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Flashcards in Endocrine Drugs Deck (68):
1

Levothyroxine

T4, thyroxine, tetraiodothyronine
- most popular drug for treating chronic hypothyroidism
- if you give a patient T4 you end up with a mixture of T3 and T4 since T4 gets converted to T3 in the periphery
- dosage can be given anywhere from once a day to once a week (depends on the degree of hypothyroidism)

2

Liothyronine

T3, triiodothyronine
- not used very often for chronic hypothyroidism - reason being that if you give only T3, pt is not receiving any T4
--> T3 is most commonly used in emergency cases of severe hypothyroidism (T3 is much more potent than T4)

3

Liotrix

T4 + T3 (4 to 1 ratio)
- controversial drug: no evidence that the mixture is any better than T4 alone. Therefore, T4 is the more popular and cheaper drug to use.

4

Propylthiouracil (PTU), Methimazole

Thioamides - treat hyperthyroidism

- both drugs inhibit thyroid peroxidase --> inhibition of iodide oxidation in the lumen --> no formation of MIT or DIT.
- PTU in addition will inhibit 5'-diodinase (which inhibits conversion of T4 to T3)
- will not see the effects of thioamides for as long as 3-4 weeks after starting administration. This is because the thyroid has a lot of thyroglobulin with T3 and T4 ready to go when the thioamide is administered.

Methimazole is recommended higher than PTU because PTU has an associated risk of very serious liver toxicity. PTU is generally only used if patients are not responding to Methimazole.
The one exception to this rule is pregnancy - in pregnancy, PTU is recommended. Both drugs cross the placenta but Methimazole does so more easily, exposing the fetus to high amounts

Adverse effects of both Methimazole and PTU: dermatitis, hair loss, agranulocytosis

Pharmacology:
These drugs are concentrated in the thyroid - 4-5 half life elimination rule does not apply here.
Half life of PTU in the blood is about 1 hr, can administer every 5-6 hrs.
Half life of Methimazole is about 7 hr, administered once a day.

5

Dexamethasone

- long acting glucocorticoid
- treats hyperthyroidism
- a large dose of Dexamethasone will inhibit conversion of T4 to T3. This is important because T3 is more potent in stimulating thyroid hormone receptors than T4.
- In severe hyperthyroidism (thyroid storm), a large dose of Dexamethasone can be given.
- would not use Dexamethasone long term because dosage is high and there are many adverse side effects

6

Iodide

Preparations:
- Lugol's solution (5% iodine and 10% potassium iodide)
- Potassium iodide

Large doses of iodine will do 2 things:
1. inhibit the synthesis of thyroid hormone by inhibiting the oxidation of iodide
2. inhibit the release of T3/T4 from the thyroid

Problem: only effective for 2-3 weeks. After that, the effect will wear off and the thyroid will overcome whatever the mechanisms are of inhibition by the iodide and start cranking out T3 and T4 again. Therefore, used for only short term or for emergencies.

7

Radioactive iodine

- gamma and beta particle emitter
- taken up and concentrated in the thyroid
- kills thyroid follicular cells in a dose dependent manner --> lower T3 and T4
- too much radiation can result in hypothyroidism --> supplement with T4

8

Beta blockers

- treat the symptoms of hyperthyroid (will decrease HR and BP)
- non-selective beta blockers work better than selective beta blockers ex) propanolol
- in asthmatic patients you can substitute with a calcium channel blocker

9

Calcitriol (1,25-dihydroxycalciferol)

- vitamin D
- activated in the kidney, which acts immediately and rapidly to elevate calcium levels
- if not needed immediately, use ergosterol or cholesterol derivative (plant or animal source); less expensive than calcitriol
- half life is several hours; binds to binding proteins

10

Paricalcitol

- vitamin D analog
- treats secondary hyperparathyroidism (renal disease: not enough calcium around --> secretion of more parathyroid hormone) by decreasing serum PTH levels
- given IV
- short half life
- used in dialysis
- better than calcitriol for 2 reasons: 1. less hypercalcemia occurring 2. no major effects on bone resorption --> less bone loss
- side effects: nausea, vomiting

11

Calcipotriol

- vitamin D analog
Uses:
- suppression of tissue growth
- treats psoriasis
- efficacy equivalent to corticosteroids
- not protein bound --> short half life
- no hypercalcemia occurring as a result
- applied topically but can irritate area of application, so we don't give it on the face

12

Cinacalcet

- Calcium sensor sensitizer
- decreases PTH secretion for any given calcium plasma concentration: sensitizes the entire system to calcium so that at lower concentrations of calcium, less PTH will be secreted
- treats hyperparathyroidism of chronic renal failure
- Caution: hypocalcemia
- long half life
- drug interactions with itraconazole and erythromycin --> extensively metabolized
- adverse effects: GI upset, nausea, vomiting; rarely: hypotension, arrythmia

13

Agents used to treat postmenopausal osteoporosis

- estrogen hormone replacement therapy (no longer used)
- raloxifene
- bisphosphonates
- calcitonin
- teriparatide
- denosumab

14

Raloxifene

- treats postmenopausal osteoporosis
- estrogen agonist at the receptors on osteoblasts to suppress IL-6 production as well as other signals/cytokines like RANK-L in the activation/maturation of osteoclasts.
- drug works everywhere in the body --> increased risk for thromboembolic disorders
- decreases spinal fractures but not effective with hip fractures which is a big issue in osteoporosis

15

Bisphosphonates

- treats postmenopausal osteoporosis
- carbon analog of pyrophosphates. phosphates are an important part of bone, because calcium and other ions can bind to it

Unusual pharmacokinetics compared to other drugs:
- orally active but only 10% of the dose is actually absorbed, rest is secreted unchanged
The 10% that gets absorbed gets taken up by bone and has no effect until an osteoclast comes along to resorb that area of bone. Then, the osteoclasts take up the bisphosphonate leading to their ultimate destruction. Osteoclasts secrete acid to resorb the mineral portion of bone. Bisphosphonates inhibit the osteoclastic proton pump, decrease osteoclast formation/activation, increase osteoclast apoptosis
- very short half life

side effects:
- irritating to the GI, esp to the esophagus - do not want any reflux so patients taking bisphosphonates will want to sit up or stand for at least 30 min after taking the drug
- cannot take bisphosphonates with food because it worsens its absorption and you might get risk of GERD --> take with glass of water before eating in the morning
- poor renal function if you have accumulation of too much drug
- very small risk of severe osteoporosis of the jaw and the long bones of the legs

Nitrogen containing bisphosphonates:
- inhibit a step in mevalonic acid pathway involved in protein prenylation (Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein)
- mevalonic acid = branched fatty acid that gets connected to certain genes necessary for activation
this is called farnesylation.
Attached RAS protein allows these farnesylated proteins to be inserted in membranes.
N containing bisphosphonates seem to interfere with this insertion --> signal not there --> turn on system --> apoptosis

16

Calcitonin

- produced by parafollicular cells aka c-cells in the thyroid
- we use salmon derived calcitonin which is cheaper and can be given cutaneously or intranasally
- not used as much as bisphosphonates in the treatment of osteoporosis
- inhibits osteoclast bone resorption by acting directly on them
- treats Paget's disease = uncontrolled formation and resorption of bone. Causes lots of pain and disfigurement

2 problems
1. tolerance develops to its effect over a few days --> give intermittently, not continuously
2. direct analgesic effects - good for treatment of Paget's disease but don't know mechanism

17

Teriparatide

- fragment of PTH
- promotes formation of bone particularly in the spine and hips
- can be used sequentially with bisphosphonates
- should not be given longer than 2 years due to risk of osteosarcoma
- Give once a day as a single subcutaneous injection. This is pulsatile exposure. Continuous exposure to PTH results in bone resorption but pulsatile exposure promotes bone formation to a greater extent than bone resorption
- usually reserved for postmenopausal women at greater risk for fractures (history, small skeleton, etc)
- can also be used in the treatment of osteoporosis associated with chronic glucocorticoid use

18

Denosumab

- human anti-RANKL antibody
- binds to and prevents the RANK ligand from binding to preosteoclasts leading to inhibition of their proliferation, differentiation, and maturation
- inhibits bone resorption and increases bone mineral density
- must be given subcutaneously, once every 6 months or once every month
- contraindicated in hypocalcemia: rash, dermatitis, and rarely, serious infections, pancreatitis, and osteonecrosis of the jaw
- approved treatment for metastatic hypercalcemia due to cancers

19

Lispro

- injected insulin
- for post prandial control
- ultra-short acting; rapid onset: peak levels in an hour
- monomer of insulin
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) --> tight glycemic control using insulin is contraindicated in infants

20

Regular crystaline insulin

- injected insulin
- for post prandial control
- short-acting
- lasts 5-7 hrs
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) --> tight glycemic control using insulin is contraindicated in infants

21

NPH insulin

- injected insulin
- for baseline glucose monitoring
- intermediate acting
- combines insulin and protamine complexed as isophane
- slow degradation of protamine allows slow onset and long duration
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) --> tight glycemic control using insulin is contraindicated in infants

22

Insulin glargine

- injected insulin
- for baseline glucose monitoring
- long acting
- slow release form, no peak, duration about 20-24 hrs --> mimics basal 24 hr insulin levels
- less chance of hypoglycemia than NPH insulin
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) --> tight glycemic control using insulin is contraindicated in infants

23

Non-insulin hypoglycemics

- initial treatment for DM type II (or DM Type I with poor glycemic control despite high insulin)
- insulin secretagogues: sulfonylureas, meglitinides
- biguanides: metformin
- insulin sensitizers: thiazolidinediones (TZD's)
- inhibitors of carbohydrate absorption: alpha-glucosidase inhibitors
- glycosurics (inhibit renal glucose reabsorption)
- amylin: pramlintide
- incretin mimetics: exenatide, sitiglipin

24

Sulfonylurea

- insulin secretagogues
- mechanism: KATP channel is made up of subunits containing sulfonylurea sites
does the same thing ATP does
artifically closes K channel --> Ca influx --> insulin secretion (pancreatic beta cell - has a high capacity glucose transporter that enables glucose to be transported relative to blood glucose (doesn't saturate) --> glucose is metabolized leading to an increase in the ATP:ADP ratio. ATP binds K+ channel. --> K channel closes --> membrane potential becomes more positive --> opening of calcium channels, Ca influx --> exocytosis of insulin containing vesicles)
- prototype drug: Glyburide (Micronase, Glynase)
- metabolized by liver to agents with low hypoglycemic potential (CYP2C9); excreted by kidney
- half life 4 hrs; duration 24 hrs
- approved for mono therapy and in combo tablet with metformin
- adverse effects: hypoglycemia, weight gain, CV complications with long term use (KATP channels are found everywhere in the body, esp in the heart)
- contraindicated in pts treated for pulmonary artery HTN with the endothelin receptor antagonist, bosetan, due to elevated liver enzymes

25

Meglitinides

- insulin secretagogue
- prototype: Repaglinide (Prandin)
- can bind to sulfonylurea receptor on KATP channels --> insulin secretion
- primarily used for controlling post prandial blood glucose elevation (good for patients with normal fasting glucose but high postprandial glucose) --> take before meals
- pharmacokinetics: well absorbed, fast onset, peak in 1 hr, half life = 1 hr
metabolized by the liver - use with caution in patients with liver dysfunction
- adverse effects: risk of hypoglycemia if meal is skipped, weight gain
- can be given mono therapy or with metformin as a combo tablet

26

Biguanide

- prototype: Metformin (Glucophage)
- mechanism of action: activates AMPK (AMP activated protein kinase) in the periphery. when AMP levels are high and ATP is low, this enzyme becomes activated, inhibiting processes that use ATP and stimulates processes that produce it
--> decreased gluconeogenesis, enhance glycolysis and ATP production, decreases FA synthesis, increases oxidation of FA (no weight gain, moderate lipid-lowering effect), and translocation of GLUT4 in skeletal muscle
- good for obese puts with DM type II because it does not cause weight gain
- lowers fasting glucose levels, NOT post prandial
- can be given as mono therapy or in combo with insulin, sulfonylureas, meglitanides, TZD's, alpha-glucosidase inhibitors, uncertain mimetic and pramilintide
- no hypoglycemia with mono therapy, although can occur in combo or with alcohol
- pharmacokinetics: rapidly absorbed through the intestine; peak concentrations in 2 hrs
half life is 1.5-3 hrs, excreted unchanged by the kidney
drug interactions: Cimetidine competitively inhibits renal tubular excretion of metformin
- adverse effects: GI effects in 20% of patients (dose related and often transient), reduced B12 absorption, contraindicated in patients with renal disease, alcoholism, or tissue anoxia (cardiopulmonary dysfunction) due to risk of lactic acidosis (If you have a situation where there's tissue anoxia and you're not moving substrate through the Krebs cycle and ox phos, you divert over to lactate instead of pyruvate during glycolysis. This can lead to lactic acidosis if you're pushing substrate too quickly through glycolysis which is what metformin can do when it lowers blood gluocse. )

27

Thiazolidinediones (TZDs)

- prototype: Pioglitazone (Actos)
- insulin sensitizer: increase glucose uptake and utilization in skeletal muscle and adipocytes; alter differentiation of preadipocytes (shift from visceral metabolically active type to less active subcutaneous type)
- mechanism: unclear; TZDs are ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is a nuclear receptor - involved in expression and modulation of insulin responsive genes. Unfortunately, expression is much higher in adipocytes than muscle --> predisposition for weight gain
- TZD's act right at the site of DM type 2 defect --> may slow the progression of DM type II
- TZD's = insulin mimetic but not an insulin secretagogue
- no risk of hypoglycemia when given alone
- approved as mono therapy and with metformin
- metabolized by P450
- adverse effects:
hepatotoxicity (periodic liver enzyme monitoring recommended), CV problems, bladder cancer, weight gain, fluid retention, contraindications = liver disease or advanced CHF

28

alpha-glucosidase inhibitors

- prototype: Acarbose (Precose)
- mechanism: competitive inhibitor of intestinal alpha-glucosidase --> decrease starch metabolism to glucose = postprandial glucose control
- take before every meal
- no hypoglycemia when taken alone
- approved for mono therapy or in combo with sulfonylureas or metformin
- adverse effects: GI, hypoglycemia with sulfonylureas (give dextrose since Acarbose interferes with sucrose metabolism to glucose)
- contraindicated in patients with chronic or IBD or renal impairment. can elevate liver enzymes.
- no weight gain in mono therapy

29

Glycosuric

- prototype: Canagliflozin
- SGLT-2 inhibitors (sodium glucose co transporter) - blocks glucose reuptake in renal tubules
- reduces HbA1C, body weight, and systolic BP
- low hypoglycemia risk
- side effect: urogenital infections

30

Amylin

- prototype: Pramlintide (Symlin)
- co secreted with insulin
- decreases glucagon release, slows gastric emptying, decreases food intake --> improves fasting glucose and decreases body weight (good for obese pts)
- acts non receptors in the area pastrami which has projections to the hypothalamus and amygdala
- can be given in mono therapy and in combo with insulin (must carefully reduce insulin by 50% initially since amylin decreases glucagon so you can't protect against hypoglycemia) or metformin
- self administered injection at meal times
- cleared in kidney
- side effects: nausea, possible hypoglycemia
- contraindicated in gastroparesis and history of frequent hypoglycemia
- drug interactions: drugs that require high threshold activity may be impaired by decreased gastric emptying (any drug that you want to get into the pt's bloodstream fast should not be given at the same time as pramlintide which slows gastric emptying )

31

Incretin mimetics

- GIP-1 and GLP-1 (gastrin inhibitory peptide and glucagon-like peptide)
- peptides produced by intestine and brain (nucleus solitarius)
- action: potentiate glucose induced insulin release (only when its high), may delay beta cell apoptosis, inhibit glucagon, inhibit gastric secretion, decrease food intake (CNS mediated)
--> decrease fasting and postprandial glucose, HbA1C, body weight

32

Exenatide (Byetta)

- incretin mimetic
- GLP-1 receptor agonist
- self injection - pre filled pen, BID
- cleared by kidney
- side effects: transient nausea, vomiting, headache, hypoglycemia with sulfonylureas
- contraindications: gastroparesis, renal disease
- interactions: shouldn't be taken with drugs that require rapid absorption due to delayed gastric emptying; warfarin (increased prothrombin time)
- can be given in mono therapy or in combo with insulin
- weight loss due to decreased food intake (CNS)

33

Sitagliptin (Januvia)

- incretin mimetic
- dipeptidyl peptidase (DPP-4) inhibitor (prevents GLP-1 degradation)
- orally administered --> mild effects and mild side effects
- no GI side effects
- weight neutral
- more modest decrease in glucose and HbA1C compared to Exenatide
- cleared by the kidney (contraindicated in renal disease)
- interactions: few recorded, increased digoxin concentration
- can be used in mono therapy or in combo with metformin

34

Bromocriptine, Cabergoline

- dopamine agonists
- suppress prolactin production - shrinks prolactinoma

Usual symptom that brings hyperprolactinemia pt in to see doctor is infertility
Cabergoline = dopamine agonist; dopamine can activate beta1 receptors in the heart and alpha1 receptors in smooth muscle vasculator --> does opposite of what you think - decrease BP; pts can show dizziness or orthostatic HTN
Cabergoline binds to beta1 receptors and alpha1 receptors but it is such a poor agonist at the receptors that it's essentially acting like an antagonist
prevent epi and norepi from activating those receptors which are much better agonists than cabergoline


dopamine agonists like Cabergoline lower GH levels in acromegalics (does not affect GH levels in normal subjects)

35

Octreotide

- somatostatin analog
- suppresses GH release in growth hormone cell adenoma

Octreotide - half life of 1.5 hours but comes in diff preparations that make it easier to use; comes in depo form that will slowly release octreotide; depo form is injected subcutaneously once every 8-10 hrs; also exists as a subcutaneous implant given once a month; in those pts which octreotide does not lower GH levels, cabergoline is given. dopamine agonists lower GH levels in acromegalics (does not affect GH levels in normal subjects)
Techncially somatostatin can be used but it has a very short half life (2-3 min long)

36

Cyproheptadine, Valproate

Cyproheptadine: first gen anti-histamine
Valproate: anti-convulsant

- lower ACTH levels

37

Ketoconazole

- inhibits production of cortisol in the liver

38

Aminoglutethimide, Metyrapone

- kills adrenal cells

39

Mitotane

- treats adrenocortical carcinoma

40

Pasireotide

- pan somatostatin receptor
(somatostatin = inhibitory hormone for ACTH)
approved for Cushing's patients with hyperglycemia

41

Hydrocortisone

- glucocorticoid
- short-acting (8-12 hrs)
- 1:1 anti-inflammatory:salt retaining activity

42

Prednisone

- glucocorticoid
- intermediate acting (18-36 hrs)
- 4:0.3 (mostly anti-inflammatory, little salt retaining)

43

Betamethasone, Dexamethasone

- glucocorticoid
- long-acting (1-3 days)
- only anti-inflammatory activity
- Betamethasone is most commonly used for fetal lung maturation

44

Fludrocortisone

- mineralocorticoid
- 10:125 (mostly salt retaining activity, little anti-inflammatory)

45

Spironolactone


- used to treat HTN
- competitively inhibtis binding of aldo to aldo receptor
- used to treat certain cases of kidney failure such as diabetic nephropathy where aldosterone, which for some reason accelerates the progression of diabetic nephropathy, have come back to normal (aldosterone breakthrough) after patients have been treated with ACE inhibitors or angiotensin receptor antagonists

46

Aminoglutethimide


- not frequently used
- inhibits CYP11A1, an enzyme used to convert cholesterol to pregnenolone, the first step in the production of steroid hormones
- used to treat adrenal tumors where lots of steroid hormones are being produced

47

HMG (human menopausal gonadotropin)

mixture of LH and FSH; isolated from the urine of post menopausal women who were not taking estrogen replacement therapy
no feedback inhibition on hypothalamus --> a lot of GnRH, LH, and FSH being produced that spill out in the urine
HMG used in problems of infertility when women are not producing enough FSH to help stimulate maturation of ovarian follicles
recombinant LH/FSH are available - very very expensive whereas HMG is only very expensive but no advantage seen yet over HMG

48

HCG (human chorionic gonadotropin)

very similar in structure to LH (LH agonist) produced by the placenta - isolated from the urine of pregnant women or placenta

49

Gonadorelin

synthetic version of GnRH (identical in structure), used to treat variety of infertility issues in males and females when not enough GnRH is being produced
difficult to use - release of GnRH is very complicated, it's pulsatile, etc
when using gonadorelin, administration has to mimic the pattern of GnRH --> need to walk around with programmed infusion pump - getting gonadorelin in physiological GnRH release manner

50

Leuprolide

long acting GnRH agonist

Leuprolide activates GnRH receptors. Initially, when it binds and activates it, you actually increase FSH and LH release - this occurs for about 3 days
After this you see downregulation of GnRH receptors because of the time in which the Leuprolide occupies the recepors
Usually a molecule of GnRH will bind to its receptor for a fraction of a second and then comes off
Leuprolide binds to GnRHR and remains bound to it for minutes-hour. This triggers the response of the cell to downregulate its GnRHR's. After about 3 days, you see a drop in FSH and LH production by the anterior pituitary. If you give large enough dose of Leuprolide, you can completely turn off FSH and LH production.
Can be used in precocious puberty, withdraw in a more age appropriate time

Leuprolide = very popular for endometriosis; will lower estrogen levels; will also treat estrogen dependent breast cancer; used in combo with Letrozol (aromatase inhibitor) for premenopausal women with estrogen dependent breast cancer.
When Leuprolide is used to treat estrogen dependent breast cancer, you need some kind of estrogen antagonist at least initially when the Leuprolide is given. this is because the female pt will produce more FSH and LH and estrogen for the first 3 days of Leuprolide treatment
--> you need something like Tamoxifen (estrogen receptor modulator - antagonist here) so that the additional boost in estradiol production during the first 3 days does not have an adverse effect on the breast cancer

Leuprolide is also used in males to treat prostate cancer and androgen dependent disorders

In women the biggest complaint taking Leuprolide is you start to see signs of menopause bc you're suppressing estrogen

51

Vasopressin

Vasopressin acts through 2 diff receptors: V1 and V2
For therapeutic indications, vasopressin is not used bc its half life is about 20 min.

V1 receptor is responsible for vasoconstriction --> IV vasopressin is used to stop excessive bleeding esp from esophageal varices
also used to treat reabsorption of water by the kidney, diabetes insipidus, and enuresis (bed wetting in children)

52

Desmopressin

Desmopressin: can be inhaled or given orally (the one peptide still effective after oral administration) GI tract will break down 99% of desmopressin but 1% has effects. Only acts at the V2 receptor, not the V1 receptor.

Desmopressin is used to increase the reabsorption of water by the kidney, treat diabetes insipidus, and enuresis (bed wetting in children)

Desmopressin is also used to treat von Willebrand disease and type A hemophilia
Will activate the V2 receptor, facilitating the release of vWF and factor VIII from vascular endothelial cells. In order for it to be effective, you need some vWF and some factor VIII present --> will work for mild types of vWF disease and type A hemophilia. In severe cases of vWF disease and hemophilia where you have no or inactive vWF and factor VIII, desmopressin won't work.

Desmopressin also enhances platelet activation in inherited platelet disorders. Desmopressin, when given to those patients, return their platelet numbers to normal. Don't know mechanism.

53

Uterotrophic drugs

functions:
- induce or augment labor
- suppress uterine contractions
- chemical induction of abortion
- control post-partum hemorrhage from uterine atony

54

Oxytocic drugs:
Oxytocin
Ergonovine and methyl ergonovine
Prostaglandin F2alpha (Dinoprost)
Prostaglandin E2 (Dinoprostone)

Oxytocin is very similar in structure to vasopressin
only drug approved by FDA for augmentation or induction of contractions during labor
Oxytocin induces rhythmic contractions of the uterus. Contractions cut off blood supply to the baby
Too much --> too forceful contractions --> can rupture the uterus --> cut back on infusion rate; cleared rather quickly
not used in chemical induction of abortion - OCT receptors in the uterus appear in the third trimester of pregnancy
OCT is also the first drug of choice to treat post partum hemorrhage in uterine atony
anyone with baby in hospital will be given an IV line during labor and once the baby is delivered they will receive oxytocin, will not even wait to see if there's hemorrhage
however oxytocin is not always effective - if it doesn't work, try Ergonovine and methyl ergonovine, which cause sustained uterine contractions (usually given IM)
But they might not always work either --> PG F2alpha - can be given as suppository in cervix or as a gel in the cervix/uterus or directly into the uterus --> contractions
PGF2alpha is also oftentimes used with other drugs for chemical induction of abortion
Methotrexate - common drug used for abortion, kills the embryo
PGF2alpha is then given to help expel it from the uterus

PGE2 at high enough dose will also cause uterine contraction
usually used to treat cervical effacement during labor.
in order for baby to come out, you need cervical effacement
need the cervix which normally looks like a column to have a funnel shape (widening to allow passage of baby). need cervical effacement to occur before baby can be delivered
if contractions are occurring but effacement is not, PGE2 is given, usually as a suppository in the cervix attached to a string. in about 12 hours or so you will see effacement occur. once effacement occurs you pull whats left of PGE2 out and proceed with delivery

55

Magnesium sulfate

- tocolytic drug
given IV - not sure what mechanism is, maybe some competition with calcium. chance of going from suppression of labor to suppression of breathing for mother is very close
Mag sulfate suppresses contractions of labor but can also suppress other things
always have calcium glucurate ready which will compete with magnesium sulfate in case mom stops breathing

anti seizure effects for ecclampsia

56

Terbutaline

- tocolytic drug
activation of beta2 receptor during third trimester of pregnancy will reduce uterine contractions. usually administered IM or IV
- preferred over mag sulfate

57

Estradiol
Estriol
Estrone

Estradiol = prototype estrogen; much more potent at activating the estrogen receptor than estriol and estrone

- help control the synthesis of a variety of proteins made in the liver and then secreted into the plasma
- control bone resorption: estrogen in women and androgens in men stimulate osteoblast production of OPG, which binds RANKL of same osteoblast - problem for post menopausal women (estrogens after menopause are about 10% levels in premenopausal women)
- integral role in menstrual cycle proliferative phase - estrogen levels slowly increase in the absence of progesterone --> proliferative effect on endometrium
- replacement therapy for premenopausal women (ex- premature ovarian failure) and postmenopausal women with high risk for osteoporosis. For post menopausal women not at high risk for osteoporosis, recommend estrogen therapy not exceed 1-2 yrs - risk for heart attacks, stroke, breast cancer, etc. Exception: women with hysterectomies given unopposed estrogen = no difference in the rate of heart attacks and breast cancer
- oral contraceptives, which inhibit ovulation and render endometrium inappropriate for implantation. contain both estrogen and progestin. OC's can also be used for other things besides contraception like endometriosis. the estrogen is very good at exerting feedback inhibition on the hypothalamus so that GnRH and thus estrogen levels go down, suppressing the growth of the piece of endometrium

- prep: transdermally, orally
drug like estradiol which is extremely lipid soluble; when administrated, all E particles clump together and they don't dissolve/go into solution to be absorbed --> pass right through the GI tract
now there are micronized estrogens - different preparation method - take estrogen and make it very small, increase surface area tremedously, and now some can dissolve and be absorbed --> effective after oral administrations
Estrogens can also be conjugated: liver conjugates estradiol with inorganic sulfate --> estradiol sulfate
conjugation with glucuronic acid = another molecule that can be attached --> conjugated estrogens
effective after oral administration
Estrogens can also be esterified --> Estradiol Valerate
Estrogens can also be synthetic - Synthetic steroidal estrogens: ethinyl estradiol (active ingredient in most oral contraceptives), mestranol.
- Synthetic nonsteroidal estrogens: diethylstilbesterol (DES)

Adverse effects/toxicities:
- mild to moderate: nausea, postmenopausal bleeding, changes in serum proteins, headaches
- moderate to severe:
fluid retention (increase synthesis of angiotensinogen)
HTN (reversible)
gall bladder disease (usually in elderly women. least risk category of estrogen = conjugated estrogens)
clotting disorders (estrogens increase liver synthesis of clotting factors)
MI (post menopausal estrogen replacement therapy and premenopausal women in high risk category for MI)
cancer: endometrial (15 fold increase risk if unopposed estrogen), breast (post menopausal estrogen therapy), vaginal
teratogenicity --> contraindicated in pregnancy

Drug interactions:
1. Metabolized by P450 3A4, which is induced by Griseofulvin and Rifampin
2. Metabolism of OC ethyl estradiol: glucuronidation of ethyl estradiol --> ethinyl estradiol glucuronide (EEG). EEG undergoes enterohepatic cycling: EEG gets into bile, EEG goes along with it into SI, in which there are bacteria that will want the glucuronic acid --> breaks the bond between EE and glucuronic acid in some of EEG. Molecules of EE are reabsorbed, go back to the liver. EEG that didn't get broken down are excreted in the feces.
if subject is taking EE as OC and given penicillin, carbapenem or tetracycline we see reduction of bacteria in small intestines
reduction of bacteria in small intestines --> less EE produced from EE-gluc --> more EE-gluc that goes out in the feces and fewer EE going back into the liver/body
This has the potential to lower the levels of EE in the body since the elimination now is enhanced
It is possible that the levels of EE can become low enough in the body that you now lose the therapeutic effect of the EE (woman becomes fertile again)

58

Tamoxifen

- antiestrogen
- selective estrogen receptor modulator (SERM)

Tamoxifen = antagonist of estrogen in estrogen dependent breast cancer cells
used to treat estrogen dependent breast cancer and used to reduce the risk of a recurrence of estrogen dependent breast cancer

Tamoxifen binds to estrogen receptor --> dimer of estrogen receptor element forms however the normal co-regulatory proteins can't bind to the complex of tamoxifen and ER. The complex can't acetylate histone proteins --> transcription is turned off --> cancer cells die

Tamoxifen acts as a partial agonist in the endometrium of the uterus
Tamoxifen binds to the ER in the endometrium, binds to the ERE. Different set of co regulator proteins - can bind to tamoxifen/ER complex. but don't fit in an optimal configuration
you have some acetylation occuring --> no transcription compared to estradiol but nonetheless you still have transcription occuring
Tamoxifen = partial agonist in endometrium
if you have an estrogen stimulating the endometrium unopposed which is essentially what tamoxifen does (not as good but still agonist) --> after 5 years of Tamoxifen administration there is an increased risk of endometrium cancer
This increased risk outweighs the protective effect it gives against breast cancer recurrence
Therefore Tamoxifen is only administered for 5 years, then it is stopped

Tamoxifen is generlaly used in pre menopausal women

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Raloxifene

- antiestrogen
- selective estrogen receptor modulator (SERM)

Raloxifene acts just like Tamoxifen
Will antagonize effects of estrogen in breast cancer
but does NOT act on the endometrium -> no increased risk of endometrial cancer
however right now it is only approved for used in post menopausal women because there is no data yet for pre menopausal women
Also has side effect of extreme hot flashes - limits its use

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Clomiphene

- antiestrogen
- selective estrogen receptor modulator (SERM)

drug that is used sometimes to treat some type of infertility. A very good antagonist at the estrogen receptors in the hypothalamus
Pt with low LH and FSH or if estradiol and progesterone levels are low --> Clomiphene tricks the hypothalamus into thinking there's not enough estrogen (prevents endogenous E from inducing feedback inhibition)

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Fulvestrant

- selective estrogen receptor downregulator (SERD)

These drugs so far are used for post menopausal women to treat estrogen dependent breast cancer. They are used when other first line drugs like Raloxifene and aromatase inhibitors are ineffective.

These drugs bind to the ER but the ER stays as a monomer in the cytosol and gets broken down --> prevent E from binding to ER --> loss of ER because the monomer is being broken down

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Letrozole

- Aromatase (P450 19A1 aka estrogen synthetase) inhibitor
inhibits testosterone --> estrone
- used to treat estrogen dependent breast cancer itself in post menopausal women, not used by itself in premenopausal women (not approved yet)

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Plan B

dose of Levonorgestrel, a synthetic progesterone. Effective after unprotected sex up to 72 hours.

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Oral contraceptives

1. pills
as oral contraceptives "mini pills"
projestin alone oral contraceptive is equally as effective in combination OC's in theory but not in practice
effectiveness of combo OC's run around 96-99% effective
99% effective: for every 100 women taking the OC, 1 will get pregnant
for projestin only, 88-90% effective --> why they're not as popular as combination
reason why effectiveness is lower is bc their administration is very time sensitive
OC's that consist of 100% projestin have to be given at the same time of day every day - there's a 3 hr window every day that you can take it
combo: much less time sensitive; can forget and skip a day and there is not much change in chance of getting pregnant
use projestin ony if woman has hard time/side effects with combo

2. contraceptive implants
projestin only
injected subcutaneously, will continue to release projestin over a period of many weeks/months
inhibit ovulation, render endometrium inappropriate for implantation to occur, mucus production in cervix
as effective as combo OC's
projestin only contraceptives render endometrium implantation not to occur and mucus production in cervix but may or may not have inhibition of ovulation
plan B may or may not inhibit ovulation, depends on time of occurrence

3. depo contraceptives
IM injection of projestin contained in polyethylene glycol
projestin is slowly released over a period of weeks-months
depo form inhibits ovulation as well as endometrial effects

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Progestins

Indications:
1. replacement therapy - progesterones given in combination with estrogen
when estrogen is given opposed ,you get reduced risk for endometrial cancer
this also applies to combination oral contraceptives
2. contraception
3. endometriosis - stops the growth of the endometrium from estrogen and turns it into a secretory endometrium

Preparations:
1. natural progestins - progesterone
2. esterified progestins - hydroxyprogesterone caproate
3. synthetic progestins - levonorgestrel (most common progestin used in OC's whether used alone or in combo with estrogen)

Side effects: most side effects occur from the ability of progestins to occupy receptors of other steroid hormones and act as agonists or antagonists
Natural progestins: anti-estrogenic
Esterified progestins: androgenic, anti-estrogenic
Synthetic progestins: anti-estrogenic, anti-androgenic

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Mifepristone

- Antiprogestin

chemical induction of abortion
effective up to 7 weeks gestation

during the first 7 weeks in order for the embryo to remain implanted you have to have high levels of progestin present
antagonist of progesterone at progesterone receptor is given --> causes endometrium to become unstable
implanted embryo will detach from wall of uterus

also used for treatment of endometriosis

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Androgens

- required for normal maturation
- maintain normal sperm production
- increase protein synthesis in muscle
- increase hemoglobin levels
- alters bone resorption in males the same way estrogen does in females

Indications
1. replacement therapy
2. cachexia - androgens have an anabolic effect
3. osteoporosis - males get gradual reduction of androgen levels as they grow older just as women do with estrogen
4. endometriosis
5. fibrocystic breast disease
both endometriosis and fibrocystic breast disease are estrogen dependent disorders
treatment: Danazol (synthetic androgen) - can be administered to women and exerts feedback inhibtion on the hypothalamus
when given to women, she produces less GnRH --> LH and FSH go down --> dec LH = dec production of endogenous estradiol, which fuels endometriosis and fibrocystic breast disease

Preparation:
1. natural androgens - testosterone
2. esters of testosterone - testosterone enanthate
3. synthetic androgens - Danazol

Side effects and toxicities:
1. masculinization in women
2. feminization in men - 1st symptom is usually gynecomastia. Androgen is a substrate for aromatase, which converts testosterone to estradiol.
3. acne - androgens stimulate the sebaceous glands
4. decreased spermatogenesis and steroidogenesis
5. liver disorders - increase in enzymes indicative of liver damage
6. hepatocellular carcinoma?
7. heart disease

Anabolic steroids: there are some androgen drugs that have 3-6x more anabolic activity than androgenic activity.
anabolic steroids often abused by athletes/body builders
abused usually at levels 10x higher than legitimate therapeutic indication of use
problem with this: side effects that we discussed as well as heart valve problems, brain tumors, cancers, behavioral disorders (uncontrolled episodes of rage - roid rage)

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Finasteride, Flutamide

- Antiandrogens
- Given orally

- Finasteride: drug that inhibits 5 alpha reductase.
Testosterone is converted to DHT (dihydrotestosterone) by 5 alpha reductase. DHT is the active form - binds to receptor and activates it. --> Finasteride lowers androgenic activity
Used for benign prostatic hyperplasia and male patterned baldness

- Flutamide: binds the AR and acts as antagonist - prevents any DHT/testosterone from binding to the AR and activating it. Used for BPH and prostate cancer.