtesy of Dr. James Fishback, Department of Pathology, University of Kansas

Medical Center.

Hypothyroidism: Clinical presentation

o Neonates (note that cretinism may be present at birth, but usually is

apparent within the first few months after birth as a function of the extent

of thyroid failure)

manifestations:

physiologic jaundice

constipation

somnolence

feeding problems

Since early clinical diagnosis may be difficult and early treatment is

necessary to ensure normal intellectual development,all neonates

should be screened for hypothyroidism by measuring serum T4 or TSH

o Young Children:


15/21

coarse features, protruding tongue, broad, flat nose, widely set eyes,

dry skin, coarse hair. impaired mental development, retarded bone age,

epiphyseal dysgenesis, delayed dentition.

o Older Child:

retardation of linear growth, delayed puberty

poor school performance

o Adult:

fatigue, lethargy, constipation, cold intolerance,

slowing of intellectual and motor activity

lessened appetite; increased weight

dry skin; dry hair (may fall out)

deeper, hoarser voice

With Advanced Disease: (florid myxedema)

dull, expressionless facies, sparse hair, periorbital puffiness ,

large tongue, rough and doughy skin (cool, pale)

enlarged heart (dilation, pericardial effusion)

adynamic ileus

Without treatment: myxedema coma possible with respiratory

depression and increased PCO2

o Laboratory Tests :

single most useful: serum TSH

increased levels in thyroprivic and goitrous

normal or undetectable in pituitary or hypothalamic

hypothyroidism

in hypothalamic hypothyroidism: TSH

hypersecretion is associated with hypersecretion of

other pituitary hormones

All hypothyroidism:

decreased serum T4 and free T4I

serum T3 may be decreased less than serum serum T4

Some other abnormal laboratory results:

increase serum cholesterol (hypothyroidism of thyroid

origin)


16/21

increased creatinine phosphokinase

increased aspartate transaminase

indications of pernicious anemia

Pharmacological treatment:

o Synthetic hormones:

levothyroxine, preferred

liothyronine

liotrix (combination of new L-thyroxine and liothyronine)

o Neonatal, infantile, and juvenile hypothyroidism : early full replacement

therapy vital to improve likelihood of:

normal intellectual development

normal growth

o If neonatal, infantile, and juvenile presentations result from pituitary and

hypothalamic hypothyroidism, treatment with hydrocortisone should precede

thyroid replacement therapy:

Rationale:acute adrenocortical insufficiency may because by the

increase in metabolic rate with increase glucocorticoid clearance

following thyroid hormonal treatment

o Adults:

rapid treatment desirable especially in patients with:

11 myxedema coma

1 1 hypothyroid patients needing to undergo emergency surgery (these patientshave extreme sensitivity to CNS depressants);

IV levothyroxine with hydrocortisone may be

appropriate

to patients with myxedema coma and systemic illness may have

reduced ability to convert T4 to T3. In these cases supplemental

liothyronine may be added to levothyroxine.

*- Thyroprivic: refering to lack of thyroidhormone (e.g. removal of the gland or

suppression of glandular function)

Thyrotoxicosis:


17/21

Definition:clinical, physiological, biochemical consequences when tissues respond

to excess thyroid hormone

Most important causes: those associated with prolonged hormone

overproduction by the thyroid.

Causes:

o Extra-pituitary unregulated thyroid stimulation:

1. Graves' disease

2. Hashimoto's disease

3. trophoblastic tumor

o Chronic thyroiditis

o Excessive TSH secretion by pituitary tumor (rare)

o Autonomous thyroid gland hyperfunction

o Ingestion of meat contaminated with animal thyroids ("hamburger toxicosis")

Hyperthyroidism is only associated with conditions in which thyroidal hyperfunction

leads to thyrotoxicosis.

Graves' disease

Three major presentations:

o hyperthyroidism with diffuse goiter

o dermopathy

o ophthalmopathy

Thyroid Pathology :

o soft, enlarged, vascular

o Parenchymal hypertrophy/hyperplasia

o Lymphocytic infiltration (suggesting the immunological nature of thedisease)


18/21

"Diffuse toxic goiter of Graves disease, gross, showing symmetric, non-nodular

hypervascular enlargement of the thyroid"

1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of

Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

Graves' disease: other involvements

o generalized lymphoid hyperplasia and infiltration

o spleenic or thymic enlargement

o Thyrotoxicosis associated with:

skeletal muscle fiber degeneration

cardiac enlargement

diffuse liver fibrosis with fatty infiltration

skeletal decalcification

body tissue loss

Ophthalmopathy:characterized by --

1. inflammatory orbital content infiltrate (lymphocytes, mast cells, plasma cells)

2. enlargement of orbital musculature (lymphocytes infiltration, mucopolysaccharides,

edema, fat)

3. eventually -- muscle fiber degeneration; loss of striations; fibrosis

Dermopathy:


19/21

o dermal thickening (lymphocytes infiltration; mucopolysaccharides)

Clinical Presentations:-- Thyrotoxicosis

o Common manifestations (thyrotoxicosis)

nervousness, insomnia, tremors, frequent bowel movements, heatintolerance, sweating, emotional instability

weight loss despite adequate or increased appetite

muscle weakness

oligomenorrhea/amenorrhea in premenstrual women

dyspnea

palpitations

exacerbation of angina/cardiac failure (older patients)

o Ocular Presentations: -- distinct from ophthalmopathy associated with

Graves' disease; ocular signs mainly due to excessive sympathetic stimulation

characteristics stare (widening palprebral fissures)

lid lag

infrequent blinking

failure to wrinkle brow upon upward gaze

o Cardiovascular effects:

wide pulse pressure

sinus tachycardia

atrial arrhythmias (particularly atrial fibrillation)

systolic murmurs

occasionally heart failure

Clinical Presentations: Graves' disease

o Common manifestations:

hyperfunctioning goiter

asymmetric, lobular

ophthalmopathy

Two components: spastic and mechanical

spastic-- stare, lid lag, lid retraction


20/21

proptosis (sensitive to antiadrenergic agents)

including:

1. ophthalmoplegia

2. periorbital swelling

3. conjunctivitis

4. corneal ulceration, optic neuritis, optic

atrophy

Diagnosis:

in addition to physical manifestations described earlier:

undetectable TSH

Usually increased values of T4 and T3.

Thyroid Storm:

o Fulminating increase in symptoms of thyrotoxicosis

o "Medical storm" is now likely to be seen in undertreated patients.

o Precipitated by surgery or complicating illness, often sepsis.

o Presenting syndrome:

extreme irritability

coma or delirium

high fever, 41oC

tachycardia

hypotension

vomiting

diarrhea

o Treatment:

manage dehydration: IV glucose/Saline, vitamin B complex

glucocorticoids (possible reduction in adrenal reserve; increase

glucocorticoid requirement and thyrotoxicosis

digitalis may be required to control elevated ventricular rates in the

presence of atrial fibrillation

Block hormone synthesis by large dose propylthiouracil; followed by

large doses of iodine, oral or parenteral; sodium ipodate may be usedinstead of iodine


21/21

Propranolol (adrenergic antagonist) important in the absence of CHF

Combination treatment with propylthiouracil, iodine, dexamethasone is

likely to result in serum T3 levels returning to normal within one to two

days.



Wartofsky, L., Diseases of the Thyroid, In Harrison's Principles of Internal Medicine

14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S.


2034

FKG3 Tambahan - Hormone Thyroid

Documents

Transcript of FKG3 Tambahan - Hormone Thyroid