thyroid & antithyroid drugs - minia · anti -thyroid drugs-they are used in the treatment of...

Fourth year Pharmacy Students

Clinical Pharmacology Lectures

Prof. Dr. Gehan Hussein H. Heeba

Faculty of Pharmacy Faculty of Pharmacy

Department of Department of

Pharmacology and Pharmacology and

ToxicologyToxicology

Thyroid & Antithyroid Drugs

• Hypothalamic cells secrete thyrotropin-releasing

hormone (TRH).

• TRH is secreted into capillaries of the pituitary

portal venous system, and in the pituitary gland

• TRH stimulates the synthesis and release of • TRH stimulates the synthesis and release of

thyroid-stimulating hormone (TSH).

• TSH in turn stimulates an adenylyl cyclase–

mediated mechanism in the thyroid cell to increase

the synthesis and release of T4 (thyroxin) and T3.1Prof. Dr. Gehan H. Heeba

1- Ingested iodine is converted into iodide and absorbed into the blood.

2- Iodide trapping: iodide is actively removed from the blood by thyroid gland (stimulated by TSH and decreased by I-).

3- Thyroidal iodide is oxidized to iodine by thyroperoxidase enzyme.

4- Iodine organification: iodination of tyrosine to monoiodotyrosine (MIT) and diiodotyrosine (DIT).monoiodotyrosine (MIT) and diiodotyrosine (DIT).

5- MIT and DIT are coupled to form T3 and T4 which stored in the follicles.

6- T3 and T4 bound to thyroglobuline in the gland and they are pharmacologically inactive. T3 and T4 are librated from thyroglobuline by protease enzyme (high concn of I2 and I-

inhibite protease enzyme and decrease the release of thyroid hormones).

• Drugs that inhibit thyroid hormones synthesis:

Step 2-------------- ionic inhibitors e.g. nitrate ions, thiocyanate, Step 2-------------- ionic inhibitors e.g. nitrate ions, thiocyanate, perchlorate.

Steps 3, 4, 5-------- thiourea drugs, sulfonamides, PABA.

Steps 4, 5, 6--------- iodide ions

Some drugs can cause hypothyrodism and goiter---e.g. phenylbutazone, lithium.

2Prof. Dr. Gehan H. Heeba

• Cellular mechanism of thyroid hormones

T4 and T3, dissociated from thyroid-binding proteins, entering the cell by diffusion or possibly by active transport.

Within the cell, T4 is converted to T3 by 5'-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3 receptor protein, and lead to increased formation of RNA and subsequent protein synthesis. This is consistent with the observation that the action of thyroid is manifested in vivo with a time lag of hours or days after its administration.


Regulation of transcription by thyroid hormones. T3 and T4 are triiodothyronine and thyroxine, respectively. PB, plasma binding protein; F, transcription factor; R, receptor; PP, proteins that bind at the proximal promoter).


Physiological and pharmacological actions of thyroid hormones:

► They produce general increase in the basal metabolic rate, i.e. increase oxygen consumption and CO2 outlet and increases energy production.

► Effect on carbohydrates: increase blood glucose level, increase glycogenolysis, i.e. insulin antagonist.increase glycogenolysis, i.e. insulin antagonist.

► Effect on protein metabolism: catabolic hormone, decrease body weight, increase gluconeogenesis and protein catabolism.

► Effect on fats: stimulate fat metabolism, increase lioplysis and decrease blood cholesterol level.

► Effects on CNS: CNS stimulation, insomnia, restlessness, anxiety, tremors.

► Effect on CVS: they increase the sensitivity of the heart to sympathetic stimulation (E and NE)------tachycardia.sympathetic stimulation (E and NE)------tachycardia.

► Effect on development: important for normal growth and development and maintenance of fertility.


Two diseases are related to the hormone-producing activity of the

thyroid gland:

• Hypothyroidism—a decrease in the amount of thyroid

hormones manufactured and secreted.

• Hyperthyroidism—an increase in the amount of thyroid

hormones manufactured and secreted.hormones manufactured and secreted.

-A severe form of hyperthyroidism, called thyrotoxicosis or

thyroid storm, is characterized by high fever, extreme

tachycardia, and altered mental status.

-Thyroid hormones are used to treat hypothyroidism and anti-

thyroid drugs and radioactive iodine are used to treat

hyperthyroidism


Hypofunction (hypothyrodism)

Hypothyroidism can occur with or without thyroid enlargement (goiter). The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of a low free thyroxine (or low free thyroxine index) and elevated serum TSH.

► In childhood-----it produce Cretinism, which characterized by ► In childhood-----it produce Cretinism, which characterized by being short, mentally and physically retarded.

► In adults--------it produce Myxoedema, which characterized by decrease in basal metabolic and decrease in heart rate, increase in body weight, apathy, and dry waxy swelling of the skin.

►Simple goiter-------it is increase in the size of thyroid gland due to deficiency of iodine, so thyroxin is not formed, so TSH level is increased.

• It is very rarely life-threatening and adverse effects such as

osteoporosis and atrial fibrillation may result from prolonged

over treatment.


• The initial dose of T4 will depend on the patient's

age, severity and duration of disease, and the co-

existence of cardiac disease.

• In young, healthy patients with disease of short

duration, T4 may be commenced in a dose of 50-

100µg/kg daily. As the drug has a long half-life it 100µg/kg daily. As the drug has a long half-life it

should only be given once daily.

• The most convenient time is usually in the morning.

• After 6 weeks on the same dose, thyroid function

tests should be checked.

• The TSH concentration is the best indicator of the

thyroid state and this should be used for further thyroid state and this should be used for further

dosage adjustment. Clearly, a raised TSH

concentration indicates either inadequate treatment

or poor compliance.


Preparations of thyroid hormonesNatural hormone preparations:

Thyroid extract from beef or sheep thyroid gland, contain

standard quantity of T3 and T4 (dried thyroid tab. 60 units).

Synthetic hormone preparations:

Levothyroxin sodium ----- synthetic T4 (eltroxine tab.)

Liothyronine sodium ------- synthetic T3 (tetroxine tab.)Liothyronine sodium ------- synthetic T3 (tetroxine tab.)

Liotrix----------------------- mixture of T4 and T3 in a ratio of

4:1

- The use of desiccated thyroid rather than synthetic

preparations is never justified, since the disadvantages of

protein antigenicity, product instability, variable hormone

concentrations, and difficulty in laboratory monitoring far

outweigh the advantage of low cost.outweigh the advantage of low cost.

- 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), which permits once-daily

administration.14Prof. Dr. Gehan H. Heeba

• In addition, T4 is converted to T3 intracellularly; thus,

administration of T4 produces both hormones.

• - Although liothyronine is 3-4 times more potent than

levothyroxine, it is not recommended for routine

replacement therapy because of its shorter half-life (24

hours), which requires multiple daily doses; its higher hours), which requires multiple daily doses; its higher

cost; and the greater difficulty of monitoring its

adequacy of replacement by conventional laboratory tests.

Furthermore, because of its greater hormone activity and

consequent greater risk of cardiotoxicity, T3 should be

avoided in patients with cardiac disease. It is best used

for short-term suppression of TSH.

Therapeutic uses of thyroid hormones:Therapeutic uses of thyroid hormones:

• As replacement therapy in hypothyroidism, in

cretinism (10 ug/kg/day for infant less than 6 months)

and myxoedema (50 ug/kg/day).

• In goiter disease that is not responding to iodine

therapy.15

Side effects of thyroid hormones

•Nervousness, increase body temp. and decrease body weight.

•Anginal pain, cardiac arrhythmias and heart failure.

•Overdose cause signs and symptoms of hyperthyroidism.

Interactions

1- When administered with cholestyramine or colestipol there is

a decreased absorption of the oral thyroid preparations. These a decreased absorption of the oral thyroid preparations. These

drugs should not be administered within 4 of 6 hours of the

thyroid hormones.

2- When administered with the oral anticoagulants there is an

increased risk of bleeding. It may be advantageous to decrease the

dosage of the anticoagulant when a thyroid preparation is

prescribed.

3-There is a decreased effectiveness of the digitalis preparation if

taken with a thyroid preparation.taken with a thyroid preparation.


Simple goiter

►A dietary deficiency of iodine, if prolonged,

causes a rise in plasma TRH and eventually an causes a rise in plasma TRH and eventually an

increase in the size of the gland. This condition

is known as simple or non-toxic goiter.

Another cause is ingestion of goitrogens.

►The enlarged thyroid usually manages to

produce normal amounts of thyroid hormone,

although if the iodine deficiency is very severe, although if the iodine deficiency is very severe,

hypothyroidism may supervene.


Hyperfunction (hyperthyroidism or thyrotoxicosis- Grave`s disease):

• Characterized by decrease in the body weight, increase in heart rate, anxiety, nervousness, tremors, and exophthalmus.


Anti-thyroid drugs-They are used in the treatment of

hyperthyrodism and in preoperative preparation

before thyroidectomy.

-Reduction of thyroid activity and hormone effects

can be accomplished by agents that interfere with can be accomplished by agents that interfere with

the production of thyroid hormones; by agents that

modify the tissue response to thyroid hormones; or

by glandular destruction with radiation or surgery.

- "Goitrogens" are agents that suppress secretion

of T3 and T4 to subnormal levels and thereby

increase TSH, which in turn produces glandular

enlargement (goiter). enlargement (goiter).

-The antithyroid compounds used clinically include

the thioamides, iodides, and radioactive iodine.


1- thiouria drugs (Thioamides)• Propylthiouracil, methimazole, carbimazole

• Mechanism of action: they prevent hormone synthesis by inhibiting peroxidase enzyme (inhibit iodide oxidation), iodine organification and coupling of MIT and DIT.and coupling of MIT and DIT.

• They absorbed from GIT with slow onset of action and short t1/2

• They can cross the placenta and pass in the milk causing goiter in the fetus and nursing infants (cretinism).

• Side effects include: arthralgia, jaundice, rashes, vomiting, agranulocytosis. Longer use increase vomiting, agranulocytosis. Longer use increase TSH and increase the size of the gland.


- Carbimazole, which is converted to

methimazole in vivo, is widely used.

-Methimazole is about ten times more potent

than propylthiouracil.

-Both thioamides (propylthiouracil and

methimazolemethimazole) cross the placental barrier and are

concentrated by the fetal thyroid, so that caution

must be employed when using these drugs in

pregnancy


2- Iodide

• - Potassium iodide and lugol`s solution (5% I2 + 10% KI)------ taken orally.

• - Iodide salts inhibit iodination of tyrosine and

thyroid hormone release; these salts also

decrease the size and vascularity of the decrease the size and vascularity of the

hyperplastic thyroid gland.

• -Their onset of action occurs rapidly, within 2–

7 d. However, the effects are transient; the

thyroid gland “escapes” from the iodide block

after several weeks of treatment.

• -Iodide salts are used in the management of

thyroid storm and to prepare patients for thyroid storm and to prepare patients for

surgical resection of a hyperactive thyroid.

• -Adverse effects include rash, drug fever,

metallic taste, bleeding disorders, and, rarely,

anaphylactic reactions.


• Potassium perchlorate, potassium thiocynate, potassium nitrate.

• block uptake of iodide by the gland through competitive inhibition of the iodide transport mechanism. Since these effects can be overcome by large doses of iodides, their effectiveness is somewhat unpredictable.

• The major clinical use for potassium perchlorate is to block thyroidal reuptake of I– in patients with iodide-induced hyperthyroidism (eg, amiodarone-induced hyperthyroidism). amiodarone-induced hyperthyroidism).

• However, potassium perchlorate is rarely used clinically because it has been shown to cause aplastic anemia.

4- Radioactive iodine

• Radioiodine, given orally, is selectively taken up by thyroid and

damages cells; it emits short-range β radiation, which affects only

thyroid follicle cells.

It is used in: 1-Hyperthyroidism (in elderly patients with heart

diseases or relapse after surgery).

2-Metastatic thyroid carcinoma 2-Metastatic thyroid carcinoma

• -Contraindicated in young patients, pregnancy, and lactation.

• -Side effects: slow onset (months), hypothyroidism will eventually

occur, carcinogenicity.


5- B blockers:

• antagonize the effect of thyroid hormones on the

heart while awaiting the response to anti-thyroid

drugs.

• Beta blockers without intrinsic sympathomimetic

activity are effective therapeutic adjuncts in the activity are effective therapeutic adjuncts in the

management of thyrotoxicosis since many of these

symptoms mimic those associated with sympathetic

stimulation.

• Propranolol, the B-blocker, most widely studied and

used in the therapy of thyrotoxicosis.

6- Guanethidine:Eye drops containing guanethidine, a noradrenergic-Eye drops containing guanethidine, a noradrenergic-

blocking agent, are used to ameliorate the

exophthalmos of hyperthyroidism (which is not

relieved by antithyroid drugs); it acts by relaxing the

sympathetically innervated smooth muscle that

causes eyelid retraction.


Sites of action of some antithyroid drugs. I–, iodide ion; I°, elemental iodine. Not shown: radioactive iodine (I 131), which destroys the gland through radiation.


thyroid & antithyroid drugs - minia · anti -thyroid drugs-they are used in the treatment of...

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