Thyroid Hormones

Thyroid Hormones

Eric Lazartigues, Ph.D.Department of Pharmacology

[email protected](504) 568-3210

O

I

I

I

I

HO

I2 + HO

Tyrosine

C C COOH

H H

H NH2

90 % Thyroxine (T4)

deiodinase

Bound to plasma proteins: TBG

C C COOH

H H

H NH2

HO

MIT

C C COOH

H H

H NH2

HO

DIT

I

I

IC C COOH

H H

H NH2

I

I

OHO

I

C C COOH

H H

H NH2

T3 (active)

Reverse T3 (inactive)

O

I

I I

HO C C COOH

H H

H NH2

Blood

Biosynthesis of Thyroid Hormones: Steps 1 and 2

1

2

Follicular cell

Step 1: Iodide uptake: Na/I Pump (symporter)- ATP dependent.Inhibited by ClO4

- and SCN-

Activated by TSH (↓stores iodine→↑ uptake)

Step 2: Oxidation of iodide and iodination of thyroglobulinThyroid peroxidase (TPO) (apical surface)Fomation of MIT and DITStorage in the lumen of thyroid follicleInhibited by PTU and MMI

Biosynthesis of Thyroid Hormones: Steps 3 and 4

Blood

1

2

Follicular cell

3

4

Step 3: Coupling of iodotyrosine residues to generate iodothyronines.Thyroid peroxidase.Formation T4 (DIT+DIT) and T3 (MIT+DIT)Activity: [TSH] and iodide availabilityInhibition: PTU, MMI

Step 4: resorption of the TRG colloid into cellEndocytosis of TRG via receptor: megalinInhibition: Colchicine, Li2+, I-, cytochalasine B

Biosynthesis of Thyroid Hormones: Steps 5 to 7

Blood

1

2 3

4

Step 5: Proteolysis of TRG.Colloid droplets fuse with lysosomesEnhanced by TSHEndopeptidases: TRG→intermediatesExopeptidates: intermediates→MIT+DIT90% T4 and 10% T3

Step 6: Recycling of IodineI- →TRG

56

7Step 7: conversion T4→T35’deiodinase

Gs AC

cAMP

Protein Kinase A

(+)

TSH

Increased Increased Increased IncreasedDNARNAProtein

Cell sizeCell numberFollicle formation

Trapping of IIodinationEndocytosis of colloidThyroglobulin degradation

Glucose oxidationNADPH generation

Growth Hormone Synthesis

Figure 4 : Effects of TSH on thyroid gland

TSH

TRHHypothalamus

TRH release synthesis

TSH

T4,T3 T4

T4

T4

SomatostatinDopamine

TSH Long Loop

Thermal Caloric

Signals

T3

T3

T4

T3

Figure 5. Axis for Thyroid Control

Thyroid

Tissue

Pitu

itary

Hor

mon

e

Nor

mal

Low

Low

Normal High

Hig

h

Target Hormone

Primary Hyperthyroidism

Secondary Hypothyroidism

Primary

Pituitary

Failure Autonomous Secretion of Target Gland Hormone

hypothyroidism

Hormone Pairs and Thyroid Disorders

SecondaryHyperthyroidism

Pituitary tumorHashimoto’s

Grave’s disease

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

T4T3

T3TR

mRNA

Proteins for growth and maturation

Na+, K+- ATPase MitochondriaRespiratory enzymes

O2 Consumption Metabolic rate

CO2UreaVentilationRenal FunctionMuscle MassAdipose Tissue

ThermogenesisSweatingInsensible water loss

SubstratesO2

Cardiac OutputVentilation

Food IntakeMobilization of stored fat, carbohydrates and Proteins

Other enzymes, proteins

Nucleus

Cytoplasm

Whole Body Effects

(permissive)

Tissue deiodinase

Intracellular Effects

ATP use

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 toneiii). memory

Sympathetic Nervous System.

1. Synergizes with sympathetic nervous system.

i). Promotes increases in -adrenergic receptor and Gs proteins.

ii). Important for metabolic and cardiac effects of thyroid hormone.

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

cap

I-I-

I-

Na

1

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.

Treatments

I- 3Io

Io

MIT

DITT3

T4

TPX

MIT

DITT3

T4

MIT

DITT3

T4

DIT

DITMIT

MIT

4

Other: Side effects headaches drowsiness or dizziness. immunosupression

Iodination of Thyroglobulin and Coupling Reaction (thyroperoxidase)

Thionamides or thioureylenes : propylthiouracil, methamizole, carbimazole

Properties

Propylthiouracil MethamizolePlasma protein binding 75% ~ 0Plasma half-life 75 min ~ 4-6 hrsConcentrated in the thyroid Yes YesDrug metabolism in liver disease Normal DecreasedDosing Frequency 1to 4 times daily Once or twice dailyTransplacental Passage Low HighLevels in breast milk Low HighBlocks peripheral T4 conversion Yes NoSide Effects common 1:500

Rashes, joint painAgranulocytosis

Rashes, joint painAgranulocytosis

Drug-drug interactions: especially: warfarin, digoxin, beta-blockers

Rx For Hyperthyroidism - 2

Methimazole

TreatmentsI-

3Io

Io

MIT

DITT3

T4

TPX

MIT

DITT3

T4

MIT

DITT3

T4

DIT

DITMIT

MIT

4

Rx For Hyperthyroidism - 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.

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

- -blockers (propranalol) to counteract effects on SNS and heart

Primary Hypothyroidism T4 and T3TSH

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 deficiencyLithium

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/T3Barbiturates: 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