Thyroid and AntithThyroid and Antithyroid Drugsyroid Drugs

Peng QingPeng Qing

Objectives Objectives

You should:You should:- be able to describe the physiology of be able to describe the physiology of

thyroid.thyroid.- be able to describe the drugs used in be able to describe the drugs used in

the treatment of thyroid disorder the treatment of thyroid disorder including the mechanisms of action, including the mechanisms of action, clinical uses and adverse reactions.clinical uses and adverse reactions.

Thyroid physiologyThyroid physiology

Thyroid hormones includes Thyroid hormones includes tetraiodottetraiodothyronine hyronine (T(T44) and ) and triiodothyroninetriiodothyronine(T(T33).).

Normalize growth and development, bNormalize growth and development, body temperature, and energy levels. Tody temperature, and energy levels. These hormones contain 65% and 59% hese hormones contain 65% and 59% (respectively) of iodine as an essential (respectively) of iodine as an essential part of the molecule.part of the molecule.

Thyroid physiologyThyroid physiology

Calcitonin, the second type of thyroid Calcitonin, the second type of thyroid hormone, is important in the regulatiohormone, is important in the regulation of calcium metabolismn of calcium metabolism

Iodide MetabolismIodide Metabolism Iodide (IIodide (I--) intake is via the gastrointestinal ) intake is via the gastrointestinal

tract from food, water, or medication.tract from food, water, or medication. The recommended daily adult intake is 15The recommended daily adult intake is 15

0μg (200μg during pregnancy).0μg (200μg during pregnancy). The thyroid gland takes up about 75μg a dThe thyroid gland takes up about 75μg a d

ay for hormone secretion.ay for hormone secretion.

Thyroid physiology

Biosynthesis of Thyroid HormoneBiosynthesis of Thyroid Hormone1.1. Iodide trappingIodide trapping((摄取摄取 ): iodine pump, ): iodine pump, 2.2. Iodide organificationIodide organification (Iodide activation and (Iodide activation and

Tyrosine iodized): iodide is oxidized by thyroiTyrosine iodized): iodide is oxidized by thyroidal peroxidase(dal peroxidase( 过氧化酶过氧化酶 ) to iodine, in which f) to iodine, in which form it iodinates tyrosine residues (orm it iodinates tyrosine residues ( 酪氨酸酪氨酸残残基基 ) within the thyroglobulin molecule to form ) within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine monoiodotyrosine (MIT) and diiodotyrosine (DIT). (DIT).

3.3. CombineCombine: DIT+DIT→T: DIT+DIT→T44, DIT+MIT →T, DIT+MIT →T33..4.4. ReleaseRelease: proteolysis and exocytosis. T: proteolysis and exocytosis. T44＞＞ 90%.90%.

The process of proteolysis is also blocked bThe process of proteolysis is also blocked by high levels of intrathyroidal iodide.y high levels of intrathyroidal iodide.

Control of Thyroid Control of Thyroid FunctionFunction

1.1. Hypothalamic(TRH)- Hypothalamic(TRH)- Pituitary (TSH)- ThyrPituitary (TSH)- Thyroid (Toid (T44 and T and T33).).

2.2. Autoregulation of the Autoregulation of the thyroid gland: relatethyroid gland: related to the level of iodind to the level of iodine in the blood.e in the blood.

Peripheral Metabolism of Peripheral Metabolism of Thyroid HormonesThyroid Hormones

BASIC PHARMACOLOGY OF BASIC PHARMACOLOGY OF THYROID & ANTITHYROID THYROID & ANTITHYROID

DRUGSDRUGS

Thyroid hormonesThyroid hormones

ChemistryChemistry

The synthetic dextro (D) isomer of thyroxiThe synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4ne, dextrothyroxine, has approximately 4% of the biologic activity of the L isomer a% of the biologic activity of the L isomer as evidenced by its lesser ability to suppress evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidis TSH secretion and correct hypothyroidism.sm.

Physiological and Pharmacological Physiological and Pharmacological EffectsEffects

1.1. Maintain normal growth and developmenMaintain normal growth and developmentt: : critical for nervous, skeletal, reproductive tissues.critical for nervous, skeletal, reproductive tissues. Depend upon protein synthesis. Depend upon protein synthesis.

Child —— cretinism(Child —— cretinism(呆小病呆小病 ,,克汀病克汀病 ): irreversibl): irreversible mental retardation(e mental retardation(智力低下智力低下 ) and dwarfism() and dwarfism(矮矮小小 ) )

Adult —— myxedema(Adult —— myxedema(粘液性水肿粘液性水肿 ): ): 2.2. Promote energy metabolism and calorigePromote energy metabolism and calorige

nesisnesis: : basal metabolic rate (BMR)basal metabolic rate (BMR)↑↑3.3. Sympathetic nervous system overactivitySympathetic nervous system overactivity: :

increase increase numbers of numbers of β-β-receptor receptor or enhanced aor enhanced amplification of the mplification of the ββ receptor signal receptor signal

PharmacokineticsPharmacokinetics

Rapidly absorbed when taken orally, but the Rapidly absorbed when taken orally, but the absorption rate of Tabsorption rate of T44 was affected by intestin was affected by intestinal contents.al contents.

Oral bioavailability of current preparations Oral bioavailability of current preparations of L-thyroxine averages 80%. In contrast, T3 of L-thyroxine averages 80%. In contrast, T3 is almost completely absorbed (95%) is almost completely absorbed (95%)

T3 is not recommended for routine replaceT3 is not recommended for routine replacement therapy because of its shorter half-life.ment therapy because of its shorter half-life.

Malabsorption when taken orally in severe Malabsorption when taken orally in severe myxedema(myxedema(粘液水肿粘液水肿 ).).

Mechanism of ActionMechanism of Action

Gene effects:Gene effects: TT33 nuclear receptor → mRNA → protein sy nuclear receptor → mRNA → protein sy

nthesis (eg, Nanthesis (eg, Na++/K/K++ ATPase) ATPase) Non-gene effects:Non-gene effects:

Receptors in cell membrane, mitochondriReceptors in cell membrane, mitochondrion(on(线粒体线粒体 ), ribosome(), ribosome(核蛋白体核蛋白体 ) → influe) → influencing post-transcriptional process, energy ncing post-transcriptional process, energy metabolism, transportation of membrane.metabolism, transportation of membrane.

The affinity for TThe affinity for T44 is about ten times is about ten times lower than that for Tlower than that for T33..

The number of nuclear receptors mThe number of nuclear receptors may be altered to preserve body homeay be altered to preserve body homeostasis(ostasis( 内环境稳定内环境稳定 ). eg, starvation, ). eg, starvation, malnutrition, obesity→ R↓malnutrition, obesity→ R↓

Clinical UsesClinical Uses

1.1. Cretinism(Cretinism( 呆小病呆小病 ,,克汀病克汀病 ))2.2. Myxedema(Myxedema( 粘液性水肿粘液性水肿 ))3.3. Simple goiter(Simple goiter( 单纯性甲状腺肿单纯性甲状腺肿 ), Suppr), Suppr

ession of TSHession of TSH

Thyroid PreparationsThyroid Preparations

Synthetic or of animal origin.Synthetic or of animal origin.

Synthetic levothyroxine is the preparatSynthetic levothyroxine is the preparation of choice for thyroid replacement ion of choice for thyroid replacement and suppression therapy because of its and suppression therapy because of its stability, content uniformity, low cost, stability, content uniformity, low cost, lack of allergenic foreign protein, easy lack of allergenic foreign protein, easy laboratory measurement of serum levelaboratory measurement of serum levels, and long half-life (7 days). ls, and long half-life (7 days).

Adverse ReactionsAdverse Reactions

Palpitation(Palpitation( 心悸心悸 ), hand tremor, sweati), hand tremor, sweating, lose weight, insomnia(ng, lose weight, insomnia( 失眠失眠 ).).

Diarrhea, vomiting, fever, angina pectDiarrhea, vomiting, fever, angina pectoris(oris(心绞痛心绞痛 ) ——β-blocker) ——β-blocker

Antithyroid agentsAntithyroid agents Thioureas (thioamides)Thioureas (thioamides) Iodine / iodideIodine / iodide Iodine-131 (Iodine-131 (131131I)I) β-adrenoceptor antagonistsβ-adrenoceptor antagonists

ThioureasThioureas

Classification: 1. Thiouracils: methlthyiouracil (MT

U), propylthiouracil (PTU)

2. Imidazoles: methimazole (tapaz

ole), carbimazole

PharmacokineticsPharmacokinetics

PTU is rapidly absorbed, reaching peaPTU is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavak serum levels after 1 hour. The bioavailability of 50-80% .ilability of 50-80% .

Methimazole is completely absorbed. IMethimazole is completely absorbed. It is readily accumulated by the thyroid t is readily accumulated by the thyroid gland and has a volume of distribution gland and has a volume of distribution similar to that of PTU. similar to that of PTU.

Cross the placental barrier and are conCross the placental barrier and are concentrated by the fetal thyroid. centrated by the fetal thyroid.

Mechanism of actionMechanism of action Prevent hormone synthesis by inhibiting the Prevent hormone synthesis by inhibiting the

thyroid peroxidase-catalyzed reactions and bthyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, thlocking iodine organification. In addition, they block coupling of the iodotyrosines. ey block coupling of the iodotyrosines.

Inhibit the peripheral conversion of T4 to T3 .Inhibit the peripheral conversion of T4 to T3 . Since the synthesis rather than the release of Since the synthesis rather than the release of

hormones is affected, the onset of these agehormones is affected, the onset of these agents is slow, often requiring 3-4 weeks before nts is slow, often requiring 3-4 weeks before stores of T4 are depleted.stores of T4 are depleted.

Clinical UsesClinical Uses

1.1. therapy of hyperthyroidism(therapy of hyperthyroidism(甲亢甲亢 ): 1~2 y): 1~2 year of treatment course.ear of treatment course.

2.2. preoperative preparation of thyroidectopreoperative preparation of thyroidectomy: adding iodine / iodide.my: adding iodine / iodide.

3.3. therapy of thyroid crisis: large dose ioditherapy of thyroid crisis: large dose iodine / iodide + PTUne / iodide + PTU

ToxicityToxicity

Allergic reaction: maculopapularAllergic reaction: maculopapular((斑丘斑丘疹的疹的 )) pruritic pruritic((搔痒搔痒 )) rash (4-6%), accom rash (4-6%), accompanied by fever. panied by fever.

Nausea and gastrointestinal distress.Nausea and gastrointestinal distress. AgranulocytosisAgranulocytosis( 0.1-0.5%) ( 0.1-0.5%) GoiterGoiter((甲状腺肿甲状腺肿 )) and hypothyroidism: and hypothyroidism:

Iodine / iodideIodine / iodide

Liguor iodine Co (Lugol’s solution): Liguor iodine Co (Lugol’s solution): 5% iodine + 10% KI5% iodine + 10% KI

KI or NaIKI or NaI

Pharmacological EffectPharmacological Effect Small doseSmall dose: : prevent simple goiterprevent simple goiter. . iodisiodis

ed salts 20mg/kg-30mg/kged salts 20mg/kg-30mg/kg Large doseLarge dose(>6mg/d): (>6mg/d):

1.1. Inhibit thyroid hormone releaseInhibit thyroid hormone release:: inhibit inhibit glutathione reductaseglutathione reductase((谷胱甘肽还原酶谷胱甘肽还原酶 )) → GSH↓ → GSH↓

2.2. Inhibit thyroid hormone synthesisInhibit thyroid hormone synthesis: : inhiinhibit thyroidal peroxidase → tyrosine iodized anbit thyroidal peroxidase → tyrosine iodized and combining ↓d combining ↓

3.3. Decrease the size and vascularity of the Decrease the size and vascularity of the hyperplastic(hyperplastic(增生的增生的 ) gland) gland:: anti-TSHanti-TSH

Clinical UsesClinical Uses

1.1. preoperative preparation of preoperative preparation of hyperthyroidismhyperthyroidism

2.2. therapy of thyroid crisistherapy of thyroid crisis: large dose : large dose iodine / iodide + PTUiodine / iodide + PTU

3.3. radiation emergenciesradiation emergencies

Adverse ReactionsAdverse Reactions::1.1. Common response: Common response: metallic taste, rhinorrmetallic taste, rhinorr

heahea((鼻溢液鼻溢液 )), conjunctivitis, conjunctivitis((结膜炎结膜炎 )), swollen sali, swollen salivaryvary glands, mucous membrane ulcerations, glands, mucous membrane ulcerations, bleeding disordersbleeding disorders. .

2.2. Inducing thyroid function disturbance:Inducing thyroid function disturbance: hyperthyroidism or hypothyroidismhyperthyroidism or hypothyroidism crossing the placenta and entering milk →crossing the placenta and entering milk → ii

nfluencing newborn or infant thyroid functnfluencing newborn or infant thyroid function.ion.

RadioiodineRadioiodine

131131I, I, tt1/21/2=8d.=8d.

Administered orally in solution as sodiAdministered orally in solution as sodium um 131131I. Rapidlly absorbed. ConcentratI. Rapidlly absorbed. Concentrated by the thyroid.ed by the thyroid.

Pharmacologic EffectsPharmacologic Effects

ββ rays (99%), penetration range of 2mm, rays (99%), penetration range of 2mm, destruction of the thyroid parenchyma destruction of the thyroid parenchyma((实质实质 ))..

γrays (1%), can be monitored out of the γrays (1%), can be monitored out of the body—— thyroid iodine uptake.body—— thyroid iodine uptake.

Clinical usesClinical uses

1.1. Determination of thyroid iodine Determination of thyroid iodine uptake: uptake:

2.2. therapy of hyperthyroidism: therapy of hyperthyroidism: Advantages of radioiodine include Advantages of radioiodine include

easy administration, effectiveness, easy administration, effectiveness, low expense, and absence of pain.low expense, and absence of pain.

Fears of radiation-induced Fears of radiation-induced genetic damagenetic damage, leukemia, and neoplasia.ge, leukemia, and neoplasia.

large dose → hypothyroidismlarge dose → hypothyroidism Not for patient less than 20y, pregnant wNot for patient less than 20y, pregnant w

omen or nursing mothers, and renal malomen or nursing mothers, and renal malfunction; thyroid crisis, severe infiltrativfunction; thyroid crisis, severe infiltrative exophthalmos(e exophthalmos(突眼突眼 ), and thyroid iodi), and thyroid iodine non-uptake.ne non-uptake.

β- adrenoceptor antagonistsβ- adrenoceptor antagonists Beta blockers cause clinical improvement of Beta blockers cause clinical improvement of

hyperthyroid symptoms but do not typically hyperthyroid symptoms but do not typically alter thyroid hormone levels. alter thyroid hormone levels.

β- adrenoceptor antagonists without intrinsiβ- adrenoceptor antagonists without intrinsic sympathomimeticc sympathomimetic((拟交感拟交感 ) ) are the agents of are the agents of choice.choice.

Propranolol at doses greater than 160 mg/d Propranolol at doses greater than 160 mg/d may also reduce T3 levels approximately 20may also reduce T3 levels approximately 20% by inhibiting the peripheral conversion of % by inhibiting the peripheral conversion of T4 to T3.T4 to T3.

Advantages:Advantages:1.1. Influence to thyroid function tests is low.Influence to thyroid function tests is low.2.2. No interference to the effect of thioureas No interference to the effect of thioureas

on thyroid.on thyroid.3.3. Not increase the size and fragility of the gNot increase the size and fragility of the g

land land Clinical UsesClinical Uses1.1. Hyperthyroidism:Hyperthyroidism:2.2. thyroid crisis: i.v.thyroid crisis: i.v.3.3. preoperative preparation: β- adrenoceptopreoperative preparation: β- adrenocepto

r antagonist + PTU + large dose iodine / ior antagonist + PTU + large dose iodine / iodide dide

Summary Summary

Thyroid hormoneThyroid hormone Antithyroid drugsAntithyroid drugs• Thioureas (thioamides)Thioureas (thioamides)• Iodine / iodideIodine / iodide• Iodine-131 (Iodine-131 (131131I)I)• β-adrenoceptor antagonistsβ-adrenoceptor antagonists