Drugs Flashcards
First gen antihistamines
Brompheniramine, cyproheptadine, diphenhydramine, promethazine, hydroxyzine, pyrilamine
Most sedating first gen antihistamines
diphenhydramine, promethazine (ethanolamines, phenothiazines)
First gen antihistamines with anti-cholinergic effects
diphenhydramine, promethazine
First gen antihistamines with local anesthetic effect
promethazine and pyrilamine
First gen antihistamines with anti-serotonin effect (headaches)
cyproheptadine and azatadine
First gen antihistamines with weak alpha-adrenergic antagonism
Phenothiazines (promethazine)
Second gen antihistamines
loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine
Second gen antihistamine that has been withdrawn
Terfenidine
Second gen antihistamines with no anti-muscarinic activity
fexofenadine, cetirizine
Active metabolite of terfenadine
Fexofenadine
Active metabolite of hydroxyzine
Cetirizine
What other actions might cetirizine have?
Block LTC4 (contracts SM of bronchioles), migration of neutrophils, and infiltration of eosinophils
topical antihistamines (eye drops and nasal spray)
olopatadine, azelastine, KETOTIFEN
what is dimenhydrinate (Dramamine) and what is it used for?
diphenhydramine with chlorotheophylline salt, used for motion sickness
what are antihistamines used for motion sickness?
dimenhydrinate (Dramamine), meclizine (Antivert), promethazine (Phenergan)
why would you use an antihistamine (i.e. parenteral diphenhydramine) with epinephrine?
to treat anaphylaxis
What should you not mix first gen antihistamines with?
alcohol, anxiolytics, antipsychotics
Which drugs are contraindicated in urinary retention and narrow angle glaucoma, and why?
first gen antihistamines and (des)loratadine bc they have anti-muscarinic effects
What drug(s) causes extrapyramidal effects, and what are those effects?
promethazine (phenothiazine) - dystonia, akathisia, Parkinsonian rigidity
Mechanism of CNS depression by antihistamines
Histamine action on H1 receptors in the thalamic relay cell maintains their depolarization so they do not fire action potentials (wakefulness) but antihistamines remove this so the cells hyperpolarize and fire bursts of action potentials which lead to sleep
Antacids
NaHCO3, CaCO3, Al(OH)3, Mg(OH)3
Neutralizing capacity of NaHCO3 and adverse effects
High neutralizing capacity; fluid retention
Neutralizing capacity of CaCO3 (Tums) and adverse effects
Moderate neutralizing capacity; milk-alkali syndrome
Neutralizing capacity of Al(OH)3 (Alternagel) and adverse effects
High neutralizing capacity; constipation
Neutralizing capacity of Mg(OH)3 and adverse effects
High neutralizing capacity; diarrhea
What is the formula of Maalox/Mylanta?
Al(OH)3 and Mg(OH)3
What is Gaviscon (sodium alginate and antacids) and how does it work?
Viscous, weak base which prevents reflux and is effective in GERD (used for heartburn and indigestion)
What is Mylicon/Phazyme (Simethicone) and how does it work?
It is a mild surfactant which enhances release of gas (used to relieve pain from gas)
What does liver enzymes/drugs does cimetidine inhibit?
CYP2C6 and 2D9: warfarin, phenytoin, theophylline, benzodiazepines, sulfonylureas
What are side effects of cimetidine?
CNS effects when given IV to elderly pts (confusion, delirium, headaches), antiandrogen (gynecomastia, impotence), inhibition of estradiol metabolism (galactorrhea), thrombocytopenia
2nd gen H2 antagonists
Ranitidine (Zantac), Nizatidine, Famotidine (Pepcid)
Features/effects of 2nd gen H2 antagonists
increased bioavailability of ethanol (except famotidine), reduced interactions with the CYP450 system, greater potency, longer half life
Proton pump inhibitors
omeprazole, lansoprazole, raberprazole, pantoprazole
How does omeprazole become activated?
Omeprazole travels to the parietal cell where it is protonated and becomes sulfenic acid, then it becomes dehydrated to cyclic sulfenamide and then binds irreversibly (forming a disulfide complex) to the H/K-ATPase
How long is the plasma half-life of PPIs, and how long is their duration of action?
plasma half-life: 1 hour
duration of action: 24 hours
What drugs’ metabolism is affected by the increase in gastric pH after taking PPIs?
digoxin, ketoconazole (require acidity for GI absorption)
What liver enzymes/drugs does omeprazole inhibit?
CYP2C19: diazepam, warfarin, phenytoin are increased, clopidogrel activity reduced
What drug can cause a vitamin B12 deficiency and why?
omeprazole, because it decreases the oral bioavailability of vit B12
Is the risk of osteoporotic fracture increased with PPIs?
Yes - long term use increases the risk of fracture
What is acid rebound?
Decreased acidity of the stomach leads to less somatostatin release and inhibition of gastrin, leading to hypergastrinemia, and increased gastric acid secretion upon withdrawal of acid-suppressing meds (occurs more commonly with H2 antagonists)
Sucralfate
Aluminum hydroxide complex of sucrose, polymerizes in the acidic pH and forms a protective barrier on injured mucosal tissue (ulcers), poorly absorbed, may reduce the absorption of tetracycline, phenytoin, and digoxin
Misoprostol
semi-synthetic prostaglandic E1 derivative, acts on parietal cells to reduce acid secretion, acts on superficial epithelial cells to increase mucous production, used in combo with long-term NSAIDs, adverse effects include diarrhea and causing abortion
How do you treat an H. pylori infection?
combo of bismuth salt + PPI/H2 blocker + abx (metranidazole, tetracycline, amoxicillin, clarithromycin) + ranitidine bismuth citrate
bismuth subsalicylate (Pepto Bismol)
converted in GI tract to bismuth salts and salicylic acid, used to treat mild diarrhea and part of a combination therapy for H. pylori, has antibacterial, antiviral, and antisecretory activity
metoclopramide
dopamine (D2) receptor antagonist which leads to increased Ach release and GI contraction; action at D2 receptor in area postrema also gives this drug anti-emetic action; used post-op and in diabetics for gastrioparesis, to relieve GERD, to facilitate small-bowel intubation, anti-emetic; side effects are sedation, Parkinson-like and extrapyramidal Sx, hyperprolactinemia (galactorrhea, gynecomastia, breast tenderness)
erythromycin
motilin agonist, but tolerance develops rapidly
5HT4 agonists (prokinetic)
cisapride
tegaserod - withdrawn bc cardiovascular toxicity
prucalopride - not available in the US
linaclotide
prokinetic; increases activity of guanylate cyclase (increases cGMP which decreases activity of pain fibers in the submucosa and increases activity of the CFTR pump which pumps Cl and HCO3 into the lumen), used to treat IBS/constipation/idiopathic constipation; taken 30 min before first meal; main adverse effect is diarrhea; not absorbed systemically
bulk-forming laxatives
psyllium, methylcellulose, bran, milk of magnesia - non-absorbable and form hydrophilic mass in the presence of water
osmotic laxatives
lactulose, polyethylene glycol - increase water in the intestinal lumen by osmotic force, leading to distension and an increase in peristalsis
stool softeners
docusate sodium, mineral oil, glycerin (surfactants and lubricants) - incorporate into stool to make passage easier, lubricate lower bowel to prevent stool impaction, can reduce the absorption of fat-soluble vitamins
anticholinergic anti-diarrheals
bentyl, dicyclomine
opiate anti-diarrheals
diphenoxylate (formulated with atropine for anti-muscarinic effects and decreased risk of abuse) and loperamide slow gastric emptying, do not cross BBB well, risk of constipation, contraindicated in ulcerative colitis and bacterial diarrhea
kaolin
magnesium aluminum silicate combined with pectin which absorbs bacterial toxins and fluid, reducing stool liquidity
fiber
anti-diarrheal
alosetron
5HT3 receptor antagonist, used in women with IBS and diarrhea, can cause severe constipation requiring hospitalization/surgery and ischemic colitis, blocks visceral afferent pain sensation and decreases colon motility, restricted use
D2 antagonist anti-emetics (area postrema)
promethazine, prochlorperazine
anticholinergic/antihistamine anti-emetics (nucleus of solitary tract)
meclizine, scopolamine
5HT3 receptor antagonist anti-emetics (nucleus of solitary tract)
ondansetron, granisetron: prevent activation of chemoreceptor trigger zone and vagal afferents to vomiting center; combined with aprepitant and dexamethasone; used prophylactically for vomiting associated with anesthesia or for chemotherapy-induced nausea and vomiting
Cannabinoid anti-emetics
dronabinol, nabilone: used for nausea/vomiting associated with chemotherapy; synthetic THC (tetrahydrocannabinol); used in pts who are refractory to other anti-emetics; may cause psychoactive effects
human insulin cDNA in plasmid expressed in E. coli
Humilin (Lilly)
human insulin cDNA in plasmid expressed in transformed yeast
Novolin
ultra rapid onset/short action insulins names, onsets, peaks, duration, appearance
Lispro, Aspart, Glulisine; onset in 15 min; peak around 1-1.5 hours; duration 3-6 hours; appearance clear
rapid onset/short action insulin name, onset, peak, duration, appearance
Regular (R); onset in 30 min-1 hr; peak 2-4 hours; duration 8-12 hours; appearance clear
intermediate onset/action insulin name, onset, peak, duration, appearance, method of administration
NPH (neutral protamine hagedorn)(N); onset in 1-1.5 hrs; peak 4-12 hours; duration 24 hrs; appearance cloudy; injected subcutaneously
slow onset/long action insulins names, onsets, peaks, duration, appearance
Glargine, Detemir, Degludec; onset 1-2 hrs; peak 4-9 hrs; duration >24 hours; appearance clear
lispro
the P28 (proline) and K29 (lysine) positions are reversed, decreasing self-association (dimer and hexamer formation) of the insulin, and decreasing time to onset (injected immediately before meals)
aspart
P28 switched to aspartate, rapid onset, injected immediately before meals
glulisine
Asn3 and Lys29 are switched to Lys and Glu, rapid onset, injected immediately before meals
glargine
Asn21 of alpha-chain is changed to Gly, and 2 Arg are added to the end of the beta-chain, long acting, once daily injection; pH of 4 and precipitated when neutralized (post-injection)
detemir
Thr30 of the beta-chain is delected, Lys29 is myristylated, binds serum albumin, injected twice daily
degludec
Thr30 of beta-chain is replaced by gamma-Glu/c16 fatty acid, binds serum albumin, injected twice daily
what are some mixtures of short/long acting insulins?
NPH + R = humulin; NPL (neutral protamine lispro) + lispro = humalog
what insulins can be administered subcutaneously?
all preparations
what insulins can be administered via a insulin infusion pump?
buffered regular, all fast-acting (lispro, aspart, glulisine)
what insulins can be administered via an IV?
regular, for severe ketoacidosis or hyperglycemia
what insulins can be administered via inhalation?
Afrezza, or dry powder form of regular human insulin
What is afrezza used for and when is it contraindicated? What is a possible consequence?
used for preprandial insulin; contraindicated with asthma or COPD; may reduce lung fxn (decreased FEV)
what are adverse reactions to insulin?
hypoglycemia, lipodystrophy, lipoatrophy, or insulin resistance
agents which increase blood glucose
glucocorticoids, thyroid hormone + calcitonin, somatropin, oral contraceptives, catecholamines, isoniazid, phenothiazines, morphine
agents which increase risk of insulin hypoglycemia
beta blockers, ACE inhibitors, somatostatin, anabolic steroids, ethanol, MAO inhibitors, fluoxetine, exercise
sulfonylureas mechanism/effects
sulfonylurea binds to receptor, inactivates K+ channel and depolarizes the cell, activates voltage-gated Ca++ channels and increases exocytosis of insulin-containing granules, thus increasing Phase 1 insulin release; also increases beta cell sensitivity to glucose
first generation sulfonylureas
tolbutamide, tolazamide, chlorpropamide
second generation sulfonylureas
glipizide, glyburide, glimepiride
repaglinide
non-sulfonylurea hypoglycemic agent, taken preprandially, quick onset
starlix (nateglinide)
non-sulfonylurea K+ channel blocker, specific for pancreas vs. CV tissue, shorter T0.5 than repaglinide so lower risk of hypoglycemia, preprandial, synergistic with metformin
glinides
repaglinide (Prandin), nateglinide (Starlix), mitiglinide (Glufast)
adverse effects of sulfonylureas
prolonged hypoglycemia (bc of long half-life), neurological damage and death (due to hypoglycemia), weight gain, GI problems
drug interactions causing hyperglycemia with sulfonylureas by enhancing their action
salicylates, sulfonamides, phenylbutazone (NSAID), clofibrate
drugs interactions causing hyperglycemia with sulfonylureas by causing hypoglycemia also
alcohol, high dose salicylates
What are effects of glucagon-like peptide?
stimulates insulin secretion and increases sensitivity to insulin, suppresses glucagon secretion, slows gastric emptying, reduces food intake, increases beta-cell mass and function
By what pathway does GLP-1 lead to increased beta cell mass?
GLP-1 + receptor –> GPCR beta gamma subunit –> ERK 1/2 phosphorylation –> increased gene transcription and beta cell proliferation
GLP-1 analogs
exenatide, victoza, tanzeum, dulaglutide
exenatide and victoza
GLP-1 analogs; co-administered with metformin, TzDs, or sulfonylureas; adverse effects are nausea, vomiting, pancreatitis, and thyroid cancer (monitor calcitonin levels)
tanzeum
GLP-1 analog with a long half life because it is bound to serum albumin, injected SQ once/week
dulaglutide
GLP-1 analog bound to IgG Fc, slowly released by reduction of the linking disulfide bonds, risk of thyroid C-cell tumors and contraindicated in patients with a family history of medullary thyroid cancer
glucagon-like peptide 1 modulators (inhibitors of DPP-4)
januvia, nesina, tradjenta, onglyza
januvia, nesina, tradjenta, onglyza - features and adverse effects
administered once daily, may facilitate weight loss, may be co-administered with metformin and TzDs, side effects: nausea, vomiting, constipation, headache, severe skin reactions, possible increased risk of infections (reduced white count) and cancers
metabolism of januvia and nesina
not extensively metabolized, excreted in urine
metabolism of tradjenta
not extensively metabolized, excreted in feces
metabolism of onglyza
metabolized by CYP3A4/5, major metabolite is active, excreted in urine
symlin
amylin analog, peptide hormone, slows gastric emptying, decreases food intake, decreases glucagon secretion, blunts postpradial blood glucose rise, used with insulin
acarbose, miglitol
alpha glucosidase inhibitors; decreases carbohydrate absorption from the intestinal epithelium by inhibiting alpha glucosidases (maltase, sucrase, glucoamylase) on the brush border
adverse effects of acarbose and miglitol
diarrhea, nausea, flatulence, acarbose can cause liver damage at higher doses
sodium-glucose transporter 2 (SGLT2) inhibitors
canagliflozin, dapagliflozin, empagliflozin: increase glucose excretion in urine
canagliflozin, dapagliflozin, empagliflozin
orally active, increases risk of genital/UT infections, increased urine flow/volume, increased risk of hypoglycemia with sulfonylureas and insulin, contraindicated in patients with renal impairment, do not use DAPAGLIFLOZIN in patients with bladder cancer
metformin
anti-hyperglycemic agent, lower risk for hypoglycemia than sulfonylureas, activator of AMP-activated kinase (AMPK), in liver decreases gluconeogenesis and in muscle/fat increases glucose uptake and glycolysis
metformin mechanism in muscles
AMP accumulates in muscles while exercising and activates AMPK, which phosphorylates TBC1D1/4 which promotes GTPase activity of Rab, which dissociates from GLUT4 and allows it to translocate to the membrane
adverse effects of metformin
possible lactic acidosis, decreases B12 absorption
what effect does metformin have on the blood lipid profile?
decreased serum LDL and triglycerides
thiazolidinediones
rosiglitazone, pioglitazone (restricted prescribing due to CV toxicities, hepatotoxicity, and increased risk of bladder cancer)
when are rosiglitazone and pioglitazone contraindicated?
CHF
what is the mechanism of rosiglitazone and pioglitazone?
activate peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor (particularly in adipocytes) - reduces insulin resistance and increases target cell response to insulin
what happens to resistin, TNFalpha, and adiponectin in response to TzDs?
resistin and TNFalpha decrease, and adiponectin increases
What adipokines are elevated in obesity?
leptin, angiotensinogen (AGE), plasminogen activator inhibitor 1 (PAI-1)
What happens during growth of eunuchs and why?
Grow with long limbs and short torsos, because gonadal steroids promote epiphysial fusion
somatropin, somatrem
growth hormones injected once daily, somatropin is less antigenic than somatrem
nutropin depot
encapsulated form of somatropin, injected IM once or twice monthly
side effects of growth hormone therapy in children
intracranial hypertension, visual changes, headache, nausea, type 2 DM, scoliosis
side effects of growth hormone therapy in adults
peripheral edema, arthralgias, carpal tunnel syndrome, myalgias, mild to moderate nausea and headache, increases mortality in critically ill patients?
mecasermin/mecasermine rinfabate
reconbinant IGF-1 and IGF-1/IGFBP-3; treat Laron-type dwarfism for example (GHR deficient, GH high, low plasma IGF-1, inheritable)
sermoralin acetate
growth hormone releasing agonist - works on pituitary gland to make it release more GH (from Google)
lanreotide, octreotide, pasireotide
somatostatin analogs which suppress GH release from growth hormone secreting tumors derived from growth hormone producing pituitary cells; all have greater affinity for SSTR2 and SSTR5 than other receptors, which are more important for GH inhibition
pegvisomant
growth hormone antagonist which treats acromegaly - binds to the GH receptor and does not allows it to dimerize but not activate downstream pathways
bromocriptine, carbegoline
dopamine agonists (prolactin antagonists) which activate D2 receptors, used to treat growth hormone secreting tumors derived from lactotrophic pituitary cells; also treats tumors which secrete BOTH GH and prolactin
features of dopamine agonists (bromocriptine, carbegoline)
circulate bound to albumin, administered orally, metabolized and excreted in feces
adverse reactions to dopamine agonists (bromocriptine, carbegoline)
nausea, headache, fatigue
chorionic gonadotropin for injection
Pregnyl; purified from urine of pregnant women, has LH activity, used to treat infertility after doses of menotropins
menotropins
menopur, pergonal, humegon, repronex; LH and FSH activities; purified from the urine of post-menopausal women; treats infertility by causing ovulation (with Pregnyl)
urofollitropin
FSH activity; purified from the urine of menopausal women; same use as menotropins
follitropin-alpha and follitropin-beta
recombinant human FSH; used instead of menotropins; half lives are shorter than human FSH because of different carbohydrate moieties
recombinant human LH
lutropin alfa; used in combo with follitropin-alpha for women with LH deficiency but not to induce ovulation
recombinant human chorionic gonadotropin
choriogonadotropin alfa
Clomiphene
anti-estrogen used to induce ovulation in polycystic ovarian syndrome
What drugs cause ovarian hyperstimulation
clomiphene and menopausal gonadotropins
What adverse effect can occur in men treated with gonadotropins?
gynecomastia
Thyrogen (thyrotropin)
half life 22 hours, removed by kidney, binds to TSH receptor and induces increased cAMP and increased TH production, used in tests involving radioactive iodine uptake by residual thyroid gland or metastasized thyroid carcinoma
gonadorelin hydrochloride
GnRH for injection; diagnostic purposes; can cause headache, light-headedness, nausea, and flashing
leuprolide acetate
GnRH for injection
histrelin acetate
GnRH for injection
nafarelin acetate
GnRH for nasal spray
goserelin acetate
GnRH analog
triptorelin pamoate
GnRH analog for injection
ganirelix
GnRH antagonist; injected SQ; suppresses LH for assisted reproductive technology programs
cetorelix
GnRH antagonist; injected SQ; suppresses LH for assisted reproductive technology programs
abarelix
GnRH antagonist; injected SQ; treats advanced prostate cancer
degarelix
GnRH antagonist; injected SQ; treats advanced prostate cancer
synthetic gonadotropin releasing hormone characteristics
D-amino acids at position 6 (decrease proteolysis), ethylamide substituted for glycine at position 10 (increase affinity to receptor); used to treat female or male infertility (hypogonadotropic hypogonadism); constant use can lead to menopause-like Sx
what does a weak response of LH to injected GnRH mean? what about a strong response?
weak response - pituitary dysfunction
strong response - hypothalamic lesion
pasireotide
long acting somatostatin analog, used for acromegaly when surgery has not worked or is contraindicated
sandostatin (octreotide acetate)
SST analog; used for metastatic carcinoid tumors, VIP-secreting adenomas, gastrinomas, gucagonoma, watery diarrhea-hypokalemia-and-achlorhydria syndrome (WDHA), acromegaly
effect of octreotide acetate on GH vs insulin
better at suppressing GH than insulin, so useful for treatment of conditions because it doesn’t cause concurrent hyperglycemia
side effects of octrotide acetate
nausea, abdominal cramps, flatulence, steatorrhea
oxytocin (pitocin, syntocinon)
oxytocin; IV or nasal spray
vasopressin (pitressin)
synthetic vasopressin
desmopressin acetate
synthetic vasopressin with only ADH effect (little to no pressor effect); IV/SQ injection or nasal spray
conivaptan HCL
vasopressin receptor antagonist; V1a and V2 antagonist; treats hyponatremia
tolvaptan
vasopressin receptor antagonist; V2 > V1 receptors; treats hyponatremia
demeclocycline
tetracycline antibiotic; suppresses ADH action through attenuation of cAMP production
levothyroxine sodium
soidum salt of synthetic thyroxine available in tablets and for injection, most patients take this
liothyronine sodium
sodium salt of triiodothyronine available in tablets or for injection; risk of cardiac toxicity
liotrix
mixture of sodium salts of levothyroxine and liothyronine
radioactive iodine 131
destroys thyroid gland; used to treat thyrotoxicosis in older patients; contraindicated in pregnancy and nursing; used to diagnose disorders of thyroid fxn
propylthiouracil (PTU)
thioamide, interferes with thyroid hormone synthesis by interfering with thyroid peroxidase enzyme by inactivating the oxidized heme of the peroxidase; PTU inhibits peripheral conversion of T4 to T3 by inhibiting type 1 deiodinase; used in pregnancy because it doesn’t cross the placenta as much
methimazole
thioamide, interferes with thyroid hormone synthesisby interfering with thyroid peroxidase enzyme by inactivating the oxidized heme of the peroxidase; preferred over PTU generally
potassium iodide (lugol’s solution, SSKI, thyroshield, tablets)
preparations of iodide for hyperthyroidism
ipodate
iodinated contrast media which inhibits the deiodination of T4 to T3; used for thyroid storm when thioamides and iodides are contraindicated
amiodarone
has a very high iodine content
fluoxymesterone
anabolic steroid with androgenic properties; oral admin
methyltestosterone
Type B androgen preparation; 17alpha alkylation slows inactivation in liver, can cause liver damage; androgenic steroid; oral admin
nandrolone decanoate
Type C androgen preparation; androgens with changes in the ring structure; anabolic steroid
oxandrolone
anabolic steroid
oxymetholone
anabolic steroid
testosterone cypionate in oil
androgenic steroid; IM injection
testosterone transdermal system
skin patch, keeps serum testosterone levels from fluctuating as much
testosterone enanthate in oil
Type A androgen preparation; esterification of 17beta-hydroxyl group with carboxylic acids (more soluble in lipid vehicles for injection); androgenic steroid; IM injection
abiaterone
inhibits 17alpha hydroxylase enzyme (blocks formation of testosterone upstream)
bicalutamide
non steroid; competitively inhibits androgen receptor
danazol
weak androgen used to treat endometriosis
dutasteride
competitively inhibits 5alpha reducutase; treats BPH
finasteride
competitively inhibits 5alpha reductase; treats BPH
flutamide
non steroid; blocks androgen action by competitively binding to the androgen receptor
nilutamide
non steroid; competitively inhibits androgen receptor
fludrocortisone
F at 9alpha, leads to edema bc of Na+ retention, used for mineralocorticoid replacement therapy
tissue half life 8-12 hours
prednisone/prednisolone
core structure: cortisol
prednisone has a ketone at the 11beta position and a DB between C1 and C2
prednisolone has a hydroxyl at the 11beta position and a DB between C1 and C2
intraconvertible by 11beta hydroxysteroid dehydrogenase
tissue half life 12-36 hours
methylprednisone
core structure: cortisol
methylated at 6alpha position
potency similar to prednisolone
tissue half life 12-36 hours
triamcinolone
core structure: cortisol F at 9alpha position, hydroxyl at 16alpha position potency similar to prednisone low oral bioavailability increased hydrophilicity tissue half life 12-36 hours
dexamethasone, betamethasone
16alpha hydroxyl (enantiomers) tissue half life 36-54 hours
topical glucocorticoids
triamcinolone acetonide
betamethasone valerate
higher lipophilicity so better potency in topical applications
21-chlorocorticoids
clobetasol propionate (21-chloro analog of betametasone 17-propionate)
halobetasol propionate
halcinonide
high potency, topical application
fluticasone propionate
mometasone furoate
medium potency
topical corticosteroids
poor dissolution into inflamed tissue despite high lipophilicity and high binding affinity
inhaled glucocorticoids
triamcinolone acetonide (acetonide is resistant to hydrolysis, more potent than prednisolone, also a topical glucocorticoid) beclomethasone dipropionate (converted to 17 monopropionate by hydrolysis, more potent than dexamethasone)
other inhaled glucocorticoids
flunisolide, budesonide, mometasone furoate (also a medium potent topical), fluticasone propionate (also a medium potent topical steroid)
ethinyl estradiol, mestranol, quinestrol
17alpha alkylated estrogens, enhanced oral bioavailability
estradiol valerate, estradiol cypionate
esterification of 17beta hydroxyl, slows absorption from injection site and prolongs action
premarin
pregnant mare urine, mixture of estrogens (estrone sulfate 50-60% and equilin sulfate 20-30%)
tamoxifen, toremifene
prodrug which is oxidized in vivo, partial estrogen agonist, used to treat/prevent breast cancer; weak estrogen agonist at endometrial cells, increases risk for thrombus, prevents osteoporosis (toremifene is similar)
raloxifene, bazedoxifene
SERM (selective estrogen receptor modulator), prevents osteoporosis, decreases LDL, pro-thrombotic, decreases risk for breast cancer, does not stimulate endometrial cells, may cause hot flashes
clomiphene
SERM, increases secretion of FSH and LH by inhibiting negative estradiol feedback. used in polycystic ovary syndrome to stimulate ovulation
fulvestrant
selective estrogen receptor downregulator, pure receptor antagonist, used in patients who have become resistant to tamoxifen
anastrozole, letrozole, exemestane
aromatase inhibitors (blocks conversion of testosterone to 17 beta estradiol), used in pts whose breast cancer has become resistant to tamoxifen
norethindrone
used as progestin component in several formulations of oral contraceptives (mono-, bi-, and tri-phasic preparations)
ethynoldiol diacetate
progestin?
norgestimate –> levonorgestrel
norgestimate is prodrug, high oral bioavailability of levonorgestrel (2nd gen progestin); levonorgestrel is used in high dose as Plan B
desogestrel –> etonogestrel
3rd gen progestin, prodrug desogestrel converted to etonogestrel, similar to levonorgestrel, high oral bioavailability, used in nuvaring and nexplanon
drospirenone
4th gen progestin, antimineralocorticoid activity, negates side effects of ethynyl estradiol in combo therapy, antiandrogenic and no antiestrogen activity (desirable)
medroxyprogesterone acetate
1st gen progestin, used for depo-provera
mifepristone
progesterone antagonist, postcoital contraceptive, used with misoprostol (PGE) as abortifacient
danazol
used for endometriosis, inhibits surge of LH and FSH and suppresses ovarian fxn, contraindicated with hepatic dysfunction and pregnancy
phenytoin, rifampin
increases drug metabolizing enzymes in the liver, may interact with oral contraceptives
tetracyclines
suppress gut flora that participate in enterohepatic recycling
PTH
deletion of aa 1 and 2 eliminates activity; increases resorption of Ca2+ from collecting tubules (ECaC/TrpV5), increases Ca2+ resorption from bone, increases PO4 loss in urine, increases 1,25 (OH)2 D3 production by kidney; PTH release triggered by low serum Ca2+ levels and GPCR that binds Ca2+
vitamin D
increases Ca2+ and PO4 absorption from small intestine via ECaC2/TrpV6 on brush border; inhibition of PTH; calbindins and vit D binding protein
calcitonin
inhibits osteoclast bone resorption, increases Ca2+ and PO4 loss in urine (blocks resorption), stimulated by high serum calcium levels; Salmon and Human; used for paget’s, hypercalcemia (loses efficacy), osteoporosis >5 yrs postmenopause (alternative treatment)
bisphosphonates
first line for osteoporosis; inhibit bone resorption; 50% of absorbed dose (10%) accumulates in bone; adverse effects = nausea, vomiting, diarrhea, “dronates”
denosumab
humanized monoclonal Ab against RANKL; used for osteoporosis (2nd line); treats osteoporosis in postmenopausal women with a history of fractures, high risk of fractures, or intolerance to bisphosphonates; adverse effects are hypocalcemia, osteonecrosis of the jaw, atypical femur fractures, musculoskeletal pain, severe infections, and skin reactions
teriparatide
second line for osteoporosis; amino acids 1-34 of parathyroid hormone produced in E. coli; stimulates osteoblast when injected SQ daily with oral Ca2+ and vit D; can cause orthostatic hypertension, hypercalcemia, arthralgias, and allergic reactions; interacts with PTH/PTHrp receptor (GPCR) on osteoblasts and kidney cells
vitamid D analogs
zemplar, hectorol (prodrug hydroxylated by CYP 27 in liver); inhibit secretion of PTH with less effect on serum Ca2+ than 1,25 (OH)2 vit D3; treats secondary hyperparathyroidism; given 3X per week by IV or oral
cinacalcet
treatment of secondary hyperparathyroidism in chronic kidney disease with dialysis (loss of 1,25 (OH)2 vit D3 production); decreases serum PTH levels and serum Ca2+ levels
what is the mechanism of bisphosphonates
inhibits farnesyl pyrophosphate synthase (FPPS) and disrups prenylation of proteins in osteoclasts,
how does teriparatide increase bone mass?
when administered constantly, increases RANKL (which signals for osteoclast formation) and decreases OPG (osteoprotegerin); when administered intermittently, increases pre-osteoblasts called cbfa1 and leads to increased osteoblast number/fxn and increased bone mass and strength
what is the mechanism of denosumab?
binds to RANKL and prevents activation of RANK on osteoclast precursors, preventing differentiation of osteoclasts; injected SQ every 6 mo and pts concurrently take Ca2+ and VitD daily
factors released from osteocytes that upregulate osteoblast/clast activity
prostaglandins, nitric oxide, dentin matrix protein 1
factors released from osteocytes that downregulate osteoblast/clast activity
sclerostin, osteocalcin, matrix extracellular phosphoglycoprotein (MEPE)
Paget’s disease
uncontrolled osteoclastic bone resorption and secondary poorly organized bone formation; Sx: bone pain, bone deformities, loss of hearing, hypercalcemia, may be caused by slow-acting virus
how do loop diuretics (eg furosemide) affect serum Ca2+ levels?
the increase Ca2+ excretion because there is a decreased driving force for uptake with inhibition of Na+/K+/2Cl- co-transporter
how do thiazides affect serum Ca2+ levels?
decreased Ca2+ excretion because increased driving force for uptake with inhibition of Na/Cl transporter in distal tubule
How do PPIs and H2 antagonists affect serum Ca2+ levels?
decreased acidity of stomach decreases Ca2+ absorption (omeprazole may inhibit bone resorption)
How do carbemazepine, isoniazid, theophylline, and rifampin affect serum Ca2+ levels?
they induce Vit D catabolic P450s, leading to lower serum Ca2+??
which bisphosphonates treat Paget’s?
PagET’s
pamidronate
tiludronate
etidronate
which bisphosphonates treat osteoporosis
RAIZ risedronate alendronate ibandronate zoledronate (once/year infusion)
second line treatments for osteoporosis
estrogens and SERMs: estradiol, premarin, raloxifene (least cancer risk, but inc. risk of VTE and stroke)
teriparatide vs bisphosphonates
teriparatide builds bone mass at a higher rate than bisphosphonates, but they may cause bone cancer so reserved for severe cases of osteoporosis; also teriparatide must be injected daily
treatment of hyperphosphatemia and prevention of calcific uremic arteriolopathy
lanthanum carbonate (decreases PO4 and Ca2+) and sevelamer (decreases serum PO4 selectively)
