Endocrinology Flashcards
Peptide vs. Steroidal Agents
Peptide- cell surface receptor, signal transduction pathway via receptor autophosphorylation/tyrosine kinase cascade, PLC, IP3, DAG, adenylate cyclase, cAMP, PKA, etc
Injected, short half-life, frequent dosages, not orally active
Steroidal- intracellular receptor (cytoplasmic or nuclear), ligand-receptor direct binding to DNA
Very lipophillic
Tissue specific effects of insulin
Muscle and adipocyte- stimulation of glucose uptake
Liver and muscle- inhib glycogenolysis, stim glycogen synthesis
Liver- inhib gluconeogenesis
Adipocyte and liver- inhib lipolysis, stim fatty acid synthesis and esterification
Adipose- stim LPL
Liver and adrenals- stim cholesterol synthesis
Hypothalamus- suppresses appetite
All cells- stim amino acid uptake, stim protein synthesis, inhib protein degradation, stim DNA synthesis and cell proliferation, inhib apoptosis
Insulin preparations
Short acting synthetic (given with zinc for stability, clear solutions, neutral pH):
lispro- reverses amino acids B28 and B29, decreased hexamer stability
aspart- replacement of B28 proline with aspartic acid, decreased hexamer stability
glulisine- replacement of B29 lysine with glutamic acid, replacement of B3 asparagine with lysine, decreased hexamer stability
Short-acting (given with zinc for stability):
Regular (crystalline)
Intermediate-acting:
NPH (isophane)- protamine (protein that binds insulin) combined with insulin in phosphate buffer, prefered over lente, given as 70% NPH and 30% regular insulin
Lente- precipitate of insulin with increased zinc in acetate buffer. Can’t premix this, so NPH is more preferred
Long-acting:
Ultralente- increased zinc concentrations in acetate buffer. Very variable, has been replaced by glargine and detemir.
Glargine- pH of 4.0, 2 arginine residues added to C terminus of B chain and replace asparagine A21 with glycine to stabilize hexamer formation
Detemir- deleted B30 threonine and attached myristic acid to B29 lysine to stabilize hexamer formation and increases albumin binding
Sulfonylureas
MOA- stimulated insulin release via closing ATP sensitive K channels, may also potentiate insulin exocytosis by direct effect on binding proteins in secretory granules
Orally Active
Side effect- hypoglycemia
1st gen- tolbutamide, chlorpropamide (alcohol induced flush, hyponatremia), tolazamide (longer half life so harder to manage blood sugar in elderly)
2nd gen (100x more potent than 1st gen, short half-life)- glyburide, glipizide, glimepiride
Meglitinides
Repaglinide and nateglinide
Similar MOA to sulfonylureas in closing K channels
No direct effect on insulin exocytosis
No sulfur in structure (differs from sulfonylureas), so they don’t have problems with allergic responses to sulfur
Metformin
Does not cause hypoglycemia bc does not increase insulin, but it does increase the peripheral actions of insulin through AMPK
Decreases hepatic glucose output
Contraindicated with renal impairment, hepatic disease, and history of lactic acidosis (this last one is not a big deal with metformin)
Pioglitazone, rosiglitazone, troglitazone
Thiazolidinediones (drug class)
Increases insulin action by increasing glucose transporters
Binds to nuclear receptors PPARgama, regulates gene transcription, especially GLUT4
Troglitazone associated with liver failure, but need to monitor liver function with all of these drugs
Side effects- fluid retention, edema, weight gain, increase risk of heart failure (rosiglitazone and pioglitazone), increase risk of MI and stroke (rosiglitazone), increase risk of bladder cancer (pioglitazone)
Acarbose and miglitol
alpha-glucosidase inhibitors
decrease carb absorption
side effects- flatulence, diarrhea, abdominal pain
Colesevelam
bile acid binding resin
By weird mechanisms, it also lowers blood glucose
Used for type II diabetes
Exenatide
glucagon-like peptide-1 analog (GLP-1)
augments glucose-dependent insulin secretion
given by injection
also liraglutide
Sitagliptin
inhibitor of dipeptidyl peptidase-4 (DPP-4), which is the enzyme that degrades incretins like GLP-1
also saxagliptin
Pramlintide
synthetic analog of amylin
modulates postprandial glucose levels
suppresses glucagon release
delays gastric emptying
CNS anorectic effects
given as preprandial subQ injection
Drug Interactions
Hypoglycemic- ethanol, salicylates, beta-antagonists
Hyperglycemic- epinephrine, beta2-agonists, glucocorticoids, tacrolimus, thiazide diuretics, ca-channel blockers, clonidine, phenytoin, glucagon, diazoxide (can treat hypoglycemic episodes by binding to K channel and keeping it open, decreasing insulin release)
B-agonists main effects are peripherally, not at the pancreas
Vasopressin (ADH)
Receptors:
V1- PLC, PI hydrolysis, Ca, PKC, acts on vascular smooth muscle
V2- adenylate cyclase, cAMP, PKA, acts on principal cells and renal collecting duct
Desmopressin is synthetic analog that hits V2 selectively
Desmopressin
selective V2 agonist on principal cells in collecting duct
Treatment for Central and Nephrogenic Diabetes Insipidus
Central- desmopressin, chlorpropamide (enhances signal transduction), carbamazepine, clofibrate
Nephrogenic- lots of water intake, thiazide diuretics, indomethacin, amiloride (for lithium induced DI)
Treatment for SIADH
Water restriction, hypertonic saline
Demeclocycline (intereferes with V2 signal transduction), loop diuretics, lithium (last resort)
Conivaptan and tolvaptan- ADH receptor antagonists
Oxytocin (Pitocin)
Stimulates uterine contraction
Stimulates milk ejection from mammary glands
Major use is to induce labor
Other agents that stimulate uterine contraction
Can use these to treat post-partum hemorrhage
PG analogs in therapeutic abortion- misoprostol (PGE1 analog), dinoprostone (PGE2 analog)
Ergonovine/methylergonovine
Tocolytic agents
These relax uterine smooth muscle to prevent or arrest preterm labor
Beta2 selective agonists- terbutaline, ritodrine: relax smooth muscle
Nifedipine- Ca channel blocker: relax smooth muscle
Indomethacin- PG biosynthesis inhibitor, can also cause pre-mature closure of ductus arteriosus (adverse effect)
Atosiban- oxytocin receptor antagonist
GH agents
Somatropin
Mecasermin- recombinant IGF1 with binding protein, given for GH resistance (like in Loron type dwarfism)
LH agent
hCG (human chorionic gonadotropin)- acts at LH receptor
FSH agents
Menotropins- LH and FSH activity (horse urine)
Urofolitropin- mainly FSH (horse urine)
Follitropin- recombinant FSH
TSH agent
Thyrotropin- diagnostic agent used for thyroid cancer to enhance radioactive iodine uptake
Don’t really use for treatment, too expensive and it would be dumb
ACTH agent
Cosyntropin- diagnostic use
GHRH Agents
All diagnostic agents
Sermorelin- some therapeutic use, hard to mimic the pulsatile release
TRH and CRH
GnRH agents
gonadorelin- often given in pulsatile form (IV) to stimulate LH/FSH release, short-acting
Long-acting agents (some LH/FSH stim, but later get suppression):
leuprolide- subcutaneous
histrelin- subcutaneous
nafarelin- nasal spray
goserelin- subcutaneous
triptorelin- IM
ganirelix- GnRH receptor antagonist
cetrorelix- GnRH receptor antagonis
used for adjunct to infertility treatment, treatment of precocious puberty, chemical castration, prostate and breast cancer, endometriosis, and leiyomyomasassss
D2 Receptor agonists
Used to treat pituitary adenoma, especially prolactinomas and GH adenomas
Bromocriptine, cabergoline
Used to decrease prolactin secretion, “paradoxical” used to decrease GH release
Somatostatin analogs
Used to treat pituitary adenomas
Octreotide, lanreotide
Resistant to enzyme degradation, longer half-life
More selective action, more pituitary and less GI and pancreas
GH receptor antagonist
Used to treat pituitary adenoma
Pegvisomant
Thyroid hormones
Levothryoxine- T4
Liothyronine- T3
Liotrix- T4 and T3
Use nuclear receptors
Used to treat hypothyroidism, cretinism, suppresses TSH in treatment of thyroid cancer
High doses causes cardiac arrhythmias
Drug interactions- estrogens increase binding of T4 to TBG, glucocorticoids and androgens and salicylates decrease binding of T4 to TBG, propranolol and glucocorticoids and PTU and amiodarone and radiology contrast agents inhibit T4 to T3 conversion
Propylthiouracil
Inhibits thyroid hormone synthesis via a few different mechanisms: Inhibits peroxidase oxidation of iodide and inhibits coupling reactions of DIT and MIT. Inhibits peripheral deiodination of T4 to T3 (could make a difference if there is severe thyroid excess, would be better than methimazone in this regard)
75 min half-life (shorter than methimazole)
Can cause agranulocytosis (rare), fever, rash
Methimazole
Inhibits peroxidase oxidation of iodide and inhibits coupling reactions of DIT and MIT
Half life of 4-6 hours
Less frequent dosing, easier for patients
Can cause agranulocytosis (rare and would happen early on), fever, rash and obviously, hypothyroidism
Thiocyanate, perchlorate, fluroborate
Anti-thyroid drugs (ionic inhibitors)
Interferes with iodide concentration via blocking iodide transporter. compete with Iodide.
These are toxic agents and so not frontline drugs. Can get fatal aplastic anemia with perchlorate
Iodine131
Anti-thyroid agent
Acts the same as regular iodine
Used in older patients. Treatment with this often leads to hypothyroidism but it’s easy to bring them back to euthyroidism via thyroid hormones
Used to treat metastatic thyroid carcinoma along with TSH (enhance uptake of radioactive iodine)
Contraindicated in pregnant patients and children
I123 : diagnostic use
Glucocorticoids
Like other steroids, lipophilic and well absorbed orally.
Once in cytosol binds to GR (HSP is kicked off) and diffuses to nucleus where transcription occurs.
carbohydrate, protein, lipid “central sparing, peripheral wasting”
Uses: replacement therapy, Congential adrenal hyperplasia (ex: 21 alpha hydroxylase def), inflammatory states, asthma, immunosuppressive (transplant), ulcerative colitis
Overdose will look like a Cushing’s patient. Exogenous cortisol will cause feedback inh on Pituitary will result in decreased ACTH: Adrenals will atrophy
Mineralocorticoids
Aldosterone
Increased Na reabsorption in distal nephron/ collecting duct
Increase water absorption, K secretion, H secretion, bicarbonate generation
Fludrocortisone is an aldosterone like drug (125X) with cortisol effects 10X cortisol
Adrenocorticosteroids
Adverse: adrenal suppression during replacement therapy, fluid and electrolyte abnormalities, edema, hypertension, cataracts, osteoporosis, growth suppression in children
In kidney, cortisol gets converted to cortisone by 11B-HSD so that there are no aldosterone like effects by cortisol binding the MR. Enzyme inhibited by licorice
Oral prednisone gets converted to prednisolone by the liver using 11B-HSD. With liver disease, give prednisolone, don’t mess around.
Prednisone is 4X GR and 0.8 MR.
Triamcinolone, Betamethazone, Dexamethasone are 5X, 25X, 25X more potent on GR, respectively (and 0 on MR) Could be useful in treating someone with congestive heart failure; don’t cause more water retention but could help other problem, like inflammatory state.
Dexamethasone suppression test: If ACTH is suppressed, it is coming from pituitary (Cusing disease state). If not suppressed, look for ectopic source like lung carcinoma.
Spironolactone and eplerenone
MR (aldosterone) antagonist
Side effects- hyperkalemia, metabolic acidosis, impotence, gynecomastia (androgen effects mainly spironolactone)
Used when there is a state of corisol or aldosterone excess.
Mifepristone
GR antagonist (not a pure antagonist)
Developed as a progestin receptor antagonist
If treating a female patient at child bearing age, be cautious
Mitotane
Inhibits biosynthesis of adrenocorticosteroids
Adrenal lytic agent, used to treat inoperable adrenocortical carcinoma.
Ketoconazole
Inhibits P45017alpha (17,20 lyase) and P450acc (at high doses)
SCC cuts down everything (androgen, cortisol, aldosterone) so it’s a messy approach to bring down adrenocorticoids
anti-androgen
Metyrapone and etomidate
Anti-adrenocorticoids
Inhibits P45011beta (11-hydroxylase)
Estrogens
Estradiol- rarely used because it has a very high first pass effect in liver
Ethinyl estradiol- synthetic etrogen with ethinyl substitution at C17, decrease first pass hepatic metabolism, increase oral bioavailability, high potency, used as oral contraceptive
Estrone sulfate- conjugated estrogen, less potent, used in post-menopausal replacement therapy. Worried about breat, ovarian, and uterine cancer with estrogen, so avoid high potency drugs like ethinyl estradiol.
Adverse effects- thromboembolic disease (especially smokers), breast and uterine carcinoma (they are estrogen dependent cancers)
Benefits- decreases pregnancies with associated pathologies, osteoporosis, vasomoter symptoms, cardiovascular disease (HDL up, LDL down), vaginitis, and skin thinning
Clomiphene
Anti-estrogen
Primary estrogen antagonist effect in pituitary but it’s not very good anywhere else. Pituitary doesnt sense estrogen levels so there is no feedback inhibition; FSH and LH will be increased, which is beneficial for fertility
Main use is to induce ovulation
Fulvestrant
Anti-estrogen and selective estrogen receptor modifier
Full estrogen receptor antagonist
Used to treat breast cancer with disease progression after tamoxifen therapy
Tamoxifen and toremifene
Tamoxifen- mixed agonist and antagonist properties, anti-estrogen in breast cancer, estrogenic action on endometrium (negative: due to cancer), estrogenic bone actions (positive: less likely to cause osteoporosis)
Main use is for breast cancer
Toremifene- derivative of tamoxifen. “me too” drug
Raloxifene
Estrogenic in bone (positive effect)
Anti-estrogen in breast and endometrium (positive effects)
This drug is awesome, so why don’t we use this all the time? The debate is, is it as good as tamoxifen in treating breast cancer? Time will tell.
Progesterone derivatives
progesterone is not too terribly useful by itself. High first pass metabolism by liver and low oral bioavailability
Hydroxyprogesterone caproate- parenteral use only
Medroxyprogesterone acetate- can be used orally, used in post-meopausal replacement therapy
19-nor compounds
Progesterone analogs
Don’t have carbon 19 (nor 19)
norethindrone, norgestrel- potent and high oral bioavailability, used in oral contraceptives, androgenic
Adverse: (acne, weight gain, lowers HDL, raises LDL)
norgestimate, desogestrel- less androgenic activity
drospirenone- progestin agonist, spironolactone derivative (MR antagonist)
mifepristone- an anti-progestin, GR antagonist. RU-486 abortion drug with some controversy in this country
Mifepristone
Anti-progestin, receptor antagonist
for abortions, signals there is no progestin and so there is a signal to menstruate. In the US, not approved for post-coital contraception
Oral Contraceptives
Estrogen stays the same (usually they build during menstrual cycle) so this is non-physiological
estrogen and progestin combinations- can be monophasic, biphasic, or triphasic, suppresses LH/FSH and ovulation. *don’t be silly and memorize the composition of various oral contraceptives
monophasic is the most non-physiologic. Biphasic has higher dose of progestin for the last 11 days. The first 10 days will have lower progestin so there will be less androgen side effects with biphasic preps. Why not take drug last 7 days? allow menstruation. Triphasic is safer than biphasic because every 7 days progestrone is increased stepwise. Triphasic is most physiologic of all of the preps. More important to take the pill every day!
*Dont let your girl take a triphasic and skip a day of taking the pill
progestin only:
when there is a risk for estrogen related cancers.
norgestrel or norethindrone (mini-pill)
norgestrel (norplant)
MPA (depo-provera) injections that can last months to years for convenience
levonorgestrel (Plan B),
ulipristal (progesterone receptor modulator, suppress LH surge and ovulation)
Progestin only compds increase cervical mucus thickening (sperm barrier), alters endometrium to impain implantation
Hormone treatment of breast cancer
Selective estrogen receptor modifiers- tamoxifen, toremifene, raloxifene, fulvestrant
Aromatase inhibitors (non-steroidal)- have a nitrogen-containing heterocyclic moiety, binds heme of cyp450, competitive reversible inhibitors of aromatase, anastrozole, letrozole
Aromatast Inhibitors (steroidal)- similar to androgen substrates in structure, suicide inactivators (irreversible), very potent exemestane
Trastuzumab
Breast cancer treatment
Monoclonal antibody directed against the gene product of HER2/erbB-2/NEU oncogene
Inhibits tyrosine kinase activity (EGF receptor) of oncogene product
30-35% of breast cancers overexpress HER2/erbB-2, associated with highly metastatic, aggressive disease with poor prognostic outlook
cardiovascular side effects
Lapatinib
Inhibits erbB-1 and erbB-2 tyrosine kinase activity
Binds to internal site on receptor and also inhibits activity of truncated form of the HER2 receptor lacking binding domain
Fairly new so not known if it’s better than trastuzumab or not
Like trastuzumab, used for Non estrogen dependent cancer?
Testosterone esters
Type of androgen
Esterification makes it more lipid soluble
Testosterone propionate- short acting (2-3 times/week)
Testosterone cypionate- long acting (once every 2-4 weeks)
Testosterone enanthate- long acting (once every 2-4 weeks)
These are what we use, forget the oral androgens
Used to treat- primary hypogonadism and improve nitrogen balance, also treat (rarely though) anemia, osteoporosis, and breast cancer
Danazol, fluoxymesterone, methyltestosterone
Testosterone that is alkylated at C-17alpha postions, this decreases hepatic metabolism, increases oral bioavailability, but unfortunately they hang out and increases hepatic toxicity.
Oral androgens are rarely prescribed, but body builders still take these via black market.
Used to treat hereditary angioneurotic edema
Leuprolide
Anti-androgen
Long-acting GnRH analog downregulates receptor in pituitary and less FSH and LH
Treatment in precocious puberty, prostate cancer
Ganirelix
Anti-androgen
GnRH antagonist
Spironolactone
Anti-androgen
CYP17 inhibitor
Androgen receptor antagonist, used to treat hirsutism (lots of hair where it shouldn’t be…ie bearded lady) in women
Finasteride and dutasteride
Anti-androgen
5alpha-reductase inhibitory (finasteride mainly Type II, and dutasteride Types I and II), decreases dihydrotestosterone action
Used to treat BPH adn male pattern baldness
Androgen receptor antagonists
Flutamide, bicalutamide, nilutamide
Increased LH and FSH due to less feedback inhibition, and increased testosterone levels (not desireable), so use GnRH analog in addition to negate this effect.
Prostate cancer Rx
Bicalutamide has less adverse effects
Drugs that inhibit sexual function
Anti-hypertensives (diuretics, beta-blockers, Ca channel blockers, vasodilators, alpha 2 agonists),
psychiatric drugs (dopamine antagonists) with increased prolactin levels
anti depressants (anti-cholinergic)
alcohol, nicotine, digoxin, cimetidine, spironolactone, endocrine drugs
Drugs that increase sexual function
Pentoxifylline- “fluidize” RBCs, improve blood flow
Yohimbine- alpha 2 receptor antagonist
Sildenafil, tadalafil, vardenafil- cGMP phosphodiesterase inhibitor. color vision side effects
Phentolamine- alpha receptor antagonist. Improves blood flow to tissues. Orthostatic hypotension
Apomorphine- dopamine agonist
Alprostadil- prostaglandin E1, intraurethral app, intracavernosal injection
Metronidazole
Treatment of STDs
Active against anaerobic protozoal parasites
Treats T. Vaginalis
Growing resistance to this
Quinolones
Treatment of STDs
ciprofloxacin, levofloxacin, ofloxacin
Treatment for chlamydia, gonorrhea
Contraindicated in pregnancy
Penicillin
Treatment of STDs
Treats syphilis and sensitive gonococcal strains, although most gonococcal are penicillin resistant nowadays
Ceftriaxone
Treatment of STDs
3rd gen cephalosporin
Therapy of choice for gonorrhea
Doxycycline
Treatment of STDs
Treats chlamydia, but not recommended for gonococcal infections
Safe for patients with renal impairment because it’s not renally eliminated
Not recommended in pregnancy
Azithromycin
Treatment of STDs
Treatment of chlamydial infections and nongonococcal urethritis
1 time dose treatment
Acyclovir, valcyclovir, famciclovir
Treatment of STDs
Treats HSV type 2
*for pharm this phase, just know what drug used to treat which bug. He’s not concerned with the other details
Foscarnet and ganiclovir
Treatment of STDs
Treats CMV infection
Vit D analogs
ergocalciferol- D2, Cholecalciferol- D3 require 25-hydroxylation in liver
calcifediol- (25-OH -cholecalciferol), requires 1-hydroxylation in kidney: use if there is just a liver problem
calcitriol (1,25-dihydroxycholecalciferol): if kidney problems use this drug
Calcitonin
Salmon form is more potent, has direct effect on osteoclast to decrease bone resorption, decrease calcium and phosphate reabsorption in kidney
Used when there are hyperactive osteoclasts
Estrogens/Selective estrogen receptor modifier (SERM) effect on bone
Acts on osteoblasts to decrease osteoclast recruitment and activation
Estrogens cause synthesis of OPG which is a decoy receptor for ODF (rank ligand). Less rank ligand will interact with the rank receptor on osteoclast and so less osteoclasts will be activated. Beneficial in osteoporosis by decreasing bone resorption
Androgens can be converted to estrogens by aromatase so treating osteoporosis with androgen is maybe useful
PTH, Teriparatide
intermittent administration promotes bone growth, often combinde with alendronate
Estrogens, calcitonin decrease bone loss; PTH actually causes bone deposition
Glucocorticoids affect on Ca, VitD, etc
antagonize vit D stimulated intestinal calcium absorption, stimulate renal calcium excretion, block bone collagen synthesis, increase PTH stimulated bone resportion
Negative effect in terms of osteoporosis
Denosumab
Human monoclonal antibody against RANKL
Mimics effect of OPG
New again, awaiting results
woman has osteoporosis but has risk for breast cancer (BRCA1/2) and so how do you treat her? Denosumab obviously
Other non-hormonal agents that act on Ca, bone mineralization, etc
Ca supplements: calcium chloride, calcium carbonate (oral)
Thiazide diuretics- reduce renal Ca excretion, useful to inhibit renal Ca stone formation
Fluoride- accumulates in bone and teeth, may stabilize hydroxyapatite, increases bone volume, may increase osteoblast activity, toxicities limit use. No good systemic way to administer
Cinacalcet
calcium sensor mimetic, enhances sensitivity of parathyroid gland to free ionized Ca to suppress PTH
Plicamycin
Cytotoxic antibiotic that also decreases plasma clacium concentrations by inhibitin bone resporption
Oral Sodium Phosphate
binds cree ionized Ca
high risk procedures
Edetate disodium (EDTA)
Ca chelator
high risk procedures
Bisphosphonates
Decrease osteoclast function/ decrease bone resorption
Resembles pyrophosphate. Osteoclast eats it and apoptosis ensues
etidronate, pamidronate, alendronate, risedronate, tiludronate, zoledronate, ibandronate
retard formation and dissolution of hydroxyapatite, decreases osteoclast function
etidronate and tiludronate- metabolized into ATP analot and accumulates in osteoclasts which impairs cell function and viability, induces apoptosis, no gastric irritation with etidronate
alendronate- inhibit protein prenylation which is important for osteoclast function, less side effect of decrease bone mineralization
all have gastric irritation except etidronate
zoledronate has some renal toxicity
Treatment of osteoporosis
Estrogens (front line), bisphosphonates, Vit D analogs, calcitonin, Ca supplements, thiazides
Treatment of hypercalcemia
Bisphosphonates, calcitonin, plicamycin, gallium nitrate, phosphates, glucocorticoids
Treatment of hypocalcemia
Vit D analogs, calcium supplements
Treatment of hypoparathyroidism
Vit D analog
Treatment of hyperparathyroidism
Cinacalcet
Iodide
Wolf Chaicoff effect: give exogenous Iodide from sources like amiodarone, Lugol’s soluthion, radiology contrast agents. Iodide is toxic to cell and there is a shut down in T4 and T3 synthesis.
Quick effect to make someone euthyroid before surgery. Also for thyrotoxic crisis (thyroid storm)
Thyroid escape: downregulate Na/I receptors and so high levels of Iodide will no longer inhibit thyroid hormone production (after about 10 days of experiencing wolff-chaikoff effect). So long term treatment choice would be PTU or methimazole
