180. Pituitary/Thyroid/Adrenal Pharmacology Flashcards
Vasopressin binds this GPCR that then couples to Gq/PLC
Leads to vascular effects:
- IP3 –> calcium release –> vasoconstriction
CNS effects:
- bonding
- depression
V1 receptor
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)
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
Adverse effects:
- increases in liver transaminases
- lipohypertrophy
- possible loss of negative feedback, resulting in growth of GH-secreting adenomas
- compulsive behavior
Pegvisomant
Desmopressin prefers which receptor over which other one?
V2»_space;» V1
Vasopressin synthetic analog
Desmopressin
Adverse effects:
- arthralgias, myalgias
- peripheral edema
- carpal tunnel
- intracranial HTN
- insulin resistance (sometimes improved sensitivity d/t reduced visceral fat)
GH
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
2 things that negatively regulate GH
Dopamine and somatostatin
Inhibits thyroglobulin proteolysis and hormone release
Adverse effects:
- cross placenta and can cause fetal hypothyroidism
- not useful for long-term treatment
KI
Most toxic steroid synthesis blocker
Used to treat carcinomas
Mitotane
Blocks cholesterol side chain cleavage
Aminoglutethimide
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
Levothyroxine is which thyroid hormone
T4
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
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
Can cause hepatoxicity but is the drug to treat pregnant patients
PTU
Acute loss of adrenal function requires __ w/ salt and water
Glucocorticoids
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
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
Thyroid hormones should be prescribed as:
__ for pregnant patients
__ for elderly and pts w/ CAD
Higher
Lower
For myxedema coma, T3 is administered through __ or else thyroid hormones are orally effective
IV
Used as suppressive therapy after thyroidectomy for malignancy
Thyroid hormones
Adverse effects:
- hypoglycemia
- lipohypertrophy
- intracranial HTN
- slipped epiphyses
- scoliosis
Contraindicated in pts w/ active or suspected neoplasia
- cancer patients
IGF-1 agonists
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
GH
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
