Download Antithyroid drugs

Thyroid hormones and
antithyroid drugs
Metabolism of thyroid hormones
1. Uptake of iodide
2. Activation of iodide (peroxidase),
and iodination and coupling of
tyrosine
3. Formation of thyroxine (T4) and
triiodothyronine (T3) from
iodotyrosine
4. Secretion of thyroid hormones
(proteolytic enzymes)
5. Regulation by thyroid stimulating
hormone (TSH), T4, T3
Regulation of the secretion
of thyroid hormones
(feedback inhibition)
Pharmacology of thyroid hormones
 1. Normalizing growth and development
 2. Promoting body metabolism

Body temperature; energy levels, ect.
 3. Enhancing sympathetic activity
Clinical uses of thyroid hormones
 1. Treatment of hypothyroidism
 Hypothyroidism
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1.8% of total population.
Incidence increases with age.
2-3% of older women.
More common in females.
Etiology
PRIMARY HYPOTHYROIDISM
 Hoshimoto’s thyroiditis-most common
 Irradiation of thyroid
 Surgical removal
 Late stage invasive fibrous thyroiditis
 Iodine deficiency
 Drug therapy (Lithium)
 Infiltrative Diseases:
Sarcoidosis, Amyloidosis
Scleroderma, Hemochromatosis
SECONDARY HYPOTHYROIDISM
 5% of cases.
 Pituitary or hypothalamic neoplasm.
 Congenital hypopituitarism.
 Pituitary necrosis (Sheehan’s syndrome)
Common signs and symptoms
Cretinism: a situation induced by a insufficiency of thyroid
hormone at birth and during minority,
 execute growth, twined facial features, increased tongue
and mental detainment
Adult:
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Fatigue, weakness, weight gain, cold intolerance
Coarse, dry hair, dry and rough pale skin, hair loss
Muscle cramps and frequent muscle aches
Constipation(便秘)
Depression
Memory loss
Abnormal menstrual cycles, decreased libido
 Myxedema
 describes a specific form of cutaneous and
dermal edema secondary to increased
deposition of connective tissues, as seen in
various forms of hypothyroidism
Thyroid Hormone Replacement
 Levothyroxine (左甲状腺素) is commonly used
 It can cause increases in resting heart rate and blood
pressure
 So replacement should start at low doses in older and
patients at risk for cardiovascular compromise
 Myxedema Coma
 Below normal temperature, decreased breathing, low blood
pressure, low blood sugar, unresponsiveness
 Hydrocortisone, T3 (fast)
Clinical uses of thyroid hormones
 2. Simple goiter (单纯性甲状腺肿)
Supply iodide--iodide deficiency
Thyroid hormones
Surgery—nodule
 3. Treat after thyroid cancer surgery to reduce TSH
level to inhibit recurrence of cancer
迟钝
触痛
Antithyroid drugs
Hyperthyroidism
 Graves Disease is the most common cause of hyperthyroidism
(60-80%) of all cases.
 Graves Disease is caused by an abnormal immune system
response that attacks the thyroid gland, and it causes too much
production of thyroid hormones.
 Antibodies serve as agonists to the TSH receptors on the
thyroid’s surface, causing thyroid growth and activation of
hormone synthesis and secretion.
 Females are affected more frequently than men 10:1.5
 Incidence peaks from ages 20-40
Signs and Symptoms
 Hyperthyroidism is characterized by a high state of
excitability, intolerance to heat, increased sweating, mild
to extreme weight loss, diarrhea, muscle weakness,
osteoporosis, Graves acropachy, palpitation, arrhythmia,
nervousness, extreme fatigue but inability to sleep, and
tremor of the hands.
 Exophthalmos
 Goiter
Symptoms of the patient with hyperthyroidism
Thyroid crisis
 - life threatening clinical extreme of hyperthyroidism
- F>M
- mortality 10-20% with treatment
- FT3 and FT4 correlate poorly with severity of condition: condition is
essentially an inability of end-organs to modulate their response to
excess thyroid hormone
 Aetiology
 - usually occurs in patients with poorly controlled or unrecognized
hyperthyroidism
- precipitated by intercurrent illness, in particular:
 infection
 trauma
 surgery
 uncontrolled DM
 labour
 eclampsia
Thyroid crisis clinical features
 Exacerbation of features of hyperthyroidism
- hyperpyrexia. May be extreme (>39oC) and is generally
considered essential to diagnosis.
- confusion, fits, coma, muscle weakness. Very common.
- arrhythmias, cardiac failure. Decreasing pulse rate and BP with
the development of shock are associated with poor prognosis
- vomiting, diarrhea. Occasionally jaundice: associated with poor
prognosis
- hyperkalaemia relatively common (15%) but rarely a problem
in itself
- rarely apathetic hyperthyroidism (usually elderly patients) may
present in crisis with features of profound exhaustion,
hyporeflexia, severe myopathy, marked weight loss and
hypotension
Therapy for Hypothyroidism
 antithyroid drugs: thiourea derivatives
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iodine and iodides
 receptor antagonists
 radioiodines: 131I
 surgery subtotal thyroidectomy
Antithyroid drugs
Thiourea derivatives
Thiouracil ---- methylthiouracil (MTU，甲硫氧嘧啶)
propylthiouracil (PTU，丙硫氧嘧啶)
Imidazoles ---- thiamazole (TAPAZOLE，甲巯咪唑，他巴唑)
carbimazole (卡比马唑)
丙硫氧嘧啶
甲巯咪唑
thiamazole
卡比马唑
Antithyroid drugs
Thiourea derivatives
 1. Pharmacological effects
 (1) Inhibiting the formation of thyroid hormones by
inhibiting the iodination and coupling

Symptom relieving: 2~3 weeks

Basic metabolic rate returning: 1~2 months
 (2) Inibiting peripheral deiodination of T4: T4  T3 
(propylthiouracil)
 (3) Decrease the carbohydrate metabolism mediated by
β-receptor
 (4) Immunosuppress action, decrease TSI
Mechanism of inhibition of thyroid hormone synthesis
by thiaureas
Antithyroid drugs
Thiourea derivatives
 1. Pharmacological effects
 (1) Inhibiting the formation of thyroid hormones by
inhibiting the iodination and coupling

Symptom relieving: 2~3 weeks

Basic metabolic rate returning: 1~2 months
 (2) Inibiting peripheral deiodination of T4: T4  T3 
(propylthiouracil)
 (3) Decrease the carbohydrate metabolism mediated by
β-receptor
 (4) Immunosuppress action, decrease TSI
Mechanism of inhibition of thyroid hormone synthesis
by thiaureas
Antithyroid drugs
Thiourea derivatives
 1. Pharmacological effects
 (1) Inhibiting the formation of thyroid hormones by
inhibiting the iodination and coupling

Symptom relieving: 2~3 weeks

Basic metabolic rate returning: 1~2 months
 (2) Inibiting peripheral deiodination of T4: T4  T3 
(propylthiouracil)
 (3) Decrease the carbohydrate metabolism mediated by
β-receptor
 (4) Immunosuppress action, decrease TSI
Antithyroid drugs
Physiological process
 Absorption： easy to be absorbed when taken orally. Thiouracil is
the most fast to be absorbed. The bioavailability is 80％ and the
plasma protein binding rate is 75%. 20－30 min after administration,
the drug turns to become effective with T1/2 of 2h. Imidazole is
absorbed slowly. T1/2 of tapazole is 4.7h.
 Distribution：organs generally all over the body and can pass the
placenta. The concentration in lacto is about 3 times as in blood.
 Metabolism：Mainly in liver, fast. 60％ are destroyed in vivo，the
rest are eliminated by urine in a conjugative form. Carbimazole
functions after turning into tapazole in vivo.
Antithyroid drugs
 2. Clinical uses
 (1) Non-operative therapy of hyperthyroidism:
For who has mild symptoms and who is not suitable to have
operations and 131I radiotherapy.
Give Larger dose at the beginning. After 1~3 months , symtoms
decreased and basal metabolic rate returns to almost normal.
Reduce to maintaining dose with a period of 1~2 years. Also can be
used as adjunctive therapy of 131I radiotherapy.
 (2) Preoperative therapy of hyperthyroidism:
prevent thyroid crisis
combined with larger dose of iodide
 (3) Thyrotoxic crisis: propylthiouracil combined with larger
dose of iodide
Antithyroid drugs
 3. Adverse effects
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(1) Agranulocytosis (0.3%~0.6%)
(2) Hypersensitivity
(3) GI reactions
(4) Goiter
 4. Notes
 periodic inspection of hemogram. The medication should be
stopped if the symptoms as pharyngalgia, fever occur. Female
during lactation period should be cautious.
Antithyroid drugs
Iodine and iodides
 1. Pharmacological effects
 (1) Small doses: simple goiter
 (2) Larger doses: inhibiting glutathione reductase to
reduce the proteolysis and release of thyroid
hormones, and inhibit peroxidase to reduce synthesis.
 After two week use, I uptake is inhibited, hyperthyroidism. So not
treat hyperthyroidism along.
 After iodide use, the thyroid vascularity is reduced, and the gland
becomes much firmer, the cells become smaller.
Wolff-Chaikoff效应
Mechanism of iodides
Antithyroid drugs
Iodine and iodides
 1. Pharmacological effects
 (1) Small doses: simple goiter
 (2) Larger doses: inhibiting glutathione reductase to reduce the
proteolysis and release of thyroid hormones, and inhibit
peroxidase to reduce synthesis.

After two week use, I uptake is inhibited, hyperthyroidism recurrent. So
not treat hyperthyroidism alone.

After iodide use, the thyroid vascularity is reduced, and the gland
becomes much firmer, the cells become smaller (inhibiting TSH release).
Antithyroid drugs
 2. Clinical uses
 (1) Small doses: simple

常用复方碘溶液，又称卢戈氏液，含碘
5%，碘化钾10%。也有单用碘化钾或
碘化钠的，《神农本草经》记载用海带
治“瘿瘤”，是最早用含碘食物治疗甲
状腺病的文献。
goiter
Add 1/10000~1/100000 potassium iodide or sodium iodide to salt
could prevent the desease. Early stage potassium iodide (10mg/d)
or Lugol’s solution (0.1ml or 0.5 ml/d)
 (2) Larger doses:
 Preoperative therapy of hyperthyroidism: Lugol’s
solution combined with thiourea derivatives (for 2 weeks)
 Thyrotoxic crisis: combined with thiourea derivatives
(propylthiouracil)
Antithyroid drugs
 3. Adverse effects
 (1) Acute effects: hypersensitivity, angioedema,
swelling of the larynx
 (2) Chronic intoxication (iodism)
 (3) Thyroid dysfunction: exacerbation of
hyperthyroidism, hypothyroidism, thyroid goiter .
 newborn thyroid goiter--pregnant and lactant women should
take the drug with caution.
Antithyroid drugs
 Receptor antagonists
 1. Pharmacological effects
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(1) Heart: 1 block, HR
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(2) CNS: relieving anxiety
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(3) Presynaptic 2 receptor: NE release 

(4) Inhibiting the conversion of T4 to T3
 2. Clinical uses

Adjuvant therapeutic drug prevent hyperthyroidism and
thyrotoxic crisis.
不干扰硫脲类的抗甲状腺作用，对甲状腺功能测定实验影响小。
Antithyroid drugs
Radioiodine
131I, 125I, 123I
 1. Pharmacological effects
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
131I
is rapidly absorbed, concentrated by the thyroid, and into storage
follicles.
Its effects depends on emission of beta rays and a penetration range of
500-2000μm, the thyroid was destructed within a few weeks after
administration.
 2. Clinical uses

Hyperthyroidism in long course, and other drugs can not control the
symptom. 适用于不宜手术或手术后复发及硫脲类无效或过敏的患者

Diagnosis. ( ray generated by 131I accounts for 1％ and can be detected
in vitro. It is usually used in the examination of thyroid iodine uptaking
function )
Hyperthyroid-- iodine uptake rate high, time of iodine uptake peak antelocation
Hypothyroid--iodine uptake rate low, time of iodine uptake peak retroposition
Antithyroid drugs
Radioiodine
131I, 125I, 123I
 3. Adverse effects
 Hypothyroidism.
 Radioactive iodine should not be administered to pregnant
women or nursing mothers, since it cross the placenta and is
excreted in breast milk.
Case part1
 A 47-year-old woman consulted her physician because of heart
palitations, tremulousness, weight loss of 7 lb, and heart
intolerance, all of which had started 6 weeks previously.
Physical examination revealed a resting heart rate of 110 bpm,
BP of 150/70, and a diffusely enlarged thyroid gland. She had a
fine tremor of her outstretched hands, a wide-eyed stare, and ‘lid
lag.’ She was started on treatment with propranolol, 40 mg three
times daily, and was sent for laboratory tests. The results
showed a free thyroxine (T4) level of 40 pmol/L (nomal 9~25
pmol/L) and a free triiodothyronine(T3) level of 10.6 pmol/L
(nomal 3~9 pmol/L). Thyroid-stimulating hormone (TSH) was
undetectable, but thyroid-stimulating globulins were markedly
elevated.
Case part1
 A 47-year-old woman consulted her physician because of heart
palitations, tremulousness, weight loss of 7 lb, and heart
intolerance, all of which had started 6 weeks previously.
Physical examination revealed a resting heart rate of 110 bpm,
BP of 150/70, and a diffusely enlarged thyroid gland. She had a
fine tremor of her outstretched hands, a wide-eyed stare, and ‘lid
lag.’ She was started on treatment with propranolol, 40 mg three
times daily, and was sent for laboratory tests. The results
showed a free thyroxine (T4) level of 40 pmol/L (nomal 9~25
pmol/L) and a free triiodothyronine(T3) level of 10.6 pmol/L
(nomal 3~9 pmol/L). Thyroid-stimulating hormone (TSH) was
undetectable, but thyroid-stimulating globulins were markedly
elevated, confirming the diagnosis of Graves’ disease.
How to deal with her then?
Case part2
 The patient was started on propylthiouracil 200mg twice daily,
and the propranolol was continued. She became euthyroid (甲状
腺功能正常) in 6 weeks, and the propranolol dose was gradually
reduced and finally discontinued. She continued receiving a
maintenance dose propylthiouracil (50 mg twice daily) for 1 year,
after which the drug was discontinued. She remained well for 4
years, but the symptoms of hyperthyroidism then recurred.
Treatment with propranolol and propylthiouracil was reinitiated
on the same dosages as before to normalize the thyroid
hormone levels and provide symptomatic relief. However, after 7
weeks she developed an itchy, red, maculopapular rush over
her whole body. The propylthiouracil and propranolol were
therefore discontinued and she was given Na131I in a dose of
370mBp(10mCi) by month for definitive control of her
hyperthyroidism.
Why use 131I here?
Case part3
 Three months later the patient returned, complaining of lethargy,
tiredness, a felling of coldness at normal room temperature,
puffiness around the eyes, and constipation(便秘). Laboratory
tests showed a free T4 level of 8 pmol/L (nomal 9~25 pmol/L),
free T3 level of 3.0pmol/L (nomal 3~9 pmol/L), and a TSH level
of 25Mu/mL (nomal 0.6~4Mu/mL), conferming a diagnosis of
hypothyriodism. She was started on levothyroxine 0.1 mg daily.
Six weeks later, a blood test showed a TSH level of 3.2Mu/mL,
and the patient’s complaints had disappeared. She has
remained well on this therapy for the past 2 years.
Why use levothyroxine here?