Endocrine Pharmacology Thyroid Flashcards
Where does the thyroid sit and what is the functional unit
Follicles;
Thyroid hormones:
Iodine-containing amino acids
-thyroxine (T4)
-Triiodothyronie (T3)
-Thyroglobulin (Tg)
H-P-T axis
hypothalamic (TRH)-pituitary(TSH)-thyroid axis(T4+T3)
Tissues: nuclear and membrane receptors: T4 is converted to T3
Liver:conjugation/excretion
how is T3 and T4 made and what are they converted to
Enzymes add iodine to thyroglobulin to make it. (TPO); organification: iodide is converted to iodine and added to TG
most t3 comes from conversion at tissue site
Thyroid Hormones; where does it come from, how is it moved
-The iodine necessary for synthesis for thyroid hormones
comes from food/ supplements. Sea salts do not contain iodide
-Iodine is converted to iodide in the gut
-iodide is an active process and highly concentrated in the thyroid gland
-iodide is organified in the colloid of the follicle; the addition of iodide to TG
What is iodide active transport is mediated by and what does it do
sodium-iodide symporter (NIS)
-NIS is a membrane protein that mediates active iodide uptake by the thyroid
-It is a specialized system that assures that adequate dietary I- accumulates in the follicles and becomes available for T4 and T3 biosynthesis
T3 + T4 potency and where they are mostly at
T3 is 10x more potent than T4
-t4 is solely from the thyroid
-t3 is 20% from thyroid and 80% peripheral deiodination
How does I get oxidized
I must be oxidized to iodinate Tyrosyl reidues of Tg
Iodination of the tyrosyl residues than forms monoidotyrosine (MIT) and diiodotyrosine (DIT) which are coupled to form T4 primarily or T3
-Reactions are catalyzed by Thyroid peroxidase (TPO)
TPO uses H2O2
Drugs and conditions that increase T4 and T3 by increasing TBG
Drugs: oral contraceptives and other sorces of estrogen, methadone, heroin, clofibrate
Conditions: pregnancy, infectious/chronic active hepatitis, HIV infection, genetics
Thyroid functions + pathophysiology
-essential for normal brain development and growth
-Critical for sexual maturation
Pathophysiology: metabolic disorders, hypo/hyperthyroidism, autoimmune disease and cancer
Thyroid hormone receptor and what it does and its implications
thyroid hormone receptor beta (TRB) is a tumor suppressor in thyroid, breast and others
TRB also promotes myelinization
Implications: multiple sclerosis; repair potential following brain and spinal cord injury; treatments for metabolic disease
Thyroid hormone and metabolic activities
Thyroid hormones (T3) regulate of overall body metabolism
-T3 increases basal metabolic rate
Calorigenic effects
-T3 increases oxygen consumption in most peripheral tissues
-Increases body heat production
Metabolic effects:
-Stimulates lypolysis, and cholesterol metabolism; stimulates rapid removal of LDL, and stimulates carbohydrate metabolism
How many develop thyroid issues and who is more susceptible
12% of US population
-women are 5-8x more likely than men
thyroid cancer: 3-5% and increasing
What is hypothyroidism and what does it mean, how is it caused
it is a disorder where the thyroid fails to secrete an adequate amount of thyroid hormones
-most common thyroid disorder
Cause: primary thyroid gland failure; diminished stimulation of the thyroid gland by TSH…
What is Hashimoto and what does it mean and what do people present with, commonly associated with…
chronic autoimmune disease… occurs when there is a severe defect in the thyroid hormone synthesis
-characterized by destruction of the thyroid glad by autoantibodies against thyroglobulin, thyroperoxidase, and other thyroid tissue components
Present with: hypothyroidism, painless goiter, and other overt signs
Associated with: type 1 diabetes, autoimmune with other autoimmune diseases
Hyperthyroidism
excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues
Hyperthyroidism underlying causes
Causes: toxic diffuse goiter (graves disease)
-toxic uniodular or multinodular goiter
-painful subacute thyroiditis
-silent thyroiditis
-toxic adenoma
Graves disease (Toxic diffuse goiter)
Most common cause of hyperthyroidism
-60-90% of cases
-females more than males
-possibly related to defect in immune tolerance
-high levels of thyroid hormones, T4 and T3 will cause decrease in pituitary TSH levels
Thyroid Nodular Disease
Thyroid gland nodules are common in the general population
-palpable nodules= 5% mainly in women
-most are benign, 8-10% with nodules have thyroid cancer
What are the symptoms of goiter/disease
most are asymptomatic; they may be toxic or nontoxic
What drugs are used in the treatment of hypothyroidism
Triiodothyronie (T3) and levothryoxine (T4)
Levothyroxine is used in most cases
Compare and contrast Triiodothyronine and levothyroxine
levothyoxine : T4 is used for replacement and supression therapy, it is stable and has a long half-life (7 day) which permits once-daily administration. T4 is used to convert t3 in the body
Triiodothyronie: faster acting, shorter half life, and costs more than T4
What is a drug that has both T3 and T4?
liotrix; it is an oral mixture of the two synthetic hormones in a 4-1 ratio by weight
What are the classifications for drugs used to treat hyperthyroidism
Thioamides: hormone synthesis inhibitors
Iodides: hormone release inhibitors
Glandular destruction with radioactive iodine or surgery
inhibit ionic trapping
What are some antithyroid drugs and what do they do
Thioamines, propylthiouracil (half-life of 1.5) , and methimazole (half-life of 6 hours)
They: are rapidly absorbed, reaching peak serum levels after 1 hour
Adverse effects: reactions occur in 3-12% of patients with a rash and fever being most common. Agranulocytosis (reversible)(low wbc count)
Thioamides accumulate in the thyroid- so plasma half-life does not affect the duration of action
Most important effect: block iodination of tyrosine residues of thyroglobulin
onset of action is flow- because synthesis not release
What are iodides and what kind of drugs do they produce + what are some disadvantages +what happens with chronic use + how does autoimmune thyroid diseases (ex. graves) impact treatment?
antithyroid drugs; major action= inhibit hormone release
Rapid improvement with iodide treatment is used for “thyroid storm”
disadvantages: increase in iodine stores which may slow onset of thioamide action, fails to work after initial treatment period (Wolff-chaikoff effect)
Chronic use: hypothyroidism, goiter, salivary gland inflammation
Autoimmune thyroid diseases like graces means there is autoregulation of iodine and greater sensitivity so it is more effective
What is thyroid storm and what are symptoms
also called thyrotoxic crisis happens when there is a large release of thyroid hormone in a short amount of time. rare complication of hyperthyroidism.. threatening
symptoms: rapid heartbeat, high temp, high BP (hypertension), yellowing of skin and eyes (jaundice), severe agitation and confusion, loss of consciousness
What is radioactive iodine classified as and what is it used for + half life + adverse effects
131I is used ONLY for treatment of thyrotoxicosis
it is a Beta emitter, with half-life of 5 days and penetration range of 400-2000
Adverse reactions: genetic damage, leukemia, thyroid cancer, damage to fetal thyroid
what are some Ionic inhibitors and what they do +adverse effects
-perchlorate blocks iodide from entering thyroid at the NIS symporter
-thiocyanate
Adverse effects: serious toxicity
What are beta blockers and what do they do
They do not inhibit the production of thyroid hormones but they block the effects of hormones on the body
may provide rapid relief to irregular heartbeats, tremors, anxiety or irritability, heat intolerance, sweating, diarrhea and muscle weakness
Thyroid hormone receptors and the treatment of other diseases
-Thyroid hormone receptor alpha predominantly in cardiovascular and brain
-Thyroid hormone receptor beta predominantly in liver
-thyroid receptor beta is a tumor suppressor in a multitude of tissues
How prevalent is thyroid cancer
-most common endocrine cancer
-incidence increasing
-both large and microcarcinomas, better detction, enviro + lifestyle factors
4x more likley in women than men
-invasive, lethal tumor
What are some risk factors for thyroid cancer
radiation exposure, gender/age, thyroid disease, diet/obesity, genetic mutations, environmental factors
endocrine disruptors
-perchlorate (propellant)
-bisphenol A BPA (plastics, polycarbonates)
-flame retardants: PBDEs derivatives
-flooring, cosmetics
-PFOA/PFOS…C8 (non-stick coating)
-DDT, DDE (pesticides, breakdown products)
-synthetic estrogen (Pharmaceuticals)
endocrine disrupting chemicals with their impacts on health
-little evidence to prove exposures cause health impacts but…
-increases in thyroid cancer; relationship to other cancers
- Disruption of thyroid system; neurodevelopmental changes; metabolic changes
-declines in male/female fertility
-abnormalities in M/F reproductive organs
-increases in immune/autoimmune diseases, and some neurodegenerative diseases
What are some Key Public health concerns
-increase in endocrine-related disorders in humans
-age
-latency effect (exposure early with disease outcome later)
-dose response (low level in environ… but doses at critical developmental stages in life)
-transgenerational effects (EDC exposure… epigenomic +genomic effects)
-Mixtures of chemicals and continued exposure
The thyroid is… a what for environmental EDCs
a target…
BPA, phthalates, and perchlorate is also associated
-higher EDC concentrations in umbilical cord blood or urine from pregnant women is associated w/ poorer performance on cognition + neurobehavior
what is perchlorate and what does it do
Perchlorate blocks radioactive iodine uptake (RUI)
REMEMBER: Iodine is essential for the synthesis of thyroid hormones; without iodine… low TH, high TSH, goiter, higher risk of developmental and metabolic disease and cancer
What does BPA do
inhibits TR-mediated transcription and TH mediated phenotypic changes (metamorphosis)-
Thyroid and infants
newborns have no thyroid hormone
-develop TH faster
-sensitive to small reductions in TH
-permanent effects from Th inefficiency
Hyperthyroidism-thyrotoxicosis… state summary info
Too much TH
Graves’ disease: autoimmune
Toxic nodular goiter
Excessive intake of iodine
“Thyroid storm” is an extreme hyperthyroidism (e.g. infections, pregnancy, cardiac emergencies)
Hypothyroidism
Not enough TH
Hashimoto’s thyroiditis: autoimmune
Postpartum thyroiditis
Benign thyroid disease
Goiter-iodine insufficiency
Thyroid cancer
Increasing 5%/year: papillary, follicular, anaplastic, medullary
