Endocrine Pharm Flashcards
Cabergoline
Bromocriptine
Dopamine agonist
- DA from hypothalamus tonically inhibits Prolactin
- -prevent breast tenderness & engorgement
- -inhibit lactation
- -amenorrhea & galactorrhea
- –hyper-prolactinemia due to pituitary adenomas
- -paradoxically ↓ GH from GH-adenoma
- –DA usually ↑ GH release
- Cabergoline is more effective at ↓ prolactin
- -tolerated better
- -longer half life (2x week vs daily)
- may cause erythromelalgia*
- CI:
- -pregnancy unless they have prolactin-tumor
- -ergot related drugs
- -syncopal migranes
- inhibits excessive SNS tone (DIABETES)
- ↑ suppression of hepatic glucose production
- -↓ fasting & postmeal plasma FFA & TG levels
- ↓ cardiovascular end point problems in diabetics
Sermorelin
GHRH agonist
- GH deficiency treatment
- not as effective as GH
-determine origin of GH deficiency (hypo vs. pit)
Growth Hormone
- ↑ longitudinal bone growth
- ↑ mineral density after epiphyseal closure
- *↑ gluconeogenesis in hepatocytes
- *↓ glucose utilization in Muscle & Adipose (anti-insulin)
- *↑ lipolysis in adipocytes
- ↑ muscle mass → GH deficient individuals
- ↑ IGF-1 → most anabolic/growth effects
- -IGF receptor is RTK
- –binds insulin with 1/2 affinity
Somatropin
–Somatrem
GH agonist
- treat Growth Failure
- -GH deficiency (mainly children)
- -chronic renal disease
- -Turner’s syndrome
- cachexia im AIDS wasting
- ↑ GI function in short bowel syndrome
Adverse Effect:
- fluid retention, edema → ↓ w/ time
- musculoskeletal pain & stiffness
- Hyperglycemia → C.I. DM
- Hypothyroidism → C.I. hypothyroidism
- Somatrem is more immunogenic at **injection site
Mecasermin
IGF-1 agonist
- individuals who are not responsive to GH therapy (due to mutations of IGF or GH receptors, Ab to GH)
- -not as effective as GH therapy
- higher incidence of Hypoglycemia
- not FDA approved
Octreotide
–Lanreotide
Somatostatin analog
- ↓ secretion of pituitary & GI hormones
- -serotonin, gastrin, VIP, insulin, glucagon secretin
- -GH, thyrotropin
- ↑ intestinal absorptions of water & electrolytes
- ↓ pancreatic & gastric acid secretions
- ↑ intestinal transit time
USE:
- GH excess (acromegaly)
- other hormone secreting tumors
- excessive diarrhea
- ↓ tumor size/growth
ADVERESE:
- GI in 1/2 but subside
- gallstone & gallbladder sludge
- bradycardia, conduction disturbances
CONTRA:
- gall bladder disease
- DM
- thyroid problems (↓ TSH)
Pegvisomant
GH Antagonist
- return IGF-1 levels to NORMAL
- GH excess syndromes (acromegaly)
-may cause growth GH-secreting tumor (lack of neg feedback)
Gonadorelin
GnRH agonist–short acting
- pulsed IV administration → ↑ FSH & Prolactin release
- not available in US anymore
-treats infertility (ovulation & spermatogenesis)
-less likely to cause ovarian hyper stimulation & multi births
than direct LH or FSH
Leuprolide
- -Goserelin
- -Nafarelin
GnRH agonist–long acting (inhibits HPG activity)
- initially causes surge in of gonadotropin
- -tonic GnRH → ↓ receptors in pit & ↓ gonadotropin
- inhibits HPG axis activity
- -↓ testosterone & spermatogenesis
- *↓ androgen production in Prostate cancer
- *precocious puberty
- chemical castration
- treats endometriosis, PCOD, uterine leiomyomas
- Menopausal symptoms in women
- testicular atrophy in men
- -counter act testosterone sure w/ metastatic prostate tumors
-CI in pregnancy & breast feeding
Nafarelin is a nasal spray
Cetrorelix
–Ganirelix
competitive GnRH receptor antagonist
- suppresses LH → lower doses
- suppresses FSH → higher doses
- Suppression is used for Assisted Reproductive Technologies
- endometriosis & uterine fibroids
uFSH (Urofollitropin)
- -Follitropin alfa
- -Follitropin beta
FSH agonist
Follicular Phase
-FSH → development of ovarian follicles
→ estrogen synthesis (granulosa cells)
Men
-FSH → spermatogenesis & ABP in sertoli cells
Adverse Effect:
- ovarian enlargement
- Ovarian hyperstimulation syndrome (enlarge & fluid accum)
- Multiple births
- gynecomastia
- precocious puberty
uFSH → purified hMG; only FSH
- Follitropin is recombinant human FSH
- -more consistant
- -no urinary contaminants
hMG, Menotropins
gonadotropin mixture (used as FSH)
-isolated from urine of postmenopausal women
(no estrogen → no inhibition → ↑ FSH)
Human chorionic gonadotropin
- -Choriogonadotropin alfa (recombinant hCG)
- -Lutropin (recombinant LH)
LH agonist
-↑ w/ sustained high levels of estrogen
-LH → stimulates ovulation & luteinization of follicles
→ progesterone synthesis in luteal cells
→ testosterone synthesis in Leydig cells
- hCG first followed by hMG → male infertility
- hMG given first (9-12days) then hCG → ovulation
- hCG has longer half life than LH
- -differentiate b/w hypogonatotropic hypogonadism & constitutional delay of puberty (HH → no ↑)
-Lutropin only for use w. Follitropin alfa
Adverse Effect:
-ovarian enlargement
-Ovarian hyperstimulation syndrome (enlarge & fluid accum)
-Multiple births
-gynecomastia
-precocious puberty
Estrogen
- Ovary: prepare follicle cells for ovulation (w/ FSH)
- Uterus: endometrial cell division & growth (follicular phase)
- Vaginal epithelium proliferation
- Endocervical glands: regulates composition of mucus
- Breasts: ↑ ductal epithelial cells → pregnancy & puberty
- Puberty: 2º sex characteristics & closing of epiphysis
- -stromal & accessory sex organs in males
- Bone: maintain mass & prevent resorption
- Clotting: ↑ synthesis of cutting proteins & ↑ platelet adhesiveness
Metabolic: ↑ synthesis of liver proteins (binding globulins)
- ↑ HDL & ↓ LDL
- Na & H2O retention
Estradiol (endogenous)
Estrogen
- Primary hypogonadism–deficient pts age 11-13 → puberty
- postmenopausal HRT
- oral contraceptive
- suppress ovulation
- adrogen dependent cancers (prostate)
- -lowers serum testosterone → remission
Adverse: (dose dependent)
- migraines
- ↑ blood clotting and platelet aggregation (embolism
- HTN
- gallbladder disease
Contraindicated:
- estrogen dependent neoplasm (breast carcinoma
- thromboemoblic disorder
- pregnancy
- not orally active
- -creams or patches
Tamoxifen
–Toremifene ( ↑ HDL)
Anti-estrogen
-Selective estrogen receptor modulator (SERM)
- Antagonist → Breast
- –Agonist → Uterus & Bone
DOC: estrogen dependent breast cancer in premenopausal women
- in other tissues acts like AGONIST
- -prevents bone loss
- -may ↓ HDL
- -does not relieve hot flashes
-↑ risk of uterine cancer (agonist at uterus)
CI: Thromboembolic disease & Breast feeding
Raloxifene
Anti-estrogen SERM
- Antagonist → Breast and **Uterus (↓ uterine cancer)
- -Agonist → bone & liver
- **prevents post-menopausal osteoporosis
- ↓ RISK of invasive breast cancer
- -postmenopausal women w/ osteoporosis
- ↓ LDL in post-menopausal women
- may be used for HRT**
Adverse:
- hot flashes
- DVT, leg cramps
Clomiphene
Anti-estrogen SERM
- Antagonist → hypothalamus (inhibits neg. feedback)
- Agonist → everywhere else
- DOC: Infertility treatment in women w/ intact HPG axis
- -↑ LH and FSH secretion
- -reset ovarian responsiveness → ovulation
Adverse:
-multiple pregnancies
Fulvestrant
Anti-estrogen
- pure estrogen receptor antagonist
- treat Tamoxifen resistant tumors (breast cancer)
Anastrozole
–Letrozole
Aromatase inhibitor (aromatase only in granulosa cells)
- Non-steroidal competitive inhibitors of Aromatase
- breast cancer in post menopausal women?
*Exemestane
Aromatase inhibitor (aromatase only in granulosa cells)
-Steroid → irreversible inhibitor of aromatase
- DOC: breast cancer in postmenopausal women
- 2nd line for breast cancer in postmenopausal women whose cancer progressed during tamoxifen therapy
Adverse:
-Menopausal symptoms
Contra:
- Premenopausal women
- Pregnancy → category X
Progesterone
Progestin (Pregnane) (Tocolytic)
- Converts uterus to secretory state
- -needed to maintain pregnancy (↓ contractility)
- Endocervical glands → mucus composition
- Breast → lobuloalveolar development (preg. & puberty)
- ↑ body temp
-antagonize mineralcorticoid receptor
Use:
- *Oral contraceptive w/ or w/o Estrogen
- *prevent endometrial hyperplasia in HRT
- Treat: dysmenorrhea, endometriosis, hirsutism, uterine bleeding disorders
- -when Estrogen is CI
- ***-treat Endometrial cancer (mxn unknown)
Adverse:
- may ↓ HDL
- depression or drowsiness
TOCOLYTIC
- maintains length of pregnancy if given prophylactically from 16-37th week or delivery
- only use in women w/ history of birth <37 weeks
- not effective for acute preterm labor
–Desogestrel
Progestin (Gonane)
- selective progestin activity
- low to no androgenic properties
Mifepristone
Anti-progestin
- blocks binding of progesterone → progesterone receptor
- antagonizes glucocorticoid receptor → CUSHINGS
- terminates pregnancy
- -given w/ misoprostol
- prevent implantation if take w/in 72 hrs
CI:
- pregnancy or breastfeeding
- glucocorticoid therapy
Danazol
Anti-progestin
- Weak progestin, androgen and glucocorticoid →
- –suppresses ovarian function
-treat Endometriosis**
Adverse:
-hirsutism, deepening voice, acne, oily skin
Contra:
- liver dysfunction
- pregnancy or breastfeeding
–Drospirenone /ethinyl estradiol (Yaz)
Phenytoin, carbamazepine, StJW → ↓ effectiveness
OC ↓ effectivness of:
- anticoagulants
- anticonvulsants
- TCA
- guanethiden
- warfarin
- ORAL hypoglycemic agents
-combo of estrogen & spironolactone derivative
–mineralcorticoid antagonist
- ↓ water retention → reduces PMDD symptoms
- very low androgenic properties
- Inhibit ovulation → no LH surge
- ↓ implantation → change cervical mucosa & endometrium
- discontinuation → withdrawal bleeding at end of cycle
- ↓ endometrial & ovarian cancer
- ↓ acne
- ↓ PCOS
ADVERSE:
estrogen → weight gain, nausea, edema
Progestin → weight gain & depression
-thromboembolic & clotting disorders**
–↑ synthesis of coagulation factors & fibrinogen
–↑ risk of thromboembolic and clotting disorders
–↑ risk if >35 and smoke
-mild HTN
-Migraine (may be warning of stroke)
-Teratogenic - 1st trimester
-↓ Fertility → gonadotropin for 3 months after stopping
-Breast feeding
ABSOLUTE CI:
- *Thromboembolic phenomena
- *estrogen dependent neoplasms
- thrombophlebitis
- cerebrovascular disorders
- pregnancy
Testosterone
- -Methyltestosterone
- -Fluoxymesterone
- -Oxymethalone
- -Oxandrolone
Androgen
Virilizing (Androgenic) effects:
- spermatogenesis
- sexual development
Anabolic effects:
- ↑ bone density
- *↑ AA incorporation into muscle
- ↑ RBC mass
- antagonize catabolic effects of glucocorticoids
MEN → testicular deficiency
-avoid use for impotence in aging → ↑ risk prostate cancer
FEMALES → hypopituitarism (estrogen & androgens
-BOTH → protein loss
Adverse effects: MEN: -Inhibits release of LH and FSH --↓ testosterone production --↓ spermatogenesis WOMEN: -masculinization- deep voice, clitoral enlargement -loss of gonadotropins (atrophy of breast & uterus) -pregnant → pseudo-hermaphroditism BOTH -oily skin, acne -↓ HDL -psychological changes→ aggression, depression, psychosis
CI
-children → closes epiphyseal plate
Ketoconazole
Androgen synthesis inhibitor
-antifungal → need 4x anti fungal dose
- inhibits 17α hydroxylase → ↓ androgens then ↓ cortisol
- -higher dose inhibit cholesterol → pregnenolone (all steroids)
Women:
-hirsutism, premenstrual syndrome, cystic acne
Men
- prostate tumors
- SE of gynecomastia, ↓ libido, impotence
- HIGH DOSES in Cushing’s before surgery or radiation
- -**most effective inhibitor of steroid synthesis in pts w/ Cushings DISEASE (problem at pituitary; ↑ ACTH)
Spironolactone
Androgen synthesis inhibitor & Anti-androgen
- mineralcorticoid antagonist
- -competes w/ aldosterone for binding at low doses
- -competes for androgen & estrogen receptors at *↑ doses
- reduces 17α-OH activity→ ↓ glucocorticoids & androgens
Use:
- *hirsutism & PMS
- *precocious puberty (both sexes)
- HTN
- primary aldosteronism
- *ascites w/ cirrhosis
Adverse:
- hyperkalemia
- gynecomastia & impotence → men
- menstrual irregularites → women
Flutamide
- -Bicalutamide
- -Nilutamide
Anti-androgen
-↓ male accessory sex organ function
Use:
- prostate cancer w/ **Leuprolide (GnRH agonist)
- topically → male pattern baldness, hirsutism
Adverse:
- mild hepatotoxic
- Bicalutamide is less hepatotoxic
- -1x day dosing
- affects libido
Finasteride (Propecia)
–Dutasteride
5α-reductase inhibitors
- ↓ DHT
- ↑ testosterone
- ↑ TSH
- ↓ total serum PSA
- supress male sex accessory organ (prostate) w/o affecting libido
Use:
- BPH
- male pattern baldness
Adverse:
- impotence (ejaculation dysfunction too)
- ↓ libido
CI:
- pregnancy → teratogenic to male fetus
- may mask ↑ PSA due to prostate cancer
Corticotropin
-Cosyntropin
ACTH → ↑ glucocorticoids & androgens
- used diagnostically to distinguish b/w 1º (adrenal malfunction) and 2º (pituitary malfunction) adrenocortical insufficiency
- 1º = Addisons
- if ↑ in cortisol → pituitary problem
- no ↑ in cortisol → adrenal malfunction
Fludrocortisone
Mineralcorticoid–zona glomerulosa
(when and why)
- has both mineralcorticoid & glucocorticoid activity
- -high glucocorticoid
- -much more significant mineralcorticoid properties
- -(10 : 250)
- effects similar to aldosterone
- -↑ Na and H2O retention
- -↑ K and H loss
-use: salt-losing adrenogenital syndrome
–given w/ cortisone for replacement therapy in
–→ 1º adrenal insufficiency (problem w/ adrenal)
2º adrenal insufficiency → just cortisone
Aminoglutethimide
Mineralcorticoid synthesis inhibitor (tx cushing syndrome)
- inhibits cholesterol → pregnenolone (opposite of ACTH)
- -inhibits ALL steroid synthesis
- -inhibits aromatase enzyme– estrogen synthesis
-Tx in Cushing SYNDROME (not at pituitary)
–adrenal carcinoma or ectopic ACTH-tumor
-Tx Metastatic Breast and Prostate cancer that has not
responded to tamoxifen or anti-androgen
- can cause adrenal insufficiency → give w/ corticosteroids
- inhibits estrogen synthesis
- less effect on testosterone
Mitotane
Adrenocorticolytic (tx cushing’s DISEASE)
- selective atrophy of Zona Fasciculata & Reticularis
- -binds mitochondrial proteins → ↓ synthesis of corticosteroids
- 1º adrenal carcinoma when surgery or rad not possible
- can produce remission of Cushing’s DISEASE (at pituitary)
-severe GI distress
Metyrapone
Glucocorticoid synthesis inhibitor
- selective inhibitor of 11β-hydroxylase terminal enzyme in cortisol synthesis
- -↓ cortisol levels
- -↓ deoxycorticosterone → ↓ aldosterone
- -↑ 11-deoxycortisol → sustains aldosterone function w/o much glucocorticoid effect
- tests of adrenal function & short term management of Cushings
- only drug in this class → pregnant women
- hirsutism → androgen shunt
Glucocorticoid Effects
FAT, CHO, PROTEIN
- **↑ gluconeogenesis & glycogen storage → LIVER
- -catabolize protein → neg. nitrogen balance
- -↑ AA in blood
- -↑ activity & amount of enzymes
- **↑ Lipolysis
- -↑ plasma FFA
- **redistribution of body fat → moon face, buffalo hump
- **Antagonizes insulin → hyperglycemia & glycosuria
- -↓ glucose use in muscle and fat
CARDIOVASCULAR (can treat shock)
- ↑ vasc. responsiveness to SNS → hypertension
- ↑ cardiac output
- some Na and H2O retention → edema
- -↓ K+
ENDOCRINE
- immediate → ↓ release of CRH → ACTH
- Chronic → ↓ other endocrine systems
- -GH
- -LH → sex hormones → ↓ reproduction
- -TSH → Thyroid
- ↑ PTH → ↑ osteoclast → less Ca in bone
- Inhibits action of Vit D → ↓ Ca deposition into bones
- ↑ Epinephrine production in adrenal medulla
- ↓ catecholamine re-uptake
IMMUNE
- ↓ inflammatory & immunological responses (ulcers)
- -blocks all steps in inflammatory process
- -inhibits PLA2, COX2, Cytokines (TNFα), IgE (histamine)
- blocks early (edema, fibrin, PMN migration, phagocytosis)
- blocks late (collagen synthesis & deposition) wound heal
- Lympholytic effects (CLL & MM)
CNS
- mood elevation, insomnia, restlessness, anxiety
- depression or psychosis
GI
-peptic ulcers → ↓ immune response to H. pylori
Misc. side effects of long term use
- cataracts
- ↑ intraocular pressure
- glaucoma
- acne, skin atrophy/thinning, striae, bruising
CI → none for adrenocortical insufficiency -systemic bacterial infection -poorly controlled diabetes -osteoporosis peptic ulcer -heart disease or HTN w/ CHF
Hydrocortisone aka cortisol
-Cortisone (prodrug)
- EQUAL mineralcorticoid & glucocorticoid (1 : 1)
- replacement therapy → adrenal insufficiency
- -2º adrenal insufficiency (Addison’s)
- fludrocortisone → 1º insufficiency
- Cortisone is same except:
- -must be converted to hydrocortisone by liver
- -has 80% anti-inflammatory & sodium retaining potency
Prednisone (prodrug)
Prednisolone
Higher anti-inflammatory effects & minor salt-retaining
(4 : 0.3)
- Prednisone must be converted to prednisolone in liver to be active
- asthma treatment
Triamcinolone
Methylprednisolone
Highest anti-inflammatory effects & NO salt-retaining
(5 : 0)
-asthma treatment
