SM_181b: Pituitary/Adrenal/Thyroid Pharmacology Flashcards
Describe basic progression of hypothalamic signaling
Basic progression of hypothalamic signaling
Vasopressin (ADH) is a ____ hormone made in the ____
Vasopressin (ADH) is a peptide hormone made in the posterior pituitary
Vasopressin is secreted in response to ____ or ____ and functions to ____ and ____
Vasopressin is secreted in response to decreased blood pressure and hypertonicity and functions to raise blood pressure and promote water reabsorption
(fluid homeostasis)
Desmopressin is a ____ of vasopressin
Desmopressin is a synthetic long-acting analog of vasopressin
(1-desamino-8-D-arginine vasopressin)
Vasopressin and analogs act through ____
Vasopressin and analogs act through GPCRs
Vasopressin action on V1 receptor involves ____
Vasopressin action on V1 receptor involves coupling to Gq and PLC
- PLC converts PIP2 to DAG and IP3
- Vascular effects: IP3 -> Ca release -> vasoconstriction
- CNS effects: bonding, depression
Vasopressin action on V2 receptor involve ____
Vasopressin action on V2 receptor involve coupling to Gs / adenylate cyclase to increase cAMP and PKA
- Increases water reabsorption from collecting duct through insertion and stabilization of aquaporin-containing vesicles
- Increases factor VIII and VWF
Desmopressin has much ____ antidiuretic / pressor activity than vasopressin and acts preferentially on ____ receptor
Desmopressin has much more antidiuretic / pressor activity than vasopressin and acts preferentially on V2 receptor
Vasopressin is used in treatment of ___
Vasopressin is used in treatment of central diabetes insipidus
- Caused by inadequate secretion of endogenous vasopressin
(also used to stop bleeding from esophageal varices, desmopressin used to stop bleeding in Hemophilia A and von Willebrand’s disease)
Nephrogenic diabetes insipidus is ____
Nephrogenic diabetes insipidus is impaired renal response to vasopressin
- Congenital or drug-induced (lithium)
Nephrogenic diabetes insipidus is treated with ___
Nephrogenic diabetes insipidus is treated with thiazide diuretics
SIADH is treated with ____ such as ____ and ____
SIADH is treated with vasopressin receptor antagonists such as conivaptan and tolvaptan
- Tolvaptan is more selective for V2 receptors and is orally effective but can be hepatotoxic
- Etiology of SIADH: malignancy, head injuries, drugs (psychotropics, sulfonylureas, vinca alkaloids)
Oxytocin is similar in structure to ____
Oxytocin is similar in structure to oxytocin
(9 amino acid peptides)
Oxytocin activates ____
Oxytocin activates GPCRs on smooth muscle for contraction
- Gq -> PLC -> Ca -> calmodulin -> myosin
- Promotes release of prostaglandins and leukotrienes
Oxytocin is used to ____ and ____
Oxytocin is used to induce labor under restricted conditions and control postpartum uterine hemorrhage
- Induce labor under restricted conditions: when early vaginal delivery is complicated (eclampsia), when labor is protracted or arrested
- Hepatic and renal metabolism
Growth hormone is a ____ produced in the ____
Growth hormone is a 191-amino acid peptide produces in somatotropes of the anterior pituitary
Growth hormone is positively regulated by ____ and negatively regulated by ____ and ____
Growth hormone is positively regulated by GHRH and negatively regulated by somatostatin and dopamine
Describe the action of growth hormone
Growth hormone action
- Stimulates longitudinal growth of bone until epiphyseal closure
- Increases muscle mass
- Decreases central adiposity
- Reduces sensitivity to insluin
GH deficiency during childhood / adolescence results in ____, ____, and ____
GH deficiency during childhood / adolescence results in short stature, decreases muscle mass, and increased body fat
GH acts through homodimeric ____ membrane receptors
GH acts through homodimeric tyrosine-kinase linked membrane receptors (JAK)
- JAK causes activation of STAT proteins and subsequent downstream effects
Most of the actions of GH are mediated through hepatic production of ____
Most of the actions of GH are mediated through hepatic production of insulin-like growth factor-I (IGF-I)
- IGF-I synthesis can also be stimulated by other agents
- IGF-I and GH can downregulate GH secretion
____ and ____ are GH agonists
Somatropin and somatrem are GH agonists
- Somatropin: recombinant peptide that is identical to native human GH
- Somatrem: has additional methionine, prolonging half life
Describe uses of GH
GH uses
- Replacement in children with GH
- Other causes of short stature (Turner, Prader-Willi, chronic renal insufficiency, idiopathic short stature)
- Used for AIDS wasting, malabsorption
- Abused as anti-aging remedy
- Illegally used in sports
____ and ____ are IGF-1 agonists
Mecasermin and mecasermin rinfabate are IGF-1 agonists
- Mecasermin: recombinant form of IGF-1
- Mecasermin rinfabate: contains IGF-1 and IGF-1 binding protein IGFBP-3, which prolongs half life
IGF-1 agonists are used to ____
IGF-1 agonists are used to promote growth and normalize metabolism in IGF-1 deficiency resistant to GH
(mecasermin, mecasermin rinfabate)
Acromegally results in ____ leading to ____
Acromegally results in GH excess leading to abnormal growth of bone and cartilage
____, ____, and ____ are drug treatments for GH excess
Somatostatin analog octreotide, GH receptor antagonist pegvisomant, and dopaminergic agonists are drug treatments for GH excess
Octreotide is ____ than somatostatin in inhibiting GH secretion
Octreotide is more potent than somatostatin in inhibiting GH secretion
Otreotide acts through ____ receptors to activate ____ and ____
Otreotide acts through somatostatin receptors receptors to activate K channels and protein phosphotyrosine phosphotases
- Somatostatin receptors: family of GPCRs that couple through Gi
Octreotide acts to ____
Octreotide acts to inhibit GH secretion
- Also inhibits secretion of TSH, ACTH, glucagon, gastrin, insulin
Octreotide is used for ____, ____, ____, and ____
Octreotide is used for acromegaly, other hormone-secreting tumors, secretory diarrhea from chemotherapy, and dumping syndrome after gastric surgery
____ is a long acting analog of octreotide
Lanreotide is a long acting analog of octreotide
(somatostatin analog -> GH antagonist)
Pegvisomant is a ____ that is a ____
Pegvisomant is a modified mutant form of growth hormone that is a GH receptor antagonist
Pegvisomant functions to ____
Pegvisomant functions to allow receptor dimerization but blocks subsequent signaling, preventing activation of JAK-STAT and secretion of IGF-1
(GH receptor antagonist)
Pegvisomant is used to treat ____
Pegvisomant is used to treat acromegaly
____ and ____ are D2 agonists
Bromocriptine and cabergoline are D2 agonists
- GH antagonists
- Semisynthetic ergot alkaloids
Describe the mechanism of bromocriptine and cabergoline
Bromocriptine and cabergoline mechanism
- Selective dopamine D2 receptor agonists
- Mimic effects of dopamine to inhibit GH production and secretion
- Even more effective in inhibiting prolactin
Bromocriptine and cabergoline are used to treat ____ and ____
Bromocriptine and cabergoline are used to treat acromegaly and hyperprolactinemia / galactorrhea resulting from injuries/tumors/drugs
Cabergoline is ____ potent and has ____ half life than bromocriptine
Cabergoline is more potent and has longer half life than bromocriptine
Somatostatin ____ growth hormone
Somatostatin inhibits growth hormone
Thyroid hormones are ____
Thyroid hormones are iodinated dipeptides derived from tyrosine residues on the protein thyroglobulin in the thyroid gland
T4 is ____
T4 is levothyroxine / thyroxin
T3 is ____
T3 is triiodothyronine / liothyronine
Thyroid hormones act through ____ to regulate ____
Thyroid hormones act through nuclear receptors to regulate genes
- Receptor distribution varies: B1 > a1 in liver, a1 > B1 in heart, B2 in hypothalamus, a2 inactive and non-binding
Thyroid hormones act on ____ receptors, which interact with response elements as ____
Thyroid hormones act on nuclear receptors, which interact with response elements as heterodimers (e.g. RXR/TR)
Thyroid hormones are critical for development of the ____ and ____
Thyroid hormones are critical for development of the CNS and skeleton
Perinatal thyroid hormone deficiency can result in ____, ____, and ____
Perinatal thyroid hormone deficiency can result in mental impairment, learning disabilities, and skeletal defects
Describe non-development actions of thyroid hormones
Non-development actions of thyroid hormones
- 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
Describe target genes of thyroid hormones
Target genes of thyroid hormones
- Myelin basic protein: brain development:
- Ca2+ ATPase in skeletal muscle: calorigenic effects
- Ion channel protein in pacemaker: chronotropic effect
- B-adrenergic receptor: potentiate cardiac adrenergic effects
- IGF-I: bone formation
Describe the hypothalamus-pituitary-thyroid axis
Hypothalamus-pituitary-thyroid axis
- TRH (hypothalamus)
- TSH (pituitary)
- T3, T4 (thyroid)
- T3 and T4 negatively regulate TRH and TSH
Thyroid hormones are used as ____
Thyroid hormones are used as suppressive therapy after thryoidectomy for malignancy
Measuring TSH is a sensitive test for determining ____ and ____
Measuring TSH is a sensitive test for determining thyroid hormone status and effectiveness of anti-thyroid therapy
Even though T3 has more favorable pharmacokinetic properties, T4 is the preparation of choice due to ____ and ____
Even though T3 has more favorable pharmacokinetic properties, T4 is the preparation of choice due to more convenient dosage (qd) and lower risk
Thyroid hormone is used to treat ____
Thyroid hormone is used to treat hypothyroidism
- Due to Hashimoto’s thyroiditis, synthetic enzyme defects, destruction of thyroid by medical treatments, and secondary hypothyroidism
Describe effects of thyroid hormone replacement
Thyroid hormone replacement effects
- Metabolic: improve energy metabolism and reproductive function
- Cardiac: inotropic and chronotropic effects
- Hepatic: increase cholesterol metabolism
Thyroid hormone agents selective for ____ have been developed as cholesterol lowering drugs
Thyroid hormone agents selective for TR-beta have been developed as cholesterol lowering drugs (VK2809)
- Hepatic effects on cholesterol metabolism mediated mainly by TR-beta receptors
- Unwanted cardiac effects mediated through TR-alpha receptors
Chronic excess of thyroid hormones can result in ____, ____, ____, ____, ____, and ____
Chronic excess of thyroid hormones can result muscle weakness, anemia, infertility, high output cardiac failure, bone loss, insulin resistance
Some signs of hypothyroidism ____ necessitating caution in use of thryoid hormones
Some signs of hypothyroidism can have other causes necessitating caution in use of thryoid hormones
(lethargy, fatigue, weight gain, infertility)
Hyperthyroidism involves ____
Hyperthyroidism involves hyperplasia in the thyroid
- Diffuse toxic goiter
- Toxic nodular goiter
- Thyroid adenoma
Describe symptoms of hyperthyroidism
Hyperthyroidism symptoms
- Weight loss, excessive swelling, diarrhea, anxiety, headaches
- Palpitations, angina, coronary and cerebral thromboses due to increased beta-adrenergic receptors or enhancement of signaling (cAMP)
Chronic hyperthyroidism can result in ____, ____, ____, ____, ____, and ____
Chronic hyperthyroidism can result in muscle weakness, anemia, infertility, high output cardiac failure, bone loss, and insulin resistance
Describe therapies for hyperthyroidism
Hyperthyroidism therapies
- Surgery
- Radioactive iodine (131I)
- Thioureylene / thionamide anti-thyroid drugs
- Sympatholytic agents
- Potassium iodide
Anti-thyroid therapy targets are ____, ____, ____, and ____
Anti-thyroid therapy targets are oxidation, coupling, proteolysis, and secretion
(prevent formation of T3 and T4)
Describe action of 131I to treat hyperthyroidism
131I to treat hyperthyroidism
- Gamma and beta emitter
- Administered orally, absorption is rapid
- 131I trapped, incorporated, deposited in colloid
- Released beta particles cause necrosis of follicular cells
- Symptoms of hyperthyroidism abate over weeks to months
- Not used in pregnant or nursing women
Methimazole acts by ____
Methimazole acts by inhibiting thyroid peroxidase to block iodination and coupling
Propylthiouracil acts by ____ and ____
Propylthiouracil acts by inhibiting thyroid peroxidase to block iodination and coupling and inhibits peripheral conversion of T4 to T3
Describe sympatholytic therapy for hyperthyroidism
Sympatholytic therapy for hyperthyroidism
- Beta-adrenergic receptor blockers (propranolol, atenolol)
- Control tachycardia, HTN, atrial fibrillation, during acute phase of thyrotoxicosis
- Control BP chronically
- Propranolol is a weak inhibitor of peripheral T4 to T3 conversion
Potassium iodide treats hyperthryoidism by ____
Potassium iodide treats hyperthryoidism by inhibiting thyroglobulin proteolysis and hormone release
Describe adrenal steroid pharmacology
Adrenal steroid pharmacology
- Glucocorticoid and mineralocorticoid uses related to classical actions: to restore physiologic concentrations and conditions
- Glucocorticoid uses related to anti-inflammatory, immunosuppressive, anticancer actions: require supraphysiologic concentrations
Describe mechanism of action of adrenal steroids
Adrenal steroids mechanism of action
- Interact with receptors in cytoplasm
- Release of heat shock protein Hsp90
- Exposes DNA binding domain of receptor
- Allows translocation to the nucleus
- Receptors bind as homodimers
- Interact with response elements
- Regulate target gene transcription
Glucocorticoid receptor can also interact with other transcription factors, which may play a role in _____ effects of glucocorticoids
Glucocorticoid receptor can also interact with other transcription factors, which may play a role in non-endocrine effects of glucocorticoids
Describe metabolic actions of glucocortoids
Glucocorticoid metabolic actions
- Liver: conservation of glucose (promote glycogen synthesis and stimulate gluconeogenesis)
- Connective tissues: decrease protein synthesis, promote protein breakdown -> muscle wasting, skin thinning, osteoporosis
- Adipose: fat redistribution, truncal obesity
Describe non-metabolic actions of glucocorticoids
Glucocorticoid non-metabolic actions
- Kidney: increase Ca excretion, mineralocorticoid activity results in renal NA retention, K and H excretion
- Immune system: decrease Ab production, antigen processing, decrease lymphocytes, cytokines, prostaglandins
- GI: cause thinning of mucus, increase acid and pepsin secretion, decrease Ca absorption
- CNS: euphoria, depression, psychoses, sleep disturbances, decrease threshold for electrical excitation
- Stress response: increase cardiac output, glomerular filtration rate
Addison’s disease presents with ____ and ____ and requires replacement of ____ and ____
Addison’s disease presents with muscle weakness and low blood pressure and requires replacement of glucocorticoids and mineralocorticoids
Acute loss of adrenal function requires ____
Acute loss of adrenal function requires glucocorticoids and salt and water
ACTH deficiency requires ____
ACTH deficiency requires glucocorticoid replacement
Congenital adrenal hyperplasia is when ____, leading to ____ and ____
Congenital adrenal hyperplasia is when a hydroxylase essential for adrenal steroid synthesis is deficient, leading to decreased hydrocortisone / cortisol and insufficient/excess mineralocorticoids and / or androgens
- Treated with adrenal steroids
Pituitary exerts ____ on adrenal
Pituitary exerts negative feedback on adrenal
21-hydroxylase deficiency involves ____, ____, and ____
21-hydroxylase deficiency involves low glucocorticoids and mineralocorticoids, high ACTH, increased secretion of androgens
21-hydroxylase deficiency is treated with ____ and ____
21-hydroxylase deficiency is treated with glucocorticoid and mineralocorticoid replacement
11-hydroxylase deficiency involves ____, ____, and ____
11-hydroxylase deficiency involves low glucocorticoids, high ACTH, and increased secretion of mineralocorticoids and androgens
Adrenal hyperfunction can be ____ or ____
Adrenal hyperfunction can be primary or secondary to increased ACTH
- Primary: adrenal adenoma, carcinoma
- Secondary to increased ACT: pituitary adenoma, ectopic ACTH
Describe drug treatment for adrenal hyperfunction
Adrenal hyperfunction drug treatment
- Mifepristone / RU-486: glucocorticoid receptor antagonist
- Metyrapone: blocks 11-hydroxylase
- Ketoconazole: blocks multiple steps in pathway
- Aminoglutethimide: blocks cholesterol side chain cleavage
- Mitotane: most toxic, used for carcinoma
- Somatostatin analogs: suppress elevated ACTH
ACTH test is used to ____
ACTH test is used to determine etiology of pituitary-adrenal axis hypfunction (low glucocorticoids)
Exogenous ACTH will stimulate adrenal secretion if insufficiency is due to ____ but not ____
Exogenous ACTH will stimulate adrenal secretion if insufficiency is due to inadequate ACTH secretion but not adrenal failure
Metyrapone test is used to ____
Metyrapone test is used to determine etiology of pituitary-adrenal axis hypofunction (low glucocorticoids)
Blocking 11-hydroxylase with metyrapone will ____, leading to ____ and ____
Blocking 11-hydroxylase with metyrapone will decrease glucocorticoid production, leading to decreased negative feedback and increased ACTH secretion
- Used to determine extent to which pituitary is stimulated
Dexamethasone is used to ____
Dexamethasone is used to determine etiology of pituitary-adrenal axis hyperfunction (high glucocorticoids)
- Dexamethasone is potent glucocorticoid that will not interfere with assays for endogenous glucocorticoids
- Used to test whether response is repressible
- Will usually suppress ACTH from pituitary adenomas but not ectopic ACTH
Describe clinical uses of glucocorticoids
Glucocorticoid clinical uses
- Anti-inflammatory and immunosuppressive actions: decreases cytokine and prostaglandin synthesis, WBCs, antibody production and antigen processing, scar formation
- Anti-cancer actions (as chemotherapeutic agents): decrease lymphocytes, promote differentiation
Describe desirable and undesirable effects of glucocorticoids at pharmacological doses
Desirable and undesirable effects of glucocorticoids at pharmacological doses
- Desirable: anti-inflammatory, immunosuppressant, promote differentiation
- Undesirable: more glucocorticoid-mediated mineralocorticoid activity, sodium retention, hypertension
Glucocorticoids are most often bound to ___ and most frequently inactivated in the ___
Glucocorticoids are most often bound to CBG and most frequently inactivated in the liver
Describe adverse effects of glucocorticoids
Glucocorticoid adverse effects
- Hypokalemic alkalosis
- Glycosuria
- Susceptibility / masking infection
- Ulcers
- Myopathy
- Osteoporosis
- Hypercoagulability
- Psychoses
- Glaucoma
- Reproductive disturbance
- Adrenal insufficiency after steroid withdrawal
Preventing ___ in steroid withdrawal may be helpful
Preventing adrenal insufficiency in steroid withdrawal may be helpful
