Thyroid Disorders Flashcards
What are the functions of the Thyroid System?
- Breathing
- Heart rate
- Central and peripheral nervous systems
- Body weight
- Muscle strength
- Menstrual cycles
- Body temperature
- Cholesterol levels
- Much more!
What is the T3 & T4 production?
- T4 is broken to T3 (active component)
- 2-step process for making TH, by thyroid peroxidase
- Thyroglobulin - building block of thyroid synthesis
What are the Thyroid Hormone Actions?
Critical to growth and development
- Nervous, skeletal and reproductive tissues
Positive inotropic and chronotropic effects on the heart
Calorigenic effect
- Peripheral vasodilation and increased cardiac output
Increased lipolysis
- Increased LDL binding by liver cells
- Hyperlipidemia in hypothyroidism
Increased conversion of cholesterol to bile acids
- Hypercholesterolemia in hypothyroidism
What is the Thyroid Hormone Disposition?
Pharmacokinetics T4 t1/2 = 7 days
T3 t1/2 = 1 day
Metabolism of T4
20% inactivated and 80% converted to T3
(35% to T3 and 45% to rT3)
Glucuronidation and sulfation in liver
Excretion in urine and bile
Conjugates reconverted to T3 in lower GIT
Negative feedback relationship of T4 and T3 on TSH
Where is the Thyroid Hormone Synthesis?
Formed in the thyroid gland
Iodine is actively accumulated in the thyroid
- ~ 20 – 100 x [plasma]
- Stimulated by thyrotropin (TSH)
Thyroid peroxidase catalyzes:
- Organification of iodine (catalyzes)
- Condensation (to form T4 & T3)
What is the 5 steps of Thyroid Hormone Synthesis?
- Active uptake and concentration of iodide by the thyroid gland
- Oxidation of iodide by THYROID PEROXIDASE and iodination of tyrosyl groups of thyroglobulin (organification of iodide) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
- Conversion of iodotyrosyl to iodothyronyl groups by condensation of two iodotyrosyl groups
- Proteolysis of iodothyronyl groups to release thyroid hormones (T4 and T3) and reverse triiodothyronine (rT3)
- Peripheral conversion of T4 to T3 (metabolic activation), rT3 and other inactive products by oxidative deiodination and/or conjugation
Thyroid Hormone Plasma Transport:
bound to thyroxine-binding globulin (TBG) - 70%
bound to transthyretin or “thyroxine-binding prealbumin” (TTR or TBPA)
- 10-15%
Paraalbumin - 15-20%
unbound T4 (fT4) - 0.03%
unbound T3 (fT3) - 0.3%
What are the Thyroid Hormone Receptors?
Nuclear thyroid hormone receptors are ligand dependent transcription factors that are heterodimerized with retinoid-X-receptor (RXR) bound to thyroid response elements (TRE’s) of thyroid hormone target genes in thyroid responsive cells.
Thyroid Function Tests
Hypothyroid:
- T4 = low
- T3 = normal or low
- TSH = high
- Serum Thryoglobulin = LOW
Thyroid Function Tests
Hyperthyroid:
- T4 = high
- T3 = high
- TSH = low
- Serum Thryoglobulin = high
Children have higher ___ than adults –> need kid reference values
T3
Hypothyroidism:
- ~ 2% of women, 0.1% in men
- More common in women
– 14/1000 in women
– <1/1000 in men
– Hashimoto’s Thyroiditis- Autoimmune
Presentation
- Slowing of body functions
– Heart, mental acuity, strength, response to catecholamines, cold and scaly skin, sparse hair
What are the signs/sx’s of Hypothyroidism?
Puffiness (myxedema), droopy eyelids, coarse and thin hair
What is the cause of Hashimoto’s thyroiditis?
Antibodies against thyroid peroxidase and/or thyroglobulin gradually destroy thyroid gland follicles
What is the sx’s of Hashimoto’s thyroiditis?
Slower metabolism, reduced CNS activity-weight gain, fatigue, depression, bradycardia, constipation, muscle weakness, memory loss, infertility, hair loss. NOTE: HT can also cause reactive hyperthyroidism (inflammation), and thus mania, tachycardia, panic attacks. Mania due to HT is called PRASAD’S SYNDROME
Often misdiagnosed as depression or anxiety sometimes even as bipolar disorder
What is the detection of Hashimoto’s thyroiditis?
Presence of specific antibodies is diagnostic. Also see increased TSH and often lymphocyte invasion of thyroid gland
What is the Hashimoto’s Diagnosis?
- Enlargement of the thyroid, known as a GOITER
- High levels of antibodies against thyroglobulin (TG) and thyroid peroxidase (TPO), detected via blood test
- Fine needle aspiration of the thyroid (also known as a needle biopsy), which shows lymphocytes and macrophages
- A radioactive uptake scan, which would show diffuse uptake in an enlarged thyroid gland
- Ultrasound, which would show an enlarged thyroid gland
What is the Hypothyroidism Tx?
If due to iodine deficiency, then add iodine to the diet (elderly/poverty)
For gland failure, levothyroxine (T4) the treatment of choice
- Long half-life
- Lag before effects is observed
- Given at birth to prevent cretinism
Body converts T4 → T3 as required
What is Cretinism?
- lack of thyroxine from birth
- or before birth
- could be from lack of thyroid gland
- or lack of iodine in mother
- severe & irreparable mental defects
- stunted growth
- reduced growth & function of many organs
What is Hyperthyroidism?
Prevalence 0.6%
- most common between 20 – 60 yrs. of age
- More prevalent in females
Graves’ Disease
- Most common form of hyperthyroidism
- Activating Ab to TSH receptor → increased T3 and T4
Diagnosis
<40 yrs. old – mainly nervous system effects
>40 yrs. old – mainly cardiovascular effects
Catecholamine response
What are the sx’s of Grave’s Disease?
Exophthalmos or Proptosis
- Anxiety and irritability
- A fine tremor of your hands or fingers
- Heat sensitivity and an increase in perspiration or warm, moist skin
- Weight loss, despite normal eating habits
- Enlargement of your thyroid gland (goiter)
- Change in menstrual cycles
- Erectile dysfunction or reduced libido
- Frequent bowel movements
- Bulging eyes (Graves’ ophthalmopathy)
- Fatigue
- Thick, red skin usually on the shins or tops of the feet (Graves’ dermopathy)
- Rapid or irregular heartbeat (palpitations)
What is the Hyperthyroidism Tx?
Radioiodine
The treatment of choice at many centres
- 125I t1/2 = 60 days
- 131I t1/2 = 8 days (beta particles, kills cells)
- 123I t1/2 = 0.55 days –> would need quick delivery
Ionizing radiation destroys the gland
Caution with other antithyroid drugs as must be concentrated into uptake gland. Stop for 2 days before and after.
Contraindicated in pregnancy and in children
What are the Radioiodine - Precautions?
Delay in therapeutic response (2-6 month)
- depending on sx’s, may need other pharm intervention b/c of delay
Radition-induced thyroiditis
Hypothyroidism –> if destroy too much
Thyroid Cancer –> discourages some pts, may choose surgery (but also damage risk…ie parathyroids)
Pregnancy!
What are the 3 Antithyroid drugs (Thioamide drugs)?
- Propylthiouracil
- Methimazole
- Carbimazol
What is the MOA of Thioamide Drugs?
Block synthesis of thyroid hormones
- Interferes with organification of iodine – a competitive inhibitor of peroxidase (TPO)
- Blocks MIT conversion to DIT
- Inhibits coupling of iodinated tyrosines
Propylthiouracil inhibits conversion of T4 to T3*
(Think timing of effect)
DO NOT affect uptake of iodide or T4 or T3 release
Onset requires depletion of thyroid hormone stores
What is the Thioamide Drug Disposition?
- Concentrated in the thyroid gland (~100 x)
- Potency of methimazole/PTU ~ 100 x
- Disposition altered in cirrhosis and in renal failure
- Treatment: methimazole once daily and PTU every eight hours (compliance)
Thioamide Drugs - Therapeutics
- Antithyroid drug therapy adjusted and/or reduced every 4-6 weeks
- Maintenance dose
– Methimazole 5 – 10 mg/day
– PTU 50 – 100 mg/day
PTU for fast decrease in T3 due to peripheral effects – feel better faster
Pregnancy
- PTU preferred
– Crosses placenta less
– No teratogenic reports
– Only 1/10 crosses into breast milk
What is the Thioamide Drugs - SE’s
1 – 5% - fever, rash, arthritis-like symptoms
- Most common leukopenia (WBC < 4000/mm3)
- Low cross reactivity between methimazole and PTU
CAUTION
- WBC changes with thyroid status. Therefore, routine monitoring not recommended. Stop drug therapy at first sign of a sore throat and/or fever. Then determine WBC status.
- Agranulocytosis – rare and usually reversible when drug treatment is stopped.
What is the Thyroid Storm?
- Greatly increased blood temperature
- Shortness of breath
- Anxiety
- Sweating
- Tachycardia
- Chest Pain
- MI (can result in this)
So use…
Propranolol
- To ameliorate cardiovascular symptoms/toxicity
- Some suppression of T4 → T3
What are the other drugs effecting thyroid?
Dexamethasone (inhibits T4 T3)
Lithium (inhibits secretion and degradation in peripheral tissue)
Sulfonamides (interfere with organification of iodine)
Sodium nitroprusside (long term) (thiocyanate accumulation inhibits iodine uptake by the thyroid)
Amiodarone (contains lots of iodide).
SCN- (found in some foods) and ClO4- block iodide uptake.
Iodide (large doses) decreases degranulation of thyroglobulin and gland vascularity. It is useful prior to surgery but the effect disappears after a few days of intake.
What are the drugs for Thyroid Disease?
- Levothyroxine (T4)
- Radioiodine
- Methimazole
Other agents with antithyroid action – e.g. amiodarone, lithium, sulfonamides
Levothyroxine (T4):
for replacement therapy (hypothyroidism)
Radioiodine:
for hyperthyroidism except in children and in women of child-bearing age
