【Pharmacology】Drugs for pituitary and thyroid disease

Drugs for pituitary and thyroid disease 

Content:

• Hypothalamus & Pituitary
• Pituitary hormone
• Why uses as a drug?
• Therapeutic effect
• Reference

Hypothalamus & Pituitary

• The hypothalamus region lies inferior and anterior to the thalamus. 
• It connects to the pituitary gland by the stalk-like infundibulum.
• Anterior pituitary, also known as the adenohypophysis. 
• contains specialized cells that produce and secrete hormones
• The connection between the hypothalamus and anterior pituitary is the hypophyseal portal system.
• quickly & high concentration transport and exchange hormones 
• To do so, the capillaries in the portal system are fenestrated, which means have many small channels with high vascular permeability.
• Posterior pituitary, also known as the neurohypophysis.
• neuronal projections extending from the hypothalamus that produce and then directly  secrete hormones into the circulation

Pituitary hormone

Anterior:

1. Gonadotropin-releasing hormone  (GnRH):

• stimulates luteinizing hormone (LH), which in turn stimulate the reproductive functioning of the ovaries and testes 
• stimulates gonadotrophs (G) to release follicle-stimulating hormone (FSH) 

2. Thyrotropin-releasing hormone (TRH):

• stimulates specialized endocrine cells called thyrotrophs (T) to release thyroid stimulating hormone (TSH), which in turn stimulates thyroid  gland to produce and release thyroid hormones 

3. Prolactin-releasing hormone (PRH)

stimulate breast milk production through the production of prolactin

*Prolactin-inhibiting hormone (PIH): simply the neurotransmitter dopamine that acts on lactotrophs (L) to inhibit the secretion of prolactin.

4. Growth hormone-releasing hormone (GHRH):

• stimulates somatotrophs (S) to release growth hormone (GH), which in turn stimulates the liver and other tissues to produce growth stimulants called insulin-like growth factors

*Growth hormone-inhibiting hormone (GHIH): inhibits somatotrophic cell release of growth hormone

5. Corticotropin-releasing hormone (CRH)

• stimulates corticotrophs (C) to release adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to  produce and secrete certain steroid hormones

Posterior:

1. Anti-diuretic hormone (ADH)

• acts primarily on the kidney to regulate water balance in the body

2. Oxytocin

• regulates uterine contractions and milk ejection

Why uses as a drug?

Hormones produced by the hypothalamus and pituitary play a crucial role in regulating metabolism,  growth, and reproduction. Hence, many drugs have been developed to either mimic or block their effects in order to treat various endocrine disorders.  

Therapeutic effect

Anterior

1. Gonadotropin-releasing hormone  (GnRH):

Hypothalamic hormone, GnRH, is released and transported to the anterior pituitary in a pulsatile manner, where it binds to the receptors expressed by the pituitary gonadotrophs.  

The frequency of GnRH pulses changes under various physiological conditions, and varying pulse frequencies have been shown to regulate the secretion of LH and FSH. 

Drugs used in treatment of GnRH disorders:

a. GnRH agonists (upregulate the secretion of LH and FSH)

• Goserelin
• Histrelin
• Leuprolide
• Nafarelin
• They are more potent and have longer half-life than natural GnRH.
• Produce an initial stimulation of pituitary gonadotrophs → increased secretion of LH and FSH
• Followed by downregulation and inhibition of the pituitary-gonadal axis.

 Pituitary-gonadal axis

GnRH agonists

b. GnRH antagonists (downregulate the secretion of LH and FSH)

• Degarelix
• Elagolix
• Ganirelix 
• Cetrorelix
• promptly suppress pituitary gonadotropin by competitively  blocking GnRH-receptor
• avoiding the initial stimulatory phase of the agonists
• suppression of LH and FSH → inhibition of estrogen and androgen  synthesis
• effective in treatment of hormone-sensitive cancers & various gynecological disorders. 

GnRH antagonists

c. ↑ LH and FSH 

Deficiency of both LH and FSH as a result of hypothalamic or pituitary disease →infertility or subfertility both in men and women.

Stimulate spermatogenesis in men and to induce follicle development and ovulation in women👇

• Menotropins: a purified mixture of LH and FSH
• Urofollitropin: a purified form of human FSH
• Follitropin: a form of recombinant  human FSH
• Lutropin, which is a recombinant form of human LH
• Choriogonadotropin alfa: a recombinant form of human chorionic gonadotropin (hCG)
• hCG:a hormone naturally  produced by the placenta during pregnancy
• shares structural similarities with LH and thus binds to and activates the same receptor

2. Thyrotropin-releasing hormone (TRH):

Synthesization of thyroid hormones

Thyroid hormones are synthesized in the thyroid follicle.

The thyroid follicle, which is composed of intrafollicular colloid and follicular cells, serves as both factory and warehouse for the production of thyroid hormones.   

Two principle ingredients to making thyroid hormones:

1. Thyroglobulin

• Glycoprotein
• Synthesized in the  rough endoplasmic reticulum of follicular cell
• Secreted into the colloid

2. Iodide

• Actively pumped into the cell by sodium-iodide symporter
• Passively transported into the colloid along with thyroglobulin
• In the colloid, with  the help of an enzyme called thyroid peroxidase, iodide (I-) is oxidized to iodine (I0)

💪Hormone synthesis begins with the addition of iodine to tyrosyl residues on the thyroglobulin molecules in a process called iodination.  

💪Through conjugation, adjacent tyrosyl residues are paired together and the entire complex re-enters the follicular cell.

💪Inside the cell, proteolytic enzymes digest thyroglobulin thus liberating free thyroid molecules, thyroxine (T4) and triiodothyronine (T3), which  are then released into the circulation where they quickly bind to carrier proteins for transport to target cells. 

💪Free extracellular T4 and T3 enter the target cell through transporter proteins.

💪Once inside the cell, T3→T4, increases intracellular levels of the active hormone.

• T3 has greater biological activity than T4
• is regulated by deiodinase enzymes 1 and 2 (abbreviated D1 and D2) that catalyze the conversion of T4 to T3

💪Inactivate T4 to limiting the amount of T4 that can be used to form T3

• deiodinase 3 (abbreviated as D3) serves to inactivate T4 by converting it to so-called reverse T3 (rT3 for short)

💪T3 moves to the nucleus and binds to the thyroid hormone receptors (TR), which then form heterodimers with the retinoid X receptor (RXR) to induce transcription of target genes known as thyroid response elements. 

• This leads to synthesis of various regulatory proteins, which then  mediate various physiological responses. 

Drugs used in treatment of thyroid disorders:

a. Hypothyroidism

• Levothyroxine: synthetic version of T4
• Liothyronine: synthetic version of T3
• Liotrix: synthetic combination of T4 and T3
• Desiccated natural thyroid: natural thyroid hormone prepared from dried porcine thyroid containing mix of T4 and T3

b. Hyperthyroidism

• Propylthiouracil
• Methimazole
• inhibiting thyroid peroxidase that is required for oxidation of iodide 
• inhibiting coupling of iodotyrosines in thyroglobulin
• This is necessary for thyroid hormone synthesis
• Propylthiouracil: also inhibits deiodinase 1 (D1), which prevents conversion of T4 to T3. 

3. Prolactin-releasing hormone (PRH)

The secretion of prolactin is regulated by dopamine, which is secreted by hypothalamic dopaminergic neurons into the anterior pituitary via portal vessel. 

Dopamine that is released by these neurons acts on lactotrophs through D2-receptors causing inhibition of prolactin secretion. 

a. Dopamine receptor antagonist

• Insufficient prolactin levels → Failure to lactate
• Metoclopramide
• blocking D2 receptors from being stimulated → increasing prolactin secretion

b. Dopamine receptor agonists

• Excessive prolactin levels → Galactorrhea and infertility
• Bromocriptine & Cabergoline 
• stimulate D2 receptors → inhibiting prolactin secretion. 

4. Growth hormone-releasing hormone (GHRH):

Growth hormone also called somatotropin

• The pituitary secretes growth hormone
• hypothalamus releasing growth hormone-releasing hormone (GHRH)   
• the stomach releasing ghrelin. 
• Growth hormone in stimulating body growth
• to stimulate the liver and other tissues to secrete insulin-like growth factor-1 (IGF-1). 
• IGF-1 → stimulates proliferation of cartilage cells → bone growth & formation of new proteins (particularly in skeletal muscle cells) →resulting in muscle growth.  
• Growth hormone can also directly bind to fat cells, 
• break down triglycerides & suppresses their ability to take up and accumulate circulating lipids. 

a. Deficiency in growth hormone

Growth retardation or dwarfism

• injected synthetic somatotropin 👉 compensate for insufficient levels of growth hormone
• Mecasermin: a recombinant human IGF-1 product
• for pediatric patients  with growth failure and severe IGF-1 deficiency who are not responsive to treatment with  somatotropin

b. Excessive growth hormone

Gigantism in children & Acromegaly in adults

• Growth hormone-inhibiting hormone also known as somatostatin
• secreted from the hypothalamus
• inhibits the pituitary gland's secretion of growth hormone
• Octreotide & Lanreotide → binding to somatostatin receptors located on the surface of different cell types → inhibition of growth hormone secretion and its effects on target tissue. 

5. Corticotropin-releasing hormone (CRH)

Adrenocorticotropic hormone  (ACTH) on the adrenal cortex is to stimulate the synthesis and release of adrenocortical and androgen hormones.

Inside the cells of the adrenal cortex, 

• stimulation by ACTH  activates cholesterol side-chain cleavage enzyme
• catalyzes the conversion of cholesterol to pregnenolone
• the precursor of all adrenocortical hormones
• mineralocorticoids
• glucocorticoids
• androgens
• estrogens

Precursor of all adrenocortical hormones

a. Adrenocortical insufficiency

Addison’s disease: inadequate secretion of cortisol and aldosterone

• Fludrocortisone: replacing the missing hormone aldosterone with  the synthetic analog
• Hydrocortisone / Prednisone: replacing the missing cortisol with the synthetic analogs

b. Excessive cortisol production

Cushing’s syndrome

• Ketoconazole
• Mitotane
• Metyrapone
• inhibit enzymes involved in cortisol synthesis.

Posterior

1. Anti-diuretic hormone (ADH)

also known as vasopressin

When there’s a change in plasma osmolality, volume, or redistribution of blood, osmoreceptors located within hypothalamus & pressure receptors in veins,  atria, and carotids, stimulate the release of vasopressin into the circulation

Vasopressin action: 

• binding to the V2 receptors (V2R) on cells in the distal tubules and collecting ducts of the kidney
• stimulates insertion of aquaporins (water-permeable channels) into the luminal membrane
• allows water to be reabsorbed down an osmotic gradient
• urine to become more concentrated

• binding to the V1 receptors (V1R) on a vascular smooth muscle
• vasoconstriction

a. to ↑ vasopressin

• natural vasopressin
• Desmopressin (DDAVP): synthetically modified selective V2 receptor agonist
• available in oral and nasal formulations
• treat diabetes insipidus, certain bleeding disorders and nocturnal involuntary urination

b. Vasopressin receptor antagonists (to ↓ vasopressin)

• Conivaptan and Tolvaptan: blocking V2 receptors
• treat hyponatremia: syndrome of inappropriate secretion of antidiuretic hormone

2. Oxytocin

Female reproduction

In the late stage of pregnancy, stretching of tissues in the uterus and cervix 

→ Local stretch receptors to send nerve impulses to the hypothalamus

→ Pituitary to secrete oxytocin into the circulation

→ Oxytocin then travels to the uterus

→ Muscles in uterine walls to contract

→ Bringing the baby downwards
→ Stretching the cervix even more

→ Repeating the cycle until birth occurs

After the birth, oxytocin release is stimulated by the suckling of an infant at the breast

→ Triggers the synthesis and release of the oxytocin into the circulation

→ Oxytocin travels to the breast

→ Stimulates receptors in the cells of the milk ducts to initiate a contracting action

→ Forcing milk down the duct

a. Exogenous oxytocin

induce labor & inhibit postpartum bleeding

Reference

https://youtu.be/rqFvilz_Ss0

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【Pharmacology】Drugs for pituitary and thyroid disease