THYROID and ANTITHYROID DRUGS

Synthesis of Thyroid Hormones

Synthesis of Thyroid Hormones

1. Iodide Uptake

Inhibited by: thiocyanate (SCN-), perchlorate

(ClO4-)
Stimulated by TSH
Iodide in plasma : 0.2-0.4 mcg/dl
Iodide in thyroid gland: 20-50 x plasma level,
some times > 100 x plasma level.

2. Oxidation and Iodination

TPO

Iodide (I-) ------------ Iodine (I2)

Iodine + Thyroglobulin MIT DIT
Stimulated by TSH,
Inhibited by PTU, Metimazole and aminobenzene

Synthesis of Thyroid Hormones

3. Organification (Formation of T3 and T4)

Coupling of MIT + DIT T3

Coupling of DIT + DIT T4
Inhibited by PTU and methimazole

4. Secretion and conversion

Thyroid secretes mostly T4. However, T3 has a

greater biological potency.

5. Conversion in peripheral tissues

Some T4 is converted to T3 in thyroid gland,

But 80% of conversion occur in liver and kidney
Conversion is simulated by TSH
Inhibited by PTU, and b-blockers

Molecular Structures and Conversion

Tetraiodothyronine (T4)
Activation

3,5,3 triiodothyrosine (T3)

4-5 x more potent than T4

Inactivation

3,3,5 triiodothyrosine
(reverse T3)

Pharmacokinetic of Thyroid Hormone

T4 is highly protein bound,

T3 is practically unbound to protein

rapid and short duration of action
Half-life of T4:

mostly to -globulin (> 85%), and

prealbumin
Only 1 % free T4 (FT4)

In normal person: 6-7 days

In hyperthyroidism: 3-4 days
In hypothyroidism: 9-10 days

Pharmacokinetic of Thyroid Hormone

Metabolism:

Excretion:

Liver: conjugation, deiodination, deamination,

decarboxylation
Kidney: deiodination
Conjugation: with glucoronide and sulphate
enterohepatic circulation
Urine, feces

Mechanism of Action

T4 and T3 are carried to target cells by plasma

proteins in the blood.

Unbound hormones enter the cytoplasm of target

cells in the form of T4 or T3.

T4 is converted to T3 in the cytoplasma since only

T3 can work in the nucleus

T3 binds to DNA and stimulates the transcription

of DNA mRNA protein synthesis

Mechanism of Action

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PHYSIOLOGY OF THYROID HORMONE

1. Calorigenic effect increases BMR
2. Catabolic effect (high dose):
Muscle weakness, creatinuria
Bone osteoporosis
3. Carbohydrate metabolism
absorption of CHO, blood glucose,
glycogen in liver
4. Protein metabolism:
Small dose: anabolic effect
High dose: catabolic
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PHYSIOLOGY OF THYROID HORMONE

5. Lipid metabolism:
Lipolysis weight loss in hyperth/
Cholesterol synthesis , Cholesterol
metabolism by liver Blood cholesterol
(D-thyroxin: antihyperlipidemic agent)
6. Crucial role for growth
Deficiency during infancy kretinism
7. Nervous system
Irritability, restlessness, increased deep tendon
reflex
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PHYSIOLOGY OF THYROID HORMONE

8. TH and Norepinephrine (NE)

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TH increases NE secretion
TH has similar (but slower) effects with
those of NE
Cardiovascular effects of TH can be
blocked by -adrenergic blockers

Regulation of Thyroid Function

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THYROID HORMONE

Preparation

Indication

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Levothyroxine (T4): 50, 100 mcg tablets

Liothyronine (T3): 5, 25, 50 mcg tablets
Liothrix (a 4:1 ratio of T4 and T3)
Thyroid dessicated (animal origin)
Replacement therapy in hypothyroidism,
kretinism
Suppression therapy for non toxic goiter

Abnormalities of Thyroid Function

Hyperthyroidism
Hypothyroidism
SYSTEM

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HYPER

HYPO

CVS

Tachycardia, AF, heart

failure

Bradycardia

Skin

Warm, moist, sweating,

heat intolerance

Pale, cool, dry skin, cold

intolerance

Eye, Face exophtalmus

Periorbital edema, ptosis,

GI

Appetite , diarrhea

CNS

Nervousness,
hyperkinesia, emotional
lability

Appetite , constipation,
ascites
Lethargy, slowing of mental
process

Abnormalities of Thyroid Function

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SYSTEM

HYPER

HYPO

Muscular

Weakness and fatigue,

hyper reflexia,
hypercalcemia,
osteoporosis

Stiffness and muscle

fatigue, hyporeflexia, non
piting edema

Reproductive

Mens irregularity,
decreased fertility

Hypermenorrhea,
infertility, libido ,
oligospermia

Metabolic

Increased BMR

Decreased BMR

Antithyroid Drugs

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Thionamides
Anion Inhibitors
Iodides and Iodinated contrast media
Radioactive iodine
Adrenoceptor blocking agents

THIONAMIDES
(Propylthiouracil, methimazole, carbimazole)

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Mechanism of action

Inhibition of thyroxine peroxidase:

Inhibits oxidation of iodide to iodine
Inhibits iodination of thyroglobulin
Inhibits organification (formation of T3 and
T4)

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PTU, but not methimazole, inhibits

peripheral deiodination of T4
Have no influence on uptake of iodide by
the thyroid

 Kinetics
Absorption: GI tract
First pass metabolism bioavailability 5080%
Metabolism: glucoronidation by liver
Distribution:
Concentrated in thyroid gland
Placental passage: Methimazole >> PTU
PTU can be used for pregnant women

Excretion: urine, breast milk

PTU is excreted to breast milk in small quantity
can be given to nursing mother
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Plasma half-life:

Adverse Reactions (relatively low)

Agranulocytosis (methiazole > PTU)

Papular rash, Arthralgia

Preparations:

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PTU 75 minutes dosing frequency 1- 4 times/d

Methimazole 4-6 h once daily

Propylthiouracyl (PTU): tablet 100 mg

Methimazole : tablet 5, 10 mg
Carbimazole
Methylthiouracil

Indications

Treatment of hyperthyroidism
As definitive treatment of Graves disease
Thyroid storm
Suppression th/ before surgical treatment

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Suppression of TSH in non toxic goiter

Ionic Blockers

Blocks active transport of I- into Th/ gland

Rarely used

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Thiocyanate (SCN-)
Perchlorate (ClO4-)
Nitrate (NO3-)
Pertechnetate (TcO4-)
Fluoroborate (BF4-)

Iodide and Iodinated Contrast

Media

NaI, KI: available as oral preparation

Contrast media
Lugol solution : KI + I2

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Iodide: the oldest antithyroid drug

Needed in small qtt for the synthesis of
TH
In higher doses inhibits secretion of TH
Side Effects:
Hypersensitivity, GI irritation
Metallic taste, Skin erruption

Radioactive Iodine

I131 : b and g ray

Rapidly concentrated in Th/ gland,

especially in hyperthyroidism
Half-life: 8 days
Excretion: Urine

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90% b ray with low penetration

10% g ray with high penetration

In Hypothyroidism: 85-90% excreted within

24 h
In Euthyroidism: 65%
In Hyperthyroidism: 5%

Indications:

Contraindication:

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Hyperthyroidism (esp. in older patients)

Graves disease: persistence after subtotal
thyroidectomy, relaps or treatment failure.
Toxic nodular goiter
Metastatic Th/ carcinoma
Diagnostic of thyroid nodule (hot, warm,
cold)
Pregnancy
Younger patients

Adverse Reaction:

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Risk of neoplastic change

Hypothyroidism

Dose: 0.03 mcg I131 ( 4 mCi) single dose

Preparations: NaI131 capsul for oral, and
solution for iv. administration

PARATHYROID HORMONE and CALCIUM

METABOLISM
Calsium is important for normal function
of nerve and muscle, blood clotting,
enzyme function, etc
Blood calsium is regulated by three
hormones: parathyroid hormone,
calcitonin, and vitamin D.
PTH is the most important endocrine
regulator of calcium and phosphorus
concentration in extracellular fluid.
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Physiologic Effects of PTH

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Mobilization of calcium from bone: stimulate

osteoclasts to reabsorb bone mineral,
liberating calcium into blood.
Enhancing absorption of calcium from the
small intestine by indirectly stimulating
production of the active form of vitamin D in
the kidney (Vitamin D induces synthesis of a
calcium-binding protein in intestinal epithelial
cells that facilitates efficient absorption of
calcium into blood).
Suppression of calcium loss in urine and
stimulate loss of phosphate ions in urine

Control of PTH Secretion and Ca

metabolism

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Indication of PTH

Diagnostic test of pseudo hypoPTH

(insensitivity of target cell to PTH)

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Administration of PTH Blood Ca++ increase

Pseudo hypo PTH: no Ca++ response to PTH

Calcitonin
Secreted from C-cells of the thyroid gland.
Calcitonin reduces the activity of osteoclast
decreases plasma calcium concentration
Calcitonin plays a minor role in calcium
metabolism and only acts when the plasma
calcium concentration is very high
(hypercalcemia).
Administration: im, nasal spray
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Indication of Calcitonin

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Hypercalcemia due to hyper PTH

idiopathic hypercalcemia
Osteoporosis
Bone resorption due to immobilization
Vit. D intoxication

Vitamine D

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Vitamin D is produced by the skin in response to

exposure to sunlight.
Really, Vitamin D is a hormone.
The vitamin D must be chemically altered by the liver
and then the kidneys to become biologically active.

Active metabolite of vit. D3

Vit. D increases Ca absorption from GI

BISPHOSPHONATE

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Molecular Structure
OH R1

OH

O==P----O----P==O
OH R2

OH OH OH

Bisphosphonate

OH

O==P----O----P==O
OH CH2 OH
CH2-CH2-NH2

OH OH OH
O==P----O----P==O

Risedronate
Etidronate

OH CH3 OH

OH OH OH
O==P----O----P==O
OH CH2 OH
NH2

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Pamidronate

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BISPHOSPHONATE

Mechanism of action

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Suppress osteoclast activity on newly formed

resorption surface
Decrease formation of osteoclast progenitors
Decrease osteoclast recruitment
Promotion of apoptosis of mature osteoclast
Anti apoptotic effect on osteoblasts and
osteocytes

BISPHOSPHONATE
KINETICS
Poorly absorbed from GIT. Food or beverages
can decrease bioavailability significantly
Pamidronate: gastric irritation given orally
iv
High affinity to bone tissue and have long
bone retention
Not metabolised
Excreted by the kidney
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BISPHOSPHONATE

Side Effects

Contraindication

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Esophageal irritation risk of perforation should

be taken in sitting position with sufficient water
drinking
Arthralgia
Hypersensitivity
Hypersensitive to bisphosphonate
Hypocalcemia
Severe renal impairement (CCT < 35 ml/min.)
Active uper GI problems
Pregnancy

BISPHOSPHONATE

Indication

Administration

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Osteoporosis
Prevention of bone metastasis
Pagets disease
Hypercalcemia associated with malignancy
To be taken before meal (abt 30 min)
Keep sitting for at least 30 min

Preparation and Dose

Risedronat: tab. 5 mg

Alendronate: tab. 10 mg

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10 mg/day

Pamidronate: vial 15 mg/10 ml

5 mg/day

60-90 mg single infusion every 4 weeks

Clodronate: cap 400 mg, infusion 60 mg/ml x

5 ml, amp 300 mg/10 ml
Zoledronate: vial 4 mg

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