Hypothalamic and Pituitary Pharmacology

Question 1

Releasing (sermorelin) vs. replacement (recombinant GH) therapy in tx of hypo-GH

Answer 1

• Sermorelin (synthetic GHRH) is less effective than recombinant GH and not effective if GH deficient due to pituitary dysfunction.
• Recombinant GH (Somatropin, Somatrem) work indirectly to stimulate synthesis of IGF (aka somatomedins (SM)) which stimulate growth of bones and muscles directly.

Question 2

Tx of GH resistance

Answer 2

• If resistant to GH (mutated receptor), treat with recombinant IGF-1.

Question 3

Drug that stimulates release of GH

Answer 3

sermorelin

Question 4

Drugs that inhibit release of GH

Answer 4

• octreotide = analog of somatostatin
• bromocroptine = DA (D₂) receptor agonist

Question 5

Role of octreotide in GH hypersectretion treatment

Answer 5

• Analog of somatostatin → ↓ GH, glucagon, insulin, TSH release
• Long t1/2
• Selective for GH over insulin,
• subQ injection 3x/day
• Lanreotide is long-acting; IM injections q 10-14d.

Question 6

Role of bromocriptine in GH hypersecretion treatment

Answer 6

• DA receptor (D2) agonist with paradoxical
• ↓ in GH in some patients with acromegaly.
• Possibly best if tumor secretes both GH & PRL.
• Semisynthetic ergot alkaloid. Used for both GH & PRL tumors.
• Dopamine ↓ GH if it is a weird tumor where lactotrophs are secreting GH

Question 7

Structure, pharmokinetics, actions of vasopressin

Answer 7

• Vasopressin: Interacts with V1 and V2 receptors. Administered every 3 days, dosage forms include SC, IM, IV
• V1 coupled to PLC (Gq) →IP3 & DAG → ↑Ca2+ & PKC.
• V2 → Gs → ↑cAMP → ↑PKA → exocytosis of aquaporin-containing vesicles, thus ↑ water reabsorbtion

Question 8

Vasopressin action at V₁ receptors

Answer 8

• V1 coupled to PLC (Gq) →IP3 & DAG → ↑Ca2+ & PKC.
• V1a receptors in vascular smooth muscle mediate vasoconstriction.
• ↑ glycogenolysis, platelet aggregation, ACTH release (V1b), vascular smooth muscle cell growth.

Question 9

Vasopressin action at V2 receptors

Answer 9

• V2 → Gs → ↑cAMP → ↑PKA → exocytosis of aquaporin-containing vesicles, thus ↑ water reabsorbtion
• ↑ Permeability of urea (more concentrated urine) and
• ↑ NaCl transport in thick ascending limb
• ↑ Osmolarity of interstitial fluid in kidney medulla

Question 10

Drugs used to treat DI & SIADH

Answer 10

• DI: hypofunction of vasopressin, excess urine
  
  • Treat with DDAVP, vasopressin (pitressin), chlorpropamide
• SIADH: hyperfunction of vasopressin, dilutional hyponatremia
  
  • treat with demeclocycline (blocks vasopressin-induced cAMP generation)

Question 11

Causes of nephrogenic diabetes insipidus

Answer 11

• Li+ → inhibits cAMP
• Cisplatin, colchicine, gentamycin, rifampin, propoxyphene also cause it
• Chronic hypercalcemia and hypokalemia
• Mutations in receptors or aquaporins

Question 12

Causes of neurogenic diabetes insipidus

Answer 12

• Defective synthesis & release ADH due to
• Pituitary surgery
• Craniopharyngioma
• TBI
• Autoimmune disorders
• Phenytoin
• Idiopathic

Question 13

Drug causes of SIADH

Answer 13

• SSRI’s
• Amiodarone
• Carbemazapine
• Chloropromazine
• Amiltryptiline
• NSAIDS

Question 14

Possible (non-drug) causes of SIADH

Answer 14

• Pulmonary infections and cancer
• Malignancy
• CNS disorders

Question 15

Clinical manifestation of diabetes insipidus

Answer 15

• untreated central DI typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia.
• They may also have neurologic symptoms related to the underlying neurologic disease.

Question 16

Sodium levels in DI

Answer 16

• serum sodium concentration in untreated central DI is often in the high normal range, which is required to provide the ongoing stimulation of thirst to replace the urinary water losses.
• Moderate to severe hypernatremia can develop when thirst is impaired or cannot be expressed.
• This can occur in patients with central nervous system lesions who also have hypodipsia or adipsia, in infants and young children who cannot independently access free water, and in the postoperative period in patients with unrecognized DI.