Transcript Thyroid physiology

Thyroid and
Antithyroid Drugs
Peng Qing
Objectives

-
You should:
be able to describe the physiology of thyroid.
be able to describe the drugs used in the
treatment of thyroid disorder including the
mechanisms of action, clinical uses and adverse
reactions.
Thyroid physiology
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Thyroid hormones includes tetraiodothyronine
(T4) and triiodothyronine(T3).
Normalize growth and development, body
temperature, and energy levels. These hormones
contain 65% and 59% (respectively) of iodine as
an essential part of the molecule.
Thyroid physiology
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Calcitonin, the second type of thyroid hormone,
is important in the regulation of calcium
metabolism
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Iodide Metabolism
Iodide (I-) intake is via the gastrointestinal tract from
food, water, or medication.
 The recommended daily adult intake is 150μg (200μg
during pregnancy).
 The thyroid gland takes up about 75μg a day for
hormone secretion.

Thyroid physiology
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Biosynthesis of Thyroid Hormone
1.
2.
3.
4.
Iodide trapping(摄取): iodine pump,
Iodide organification (Iodide activation and Tyrosine
iodized): iodide is oxidized by thyroidal peroxidase(过氧
化酶) to iodine, in which form it iodinates tyrosine
residues (酪氨酸残基) within the thyroglobulin molecule
to form monoiodotyrosine (MIT) and diiodotyrosine
(DIT).
Combine: DIT+DIT→T4, DIT+MIT →T3.
Release: proteolysis and exocytosis. T4＞90%.
 The process of proteolysis is also blocked by high
levels of intrathyroidal iodide.
Control of Thyroid
Function

1.
Hypothalamic(TRH)Pituitary (TSH)- Thyroid
(T4 and T3).
2.
Autoregulation of the
thyroid gland: related to
the level of iodine in the
blood.
Peripheral Metabolism of Thyroid
Hormones
BASIC PHARMACOLOGY OF THYROID
& ANTITHYROID DRUGS
Thyroid hormones

Chemistry
The synthetic dextro (D) isomer of thyroxine,
dextrothyroxine, has approximately 4% of the
biologic activity of the L isomer as evidenced by
its lesser ability to suppress TSH secretion and
correct hypothyroidism.
Physiological and Pharmacological Effects
1.
Maintain normal growth and development: critical
for nervous, skeletal, reproductive tissues. Depend upon
protein synthesis.

Child —— cretinism(呆小病,克汀病): irreversible mental
retardation(智力低下) and dwarfism(矮小)

Adult —— myxedema(粘液性水肿):
2.
3.
Promote energy metabolism and calorigenesis:
basal metabolic rate (BMR)↑
Sympathetic nervous system overactivity: increase
numbers of β-receptor or enhanced amplification of
the β receptor signal
Pharmacokinetics
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Rapidly absorbed when taken orally, but the absorption
rate of T4 was affected by intestinal contents.
Oral bioavailability of current preparations of Lthyroxine averages 80%. In contrast, T3 is almost
completely absorbed (95%)
T3 is not recommended for routine replacement
therapy because of its shorter half-life.
Malabsorption when taken orally in severe
myxedema(粘液水肿).
Mechanism of Action
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Gene effects:
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T3 nuclear receptor → mRNA → protein synthesis
(eg, Na+/K+ ATPase)
Non-gene effects:
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Receptors in cell membrane, mitochondrion(线粒
体), ribosome(核蛋白体) → influencing posttranscriptional process, energy metabolism,
transportation of membrane.

The affinity for T4 is about ten times lower
than that for T3.

The number of nuclear receptors may be
altered to preserve body homeostasis(内环境
稳定). eg, starvation, malnutrition, obesity→
R↓
Clinical Uses
1.
2.
3.
Cretinism(呆小病,克汀病)
Myxedema(粘液性水肿)
Simple goiter(单纯性甲状腺肿), Suppression
of TSH
Thyroid Preparations
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Synthetic or of animal origin.
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Synthetic levothyroxine is the preparation of
choice for thyroid replacement and suppression
therapy because of its stability, content
uniformity, low cost, lack of allergenic foreign
protein, easy laboratory measurement of serum
levels, and long half-life (7 days).
Adverse Reactions
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Palpitation(心悸), hand tremor, sweating, lose
weight, insomnia(失眠).

Diarrhea, vomiting, fever, angina pectoris(心绞
痛) ——β-blocker
Antithyroid agents
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Thioureas (thioamides)
Iodine / iodide
Iodine-131 (131I)
β-adrenoceptor antagonists
Thioureas
Classification:
1. Thiouracils:
methlthyiouracil (MTU),
propylthiouracil (PTU)
2. Imidazoles:
methimazole (tapazole),
carbimazole
Pharmacokinetics
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PTU is rapidly absorbed, reaching peak serum
levels after 1 hour. The bioavailability of 5080% .
Methimazole is completely absorbed. It is readily
accumulated by the thyroid gland and has a
volume of distribution similar to that of PTU.
Cross the placental barrier and are concentrated
by the fetal thyroid.
Mechanism of action
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Prevent hormone synthesis by inhibiting the thyroid
peroxidase-catalyzed reactions and blocking iodine
organification. In addition, they block coupling of the
iodotyrosines.
Inhibit the peripheral conversion of T4 to T3 .
Since the synthesis rather than the release of hormones
is affected, the onset of these agents is slow, often
requiring 3-4 weeks before stores of T4 are depleted.
Clinical Uses
1.
therapy of hyperthyroidism(甲亢): 1~2 year of
treatment course.
2.
preoperative preparation of thyroidectomy: adding
iodine / iodide.
3.
therapy of thyroid crisis: large dose iodine / iodide
+ PTU
Toxicity
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Allergic reaction: maculopapular(斑丘疹的)
pruritic(搔痒) rash (4-6%), accompanied by fever.
Nausea and gastrointestinal distress.
Agranulocytosis( 0.1-0.5%)
Goiter(甲状腺肿) and hypothyroidism:
Iodine / iodide
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Liguor iodine Co (Lugol’s solution):
5% iodine + 10% KI
KI or NaI
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Pharmacological Effect
Small dose: prevent simple goiter. iodised salts
20mg/kg-30mg/kg

Large dose(>6mg/d):
1.
Inhibit thyroid hormone release: inhibit glutathione
reductase(谷胱甘肽还原酶) → GSH↓
2.
Inhibit thyroid hormone synthesis: inhibit thyroidal
peroxidase → tyrosine iodized and combining ↓
3.
Decrease the size and vascularity of the
hyperplastic(增生的) gland: anti-TSH
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Clinical Uses
1.
preoperative preparation of hyperthyroidism
2.
therapy of thyroid crisis: large dose iodine /
iodide + PTU
radiation emergencies
3.
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Adverse Reactions:
1.
Common response: metallic taste, rhinorrhea(鼻溢液),
conjunctivitis(结膜炎), swollen salivary glands, mucous
membrane ulcerations, bleeding disorders.
2.
Inducing thyroid function disturbance:
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
hyperthyroidism or hypothyroidism
crossing the placenta and entering milk → influencing
newborn or infant thyroid function.
Radioiodine
 131I,

t1/2=8d.
Administered orally in solution as sodium 131I.
Rapidlly absorbed. Concentrated by the thyroid.
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Pharmacologic Effects
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β rays (99%), penetration range of 2mm,
destruction of the thyroid parenchyma(实质).
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γrays (1%), can be monitored out of the body—
— thyroid iodine uptake.
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1.
2.
Clinical uses
Determination of thyroid iodine uptake:
therapy of hyperthyroidism:
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Advantages of radioiodine include easy
administration, effectiveness, low expense, and
absence of pain.
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Fears of radiation-induced genetic damage,
leukemia, and neoplasia.
large dose → hypothyroidism
Not for patient less than 20y, pregnant women or
nursing mothers, and renal malfunction; thyroid
crisis, severe infiltrative exophthalmos(突眼), and
thyroid iodine non-uptake.
β- adrenoceptor antagonists
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Beta blockers cause clinical improvement of
hyperthyroid symptoms but do not typically alter
thyroid hormone levels.
β- adrenoceptor antagonists without intrinsic
sympathomimetic(拟交感) are the agents of choice.
Propranolol at doses greater than 160 mg/d may also
reduce T3 levels approximately 20% by inhibiting the
peripheral conversion of T4 to T3.
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Advantages:
Influence to thyroid function tests is low.
2. No interference to the effect of thioureas on
thyroid.
3. Not increase the size and fragility of the gland
Clinical Uses
1. Hyperthyroidism:
2. thyroid crisis: i.v.
3. preoperative preparation: β- adrenoceptor
antagonist + PTU + large dose iodine / iodide
1.
Summary
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Thyroid hormone
Antithyroid drugs
Thioureas (thioamides)
Iodine / iodide
Iodine-131 (131I)
β-adrenoceptor antagonists