Role/ utilization of iodine in the thyroid
-Iodine is added to a tyrosine residue to create the hormones released by the thyroid
-T4 has 4 iodines
-T3 has 3 iodines
Synthesis thyroid hormones
-Iodine can increase production of the hormones when found in the diet
-Iodine can decrease production of the hormones when given pharmacologically
Transport of thyroid hormones...
must be done by transporter proteins
Metabolism and conversion of thyroid hormones
-T4 is converted to T3 by 5'-deiodinase to T3 which enters the nucleus where it binds to a specific T3 receptor protein which leads to an increased formation of RNA and subsequent protien synthesis
Which thyroid hormone is more prevalent?
Which thyroid hormone is more potent
What medication class can be used to halt conversion of T4 to T3 and to treat thyroid storms
Where is T4 best absorbed?
Duodenum and ileum where it is about 80% absorbed
How well is T3 absorbed?
Drugs that induce microsomal enzymes will do what to the metabolism of T4 and T3
Starvation does what to circulating T3 hormones and cellular T3 receptors
What does a decrease in T3 early in life result in?
Dwarfism and mental retardation
T3's action on development and functioning of nervous, skeletal, and reproductive tissue depends on what?
Protein synthesis and secretion of GH
Thyroid receptors bind to what?
Thyroid response elements found on DNA in the promotor/ regulatory regions and then activates the TRE which starts transcription
Which two genes encode thyroid receptors
THRA and THRB
What does THRA encode for and what does it regulate?
TR alpha 1 which regulates heart rate, body temperature, skeletal muscle function, and development of bone and small intestine
What does THRB encode for?
two promotors that lead to production of TRB1 and TRB2 which have unique amino terminal domains but the rest of the molecules are identical
TRB1 is involved with what?
TRB2 is involved with what?
development of cones in the retina & inner ear development- negative feedback loop by T3 on hypothalamic TRH and pituitary TSH
Effects of T3
-Tadpole to frog
-Vasodilation, brain development, growth, and thermogenesis
Hypothyroidism causes what?
Bradycardia, decreased cardiac index, pericardial infusion, increased pericardial vascular resistance, decreased pulse pressure, & increased arterial pressure
Hyperthyroidism causes what?
Tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, & increased pulse pressure
What does TH do to hepatic LDL receptors?
Increases their expression and increases the metabolism of cholesterol to bile salts
What is the most common disorder of thyroid function?
hyothyroidism (myxedema) which can be caused by an iodine deficiency or chronic automiimune thyroiditis (Hashimoto's)- antibodies against thyroid peroxidase adn against thyroglobulin
Failure of the thyroid gland
Decreases stimulation of the thyroid by TSH becuase of pituitary failure or hypothalamic failure
What are the symptoms of hypothyroidism?
Fatigue, lethargy, col intolerance, mental slowness, depression, dry skin, constipation, mild weight gain, fluid retention, muscle aches & stiffness, irregular menses, and infertility
Hyperthyroidism causes what?
-Increased levels of free TH found in serum
-also called thyrotoxicosis
What is Graves' disease?
-Most common cause of high RAIU
-Autoimmune disorder that causes an increase in TH production, diffuse goiter, & IgG antibodies that bind & activate the TSH receptor
-In caucasians, major histocompatibility alleles (HLA) B8 & DR3 are associated
What are the symptoms of hyperthyroidism?
Excessive heat production, increased motor activity, increased to catecholamines produced by sympathetic nervous system, flush/warm/moist skin, weak/tremulous muscles, rapid heart rate, increased appetite due to more energy being expended, loss of weight, insomnia, and heat intolerance
What symptoms are seen more in elderly?
Angina, arrythmias, & heart failure
Which symptoms are seen less in elderly?
Less incidence of sympathetic nervous system stimulation- apathetic hyperthyroidism
What drugs are L-T4 preparations?
Levothroid, levoxyl, synthroid, and unithroid
Where are levothyroxine sodium preps absorbed?
Stomach and small intestine (80%) but is absorbed more on an empty stomach and is associated with less variability in the TSH when taken like this on a regular basis
When do serum TSH levels peak for levothyroxine preps?
2-4 hours after oral ingestion
What is the half-life of levothyroxine sodium?
What are the potency standards for levothyroxine standards?
95-105% which has been decreased from 90-110%
Levothyroxine raises what serum ratio?
T4/T3 because 20% of circulating T3 is supplied by direct thyroidal secretion
When do you need to check serum levels for thevothyroxine?
~6 weeks because of the half life of 7 days
What is the equivalent dose for L-T4 oral and injectable?
Injectable dose is 80% of oral dose
What drugs are L-T3 preparations?
What is the absorption of L-T3?
100% with peak serum levels 2-4 hours following oral ingestion
Which has a more rapid onset of action L-T4 or L-T3?
L-T3 and requires more frequent dosing
What is the half-life of L-T3?
Is L-T4 desirable for chronic dosing?
No because the transient levels of serum T3 increase above normal levels
What dose of L-T3 yields normal serum levels of T3 in athyreotic individuals?
Does the dose of L-T3 need to be changed when a patient's TSH is low?
Yes, because of the negative feedback normally requires local generation of T3 from circulating T4
What drug is a preparation that includes T4 & T3?
Thyrolar (Iotrix) 4 (T4): 1 (T3)
What drug has a similar ratio of T4:T3?
Desiccated thyroid (Armour thyroid)
What dose of Armour thyroid is equivalent to thyroxine?
60mg (1 grain) Armour thyroid to 80mcg of thyroxine
What is the mechanism of action for antithyroid drugs?
Interfere directly with the synthesis of thyroid hormone by not allowing iodine to be added to tyrosine residues
What is the mechanism of action for ionic inhibitors?
Block the iodide transport mechanism
What is the mechanism of action for iodine?
High concentrations of iodine decrease the release of thyroid hormones from the gland and may also decrease the synthesis of hormones
What is the mechanism of action for radioactive iodine?
Damages the thyroid gland with ionizing radiation
What family do the antithyroid drugs belong to?
What is the prototypical antithyroid drug?
does the same as other antithyroid drugs but also inhibits the peripheral deiodination of T4 to T3
What is propylthiouracil used for?
thyroid storm an d severe hyperthyroidism
What is the most severe ADR for antithyroid drugs?
What is the most common ADR for antithyroid drugs?
purpuric, urticarial papular rash
What are other ADRs of antithyroid drugs?
Pain, stiffness in the joints, parasthesis, HA, nausea, skin pigmentation, and loss of hair
What is the black box warning for propylthiouracil?
associated hepatic failure (mainly in children and pregnant women)
What is methimazole's main ADR?
What are the ADRs for the iodides?
acneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders, and anaphylactiod reaction