Santos's Lectures Flashcards
Anterior Pituitary (adenohypophysis)
-INDIRECT connection w/ hypothalamus
Posterior Pituitary (neurohyphysis)
-DIRECT connection w/ hypothalamus
which 2 hypothalamic factors do NOT have any inhibitory factors?
-CRH and GnRH
Growth Hormone (GH) -aka somatotropin
- effects mediated through IGF-1 and IRS-1
- measure IGF-1 levels to look at GH levels***
-used for BONE and muscle growth, decrease fat
-pulsatile secretion at night
-
what is an inhibitor of GH used for acromegaly and gigantism?
-somatostatin and dopamine
what are the 2 somatostatin analogs?
-Octreotide and Lanreotide
Pegvisomat
-GH receptor antagonist -> blocks receptor activation but not secretion
what condition is associated w/ failed IGF-1 release?
Laron Dwarfism
GH vs IGF-1
- GH -> REDUCES insulin sensitivity -> diabetes
- IGF-1 -> insulin-like effects -> GLUT4 transporters
Somatropin
- rhGH
- targets GH receptor
- used for Noonan, prader-willi, turner syndromes
- used w/ wasting syndromes in HIV ptxs or short bowel syndrome
Mecasermine
- IGF-1 analog -> IGF-1 production at GH receptor sites
- AE -> HYPOGLYCEMIA
Prolactin
- blocked by DOPAMINE -> binds to D2 receptors on lactrotrophs
- TRH and VIP stimulate release
- lactation in mammary gland -> growth of ducts/lobules
- NOT under feedback control of peripheral hormones
Bromocriptine
-also pergolide, cabergoline, quinagolide
- dopamine receptor agonists -> blocks HYPERPROLACTINEMIA
- bind to D2 receptors on lactotrophs
-also used for Parkinson’s disease
GnRH aka Gonadorelin
-release of LH, FSH
-used for hypogonadotropic hypogonadism
-used for INFERTILITY
-
function of LH
- target theca cells -> androstenedione
- target leydig cells -> testosterone
function of FSH
- target granulosa cells -> growth of follicle and activate aromatase
- target Sertoli cells -> sperm maturation
what enzyme converts androgens to estrogen?
aromatase
intermittent (pulsatile) vs. continuous secretion of GnRH
- pulsatile GnRH release -> increase LH, FSH
- continuous GnRH release -> inhibit LH, FSH
analogs of GnRH
- Leuprolide
- GnRH
- Goserelin
- Nafarelin
- Triptorelin
-NOT used if pregnant
antagonists of GnRH
- Ganarelix
- Cetrorelix
- Abarelix
hCG
- made in placenta
- mimics LH -> acts on LH receptor
- diagnosis of PREGNANCY**
ACTH
-made from POMC** -> produces cortisol in adrenal cortex
Cosytropin
-synthetic form of ACTH
TRH
- produce T3 (more acitve) and T4 (high levels, long lasting)
- treat hypothyroidism
what enzyme converts T4 to T3?
-iodothyronin 5’-Deiodinase
stages of disease**
- primary -> LOCAL effects at target organs
- secondary -> PITUITARY related
- tertiary -> HYPOTHALAMUS related
where are the hormones in the posterior pituitary synthesized?
supraoptic and paraventricular nucleus of HYPOTHALAMUS
-stored in post. pituitary
only 2 hormones of posterior pituitary
oxytocin and ADH (vasopressin)
Vasopressin (ADH)
- regulated plasma VOLUME and OSMOLALITY
- osmoreceptors in post. pituitary and hypothalamus
Desmopressin (DDAVP)
- ADH analog
- treatment of NEUROGENIC diabetes insipidus
2 types of ADH receptors
V1 -> at arterioles for vasoconstriction; GpPCR
V2 -> at CD for H2O reabsorption; GsPCR; up regulate aquaporins
extra renal V2 receptors
release of factor 8 and vWF -> hyper coagulation
SIADH
- caused by small cell lung cancer
- treat w/ hypertonic saline or ADH antagonist
Diabetes Insipidus
Neurogenic -> no ADH secretion
Nephrogenic -> decrease response to ADH
LITHIUM can be cause
Conivaptan
- inhibit V1, V2 receptors
- for euvolemic and hypervolemic hyponatremia
- treat SIADH
Oxytocin
- for uterine contraction and milk ejection
- SMALL dose -> increase frequency and force of contraction
- LARGE dose -> sustained contraction
- LOVE HORMONE (chemical messenger)
-diagnosis: oxytocin challenge test
what happens with a really high [] of oxytocin?
+ ADH receptors
-antidiuretic and pressor activity
CYP17 (17alpha-hydroxylase)
enzyme used to form testosterone
steroid hormone binding globulin (SHBG)
-binds testosterone and estradiol for circulation
aromatase (aka CYP19)
testosterone -> estradiol
- aromataziation of the A ring
- A ring binds to ER-a and ER-b
5alpha-reductase
testosterone -> DHT
-Finasteride inhibits
how do you treat androgen deficiency?
Testosterone Ester (IM) -lasts longer and bypasses 1st pass metabolism
AR mutation associated w/ androgen deficiency?
Kennedy disease
androgens that are alkylated at 17 alpha position
- ORAL
- HEPATOTOXIC
- slower metabolism
reasons for using androgens
- male hypogonadism
- athletic performance (DHEA, androstenedione)
- gynecologic disorders
androgen side effects
- MASCULINIZATION
- men: gynecomastia, azoospermia/small testicles w/ large doses
- women: hirsutim, amenorrhea
use of anti androgens
-excess testosterone -> prostatic carcinoma and hirsutism
Testosterone Enanthate
- ester
- synthetic androgen -> binds to AR
Methyltestosterone and Fluoxymesterone
- alkylated
- binds to AR
- ORAL and HEPATOTOXIC
Flutamide
- ANTIANDROGEN
- inhibits androgen binding to AR
- for prostate cancer
- HEPATOTOXIC
- Monitor INR if used w/ WARFARIN
what is the most potent estrogen?
17-beta estradiol > estrone and estriol
regulation of estrogen
- GnRH from hypothalamus
- LH, FSH from ant. pituitary
primary uses for estrogen
- primary hypogonadism
- post-menopause
one of the main reasons estrogen is contraindicated?
thromboembolic disorders or liver disease
Tamoxifen and Toremifene
- SERM
- treat BREAST cancer
Raloxifene
- SERM
- treat OSTEOPOROSIS
Clomiphene
- SERM
- treat INFERTILITY
Fulvestrant
- estrogen ANTAGONIST
- treat BREAST cancer
Exemastane and Formestane
- aromatase inhibitors
- STEROIDAL
- type I-IRREVERSIBLE AI
Anastrozole and Letrozole
- aromatase inhibitors
- NON-STEROIDAL
- type II-REVERSIBLE AI
Progestins (progesterone)
- PR-A, PR-B receptors
- produced during LUTEAL phase -> decrease GnRH pulses -> reset HP axis
- decrease sperm penetration
- reduces aldosterone effects
Mifepristone
- antagonist of progresterone and glucocorticoid receptors
- terminate early pregnancy
-also effective post-coital
Ulipristal
- selective progesterone receptor modulator -> partial agonist to PRs
- EMERGENCY CONTRACEPTIVE
most common form of contraception
- MONOPHASIC (constant dose of both estrogen and progestin)
- fewer side effects
-estrogen + progestin -> suppress ovulation
what disorder is associated with methylation of the oxytocin receptor gene?
autism
MOA of oxytocin muscle contraction
+ PLCbeta-IP3-Ca2+ path -> + Ca2+ channels -> calmodulin -> + MLCK -> phosphorylate myosin -> contraction
more uterine contractions by stimulating prostaglandins and leukotrienes
Dinoprostone (PGF2alpha)
-oxytocic
Misoprostol (PGE1)
-oxytocic
- for cervical ripening and early pregnancy termination
- AE -> MISCARRIAGE, UTERINE RUPTURE**
- black box: can cause birth defects, abortion, premature birth, uterine rupture in pregnancy women**
Terbutaline
-tocolytic
- Adrenergic agonist (B2 selective) -> inactive MLCK
- OFF LABEL
Ritodine
B2 agonist
-only tocolytic to gain FDA approval
Nifedipine
- tocolytic
- Ca2+ channel blocker -> inhibit Ca2+ influx
Atosiban
- tocolytic
- oxytocin receptor antagonist
Iodide
- charged, inorganic
- LOW levels -> T4 synthesis
- HIGH levels -> inhibit T4 synthesis/release
TPO
- takes iodide -> iodine
- organification -> DIT, MIT
- coupling -> T3, T4
ratio of T4 to T3
5: 1
- more T4 in circulation
- T3 is active and potent
5’ Deiodinase
converts T4 -> T3 in peripheral tissues
what 2 domains does T3 bind to in the nucleus?
- TR-DBD -> + TRE
- TR-LBD -> binding of T3
-bind domains -> expression at TRE
does T3 or T4 bind to the nuclear receptors?
T3***
thyroid hormone effects on SNS
-SNS overactivity -> increase # of adrenergic beta receptors and amplifies signaling
Levothyroxine (T4)
- for hypothyroidism
- thyroid replacement and suppression therapy
-Tirosint less affected by gastric pH or coffee
Liothyronine (T3)
- NOT replacement therapy
- for short term TSH suppression
how should T4 be administered?
on EMPTY stomach -> food interferes w/ absorption
Methimazole
-treat hyperthyroidism
- 10x more potent than PTU
- 2nd-3rd trimester pregnancy
- NO liver damage, unlike PTU
Propylthiouracil (PTU)
-treat hyperthyroidism
- 1st trimester pregnancy
- AE -> HEPATITIS**
Radioactive iodine (RAI)
-treat hyperthyroidism
- 131 I***
- contraindicated in PREGNANCY
- if ptx has heart disease -> treat with methimazole
other adjunct therapy for hyperthyroidism
- B-blocker -> propanolol, metoprolol
- diltiazem
- barbiturates
- bile acid sequestrates (chelestyramine)
enzymes that make aldosterone
CYP11B2
enzymes that make cortisol
CYP11B1 and CYP17
enzymes that make androgens
CYP17
cortisol binding globulin (CBG)
transports corticoids (aldosterone and cortisol) -higher affinity for cortisol
rate limiting enzyme in steroidogenesis
CYP11A1** (cholesterol side chain cleavage)
Ketoconazole
- inhibit CYP11A1 and CYP17,20 lyase
- used for hypercortisolism
Trilostane
-inhibit 3B-OHSD
Metyrapone
-inhibit 11B-hydroxylase -> sift to androgen path
main effects of cortisol
- LIBERATE ENERGY for heart and brain
- adapt to stress/starvation
- osteoclast
- Na+ retention
- lung maturation
- initiate lactation
- inhibit PLA2*** -> no conversion to AA, prostaglandins, leukotrienes
Cushingoid Syndrome
-BUFFALO hump, MOON facies, OSTEOPOROSIS, HTN
Glucocorticoid deficiency
Hyperpigmentation (no cortisol -> excess ACTH)
the 2 long acting glucocorticoids - anti-inflammatory action
- Betamethasone (active 25-40hr.)
2. Dexamethasone (active 30 hr.)
Glucocorticoid w/ mineralcorticoid properties***
FLUDROCORTISONE***
- Salt-retention
- mineralcorticoid replacement
causes of Addison’s disease
AUTOIMMUNE or TB**
Cosytropin
- synthetic ACTH
- diagnostic b/w primary and secondary adrenal insufficiency
Hydrocortisone
- synthetic form of cortisol
- 2/3 dose in morning, 1/3 dose in evening
- treat 1ry and 2ry adrenal insufficiency
Betamethasone, hydrocortisone, beclomethasone, dexamethasone, Triamcinolone
TOPICAL anti-inflammatory
- Fluorinated -> better skin penetration***
- SKIN-LIGHTENING cosmetics
drug used to treat Cushing disease
Dexamethasone
drug used for integrity of HPA axis
Metopirone
drugs used for adrenal insufficiency and ectopic ACTH production
Cosyntropin
primary hyperaldosteronism (Conn’s syndrome)
adrenal tumor
secondary hyperaldosteronism
activation of RAS
Deoxycorticosterone (DOC)
- precursor to aldosterone
- secretion under control of ACTH
Cabergoline
- D2 receptor agonist -> decrease ACTH, PRL secretion
- treat ACTH & PRL over secretion
Corticorelin
- synthetic CRH
- diagnostic to distinguish b/w Cushing from ectopic ACTH
Etomidate
inhibits CYP11B1
- anesthetic
- decrease cortisol production at sub-anesthetic doses
Mitotane
-inhibits CYP11A1 -> treat adrenocortical carcinoma
Mifepristone
- GR antagonist
- treat hypercortisolism and anti-progesterone effect to terminate pregnancy
the 2 mineralcorticoid antagonists
- Spironolactone**
- K+ sparing diuretic
- treat primary aldosteronism
- also androgen antagonist -> treat hirsutism and acne - Eplerenone
- treat HTN, HF
- more selective
what is the active form of vit. D?
Calcitriol** aka 1,25-dihydroxyvit. D
- 1st hydroxylation in LIVER
- 2nd hydroxylation in KIDNEY
Teriparatide and Abaloparatide
- recombinant PTH 1-34
- treat osteoporosis
rhPTH 1-84 (full-length PTH)
-treat hypoparathyroidism
Raloxifene
- SERM
- beneficial on bone w/o increased risk for breast/endometrial cancer
Etidronate, Pamidronate, Alendronate…“-dronate”
- bisphosphonates
- give on EMPTY STOMACH
- not given w/ renal issues
- treat osteoporosis
Denosumab
- monoclonal Ab -> inhibit RANKL
- treat osteoporosis
- risk of infection, osteonecrosis, hypocalcemia
- can use in renal disease
Hydrochlorothiazide
- diuretic -> block Na2+ reabsorption
- enhance Ca2+ reabsorption -> treat Ca2+ oxalate stones**
Cinacalcet
- activates CaSR -> reduce PTH
- treat secondary hyperparathyroidism and parathyroid carcinoma
