Pituitary & Adrenal-Directed Pharmacology

Somatostatin analogs and GH-axis drugs

Octreotide and lanreotide. Native somatostatin has a half-life of only a few minutes. Octreotide (about 2 hours subcutaneously) and lanreotide are stable analogs that bind somatostatin receptors, mainly SSTR2 and to a lesser extent SSTR5, which signal through Gi to reduce cAMP and hormone exocytosis. Monthly depot forms (octreotide LAR, lanreotide) are used for chronic therapy. They inhibit release of GH, TSH, insulin, glucagon, gastrin, VIP and serotonin and constrict the splanchnic circulation, lowering portal pressure.

Uses. Acromegaly when surgery fails or is not possible; carcinoid syndrome flushing and diarrhea, including prevention of carcinoid crisis around procedures; VIPoma watery diarrhea; and acute variceal bleeding. Other uses include sulfonylurea overdose (suppressing insulin release), TSH-secreting adenoma and dumping syndrome. Pasireotide, which binds SSTR5 with high affinity, is used for Cushing disease and acromegaly but causes marked hyperglycemia.

Adverse effects. Suppressed CCK and gallbladder contraction cause sludge and gallstones; reduced pancreatic enzyme secretion causes steatorrhea, cramps and flatulence; and because insulin and glucagon are both suppressed, glucose may rise or fall. Bradycardia and conduction changes, reduced TSH and, with long use, low vitamin B12 also occur.

Pegvisomant. This PEGylated, mutated GH molecule binds the GH receptor but blocks productive signaling, so hepatic IGF-1 production falls and IGF-1 normalizes in most patients with acromegaly. Loss of IGF-1 negative feedback makes GH rise, and GH measurements become uninformative, so therapy is titrated to IGF-1. Liver enzymes are monitored, and because the drug does not act on the adenoma, tumor size is followed by MRI.

Somatropin and mecasermin. Recombinant GH (somatropin) treats GH deficiency in children and adults, Turner syndrome, Prader–Willi syndrome, chronic kidney disease and short stature after small-for-gestational-age birth. Adverse effects include slipped capital femoral epiphysis, pseudotumor cerebri (idiopathic intracranial hypertension), progression of scoliosis, edema, arthralgia and glucose intolerance; active malignancy is a contraindication. In Laron syndrome the GH receptor is defective, so GH is high, IGF-1 is low, and GH injections do nothing. Recombinant IGF-1 (mecasermin) bypasses the receptor; its main risk is hypoglycemia, so it is given with meals, and it can enlarge the tonsils and adenoids.

Dopamine agonists

Mechanism and uses. Dopamine is the physiologic brake on prolactin. Cabergoline and bromocriptine stimulate D2 receptors on lactotrophs (Gi, falling cAMP), reducing prolactin secretion and shrinking most prolactinomas, even macroadenomas compressing the optic chiasm, so medical therapy precedes surgery. Cabergoline has a long half-life, is taken once or twice weekly, is more effective and causes less nausea, and is the first choice; bromocriptine is taken two to three times daily but has a longer safety record in pregnancy. Both are adjuncts in mild acromegaly; bromocriptine is also used in Parkinson disease.

Adverse effects. Nausea (minimized by starting low and taking the dose at bedtime with food), orthostatic hypotension, headache and dizziness are common. More serious are impulse-control disorders (pathologic gambling, hypersexuality, compulsive shopping) and psychosis. Cabergoline is a 5-HT2B agonist, and at the high cumulative doses once used in Parkinson disease it causes fibrotic cardiac valvulopathy. Rapid shrinkage of an invasive macroadenoma can open a path through the sellar floor and cause CSF rhinorrhea.

Posterior pituitary drugs

Desmopressin. Deamination and substitution of D-arginine make desmopressin long-acting and selective for V2 receptors, with little pressor effect. In collecting-duct principal cells, V2 signals through Gs and cAMP to insert aquaporin-2 channels. Desmopressin treats central diabetes insipidus, separates central from nephrogenic DI during water-deprivation testing (urine concentrates only in central DI), and treats primary nocturnal enuresis. The main danger is hyponatremia from water retention.

Desmopressin for bleeding. Endothelial V2 stimulation empties Weibel–Palade bodies, raising plasma vWF and factor VIII several-fold. It controls bleeding in mild hemophilia A, type 1 von Willebrand disease and uremic platelet dysfunction but does nothing for hemophilia B (factor IX) or type 3 vWD, which has no vWF to release. Repeated doses cause tachyphylaxis as endothelial stores run out.

Vasopressin. Vasopressin acts on V1 receptors (Gq, IP3 and calcium, contracting vascular and splanchnic smooth muscle) and V2 receptors. It is added to norepinephrine in vasodilatory septic shock and was historically used for variceal bleeding. Its adverse effects are ischemia of the gut, digits and myocardium, and hyponatremia. By contrast, the vaptans are vasopressin antagonists: tolvaptan (oral, V2) and conivaptan (IV, V1a and V2) raise sodium in euvolemic or hypervolemic hyponatremia.

Adrenal-directed drugs

Steroidogenesis inhibitors. Ketoconazole blocks the top of the pathway: side-chain cleavage (desmolase, CYP11A1), 17,20-lyase and 11β-hydroxylase, lowering both cortisol and androgens. It is hepatotoxic, causes gynecomastia and hypogonadism, strongly inhibits CYP3A4 (drug interactions, QT prolongation) and needs gastric acid for absorption; its enantiomer levoketoconazole is also used for Cushing syndrome. Metyrapone and osilodrostat (oral) and etomidate (IV) block 11β-hydroxylase, the final step to cortisol. 11-Deoxycortisol and DOC accumulate, causing hypertension, hypokalemia and edema, and precursors shunt to androgens, causing hirsutism and acne in women. Etomidate, an anesthetic induction agent, gives rapid control in severe hypercortisolism when oral drugs cannot be used; even one induction dose transiently suppresses cortisol synthesis.

Mitotane. An o,p'-DDD compound related to the insecticide DDT, mitotane damages adrenocortical mitochondria and inhibits steroidogenesis. It treats adrenocortical carcinoma (adjuvant or advanced) and refractory Cushing syndrome. Adrenal insufficiency is expected, and glucocorticoid replacement is needed, often at high doses because mitotane induces CYP3A4 and raises cortisol-binding globulin. Other effects include nausea and diarrhea, neurotoxicity (lethargy, ataxia, confusion) and hypercholesterolemia.

Mifepristone. Rather than lowering cortisol, mifepristone blocks the glucocorticoid receptor (and the progesterone receptor). It controls hyperglycemia in Cushing syndrome when surgery has failed or is not possible. Because feedback is removed, ACTH and cortisol rise, so response is judged by clinical measures such as glucose and weight rather than by cortisol levels; the excess cortisol floods mineralocorticoid receptors and causes hypokalemia and hypertension. It is contraindicated in pregnancy.

Fludrocortisone. A 9α-fluorinated cortisol analog with potent mineralocorticoid activity, fludrocortisone replaces aldosterone in primary adrenal insufficiency and salt-wasting CAH (given with hydrocortisone) and is used for orthostatic hypotension. It is unnecessary in secondary adrenal insufficiency, because renin and angiotensin II still drive aldosterone. The dose is titrated to blood pressure, potassium and plasma renin activity; excess causes hypertension, hypokalemia and edema.