1-29 Pituitary Gland Pharmacology PDF

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Pituitary Gland Pharmacology Exam: 6 DM patho, 3 glands patho (Andy has 16Q and wants 20Q) *TESTED ON WHOLE ENDOCRINE AXIS. ORDER goes tertiary, secondary, primary. The hypothalamic-pituitary portal system  Neurons in the hypothalamus release neurotransmitters and peptides that are carried by the hypothalamicpituitary portal system to the anterior pituitary gland, where they control the release of anterior pituitary hormones o Blood vessels (portal system connecting hypothalamus and pituitary gland) o Hypothalamus releases neurotransmitters and hormones, enters portal system and travels to anterior lobe through portal system/plasma o Signals anterior lobe to release fewer hormones  Posterior pituitary hormones are synthesized in cell bodies of the neurons in the hypothalamus and then transported down axonal pathways to terminals in the posterior pituitary gland for storage which they are released into the systemic circulation o 2 lobes in gland: posterior and anterior o Direct connection of neurons, no blood connection b/w hypothalamus and posterior lobe o Posterior hormones synthesis in paraventricular and supra-aortic nuclei (hypothalamus)  Releases hormone into circulation  Hormones made by neurons, not the posterior gland itself  Indirect vascular connection between hypothalamus and anterior pituitary gland  Direct neural connection exists between hypothalamus and posterior pituitary gland General mechanism of hypothalamic-pituitary-target organ feedback (ENDOCRINE AXIS- adrenal+ pituitary+ hypothalamus)  Stimulatory hypothalamic factors corticotropin-releasing hormone (CRH)  Release of pituitary hormones ACTH  Target organ, adrenal gland produces a hormone cortisol  Cortisol negatively regulates the hypothalamic-pituitary-adrenal axis by inhibiting CRH and ACTH  ACTH also negatively regulates CRH, providing more sensitive control of the axis  primary endocrine disorder is caused by target organ pathology (ex. Adrenal gland) o disorder related to primary order- primary disorder  secondary endocrine disorder reflects pituitary disease  tertiary endocrine disorder results from hypothalamic pathology

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Anterior Pituitary Gland Cell Types, Hypothalamic Control Factors, and Hormonal Targets- ENDOCRINE AXIS -Every row is a separate endocrine axis. Which one is neg feedback inhibitor? ANTERIOR STIMULATORY INHIBITORY PITUITARY MAJOR HORMONES PITUITARY HYPOTHALAMIC HYPOTHALAMIC HORMONES TARGET PRODUCED BY GLAND CELL FACTORS FACTORS RELEASED ORGAN OF TARGET ORGAN TYPE HORMONE Somatotroph GHRH (Growth hormonereleasing hormone); Ghrelin

Somatostatin (inhibitor)

GH (Somatotropin) Don’t confuse w/ somatostatin

Liver, cartilage

Insulin-like growth factors

Lactotroph

TRH (Thyrotropinreleasing hormone)

Dopamine, somatostatin

Prolactin

Mammary gland

None

Thyrotroph

TRHhypothalamus

Somatostatin

TSH (Thyroid Thyroid stimulating gland hormone)- pituitary

Thyroxine, triiodothyronine

Corticotroph

CRH (Corticotropinreleasing hormone)hypoth

None known

Adrenocorticotropic Adrenal hormone (ACTH)cortex pitutary

Cortisol, aldosterone, adrenal androgens (produced by adrenal cortex)

None known

Luteinizing hormone (LH) and Follicle-stimulating hormone (FSH)

Gonadotroph GnRH (Gonadotropinreleasing hormone)

Gonads Estrogen, (Ovary and progesterone, testes) testosterone, inhibin

Anterior Pituitary Gland Pathophysiology of Growth Hormone axis  Normal hypothalamic-pituitary-growth hormone axis: o Hypothalamic secretion of GHRH (growth hormone releasing hormone) or ghrelin  Hypothalamus releases 2 hormones (GHRH and ghrelin) and goes to liver to release another protein (IGF1) o Release of growth hormone (GH) somatotropin o Somatostatin inhibits release of GH—FEEDBACK INHIBITION o Secreted GH then stimulates the liver to secrete insulin-like growth factor 1 (IGF-1)  Disorder: primary endocrine disorder  adrenal  Secondary disorder  pituitary  Tertiary: hypothalamic o IGF-1 also inhibits GH release from the anterior pituitary gland (negative feedback loop)  2 feedback inhibitions: hypothalamus somatostatin & GH????  ***ALL ENDOCRINE ACCESS IS CONTROLLED BY NEGATIVE FEEDBACK INHIBITION

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Pathophysiology of Growth Hormone insensitivity (deficiency)  Growth hormone insensitivity: o Liver insensitive to GH, so liver is not releasing IGF-1 o Liver unresponsive to hormone, GH produced by pituitary gland (GH insensitivity)  Pituitary producing GH but liver not responding to GH o Anterior pituitary gland secretes GH, but the liver is unresponsive to stimulation by GH o IGF-1 secretion is reduced (dashed lines) o Decreased feedback inhibition of GH release results in higher plasma levels of GH ( thick line) o No negative feedback inhibition—pituitary gland producing too much GH. Liver too insensitive to GH  Primary endocrine disorder (liver insensitive to GH)??????

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***IMAGES ON EXAM! Secondary deficiency: o Pathology lies in an unresponsive anterior pituitary gland, which secretes reduced amounts of GH o Because GH levels are low, the liver is not stimulated to produce IGF-1 o LIVER NOT PRODUCING IGF1, even tho 2’, the 1’ organ is suffering. No negative feedback inhibition. o Still have hormones released from hypothalamus Tertiary deficiency: o Hypothalamus fails to secrete GHRH appropriately (dashed line) o Lack of sufficient GHRH results in lack of adequate stimulation of GH secretion by the anterior pituitary gland and, therefore, diminished production of IGF-1 o Hypothalamus not releasing ANY hormones. No IGF from liver, no GH from pituitary

GROWTH HORMONE (GH) REPLACEMENT- Somatropin OR Somatotropin (Growth hormone), Somatrem (Analogue of GH)  Another name for GH = somatotropin  Somatostatin= inhibition  MOA: Replace or stimulate release of growth hormone  Growth failure in children with GH deficiency, Turner’s syndrome (happens in women, only 1 X chromo, no synthesis of GH), Prader-Willi syndrome, or chronic kidney disease  Idiopathic short stature  Replacement of endogenous GH in adults with GH deficiency  Turner’s syndrome- Female born with only one X chromosome  Available as depot injection  Glucocorticoids inhibit growth-promoting effect of somatropin

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GROWTH HORMONE (GH) AND INSULIN-LIKE GROWTH FACTOR REPLACEMENT- Tesamorelin (Synthetic form of GHRH), Mecasermin (Recombinant human IGF-1)  MOA: Replace or stimulate release of growth hormone or insulin-like growth factor  Tesamorelin (Synthetic form of GHRH) o HIV lipodystrophy  Abnormal fat distribution related to few HIV treatment o Monitor IGF-1 and glucose levels during therapy o Daily shot can lessen belly fat o Need to know if 1/2/3’ to know tx: want GHRH if 3’ (hypothalamus not synthesizing GHRH)  ONLY USE FOR TERTIARY DISORDER  If used for primary, nothing happens. If given GHGRH, too much GH, but nothing happens bc liver is unresponsive to GH  Somatostatin in hypothalamus decr release of inslun/glucagon, also decr relase of hormones from pituitary. Also decr GI tract hormone release (see pcol notes for DM hormones!!!)  Mecasermin (Recombinant human IGF-1) o Primary IGF-1 deficiency o Recombinant IGF-1 o Available as twice-daily and once-daily injections o GIVEN FOR PRIMARY DISORDER, LIVER NOT PRODUCING IGF1. Pathophysiology of Growth Hormone Excess (acromegaly)  In GH excess, GH is most commonly hypersecreted from an anterior pituitary adenoma (pituitary gland cancer) o Not metastatic, so cancer wont spread… benign cancer o Anterior lobe of pituitary gland adenoma o Too much GH, asks liver to produce high levels IGF1 (supposed to act like negative feedback inhibition bc of tumor in pituitary gland)  Bc of tumor- gland will keep producing GH, even if IGF1 or somatostatin, they cannot control levels of GH  Elevated, and unregulated, GH levels result in increased hepatic production of IGF-1  Because GH secretion occurs via an autonomous adenoma in the pituitary, negative feedback by IGF-1 is usually less effective  Somatostatin receptor ligands (SRLs) are the mainstay of medical therapy. Somatostatin physiologically inhibits growth hormone secretion, making it a logical treatment for somatotroph adenomas

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AGENTS THAT DECREASE GROWTH HORMONE SECRETION OR ACTION (Somatostatin receptor ligands)  Octreotide, Lanreotide (Somatostatin receptor ligands OR somatostatin analogue)  MOA: Inhibit GH release; somatostatin receptor ligands  Shared indication: Acromegaly  Octreotide only: Carcinoid syndrome  Diarrhea from vasoactive intestinal peptide-secreting tumors  Synthetic analog of somatostatin  Also used to control GI bleeding and to reduce secretory diarrhea. o Somatostatin also released in GI, which controls motion in GI tract  Octreotide and lanreotide are available in a monthly depot formulation (Administration once every 4 weeks). ***DON’T NEED TO KNOW THERAPEUTIC CONSIDERATIONS. JUST KNOW MOA AND DRUG NAMES! AGENTS THAT DECREASE GROWTH HORMONE SECRETION OR ACTION (GH receptor antagonist)  Pegvisomant (GH receptor antagonist)  MOA: Inhibit GH release (somatostatin receptor ligands: octreotide, lanreotide), antagonize GH receptor (pegvisomant)  Ind: Acromegaly (Disorder of excess growth hormone) o Works on liver (GH binds to liver), drug blocks GH receptors on liver. If pituitary produces excess GH  Patients should have yearly MRI to exclude enlarging adenoma  Effective at achieving biochemical control but also costly.  Ongoing concern for GH-induced tumorigenesis and accelerated somatotroph adenoma growth Hypothalamic-Pituitary-Prolactin Axis  Secretion of prolactin by lactotrophs cells is inhibited by dopamine acting at D2 receptor  Hypothalamic TRH (Thyrotropin-releasing hormone) and circulating estrogen stimulate prolactin release  Estrogen levels also stimulate prolactin release (NO NEG FEEDBACK INHIBITION) o GH: IGF1 acts like negative feedback inhibition, so WHAT DOES THIS MEAN?  Prolactin not signaling breast to produce hormone. No hormones produced from target organ, prolactin is released from mammary gland and targets breasts  Target organ NOT releasing any hormones/proteins  High levels TRH or dopamine problem, too much prolactin in system = HYPERPROLACTINEMIA  Dopamine: inhibits release of prolactin, inhibitory neurotransmitter o Somatostatin releases GH (see above)  Disruption of this equilibrium results in an imbalance of prolactin production  Interruption of the pituitary stalk diminishes hypothalamic dopamine delivery to lactotrophs, resulting in increased prolactin secretion

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AGENTS THAT DECREASE PROLACTIN LEVELS (dopamine d2 receptor agonist)  Bromocriptine o MOA: Inhibit pituitary prolactin release; Bromocriptine and cabergoline are dopamine D2 receptor agonist o Indication  Hyperprolactinemia  Acromegaly  Parkinson’s disease  Non-pregnancy related amenorrhea (Irregular menstrual period)-galactorrhea (Production of breast milk) syndrome o Intravaginal administration may reduce gastrointestinal adverse effects o Co-administration with antihypertensives may potentiate hypotension o Use of bromocriptine to suppress lactation in postpartum women is not recommended, only for lactation associated with non-pregnancy o PRIMARY ORGAN: BOOBS o SECONDARY ORGAN: dopa released by brain binds pituitary gland and inhibit release of prolactin  Cabergoline o MOA: Inhibit pituitary prolactin release; Bromocriptine and cabergoline are dopamine D2 receptor agonist o Ind: Hyperprolactinemia o CNS depressants have additive effects. Hypothalamic-Pituitary-Gonadal Axis (MOST IMPT ENDOCRINE AXIS)  Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus o PULSATILE: STIMULATORY o CONTINUOUS GNRH: INHIBITS RELEASE OF LH/FSH, WHICH DECR LEVELS OF ESTROGEN AND TESTOSTERONE  Stimulating gonadotroph cells of the anterior pituitary gland to secrete luteinizing hormone (LH) and folliclestimulating hormone (FSH) o Secondary: hypothalamus and pituitary o Primary: GnRH released by hypothalamus o ANTERIOR LOBE ACCESS CONTROL  LH and FSH stimulate the ovaries or testes to produce the sex hormones estrogen or testosterone, respectively, which inhibit further release of LH and FSH o Target ovaries and testes producing sex hormones  Increasing estrogen levels that are secreted from developing follicles during the follicular phase of the menstrual cycle induce a positive feedback, midcycle ovulatory surge of LH and FSH secretion 6

High level testosterone: neg feedback, signals pituitary to stop producing hormone Follicle phase in menstrual cycle: signals pituitary to produce more FSH/LH  When phase is over, estrogen signals pituitary to stop producing FSH/LH (POS feedback loop)  Testosterone ALWAYS NEGATIVE feedback inhibition!!! Exogenous pulsatile GnRH can be used to induce ovulation in women with infertility of hypothalamic origin o GnRH pulsatile: high level estrogen produced, negative feedback (MEN)  Always testosterone production in men (FSH/LH) o GnRH continuous- signals to stop producing FSH/LH (WOMEN)  Follicle phase, need high levels estrogen (GnRH pulsatile form)  Once follicle phase ends, GnRH continuous, hypothalamus produces GnRH in continuous form  FSH/LH levels decrease  If you want to induce ovulation  give pulsatile form GnRH. If u want to continue, give GnRH continuous Continuous administration of GnRH suppresses the gonadotroph response to endogenous GnRH and thereby causes decreased production of sex hormones Analogues of GnRH with increased metabolic stability and prolonged half-lives take advantage of this effect and are used to suppress sex hormone production in clinical conditions such as precocious puberty and prostate cancer o o

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AGENTS THAT ALTER GONADOTROPIN EXPRESSION AND INHIBIT OR STIMULATE GONADAL MATURATION AND STEROID PRODUCTION (ends with “relin”) ***NEED TO KNOW THESE CLINICAL APPLICATIONS*** don’t need to know specific drug indications, just what conditions would you give GnRH  GnRH analogues: Goserelin, Histrelin, Leuprolide, Nafarelin  MOA: Continuous: inhibit LH and FSH release (decr estrogen and testosterone); Pulsatile: stimulate LH and FSH release  Prostate cancer (goserelin, histrelin, and leuprolide only) o Want lower levels of testosterone  WANT CONTINUOUS FORMULATION  Breast cancer (goserelin only) o In breast cancer, want to control levels of estrogen WANT CONTINUOUS FORMULATION  Levels of estrogen will decrease  Endometriosis (Abnormal tissue grows outside uterine lining; goserelin, leuprolide, and nafarelin only) o Control levels of estrogen to decr growth of endothelin. Want to give GnrH  Precocious puberty (Early puberty; histrelin, leuprolide, and nafarelin only) o High levels estrogen, want decr levels  Anemia associated with uterine leiomyoma (leuprolide only)  Depot formulations that result in gonadotropin suppression and consequent decrease in gonadal steroid production  Can initially increase testosterone and estrogen levels

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AGENTS THAT ALTER GONADOTROPIN EXPRESSION AND INHIBIT OR STIMULATE GONADAL MATURATION AND STEROID PRODUCTION (ends with “relix”)  Ganirelix, Cetrorelix  MOA: Mechanism (ganirelix, cetrorelix)—GnRH receptor antagonists (binds to receptor on pituitary gland) o Decr levels of LH/FSH, eventually decr levels estrogen and testosterone  Inhibition of premature LH surges in women undergoing controlled ovarian hyperstimulation  Controlled ovulation; Prevent premature ovulation  These drugs are GnRH receptor antagonists

AGENTS THAT ALTER GONADOTROPIN EXPRESSION AND INHIBIT OR STIMULATE GONADAL MATURATION AND STEROID PRODUCTION  Follitropin (rFSH), Urofollitropin (FSH)  MOA: Mechanism (FSH)—Stimulate gonadal maturation and steroid production o Signaling more estrogen production, signal ovaries to produce high levels of estrogen. Can use for ovulation induction  IND: o Ovulation induction o Male hypogonadotropic hypogonadism (Produce no sex hormones due to problem with pituitary gland or hypothalamus)  May result in multiple fetuses.  FSH is used to stimulate ovulation for in vitro fertilization  FSH REPLACEMENT THERAPY, not sex hormone therapy o Induce release of sex hormones, however Posterior Pituitary Gland Antidiuretic Hormone (ADH; vesopressin) • Posterior lobe of the pituitary gland secretes only two hormones: antidiuretic hormone (ADH) and oxytocin • Excessive secretion of ADH causes the syndrome of inappropriate ADH (SIADH) • Excessive ADH secretion results in persistent stimulation of V1 and V2 receptors, causing hypertension and excessive water retention • ADH: REABSORBS MORE WATER FROM THE URINE BACK INTO THE BLOOD • SX: HTN, HIGH LEVELS ADH, MORE TRANSPORTERS SYNTHESIZED, WATER REABSORPTION INCR, CAUSING HTN • Inappropriate water retention can result in low extracellular sodium concentration • Still have same amt Na+, but more water in blood VASOPRESSIN RECEPTOR ANTAGONISTS for excessive ADH- Conivaptan, Tolvaptan (ENDS with -VAPTAN) • MOA: Conivaptan: antagonist at V1 and V2 receptors; Tolvaptan: selective V2 receptor antagonist o both drugs prevent vasopressin-stimulated water reabsorption via V2-coupled aquaporin channels in apical membrane of renal collecting duct cells o ADH binds to both V1 and V2 generally **DON’T NEED TO KNOW WHICH BINDS V1/V2** • IND: o Euvolemic and hypervolemic hyponatremia (Level of sodium too low in the blood; shared indications)  High volume, low Na+ levels 8

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o Heart failure (tolvaptan only) Conivaptan is relatively nonselective for V2 and V1 receptors and must be administered IV. Tolvaptan is an orally bioavailable, V2-selective agent. Conivaptan is a P450 3A4 substrate, and it is contraindicated to use this drug concurrently with P450 3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, clarithromycin, and indinavir.

DEFICIENCY OF ADH: NEUROGENIC AND NEPHROGENIC DIABETES INSIPIDUS**** • Diabetes insipidus: A disorder of salt and water metabolism marked by intense thirst and heavy urination o Low levels ADH • Neurogenic diabetes insipidus results from an inability of hypothalamic neurons to synthesize or secrete ADH o Hypothalamus produces ADH (POSTERIOR LOBE)  Hormones synthesized in nerve itself and is released from posterior lobe. No hormone is produced in posterior, only in anterior lobe  POSTERIOR LOBE = STORAGE ONLY o DISEASE: HYPOTHALAMUS NOT PRODUCING ADH o LOW LEVELS ADH SO USE ADH ANALOGUE (DESMOPRESSIN) • Nephrogenic diabetes insipidus results from an inability of renal collecting duct cells to respond to ADH o Kidneys not responding to ADH, but ADH levels are normal VASOPRESSIN ANALOGUE- Desmopressin • MOA: Synthetic analogue of 8-arginine vasopressin (ADH) • IND: o Hemophilia A o Neurohypophyseal diabetes insipidus o Primary nocturnal enuresis o Von Willebrand disease type I • Patients with nephrogenic diabetes insipidus can be treated with diuretics such as amiloride or hydrochlorothiazide o Diuretics help ease excessive urination???? (THAT MAKES NO SENSE)  Could cause mild hypovolemia?????? • Desmopressin stimulates V2 receptors, resulting in concentrated urine and thirst. o Increased urination tx nephrogenic diabetes insipidus (nml ADH, but kidneys not responding) o ADH helps you hold on to water. So more urination, but diuretics increase urination even MORE?????  Why would you be thirsty???  Given desmopressin, more reabsorption of water. In diabetes insipidus, heavy urination??? OXYTOCIN • Oxytocin is a hormone produced by the hypothalamus and secreted by the posterior pituitary gland • It’s a polypeptide hormone secreted from the posterior pituitary gland • Responsible for signaling contractions of the uterus during labor • Increases the production of prostaglandins, which move labor along and increases the contractions even more • Half life of 3-4 mins and duration of action of 20 mins • Drug of choice for labor induction • Mechanism of action: Action mediated by oxyt...