Lect.1 of 6_Hormone Receptors & Other Basic Concepts

Photo: Colorized transmission electron micrograph of an endocrine cell from the anterior pituitary gland. The secretory vesicles (brown) contain hormones.

From: Seeley’s Anatomy & Physiology 10th ed New York, NY: McGraw-Hill 2010.

1

Endocrine Pharmacology Basic Concepts  Endocrine system’s target organ are usually located relatively far from site of release of chemical mediator (hormone) of the signal  A hormone is a substance secreted by one tissue or gland that is transported via circulation to a site where it exerts its effects on different tissues  Signaling mechanisms which use enzymes, neurotransmitters, hormones, and receptors are similar (aside from distance)  Hence, basic pharmacologic principles of therapy are same  Keys to understanding endocrine pharmacology are feed-forward and feed-back mechanisms that govern how “releasing” factors in hypothalamus control release of hormones in pituitary that in turn cause release of second-tier hormones that target multiple organs within body  Hypothalamic Releasing Hormone Pituitary Trophic (Signal) Hormone Target Hormone(s) Marc Imhotep Cray, MD

2

Routes by which chemical signals are delivered to cells 1. Autocrine chemical messengers stimulates the cell that originally secreted it 2. Paracrine chemical messengers act locally on nearby cells 3. Neurotransmitters secreted by neurons that activate an adjacent cellďƒ another neuron, a muscle cell, or a glandular cell 4. Endocrine chemical messengers are hormones secreted into bloodstream by certain glands and cells– and act at a distant site Marc Imhotep Cray, MD

Modified from: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

Overall Function of Hormones  A hormone is a substance secreted by one tissue but has actions at remote tissues  Hormones maintain homeostasis by regulating processes such as development, metabolism, and reproduction  Hormones: maintain homeostasis through feedback loops  Hormones: act slowly relative to nervous system

Marc Imhotep Cray, MD

Remember: Nervous System chemical mediator (neurotransmitter) Endocrine system chemical mediator (hormone) Basic physiologic, biochemical and pharmacologic principles are same.

4

Endocrine Pharmacology Basic Concepts (2) Hormone Receptors

 There are two major classes of hormones: 1. proteins, peptides, and modified amino acids 2. steroids

 All known hormones, and drugs that mimic hormones, act via one of two basic receptor systems:  

membrane-associated receptors and intracellular receptors

1. Membrane-associated receptors Membrane-associated receptors bind hydrophilic hormones (which penetrate plasma membrane poorly), such as    Marc Imhotep Cray, MD

Insulin Adrenocorticotropic hormone (ACTH), and Epinephrine, outside the cell 5

Basic Concepts (3) Hormone Receptors cont.

1. Membrane-associated receptors transmit signals into cell by a variety of “second messenger” mechanisms, including:  Changes in cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) caused by changes in activity of cyclases  Increased phosphoinositide turnover via increased phospholipase activity  Increased intracellular Ca2+ by action on Ca2+ channels  Increased tyrosine phosphorylation on specific proteins by action of tyrosine kinases (TKR) Marc Imhotep Cray, MD

6

The four major classes of membrane receptors for hormones and neurotransmitters

Marc Imhotep Cray, MD

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

7

Basic Concepts (4) Hormone Receptors cont.

2. Intracellular receptors: Intracellular receptors bind hydrophobic (lipophilic) hormones (which penetrate plasma membrane easily) such as  Cortisol  Retinol, and  Estrogen inside cell—either in cytoplasm or nucleus  Intracellular receptors modulate transcription rate of specific target genes to change levels of cellular proteins N.B. Hormones (and Vitamins) that work via steroid receptor: estrogen, testosterone, glucocorticoids, vitamin D, aldosterone, progesterone, T3/T4 Marc Imhotep Cray, MD

8

*Mechanism using a G protein, as shown in D (Next slide)

9

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

Hormone second-messenger systems

Hormone 2nd messenger systems-Mechanism using a G protein G-protein mechanism.

1. Messenger system before hormone binding 2. After hormone binding, GTP replaces GDP on G protein.

3. GTP, attached to α subunit, dissociates from the β−γ complex and converts ATP to cAMP. 4. Hormone is released from binding site and complex returns to inactive state when GTPase cleaves GTP to GDP. Marc Imhotep Cray, MD

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition.

Wolters Kluwer, 2015

10

Hormone 2nd messenger systems: G-Protein Class, Action and Examples G Protein Subtype

Action

Examples

Modified from: McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

Marc Imhotep Cray, MD

11

Class of Receptors Used by Various Hormones Receptor Class

Hormones and Related Substances

cAMP

LH, FSH, ACTH, TSH, PTH, hCG, CRH, glucagon

cGMP

NO, ANP

IP3

GnRH, GHRH, oxytocin, TRH

Steroid receptor

Estrogen, testosterone, glucocorticoids, vitamin D, aldosterone, progesterone, T3/T4

Tyrosine kinase

Insulin, growth factors (e.g., IGF, PDGF), GH, prolactin

Redrawn after: Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

Ledger: ACTH, adrenocorticotropic hormone; ANP, atrial natriuretic peptide; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; CRH, corticotropin-releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin; IGF, insulin-like growth factor; IP3, inositol triphosphate; NO, nitric oxide; PDGF, platelet-derived growth factor; PTH, parathyroid hormone; T3, triiodothyronine; T4, thyroxine; TRH, thyrotropin-releasing hormone; TSH, thyroid stimulating hormone.

Marc Imhotep Cray, MD

12

Cellular MOA of steroid hormones  Steroid hormones are lipophilic therefore, they diffuse across plasma membrane and form complexes with cytosolic or nuclear receptors bound complexes then activate transcription of various genes  Because steroid hormones rely on the intermediary process of gene expression and protein translation it can take hours to days for their effects to manifest  Examples of steroid hormones are testosterone, estrogen, progesterone, cortisol, and aldosterone  Cholesterol is precursor to all steroid hormones  Although thyroid hormone is not a steroid hormone TH uses same cellular mechanism as steroids Marc Imhotep Cray, MD

Remember: There are two major classes of hormones: 1. proteins, peptides, and modified amino acids 2. steroids

13

MOA of peptide hormones and catecholamines  Peptide hormones and catecholamines are not highly lipid-diffusible and thus cannot cross plasma membrane  They bind to cell surface receptors (next slide), which initiate a variety of biochemical events, including o activation or inhibition of enzymes o alteration of membrane proteins, and o mediation of cellular trafficking  These processes can occur within seconds to minutes o Nevertheless, peptide hormones can stimulate gene expression as well, and this effect is delayed as it is with steroid hormones  Examples of peptide hormones are insulin, parathyroid hormone (PTH), vasopressin (antidiuretic hormone), and oxytocin Marc Imhotep Cray, MD

14

Mechanisms by which peptide and steroid hormones signal

Marc Imhotep Cray, MD

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

15

Basic Concepts (5) Hypopituitarism may be partial or complete and may result from hypothalamic disease (leading to deficiency of hypothalamic-releasing hormones) or intrinsic pituitary disease(causing pituitary hormone deficiency) Hypopituitarism may affect any of these pituitary hormones:  thyrotropin (TSH)  growth hormone(GH)  luteinizing hormone (LH)  follicle stimulating hormone (FSH) and  corticotropin (ACTH) Marc Imhotep Cray, MD

16

Basic Concepts (6)  In targeting one of these hormones of hypopituitarism  therapy for GH deficiency aims to restore normal body composition, as well as, in children, to promote linear growth  Therapy for acromegaly, caused by excessive GH secretion, includes  surgery and (or) radiation, or  use of a GH inhibitor

Marc Imhotep Cray, MD

17

Basic Concepts (7) Hypothyroidism can result from either thyroid (high TSH, low T3 &T4) or hypothalamic (or) dysfunction (low T3, T4, TSH)

 Treatment of choice is hormone substitution by using a synthetic hormone Hyperthyroidism (thyrotoxicosis) is characterized by increased metabolism, and primary treatment options include  surgery  radioactive iodine or  drugs that inhibit formation of T3 &T4 by blocking utilization of iodine Marc Imhotep Cray, MD

18

Basic Concepts (8) Principal functions of glucocorticoids involve regulation of carbohydrate metabolism and a variety of other physiologic actions Synthetic corticosteroids (eg, hydrocortisone, prednisone, and dexamethasone) are widely used as therapeutic agents in Tx of cancer and autoimmune or inflammatory-type disorders Pharmacologic treatment is also available for  insufficient adrenal function manifested as Addison disease  excess glucocorticoid exposure results in Cushing syndrome Marc Imhotep Cray, MD

19

Basic Concepts (9) Diabetes mellitus (DM) is a syndrome caused by a relative or absolute deficiency of insulin, with hyperglycemia being hallmark medical finding  DM can occur as either an early onset form (type 1) or a gradual-onset form (type 2)  In T1DM, insulin-producing β cells of pancreas are destroyed or insufficiently active, and patients require lifelong treatment with exogenous insulin  In T2DM, adequate control of disease may be achieved by means of diet and exercise if these methods fail, patients take oral hypoglycemic agents, which cause o lower plasma glucose levels o improve insulin resistance, and o reduce long-term complications (macrovascular and microvascular problems such as neuropathy, nephropathy, retinopathy and CVD) Marc Imhotep Cray, MD

20

Basic Concepts (10)  For type 1 DM Insulin is sole treatment and is sometimes also used for type 2 DM  For type 2 DM, drugs include  sulfonylureas, which stimulate insulin secretion from pancreatic β cells  metformin, a biguanide that decreases blood glucose levels by reducing hepatic glucose production and glycogen metabolism in liver and improving insulin resistance  meglitinides, which increase insulin secretion from pancreatic β cells  α-glucosidase inhibitors, which delay carbohydrate digestion and glucose absorption and  thiazolidinedione (TZD) derivatives (eg, rosiglitazone and pioglitazone), which reduce insulin resistance Marc Imhotep Cray, MD

21

Concept of negative feedback What is a feedback loop?  Hormone synthesis and release are governed at multiple levels  Hormone synthesis/release from an organ of interest typically involves regulation by a pituitary hormone, which itself is regulated by a hypothalamic hormone  This general pathway structure is commonly referred to as a hypothalamic-pituitary-(organ) axis  e.g., HPO axis refers to ovary, HPA axis refers to adrenal gland  Negative feedback occurs when a product downstream of an axis inhibits production of a reactant by which it is regulated for example, thyroid hormone inhibition of thyroid-stimulating hormone (TSH)  These relationships are often depicted using feedback loops (next 2 slide) Marc Imhotep Cray, MD

22

Regulation of hormone synthesis and secretion ď ą To best understand endocrine pharmacology it is essential understand the negative feedback principle of the hypothalamic/pituitary/ target organ axis

ď ą A negative feedback mechanism is an example of a negative effect Solid lines = positive effect Dashed lines = negative effect Marc Imhotep Cray, MD

Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010

23

Thyroid hormone feedback loop

Marc Imhotep Cray, MD

Brown TA, Brown D. USMLE Step 1 Secrets, 3rd Ed. Saunders, 2013

24

Hormones of the hypothalamic-pituitary axis

Marc Imhotep Cray, MD

McInnis M., Mehta S. Step-up to USMLE Step 1 2015 Edition. Wolters Kluwer, 2015

25

Hormone

Site of Release

Action

Stimulators

Inhibitors

PRF

Modified from: Baron SJ and Lee CI. Lange Pathology Flash Cards. New York: McGraw-Hill, 2009

26

Relationships Among Hypothalamic, Pituitary, and Target Gland Hormones HYPOTHALAMIC

PITUITARY

TARGET ORGAN

TARGET ORGAN HORMONES

GHRH (+), SRIH (–), CRH (+)

GH (+)

Liver

Somatomedins

ACTH (+)

Adrenal cortex

Glucocorticoids Mineralocorticoids Androgens

TRH (+)

TSH (+)

Thyroid

T4, T3

GnRH or LHRH (+)

FSH (+), LH (+)

Gonads

Estrogen Progesterone Testosterone

Dopamine (–), PRH (+)

Prolactin (+)

Breast

—

Redrawn after: Pazdernik TL, Kerecsen L. Rapid Review Pharmacology, 3rd Ed. Mosby, 2010

+, stimulant; –, inhibitor; ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; FSH, folliclestimulating hormone; GH, growth hormone; GHRH, growth hormone–releasing hormone; GnRH, gonadotropinreleasing hormone; LHRH, luteinizing hormone-releasing hormone; LH, luteinizing hormone; PRH, prolactin-releasing hormone; SRIH, somatotropin-releasing inhibiting hormone; TRH, thyrotropin releasing hormone; TSH, thyroidMarc Imhotephormone.

Cray, MD stimulating

27

Hormones that Integrate the HypothalamicPituitary-Endocrine Axis

Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed.

McGraw-Hill, 2011

Marc Imhotep Cray, MD

28

THE END

See next slide for further study.

Marc Imhotep Cray, MD

29

Sources and further study: eLearning Endocrine cloud folder tools and resources MedPharm Guidebook: Unit 5 Drugs Used In Disorders of Endocrine System Endocrine and Reproductive System Pharmacology eNotes Clinical Pharmacology Cases 39 to 44 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.

Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.

Marc Imhotep Cray, MD

30