LEVOTHYROXINPH4Y2-3

GROUP 1 JACINTO, DOMILES, ENTONA, FERNANDO

GROUP 2 DELA ROSA, AGUILAR,

Levothyroxine

LEVOTHYROXINE

TYROSINE

Thyroid hormone: function

• Growth & Development

• Metabolism (Basal)

• CNS function (Hyperthyroidism= Stimulation/ Hypothyroidism= Depression)

• CV function (increase HR, CO, Blood flow)

• Body temperature

Hypothyroidism

• Inability of thyroid gland to supply sufficient thyroid hormones:

• Tetraiodothyronine/Thyroxine (T4)

• Triiodothyronine (T3)

• Calcitonin

• Classifications: Primary, Secondary, Tertiary

• Conditions: Cretinism (Child), Myxedema (Adult), Hashimotos’sthyroiditis, Endemic goiter, Sporadic goiter

• Complication: Myxedema coma

Levothyroxine (Synthroid/Unithroid//Eltroxin/Thyrax))

• DOC for Thyroid hormone replacement and suppression therapy

• Treats hypothyroidism (normalize thyroid levels= Euthyroid)

• Synthetic

• 25ug up to 300ug white pill no dye (hypoallergenic)

• No T3-induced side effects (but 85% of T3 comes from T4 conversion)

• Pregnancy category: A

Levothyroxine Advantages

• Stability

• Content uniformity

• Cheap

• Lack allergic foreign protein

• Easy laboratory measurement of serum levels

• Long half life (7 Days), once daily administation

MOA

Activation of nuclear receptors results in gene expression with RNA formation and protein synthesis

Levothyroxine acts like the endogenous thyroid hormone thyroxine. In the liver and kidney, T4 is converted to T3, the active metabolite. In order to increase solubility, the thyroid hormones attach to thyroid hormone binding proteins, thyroxin-binding globulin, and thyroxin-binding prealbumin (transthyretin). Transport and binding to thyroid hormone receptors in the cytoplasm and nucleus then takes place. Thus by acting as a replacement for natural thyroxine, symptoms of thyroxine deficiency are relieved.

Levothyroxine (T4)

• Average dose 1.6 ug/kg

• Age > 50-60 or cardiac disease: must start at a low dose (12.5-25 ug/d x2 weeks, increasing by 25 ug every 2 weeks until euthyroidism or toxicity is observed)

• Recheck thyroid hormone levels every 4-6 weeks after a dose change

Pharmacokinetics

• Absorption

• 40–80% was absorbed on jejunum and upper ileum. Absorption is increased by fasting.

• Distribution

• Greater than 99% of circulating thyroid hormones are bound to plasma proteins including thyroxine-binding globulin, thyroxine-binding prealbumin, and albumin. Only free hormone is metabolically active.

• Metabolism

• The primary pathway: Deiodination. The liver is the main site where both T3

and T4 are metabolized, with T4 deiodination occurring at several other sites, including the kidneys.

• Also, Conjugation and Glucuronidationand excreted directly into the bile and the gut where they undergo enterohepatic recirculation.

• Elimination

• Half-life elimination is 6–7 days for euthyroid patients; 9–10 days for hypothyroid patients; 3–4 days for hyperthyroid patients.

• 80% in Kidney (Urine) & 20% In Feces

MOT

1. Metabolism of T4 to T3 (Active metabolite) is regulated by Negative feedback mechanism. Excess T4 suppresses secretion from the thyroid gland and the conversion of T4 to T3 in the peripheral tissues, increases the rate of disposal of both T4 and T3, and down-regulates the T3 nuclear receptors. These regulatory mechanisms afford considerable tolerance to even large overdoses of levothyroxine

2. Massive overdose can be associated with increased sympathetic activity (thus require treatment with beta-blockers).

• Very large doses of thyroid hormones are required to produce toxicity, well in excess of 20 therapeutic doses (2.0 mg of levothyroxine). Significant toxicity is unlikely after the ingestion of as much as 50 therapeutic doses (5.0 mg of levothyroxine).

• Therefore, the ingestion of 20 therapeutic doses of thyroid hormones can be considered as a conservative dose of concern.

Side effects

• The toxicity of levothyroxine is directly related to the hormone level.

• In children:

• Restlessness, insomnia

• Accelerated bone maturation and growth

• In adults:

• Increased nervousness

• Heat intolerance

• Palpitation and tachycardia

• Weight loss

• If these symptoms are present, monitor serum TSH

• Chronic overtreatment with T4 , particularly in elderly patients, can increase the risk of atrial fibrillation and accelerated osteoporosis.

• Thyrotoxicosis

Good news

• Thyroid hormone poisoning: Uncommon, Low morbidity, NO mortality (AAPCC)

Certain medicines can make levothyroxine less effective if taken at the same time. If you use any of the following drugs, avoid taking them within 4 hours before or 4 hours after you take levothyroxine:

• Multivalent cations: Calcium, Magnesium, Aluminum, Iron (Mostly antacids, Dairy products and Supplements)

• Bile acid Sequesterants: cholestyramine, colestipol

• sodium polystyrene sulfonate

• Food products: infant soy formula, cotton seed meal, walnuts, and high-fiber foods.

• Pharmacokinetic antagonism (Absorption)

CASE PRESENTATION: JANE HAS HYPOTHYROIDISM

References:

• Katzung, B et al. (2012). Basic and Clinical Pharmacology, 12th ed., pp. 681-695

• Aaron, C.K. et al (2001). Ford: Clinical Toxicology, 1st ed

• Baron, S. J. et al. Lange Pharmacology Flashcards, 2nd ed., p131