180. Pituitary/Thyroid/Adrenal Pharmacology Flashcards by Michael Peabody

Vasopressin binds this GPCR that then couples to Gq/PLC

Leads to vascular effects:
- IP3 –> calcium release –> vasoconstriction

CNS effects:

bonding
depression

V1 receptor

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Can be used for its anti-cancer actions:

decrease lymphocytes
can promote cancer cell differentiation

Used in combination w/ chemo of hematologic malignancies

Prednisone (glucocorticoids)

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Modified mutant form of GH that acts as a GH receptor antagonist

Allows receptor dimerization but blocks subsequent signaling, thus prevents activation of JAK-STAT pathway and secretion of IGF-1 from liver

Used to treat acromegaly

Pegvisomant

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Adverse effects:

increases in liver transaminases
lipohypertrophy
possible loss of negative feedback, resulting in growth of GH-secreting adenomas
compulsive behavior

Pegvisomant

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Desmopressin prefers which receptor over which other one?

V2&raquo_space;» V1

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Vasopressin synthetic analog

Desmopressin

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Adverse effects:

arthralgias, myalgias
peripheral edema
carpal tunnel
intracranial HTN
insulin resistance (sometimes improved sensitivity d/t reduced visceral fat)

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Act mainly through nuclear receptors to regulate genes
- interact with response elements as heterodimers

B1: liver
B2: hypothalamus
Alpha-1: heart
Alpha-2: inactive binding form

Thyroid hormones

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2 things that negatively regulate GH

Dopamine and somatostatin

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Inhibits thyroglobulin proteolysis and hormone release

Adverse effects:

cross placenta and can cause fetal hypothyroidism
not useful for long-term treatment

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Most toxic steroid synthesis blocker

Used to treat carcinomas

Mitotane

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Blocks cholesterol side chain cleavage

Aminoglutethimide

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Gamma and beta emitter

Administered orally; absorption is rapid

Trapped, incorporated, deposited in colloid

Released beta particles cause necrosis of follicular cells

Half life is 8 days, which most gone by 2 months

Synthesis needs to be blocked so that there is no release of radioactive hormone and precursors

Not used in pregnant or nursing women

I-131

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Levothyroxine is which thyroid hormone

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GH antagonist that is more potent than somatostatin in inhibiting GH secretion

Acts through somatostatin receptors, GPCRs that use Gi

Activates K+ channels and protein phosphotyrosine phosphates

Short duration, requires multiple doses per day through IV or SC

Long acting analog = lanreotide

Octreotide

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Used to determine the etiology of hypofunction (low glucocorticoids)

Blocking 11-hydroxylase will decrease glucocorticoid production, thus decreasing negative feedback, and increasing ACTH secretion

Used to determine the extent to which the pituitary can be stimulated
- manipulating feedback pathway

Metyrapone test

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Can cause hepatoxicity but is the drug to treat pregnant patients

PTU

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Acute loss of adrenal function requires __ w/ salt and water

Glucocorticoids

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Used to induce labor under restricted conditions:

when early vaginal delivery is indicated (eclampsia)
when labor is protracted or arrested

Control postpartum uterine hemorrhage

Oxytocin

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Liver:
- promote conservation of glucose (glycogen synthesis); stimulate gluconeogenesis (insulin antagonistic effect)

CT:
- decerase protein synthesis, promote protein breakdown resulting in muscle wasting, thinning of skin, osteoporosis

Adipose tissue:
- fat redistribution, truncal obesity

Glucocorticoids

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Thyroid hormones should be prescribed as:
__ for pregnant patients

__ for elderly and pts w/ CAD

Higher

Lower

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For myxedema coma, T3 is administered through __ or else thyroid hormones are orally effective

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Used as suppressive therapy after thyroidectomy for malignancy

Thyroid hormones

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Adverse effects:

hypoglycemia
lipohypertrophy
intracranial HTN
slipped epiphyses
scoliosis

Contraindicated in pts w/ active or suspected neoplasia
- cancer patients

IGF-1 agonists

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Type of CAH Low glucocorticoids High ACTH Increased secretion of mineralocorticoids and androgens Steroid replacement of glucocorticoid

11-hydroxylase deficiency

Used for: - replacement in children w/ GH deficiency - Other causes of short stature: Turner's, Prader-Willi, Chronic renal insufficiency, idiopathic short stature) - AIDS-wasting or malabsorption

GH treatment

Vasopressin receptor antagonists used to treat SIADH

Conivaptan and tolvaptan | - tolvaptan is more selective fo V2 receptors but can be hepatotoxic

Adverse effects: - nausea and bloating - gallstones - bradycardia (affects cardiac conduction)

Octreotide

Promote growth and normalize metabolism in IGF-1 deficiency resistant to GH

Mecasermin (IGF-1 agonist)

Control tachycardia, hypertension, A-Fib, during the acute phase of thyrotoxicosis Control BP chronically Weak inhibitor of peripheral T4 --> T3 conversion

Propranolol

Secreted in response to decreased blood pressure and hypertonicity (hypernatremia) Raises BP and promotes water reabsorption Master regulator of fluid homeostasis

Vasopressin (ADH)

Vasopressin receptor that increases factor VIII and vWF

V2 receptor

Activates GPCRs on smooth muscle for contraction - Gq --> PLC --> Ca2+ - calmodulin - myosin Promotes release of prostaglandins and leukotrienes - important for smooth muscle control

Oxytocin

Adverse effects: - uterine rupture, fetal distress - activation of vasopressin receptors at high dose d/t structural similarity

Oxytocin

Therapies for __: - surgery to resect glands - I-131 radiation - thionamides - sympatholytic agents (Beta-blockers) - KI

Hyperthyroidism

Used to determine the etiology of hypofunction (low glucocorticoids) Exogenous ACTH will stimulate adrenal secretion if the adrenal insufficiency is due to inadequate ACTH secretion (pituitary insufficiency), but not if the insufficiency is d/t adrenal failure

ACTH test

Contains IGF-1 and the IGF-1 binding protein IGFBP-3, which prolongs the half-life

Mecasermin rinfabate

Used to stop bleeding in hemophilia A and von Willebrand's disease

Desmopressin

Treatment of central diabetes insipidus Stop bleeding from esophageal varices

Vasopressin

Stimulates longitudinal growth of bone until epiphyseal plate closure Increases muscle mass Decreases central adiposity Reduces sensitivity to insulin

Growth hormone

Most glucocorticoids are inactivated in the __

Liver

Most common treatment of adrenal hyperfunction (2 things) Can be primary - adrenal adenoma, carcinoma - or secondary to increased ACTH - pituitary adenoma, ectopic ACTH

Surgery or radiation

Adverse effects: - weight loss - excessive sweating - diarrhea - anxiety - headaches - palpitations, angina - coronary and cerebral thromboses Chronic excess can result in muscle weakness, anemia, infertility, high output cardiac failure, bone loss, insulin resistance

Thyroid hormones

Adrenal steroids interact with receptors in the cytoplasm, resulting in the release of __ This exposes the DNA binding domain of receptor and allows translocation to the nucleus

Hsp90

T4 is the preparation of choice in most situations: why?

``` More convenient dosage (QD - longer half-life) Lower risk (less potent) ```

Inhibits: - GH secretion - TSH secretion - ACTH secretion - glucagon secretion - gastrin secretion - insulin secretion Uses: - acromegaly - other hormone-secreting tumors - secretory diarrhea from chemo - "dumping syndrome" after gastric surgery

Octreotide

Can be used for anti-inflammatory and immunosuppressive actions: - decrease synthesis of prostaglandins and leukotrienes (inflammatory cytokines) - decrease lymphocytes, monocytes, eosinophils, basophils - decrease Ab production and Ag processing - decrease scar formation Useful in palliative treatment of RA, lupus, and other systemic and local inflammatory disorders

Hydrocortisone

Recombinant peptide that is identical to native human GH and used to treat GH deficiency

Somatropin

Semisynthetic ergot alkaloids Mechanism: - selective dopamine D2 receptor agonists - mimic effects of dopamine to inhibit GH production and secretion - even more effective in inhibiting prolactin

Cabergoline and bromocriptine

Treatment for nephrogenic diabetes insipidus - can be caused congenitally or by drugs like lithium - decreases urine output through a paradoxical path

Thiazides

ACTH deficiency requires __ replacement

Glucocorticoid

Glucocorticoid receptor antagonist

Mifepristone

Addison's disease: - characteristics include muscle weakness and low BP - requires replacement of what??

Mineralocorticoids and glucocorticoids

Adverse effects: - undesired vasoconstriction, especially in pts w/ CAD - nausea, abdominal cramps, HAs, and allergic reactions

Vasopressin

Recombinant form of IGF-1

Mecasermin

Critical for development of the CNS and skeletal system Metabolic: optimize energy metabolism and reproductive function Cardiac: inotropic and chronotropic effects; potentiate effects of sympathomimetic amines Hepatic: increase cholesterol metabolism; effects on glucose metabolism cause insulin resistance Skeletal: possibly promote osteoporosis

Thyroid hormones

GH acts through homodimeric __-__ linked membrane receptors JAK is then activated which activates STAT proteins --> go to nucleus to be transcription factors

tyrosine-kinase

Steroids need to be tapered off after the drug is no longer needed to control symptoms to avoid __ __ Can ruin the feedback system overall and the pituitary will no longer secrete ACTH

Adrenal insufficiency

Type of CAH Low glucocorticoids and mineralocorticoids High ACTH Increased secretion of androgens Steroid replacement of mineralocorticoids and glucocorticoids

21-hydroxylase deficiency

Adverse effects: - pruritic rash, arthralgia most common - agranulocytosis

Thionamides

Uses: - acromegaly - hyperprolactinemia and galactorrhea Orally effective

Cabergoline

Uses related to anti-inflammatory, immunosuppressive, anticancer actions requires supraphysiologic concentrations

Glucocorticoids

Used to determine the etiology of hyperfunction (high glucocorticoids) Potent glucocorticoid is used that will not interfere with assays for endogenous glucocorticoids to test whether the response is suppressible Test will usually suppress ACTH from pituitary adenomas, but not ectopic ACTH

Dexamethasone Test

Abnormal growth of bone and cartilage is characteristic of __ Treatments include surgery, radiation, and drugs

Acromegaly

__ deficiency during childhood and adolescence results in short stature, decreased muscle mass, and increased body fat

Blocks multiple steps in the steroid synthesis pathway

Ketoconazole

Kidney: - increase calcium excretion Immune system: - decrease antibody production, antigen processing, decrease lymphocytes, cytokines, and prostaglandins GI: - cause thinning of mucus, increase acid and pepsin secretion, decrease calcium absorption

Glucocorticoids

Adverse effects: - nausea and vomiting - HA - orthostatic hypotension - rare effects: nasal congestion, digital vasospasm, hallucinations, psychoses, nightmares, congestion - has been associated with valvular heart disease

Cabergoline

Vasopressin binds this GPCR that then couples to Gs/adenylate cyclase, increase cAMP, PKA Increases water reabsorption from collecting duct through insertion and stabilization of aquaporin-containing vesicles (Aquaporin 2)

V2 receptor

Blocks 11-hydroxylase

Metyrapone

Inhibit TPO, blocking iodination and couplng __ also inhibits peripheral conversion of T4 to T3 Slow onset, 3-4 weeks, because stored hormone can still be released

Thionamides (methimazole and PTU) | PTU

GH analog with an additional methionine which prolongs its half-life

Somatrem

Most of the actions of GH are mediated through hepatic production of __ - can also be stimulated by other agents - __ and GH can down-regulate GH secretion

IGF-1