Basic concepts in endocrine pharmacology

Hormone

·         Hormone produce intense biological activity that is produced by specific cells in the body and it transported through circulation on its target cells.

Body function

Major regulator hormones

·         Fuel

·         Insulin, glucagon, growth hormone

·         Metabolic rate

·         Tri-iodothyronine, thyroxine

·         Somatic growth

·         Growth hormone, insulin

·         Sex and reproduction

·         Gonadotropins, androgens, estrogens, progestin

·         Circulating volume 

·         Aldosterone, Anti-diuretic hormone

·         Adaptation to stress

·         Glucocorticoids, adrenaline

·         Calcium balance

·         Parathormone, calcitonin, vitamin D

·         Hormone are secreted by the endocrine or ductless glands; these are:

1.       Pituitary

a)       Anterior lobe:

o    Growth hormone (GH), prolactin (Prl), adrenocorticotropic hormone (ACTH, corticotropin),  thyroid stimulating hormone (TSH, thyrotropin),

o    Gonadotropins: Follicle stimulating hormone (FSH), and luteinizing hormone (LH).

b)      Posterior lobe:

 

o    Oxytocin, anti-diuretic hormone (ADH)

1.       Thyroid

o    Thyroxine (T4), tri-iodothyronine (T3), calcitonin.

2.       Parathyroid

o    Parathormone (PTH)

3.       Adrenals

                                             i.            Cortex: Glucocorticoids (hydrocortisone), mineralocorticoids (aldosterone), sex steroids (dehydroepiandrosterone)

                                           ii.            Medulla: Adrenalin, Nor-adrenalin

4.       Pancreas

o    Insulin, glucagon

5.       Gonads

o    Androgens (testosterone)

o    Estrogens (estradiol)

o    Progestin (progesterone)

MECHANISM OF HORMONE ACTION

1.       At cell membrane receptor

Mechanism

Hormones

a)       Alteration of intracellular cAMP → Ca2+ activation (sometime act as third messenger)

Adrenalin, glucagon, TSH, FSH, Vasopressin (V2)

b)      Through IP3/DAG pathway → PKc → Ca2+

Vasopressin (V1), oxytocin

c)       Direct transmembrane activation of tyrosine protein kinase

Phosphorylation

Regulation of various enzyme

Insulin, GH, prolactin

2.       At cycloplasmic receptors

·         Penetrating cell membrane, hormone combines with a cytoplasmic receptor

Exposes its DNA binding domain

Migrate to nucleus and binds to specific genes

DNA mediated mRNA synthesis

Steroid hormone: glucocorticoids, mineralocorticoids, androgens, estrogens, progestins, calcitriol

3.       At nuclear receptor

·         The hormone penetrates the nucleus

Combine with receptor

Alter DNA-RNA mediated protein synthesis

Thyroid hormone: T3, T4

 

PITUITARY

Growth hormone

·         It is 191 amino acid single chain peptide, molecular weight 22000

·         Increase the size of the body part EXCEPT Brain, Eye (Independent).

·         GH acts on the cell surface JAK-STAT protein kinase.

↓ Binding

                                                GH-Receptor (Dimer)

                                                                ↓

                                                Conformational changes

                                                                ↓ Activate

                                                JAK-STAT tyrosine protein kinase

                                                                ↓

                                                Regulate gene expression 

·         Metabolic action of GH are exerted indirectly through the peptides called somatomedins or Insulin like growth factor (IGF 1-2)

·         IGF-Extracellular mediators of GH response

 

·         IGF produced by other target cells promotes lipogenesis and glucose intake by muscle.

Regulation of secretion

·         GH secretion increase or decrease by the action of cAMP.

·         Somatostatin → inhibit Ca2+channels and open K+ channel.

·         Increase plasma free fatty acid → inhibit the secretion of GH

·         Dopaminergic agents → increase GH release.

Causes

·         Increase GH → Gigantism

·         Decrease → Dwarfism

·         Hyperlipidemia

Therapeutic uses

·         Dwarfism

·         Prader-willi syndrome

·         Maintain, build and repair of tissues

·         Management of AIDs wasting syndrome.

Experimental uses

·         Infertility, chronic catabolic state

·         Inflammatory bowel disease

·         Burn injury

Adverse effects

·         Decrease immunogenicity

·         Lipodystrophy (Abnormal distribution of fat in the body)

·         Glucose intolerance

·         Hypothyroidism

·         Salt and water retention

·         Myalgia (muscle pain)

·         Headache

Growth hormone inhibitor

·         Somatostatin

·         Octreotide

·         Lanreotide

·         Pegvisomant

PROLACTIN

·         It contains 199 amino acid single chain peptide of molecular wt. 23000 (similar to GH).

Physiological function

·         It primarily stimulus with the conjunction with estrogen, progesterone and several hormone.

·         Prolactin causes development and growth of breast during pregnancy.

·         The ductal and acinar cell induce synthesis of milk and lactose.

·         Prolactin may affect immune response through action on T-lymphocytes.

 

·         Overproduction of prolactin causes lactational amenorrhea.  

Regulation

·         Secretion of prolactin is inhibited by dopamine acting at D2 receptors (pituitary lactotrope D2 receptor).

·         Dopamine agonist: decrease plasma prolactin level.

·         Dopamine antagonist (chlorpromazine, haloperidol, metoclopramide, and reserpine) → causes hyperprolactinemia.

Prolactin inhibitor

1)       Bromocriptine

2)       Cabergoline

·         Decrease prolactin release from pituitary by activating D2 receptor on lactotrope.

·         Increase GH release → (Acromegaly)

·         CNS → Anti-parkinsonism, behavioral effects (like levodopa)

·         Produce nausea and vomiting

·         Decrease GIT motility.

Pharmacokinetics

·         1/3 oral dose of the Bromocriptine is absorbed.

·         Due to fast pass metabolism bioavailability is lowered.

·         Metabolized and excreted in bile.

·         Plasma t ½ is 3-6 hours.

Side effects

·         In early stage: Nausea, vomiting, constipation, nasal blockade, hypotension.

·         Late stage: Behavioral alteration, mental confusion, hallucination, psychosis.

Uses

·         Hyperprolactinemia

·         Acromegaly

·         Parkinsonism

·         Diabetic mellitus

·         Hepatic comma

ADRENOCORTICOTROPIC HORMONE (CORTICOTROPIN)

·         39 amino acid single chain   peptide, molecular wt. 4500 derived from a large peptide pro-opiomelanocortin (molecular wt. 30000).

Physiological function

·         ACTH target adrenal cortex and bind to its specific receptor.

·         Activate GPCR and increase cAMP, which turn stimulate adrenocorticoid synthesis pathway – cholesterol → pregnenolone.

 

·         Synthesis and release adrenocorticosteroid and the adrenal androgen. 

Therapeutic uses

·         Primarily for the diagnosis disorder of pituitary adrenal axis.

·         Injected i.v. 25 IU causes increase in plasma cortisol if the adrenal are functional.

·         ACTH does not offer because MORE inconvenient, expensive as well as less predictable.

Adverse effects

·         Osteoporosis

·         Hypertension

·         Peripheral edema

·         Hypokalemia

·         Infection

GONADOTROPINS (GNs)

·         Anterior pituitary secrete two GNs

                                 i.            FSH (Follicle stimulating hormone)

                               ii.            LH (Luteinizing hormone)

·         Both are glycoprotein containing 23-28% sugar and consist of two peptide chains.

·         α-Chain: FSH and LH (92 amino acid)

·         β-Chain: FSH (111 amino acid), LH (121 amino acid)

FSH

·         Female: Includes follicular growth, development of ovum and secretion of estrogens. (FSH receptor is expressed on somniferous sertoli cells).

·         Male: Spermatogenesis

LH

·         Female: Regulate the length and order of the menstrual cycle.

·         Male: Stimulate testosterone secretion.

Role

·         Both LH and FSH are GPCR → Activate cAMP production

↓ Stimulates

                                                                                Gametogenesis

                                                                                                ↓ Conversion of

 

                                                                                Cholesterol → Pregnenolone 

Adverse effects

·         Ovarian hyper-stimulation

·         Pain in lower abdomen

·         Allergies

·         Edema

·         Headache, mood changes.

Uses

·         Amenorrhea and infertility (Non ovulation due to polycystic ovaries).

·         Hypogonadism in male

·         Cryptorchidism (Testicle fail to descend from the abdomen into the scrotum).

Thyroid and antithyroid drugs

·         The thyroid hormone is of two types;

                                 i.            Iodine containing amino acids

§  Thyroxine (T4)

§  Triiodothyronine (T3)

                               ii.            Peptides

§  Calcitonin

·         The iodine containing amino acids are produced by thyroid follicles and have broad effects on growth, developments and metabolism.

·         Calcitonin is produced by interfollicular “C” cells and biologically important in calcium metabolism.

Synthesis and transport of thyroid hormone

1.       Iodine uptake

·         The iodide is uptake by “Na+ iodide symporter (NIS)” and to concentrate this anion (I2).

·         The trapping is stimulated by TSH by inducing and activating NIS.

2.       Oxidation and iodination

·         Iodide trapping by follicular cells is carried across the apical membrane by the transporter “pendrin” and oxidized by the membrane bound thyroid peroxidase enzyme to linked (I+) ion OR hypoiodus acid (HOI) OR enzyme linked hypoiodate (E-OI) with the help of H2O2.

·         These iodines combine with tyrosil residues of thyroglobulin to form;

Monoiodotyrosine (MIT) and

Diiodotyrosine (DIT)

3.       Coupling

·         Pairs of iodinated tyrosine residues couple together to form T3 and T4.

·         The formation of T4 is much more than T3, but in case of I2 deficiency relatively more MIT is available and more T3 is formed.

·         Coupling is an oxidative reaction, hence coupling and oxidation of iodide are stimulated by TSH.

·         The same thyroid peroxidase is catalyzed the reaction of coupling.

4.       Storage and release

·         Thyroglobulin containing iodinated tyrosil and thyronil residue is transported to the interior of the follicles and remains stored as thyroid colloid.

·         The coupling residue is taken back into the cells by endocytosis and broken down by lysosomal proteases to form T4 and T3.

·         The T4 and T3 is then secreted into the circulation.

·         Both colloid uptake and proteolysis are stimulated by TSH.

5.       Peripheral conversion of T4 to T3

·         Peripheral tissues like liver and kidney convert T4 to T3.

·         The target tissues take up T3 from circulation and T4 is taken up by brain and pituitary and converts T4 to T3 with in their own cells.

·         The same amount of T3 and reverse T3 (rT3) are produced in the periphery.

·         The conversion of T4 to T3 is carried out by the enzyme iodothyronine deiodinase which exists in 3 forms; that is D1, D2, and D3.

D1: generates both T3 and rT3 (Propylthiouracil block D1 form)

D2: generates T3 (Amiodarone)

D3: generates rT3 (Amiodarone)

 

Conversion of T4 to T3 (Propranolol high dose)

MECHANISM OF ACTION

·         Both T3 and T4 penetrate cells by active transport and combining with a nuclear thyroid hormone receptor (TR) → (Steroid and Retinoid).

·         Steroid receptor: the TR residues in the nucleus even in the unliganded inactive state.

·         It bound to thyroid hormone response element (TRE) along with corepressors.

 

·         When T3 binds to the ligand-binding domain of TR, it heterodimerizes with retinoid X receptor (RXR), undergoes conformational changes induces gene transcription and production of protein synthesis.

PHARMACOKINETICS

·         Nearly 75% oral bioavailability.

·         Severe hypothyroidism may reduce oral absorption.

·         Administration in empty stomach.

·         Sucralfate, Iron, Calcium and Proton Pump Inhibitor inhibit L. thyroxine absorption.

·         Rifampin, Phenytoin, and Carbamazepine (CYP3A4 inducer) accelerate metabolism of T4.

USES

1.       Cretinism

·         Severe physical and mental retardation.

·         Treatment thyroxine (8-12 microgram/kg) as early possible.

2.       Myxedema

·         Low HR

·         Weight gain

·         Weakness

·         Goiter

3.       Myxedema coma

·         Loss of brain function

4.       Nontoxic goiter

·         Nodular enlargement of the thyroid gland.

5.       Thyroid nodule

·         Solid or fluid filled lumps.

·         Most thyroid nodules are not serious and don’t cause symptoms.

6.       Papillary carcinoma of thyroid.

·         A cancer of the thyroid.

7.       Empirical uses

·         Also, T4 has been used in

Refractory anemias

Mental depression

Menstrual disorder

Chronic / non-healing ulcer

 

Obstinate constipation  

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