Endocrine Pharm Flashcards
What are the two forms of insulin that can be given IV?
Lispro and regular - these are the only solution-form of insulin (others are suspension)
Which insulins have the fastest onset?
Lispro and regular, when given IV work within 2-4 min
What is unique about glargine?
It has no peak activity → used for basal glucose control & no risk of hypoglycemia
What kind of receptor does insulin bind? What happens next?
Tyrosine kinase → autophosphorylation of receptor → allows binding of IRS-1, which becomes phosphorylated → allows binding of SH2 domain proteins, which become phosphorylated → lots of enzyme activity, especially phosphatases → enzymes dephosphorylated to be activated/inactivated, some changes in gene expression (lipoprotein lipase, FA synthase, glucokinase) – SEE BIOCHEM SECTION
What are 3 ketoacids in DKA?
- acetoacetate
- β-hydroxybutyrate
- acetone → fruity breath (no E-delivering activity)
What energetic molecules can β-OHbutyrate give rise to? Where are these molecules used?
1x NADH
2x Acetyl-CoA
- used mainly by muscle tissue (e.g. heart), renal cortex, brain (only if period of prolonged starvation)
What energetic molecules can acetoacetate give rise to?
2x Acetyl-CoA
What is the treatment for DKA?
- regular insulin
- glucose
- fluid and electrolytes (esp. watch for hypokalemia)
What is the effect of insulin on K+ in the body?
insulin drives K+ into cells
What type of glucose transporters are on β cells in the pancreas? What is significant about the pharmacodynamics of this receptor?
GLUT 2 - has very high Km (thus low affinity for glucose) so it is only active when high glucose in blood (e.g. after meals)
How does elevated glucose → insulin release in β cells?
Glucose → gets in cell through GLUT 2 → ↑ ATP → closes K+ channel → depolarization → open voltage-gated Ca2+ channel → ↑ Ca2+ in cell → exocytosis of insulin
What do sulfonureas do? Do they work in T1DM?
block the K+ channel in β cells, mimicking the effect of ↑ ATP; don’t work in T1DM b/c these patients don’t have β cells
What drugs work oppositely to sulfonureas?
diazoxide and minoxidil: direct acting vasodilators that open ATP-dependent K+ channels → hyperpolarization → ↓ insulin release → drug-induced diabetes
What is acetohexamide? What is unique about it?
A first generation sulfonurea; it has an active metabolite → very long duration of action → be careful with renal function
What is tobutamide? What is unique about it?
A first generation sulfonurea; can use in kidney patients b/c no renal tox
What is chlorpropamide? What is unique about it?
A first generation sulfonurea; causes disulfaram-like reaction and SIADH (like carbamazepine)
What are the second generation sulfonureas and their side effects?
GLYburide - ↓ dose in renal pt. or will cause hypoglycemia
gLIPizide - ↓ dose in hepatic pt.
What are the general side effects for sulfonureas?
- hypoglycemia in fasting state (e.g. at 2-3 AM)
- weight gain
- hypersensitivity (SULFONureas have a sulfur group)
- drug interactions (highly plasma protein bound, p450 processed)
What drugs would interact with sulfonureas?
- p450: cimetidine
- hypoglycemia: insulin
- compete for protein binding sites → hypoglycemia: salicylates, sulfonamides
What drug is thought to bypass insulin receptors in cells? How? What are the side effects? What is a notable exception?
Metformin - thought to stimulate PPAR transcription factors directly; since it burns glucose can cause lactic acidosis (rare; contraindicated in renal failure for this reason), GI distress is most common side effect; does not cause hypoglycemia
What is the mechanism of action of acarbose and miglitol?
inhibit α-glucosidase → ↓ breakdown of sugars → ↓ absorption → ↓ post-prandial hyperglycemia and ↓ demand for insulin (may improve insulin sensitivity)
What are the side effects of thiazolidinediones?
- thia = hypersensitivity, lipid sol → hepatotox
- azol = potentiate effects of EtOH
- weight gain
- edema
- heart failure
What do the thiazolidinediones (glitazones) do?
bind to PPAR-gamma → mimic actions of insulin:
- ↓ gluconeogenesis via: ↑ PFK2 → ↑ fructose 2,6- bisphosphate → dephosphorylation/inactivation of fructose-1,6-bisphosphatase (rate limiting step)
- ↑ insulin receptors
What are 2 ways glitazones and metformin ↓ blood glucose?
- enhance uptake in skeletal mm. through ↑ GLUT 4 receptors
2. inhibit glucose production by liver (↓ gluconeogenesis)
What is exenatide? What is a similar drug?
A GLP-1 receptor agonist (incretin) that ↑ insulin release from β cells and ↓ glucagon produciton from α cells; liraglutide
What is sitagliptin? What other drugs share its mechanism of action?
inhibits dipeptidyl peptidase (DPP-4) → prevents GLP-1 inactivation; linagliptin, saxagliptin
When is hypercoagulability an issue with estrogen therapy?
at high doses or if patient is predisposed
When is endometrial cancer an issue in estrogen therapy?
it is a real risk of unopposed E therapy; use progestin to eliminate risk
What is DES (diethylstilbestrol)?
A synthetic estrogen that, when taken by pregnant ♀ → increased risk of clear cell vaginal adenocarcinoma in offspring
What is premarin?
conjugated equine estrogens: natural estrogen isolated from the urine of pregnant mares (hence premarin) - this is the only estrogen without -est- in name
What is norethindrone?
a progestin - the only that’s not obvious by the name
What’s unique about Desogestrel?
it’s a synthetic progesterone without androgenic or anti-estrogenic effects
What effect do progestins have on lipids?
↑ LDL and ↓ HDL (ok when preg b/c need more cholesterol, but not good for later → athero)
What effect do progestins have on glucose metabolism?
cause glucose intolerance
What effect do progestins have on androgen hormones?
↑
What is mefepristone?
blocks glucocorticoid and progestin receptors; used with prostaglandins as morning after pill
What is the main hormonal purpose of oral contraceptives?
suppress the LH surge that causes ovulation
Side effects of OCTs?
these are mostly progestin, so:
- ↑ androgens → acne, hirsutism
- ↑ LDL, ↓ HDL
- weight gain, tiredness, depression
What is the most important point to remember about OCT drug interactions?
p450 inducers (e.g. phenytoin, rifampin) → ↓ levels of OCT → ↑ chance of unwanted pregnancy
What are the additional benefits of OCTs (besides avoiding pregnancy)?
- ↓ risk of endometrial and ovarian cancer (antag. E)
- ↓ dysmenorrhea
- ↓ endometriosis (can be used in tx of chocolate cysts)
- ↓ PID (change pH of cervical/vaginal area)
- ↓ osteoporosis (if there is some estrogen in pill)
Can OCTs cause tumors?
Yes, liver adenocarcinoma which is benign but highly vascularized → can cause retroperitoneal bleed in highly active ♀; tend to regress when stop taking OCT
Explain the synthesis of thyroid hormones
- active accumulation of iodide into thyrocyte
- organification/oxidation of iodide to iodine by thyroid peroxidase
- iodination of tyrosine resides on thyroglobulin to MIT or DIT
- coupling of MIT/DIT + DIT = T3/T4
- proteolysis → release of thyroglobulin
- goes into bloodstream and converted to active T3 form by deiodinase
What do thioamides do?
inhibit thyroid peroxidase (oxidation, iodination, coupling, and at high doses proteolysis step)
What drug inhibits deiodinase in the periphery?
propylthiouracil propranalol (the only β blocker that does this)
What drug is used for a thyroid storm (thyrotoxicosis)?
propranolol - improves symptoms (tachycardia, central ↓ response to NE/E → calms pt.) and blocks conversion of T4 to T3
What are the two thioamides used for hyperthyroidism? Which is safer in pregnancy (i.e. won’t cause hypothyroidism)?
Propylthiouracil (safer because 90% albumin bound)
Methimazole (<10% albumin bound)
What is Lugol’s preparation? When could it be used?
Potassium iodide + iodine
- Could be used preoperatively in thyrotoxicosis to ↓ gland size, fragility, and vascularity (via negative feedback)
- Not used for long-term b/c thyroid escape after 10-14 d
When is radioactive iodine 131 used?
imaging of thyroid gland to check the activity of cancer nodules, and as therapeutic way to kill thyroid cancer
Can GH be given to patients with hypopituitarism?
No, it’s a large peptide → doesn’t solubilize easily in IV and is digested if given orally; have to give analogs
What are the GH analogs?
somatran and somatropin (soma = body, tropin = growth agent)
What are GH analogs used for?
- pituitary dwarfism
2. osteoporosis
What drug is used for acromegaly? What are some other uses for this drug?
octreotide, a somatostatin analog
other uses: carcinoid, gastrinoma, glucagonoma, esophageal varices
What is the analog hormone for ACTH? When is it used?
cosyntropin, used for infantile spasms (which seem to be due to hypoglycemia; ACTH → cortisol → gluconeogenesis)
Which drugs are GnRH analogs?
Leuprolide
Nafarelin
What are GnRH analogs useful for?
- advanced prostate cancer
- endometriosis
- hypogonadal state (pulsatile delivery)
What is prolactin inhibiting factor (PIH)?
dopamine
What do we give to agonize dopamine? What do we use these for?
bromocriptine
pergolide
used for hyperprolactinemia
What are the side effects of bromocriptine or pergolide?
Dyskinesias, nausea, vomiting, psychosis
When do we use desmopressin?
- central DI
- hemophilia A and vWD (↑ vWF which also ↑ factor VIII)
- primary nocturnal enuresis
What drug is a PTH analog? What is it used for? What considerations should be made?
Teriparatide - if given in bursts (e.g. 1xd) → stim. osteoblast → new bone growth, as tx. for some forms of osteoporosis
Considerations:
1. Continuous dose would → ↑ osteoclast activity
2. Can not use for > 2 years because ↑ risk of osteosarcoma
