د. قاسم ادوية 3\4\2018
عدد الاوراق ( 3 ) م\3\موصل lec:9Drugs for thyroid disorders
Thyroid Hormones
The thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function. The two major thyroid hormones are triiodothyronine (T3; the most active form) and thyroxine (T4). inadequate secretion of thyroid hormone (hypothyroidism) , if an excess of thyroid hormones is secreted (hyperthyroidism).
Thyroid function
Thyroid function is controlled by a tropic hormone, thyroid-stimulating hormone (TSH; thyrotropin).. TSH generation is governed by the hypothalamic thyrotropin-releasing hormone (TRH). TSH action is mediated by cAMP and leads to stimulation of iodide (I- ) uptake. Oxidation to iodine (I2) by a peroxidase is followed by iodination of tyrosines on thyroglobulin. Condensation of two diiodotyrosine residues gives rise to T4, whereas condensation of a monoiodotyrosine residue with a diiodotyrosine residue generates T3, which is still bound to the protein. The hormones are released following proteolytic cleavage of the thyroglobulin. Most of the hormone (T3 and T4) is bound to thyroxine-binding globulin in the plasma.
THYROID HORMONE PREPARATIONS FOR HYPOTHYROIDISM:
1. Levothyroxine (T4):
It is the drug of choice for most patients who require thyroid hormone replacement.
Pharmacokinetics: Much of an administered dose of Levothyroxine is converted to T3 in the body. The hormone has a prolonged half life (about 7 days).
Therapeutic uses
1. Levothyroxine is indicated for all forms of hypothyroidism, regardless of cause.
2. Levothyroxine is used to maintain proper levels of thyroid hormones following thyroid surgery, irradiation , & treatment with antithyroid drugs.
Adverse effects
Toxicity is directly related to T4 levels and manifests itself as nervousness, heart palpitations and tachycardia, intolerance to heat, and unexplained weight loss.
Thyrotoxicosis may result if the dosage is excessive.
Drugs interactions.
1. Drug that reduce Levothyroxine absorption:
Cholestyramine, Colestipol, Calcium supplementation, Sucralfate, Aluminum containing antacids, Iron.
2. Warfarine : Levothyroxine accelerates the degradation of vitamin K-dependant clotting factors.
3. Catecholamines: thyroid hormones increase cardiac responsiveness to catecholamine.
4. Levothyroxine can increase requirements for insulin & digitalis.
The hormones are metabolized through the microsomal P450 system. Drugs that induce the P450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of the thyroid hormones
Routes of drug administration: Levothyroxine is almost always administered by mouth. Oral dose should be taken on an empty stomach to enhance absorption. Dosing is usually done in the morning before breakfast.
IV administration is used for myxedama coma & for patients who cannot take Levothyroxine orally.
For most hypothyroid patients, replacement therapy must be continued for life. Treatment provides symptomatic relief but does not produce cure.
Liothyronine (T3):
Liothyronine is a synthetic preparation of T3. Liothyronine differs from levothyroxine in 3 important ways:
1. Liothyronine has a shorter half life & shorter duration of action.
2. Liothyronine has a more rapid onset of action.
3. Liothyronine is more expensive.
These properties make Liothyronine less desirable than levothyroxine for long-term use.
Liotrix
Liotrix is a mixture of synthetic T4 plus synthetic T3 in a 4:1 fixed ratio ( this ratio is similar to the ratio of these hormones in plasma).
Since levothyroxine alone produces the same ratio of T4 to T3, liotrix offers no advantages over levothyroxine for most indications.
Π. Drugs for hyperthyroidism:
1. Propylthiouracil:
Therapeutic response to PTU result primarily from blockade of thyroid hormone synthesis. Blockade occurs in two ways:
1. PTU prevents the oxidation of iodide, thereby inhibiting incorporation of iodine into tyrosine.
2. PTU prevents iodinated tyrosines from coupling. Both effects results from inhibiting peroxidase, the enzyme that catalyzes both reactions.
In addition, PTU acts in the periphery to suppress conversion of T4 to T3.
Pharmacokinetics
PTU is rapidly absorbed following oral administration.
Therapeutic actions begin within 30 minutes.
The plasma half life is short (about 2 hours).
The drug can across the placenta & can enter breast milk.
Uses
PTU has four applications in hyperthyroidism:
1. PTU can be used alone as the sole form of therapy for Graves diseases.
2. PTU can be employed as an adjunct to radiation therapy.
3. PTU can be given to suppress thyroid hormone synthesis in preparation for thyroid gland surgery.
4. PTU is given to patients experiencing thyrotoxic crisis.
Side effects
1. Agranulocytosis.
2. Hypothyroidism.
3. Neonatal hypothyroidism & goiter.
4. Rash.
5. Nausea, arthralgia, headache, dizziness, & parasthesia.
Methimazole
Methimazole is similar to PTU. However, in contrast to PTU, Methimazole does not block conversion of T4 to T3 in the periphery.
It crosses the placenta more readily than PTU , therefore PTU is preferred.
3. Iodide products ( Non radioactive):
A. Strong iodine solution (Lugol,s solution):
Lugol,s solution is a mixture containing 5% elemental iodine & 10% potassium iodide.
The iodine undergoes reduction to iodide within the GIT prior to absorption.
Mechanism of action:
When present in high concentration, iodide has a paradoxical suppressant effect on the thyroid which is brought about in three ways:
1. High concentration of iodide decreases iodine uptake by the thyroid.
2. High concentration of iodine inhibit thyroid hormone synthesis by suppressing both the iodination of tyrosine & the coupling of iodinated tyrosine residues.
3. High concentration of iodine inhibit release of thyroid hormone into blood stream.
Uses : Lugol,s solution is given in preparation for thyroidectomy.
Plasma levels of thyroid hormones are reduced with PTU before initiating Lugol,s solution.
Then Lugol,s solution along with PTU is administered for the last 10 days prior to surgery.
Adveres effects :
Chronic ingestion of iodine can produce iodism. Sign & symptoms include a brassy taste, a burning sensation in the mouth & throat, soreness of the teeth & gums, frontal headache, coryza, salivation & skin eruption.
B. Sodium iodide ( IV):
Sodium iodide is employed for the acute management of thyrotoxic crisis. Benefits derive from the ability of high concentration of iodide to rapidly suppress thyroid hormone release. It is used in combination with PTU & propranolol.
Potassium iodide Potassium iodide can be used to treat Graves disease & thyrotoxic crisis. It has the same effects as Lugol,s solution.
Propranolol
Propranolol can suppress tachycardia & other symptoms of Graves disease .
Benefits derived from B-adrenergic blockade, not from reducing levels of T3 & T4.
One advantage of it is that its effects occur rapidly.