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282 Cards in this Set
- Front
- Back
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Heat Shock Proteins
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Steroid Hormone Receptors in Cytoplasm are sequestered by Heat Shock Proteins. Hormones displace HSPs and translocated to nucleus.
Hormones tha tdo this: glucocorticoirds, mineralcorticoids, androgens, progesterone & estrogens |
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Thyroid hormone receptor family
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thyroid hormone receptors
retinoic acid receptors estrogen receptor vitamin D receptors located in cytoplasm, mediate translocation to nucleus upon binding |
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Production and Storage of Hormones
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Protein/Peptide produced & stored in secretory vesicles
With Steroid Hormones synthesis = release; all synthesis is regulated by the conversion of cholesterol to pregnenlone; the final hormone produced depends on what downstream enzymes are present; thyroid hormones are lipophilic, but are stored in thyroglobulin, released 2* to upstream signals |
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Oral/Non Oral Hormones
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Peptide Hormones would be digested, cannot be oral
Steroid & Thyroid hormones lipophlic, may be oral |
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Prolactin:
regulation, fnx, clincial use |
Tonic inhibition by DA from median eminence of hypothalamus
secretion stimuli: physical/emotional stress, suckling, TRH, phenothiazine DA antagonists (classical antipsychotics) stimulates milk production if levels of estrogen, progesterone, corticosteroids & insulin at appropriate levels no clinical use for prolactin |
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Bromocriptine
Indications/Effects, Pharmacokinetics, Side Effects, Contraindications |
DA agonsist; DA from median eminience of hypothalamus tonically inhibits prolactin.
Tx pituitary prolactinomas when surgery fails [Used to inhibit lactation, prevent breast engorgement, tenderness paraxodically decreases GH secretion from GH secreting adenomas] Dosing is 1/day Side effects: nausea, lightheadedness, orthostatic hypotension, fatigue, psychosis contraindicated in pregnant women without prolactinoma Cabergoline longer λ, more effective, better tolerance |
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most common pituitary adenoma
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prolactinoma
50% cure rate with surgery Rx: DA agonists inhibit prolactin secretion DOC: Cbergoline more effective, longer λ, better toelrance |
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Cabergoline
Indications/Effects, Pharmacokinetics, Side Effects, Contraindications |
DA agonsist; DA from median eminience of hypothalamus tonically inhibits prolactin.
Tx pituitary prolactinomas when surgery fails [Used to inhibit lactation, prevent breast engorgement, tenderness paraxodically decreases GH secretion from GH secreting adenomas] Dosing is 1/week Side effects: nausea, lightheadedness, orthostatic hypotension, fatigue, psychosis contraindicated in pregnant women without prolactinoma Cabergoline longer λ, more effective, better tolerance than Bromocriptine |
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GH axis
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Hypothalamus releases GHRH--inhibited by somatostatin
GH aka "somatotropin": 191 AA peptide; target ts: bone, liver, adipocyte, muscle --> release IGF-1; IGF-1: RTK → anabolic growth ↑ longitudinal bone growth, minearal density in bones ↑ Hepatic GNG, Adipocytic lipolysis ↑ muscle mass ↓ glucose utilization (anti-insulin) IGF-1 decreases GHRH & GH release |
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Somatotropin
Mechanism, Uses, Pharmacokinetics, Side Effects, Contraindications |
native recombinant human Growth Hormone
Used for treating growth failure mainly in children w/ GH deficiency PhKS.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism [Also used for: Cachexia, increased well being in adults w/ GH deficiency, improved bowel fnx in adults with short bowel syndrome, growth failure from chronic renal diseases & the partial GH resistance of Turner syndrome] [Addt'l side effects: injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria] [Addt'l contraindications: 1/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma] |
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Somatotrotrem
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somatotropin + methionine residue at N+ terminus
Used for treating growth failure mainly in children w/ GH deficiency PhKS.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism [Also used for: Cachexia, increased well being in adults w/ GH deficiency, improved bowel fnx in adults with short bowel syndrome, growth failure from chronic renal diseases & the partial GH resistance of Turner syndrome] [Addt'l side effects: injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria] [Addt'l contraindications:w/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma] |
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Sermorelin
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Synthetic GHRH
Not as effective as GH therapy Used diagnostically |
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Mecasermin
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Recombinant human IGF-1:
not as effective as GH Rx's somatotropin/somatorem, but effective in pts with GH receptor or IGF-1 KO mutations. PhK: 2x/day injx SE's: hypoglycemia & cellular proliferation because it is unbound + GH side effects {Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism [injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria]} CI's: Same as GH {DM, Hypothyroidism [w/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma]} Mecasermin rabinifate is better but has lost the patent suite |
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Mecasermin rabinifate
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Recombinant human IGF-1 + IGF Binding Protein 3 to ↑λ
not as effective as GH Rx's somatotropin/somatorem, but effective in pts with GH receptor or IGF-1 KO mutations. PhK: 1x/day injx SE's: GH side effects {Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism [injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria]} CI's: Same as GH {DM, Hypothyroidism [w/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma]} Mecasermin rabinifate is better but has lost the patent suite |
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Mecasermin vs Mecasermin rabinifate
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Mecasermin rabinifate lost the patent suit and must now be used off label
Mecasermin = IGF-1 Mecasermin rabinifate = IGF-1 + IFG Binding Protein 3 to ↑λ Only need 1 injx of MR/day compared to 2x M/day Mecasermin has higher incidence of hypoglycemia and cellular porliferation because it is unbound |
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Octreotide
Use, PhK, SE, CI's |
Somatostatin analogue
inhibits secretion of pituitary and GI hormones: Serotonin, Gastrin, VIP, insulin, glucagon, secretin, motilin, pancreatic polypeptide, growth hormone, & thyrotropin ↓ pancreatic & gastric acid secretn → ↑ intestinal transit time → ↑ intestinal absorption H2O & elytes, Theraputic Uses: Acromegaly (GH excess), excessive diarrhea, Hormone secreting tumors (VIPoma, carcinoids)-- Can reduce tumor size/growth PhK: Sc 3x/day, (lantrotide is 1/mo); serum λ 1.5 h, biologically active for 9h SE: GI effects subside, gallstones/sludge in 25%, [cardiac problems- bradycardia/condxn disturbances] CI's: Gallbaldder disease, DM, Cardiac disease, Thyroid problems (somatostatin inhibits TSH) |
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Lantreotide
Use, PhK, SE, CI's |
Somatostatin analogue
inhibits secretion of pituitary and GI hormones: Serotonin, Gastrin, VIP, insulin, glucagon, secretin, motilin, pancreatic polypeptide, growth hormone, & thyrotropin ↓ pancreatic & gastric acid secretn → ↑ intestinal transit time → ↑ intestinal absorption H2O & elytes, Theraputic Uses: Acromegaly (GH excess), excessive diarrhea, Hormone secreting tumors (VIPoma, carcinoids)-- Can reduce tumor size/growth PhK: s.c. 1/mo (ocretide is 3/day); serum λ 1.5 h, biologically active for 9h SE: GI effects subside, gallstones/sludge in 25%, [cardiac problems- bradycardia/condxn disturbances] CI's: Gallbaldder disease, DM, Cardiac disease, Thyroid problems (somatostatin inhibits TSH) |
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Pegvisomant
Use, PhK, SE, CI's |
GH receptor antagonist
GH excess syndromes (acromegaly): returns IGF-1 levels to normal in 97% of pts SE: lack of feedback → growth of GH secreting tumor [reversible heptatotoxicity] Contraindications: Hepatic disease |
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HPG Axis
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lecture 27
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GnRH
agent, λ, fnx |
hypothalamic decapeptide w/ pulsetile release
serum & biological λ is very short pulse freq determines which peptide released tonic administration will downregulate GnRH receptors and ultimately decrease gonadotropin release |
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Gonadorelin
fnx, PhK |
GnRH agonist not available in the US
extremely short λ, pulsed IV → Tx infertility less likely to cause ovarian hyperstimulation and multiple births than direct administration of LH and FSH [Dxtic for hypogonadotrpic hypogonadism] |
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Leuprolide
fnx, uses, SE, CI |
GnRH agonst: continuous administration causes an initial gonadotropin surge followed by ultimate inhibition of gonadotropin release
to reduce androgen prodxn in prostate cancer (initial surge is problematic esp if metastatic → bone bain, add antiandrogen) to delay precocious puberty SE: Menopausal sx, testicular atrophy [ovarian cysts, osteoporosis] CI: Pregnancy & breast feeding [PhK: SC or IM weekly; addt'l uses: to terminate endogenous LH surge when stimulating w/ exogenous gonadotropins for ART; endometriosis, polycystic ovarian disease, and uterine leiomyomas; chemical castration] |
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Goserelin
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GnRH agonst: continuous administration causes an initial gonadotropin surge followed by ultimate inhibition of gonadotropin release
to reduce androgen prodxn in prostate cancer (initial surge is problematic esp if metastatic → bone bain, add antiandrogen) to delay precocious puberty SE: Menopausal sx, testicular atrophy [ovarian cysts, osteoporosis] CI: Pregnancy & breast feeding [PhK: SC or IM weekly; addt'l uses: to terminate endogenous LH surge when stimulating w/ exogenous gonadotropins for ART; endometriosis, polycystic ovarian disease, and uterine leiomyomas; chemical castration] |
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Nafarelin
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GnRH agonst: continuous administration causes an initial gonadotropin surge followed by ultimate inhibition of gonadotropin release
to reduce androgen prodxn in prostate cancer (initial surge is problematic esp if metastatic → bone bain, add antiandrogen) to delay precocious puberty SE: Menopausal sx, testicular atrophy [ovarian cysts, osteoporosis] CI: Pregnancy & breast feeding [PhK: nasal spray; addt'l uses: to terminate endogenous LH surge when stimulating w/ exogenous gonadotropins for ART; endometriosis, polycystic ovarian disease, and uterine leiomyomas; chemical castration] |
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Cetrorelix
Fnx, Use, Phk |
GnRH competitive antagonist: suppresses LH at lower doses and FSH at higher doses
Use: suppress endogenous LH and FSH for ART (better than leuprolide), [endometriosis & uterine fibroids] PhK: injected sc by pt, well tolerated (sibling drug: ganirelix) |
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Ganirelix
Fnx, Use, Phk |
GnRH competitive antagonist: suppresses LH at lower doses and FSH at higher doses
Use: suppress endogenous LH and FSH for ART (better than leuprolide), [endometriosis & uterine fibroids] PhK: injected sc by pt, well tolerated (sibling drug: Cetrorelix) |
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FSH
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secreted in response to low frequency GnRH pulses
larg amts required for dvlpt of ovarian follicles & granulosa cells → estrogen production; high sustained estrogen → positive feedback on LH → LH surger, ovluation [secretion is increased in post-menopausal women] in men it stimulates permatogenesis [& synth of androgen binding protein in Sertoli cells] |
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Human menopausal gonadotropins
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aka menotropins
used as an FSH drug , contains both FSH and LH drug [isolated from urine of post-menopausal women] Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Menotropins
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aka Human menopausal gonadotropins
used as an FSH drug Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Urofollitropin
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FSH
Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Follitropin alpha/beta
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recombinant human FSH
Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty not more effective than cheaper Urofollitropin or Menotropin, but people generally don't like the idea that they are taking a drug captured form someone's pee |
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human Chorionic Gonadotropin
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similar strx to LH/binds LH receptors, longer λ; IM injx
Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Choriogonadotropin alfa
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recombinant protein of hCG; similar strx to LH/binds LH receptors, longer λ; s.c.
Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Lutropin
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Recombinant LH only approved for combination use with Follitropin alfa (recombinant human FSH)
Uses: correcting hypognadism, dx'ing delayed puberty, correcting infertility Men: LH → ↑ Testosterone, FSH → spermatogenesis Women: FSH for 10 days → stim'd ovaries & estrogen prodxn, single LH dose → induces ovulation SE: ovarian enlargement, ovarian hyperstimulation syndrome, multiple births, gynecomastia [HA, depression, edema, precocious puberty] C/I's: sex steroid dependent neoplasia, precocious puberty |
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Natural estrogens
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estradiol, estrone, estriol
estradiol produced in ovary of non-pregnant premenopausal women ovarian prodxn regulated by LH and FSH estrone and estriol formed in liver, kidney adipose, SkM, brain and testes: accounts for all the estrogens in males and postmenopausal women no natural estrogen is orally active |
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Estrogen metabolism
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enterohepatic circulation
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Physiologic effects of estrogens on target tissues
Ovary, Uterus, Cervix, Vagina, Breasts, Skin, SkM, Heart, Liver et al |
Ovary: induction of LH receptor on granulosa cells → dvlpt of corpus luteum
Indxn of E2 receptors on granulosa cells → growth of follicle induction of FSH receptors on granulosa cells → positive feedback proliferation of granulosa cells, dvlpt of antral follicles Fallopian tubes: ↑ number of sterocilia & rate of beating Uterus: endoemtrial cell division & growth (follicular phase) Myometrium: increases contraxns & oxytocin receptors Endometrium: thickens, increases permeability & vascularization; synth's receptors for progresterone on uterine cells. Cervix: increases distensibility, thihn, watery alkaline mucus at opening vagina: epithelial proliferation, ↑ secretions Mammary glands: req'd for growth: ↑ ductal growth, nipple size & pigmentation Adipose: ↑ subcu fat deposition on hips and breasts SkM: Epiphyseal closure, Ca2+ uptake; antagonizes PTH, ↓ cytokine prodxn, inhibits osteoclasts Heart: arterial vasodilator, ↓ athersoclerosis Liver: high HDL, low LDL, ↑ clotting proteins and hormone binding proteins SHBG, CBG, TBG Other: ↑ platelet adhesivenss, ↑ absorption of NaCl & H2o → bloating, inhibits body hair growth except axillary and pubic |
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Synthetic estrogens
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Potent estrogens only found in combination OCP's
ethinyl estradiol mestranol |
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Conjguated estrogens
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used for hormone replacement therapy
Conjugated equine estrogens (pregnant mare urine) Synthetic conjugated estrogens (soy) Esterified estrogens Estropipate |
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Non-steroidal estrogens
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DES diethylstillbestrol
estrogenic activity exposure in utero linked to vaginal cancers in daughters much later |
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Estrogens:
Indications, Side Effects, Contraindications |
Primary Hyogonadism to stimulate dvlpt of puberty & growth
HRT Oral Contraceptives [dysnfx uterine bleeding in absence of organic pathology, suppress ovluation in women with intractable dysmenorrhea/excessive ovarian androgen secretion, Tx of androgen dependent cancers (prostate)] PhK: liver metabolism, avoided with local admin SE: Migraines, Thromboembolism/Blood Clotting [Uterine hyperplasia, nausea, breast tenderness, gallladder disease, htn, hyperpigmentation] Contraindications: Estrogen dependent neoplasms (breast cancer), thromboembolitic disorders [Undx genital bleeding, htn, liver disease, smoking, pregnancy (malignant adenocarcinomas in 0.1%] |
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Tamoxifen
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Antiestrogen SERM Selective Estrogen Receptor Modulator
Agonist in uterus and Bone → prevents bone loww Antagonist in breast DOC for estrogen dependent breast cancer SE: ↑ risk for uterine cancer, [may ↓ HDL, hot flashes, N/V] C/I: Thromboembolytic Disease, Breast Feeding Toremifine is similar to Tamoxifen but ↑ HDL |
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Toremifine
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Antiestrogen SERM Selective Estrogen Receptor Modulator
Agonist in uterus and Bone → prevents bone loww Antagonist in breast DOC for estrogen dependent breast cancer SE: ↑ risk for uterine cancer, [hot flashes, N/V] C/I: Thromboembolytic Disease, Breast Feeding Tamoxifen is similar to Toremifine but ↓ HDL |
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Raloxifene
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Antiestrogen SERM Selective Estrogen Receptor Modulator
Antagonist in breast and uterus Agonist in liver in bone Used to prevent post-menopausal osteoporosis [Lowers total serum LDLin post-menopausal] [Does not relieve hot flashes] |
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Clomiphene
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Anestrogen SERM: selective estrogen receptor modulator
Typical DOC for infertility with intact HPG axis: [1q5 5d oral course] Antagnoizes negative feedback of estrogen in hypothalamus Stimulates LH &FSH → ovulation SE: multiple pregnancies [hot flashes, HA, constipation, allergic reactions; enlarges ovaries] |
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Fulvestrant
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Full estrogen receptor antagonist
Used in pts with tamoxifen resistant tumors produces menopausal sx |
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Aromatase inhibitors:
names, uses, SE |
Anastrozole & Letozole are competitive inhibitors; Exemestane is irreverisble
None inhibit adrenal steroid synth Used for: breast Ca in postmenopausal women Advanced breast CA after tamoxifen failure [SE: diarrhea, abdominal pain w/ N/V, hot flashes, joint pain] |
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Progesterone
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Produced by corpus luteum or fetal/placental unit in pregnancy; regulated by LH
Utuerus: converts to secretory state, maintains pregnancy, suppresses contractility during pregnancy endocervical glands: thick acidic mucus, poor envt for sperm, ↓ distensibility Vaginia: decreases proliferation of epithelial layer Breasts: ↑ branching of ductal system, stimulates lobuloalveolar dvlpt Thermogenic: ↑ Bodyt Temp ↑ Appetite Kidney: competes with aldosterone, ↓ Na reabosprtion |
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Pregnanes
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Progestine Derivates which antagonize the mineralcorticoid receptor
Progesterone Medroxyprogesterone Megestrol acetate Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Estranes
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19-norestrosterones: Norethindron, Norethrindrone acetate:
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Gonanes
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13-ethyl derivates of norethindrone
Desogestero, Norgestimate, Norgestrel Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Mifepristone
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blocks binding of progesterone receptor
pregnancy termination (used in combo w/ misoprostol) antagonizes glucocorticoid receptor [prevent implantation w/in 72 h, indxn of labor at 3rd trimester following fetal death] [SE: GI, abdominal, pelvic pain, vaginal bleeding] C/I's: Pregnancy or breast feeding, [glucocorticoid Rx, anemia or anticoagulants] |
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Danazol
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Weak progestin, androgen, and glucocorticoid which suppresses ovarian fnx
Used to tx endometriosis [SE: common but fairly mild long list] C/I: Liver dysnfx, preganancy, breastfeeding] |
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A good combination pill for contraception
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Drospienone/ethinyl estradiol
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Combination Oral contraceptives
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99.9% effective
inhibit ovulation chance cervical mucus to block sperm (thick, acidic) change endometrium: ↓ implatation progestin withdrawal initiates bleeding at the end of the cycel Most common estrogens: ethinyl estradiol or mestranol Most common progestins: Levonorgestrel and norethindrone E:P ratio more important than amt of each high E = many side effectds |
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Contraceptives with Staging
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Vary the E:P ratio in 21 days + 7 days of placebo
monophasic, biphasic and triphasic triphasic minimize effects by mimicking natural cycle |
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Seasonale
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84 pills of lovenorgestrel/ethinyl estrdiol + 7 pills of nothing
higher ethinyl estradiol than seasonique 91 day cycle, breakthrough bleeding more likely esp in first year |
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Seasonique
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84 pills of levonorgestrel/ethinyl estradiol and 7 pills
lower ethinyl estradiol than seasonale 91 day cycle, breakthrough bleeding more likely esp in first year |
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Lybrel
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only levonorgestrel/ethinylestradiol w/ no breaks in dosing (continuous)
breakthrough bleeding more common, esp first year hard to distinguish if you become pregnant |
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Yasmin
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drospirenone/ethinyl estradiol
drospirenone is both a progesterone agonist and a mineralcorticoid antagonist the only combination pill FDA approved for reducing PMDD syx anti-androgenic properties |
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NuvaRing
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3 weeks upply of etonogesterel & ethinyl estradiol
alternative to roal |
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combination oral contraceptive which produces bioidentical estradiol
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Natazia: combination pill of dienogest/destradiol valerate;
estradiol valerate directly converted into estradiol in body [4 phase cycle optimizes anovulation, dienogest is a selective progestin, with anti-androgenic proeprties] |
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Oral Contraceptive for breast feeding
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Minipill contraceptive: progestin-only: change endometrium to decrease implantation
~93% effective, used for breast feeding and adolescents (prevents estrogen effects on bone growth) [SE: weight bain, breakthrough bleeding, depression] |
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Oral Contraceptive for adolescents
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Minipill contraceptive: progestin-only: change endometrium to decrease implantation
~93% effective, used for breast feeding and adolescents (prevents estrogen effects on bone growth) [SE: weight bain, breakthrough bleeding, depression] |
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IUC contraceptive
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Mirena: releases levonorgestrel
99.9% effective brith control for up to 5 years |
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Contraceptive: single silastic tube implanted in the arm;
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Implanon: etonorgestrel filled
>99.9% for 3 years |
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1/3 mo injection contraceptive
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Depo-provera:
once/3 mo depot injection of medroxyprogesterone progesterone only oral contraceptive |
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Post coital oral contraceptives
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Plan B: high dose levonorgestrel only pill taken w/in 72h → inhibits implantation, sooner is more effective overall ~90% effective
available w/o perscription to 18+yo Preven: Plan B + ethyinyl estradiol Mifepristone: blocks progestin binding to progesterone receptor, mainly used as an abortifacent in combo w/ prostaglandin. can be used to prevent implantation w/in 72h |
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Adverse effects of oral contraceptives
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Important: Cardiovascular problems (Women >45, smoking), mild htn, migraine, MI/Stroke, cholestatic jaundice/gallbladder disease, teratogenesis, fertility suppression 3+ mo after discontinuation.
[Run of the Mill: Weight Gain, Nausea, Edema, Depression, Breakthrough bleeding with progestins alone or too litter estrogen; problem with one contraceptive → try another] |
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Beneficial Effects of Oral Contraceptives
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Reduced risk for endoemtrial and ovarian cancer (50% reduction w/ 2 years use, protection continues for 15 years)
many other reduced risks (ectopic pregnancy, iron deficiency anemia, RA, ovarian cysts, etc) consensus: saves thousands of lives & hospitalizations every year. |
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Contraindications of oral contraceptives
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Absolute
Thromboembolitic phenomena Estrogen dependent Neoplasms Pregnancy Relative: Liver disease [ pre-epiphyseial closure, asthma, eczema, migraines, htn, diabetes, optic neuritis, netrobulbar neruitis, seizures, smoking & over 35] |
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Natazia
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combination pill of dienogest/destradiol valerate;
estradiol valerate directly converted into estradiol in body [4 phase cycle optimizes anovulation, dienogest is a selective progestin, with anti-androgenic proeprties] |
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Minipill contraceptive
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progestin-only: change endometrium to decrease implantation
~93% effective, used for breast feeding and adolescents (prevents estrogen effects on bone growth) [SE: weight bain, breakthrough bleeding, depression] |
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Depo-provera
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once/3 mo depot injection of medroxyprogesterone
progesterone only oral contraceptive |
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Implanon
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single [etonorgestrel filled] silastic tube implanted in the arm;
>99% efective for up to 3 years |
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Mirena
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IUC releases levonorgestrel
99.9% effective brith control for up to 5 years |
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Plan B
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oral post coital contraceptive
high dose levonorgestrel only pill taken w/in 72h sooner is more effective overall ~90% effective inhibits implantation available w/o perscription to 18+yo |
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Preven
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Similar to plan B but also contains ethyinyl estradiol
Plan B: oral post coital contraceptive high dose levonorgestrel only pill taken w/in 72h sooner is more effective overall ~90% effective inhibits implantation available w/o perscription to 18+yo |
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Mifepristone
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Post coital contraceptive
blocks progestin binding to progesterone receptor, mainly used as an abortifacent in combo w/ prostaglandin. can be used to prevent implantation w/in 72h |
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Drug interactions of OCP's
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drugs which induce microsomal enzymes decrease effectiveness
antibiotics decrease effectivenss (disrupt enterohepatic circulation) OCP's decrease the effectivness of anticoagulants, anticonvulsants, TCA's, guanethidine, warfarin, and oral hypoglycemic agents |
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Menopause
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Reduced ovarian response to gonadotropins: ↓ ovarian steroids, ↑ gonadotropins
Vasomotor problems: hot flashes [ HA, palpitations, insomia/night sweats] Genito-urinary problems: no trophic estrogen → vaginal dryness, atrophy & pain Osteoporosis: 50% spinal compression fractures by 75, 20% hip fractures by 90 Heart disease: ↑ cholesterol & LDL, ↓ HDL |
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Advantages & Concerns of HRT
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↓ Menopause Sx, osteoporosis ±↓ hot flashes, sleep disturbances, mood swings
Concerns: Endoemtrial cancer --progestins reduce Breast CA (small risk)- SERMs like Tamoxafin, Toremfene, Raloxifen ↓ Gallbaldder disease (2.5x) Cardiovascular events --esp if women smokes, --cardioprotective if <60 yo <10 years after menopause, benefits > risks: healthy young women should have no fears about its use. >10 years, risks > benefits |
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Estrogen only HRT
|
proliferation of endometrial tissue → CA
supplement with progestins to promote withdrawal and bleeding Indicated after a histerectomy where progestins are not needed |
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Hormone replacement therapy indications in young women
|
girls in whom ovarian dvlpt does not occur
women who have ovaries removed prior to menopausal age |
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Hormonal Rx Breast CA
|
effective in CA's with high affinity estrogen/progesterone receptors
Tamxifen, Raloxifene progestins some use in CA |
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Endometrial CA Rx
|
progesterone produces remission in 1/3 of endometrial CA's
mechanism unknown |
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Prostate CA Rx
|
estrogen tx can cause remission in 2/4 of prostate cancers.
Estrogens lower serum testosterone and directly antagonize androgens |
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rate limiting step in testosterone synthesis
|
conversion of cholesterol to pregnenlone
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androstendione
|
natural androgen
synthezied in adrenal gland and testes from ovaries in women: peak during leteal phase |
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|
plasma levels of testosterone by age
|
low until puberty in boys
begin to decrease signifantly about age 70 |
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5 alpha reductase
|
in accessory sex organs and other tissues
converts testosterone into 5 DHT, more potent than testosterone |
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Physiologic Effects of Androgens
|
-Virilizing: spermatogenesis, sexual development
-Anabolic: ↑ bone density, AA incorporation into muscle, RBC mass, anatongizes glucocorticoid catabolism -Puberty: 2ndry male sexual characteristics |
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Indications for Testosterone Use in Men
|
Men:
testicular deficiency 2* to hypogonadism AVOIDED in Aging/Impotence → prostate CA [anemia (replaced by EPO] Women: hypopituitarism (req's both estrogens and androgens: methyl-testosterone + diethylstilbesterol) Both sexes: nephrosis, debiliated pts with negative Nitrogen balance [short stature] |
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Adverse effects of testosterone Use
|
inhibits relase of LH & FSH
Men: ↓ testosterone prodxn, spermatogenesis ↑ prostate CA' Women: uterine atrophy, breast shrinkage, mesnstraual irregularity; reversibe masculinization: deep voice, baldness, hirsutism, clitorial enlargement); Pregnants → pseudohermaphroditism Both: oily skin & acne, ↓ HDL, psychological changes: agression, depression, altered sex drive, psychosis [ ↑ LDL, baldness, fluid retention, slepe apnea] |
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Contraindications to Androgens
|
Pregnancy, Young Child (Epiphyseal palte)
Andorgen dependent neoplasms (prostate CA) Aplastic anemia Hepatic Carcinomas |
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List Androgens
by inceasing ration of Anabolic: Androgenic activity |
Testosterone
Methylestosterone Fluoxymesterone Oxymethalone Oxandrolone |
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List the antandrogens
|
-Ketoconazole: inhibits androgen synth at 4x antifungal dose
-Spironolactone: reduces 17alpha OH activity, mineralcorticoid antagonist which competes for androgen and estrogen receptors at high doses -Flutamide: no-steroidal androgen receptor antagonist: reduces male sex accessory organ fnx -Bicaltamide: androgen receptor antagonist -Nilatamide androgen receptor antagonist -Finasteride & Dutasteride: inhibit 5alpha reductase -Estrogens inhibit LH secretion -GnRH analogues and antagonists suppess LH and FSH |
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Use of antandrogens
|
hirsutism, PMS & severe cystic acne
used in men to treat prostate tumors gynecomastia is the common side effect |
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Spirolactone as an antrandrogen
mech, uses |
reduces 17alpha OH activity, mineralcorticoid antagonist which competes for androgen and estrogen receptors at high doses
hirsutism, PMS precocious puberty in both sexes |
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Flutamide
mech, uses, SE |
no-steroidal androgen receptor antagonist: reduces male sex accessory organ fnx
Used for prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness Reversibly hepatotoxic Being replaced by bicalutamide --only req's 1/day dose & less hepatotoxic |
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Bicalutamide
mech, uses, SE |
like Nilutamide: an androgen receptor antagonist: reduces male sex accessory organ fnx
Used for prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness replacing similar drug flutamide because less hepatotoxic & only requires one day dosing |
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Nilutamide
mech, uses, SE |
like Bicalutamide: an androgen receptor antagonist: reduces male sex accessory organ fnx
Used for prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness |
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Finasteride
mech, uses, SE |
like dutasteride: a 5α-reductase inhibitor (no DHT)
supresses male sex accessory organs without affecting libido [↓ DHT & PSA; ↑ total Testosterone & TSH] used for male pattern baldness BPH (shrinks gland!) C/I: teratogenic reduces PSA, may mask true Prostate CA |
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Dutasteride
mech, uses, SE |
like finasteride: a 5α-reductase inhibitor (no DHT)
supresses male sex accessory organs without affecting libido used for male pattern baldness BPH (shrinks gland!) C/I: teratogenic reduces PSA, may mask true Prostate CA |
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DOC for Growth Failure Due to GH Deficiency
PhK, Main SE's, & Contras |
Somatotropin: recombinant native human GH
Somatotrem: Somatotropin + methionine at N+ terminus PhK: S.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism |
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DOC IGF-1 KO Mutation
|
Mecasermin rabinifate: Recombinant human IGF-1 + IGF Binding Protein 3 to ↑λ
not as effective as GH Rx's somatotropin/somatorem, but effective in pts with GH receptor or IGF-1 KO mutations. PhK: 1x/day injx SE's: GH side effects {Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism [injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria]} CI's: Same as GH {DM, Hypothyroidism [w/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma]} Mecasermin rabinifate is better but has lost the patent suite |
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DOC GH Receptor KO Mutation
|
Mecasermin rabinifate: Recombinant human IGF-1 + IGF Binding Protein 3 to ↑λ
not as effective as GH Rx's somatotropin/somatorem, but effective in pts with GH receptor or IGF-1 KO mutations. PhK: 1x/day injx SE's: GH side effects {Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism [injx site rxn, ↑ Intracranial P, hypoglycemia, glycosuria]} CI's: Same as GH {DM, Hypothyroidism [w/in 1 year of leukemia tx, acute respiratory insufficiency, acute critial illness 2* to visceral surgery/trauma]} Mecasermin rabinifate is better but has lost the patent suite |
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Acromegaly
Rx's |
Somatostatin analogues: ocreotide or lantreotide: will inhibit GH secretion
Pegvisomant: GH receptor antagonist, returns [IGF-1] to normal in 97% of pts! |
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Hormone Drug for Excessive Diarrhea
PhK, Main SE & CI's |
Somatostatin analogue: ocreotide or lantreotide:
inhibit secret'n of pituitary and GI hormones: Serotonin, Gastrin, VIP, insulin, glucagon, secretin, motilin, pancreatic polypeptide, growth hormone, & thyrotropin ↓ pancreatic & gastric acid secretn → ↑ intestinal transit time → ↑ intestinal absorption H2O & elytes, PhK: s.c. lantreodie 1/mo, ocretide is 3/day SE: GI effects subside, gallstones/sludge in 25%, [cardiac problems- bradycardia/condxn disturbances] CI's: Gallbaldder disease, DM, Cardiac disease, Thyroid problems (somatostatin inhibits TSH) |
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Hormone Drug for Carcinoid Tumors
PhK, Main SE & CI's |
Somatostatin analogues: ocreotide or lantreotide: can reduce tumor size and growth
inhibit secret'n of pituitary and GI hormones: Serotonin, Gastrin, VIP, insulin, glucagon, secretin, motilin, pancreatic polypeptide, growth hormone, & thyrotropin PhK: s.c. lantreodie 1/mo, ocretide is 3/day SE: GI effects subside, gallstones/sludge in 25%, [cardiac problems- bradycardia/condxn disturbances] CI's: Gallbaldder disease, DM, Cardiac disease, Thyroid problems (somatostatin inhibits TSH) |
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DOC: reduce androgen production in prostate cancer
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Leuprolide, goserelin, nafarelin; GnRH agonsts: continuous administration causes an initial gonadotropin surge followed by ultimate inhibition of gonadotropin release
SE: Menopausal sx, testicular atrophy [ovarian cysts, osteoporosis] CI: Pregnancy & breast feeding [PhK: SC or IM weekly; nafarelin nasal spray; addt'l uses: to terminate endogenous LH surge when stimulating w/ exogenous gonadotropins for ART; endometriosis, polycystic ovarian disease, and uterine leiomyomas; chemical castration] |
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DOC: precocious puberty
|
Leuprolide, goserelin, nafarelin; GnRH agonsts: continuous administration causes an initial gonadotropin surge followed by ultimate inhibition of gonadotropin release
SE: Menopausal sx, testicular atrophy [ovarian cysts, osteoporosis] CI: Pregnancy & breast feeding [PhK: SC or IM weekly; nafarelin nasal spray; addt'l uses: to terminate endogenous LH surge when stimulating w/ exogenous gonadotropins for ART; endometriosis, polycystic ovarian disease, and uterine leiomyomas; chemical castration] |
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DOC suppress endogenous gonadotropins for ART
Fnx, PhK |
Cetrorelix & ganirelix: GnRH antagonist: suppresses LH at lower doses and FSH at higher doses
PhK: injected sc by pt, well tolerated |
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Distinguishing between hypogonadotropic hypogonadism adn constitutional delay of puberty
|
after a single hCG injection
hh: low estradiol and low testosterone const: increased estradiol and testosterone |
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|
Inducing spermatogensis in hypogonadotropic hypogonadal men
|
hCG is given to increase testosterone then hMG (FSH) is injected for SEVERAL MONTHS
>50% of men become fertile after this treatement |
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|
ethinyl estradiol
|
synthetic estrogen: Potent estrogens only found in combination OCP's
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Diethylstillbestrol
|
DES
non-steroid with estrogenic activity |
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mestranol
|
synthetic estrogen: Potent estrogens only found in combination OCP's
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Conjugated equine estrogens
|
from pregnant equine mares
conjugated estrogen used for HRT |
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Synthetic conjugated estrogens
|
from soy
conjugated estrogen used for HRT |
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Esterified estrogens
|
conjugated estrogen used for HRT
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Estropipate
|
conjugated estrogen used for HRT
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DOC Primary hypogonadism in females
PhK, major SE & CI |
Estrogens
PhK: liver metabolism, avoided with local admin SE: Migraines, Thromboembolism/Blood Clotting [Uterine hyperplasia, nausea, breast tenderness, gallladder disease, htn, hyperpigmentation] Contraindications: Estrogen dependent neoplasms (breast cancer), thromboembolitic disorders [Undx genital bleeding, htn, liver disease, smoking, pregnancy (malignant adenocarcinomas in 0.1%] |
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DOC: postmenopausal HRT
PhK, major SE & CI |
Estrogens
PhK: liver metabolism, avoided with local admin SE: Migraines, Thromboembolism/Blood Clotting [Uterine hyperplasia, nausea, breast tenderness, gallladder disease, htn, hyperpigmentation] Contraindications: Estrogen dependent neoplasms (breast cancer), thromboembolitic disorders [Undx genital bleeding, htn, liver disease, smoking, pregnancy (malignant adenocarcinomas in 0.1%] |
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DOC: Estrogen Dependent Breast Cancer
|
Toremefine, Tamoxifen: Antiestrogen SERM Selective Estrogen Receptor Modulator
Agonist in uterus and Bone → prevents bone loww Antagonist in breast DOC for estrogen dependent breast cancer SE: ↑ risk for uterine cancer, [may ↓ HDL, hot flashes, N/V] C/I: Thromboembolytic Disease, Breast Feeding Toremefine ≈ Tamoxifen, but ↑'s HDL |
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DOC: preventing postmenopausal osteoporosis
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Raloxifene: Antiestrogen SERM Selective Estrogen Receptor Modulator
Antagonist in breast and uterus Agonist in liver in bone Used to prevent post-menopausal osteoporosis [Does not relieve hot flashes] |
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DOC: infertility w/ intact HPG axis
|
Clomiphene: Anestrogen SERM: selective estrogen receptor modulator
Typical DOC for infertility with intact HPG axis: [1q5 5d oral course] Antagnoizes negative feedback of estrogen in hypothalamus Stimulates LH &FSH → ovulation SE: multiple pregnancies [hot flashes, HA, constipation, allergic reactions; enlarges ovaries] |
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DOC: pts with tamoxifen resistant breast tumors
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Fulvestrant: Full estrogen receptor antagonist
produces menopausal sx |
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Anastrozole
|
w/ Letozole are competitive Aromatase inhibitors;
do not inhibit adrenal steroid synth Used for: breast Ca in postmenopausal women Advanced breast CA after tamoxifen failure [SE: diarrhea, abdominal pain w/ N/V, hot flashes, joint pain] |
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Letrozole
|
w/ Anastrozole competitive aromatase inhibitors
do not inhibit adrenal steroid synth Used for: breast Ca in postmenopausal women Advanced breast CA after tamoxifen failure [SE: diarrhea, abdominal pain w/ N/V, hot flashes, joint pain] |
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Exemestane
|
irreverisble arromatase inhibitor
do not inhibit adrenal steroid synth Used for: breast Ca in postmenopausal women Advanced breast CA after tamoxifen failure [SE: diarrhea, abdominal pain w/ N/V, hot flashes, joint pain] |
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Medroxyprogesterone
|
A Pregnanes = Progestine Derivates which antagonize the mineralcorticoid receptor, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Megestrol acetate
|
A Pregnanes = Progestine Derivates which antagonize the mineralcorticoid receptor, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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the only combination pill FDA approved for reducing PMDD syx
|
Yasmin: drospirenone/ethinyl estradiol
drospirenone is both a progesterone agonist and a mineralcorticoid antagonist anti-androgenic properties |
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Norethindron
|
an Estrane: 19-norestrosterones, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Norethrindrone acetate
|
an Estrane: 19-norestrosterones, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Desogesterol
|
a gonane: 13-ethyl derivates of norethindrone, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Norgestimate
|
a gonane: 13-ethyl derivates of norethindrone, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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Norgestrel
|
a gonane: 13-ethyl derivates of norethindrone, a progestin
Used for: in OCP's alone or in combo Prevention of endometrial hyperplasia with HRT [Maintenance of Pregnancy] [Dysmenorrhea, endometriosis, hirsutism, uterine bleeding, when estrogens are contraindicated.] [SE: ±↑BP, may reduce [HDL] depression and drowsiness] |
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DOC: Prevention of endometrial hyperplasia w/ HRT
|
any progesterone/progestin
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DOC: endometriosis
|
Danazol: Weak progestin, androgen, and glucocorticoid which suppresses ovarian fnx
Used to tx endometriosis [SE: common but fairly mild long list] C/I: Liver dysnfx, preganancy, breastfeeding] |
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91 day cycle
|
Seasonale & Seasonique
84 pills of levonorgestrel/ethinyl estradiol and 7 pills Seasonique has lower ethinyl estradiol than seasonale breakthrough bleeding more likely esp in first year |
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Oral Contraceptive w/ continuous amenorrhea
|
Lybrel: levonorgestrel/ethinylestradiol w/ no breaks in dosing (continuous)
breakthrough bleeding more common, esp first year hard to distinguish if you become pregnant |
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Methylestosterone
|
Androgen
1:1 Androgenic: Anabolic activity |
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Fluoxymesterone
|
Androgen
1:2 Androgenic: Anabolic activity |
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|
Oxymethalone
|
Androgen
1:3 Androgenic: Anabolic activity |
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Oxandrolone
|
Androgen
~1:8 Androgenic: Anabolic activity |
|
|
Drugs combined with GnRH Tx for Prostate CA to ↓ initial tumor flare
|
Flutamide, Bicalutamide, Nilutamide
androgen receptor antagonists: reduces male sex accessory organ fnx prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness Bicalutamide replacing Flutamide because less hepatotoxic & only req's1qd dosing |
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Drugs used topically for Hirsutism
|
Flutamide, Bicalutamide, Nilutamide
androgen receptor antagonists: reduces male sex accessory organ fnx prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness Bicalutamide replacing Flutamide because less hepatotoxic & only req's1qd dosing |
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Drugs used topically for Baldness
|
Flutamide, Bicalutamide, Nilutamide
androgen receptor antagonists: reduces male sex accessory organ fnx prostate CA to suppress tumor flare when beginning Tx w/ long acting GnRH agonist. Used topically for hirsutism & baldness Bicalutamide replacing Flutamide because less hepatotoxic & only req's1qd dosing |
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Drugs used for BPH
|
Finasteride & Dutasteride: a 5α-reductase inhibitor (no DHT)
supresses male sex accessory organs without affecting libido used for male pattern baldness BPH (shrinks gland!) C/I: teratogenic reduces PSA, may mask true Prostate CA |
|
|
Drugs used for Male Pattern Baldness
|
Finasteride & Dutasteride: a 5α-reductase inhibitor (no DHT)
supresses male sex accessory organs without affecting libido used for male pattern baldness BPH (shrinks gland!) C/I: teratogenic reduces PSA, may mask true Prostate CA |
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|
Drug used to treat precocious puberty in either sex
|
Spirolactone: reduces 17alpha OH activity, mineralcorticoid antagonist which competes for androgen and estrogen receptors at high doses
hirsutism, PMS precocious puberty in both sexes |
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[Rx used to inhibit lactation, prevent breast engorgement & tenderness]
|
Cabergoline & Bromocriptine: DA agonists;
--pituitary prolactinomas when surgery fails (DA from median eminience of hypothalamus tonically inhibits prolactin) --inhibit lactation, prevent breast engorgement, tenderness --paraxodically decreases GH secretion from GH secreting adenomas] Dosing is 1/day for Bromocriptin, 1/week for Carbergoline Side effects: nausea, lightheadedness, orthostatic hypotension, fatigue, psychosis contraindicated in pregnant women without prolactinoma Cabergoline longer λ, more effective, better tolerance |
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|
[Rx used to inhibit GH secretion from GH secreting adenomas
|
Cabergoline & Bromocriptine: DA agonists;
--pituitary prolactinomas when surgery fails (DA from median eminience of hypothalamus tonically inhibits prolactin) --inhibit lactation, prevent breast engorgement, tenderness --paraxodically decreases GH secretion from GH secreting adenomas] Dosing is 1/day for Bromocriptin, 1/week for Carbergoline Side effects: nausea, lightheadedness, orthostatic hypotension, fatigue, psychosis contraindicated in pregnant women without prolactinoma Cabergoline longer λ, more effective, better tolerance |
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[IGFR
|
Insulin like growth factor receptor
Receptor Tyrosine Kinase → anabolic growth ↑ longitudinal bone growth, minearal density in bones ↑ Hepatic GNG, Adipocytic lipolysis ↑ muscle mass ↓ glucose utilization (anti-insulin) Insulin also binds IGFR, abut at 1/2 affinity |
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[Rx for treating growth failure in children with GH deficiency
PhK, Main SE's & Contras |
Somatotropin: recombinant native human GH
Somatotrem: Somatotropin + methionine at N+ terminus PhK S.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism |
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[Rx used for treating cachexia
PhK, Main SE's & Contras |
Somatotropin: recombinant native human GH
Somatotrem: Somatotropin + methionine at N+ terminus PhK S.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism |
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|
[Rx used w/ Turner syndrome
PhK, Main SE's & Contras |
Somatotropin: recombinant native human GH
Somatotrem: Somatotropin + methionine at N+ terminus PhK S.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism |
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|
[Rx for increases lean body mass and sense of well-being in adults
PhK, Main SE's & Contras |
Somatotropin: recombinant native human GH
Somatotrem: Somatotropin + methionine at N+ terminus PhK S.C. or I.M: circulating λ 20 min, Biological λ ~13h, typically daily evening injx SE: Fluid Retention & Edema (tolerance dvlps), Musculoskeletal pain, stiffness; Hyperglycemia, Hypothyroidism CI: DM, Hypothyroidism |
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|
Bromocriptine
|
DA agonist ↓ SNS tone enhanced suppression of hepatic GNG
Fnx: reduces CV problems in diabetics by 40%, unknown mechanism [PhK: oral w/in 2h waking; cycloset is quick release form, biliary elimination SEfx: mild & transient. non cycloset: psychosis, fibrotic complications Contras: pregnant & nursing] |
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Some awesome comparative charts slides 50 & 51 of Antidiabetic agents ppt
|
see ppt
alo the whole workshop on diabetes management I'm not going to make that into cards until later |
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Glucagon
|
↑ blood glucose by mobilizing hepatic glucagon WHEN AVAILABLE
[potently inotropic & chronotropic efx on heart, used in beta blocker OD profound GI relax'n, used in radiology parenteral admin, gradual onset juveniles respond poorly] |
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Proglycem
|
non-diuretic thiazide, vasodilator & hyperglycemic
used to tx inulinoma [inhibits insulin secretion, ↓ peripheral glucose use, ↑ hepatic prodxn PhK: oral, 30hλ SEfx: hyperglycemia w/ ketosis, non ketotic HHS coma Na+H2O retention, hypotention GI irritation hyperuricemia throbocytopenia, neutropenia excessive hair growth in children] |
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Uterine contraxn & relaxn
Physiology, Hormones |
Contraxn: estrogens, prostaglandins, oxytocin, mechanical stretching
Relaxn: β agonists, progesterone, EtOH, MgSO4 # & sensitivity of oxytocin receptors in uterus ↑ just prior to deliver oxytocin is DOC for inducing labor at term uterus is generally resistant tos stimulating drug in 2nd trimester, but prostaglandins can cause strong labor-like contractions and are useful for inducing abortions |
|
|
Postpartum hemorrhage
|
effects ~1/8 pregnancies
1/4 of all delivery assoc. deaths normally contraction of myometrium compresses spiral arteries preventing blood loss; uterine atony causes majority of all PPH's [overdistention, infx, relaxant rx's, prolonged labor fatigue, inversion, retained placenta] placental flow ~500ml/min normal blood loss ~500ml, 1L if C section 1st line tx: massage stimulates endogenous oxytocin |
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Oxytocin
|
cyclic octapeptide stored in posterior pituitary normally released in response to suckling & cervical pressure
DOC for term labor induction; IV infusion for timed on-off contraxns, augments labor in pts with dysfnxnal uterine interia Used IM for preventing hemorrhage by contracting myometrium & clamping down on spiral artereis Nasal application for milk let down reflex SEfx: Anaphylaxis, Uterine rupture w/ large dose, Water intoxication w/ convulsions because of ADH like effect, a serious problem with large prolonged infusionn; sinus bradycardia of fetus w/ premature venticular contraxns & arrhythmias; fetal death due to extreme uterine contraxn [PhK: 4mλ, liver&kidney met'sm Contras: malpresentation, cephalopelvic disproportion, placenta previa, uterine scar from previous C section, unengaged head, cervical scarring] |
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|
Ergot Alkaloids
|
Ergonovine meleate, methylergonovine maleate: activate serotonin & α adrenergic receptors to contract uterine smm
used after completion of labor & placental deliver to decrease uterine bleeding--2nd line after oxytocin failure Contras: obliterative vascular diases or CAD; should NEVER be used to induce labor: strong continuous contraxns will suffocate baby PhK: rapid action IV, 10 min delay oral; effect lasts hours SEfx: contracts all Smm → htn, angina, MI |
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|
Dinoprostone
|
Synthetic E2 prostaglandin
gel form used for cerivcal ripening for term deliver or to expel uterine contents for abortions intrauterine fetal death/abortion: vaginal suppository q4h until abortion SEfx: one of the 4 top diarrheagenic Rx's; [fever, HA, many common non-serious] Contras: should not be used for abortions in pts w/ acute pelvic inflammation, acute cardiac pulmonary, renal orhepaticdiseases; asthma, htn, anemia, jaundice or epilepsy (all bolded); [precaut'n for cervical ripening: problems like fetal distress, Hx of diffulct deliveries or C section] |
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|
4 Top Diarrheagenic Drugs
|
Metofrmin
Quinidine Erythromycin Dinoprostone |
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|
Carboprost tromethamine
|
synthetic PGF2α;
Used to induce 2nd trimester abortion [16h, 95% successful] Postpartum bleeding 3rd line after oxytocin & ergots SEfx: Vomiting & Diarrhea [systemic PG actions look like anaphylactic shock, fever rashes] Contras: should not be used in pts w/ acute pelvic inflammation, acute cardiac pulmonary, renal orhepaticdiseases; asthma, htn, anemia, jaundice or epilepsy (all bolded); [PhK: IM admin, 8mλ ] |
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|
Premature Labor most common risk factors
|
Hx previous prematurity or miscarriages
multiparous anatomical problems Tob, EtOH, Drugs Infx High BP, Diabetes Under or Overweight before pregnancy Improper (too much/not enough) weight gain during pregnancy stress (domestic violence) |
|
|
Uterine relaxants for preterm deliver
|
No option is DOC or FDA approved
prolong enough to give corticosteroids to stimulate lung dvlpt Magnesium Sulfate (unknown mech) 1st Line Nifedipine L-type Ca2+ blocker becoming 1st line Indomethacin- reduces prostaglandin synthesis -Top Tier Progesterone- prophylactically Nitroglycerine- emergency use only in case of uterine rupture. Ethanol- used in rural emergencies β2 agonist Terbutaline - black box warning vs tocolysis |
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|
MgSO4
|
1st line drug to delay labor- NOT FDA APPROVED
Relaxes uterus, unknown mech, probably direct effect FDA approved vs. to prevent pre-eclampsial convulsions and vs eclampsia PhK: IV, slow admin (too fast, hypotension, asystole) SEfx: Circulatory collapse, Cardiac/CNS/respiratory depression; depressed DTRs, muscle paralysys, lethargy, hypothermia. [Contras: should not be used with Ca2+ channel blockers (Nifedipine)] |
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Nifedipine
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NOT ACTUALLY FDA APPROVED TO TX PRE-TERM LABOR
L type Ca2+ channel blocker inhibits Smm contraxns becoming a first line drug to delay labor [Contras: should not be used with MgSO4] |
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Indomethacin vs Preterm Labor
|
NOT FDA APPROVED
Top Tier Rx (not first line: MgSO4, Nifedipine) reduces prostaglandin synth, SEfx: partial closure of ductus arteriosus, [impaired fetal renal fnx, bronchopulmonary dysplasia & persistent neonatal pulmonary hypertension; Maternal effects of NSAID: GI irritation, peptic ulceration, thrombocytopenia, allergic rxns, HA & dizziness] |
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Progesterone vs. Preterm Labor
|
Recommended by the American College of Obstetricians
when given PROPHYLACTICALLY recommended for high risk women w/ hx preterm Approved for use in ART to maintain luteal phase following IVF or ICSI Problem: progesterone is already at extremely high levels in pregnancy. You need to add a ton to get an effect. |
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Nitroglycerin vs Preterm Labor
|
Emergency use only in case of uterine rupture
Given IV there will be a ~1 minute uterine relaxon w/in ~1min [Contras: hypovolemia, anemia, ↑intracranial pressure, constrictive pericarditis/pericardial tamponade & hypersensitivity] |
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Ethanol vs Preterm Labor
|
Used in rural areas
direct relaxant for up to 10 hours |
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Terbutaline vs Preterm Labor
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β2 Agonist
FDA black box warning vs use in tocolysis |
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HPA Axis
|
Hypothalamic Pituitary Adrenal Axis
CRH released during stress ACTH 39AA, derived from POMC 1-24 req'd for full bioactivity 1-13 identical to α-MSH Adrenal corticosteroids → biological fnx at ts, negative feedback on CRH & ACTH |
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Corticorelin
|
synthetic CRH
used to distinguish Cushing's from ectopic ACTH secretion |
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Corticotropin
|
synethetic ACTH, 39AA's
used to distinguish btw 1° (adrenal) and 2° (pituitary) adrenocortical insufficiency |
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Corticosyntropin
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ACTH1-24
ACTH is 39 AA's only first 24 req'd for full biological activity used to distinguish btw 1° (adrenal) and 2° (pituitary) adrenocortical insufficiency |
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The zonas of the adrenal cortex
|
Zona granulosa- exterior:activated by AT2 & K to produce Aldosterone; ACTH is minor stimulus. Aldosterone not bound by plasma proteins, binds nuclear receptor to ↑ Na+ and H2O retention, K+ & H+ excretion
Zona fasiculata: middle: activated by ACTH to produce Cortisol Zona reticularis: interior: produces adrenal androgens |
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Fludrocortisone
|
Both Mineralcorticoid & Glucocorticoid Activity, with M>>G;
Like aldosterone ↑ Na+ and H2O retention, K+ & H+ excretion Given as needed with glucocorticoids for replacement therapy in adrenocortical insufficiency. Else given in salt-losing adrenogenital syndrome |
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Cortisol
|
The major endogenous glucocorticoid: secreted in a daily rhthm, the body's way to cope with stress (emotional, physiologic)
Negative feedback is overruled by stress! 90% plasma protein bound to CBG & albumin; high corticosteroid concentrations saturate CBG & only free corticosteroids have action on nuclear receptors Antagonizes insulin → ↑ circulating glucose, FA's & AA's Redistributes body fat → centrally ↑ vascular respone to SNS stim by blocking catecholamine reuptake Some Na+ & H2O retention, much less potent than mineralcorticoids ↑ CO via ↑ Blood Volume ( ≈stroke volume) & catecholamines ↓ GH, TSH, LH, inhibits vitamin D (bone Ca2+ deposition) ↓ WBC # & fnx Blocks all steps of inflammation via PLA2, COX2, Cytokines, IgE Suppresses wound healing: no edema, fibrin, PMN migration, chemotaxis; no collagen synth/deposition ↑ Epinephrine & PTH (Ca2+ bone loss) CNS effects: Mood elecation, insomnia, restlessness, anxiety, depression, psychosis GI: PUD (Hepatic Met'sm, Renal elimn; urine levels of metabolites used diagnostically.) |
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Cushings Disease vs Cushing's Syndrome
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Disease: ACTH secreting pituitary tumor
Syndrome: excess Cortisol 2° to exogenous glucocorticoids, adrenal tumor, ACTH secreting ectopic (lung) tumor HTN, DM, Osteoporosis Dysmenorrhea Thin Skin,easy bruising &poor wound healing Peripheral wasting & Central Obesity: Buffalo Hump, Moon face with plethoric red cheecks |
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Dexamethasone suppression test
|
1. Measure baseline [cortisol] in AM
2. Administer dexamethasone in PM 3. Measure [cortisol] following morning Normal: extreme suppression of cortisol Cushing's Disease: 50% suppression (ACTH secreting pituitary tumor) Cushing's Syndrome: [cortisol] unchanged (Adenocortical tumor) |
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1*, 2° Adenocortical Insufficiency
|
1° aka Addison's Disease is an Adrneal malfnx
Tx: glucocorticoid & minerocorticoids & ↑ for stress 2° is a pituitary malfnx: no ACTH glucocorticoids typically enough (RAAS activates minerocorticoids) |
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Congenital Adrenal Hyperplasia
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lack of steroidogenic enzymes
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Addison's Disase
|
1° adrenocroticoisnufficiency: an adrenal malfunction at the level of the adrenal gland
Causes: 80% autoimmune 15% TB, else carcinomatous destrx, hemorrhage/infarction Sx: weakness, anorexia, weight loss; hyperpigmentation from ↑ ACTH w/o negative feedback Hypotension, GI problems Hypoglycemia, salt craving, poor response to stress ↓ Urinary cortisol and ↑ ACTH [Loss of axillary & pubic hair in females] --Addisonian crisis: acute complication = dehydration, circulatory collapse, hypoglycemia, hyperkalemia, N/V |
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Hydrocortisone
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is cortisol
exhibits both minralcorticoid & glucocorticoid properties used for repalcement Tx for adrenal insufficiency |
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Cortisone
|
must first be converted to hydrocortisone (cortisol) to be active
both minralcorticoid & glucocorticoid properties used for repalcement Tx for adrenal insufficiency |
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Prednisone
|
Glucocorticoid > Mineralcorticoid
Prednisone is the most commonly prescribed oral glucocorticoid Prednisone must first be conferted to prenisolone in the liver to have fnx |
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Prenisolone
|
Glucocorticoid > Mineralcorticoid
Prednisone is the most commonly prescribed oral glucocorticoid Prednisone must first be conferted to prenisolone in the liver to have fnx |
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Triamcinolone
|
like methylprednisolone, High Glucocorticoid Activity, virtually no mineralcorticoid activity
Newer generation of drugs are like this |
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Methylprednisolone
|
like triamcinolone, High Glucocorticoid Activity, virtually no mineralcorticoid activity
Newer generation of drugs are like this |
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Dexamethasone
|
preferred glucocorticoid for cerebral edema because can enter CNS
also used when endogenous cortisol levels must be monitored (no cross rxn) long acting, directly injected into inflammed joints in RA |
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Fluticasone
|
flonase
most commonly prescribed glucocorticoid for inhaled/inrtanasal use |
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Logic behind various preparations of glucocorticoids
|
Oral = long term
Injx = emergency or depot Inhalation/Intranasal for asthma/rhinitis Topical preparations: almost no absorption, good for local fnx --more potent only used on thick skin --damaged skin ↑ systemic absorption --repeated applciation → depot effect |
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Tx: Adrenocortical insufficiency
|
single large dose if suspected: avoids negative feedback of long term tx
glucocorticoids alone or with glucocorticoid + mineral corticoid acute insufficiency = addisonian crisis = life threatening cardiovascular collapse use ↑ amts in times of stress 2x for minor stress up to 10x for major stresses acute insufficiency can be life trheatening! (Cardiovascular collapse!) 1° no adrenal cortex: glucocorticoids & mineralcorticoids 2° no ACTH: glucocorticoids enough, RAAS |
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Addisonian crisis
|
acute complication = dehydration, circulatory collapse, hypoglycemia, hyperkalemia, N/V
may be precipitated by abrupt withdrawal from chronic therapy Tx: IV saline + glucose + glucocorticoid |
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Tx: leukemias, lymphomas
|
lympholytic effects of glucocorticoids
autimmune lympholytic anemia responds well also |
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Tx: shock
|
high dosese of glucocorticoids restore CO & BP by sensitizing the body to SNS stim
combined with DA to preserve renal perfusion |
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Tx: anaphylaxis
|
epinephrine, antihistamines and glucocorticoids
glucocorticoid restore CO & BP, by sensitizing the body to SNS stim |
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Tx: RA
|
direct glucocorticoid injection into joints
long acting drug dexamethasone used ↓ inflam & pain, not curative |
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Tx: asthma
|
Advair = flutacasone + salmeterol
Inhaled Glucocorticoid + β2 agonist glucocorticoid ↑ sensitivity to β2 agonism, reduces likelyhood of dvlping COPD Oral glucocorticoid used in pts not controlled by inhaled combo |
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Uses of glucocorticoids
|
Replacement therapy for adrenocortical insufficiency: single large dose if suspected
Lympholytic for leukemias, lymphomas, autoimmune hemolytic anemia Augment SNS sensitivity in shock, anaphylaxis: life saving Palliative in RA Inhaled w/ β2 agonistin asthma, oral for uncontrollable Intranasal for rhinitis Antiinflammatory for SLE, allergies, hypersensitivies like colitis, crohn's nephrotic syndrome, sarcoidosis Topical preparations for dermatology & opthalmology Immunosuppression for Oral transplants |
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Theraputic guildlines for glucocorticoid use
|
Lowest effective dose, only as long as necessary
negative feedback will inhibit ACTH prodxn: chronic tx will ↓ HPA for months Many averse effects with long term hidg dose therpay Start with a sufficient dose to control the problem slow tapering once inflam is under control --use locally when possible: topical, inhaled, joint injxn --give on alternate days to decrease HPA axis suppression --short term therapy not likely to cause problem |
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Glucocorticoid Adverse Effects
|
Osteoporosis is the most damaging & tx-limiting effect, directly proprotional to dose & duration
~40% of chronic tx regimens → fracture, commonly rib & vertebreal Must supplement chronic tx w/ Ca2+, vitamin D & bisphosphonates --Osteonecrosis esp of femoral head, then humeral head & distal femur; may require joint replacement. --Lympholytic: More susceptible to serious infections while simultaneously masking fever & inflammation --GI: peptic ulcers --DM: ↓ glucose tolerance --Edema from Na+ & H2O retention, [K+ excretion] --CNS: retlessness, insomnia [psychosis, euphoria, ↑ appetite]--even w/ acute tx! --Muscle wasting of proximal limbs, breathing muscles: indication for withdrawal --Iatrogenic Adrenal Insufficiency >1 wk high dose ↓ HPA; abupt cessation or ↑ stress : addisonian crisis of cardiovascular collapse; requires gradual withdrawal & tx strategies to reduce axis depression: alternate days, morning doses --Induced Cushingoid |
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Contras to Glucocorticoids
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None in adrenal insufficiency: life saving
--Systemic bacteiral infection: [TB] --systemic viral infections: [herpes, varicella] --Poorly controlled DM --Osteoporosis --Heat disease/Htn --Immunosuppressed --Childhood, pregnancy (osteodystrophy, teratogenesis) [peptic ulcer, pyschosis, glaucoma] |
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What do you need to monitor when your pt is on glucocorticoids
|
Hyperglycemia/Glycosuria
Na+ H2O retention/HTN/Edema Hypokalemia Peptic Ulcers Osteoporosis Infx Growth & Dvlpt in Children Pregnancy -teratogenic |
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Glucocorticoid Rx interactions
|
No interactions if topical
Rx that induce cytochrome p450's ↑ glucorticoid metabolism & req ↑ dose : eg barbituates, phenytoi & rifampin; estrogen increases Corticoid Binding Glboulin, both decreasing free glucocorticoid & prolonging its λ thyroid hormone ↑ glucocorticoid met'sm NSAIDs + Corticosteroids have additive GI problems like PUD |
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Aminoglutethimide
|
off market drug for Cushing's syndrome, 2° ACTH secreting adrenal carcinoma/ectopic tumor and for Breast and prostate CA not responding to tamoxifen or anti-androgen tx
inhibits conversion of cholesterol to prenenolone: inhibits ALL STEROID synthesis SEfx: adrenal insufficiencie: corticosteroids MUST be given concomitantly [drowsiness, rash, GI, agranulocytosis, leukopenia] |
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Ketoconazole
|
orally active antifungal agent
Most effective inhibitor of steroid biosythn in Cushing's Disease, [but long term management not FDA approved] inhibits 17α-hydroxylase: ↓ cortisol, androgens & estrogens at high doses inhibits cholesterole → pregnenlone: inhibits ALL steroid synth Used for Cushing's before surgery or radiation |
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Mitotane
|
Adrenocorticolytic: causes adrenocortical atrophy in SF (cortisol) & ZR (adrenal androgens)
binds to mito proteins & inhibits synthe of corticosteroids Used for 1° adrenal carcinoma when surg/rad not possible produces remission of Cushing's Disease, [though ~1/2 will relapse] [SEfx: GI, lethargy, rash, Δhepatic fnx Contras: induces hepatic enzymes will ↑ met'sm of phenytoin & warfarin] |
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Metyrapone
|
The only anti-adrenocortical Rx allowed for pregnant women
↓ aldosterone & cortisol used for short term management of Cushing's [SEfx: GI, seddation, dizziness, rash, hirsutism] |
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Mifepristone
|
powerful antagonist of progesterone recpeotrs & at higher doses glucocorticoid receptors
used for absolutely intractable, inoperable cushings pts [SEfx: GI, amenorrhea, fatigue,] |
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Spirolactone
|
mineralcorticoid receptor antagonist, androgen receptor antagonists
Used for 1° hyperaldosteroneism, hirsutism, cirrhotic ascites [& htn] SEfx: hyperkalemia, arrthmias, menstrual abnormaliteis, gynecomastia, sedation, HA, GI, rashes] |
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Eplerenone
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Selective mineralcorticoid recpetor antagonist (vs spirolactone which also antagonises androgen receptors)
Only used for htn |
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The only anti-adrenocortical Rx allowed for pregnant women
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Metyrapone
↓ aldosterone & cortisol used for short term management of Cushing's SEfx: GI, seddation, dizziness, rash, hirsutism |
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Alendronate
|
FDA approved bisphosphonate
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Risedronate
|
FDA approved bisphosphonate
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Ibandronate
|
FDA approved bisphosphonate
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Zoledronic Acid
|
FDA approved bisphosphonate
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Etidronate
|
Off label bisphosphonate
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Pamidronate
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Off label bisphosphonate
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Human Bone Remodelling Dominance
|
Resorption Dominant
3 weeks to dig a pit 3 mos to fill it back up most drugs focus on inhibiting resporption |
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Fnx: Osteoblasts, Osteoclasts, Osteocytes
|
Osteoblasts: lay down new bone
Osteoclasts: resorb Old bone Osteocytes: signal osteoblasts & osteoclasts |
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Hormonal Control of Remodelling
|
PTH: secreted when blood Ca2+ is low: ↑ circulating Ca2+ by ↑ osteoclasts # & fnx via RANK ligand [↑ renal absoprtion & prodxn of vitamin D)
Vitamin D: ↑ circulating Ca2+ by stimulating osteoclasts through RANK ligand [ ↑ intestinal absoprtion, ↓ renal excretion] Calcitonin: secreted when Ca2+ is high ↓ circulating Ca2+ but inhibiting osteoclasts & stimulating osteoblasts; stimulated by estrogen so as to maintain bone during pregnancy |
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Osteoporosis
|
↓ amt of bone, impaired structural integrity of trabecular bone, porous, thin cortical bone
bones more likely to fracture Hip fractures carry a 14% death rate Spinal fractures more insidious: 60% don't even realize they have one! Risk Factors: postmenopausal, long term glucocorticoid use, thyrotoxicosis, EtOHism, malabsorption syndromes DOC: bisphosphates Also: Estrogens & SERMS, Ca2+ w/ Vitamin D Calcitonin, alendronate, teriparatide |
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Ca2+ & Vitamin D vs Osteoporosis
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major mechanism is by inhibitin PTH
Can't prevent or treat osteoporosis alone, will be overruled by calcitonin Best absorbed if chewable [better if taken 2x/day] Ca2+ absorption must be licensed by vitamin D |
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Calcitonin
|
Atagonizes PTH to ↓ bone resportion of Ca2+
Not a first line Rx, but used for osteoporosis Also paget's disease PhK: nasal spray or injx SEfx: Allergic rxns (foreing protein) nasal spray causes rhinitis, sinusitis injxn causes N/V |
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Teriparatide
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Recombinant PTH: the only anabolic drug for osteoporosis: intermitent adminjistration produces bone growth
mechanism not understood, but apparently intermittent spikes as opposed to continuous will cause ↑ bone formation; thus given by daily injxn Used for Osteoporosis & Hypoparathyroidism Contras: Osteosarcoma Black Label Warning: paget's disease, radiation tx, open ep[iphyses & Hx of osteosarcoma all make pt susceptible [SEfx: hypercalcemia hypercaliuria, local rxn, dizziness leg cramps] |
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Denosumab
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DENsity OSteo hUman Monoclonal AntiBody
Tx for severe osteoporosis in post-menopausal women antobdy to RANK-ligand, the facotr made by osteoblasts necessary for formation of mature osteoclasts: increases bone mass & strength in both cortical and trabecular bone SEfx: OSTEONECROSIS OF THE JAW, [hypocalcemia, cellulitis, eczema] Contras: Hypocalcemia, fix the hypocalcemia before you administer [Relative: pregnancy, lactation, kidney disease, risk for serious infx] [PhK: 1 subcu injx/mo] |
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Bisphosphonates
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FDA Approved: Alendronate, Risedronate, Ibandronate, Zoledronic Acid
Off-Label Use: Etidronate, Pamidronate DOC for post-menopausal osteoporosis [& paget's disease] PCP bond analogs of pyrophosphate: substitudes for P4 in Ca2+ binding, gets incorporated into bone and inhibits bone resorption; strenthen bone; POWERFUL DRUGS, Unknown actual mechanism of actio PhK: Oral, absorption is poor and MUST be taken on an empty stomach with a half glas of water, reamining upright for 30 minutes afterward to decrease esophageal irritation; Dosing ranges 1/d → 1/y others are IV injx SEfx: Oral → GI pain, esophageal ulceration, conspitation, diarrhea, flatulence IV → renal toxicity if given too fast, NV, osteonecrosis of jaw following detal work [mild hypocalcemia, possible afib] |
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Cinacalcet
|
Oral cacimemetic drug that binds Ca2+ sensing receptor in Parathyroid gland → blocks parathyroid release
Used for 2° hyperparathyroidism of chronic kidney disease & parathyroid carcinoma |
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The HPT axis
|
Thyroid Hormones are directly regulated by TSH and iodide
TSH ↑ from cold & stress to modulate the effects of other metabolic hormones to ↑ metabolic rate [catecholamines, insulin, cortisol, glucagon] importantly ↑ responsiveness ot catecholamines important for CNS maturation & growth in general Hypothyroidism → cretinism |
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T3 & T4
|
nuclear receptor acting hormones
T4 is most prevalent T3 is a metabolite of T4, which is 4x more effective |
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Hypothyroidsm
|
Any level of the HPT axis
slow metabolic rate, sensitivity to cold, fatigue [poor mentation, memory, thickened dry skin, bradycardia, edema] High TSH indicates failure of thyroid gland itself Low TSH indicates problem in hypothalamus or pituitary |
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Levothyroxine Sodium
|
aka T4
DOC for hypothyroidism produces euthyroidism: induces appropriate levesl of T3 and T4 PhK: should be carefully titrated to the individual with the goal of producing normal [TSH] levels. ΔTSH & ΔT4 occur slowly, so [TSH] should be monitored for ~5 weeks after adjusting dose |
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Liothyronine sodium
|
aka T3
short λ, short duration of action used in hypothyroidism to acheive normal thyroid activity faster than levothyroxine sodium (T4), but not good for maintenance tx will produce hyperthyroidism; should only be used for a few days |
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[Liotrix]
|
4:1 mixture of T4:T3 used in hypothyroidism
no advatnage over T4 alone since T4 is readily converted in body to T3 |
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Thyroid Hormone Drug interactions
|
Estrogens & Tamoxifen ↑ TBG which ↓ clinical effect
Free [T4] should be measured and doses adjusted Corticosteroids, Androgens decrease TBG: ↑ clinical effect w/ sympathetics → cardiotoxic potentiates warfarin degradation of clotting factors T4 effectors: Li+ & Iodides (incl antiarrhytmic amiodarone): inhibit release of syntheiss of thyroid hormones Antacids: interfere with absorption phenytoin, carbamazapine, rafampin: diabetic drugs req dose adjustment, pharmacodynamic interaction corticosteroids require dose adjustment because both affect metabolism [many more not in ppt] |
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Hyperthyroidism
|
Fast met'sm, tachycardia, fatigue, overheated, tremor, insomnia, diarrhea
Caused by Graves' disease: antibodies to TSH receptor → overprodxn Toxic nodular goiter: adenoma of thyroid Tx: first line therapy is pharmacologic: ↓ T4 & T3 w/ thioamides, iodide, surgical excision, targetted destrxn with Iodine-131, block the Sx with β blockers destrxn/removal may cause hypothyroidism Iodine 131 risks thyroid storm thyroidectomy: risks & costs of surgery |
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Throid Storm
|
Severe thyrotoxic crisis precipitated by trauma, infx, 131-Iodine tx
Hyperthermia, vomiting, diarrhea, tachycardic arrythmia Tx: sedation, O2, antithyroids, beta blockers, corticosteroids, fluids elytes |
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Thioamides
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Propylthiouracil (PTU) & Methylthiouracil
First line Tx for Graves hyperthyroidism Mechanism of action: ↓ synth of T4, Methylthiouracil is more potent PTU blocks conversion of T4 → T3 Effects are gradual, use β blockers vs sx will also reduce the risk for thyroid storm in Iodine 131 tx SEfx: PTU black box warning for severe liver injury, acute liver failure Itching & Skin Rash Granulocytopenia & A granulocytosis: reversible, watch for sore throat & test blood Goiter-may need to add T4 to reduce TSH [Keep dose low in pregnancy to prevent cretininsm & goiter in fetus; HA, nausea, jauncide myalgia, arthalgia, lymphadenopathy, psychosis, SLE-like syndrome] |
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Iodide
|
iodide rapidly decreases synth of T3 &* T4
Used for ~2 mo vs graves hyperthyroidism, effects wear off ↓ vascularity and causes atrophy of thryoid gland used for abut a week before surgery for decreases probabilityy of thyroid storm can use in radioactive emergencies to prevent uptake of radioactive iodine which would destroy the gland (fukashima) |
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Radioactive Iodine
|
Iodine 131 selectively taken up by thyroid gland
Small amts uptaken microCi = diagnostic Large amounts uptaken milliCi = destroys gland Used in elderly pts and pts with heart disease usually causes hypthyroidism over time and risks thyroid storm; risk of thyroid storm can be decreased by using PTU (never iodide) prior to tx |
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Propranolol vs Graves Hyperthyroidism
|
β blocker decreases the SSx of hyperthyroidsim
propranolol itself ↓ the peripheral conversion of T4 → T3, not seen with others used to prepare for surgery & while waiting for pharmacologic agnets to take effect Contraindicated in pts ith obstructive airway disease or asthma as it may cause bronchoconstrixn [Caution used in diabetics as it can enhance hypoglycemia by blocking SNS GNG] |
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Antacids
|
aluminum, magnesium, Ca2+, sodium bicarbonate: inorganic bases which neutralize acid: Used for Sx releif of heartburn, adjunct tx in GERD;
Magnesium produces diarrhea, Aluminum produces consptitation high sodium may be a problem for some pts rarely absorbed; alters absoprtion of other drgus ↓ bioavailability of phenytoin, digitalis & propranolol ↓ absorption of iron, theophylline, quinolone, antibiotics, tetracycline, isoniazid &ketoconazole ↑ sulfonamides, L-dopa & valproic acid ↑ elimination of salicylates & phenobarbital (alkalinzes urine) Pts may not inform you of antacid use, they don't consider them drugs |
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Sodium Bicarbonate
|
Fast Acting Antacid for Sx relief of heartburn & an ajunct in GERD
well absorbed → metabolic alkalosis, Na+ bad for Htn Not useful for ulcer Standard Anatacid Rx interactions: ↓ bioavailability of phenytoin, digitalis & propranolol ↓ absorption of iron, theophylline, quinolone, antibiotics, tetracycline, isoniazid &ketoconazole ↑ sulfonamides, L-dopa & valproic acid ↑ elimination of salicylates & phenobarbital (alkalinzes urine) |
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calcium carbonate
|
antacid
some absorption → alkalosis milk alkali syndrome if too much Ca2+ acid rebound not good for peptic ulcer Standard Anatacid Rx interactions: ↓ bioavailability of phenytoin, digitalis & propranolol ↓ absorption of iron, theophylline, quinolone, antibiotics, tetracycline, isoniazid &ketoconazole ↑ sulfonamides, L-dopa & valproic acid ↑ elimination of salicylates & phenobarbital (alkalinzes urine) |
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Mg hydroxide
|
poorly absorbed antacid, does not produce metabolic alkalosis → produce diarrhea; combined with aluminum hydroxide which produce conspitation
Mg2+ may accumulate in poor renal fnx Standard Anatacid Rx interactions: ↓ bioavailability of phenytoin, digitalis & propranolol ↓ absorption of iron, theophylline, quinolone, antibiotics, tetracycline, isoniazid &ketoconazole ↑ sulfonamides, L-dopa & valproic acid ↑ elimination of salicylates & phenobarbital (alkalinzes urine) |
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Aluminum Hydroxide
|
antacid which produces constipation, so combined with Mg hydroxide to cancel out
decreased renal funx allows accumulation Standard Anatacid Rx interactions: ↓ bioavailability of phenytoin, digitalis & propranolol ↓ absorption of iron, theophylline, quinolone, antibiotics, tetracycline, isoniazid &ketoconazole ↑ sulfonamides, L-dopa & valproic acid ↑ elimination of salicylates & phenobarbital (alkalinzes urine) |
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H2 antagonists
|
Cimetidine, Ranitidine, Famotidine, Nizatidine
↓ GI acid formation by blocking H2 receptors on parietal Cells: (GPRC which ↑ cAMP) Best works for nocturnal acid, now OTC; any acidic condition and presurgery Few side effects: rash, itch, HA, nausea cimetidine has antitestosterone effect with chronic high use Cimetidine inhibits the liver metabolism of many drugs, others do not! H2 & H1 antagonists may cause severe allergic reactions |
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Cimetidine
|
H2 receptor agonist notorious for inhibiting liver metabolism of:
warfarin, phenytoin, theophylline, propranolol, benzodiazepines, TCA's, nifedipine, digoxin, quinidine others do not! ↓ GI acid formation by blocking H2 receptors on parietal Cells: (GPRC which ↑ cAMP) Best works for nocturnal acid, now OTC; any acidic condition and presurgery Few side effects: rash, itch, HA, nausea cimetidine has antitestosterone effect with chronic high use H2 & H1 antagonists may cause severe allergic reactions |
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PPI's
|
-prazoles
DOC for GERD, ZE syndrfome; also used to prevent ulcers form NSAIDs; takes about 1 mo to heal a duodenal ulcer, 2 to heal a gastric ulcer; irreversibly binds H+/K+ ATPase in parietal cell, extremely effective 1/day best on empty stomach 30 min prior to meal: prodrug activated in parietal cell irreversible block of acid formation, so long lasting effect (thus the 1/day) SEfx: Minimal nausea, daiarrhea, colic; chornic use ↓ Ca2+ absorption → osteoporosis Omeprazole may inhibit P450 |
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Sucralfate
|
cytoprotective GI drug
polymerizes to provide protective barrier for cells in ulcer base contains aluminum, causes constipation take on empty stomach, upset common, forms non-absorbable complexes with dgitialis, tatracycline &^ phenytoin; rarely used |
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Misoprostol for the GI tract
|
prostaglandin E1 analuge use dto prevent ulceration by NSAIDs
also used to produce abortions: contraindicated in pregnants or those who may become pregnant SE: GI, HA, dizziness |
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Antibacteiral Agents for Ulcers
|
metranidazole, [amoxacillin, tetracycline & clarythromycin]
|
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Prokinetic Agents
|
alter neural regulation of gastric motility by stmulating cholinergic neurons, inhibiting adrenergics and modulating DA & serotonin;
metoclopramide is D2 antagonists, increases ACh; anti-mimetic, -GERD; Cramping & diarrhea common; at high doses produces parkinson's sx Bethanechol- Muscarinic Agonist Erythormycin- stimulate motilin receptors, used for diabetic gastroporesis Cisapride- off market Should not be used in pregnancy |
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IBS
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Tx: diet drugs, reduced stress
Glycopyrrolate, dicyclomine, TCA's Muscarinic antagonists Glycopyrrolate & Dicyclomine = antispasmotic TCA's for chronic pain, anticholinergic effects ↓ spasticity Stimulating 5HT4 increases ACh release & ↑ peristalisis, while 5HT3 sends pain signals to CNS alosetron is 5HT3 receptor antagnoists; given for IBS with severe diarrhea; causes conspitation, may be severe: obstruction, perforation; many contraindications (GI problems): risk benefit statement required |
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-setrons
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Antinausea agents
-setrons: Ondansetron, Ganisetron, Dolasetron, Palonosteron 5HT3 antagonists (causes the CNS discomfort); ver effective for nausea & vomitting with few side effects; not effective for motion sickness N/V Few side effects: HA, constipation, dizziness |
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prochlorperazine
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like promethazine
blcoks DA, msucarinic, histamine receptors anti-nausea/emetic used post op, highly sedating synergistic with dronabinol THC anti-emetic appetite stimulant |
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promethazine
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like prochlorperazine
blcoks DA, msucarinic, histamine receptors anti-nausea/emetic used post op, highly sedating synergistic with dronabinol THC anti-emetic appetite stimulant |
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Dronabinol
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THC cannabinoid similar to Nabilone
anti-emetic, appetite stimulant used for chemotherapy induced N/V synergistic with prochloperazine/promethazine anti-emetics |
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Bulk Forming Laxatives
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Fiber: dietary, methylcellulose, psyllium polycarbophil
High fiber diest is the best causes flatulence & bloating take with pletny of water some can bind drugs and decreease availabilities |
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Contraindications to Laxative Use
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Intestinal Blockage, PErforation, Toxic megacolon
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Osmotic Laxatives
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All produce intense effects used to prepare for bowel surgery or dx procedurrees
Magnesium hydroxide: also stimulates GI tract Sodium Salts: oral orenema Sorbitol, amnnitol, sucarlose, used as sweeteners Lactulose: used in cirrhosis to decrease NH3, causes flatulence Polyethylene glycol: prep for colonoscopy, OTC for constipation Take with lots of water! With the exception of lactulose & in liver diseases, these should onot be used chornically |
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Whole section on normal bowel function
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Dammit man there's no time!
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Mucosal Acting Laxatives
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Stimulate peristalis, enhance secretion & inhibit H2O absorption
Mild: bisacodyl, Senna Intense: caster oil, requies bile and sitmultes uterus; used for sugery & dx Caster oild not suitable when there is biliary obstrx; |
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Lubricant/Softener Laxatives
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Not very eeffective; Mech: Increase bulk
Mineral oil: 3 days at most it will preventa bsorption of fat soluble vitmains; if inhaled it can caause lipoid pneumonia; it can leak from butt, staining and embarassing; Docusate: emulsifying agent allows water to peenetrate colonic contents Glycerin: suppositories for lubrication; |
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Use of laxatives
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reduce straining
maintain soft stool sempty bowel for dx/surgical procedures decreased bowl tone geriatrics, pregnancy rid pathogens/toxins consptiation eg from opiods Conras: N/V, Abdominal cramps, undiagnosed abnomimal pain, appendicits, intestinal obstrx Overuse: dependence, fluid/elyte imbalance, spastic colitis, ulcerative colitis |
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Lubiprostone
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E1 analogue
activetes Cl- channels in luminal cells to ↑ fluid secretion softer stools with better moility, no effect on elytes, no depndence causes nausea, no systemic absorption |
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Alvimopan
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Opiod mu receptor antagonist with only peripheral effects: selective for GI tract;
useful for post-op opiod induced constipation should not be used if opiods have been used >7 days preoperativesly Warning for short term hostila use only |
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Absorbents
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anti-diarrhetics
Absorb water, form gel like mas bulk forming agents may be laxitives not very effective, most benefit to watery diarrhea |
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Opiodds vs diarrhea
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loperamide does not enter CNS, low abuse potential, may cause abodminal pain, constpiation; Available OTC
Diphenolxylate/atropine; combo w/ atropine reduces abuse ↑ effectiveness; has anticholinergic side effects: OD produces atropine poisoning. Contras: infections, decreases expulsion UC: toxic megacolon recoverign drug addicts: abuse potential |
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Bismuth salicylate
(Peptobismol) |
absorb excess water &pathogens themslves
salycilate inhibits COX --> decreases secretions, anti-inflammatory Useful for travellers diarrhea produces black tongue, mouth & stool Cotnras: allergic to aspirin, children (reyes), caution in asthmatics. Bismuth citrate should be used in these pts. |
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Sulfsalazine
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anti-inflammatory 5-aminosalicylic acid + sulfapyridine
Bacteira in GI tract activate it used in Inflammatory Bowel Disease allergic rxns possible to salicylate avoid in children for reyes |
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Simethicone
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Gas-X
coats gas, dissipates decreases blaoting and flatulence |
