Transcript T 3 - LSU School of Medicine

Thyroid Hormones
Eric Lazartigues, Ph.D.
Department of Pharmacology
[email protected]
(504) 568-3210
I
H H
H H
I 2 + HO
HO
C C COOH
C C COOH
H NH2
MIT
Tyrosine
I
H H
HO
I
I
HO
C C COOH
H H
I
C C COOH
O
I
90 % Thyroxine (T4)
DIT
HO
H NH2
I
I
H NH2
I
H NH2
C C COOH
O
deiodinase
I
I
HO
I
O
I
Reverse T3 (inactive)
H H
H NH2
T3 (active)
H H
C C COOH
H NH2
Bound to plasma proteins: TBG
Biosynthesis of Thyroid Hormones: Steps 1 and 2
2
Step 1: Iodide uptake: Na/I Pump
(symporter)- ATP dependent.
Inhibited by ClO4- and SCNActivated by TSH (↓stores iodine→↑ uptake)
Step 2: Oxidation of iodide and iodination of
Follicular cell thyroglobulin
Thyroid peroxidase (TPO) (apical surface)
Fomation of MIT and DIT
Storage in the lumen of thyroid follicle
1
Inhibited by PTU and MMI
Blood
Biosynthesis of Thyroid Hormones: Steps 3 and 4
2
3
4
Follicular
cell
1
Blood
Step 3: Coupling of iodotyrosine
residues to generate iodothyronines.
Thyroid peroxidase.
Formation T4 (DIT+DIT) and T3
(MIT+DIT)
Activity: [TSH] and iodide availability
Inhibition: PTU, MMI
Step 4: resorption of the TRG colloid into cell
Endocytosis of TRG via receptor: megalin
Inhibition: Colchicine, Li2+, I-, cytochalasine B
Biosynthesis of Thyroid Hormones: Steps 5 to 7
Step 5: Proteolysis of TRG.
Colloid droplets fuse with lysosomes
Enhanced by TSH
Endopeptidases:
TRG→intermediates
Exopeptidates:
intermediates→MIT+DIT
90% T4 and 10% T3
2
4
5
Step 6: Recycling of Iodine
I- →TRG
Step 7: conversion T4→T3
5’deiodinase
3
6
7
1
Blood
TSH
TSH
a
b
Gs b g
AC
(+)
cAMP
Protein Kinase A
Increased
DNA
RNA
Protein
Increased
Cell size
Cell number
Follicle formation
Growth
Increased
Increased
Trapping of I
Glucose oxidation
Iodination
NADPH generation
Endocytosis of colloid
Thyroglobulin degradation
Hormone Synthesis
Figure 4 : Effects of TSH on thyroid gland
Thermal
Caloric
Signals
Hypothalamus
TRH T3
Somatostatin
Dopamine
TRH  release
 synthesis
T3
TSH
TSH
T3
T4
T4
Long
Loop
Tissue
T4
T4,T3
Thyroid
Figure 5. Axis for Thyroid Control
T4
High
Hormone Pairs and Thyroid Disorders
Primary
Secondary
Hyperthyroidism
hypothyroidism
Pituitary tumor
Normal
Primary Hyperthyroidism
Pituitary
Failure
Low
Pituitary Hormone
Hashimoto’s
Autonomous Secretion of
Target Gland Hormone
Secondary
Hypothyroidism
Low
Grave’s disease
Normal
Target Hormone
High
Conditions and Factors That Inhibit Type I 5'-Deiodinase Activity
Acute and chronic illness
Caloric deprivation (especially carbohydrate) and Malnutrition
Glucocorticoids
Adrenergic receptor antagonists (e.g., propranolol in high doses)
Oral cholecystographic agents (e.g., iopanoic acid, sodium ipodate)
Propylthiouracil
T3
T4
TR
Cytoplasm
Tissue deiodinase
T3
Nucleus
mRNA
Intracellular Effects
Na+, K+- ATPase
 ATP use
Proteins for growth and
maturation
Mitochondria
Respiratory enzymes
O2 Consumption
O2
Cardiac Output
Ventilation
Whole Body Effects
Other enzymes, proteins
Metabolic rate
Substrates
Food Intake
Mobilization of
stored fat,
carbohydrates
and Proteins
(permissive)
CO2
Thermogenesis
Urea
Sweating
Ventilation
Insensible water loss
Renal Function
Muscle Mass
Adipose Tissue
Effects of Thyroid Hormone
Nervous System:
1. T3 is absolutely required for perinatal brain development.
i). Growth of cerebral and cerebellar cortex.
ii). Axon proliferation
iii). Synaptogenesis.
2. In Adults, enhances:
i). Wakefulness and responsiveness
ii). Emotional tone
iii). memory
Sympathetic Nervous System.
1. Synergizes with sympathetic nervous system.
i). Promotes increases in b-adrenergic receptor and Gs proteins.
ii). Important for metabolic and cardiac effects of thyroid hormone.
Primary Hyperthyroidism: T4 and T3,  TSH
1. Autoimmune thyroiditis: Grave’s disease
- Autoantibodies bind and activate TSH receptors
- Other: Tumor of thyroid gland.
2. Symptoms:
- Large increases in BMR
Leads to weight loss despite increased food intake.
-  Heat production: heat intolerance and excessive sweating.
-  SNS activity

Tachycardia, tremor, nervousness, wide-eyed stare
- Enlarged thyroid gland – Goiter
- Exophthalmos: Protrusion of eyeballs.
Rx For Hyperthyroidism - 1
I-
I-
c
a
p
Na
1
I-
Block Active Transport of iodide
Complex anions: monovalent, hydrated ions similar in size to
Iodide.
Thiocyanate: found in certain foods and in cigarette smoke
(in large doses, thiocyanate can also inhibit organification)
Problems- The Jim Jones effect
Perchlorate (ClO4-) – 10x more active as thiocyanate. Low
doses (750 mg per day) have been used in the treatment of
Grave’s disease. Excessive doses (2-3 g per day ) causes
increased incidence of fatal aplastic anemia.
Rx For Hyperthyroidism
Treatments- 2
Iodination of Thyroglobulin and Coupling Reaction
(thyroperoxidase)
Io 3
I-
Thionamides or thioureylenes : propylthiouracil,
methamizole, carbimazole
TPX
Io
DIT
Properties
Plasma protein b inding
Plasma half -lif e
Concentrated in the thyroid
Drug metabolism in li ver disease
Dosing Frequency
Transplacental P assage
Leve ls in b reast mil k
Blocks periphe ral T4 conve rsion
Side Effects comm on
1:500
DIT
MIT
Propylthiourac il
75%
75 min
Yes
Normal
1to 4 tim es dail y
Low
Low
Yes
Rashe s, join t pain
Agranu locytosis
Methimazole
Methamizole
~0
~ 4-6 hr s
Yes
Decreased
Once or twice dail y
High
High
No
Rashe s, join t pain
Agranu locytosis
Other: Side effects headaches drowsiness or dizziness. immunosupression
Drug-drug interactions: especially: warfarin, digoxin, beta-blockers
4 T3
MIT
DIT
DIT
T
T
MIT3 4
DIT
T3 T
MIT 4
T
MIT 4
Rx For Hyperthyroidism
Treatments- 3
Iodide: High doses cause paradoxical decrease in thyroxin
biosynthesis, at the organification step
Striking and rapid (changes in basal metabolic rate within hours)
Radioactive Iodide (131I), (IODOTOPE THERAPEUTIC)
- 80 to 150 µCi/gram (lower doses may limit rebound
hypothyroidism). This leads to partial destruction
of the gland.
- Used when prolonged treatment with anti-thyroid drugs or
surgery has not led to remission. More commonly
used
in older patients- Major disadvantage is long period
of
time required before hyperthyroidism is controlled.
Drugs that block Type I deiodinases: propylthiouracil
Drugs that block both Type 1 and Type II deiodinases: sodium
ipodate, iopanoic acid . In addition, metabolism of these drugs
lead to the release of 75-150 mgs of iodide, which can further
inhibit T4/T3 secretion. These drugs are commonly used as
radiology contrast dyes.
Io 3
ITPX
DIT
Io MIT
MIT
DIT
4 T3
DIT
DIT
T T4
MIT 3
DIT
T3 T
4
MIT
MIT
T4
THYROID STORM
1. Thyroid storm is a crisis or life-threatening condition characterized
by an exaggeration of the usual physiologic response seen in
hyperthyroidism
* High fever
* Tachycardia
* Nausea/vomiting
* Irregular heart beat
* Acute heart failure
* Confusion/disorientation
2. Usually precipitated by concurrent medical problems (infections,
stress, surgery, trauma, heart disease, diabetic ketoacidosis)
3. Treatment:
- antipyretics,
- large dose (200-400 mg) propylthiouracil because of additional
action of blocking peripheral T4 conversion
- b-blockers (propranalol) to counteract effects on SNS and heart
Primary Hypothyroidism
 T4 and T3
 TSH
1. Autoimmune disease of thyroid: Hashimoto’s disease
-Blocks hormone synthesis and glandular growth
2. Other Causes:
i). Genetic defect in or autoantibodies vs. enzymes
necessary for thyroid hormone synthesis or the conversion
of T4 to T3.
Severe iodide deficiency
Lithium
3. Symptoms:
- Myxedema: Accumulation of mucopolysaccharides
with resultant fluid accumulation .
- Decreased thermogenesis: cold intolerance
- Lethargy, sleepiness, decreased mentation
- Bradycardia.
- Lowering of upper eyelid (ptosis)
- In utero or infancy and childhood:
 Marked retardation in growth.
 Severe mental retardation due to poorly developed
nervous system.
 Known as "cretins".
Iodide replacement in small quantities (100-300 µg/day) if iodide deficiency
is suspected.
Hormone Replacement with T4 or T3 All can be given orally
Synthetic Thyroxins: Levothyroxine sodium (SYNTHROID,)
Synthetic T3: Lyothyronine sodium (L-T3)
- 80% absorption in the small intestine that is partially blocked by
Ca2+ and iron supplements
Efficacy is monitored by serum TSH levels
Adverse Effects: Rare and most often associated with excessive doses
Looks like hyperthyroidism: heat intolerance, irritability, insomnia,
nausea/vomiting, nervousness or anxiety, tremor, and weight loss.
In patients with underlying cardiac problems: angina, atrial
fibrillation, heart failure, palpitations, peripheral edema.
CONTRAINDICATIONS:
Patients with heart disease, diabetes, adrenal insufficiency and treatment for
obesity
DRUG INTERACTIONS
Estrogen:  Thyroxine-binding globulin (TBg) thereby  free T4/T3
Barbiturates:  hepatic metabolism of both Levothyroxine (SYNTHROID) and
Lyothyronine
T4/T3
Enhances the response to: anticoagulant therapy, Tricyclic antidepressants
(receptor responsiveness), vasopresors and symapthomimetics ( receptor
expression)
 Metabolism of Corticosteroids