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Flashcards in Hypothalamic Pituitary Pharmacology Deck (29):
1

Anterior pituitary hormone release

-hypothalamic hormone release under CNS control via NTs
-release of anterior pituitary hormones controlled by hypothalamic hormones
-released from neruons to portal circ to pituitary to systemic circ to act on endocrine glands

(Posterior pit release: synth in hypothal, transport to neruonal terminal in posterior pit, released into circ and act on target tissue directly)

2

Growth hormone (pharm name/info)

-Somatropin
-t1/2 25 mins, peak levels in 2-4 hours, active level persist 36 hours
-can be given SC or IM

3

Release of GH increased by, decreased by

increased by exercise, hypoglycemia, dopamine, L-DOPA, arginine, Ghrelin
-release decreased by somatostatin and decreased by dopamine agonists in acromegaly

4

Does GH work directly or indirectly?

-Indirectly
-Stimulates synthesis of IGF-1 in growth plate cartilage and liver-- linear and skeletal muscle growth
-Produces anabolic and metabolic effects: positive nitrogen balance, increased lipolysis, increased FFA and glucose

5

GH uses

-Replacement therapy in children with deficiency:
given daily at bedtime, SC, or 3x/wk IM
-If GH insensitive (Laron Dwarf), can treat with recombinant IGF-1 (mecasermin), concern w/ hypoglycemia
-Use in idiopathic short stature in kids controversial
-Treatment of poor growth due to Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency
-GH deficiency in adults (most commonly due to pituitary tumor or consequences of its treatment - surgery and/or radiation)
-wasting or cachexia in AIDS patients
-Patients with short bowel syndrome dependent on total parenteral nutrition

Illicit:
-use by athletes to increase muscle mass and improve performance despite lack of controlled studies
-use by healthy elderly for anti-aging effects: small changes in body composition and increased rates of adverse events

6

SE of GH

-generally safe in kids
-nsulin resistance and glucose intolerance may occur
-Slight increased risk for idiopathic intracranial hypertension (pseudotumor cerebri)
-Rarely pancreatitis, gynecomastia, nevus growth
-Misuse in athletes: Acromegaly, arthropathy, visceromegaly, extremity enlargement

7

Off label use of hGH is...

illegal!

8

GHRH pharmacokinetics

IV, intranasal, SC
-Adverse effects: rare, facial flushing (IV), antibody formation with continue use
-Rapidly stimulates GH synthesis and secretion
-Binds to GPCR coupled to Gs, increasing cAMP and Ca2+ levels in somatotrophs
-Ghrelin also stimulates GH release via different GPCR:
secreted by endocrine cells in stomach
stimulates appetite and increased food intake

9

GHRH uses

-diagnostic evaluation of patients with idiopathic GH deficiency
-potential use in GH deficiency children, potentially fewer SE

10

Tesamorelin

GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART), reduces excess abdominal fat

11

Somatostatin

-aka SST, Growth Hormone inhibiting Hormone, Somatotropin Release-inhibiting factor
-present in hypothalamus, NS, gut, endocrine and exocrine glands-- function varies
-Inhibits GH release via GPCR coupled to Gi decreasing cAMP and K+ channels
-Decreases secretion of gastric enzymes and acid- decreased GI motility- suppresses release of serotonin and gastroenteropancreatic peptides
-reduces insulin and glucagon release, complex effects on blood glucose
-interferes with TRH ability to release TSH

12

Somatostatin and analogs

somatostatin:
t1/2 3-4 min limiting therapeutic utility

octeotride: t1/2 90 min (duration 12 hrs); given SC every 6-12 hrs

octeotride (Sandostatin LAR depot) given IM every 4 weeks

Lanreotide: given SQ every 4 weeks

13

Uses of somatostatin analogs

Pituitary: excess growth hormone
Acromegaly (adults) and giagntism (kids)
-surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery
-Long-acting somatostatin analog is preferred pharmacotherapy- utilized after response seen to SC octeotride
-Dopamine agonists may inhibit GH secretion in some pts, but not as effective as SST analogs

Nonpituitary:
Control of bleeding from esophageal varices and GI hemorrhage (constrict splanchnic arterioles)
-Carcinoid tumors, VIP secreting tumors
-Symptoms of WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria)

14

Cabergoline

-preferred agent for adjuvant management of acromegaly with advantage of oral administration

15

Pegvisomant

GH receptor antagonist
-single daily dose, SC

16

SE of somatostatin analogs

-transient detrioration in glucose tolerance (hyperglycemia)
-abdominal cramps
-loose stools
-Cardiac effects: sinus bradycardia and conduction disturbances

17

Prolactin release and actions

-under inhibitory control by hypothalamic dopamine at D2 receptors
-main stim for release is suckling
-Stimulates milk production if appropriate levels of insulin, estrogens, progestins, and corticosteroids are present
-Stimulates proliferation and differentiation of mammary tissue during pregnancy
-Inhibits gonadotropin (FSH/LH) release and/or ovarian response to these hormones - related to lack of ovulation during breastfeeding

18

Uses of Prolactin

-hypoprolactinemia: no preparation available for prolactin deficiency
-Hyperprolactinemia (prolactinomas):
dopamine agonists decrease secretion and reduce tumor size. All available as oral preparations: Bromocriptine
Cabergoline

19

Bromocriptine

-ergot derivative, activates D1 receptors
-frequent side effects include, n/v, HA, postural hypotension, less freq: psychosis, insomnia

20

Cabergoline

-preferred agent for hyperprolactinemia
-more selective for D2 receptor and more effective in reducing prolactin secretion
-better tolerated, less nausea, may cause hypotension and dizziness.
-Concern with higher doses and valvular heart disease (agonist action at 5HT2b receptors)

21

Vasopressin

"ADH"
-parenteral admin
-t1/2 20 mins

22

Desmopressin

ADH analog that is more stable to degradation.
t1/2 1.5-2.5 hrs

23

Pharmacodynamics of vasopressin

-control of water content (distal nephrone and collecting tubules)
-Released from supraoptic nuclei of hypothalamus (stim? rising blood osmolality, decrease in circ blood volume, release inhibited by alcohol)

Renal actions:
-mediated by V2 receptors (GPCR coupled to Gs)
-increase rate of insertion of water channels into luminal membrane, increase water perm, antidiuretic effect.
-activates urea transporters, increase Na transport in distal nephron.
-Non-renal V2 actions include release of coagulation factor VIII and von Willebrand's factor.

24

ADH actions at V1 receptors

-GPCR (Gq)
-vasoconstriction at vascular smooth muscle
-BUT pressor responses occur in vivo only at much higher concentrations than those that produce maximal antidiuresis

25

Cerebral diabetes insipidus and tx

-post pit disease
-head injury, pit tumor, cerebral aneurysm or ischemia; inadequate ADH secretion

Tx: desmopressin
nasally 1-2/d
ADR: nasal irritation
orally 2-3/d
ADRs: HA, nausea, cramps, allergic rxn, water intoxication

Tx Chlorpropamide (1st gen sulfonylurea)
-potentiates action of small or residual amounts of ADH
-option if intolerant to desmopressin

26

Nephrogenic DI

-inadequate ADH actions
Congenital: diverse receptor and aquaporin mutations are known
Drug-induced:
lithium: reduces V2 receptor mediated stim of adenylyl cyclase.
Demeclocyline

Tx:
-low salt, low protein diet
-Thiazide diuretics: paradoxically reduce polyuria of pts with DI
NSAIDs: inhibit PG synthesis because PGs attenuate ADH induced antidiuresis, indomethacin has greatest efficacy

27

SIADH

-syndrome of inappropriate secretion of ADH.
-incomplete suppression of ADH secretion under hypoosmolar conditions
Drugs most commonly implicated:
-Psychotropic agents: SSRIs, haloperidol, TCAD
-sulfonylureas (chlorpropamide)
-Vinca alkaloids chemo
-Methylenedioxy methamphetamine (MDMA)

Tx of hyponatremia:
-restrict free water intake
-Demeclocyline: inhibits ADH effects on distal tubule
-V2 receptor antagonist: Tolyaptan (costly, increases thirst)
Coniyaptan: IV (hospitalized SIADH pts)
WARNING: do not correct hyponatremia too rapidly: cerebellar pontine myelinolysis

28

V1 receptor-mediated uses

-Vasopressin
-attenuates pressure and bleeding in esophageal varices via vasoconstriction of splanchnic arterioles (octeotride preferrred)
-Used as a vasopressor for tx of pts with severe septic shock
-alternative to epi in ACLS for shock refractory ventricular tachycardia/fibrillation

29

V2 receptor mediated uses

-option in nocturnal enuresis- oral desmopressin
-Von Willebrand's disease (elevated vWF) and moderate hemophilia A (elevates factor VIII) -IV desmopressin