Levothyroxine

PowerPoint Lecture Presentation for

Toxicology2015 Edition

Group 1 & Group 2PH4Y2-4

Levothyroxine

Levothyroxine

Levothyroxine - slide 2Copyright 2015. All rights reserved.

Content Introduction

Toxicokinetics

Mechanism of toxicity

Toxic dose

Clinical presentation

Diagnosis

Treatment

Levothyroxine

Introduction


Thyroid hormone Natural: Thyroxine (T4 or 3,5,3,5-tetraiodo-L-thyronine)

and triiodothyronine (T3 or 3,5,3-triiodothyronine)

Synthetic: T3 (liothyronine), T4 (levothyroxine), liotrix(both T3 and T4), desiccated animal thyroid (both T3 and

T4)

Levothyroxine

Introduction


Thyroid hormone

Levothyroxine

Introduction


Thyroid hormones What is the DOC for hypothyroidism?

Levothyroxine (T4) Synthroid

Other clinical uses

Prevention of mental retardation in newborns with thyroiddeficiency (Infantile hypothyroidism): This condition

may be avoided if thyroid supplementation occurs within

the first 2 weeks of life

TSH suppression therapy after treatment for thyroidcancer

Levothyroxine

Toxicokinetics


Absorption Site: small intestine

Between 40-80% of oral dose is absorbed from the GIT

May inhibit absorption of levothyroxine: plasma proteins, soluble dietary factors, Fe sulfate, Al hydroxide,

sucralfate, bile acid sequestrants

Increased absorption: fasting (79-81% BA)

Decreased absorption: individuals with malabsorptive states (64% BA)

Levothyroxine

Toxicokinetics


Distribution Highest concentrations: liver and kidneys

Do not cross the placenta and minimal amounts are distributed into the milk

Both T3 and T4: highly protein bound (99%), with the T4being more extensively and firmly bound

Levothyroxine

Toxicokinetics


Metabolism and Elimination Deiodinated in peripheral tissues forming T3; portions

are metabolized into acetic, lactic, and pyruvic acids

About 35% that enters the circulation is deiodinated

May undergo conjugation to form soluble glucoronides and sulfates

Peak plasma: 2-4 hours (PO)

Half-life: 7 days

Excretion: Urine (major), feces (20%)

Levothyroxine

Mechanism of Toxicity


Mechanism Binds to specific receptors (esp. nuclear receptors)

leading to protein synthesis (T3>T4)

Binds to mitochondria, thus, it can have direct effects on the plasma membrane and cellular cytoarchitecture

Excessive thyroid hormone potentiates adrenergicactivity in the cardiovascular, GI, and neurologic systems

Symptoms of overdose may be delayed 25 days after ingestion while metabolic conversion to T3 occurs

Levothyroxine



Physiologic response Increase in calorigenesis via the stimulation of heart,

skeletal muscles, liver, and kidneys, leading to an

increase in oxygen consumption

Increased cardiac contractility accounts for 30% to 40% of the increase in oxygen consumption

Increased contractility is the result of the direct positive inotropic effects of the hormones as well as an enhanced

responsiveness to endogenous catecholamines as a

result of the production of increased numbers of beta

receptors in the heart

Levothyroxine



Physiologic response Thyroid hormones also increases beta receptors in

skeletal muscle, adipose tissue, and lymphocytes and

decrease the number of alpha receptors in cardiac and

vascular tissues leading to

THYROTOXICOSIS

Tachycardia

Tremor

Anxiety

Heat intolerance

Levothyroxine

Toxic Dose


Toxic dose and risk factor Toxic: >5 mg (acute)

Euthyroid adults and children appear to have a high tolerance to the effects of an acute overdose

Patients with preexisting cardiac disease and those with chronic overmedication have a lower threshold of

toxicity

Sudden deaths have been reported after chronic thyroid hormone abuse in healthy adults

Levothyroxine

Clinical Presentation


Mild to moderate intoxication Sinus tachycardia

Elevated temperature

Flushing

Diarrhea

Vomiting

Headache

Anxiety, agitation, psychosis, and confusion

Levothyroxine

Clinical Presentation


Severe toxicity Supraventricular tachycardia

Hyperthermia, and

Hypotension

One case report of a seizure after an acute overdose

Levothyroxine

Diagnosis


Specific levels Levothyroxine (T4)

Serious poisoning is very unlikely, and blood levels may not be required unless symptoms develop over

57 days after the ingestion

In this case, obtain free T3 and T4 concentrations and total T3 and T4 levels with T3 resin uptake

Levothyroxine

Diagnosis


Other useful laboratory studies Electrolytes

Glucose

BUN

Creatinine, and

ECG monitoring

Levothyroxine

Treatment


Emergency and supportive measures ABCD

Treat seizures, hyperthermia, hypotension, and arrhythmias

Repeated evaluation over several days is recommended after large T4 or combined ingestions,

because serious symptoms may be delayed

Most patients will suffer no serious toxicity or will recover with simple supportive care

Levothyroxine

Treatment


Specific drugs and antidotes Tachyarrhythmias

Propranolol 0.010.1 mg/kg IV or

Esmolol 0.0250.1 mg/kg/min IV repeated every 25 minutes

Simple sinus tachycardia

Propranolol, 0.10.5 mg/kg PO every 46 hours

Levothyroxine

Treatment


Specific drugs and antidotes In cases of massive T4 ingestion, peripheral metabolic

conversion of T4 to T3 can be inhibited by

PTU (propylthiouracil): 610 mg/kg/day (maximum 1 g) divided into three oral doses for 57 days

Iopanoic acid: 125 mg/day orally for up to 6 days

Propranolol: 23 mg IV over an hour, then 30 mg/day IV for 5 more days

Through inhibition of 5'-deiodinase

Levothyroxine

Treatment


Decontamination Prehospital

Administer activated charcoal orally if available

Ipecac-induced vomiting may be useful for initial treatment at the scene (eg, children at home) if it can

be given within a few minutes of exposure

Hospital

Gastric lavage is NOT necessary after small to moderate ingestions if activated charcoal can be

given promptly

Levothyroxine

Treatment


Enhanced elimination Diuresis and hemodialysis are NOT useful because

thyroid hormones are extensively protein bound

Treatment with charcoal hemoperfusion, plasmapheresis, and exchange transfusion has been

employed but DID NOT appear to influence clinical

outcome

Levothyroxine

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