Pharma - 4th Asessment - Thyroid Hormones - 30 Jan 2007

ENDOCRINE SYSTEM - GLANDS • Pituitary • Thyroid • Parathyroid • Adrenals • Gonads • Islet of Langerhans

PITUITARY HORMONES • Thyroid Stimulating Hormone (TSH) • Adrenocorticotropic Hormone (ACTH) • Follicle Stimulating Hormone (FSH) • Lutenizing Hormone (LH) • Growth Hormone (GH)

THYROID HORMONES • Thyroxine (T4) • Tri-iodothyronine (T3)

ADRENAL AND GONADAL HORMONES

• Estrogen • Progestron • Testosterone • Cortisol • Aldosterone

PANCREAS-ISLET OF LANGERHANCE

• Insulin – beta cells • Glucagon – α2 cells • Somatostatin – Delta cells

HYPOTHALAMIC HORMONES • Growth hormone releasing hormone (GHRH)

• Growth hormone inhibiting hormone (Somatostatin) • Thyrotropin-releasing hormone (TRH) • Corticotropin-releasing hormone (CRH) • Gonadotropin-releasing hormone (GnRH) • Prolactin-inhibiting hormone (Dopamine)

POSTERIOR PITUITARY HORMONES

• Oxytocin

• Vasopressin (ADH) • Desmopressin

OXYTOCIN •

Myometrial contraction

• Myoepithelial cells surrounding mammary alveoli • Induce labor • Uterine inertia • Incomplete abortion

VASOPRESSIN • Vascular smooth muscle contraction

– v1 receptor • Water resorption in the collecting tubules – v2 receptor • Pituitary diabetes insipidus • Nocturnal enuresis

THYROID HORMONES-BASIC AND CLINICAL PHARMACOLOGY

• Genesis and Fate • Mechanism and Biological Actions • Clinical Features and Treatment of Hypo and Hyperthyroidism

THYROID HORMONES • Thyroxine (T4) • Tri-iodothyronine (T3) • Calcitonin

THYROID HORMONES - BIOSYNTHESIS

• Active Transport Iodide • Thyroglobulin Synthesis • Iodination of Tyrosyl Residues (organification) • Coupling of Iodotyrosines → T3 & T4

Thyroid Hormones and Antihyperthyroid Drugs TRH

Somatic cells

Negative T3 and T4 Feedback Follicular cell + -

Tf

Blood TGB TBPA TBA Tf

Liver

T3 T4 TG

Release

-

Hydrolysis

+

Phagocytosis and Pinocytosis

Follicular lumen MIT

DIT

I2 MIT DIT

Iodine Intake

Pituitary

TSH

Plasma I

-

Trapping

T4 TG

Lysosymes

I-

T3

TG

I-

Gut Principle features of the biosynthesis and metabolism of thyroid hormone(s)

THYROID HORMONE - PLASMA PROTEINS

• T4 binding Globulin (75%) • Prealbumin (Transthyretin) • Albumin

INACTIVATION Deamination Decarboxylation Conjugation (glucuronide or Sulfate)

Thyroxine

ACTIVATION

3,5,3’-Triiodothyronine (T3)

Deiodination

INACTIVATION

3,3’,5’-Triiodothyronine (reverse T3)

T3

T4

R T3

F

T3 F

R

F

PP

T4

PB

T3

T3 Cytoplasm

Pre-mRNA Nucleus

Response Protein

mRNA

ACTIONS OF THYROID HORMONES 1. Normal growth and development of nervous, skeletal and reproductive systems 2. Control of metabolism of fat, carbohydrate, protein and vitamine 3. Elevation of basal metabolic rate with concomittent increase in O2 consumption and heat production 4. Modulation of the actions of parathyroid hormone and calcitonin

Cold

Trauma

Stress

Hypothalamus Somatostatin

TRH +

-

Anterior pituitary I

-

+ Thioureylenes Iodide 131 I -

Thyrotrophin +

Thyroid T4 T3

-

HYPOTHYROIDISM • Primary – Thyroid Defect • Secondary – Pituitary disease • Target Tissues – Thyroid Hormone Resistance

PRIMARY HYPOTHYROIDISM - CAUSES • Chronic Lymphocytic Thyroiditis (Hashimoto’s Disease) • Idiopathic Hypothyroidism • Radioactive Iodine Ingestion • Iodine Deficiency or Excess • Defect in Thyroid Hormogenesis • Creatinism • Antithyroid drugs

HYPOTHYROIDISM- CLINICAL FEATURES

• Bradycardia • Poor Resistance to Cold • Mental and Physical Slowing • Skin Abnormalities (Dryness, Hair Loss, Thinning) • Puffiness (Hand, Face, Feet) • Drooping of Eyelids and Periorbital Edema

HYPOTHYROIDISM - TREATMENT • Levothyroxin (T4) {Levothroid, synthroid, Levoxyl} • Tri-iodothyronin (T3) {Cytomel, Triostat} • Liotrix (T3 & T4) {Thyrolar} • Thyroid Extract

THYROID HORMONES – SIDE EFFECTS

• Tachycardia and Arrhythmias • Insomnia • Heat Intolerance • Weight loss and Headache

MYXDEMA COMA – CLINICAL FEATURES

• Confusion and psychoses • Hypoventilation • Hypoglycemia and Hyponatremia • Hypothermia

HYPERTHYROIDISM - CAUSES • Diffuse Toxic Goiter (Grave’s Disease) • Toxic Multi-nodular Goitar • Thyroiditis • Thyroid Hormone Ingestion • TSH Secreting Adenoma

HYPERTHYROIDISM – CLINICAL FEATURES

• Tachycardia – Cardiac Arrhythmias • Body Wasting • Tremor and Nervousness, Insomnia • Excess Heat Production • Occular Abnormalities (Exophthalmos, Eyelid Retraction)

HYPERTHYROIDISM - TREATMENT • Antithyroid Drugs (Propylthiouracil Methimazol) • Radioactive Iodine • β-Adrenoceptor Antagonists (Propranolol) • Iodide Salt

THYROID STORM – CLINICAL SYMPTOMS • Hypermetabolism • Excessive Adrenergic Activity • Flushing and Sweating

THYROID STORM - TREATMENT • Propranolol, 1-2 mg, IV or 40-80 mg, PO • Diltiazem, 5-10 mg/hr, IV, 90-120 mg, PO • Sodium ipodate • Potassium iodate • Methimazol or propylthiouracil • Hydrocortisone, 50 mg every six hours

CALCITONIN – CLINICAL EFFICACY • Maintain bone density • BMD • Bone loss • Osteoclast activity • Analgesic effect

CALCITONIN – PHARMACOKINETICS • Subcutaneous (Calcimer, Miacalcin): 100-200 U/ml • Intranasal (Miacalcin): 200 IU/puff • T ½ ( < 1 hr) • Duration (few weeks)

PTH - FUNCTION • Plasma Ca++ concentration • Plasma PO4- concentration • Bone formation (low concentration)

PTH – PHYSIOLOGICAL ACTIONS • Intestinal Ca++ absorption • Renal Ca++ reabsorption • Bone Ca++ mobilization • Renal phosphate excretion

PTH – CLINICAL EFFICACY • Bone mass • BMD • Vertebral and peripheral fractures • Osteocalcin (55%) • Cross linked n-telopeptide (20%)

PTH – MECHANISM OF ACTION • Recruitment of preosteoblasts • Lifespan of mature osteoblasts • Osteoblast apoptosis • Osteocyte number and density • cAMP/protein kinase A