Pharmacology Tyroid and Antitiroid Hormon

7/23/2019 Pharmacology Tyroid and Antitiroid Hormon

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Thyroid & Antithyroid Drugs

Fig 1 Fig 2

＊ Thyroid follicles are the structural & functional units of the thyroid gland.

＊ Each follicle is surround mainly by simple cuboidal epithelium and is

filled with a colloid which mainly composed by thyroglobulin.

＊ Thyroid hormones are mainly synthesized in colloid while the simple

cuboidal epithelium undertaking thyroglobulin production iodide intake &

thyroid hormones release.



2

!!"ynthesis of thyroid hormones"ynthesis of thyroid hormones

Thyroid hormones

triiodothyronine #T$%

tetraiodothyronine #T thyro'ine%

(aterials

iodine & tyrosine

"teps

1. )odide is trapped by sodium*iodide symporter

2. )odide is o'idized by thyroidalth

yroidal peroxidase

peroxidase to iodine$. Tyrosine in thyroglobulin is iodinated and forms ()T & D)T

. )odotyrosines condensation

()T+D)T,T$- D)T+D)T,T

T hi o ami d e d r ugs

MIT: monoiodotyrosine

DIT: diiodotyrosine



$

)ntra*thyroidal synthesis and processing of thyroidal hormones

1. Iodide is taken up at the basolateral cellmembrane and transported to the apicalmembrane

2. olypeptide chains of Tg (thyroglobulin% aresynthesized in the rough endoplasmic reticulumand posttranslational modifications take place inthe /olgi

$. 0ewly formed Tg is transported to the cellsurface in small apical esicles (AV)

. ithin the follicular lumen iodide is actiatedand iodinates tyrosyl residues on Tg producingfully iodinated Tg containing MIT, DIT, T and asmall amount of T! #organification and coupling%which is stored as colloid in the follicular lumen

3. 4pon T"# stimulation illi at the apicalmembrane engulf the colloid and endocytose the

iodinated Tg as either colloid droplets (CD) orsmall esicles (MPV)

5. 6ysosomal proteolysis of the droplets oresicles hydrolyzes Tg to release its iodinatedamino acids and carbohydrates

$. T and T! are released into the circulation

%. DIT and MIT are deiodinated and the iodideand tyrosine are recycled

thyroidal

thyroidal peroxidase

peroxidase



!7egulation of thyroid function



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!!hysiological actions of thyroid hormoneshysiological actions of thyroid hormones

To normali&e growth and development , body

temperature, and energy levels

8Insufficiency' cretinism (infant child), and

myxedema (adult%-8Excess'hyperthyroid

To enhance *+" excitability sensitiity of *-" to +

T! is ! to times more potent than T in heat production/

T in colloid is about times more numerous than T! /



5

cretinism

my'edema

hyperthyroid



Table !%0. (anifestations of thyroto'icosis and hypothyroidism.

"ystem Thyrotoxicosis #ypothyroidism

"kin and appendagesarm moist skin- sweating- heat intolerance-fine thin hair- lummer9s nails- pretibialdermopathy #/raes9 disease%

ale cool puffy skin- dry and brittle hair- brittlenails

:yes face7etraction of upper lid with wide stare-periorbital edema- e'ophthalmos- diplopia

#/raes9 disease%

Drooping of eyelids- periorbital edema- loss oftemporal aspects of eyebrows- puffy nonpitting

facies- large tongue

;ardioascular system

Decreased peripheral ascular resistanceincreased heart rate stroke olume cardiacoutput pulse pressure- high*output heartfailure- increased inotropic and chronotropiceffects- arrhythmias- angina

)ncreased peripheral ascular resistance-decreased heart rate stroke olume cardiacoutput pulse pressure- low*output heart failure-:;/< bradycardia prolonged 7 interal flat Twae low oltage- pericardial effusion

7espiratory system Dyspnea- decreased ital capacityleural effusions- hypoentilation and ;=2

retention

/astrointestinal system )ncreased appetite- increased fre>uency ofbowel moements- hypoproteinemia Decreased appetite- decreased fre>uency ofbowel moements- ascites

;entral nerous system 0erousness- hyperkinesia- emotional lability6ethargy- general slowing of mental processes-neuropathies

(usculoskeletal systemeakness and muscle fatigue- increased deeptendon refle'es- hypercalcemia- osteoporosis

"tiffness and muscle fatigue- decreased deeptendon refle'es- increased alkalinephosphatase 6D? A"T

7enal system(ild polyuria- increased renal blood flow-increased glomerular filtration rate

)mpaired water e'cretion- decreased renal bloodflow- decreased glomerular filtration rate

?ematopoietic system )ncreased erythropoiesis- anemia1 Decreased erythropoiesis- anemia1

7eproductie system(enstrual irregularities- decreased fertility-increased gonadal steroid metabolism

?ypermenorrhea- infertility- decreased libido-impotence- oligospermia- decreased gonadalsteroid metabolism

(etabolic system

)ncreased basal metabolic rate- negatienitrogen balance- hyperglycemia- increasedfree fatty acids- decreased cholesterol andtriglycerides- increased hormone degradation-

increased re>uirements for fat* and water*soluble itamins- increased drug metabolism

Decreased basal metabolic rate- slight positienitrogen balance- delayed degradation ofinsulin with increased sensitiity- increasedcholesterol and triglycerides- decreased

hormone degradation- decreased re>uirementsfor fat* and water*soluble itamins- decreaseddrug metabolism

@



B "ome of T are conerted toT$ in kidney and lier

B The actions of T$ on seeral

organ systems are shown

B BMR: basal metabolic rate-

CNS: central nerous system

(echanism of actions

of thyroid hormonesT!, via its nuclear

receptor, induces

new proteins

generation which

produce effects



C

!! 7epresentatie7epresentatie drugsdr ugs

leothyro'ine #6*T leo'yl synthroid%

liothyronine #T$ cytomel triostat%

liotri' #T plus T$% #euthyroid thyrolar%

Thyroid drugs

!! harmacokineticsharmacokinetics

po easily absorbed- the bioaailablity of T is E and T$ is

C3E.

Drugs that induce hepatic microsomal enzymes #e.g. rifampin

phenbarbital phenytoin and etc% improe their metabolism.



Table !%01. "ummary of thyroid hormone kinetics.

-ariable T T!

olume of distribution 1 6 6

:'trathyroidal pool mcg 3 mcg

Daily production @3 mcg 23 mcg

Fractional turnoer per day 1E 5E

(etabolic clearance per day 1.1 6 2 6

?alf*life #biologic% @ days 1 day

"erum leels

Total3*12 mcgGd6 #5*15 nmolG6%

@*1$2 ngGd6 #1.1*2. nmolG6%

Free.@*1.5 ngGd6 #C*2pmolG6%

.2$*.2 ngGd6#$.3*5.@ pmolG6%

Amount bound CC.C5E CC.5E

Hiologic potency 1

=ral absorption E C3E 1



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!2harmacological effect

see physiological effect

! *linical use

1.?ypothyroidism< cretinism & my'edema-

2.simple goiter< for pathogeny remaining unclear

#endemic goiter directly supply iodine%

$. =thers<

! Aderse reactions

=ermuch leads to thyroto'icosis-

Angina or myocardial infarction usually appears in

ageds



)nhibition of T7? or T"? secretion withoutinduction of hypothyroidism or hyperthyroidism

Dopamine leodopa corticosteroids somatostatin metforminbe'arotene

)nhibition of thyroid hormone synthesis or releasewith the induction of hypothyroidism #oroccasionally hyperthyroidism%

)odides #including amiodarone% lithium aminoglutethimidethioamides ethionamide

lteration of thyroid hormone transport and serum total T! and T leels, but usually no modification of 3T or

T"#

)ncreased TH/ :strogens tamo'ifen heroin methadone mitotane fluorouracil Decreased TH/ Androgens glucocorticoids

Displacement of T$ and T from TH/ with transient

hyperthyro'inemia"alicylates fenclofenac mefenamic acid furosemide

lteration of T and T! metabolism 4ith modified serum T! and T leels but not 3T or T"# leels

)nduction of increased hepatic enzyme actiity0icardipine imatinib protease inhibitors phenytoincarbamazepine phenobarbital rifampin rifabutin

)nhibition of 3′*deiodinase with decreased T$increased rT$)opanoic acid ipodate amiodarone β blockers corticosteroidspropylthiouracil flaonoids

5ther interactions

)nterference with T absorption;holestyramine colestipol ciproflo'acin aluminum hydro'idesucralfate sodium polystyrene sulfonate ralo'ifene ferroussulfate calcium carbonate bran soy

)nduction of autoimmune thyroid disease withhypothyroidism or hyperthyroidism

)nterferon*α interleukin*2 interferon*β lithium amiodarone

Effect of thyroid function on drug effects

Anticoagulation6ower doses of warfarin re>uired in hyperthyroidism higherdoses in hypothyroidism

/lucose control)ncreased hepatic glucose production and glucose intolerance inhyperthyroidism- impaired insulin action and glucose disposal inhypothyroidism

;ardiac drugs?igher doses of digo'in re>uired in hyperthyroidism- lowerdoses in hypothyroidism

"edaties- analgesics)ncreased sedatie and respiratory depressant effects fromsedaties and opioids in hypothyroidsim- conerse in

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1$

;lass 7epresentatie

Thioamides

propylthiouracil

methylthiouracil

methima&ole

carbima&ole

)odides 6I, +aI7adioactie iodine

I*adrenoceptor blockers

1!1I

propranolol

ntithyroid drugs

! Drugs



1



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The thiocarbamide

group is essential for

antithyroid actiity

І. Thioamides

◆"tructure



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2harmacological action

Inhibition of the synthesis of T!T! TT

MechanismMechanism

ll thioamides inhibit peroxidase0cataly&ing reactions

Iodine organification

Iodotyrosines condensation

2ropylthiouracil also inhibit T conerting to T!

CharacteristicsCharacteristics

① 7esult appears slo4ly: in $* w hyperthyroidameliorated and in 2*$ months H(7 normalized/

② 8ong0term use leads to thyroid hyperplasia

Methima&ole is 19 times as potent as propylthiouracil

3irst choice for

thyroid crisis



1@



1

*linical use

treatment of hyperthyroid

1. (ild hyperthyroid and those surgery &

1$1

) not permitted-

2. =peration preparation-

$. Thyroid crisis #comprehensie therapy%.

Aderse reactions

1. 6ong*term use leads to thyroid hyperplasia-

2. ruritic maculopapular rash is the most commonaderse raaction

$. The seere aderse reaction is agranuloctosis



1C

Iodides (+aI, 6I)

2harmacological action

)nhibition of T$ & T release and synthesisT$ & T release and synthesis

Decrease of size & ascularity of the hyperplastic glandDecrease of size & ascularity of the hyperplastic gland

*linical use

(inistrant treatment of hyperthyroid

1. =peration preparation-

2. Thyroid crisis.

Aderse reactions

1. Acneiform rash #similar to that of bromism%-

2. "wollen saliary glands mucous membrane ulcerations and etc.



2



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7adioactie iodine #1$1)%

1!1

I is the only isotope for treatment of thyrotoxicosis. )ts therapeutic effect depends on emission of rays with an

effectie half*life of ! days & a penetration range of .*2 mm.

oman in pregnancy or lactation is forbiddenJ

I*adrenoceptor blockers

bloc;ers are effectie in treatment of thyrotoxicosis.2ropranolol is the most widely studied and used.

Pharmacology Tyroid and Antitiroid Hormon

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