Thyroid and Anti-Thyroid Drugs

Presented By :

Dr. SYED ABDUL NAVEEDM.Pharm (Pharmacology).

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Thyroid

•Thyroid gland is one of the largest gland

and highly vascularized endocrine gland

present in the body.

•It is a flat structure containing two lobes

joined by isthmus.

•It is situated anteriorly above the trachea

and just below the larynx.

•A glycoprotein know as thyroglobulin is

the main constituent,with a high

molecular weight that binds the iodine

present in organic form.2

• Thyroglobulin upon hydrolysis releases thyroid hormone,

which are considered to be iodinated tyrosine derivatives, as they are derived from l-tyrosine.

• Thyroid gland is controlled and maintained by pituitary gland and hypothalamus.

• This gland secretes three main hormones know as

Thyroxine (T4),triiodothyronine(T3), and calcitonin.

• The thyroid hormone (T3 and T4) are non-steroidal in nature and are chemically regarded as the amino acid containing iodinated diphenyl ethers.

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• Thyroxine(T4) is the major form of thyroid hormone found in circulation.

• The ratio of thyroxine and triiodothyronine released in to the blood circulation is 20:1

• Thyroid gland also secretes calcitonin that is responsible for maintaining calcium homeostasis.

• Calcitonin is produced by the parafollicular cells of the thyroid gland.

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Bio-synthesis, storage and release

• It is a complex process.

• The thyroid hormones are synthesized and stored as amino acid residues of thyroglobulin, which upon hydrolysis release the thyroid hormones.

• The inorganic form of iodine supplied through diet also play a significant role in the production of thyroid hormone.

• Biosynthesis of thyroid hormone is regulated by fluctuations in plasma levels of thyroid stimulating hormone/thyrotropin.

• Thyrotropin inturn regulates the synthesis of thyroglobulin, hydrogen peroxide and thyroperoxidase(TPO).

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Steps involved in conversion of inorganic iodide to thyroid hormone are

Uptake of iodide by the follicular cells of thyroid gland.

Oxidation of iodide.

Iodination of tyrosyl residues/formation of iodotyrosyl residues.

Formation of thyroxine and triiodothyronine from iodotyrosineby coupling reaction.

Release of T3 and T4 by proteolysis of thyroglobulin.

Conversion of T4 to T3.

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Mechanism/mode of action

• Thyroid hormone diffuses a cross the cell membrane and bind to intracellular thyroid receptors.

• After the penetration T4 gets converted to T3, which has high affinity for the thyroid receptors.

• A specific DNA sequence is identified ,and T3 bind to it.

• The receptors undergo a change in their conformation ,which stimulates transcription, results in the synthesis of proteins,

ultimately stimulating function of T3 and T4

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• Thyroid works on a delicate feedback mechanism.

• T3 and T4 synthesis in thyroid is regulated by TSH.

• If the circulation levels of T3 and T4 are high then pituitary gland decreases its sensitivity to TSH, which is secreted by hypothalamus.

• This entire process make synthesis and release of TSH low by negative feedback mechanism.

• If the T3 and T4 levels are low the Pituitary gland becomes more sensitive to thyroid regulating hormone(TRH), which is secreted by the hypothalamus.

• This stimulates TSH secretion with the release of excess thyroid hormones.

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• Thyroid gland converts iodine present in food in to thyroid hormones like T4 and T3.

• The thyroid cells absorb iodine and combine the iodine with tyrosine amino acid to form T4 and T3.

• Thyroid hormones are responsible for proper functioning, development and differentiation of all the cells of human body.

• They also helpful in regulating fats, proteins, carbohydrates and vitamine metabolism.

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Differences between T3 and T4T3 T4

Four time more potent than T4 Less potent

Peak effect reaches with in 24-48 hrs. Peak effect reaches in 6-8 hrs

Plasma protein binding capacity is less It bind more tightly to plasma proteins

It is active in vitro It is inactive invitro

Thyroid gland produce 20% of T3 Thyroid gland produces 80% of T4

T3 is the active form T4 is less active than T3

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THYROID DISORDERS

Thyroid dysfunctioning results in many unwanted changes

in metabolisum of proteins, carbohydrates,lipids .

It also exerts adverse effect on reproductive, Gastro-intestinal,

central nervous system ,and cardiovascular system.

Two types of thyroid disorders are:

• Hypothyroidism

• Hyperthyroidism

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Hypothyroidism

• It occur due to the deficiency of thyroid hormone.• Common symptoms include decreased metabolic rate increase levels of serum

cholesterol, fatique, lethargy, mental retardation etc.

Common types of hypothyroidism include:1. Cretinism• Decrease in the levels of thyroid hormone in infants or during foetal stage is

know as cretinism.

Reasons for occurrence Extreme deficiency of iodine Failure of thyroid development Defect in synthesis of thyroid hormones Presences of thyroid stimulating hormone receptor blocking antibodies.

Symptoms Yellowskin, potbelly, dwarfism, physical and mental retardation.

Treatment It can be treated by thyroxine . 12

2. Myxedema• It is a condition in which hypothyroidism results in accumulation

of mucopolysaccharide in the intercellular spaces of muscle and skin.

Reasons for occurances• Glandular tissue degeneration• Improper pituitary feed back mechanism.• Impairment in the secretions of synthesized hormones.• Impariment in biosynthesis of hormones• Excessive use of antithyroid drugs.symptoms• Dry skin, slow pulse, mental retardation, weight gain, intolerances

to cold, deep hoarse voice.Treatment• Administration of liotrix.(it is a mixture of levothyroxine sodium

and liothyronine sodium in 4:1 ratio.

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3. Myxedema coma• When hypothyroidism is left untreated for prolonged period of

time ,it results in myxedema coma. it mainly occur in old people and during cold climatic conditions.

Reasons for occurance• Neglecting the condition of hypothyroidism by providing

inadequate treatment.• Pulmonary infection, trauma, congestive heart failure, Prolonged

exposure to cold.

Symptoms• Coma, bradycardia, decrease in body temperature,

hypotension, urinary retention, pleural and peritoneal effusions, respiratory depression, dry and rough skin.

Treatment• Thyroxine sodium (150-300mcg) ,and triiodothyronine (10mcg).

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4.Simple(non-toxic) Goitre

• The word goitre refers to the enlargement of thyroid gland occur due to the deficiency of thyroid hormone production ,which ultimately results in excess realease of TSH.

The non-toxic goitre is of two types :

• Endemic goitre : occur due to the dificiency of iodine

• Sporadic goitre : occur due to the impariment in synthesis of hormones

Reasons for occurance

• Lack of dietary iodine.

• Excessive use of goitrogens.

Symptoms

• Enlargement of the neck, weight gain etc.

Treatment

• Iodine + 5-8-mg sodium iodate per kg of common salt 15

5. Adult hypothyroidism.• Hypothyroidism that occur as a result of thyroiditis, thyroidectomy is referred to as adult

hypothyroidismReasons for occurrence

• Thyroiditis, throidectomy• Excessive use of drug like I131,lithium,amiodarone and iodides.

Symptoms• Physical and mental retardation, decreased metabolic rate lethargy etc.

Treatment• L-thyroxine (50 microgram) in initial days

Increase the dose up to 100-200micro gram/day.

6. Hashimoto’s disease/auto-immune thyroditis with hypothyroidism.• It is an auto-immune disorder in which the thyroid gland gets destructed by the attack of

lympocytes, plasma cells and fibrous tissue.

Reasons for occurrence• Injury to thyroid gland• Production of auto antibodies.

Treatment• Thyroid hormone replacement therapy

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Hyperthyroidism• Occur due to the excess activity of thyroid hormones.• Excessive intake of thyroid hormone causes thyrotoxicosis.

General symptoms of hyperthyroidism includes, increased heart rate and cardiac output due to the increase in oxygen demand, increased metabolic rate, decreased levels of serum cholesterol, intolerance to glucose,glucosuria, anorexia,intolerance to thermoregulation.

Graves disease • It is autoimmune disorder.• Occurs due to the presence of autoantibodies.• igG antibodies produced by the body bind to the TSH receptor on thyroid gland instead of

TSH.• This binding stimulates the realease of thyroid hormones and ultimately results in excess

production of thyroid hormones.• The binding of auto antibodies to the TSH receptor is not controlled by any negative

feedback mechanism as in the TSH.Reasons for occurrence

• Production of autoantibodies• Excess production of thyroid hormones.

Symptoms• Enlargement of thyroid gland,patient becomes hot and flushed.

Treatment • Use of antithyroid drugs• By using radioactive iodine• By using surgery(thyroidectomy)

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Toxic uninodular/multinodular goitre

• The adenomas grow excessively and result in increased secretions of thyroxineand triiodothyronine.it mainly occurs in elderly patients.

Thyroid storm/thyroid crisis/thyrotoxic crisis

• Extreme hyperthyroidism is referred to as thyroid storm.

Reasons for occurance

• Lack of proper treatment

Symptoms

• Hyperpyrexia, tremors,mania,heart failure,

• tachycardia, vomiting, jaundice, hepatomegaly,coma.

Treatment

Initial treatment with high dose of antithyroids PTU-1200mg and then treatment with beta-blockers and iodine

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Treatment for Hyperthyroidism

• Anti-thyroid drugs—Inhibits thyroid hormone synthesis by irreversibly binding to TPO inhibiting its ability to break down iodine (I2→I-) and covalently attach it to the tyrosine residue of thyroglobulin.– Propylthiouracil

– Methimazole

– Carbamizole─Degraded to methimazole in the body.

• Radioactive Iodine.

• Thyroidectomy.

• β-Blockers used in the treatment of thyroiditis to treat symptoms.

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Anti-thyroid Drugs

• Effective in the long-term treatment of hyperthyroidism.

• 6-8 weeks before maximum effect of the drug achieved. Drug inhibits hormone synthesis, so hormones synthesized prior to drug use will continue to cause hyperthyroid condition.

• Typical side effects include headache, nausea, vomiting, itchy skin and rash, and muscle aches and pains.

• Serious liver damage, decreased red and white blood cell synthesis, as well as decreased platelet production have been reported in a few cases. The drug’s interaction with other enzymes responsible for clotting factor synthesis accounts for some of these serious side effects.

• Administering too high a dosage of anti-thyroid drugs can cause hypothyroidism.

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Anti-thyroid Drugs

• Thioamides

• Iodides

• radioactive iodine

• Beta adrenoceptor blocking agents

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Mechanism of action of anti thyroid drugs

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Thioamides

• Methimazole

• Propylthiouracil (PTU) Carbimazole

• MOA:

– inhibit synthesis by acting against iodide organification (both)

– coupling of iodotyrosines (both)

– Blocks peripheral conversion of T4 to T3 (PTU)

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Thioamides

• Pharmacokinetics:– almost completely absorbed

in the GIT

– serum half life: 90mins(PTU) ; 6 hours (methimazole)

– excretion: kidney – 24 hours (PTU) ; 48 hours (Methimazole)

– can cross placental barrier (lesser with PTU)

– Methimazole 10x more potent than PTU

– PTU more protein-bound24

Definitive therapyGraves diseaseToxic nodular goitre

PreoperativelyIn thyrotoxic patientsAlong with RAI

uses

Thioamides

• AE:

– maculopapular rash

– benign transient leukopenia

– agranulocytosis

– hepatitis (PTU) ; cholestatic jaundice (Methimazole)

– vasculitis

– lupus-like syndrome

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Iodine131

• preparations: sodium iodide 131

• MOA: trapped within the gland and enter intracellularly and delivers strong beta radiations destroying follicular cells

• Penetration range-400-2000µm

• Clinical uses: Grave’s, primary inoperable thyroid CA

• Contraindication: pregnancy

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AdvantagesEasy administrationEffectivenessLow expenseAbsence of pain

Iodine131

• Advantages

– Easy administration

– Effectiveness

– Low expense

– Absence of pain

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Iodine131

• Thioamides should be given initially and stop 3 days before radioactive iodine administration

• 131I dosage generally ranges between 185 MBq to 555MBg repeated after 6 months

• Adverse effects

– permanent hypothyroidism

– potential for genetic damage

– may precipitate thyroid crisis

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Anion Inhibitors

• Monovalent anions such as perchlorates, pertechnetate and thiocyanate can block uptake of iodide by the gland by competitive inhibition

• can be overcome by large doses of iodides

• useful for iodide-induced hyperthyroidism (amiodarone-induced hyperthyroidism)

• rarely used due to its association with aplasticanemia

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Iodinated Contrast Media

• Iodinated contrast media

Ipodate (oral)

Iopanoic acid (oral)

Diatrizoate (intravenous)

valuable in hyperthyroidism (but is not labeled for this indication)

• MOA: inhibits conversion of T4 to T3 in the liver, kidney, brain and pituitary

Another MOA is due to inhibition of hormone release secondary to iodide levels in blood

• Useful in thyroid storms (adjunctive therapy)

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Beta Blockers

• Drugs: Propranolol, Metoprolol, Atenolol

• MOA:

– Membrane-stabilizing action: inhibits T4 to T3

– Ameliorate many disturbing hyperthyroidism secondary to increased circulating catecholaminesby blocking beta receptors

• Indications: Grave’s, Thyroid storm

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Corticosteroids

• Prednisone is given for patients with Grave’s ophthalmopathy

• 1mg/kg/day (60mg/day 3 divided doses); if it should be given for more than 4 weeks, taper to decrease risk of adrenal crisis

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Thyroid storm

• Sudden exacerbation of throtoxic symptoms

• Life threatening condition

• Vigorous management

– Propanalol 1-2mg i/v or 40-80mg PO Q6h

– Diltiazim 90-120mg Po Q8-6 hrs or 5-10mgs intravenous infusion/hour

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TSH Replacement Drugs

• Thyrotropin alpha—A synthetic form of TSH. Administered intravenously.

• Used in thyroid cancer treatment.– Tumors of the hypothalamus or pituitary gland can cause the

uncontrolled release of TSH, which accumulates in the thyroid and can cause subsequent follicular or papillary cancer of the thyroid. Partial or total thyroidectomy typical.

– Following thyroidectomy, the individual is dependent on exogenous thyroid hormones to regulate metabolism, but thyrotropin alpha is also used to suppress the release of endogenous TSH, which could trigger cancerous growth again.

– Used as a diagnostic tool to determine the reoccurrence of cancer.

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Hyperthyroidism and Pregnancy

• Ideal situation- treat before pregnancy

• Pregnancy-Radioactive iodine CI

• Propylthiouracil

– Dose limitation≤ 300mgs/day

• Methimazole alternative- fetal scalp defects

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