Transcript Endocrine Pharmacology

Endocrine Physiology
Thyroid
Bob Bing-You, MD, MEd, MBA
Medical Director
Maine Center for Endocrinology
A case of fatigue
• 28 y.o. white female c/o 4 month h/o
increasing fatigue
• 2 children, ages 4 and 7
• Sleeping all day, weight up 15 lbs, labile
moods
• Dry skin, constipation, no periods for 6 mos
• She’s worried she’s pregnant….
Laboratory Testing
• Thyrotropin Stimulating Hormone [TSH] =
>100 [NR 0.27-4.2 mU/ml]
• Free T4 = 0.4 ug% [0.7-1.8]
• Total T3 = 70 ug% [80-200]
• Thyroid “antibodies” [anti-thyroglobulin,
anti-microsomal] “moderately positive”
Diagnosis?
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A. Secondary hyperthyroidism
B. Primary hypothyroidism
C. Lab error
D. Fictitious hyperthyroidism
History of the Thyroid
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1st described 1656
lubricated the trachea
vascular shunt to the brain
larger size gave grace to women
1700’s:no important physiological role
More History
• 1835: Graves noticed thyroid enlargement
and eye problems
• 1874: atrophy and deficiency noted
• 1891: Murray treated 1st case with thyroid
extract
Thyroid Hormone
• Lack of thyroid secretion causes BMR to
fall 40%
• Extreme thyroid hormone excesses can
cause BMR >60-100% above normal
• Thyroid secretion under control of anterior
pituitary gland
Thyroid Gland
• Composed of large number of closed
follicles
• Hormone stored with large glycoprotein
Thyroglobulin
• Traps iodide
Iodine
• Average ingestion 1 mg. per week
• Breads, ice cream, sea kelp
• Iodide pump on thyroid cell membrane can
concentrate in cell 40 x concentration in
blood
Hormone Biosynthesis
• Organification:
– iodide oxidized to iodine
– combines with tyrosine residues to form
monoiodotyrosine and diiodotyrosine
– MIT and DIT combine with TG to make T3 and T4
• 5-6 T4 molecules/TG, 1 T3/3-4 TGs
• Can store up to 3 months requirement
• exocytosis at colloid border for release
Thyroid Hormone Physiology
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Thyroxine, Triiodothyronine
T3 4 x more potent than T4
Free components are biologically active
99% protein-bound, mainly Thyroid
Binding Globulin [TBG]
• High affinity of TBG for T4
• Half-life T4 7 days, 1 day for T3
If you were to change T4 dose, how long
would you wait to recheck a TSH?
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A. 7 days
B. 3 weeks
C. 6 weeks
D. 10 weeks
How about T3 then?
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A. 1 day
B. 5 days
C. 6 weeks
D. None of the above.
Daily Production
• T4
– 10-15 ug/kg/day
– Or…..80 – 100 ug/day
• T3
– 30-40 ug/day
Thyroid Hormone Physiology
• Gland secretion 80% T4, 20% T3
• Deiodinase in peripheral tissues/pituitary
convert T4 to T3 and reverseT3 [rT3]
Mechanism of Action
• Free forms enter cells
• T4 converted to T3 by 5’-deiodinase
• T3 binds to nuclear receptors, RNA
formation, protein synthesis
• actions delayed by hours or days
Effects of Thyroid Hormones
• Increase metabolic rate almost all tissues
[except brain, lungs, spleen]
• Increase protein synthesis
• Increase >100 cellular enzyme systems
• Cell mitochondria increase size and number
Growth
• Can accelerate growth in children when in
excess, and vice versa
• Growth effect mainly through promoting
protein synthesis
Excess Effects on Metabolism
• Stimulates almost all aspects of
carbohydrate metabolism [e.g., glycolysis]
• Can deplete fat stores, increase FFA in
blood
• Decrease LDL
• Weight up and down!
More effects with higher levels
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Increases blood flow, vasodilation
Need for heat elimination
Heart rate very sensitive index
Increases respiratory rate and depth
Increased GI motility
Weaken muscles due to protein catabolism
Fine tremor 10-15x/second
Key Points
• Iodine physiology key to thyroid hormone
production
• Thyroid hormone effects just about
everything!
• Know differences between T4 vs. T3
A case of fatigue
• 28 y.o. white female c/o 4 month h/o
increasing fatigue
• 2 children, ages 4 and 7
• Sleeping all day, weight up 15 lbs, labile
moods
• Dry skin, constipation, no periods for 6 mos
• She’s worried she’s pregnant…..
Laboratory Testing
• Thyrotropin Stimulating Hormone [TSH] =
>100 [NR 0.27-4.2 mU/ml]
• Free T4 = 0.4 ug% [0.7-1.8]
• Total T3 = 70 ug% [80-200]
• Thyroid “antibodies” [anti-thyroglobulin,
anti-microsomal] “moderately positive”
Primary vs Secondary
• Primary: direct problem with gland
secreting end product
• Secondary: problem with gland controlling
final gland
Causes Primary Hypothyroidism
Autoimmune Thyroid Disease
[“Hashimoto’s Disease”]
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Very common [5-20 per 1000]
Women > men
Age [4th-5th decade]
Antibodies may be positive
• Surgery
• Congenital
Primary Hypothyroidism
• TSH is most sensitive test for diagnosis and
Rx adjustment
• Pituitary/Thyroid & Thermostat/Furnace
analogy
• Low long-term morbidity, no mortality
T4 supplementation
• Brand names – T4, ~$14/month
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Levoxyl
Synthroid
Unithroid
Levothroid
• Brand names – T3 ~$ 35/month
– Cytomel
– Triostat
Thyroid Pharmacokinetics
• T4 best absorbed in duodenum and ileum
– 80% oral preparation absorbed
• T3 95% absorbed
• Both less absorbed with severe
hypothyroidism
Thyroid Pharmacokinetics
• Half-life
– T4 = 7 days
– T3 = 1 day
• Oral supplementation typical route; IV
available, 75% of oral dosing
• Synthetic formulation preferred vs. animal
[“Armour”]
• Brand and generic are not the same dose!
TSH is the most sensitive test for
screening because:
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A. Least expensive
B. Comes in a thyroid panel
C. Is a pituitary hormone
D. Changes more with small T3 changes
E. Involved in negative feedback
T4 vs. T3??
• T4 is just fine
– Long-term experience of majority of healthy patients
– No case report of inability to convert to T3
• T3 advocates
– More natural, few studies showing small QOL
improvement
• Adverse effects [sx’s, a-fib, bone loss] TSH is
most sensitive test for diagnosis and Rx
adjustment
Dosing Considerations
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Weight-based
Severity of symptoms
Cardiac failure
Coronary artery disease
Renal disease
Drug Interactions
• Malabsorption
– Iron, sucralfate, bile acid resins, AlOH
• Changes in TBG
– Oral estrogen, liver inflammation [e.g. Niacin]
• Increased clearance: phenytoin,
carbamazepine
• Anti-coagulants
– Hypothyroidism prolong bleeding
Hypothyroidism & Surgery?
• Intraoperative hypotension; less responsive to
pressor agents
• Lower cardiac rate
• Slow to wean from vent
• Less fever manifestations
• More heart failure in cardiac surgery pts.
• More constipation, ileus; more confusion
• No significant increase mortality
Take-home Points - Hypothyroid
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TSH most sensitive and cost-effective test
Signs and symptoms not very specific
T4 supplementation fairly easy
Hypothyroid patients do generally well with
surgery
Questions??
A Case of More Fatigue!
• 44 y.o. white male, 2 month h/o fatigue with
exertion
• Normally runs 4-6 miles/day, more winded
• Sweats, loose stools, resting pulse up to 88
• Weight down 10 lbs. Aunt had “thyroid
problem.”
• Diagnosis?
Laboratory Testing
• TSH <0.2
• Total T4 13 [8.5 – 12.5]
• Total T3 222 [80 – 200]
And the diagnosis is….
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A. Secondary hypothyroidism
B. Quanternary hyperthyroidism
C. Primary hyperthyroidism
D. Primary hypothyroidism
E. None of the above
Primary Hyperthyroidism
• Causes
– “productive”
• Graves Disease
• Multi- or single autonomous nodules
– “destructive”
• Thyroiditis: painless or subacute
– exogenous
Graves Disease
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Women 30-60 years old
Opthalmopathy ~10%
Dermopathy <5%
TSII [Thyroid Stimulating
Immunoglobulin]
• High concordance rate, 2-hit hypothesis
[?Yersinia]
Thyroiditis
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May be viral cause for inflammation
“leaky” thyroid
Painless form often post-partum
May have antecedent URI symptoms
Drug Causes
• Amiodarone
– Long half-life, can cause productive or
destructive picture, hypothyroidism
– Blocks T4 to T3, uptake not helpful
• Lithium
– More hypo- than hyperthyroidism
• Iodinated contrast agents
Evaluation
• TSH for screening
• T 4 and T3 needed for severity
• 24 hour iodine uptake
– Productive vs. destructive
• TSII [TSH-like antibodies]
– Other antibodies non-specific [I.e., antithyroglobulin, anti-microsomal]
Hyperthyroidism & Surgery?
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More hypertension
Higher chance tachyarrhythmias
?higher catecholamine binding sites
Probably no increase mortality
Treatment - General
• Beta-blockers
– Propanolol 80-180 mg/day
• Better inhibition of T4/T3 conversion
– Good for adrenergic sx’s
– Can’t use in asthma and heart failure
• Hydration
Anti-thyroid Medications
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Propylthiouracil, Methimazole [Tapazole]
1928: rabbits fed cabbage developed goiters
Thioamides developed 1940’s
Concentrated in thyroid, inhibit biosynthesis
by blocking organification of iodine
• PTU also blocks T4/T3 conversion
Pharmacokinetics
• PTU rapidly absorbed, peak 1 hr; Tapazole
variable
• MMI ½ life = 4-6 hours
• PTU ½ life = 1-2 hours
PTU/MMI
• Immunosuppressive actions
– Decrease TSII production
– Decrease intrathyroidal T cells
• PTU more protein-bound
– Pregnancy, breast-feeding
PTU/MMI
• Dosing depends on severity
– MMI can be once a day
• Adverse effects
– Pruritis, GI 2-5%
– Metallic taste
– Rare [1/600] agranulocytosis, hepatocellular
damage
Other agents
• Saturated Solution Potassium Iodide [SSKI]
5-10 drops several times daily – also
decreases vascularity pre-op
• Lithium 300 mg qid
• Glucocorticoids
– Block T4/T3 conversion
– Prednisone 50-60 mg/day
Thyroid “Storm”
• Life-threatening, usually with underlying
major illness [e.g., acute infection]
• Fever, tachycardia, N/V, acute abdomen,
cardiac failure, agitation….continuum
• Rx = hydration, high doses of PTU and IV
glucocorticoids, then SSKI few hours later
Radioactive Iodine
• I131 for beta particles
• Usually one-time dose
• Goal= ablation with subsequent
hypothyroidism
• No long-term side effects in 50 years
• ~$1,000/treatment
Thyroiditis Treatment
• 24 hour iodine uptake <5%
• Symptomatic treatment only [beta-blockers]
• Hypothyroid phase possible, lasting 2-3
mos, may need LT4
• ~20% permanently hypothyroid
Graves Disease Treatment
• RAI vs. medical Rx vs. surgery
• 25-30% remission rate after 2 years of
medical Rx
Autonomous nodules
• Multinodular goiters
– common in elderly
– RAI preferred
• Single “hot” nodules
– RAI preferred
– Usually euthyroid post-RAI
Take-home Points - Hyperthyroid
• Graves disease vs. thyroiditis differentiation
• TSH still best screening lab
• Medical Rx 1st option for treatment over
surgery
• Cardiovascular effects biggest concern perioperatively
Euthyroid Sick Syndrome
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Low, normal, or mildly high TSH
Low Total T4
Normal Free T4 [watch out for heparin]
Low TT3 and Free T3
Euthyroid Sick Syndrome
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Blockage of T4 to T3 conversion
Less binding to TBG
“recovery phase”
Bottom line: no evidence to suggest
replacement Rx improves outcomes