Lecture 1: Drugs to Treat Thyroid Disorders

-Glucocorticoids

-Opioids

-Dopamine

Iatrogenic Causes of Decreased TSH Secretion

-Lithium

-Iodine

-Amiodarone

Iatrogenic causes of hypothyroidism that alter T3/T4 synthesis or secretion

-Rifampin

-Tyrosine Kinase Inhibitors

-β-Blockers

iatrogenic causes of hypothyroidism that alter T3/T4 metabolism

-Estrogens

-Raloxifene

-Opioids

iatrogenic causes of hypothyriodism that increase TBG

Amiodarone

-anti-arrhythmic drug

-iodinated compound

-blocks the conversion of T4 to T3 and one of its active metabolites blocks T3-receptor binding to nuclear receptors

-contributes to a transient inhibition of thyroid hormone synthesis due to an auto-regulatory mechanism within the thyroid

-the Wolff- Chaikoff effect

Levothyroxine (T4)

first line therapy for hypothyroidism

Levothyroxine (T4)

INDICATIONS

o Overt hypothyroidism

o Subclinical hypothyroidism

o Myxedema coma (IV)

o TSH suppression

o Thyroid cancer, diffuse goiters, thyroid nodules

Levothyroxine (T4)

o Synthetic thyroxine (T4)

o ~ 50% of T4 converted to T3 (active metabolite)

o T4 & T3 binds to thyroid receptor in cell nucleus to exert metabolic effects via regulation of DNA transcription and protein synthesis

-no oral solution available (crush up tablets and mix with water)

Inactive Phase

When the unliganded TR dimer bound to the thyroid hormone response element (TRE) along with corepressors acts as a suppressor of gene transcription

-MCT8

-MCT10

-OATP1C1

active transporters that bring free T4 and T3 into the cell

Active Phase

-When T3 binds to the ligand-binding domain of the thyroid receptor (TR)

-promotes disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR) on the TRE, displacement of corepressors, and binding of coactivators

on an empty stomach (1 hr before or 4 hrs after meals, or at bedtime)

how should you take Levothyroxine (T4) in order to achieve consistent blood levels?

Emergencies (Myxedema coma)

When would you use IV preparations of Thyroxine?

-If primary hypothyroidism: TSH

-If secondary hypothyroidism: Free T4

What labs do you draw before prescribing Levothyroxine?

Liothyronine

-synthetic T3 used

-shorter half life

-for hypothyroidism, myxedema coma, and T3 suppression test

-Potential role in therapy with inadequate conversion of T4 to T3

Cardiotoxicity

because Liothyronine is T3 which is more potent than T4, there is an increased risk for _________________________

Liotrix

-synthetic 4:1 mixture of T4:T3

-for hypothyroidism

-non preferred therapy bc it may cause thyrotoxicosis

Thyroid, Desiccated

-Natural dried thyroid preparation from porcine or bovine source containing T3, T4, and iodine

-for hypothyroidism

Thyroid, Desiccated

• Non-preferred therapy for hypothyroidism due to non-standardized product formulation

• "Natural" and inexpensive

• May cause thyrotoxicosis

• Antigenicity

• Odor

- Uncorrected adrenal insufficiency

- Acute MI

What are contraindications for thyroid supplementation?

o Avoid thyroid supplements for weight reduction in euthyroid patients

o Caution in patients with CV disease; reduce initial dose

o Long term use may ↑ bone resorption and ↓ bone mineral density

o Avoid in patients with thyrotoxicosis

What are some cautions to know about thyroid supplementation?

Hyperthyroidism

Symptoms of ___________________________:

• Angina, arrhythmias, myocardial infarcon, ↑ BP, tachycardia, heart failure

• Hyperactivity, irritability, heat intolerance/diaphoresis

• Abdominal cramps, diarrhea

• Weight loss

early development of the fetal brain depends on maternal thyroxine

why is adequate dosing in a pregnant hypothyroid patient so important?

one extra dose of their current thyroxine tablet twice a week

what should you advise your hypothyroid patient to do if she becomes pregnant?

4 hours

Levothyroxine should also be administered apart from prenatal vitamins and calcium by at least ______________

upper half of an age-appropriate reference range

what is your goal for T4 and free T4 levels in a hypothyroid pt under 3

1-4 weeks

When giving levothyrozine in pediatric patients, you should monitor every _____________________

Levothyroxine (T4)

drug of choice for pediatric hypothyroidism

Myxedema Coma

-thyroid crisis

-rare, due to severe decompensated hypothyroidism

Need to start immediate and aggressive therapy

-SYMPTOMS

- Hypothermia, bradycardia, advanced stages of hypothyroid symptoms, myxedema, and altered sensorium ranging from delirium to coma

Myxedema

a dry, waxy swelling of the skin with nonpitting edema.

Steroids

When a pt is in a myxedema coma, what should you give BEFORE giving levothyroxine bc it could cause an adrenal crisis?

IV glucocorticoid (hydrocortisone; dexamethasone)

first step in a treatment of a myxedema coma

↓ metabolism of vitamin K-dependent

clotting factors (↓INR & ↑clotting risk)

what is the impact of hypothyroidism on Warfarin?

↑ metabolism of vitamin K-dependent

clotting factors (↑ INR & ↑ bleeding risk)

what is the impact of hyperthyroidism on Warfarin?

↓ renal elimination

effects of hypothyroidism on Digoxin?

↑ renal elimination

effects of hyperthyroidism on Digoxin?

↓ opiate metabolism (↑ risk of sedation & respiratory depression)

Effects of hypothyroidism on Analgesic Opioids

↑ opiate metabolism (↓ risk of sedation & respiratory depression)

Effects of hyperthyroidism on Analgesic Opioids

C. Free T4

A 23-year-old woman presents for her initial visit to a primary care physician. The woman states that she is often anxious and irritable, and the physician decides to take a serum thyroid-stimulating hormone (TSH) level as a screening measure. Her serum TSH is mildly elevated, and although the patient does not have symptoms, the physician is concerned that she may have hypothyroidism. Which of the following blood tests is indicated next?

A. T3

B. T4

C. Free T4

D. Free thyroxine index

E. Resin T3 uptake

C. Propranolol, a beta receptor antagonist, is a treatment option for such patient.

A patient with hypothyroidism has been taking levothyroxine for one year. He develops tachycardia while on treatment. Which is true regarding the condition of the patient?

A. Decreased number of beta receptors may contribute to tachycardia.

B. He should be given a beta-agonist as propranolol is not effective in such conditions.

C. Propranolol, a beta receptor antagonist, is a treatment option for such patient.

D. They may also decrease the sensitivity of these beta receptors to catecholamines.

E. Thyroid hormones may lead to a decrease in the number of beta receptors in the cardiac muscle.

Methimazole

first line for pharmacological management of Hyperthyroidism (except in 1st trimester of pregnancy, thyroid storm, or intolerance)

Radioactive Iodine (131I) (RAI)

o Treatment of choice in adults Graves' disease and toxic multinodular goiter

o Ease of administration, effective, low expense, absence of pain (Advantages)

Radioactive Iodine (131I) (RAI)

o It is taken up by thyroid gland via iodide transporter

o Destroys thyroid parenchyma by emission of β-rays from the radioactive decay

• Antithyroid medications (thionamide - methimazole) until euthyroid before surgery

• Addition of iodides (sat KI, 5 gtts./day) for 7-14 days prior to surgery to ↓ vascularity of the gland

• B-blocker preoperatively and up to 7-10 days following surgery to control symptoms like tachycardia

Medications used pre- and post-operatively to support a pt getting a thyroidectomy?

-Hypothyroidism

-Vocal Cord Paralysis

-Hypoparathyroidism

What are the three most common complications of a thyroidectomy?

Thyroidectomy

INDICATIONS:

o Graves' disease with large gland, obstructive symptoms, multinodular glands, or desired pregnancy within next 12 months

o Toxic multinodular goiter or toxic adenoma

Pregnancy and Lactation

contraindiactions for RAI

Radioactive Iodine (131I) (RAI)

PRECAUTIONS

Proximity to other individuals, particularly pregnancy or children after administration.

ADVERSE EFFECTS

o Nausea, neck soreness, metallic taste.

o Hypothyroidism: Often requires levothyroxine

therapy for life (post-treatment) to maintain euthyroid.

β-Blockers

these drugs do not interfere with RAI, so they can be used for prn symptoms

Thioamides and Iodide

What two treatments are stopped before RAI bc they can impair uptake?

Thioamides

Methimazole (MMI)

Propylthiouracil (PTU)

Thioamides

-block thyroid hormone synthesis by inhibiting TPO

-interfere with organification and coupling of mono- and diiodotyrosine

Propylthiouracil (PTU)

Which Thioamide inhibits peripheral conversion of T4 to T3?

Thioamides

INDICATIONS

o Hyperthyroidism (thyrotoxicosis)

o Thyroid storm (off-label)-PTU preferred

o Methimazole: off-label use for iodine and amiodarone-induced thyrotoxicosis

3-4 weeks

Thioamides require how long to produce a euthyroid state?

Methimazole (MMI)

Which Thioamide is 10x more potent?

Methimazole (MMI)

the anti-thyroid drug therapy of choice in adults and children

Propylthiouracil (PTU)

Thioamide that should be reserved for use:

o during the first trimester of pregnancy

o in thyroid storm

o in patients experiencing ADRs to other thioamide

Thioamides

ADVERSE EFFECTS

o Nausea and GI distress

o Maculopapular rash (4-6%)

o Arthralgias and fever

o Lupus-like syndrome

o Hypothyroid symptoms if overtreated

o Agranulocytosis (rare but fatal)

o Altered taste/smell: MMI

o Hepatotoxicity: (black box warning PTU)

LFTs >5x ULN (absolute)

LFTs 2-3x ULN (relative)

contraindications for Thioamides

Agranulocytosis

-usually occurs within the first 2-3 months of thioamide treatment

-all pts should be educated on the signs and symptoms

-effect is usually reversible upon discontinuation of therapy.

Agranulocytosis

-drop in white blood cell count

-febrile illness or develops pharyngitis

Treatment benefits outweigh risks

Thioamides can cross the placenta and cause fetal hypothyroidism, yet they are still the first line treatment option... Why?

Methimazole (MMI)

avoid using during first trimester of pregnancy bc it can cause:

-embryopathy

-congenital skin defects

-aplasia cutis

Iodides

-saturated solution of potassium iodide (SSKI): 35 to 50 mg of iodine per drop

-Lugol's solution (potassium iodide-iodine: 5-8 mg iodine/drop)

Iodides

• inhibit organification (Wolff-Chaikoff effect)

• block of thyroid hormone release within hours (through inhibition of thyroglobulin proteolysis)

• decreases the size and vascularity of hyperplastic thyroid glands

Iodides

INDICATIONS

• Preparation for surgical thyroidectomy in patients with Graves' disease

• Adjunct for thyroid storm

• Only used short term

Iodides

LIMITATIONS

o Avoid using in patients who will likely have radioactive iodine therapy

o Do not use alone (resistance 2-8 weeks)

o Exacerbation of thyrotoxicosis

o Precipitate hyperthyroidism in euthyroid individuals (Jod-Basedow disease)

Toxic Multinodular Goiter

contraindications for Iodide solutions

fetal goiter may form

why should you avoid chronic use of iodide solutions in pregnancy?

-Metoprolol

-Atenolol

-Propanolol

β-Blockers without intrinisic sympathomimetic activity "ISA"

β-Blockers

-effective therapeutic adjuncts in the management of thyrotoxicosis since many of the symptoms mimic those associated with sympathetic stimulation

-cause clinical improvement of hyperthyroid symptoms but do NOT typically alter thyroid hormone levels.

β1-selective Blocker

If pt has an active airway disease, which β-Blockers should you use?

Propanolol

the β-Blockers that has been most widely studied and used in therapy of thyrotoxicosis

β-Blockers

-Block thyrotoxicosis sensitization of catecholamines

-Predominately added on to control adrenergic symptoms of hyperthyroidism (CV: tachycardia, hypertension, atrial fibrillation)

Hypotension and Bradycardia

the two main adverse effects of β-Blockers

β-Blockers

Off-label uses

o Thyroiditis, hyperthyroidism

-Used as adjunct with antithyroid drugs, RAI, or iodine in Graves' disease or toxic nodules In preparation for surgery

o Thyroid storm

D

MMI and PTU are classified as FDA pregnancy category ______

Methimazole (MMI)

drug of choice for children treated with antithyroid drug therapy

Radioactive Iodine (131I) (RAI)

• Acceptable for children > 10 years old, and select children aged 5-10 years based on dosing limitations (i.e., based on weight)

• Requires lifelong thyroid replacement therapy with levothyroxine

Thyroidectomy

preferred treatment when definitive therapy necessary and child does not qualify for radioactive iodine (i.e., too young)

Thyroid Storm

• Hyperpyrexia, tachycardia, tachypnea, dehydration, delirium or psychosis, coma, nausea, vomiting and diarrhea

• Average duration of clinical decompensation around 72 hours

• Symptoms may persist up to 8 days

1. Supportive care (oxygen, treat fever, treat dehydration, and nutritional needs)

2. Beta blocker

3. Thioamides

4. Saturated solution of KI (SSKI) to inhibit thyroid hormone release (at least 1 hr after step 3)

5. Glucocorticoids to prevent peripheral conversion of T4--> T3 &, prevent adrenal crisis

6. Bile acid sequestrant (Cholestyramine) to prevent free thyroid hormone reabsorption

7. Treat all triggers of the storm

8. Definitive therapy

Management of Thyroid Storm

Cholestyramine

-bile acid sequestrant

-binding resin that can be used for the short-term control of hyperthyroid symptoms. It binds thyroid hormone that undergoes enterohepatic recirculation, and thereby enhances thyroid hormone clearance.

C. Propylthiouracil

A diagnosis of hyperthyroidism is made. Which of the following is the best drug to start this patient on if she is planning a pregnancy in the near future?

A. Hydrochlorothiazide

B. Methimazole

C. Propylthiouracil

D. Synthroid