ENDO Pharm Flashcards by Kelly Laurent

What are hormones that counter insulin?

Cortisol
Epi and NE
Glucagon
GH

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Insulin regulates glucose uptake and metabolism in all tissues except…

CNS
Peripheral Neurons (including retina)
Renal medullary cells
cells lining the blood vessels
liver cells (but insulin does affect glucose metabolism)

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What type of receptor does insulin act on?

tyrosine kinase.

Insulin receptor autophosphorylates on tyrosine residues and phosphorylates IRS-1 on multiple tyrosine residues.

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In type 1 DM, what hormones are unopposed?

cortisol
Epi and NE
Glucagon
GH

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What insulin preparation has no peak of activity?

Insulin glargine

Maintains glucose at 130 mg/dL for about 20 hr.

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Which insulin preparation has the quickest onset?

Insulin lispro

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What are the two short acting insulin preparations?

insulin aspart (duration 3-5 hr)
insulin glulisine (duration 1-2.5 hr)
both have an onset of 0.-0.25 hr

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How can you give insulin?

NOT orally

Subcutaneous injection, portable pen injectors, nasal spray, insulin pumps, powdered insulin that is inhaled.

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How do you treat type II diabetes?

DIET AND EXERCISE

Oral hypoglycemics and euglycemics

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Name five sulfonylureas, to include the 2nd generation sulfonylureas. What do they treat?

Oral hypoglycemics for Type II DM
Tolbutamide (1st generation)
Glyburide, glipizide, gliclazide, glimepiride (2nd generation)

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What is the mechanism of action of sulfonylureas?

“Bind to K+ channels of B cells, depolarize cells, release insulin”
Bind to the same K+ channel on membrane of pancreatic B cells that is regulated by glucose metabolism.
K+ channels close -> membrane depolarizes -> Causes Ca2+ channels to open -> helps release of insulin

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Adverse effects of sulfonylureas?

Prolonged and severe hypoglycemia -> can be fatal!

Symptoms: sweating, hunger, paresthesis, tremor, anxiety

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What is a drug that is not a sulfonylurea but acts just like one on the K+ channels?

repaglinide

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What is Metformin mechanism of action?

Reduces hepatic glucose output by inhibiting gluconeogenesis

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What is the benefit of using Metformin to help Type II DM patient’s hyperglycemia?

It never causes hypoglycemia!

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What are some adverse effects of Metformin?

Lactic Acidosis (seen in patients with renal failure or CHF)
2% patients experience diarrhea

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What is Acarbose mechanism of action?

What does is treat?

Acts by inhibiting carbohydrate breakdown in the intestine (alpha-glucosidase inhibitor)
Reduces glucose uptake from intestine -> reduces postprandial spike in blood glucose
Helps with hyperglycemia in DM Type II

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Adverse effects of acarbose?

Alone will not cause hypoglycemia, but if taken with sulfonylurea and hypoglycemia occurs-> take GLUCOSE and not SUCROSE
Adverse effects: abdominal bloating, diarrhea, flatulence.

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Name three thiazolidinediones.

What are they known asn for type II DM?

Pioglitazone, rosiglitazone, ciglitazone

AKA “glitazones”

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Pioglizazone
MOA:?
SE:?

MOA: selective PPARy agonists; increase insulin sensitivity, possibly by inc. glucose transporters (GLUT4) in muscle & adipose, also decreases gluconeogenesis in liver.
SE: does NOT cause hypoglycemia; no liver toxicity. can be combined with sulfonylureas or metformin.

What drugs that help with hyperglycemia never cause hypoglycemia?

Pioglitazone
Metformin
Sitagliptin

What endogenous compound does Exenatide mimic?

Glucagon-like-peptide-1 (GLP-1): a peptide released from the GI tract when food enters

GLP-1 stimulates what cells to release what hormone?

GLP-1 travel via the blood to B cells where it stimulates insulin release and inhibits glucagon release.

What compound is an orally active “dipeptidyl peptidase-4” inhibitor? MOA?

Sitagliptin
Prevents breakdown of endogenous glucagon-like peptide-1 (GLP-1).
Also reduces hemoglobin A1C
does NOT cause hypoglycemia

What is GLP-1's function?

It is a potent stimulator of insulin release in a glucose-dependent manner, and inhibits glucagon release.

Canagliflozin What does it treat? MOA:

Type II DM MOA: Sodium-glucose-co-transporter-2 inhibitor (SGLT2) Since almost 100% of glucose is reabsorbed back into blood in proximal tubules by SGLT2, canagliflozin causes some glucose to be lost in the urine by inhibiting SGLT2

What are some benefits of using canagliflozin after 26 weeks of treatment?

- 1% reduction in HbA1c - reduction of fasting glucose - loss of ~2.5 kg

What were some adverse effects of canagliflozin?

~10% inc. in genital mycotic infections (male and female) -inc UTI diuretic effect with volume depletion some reports say hyperkalemia, hypermagnesemia and hyperphosphatemia

What factors stimulate GH release?

``` Hypoglycemia Amino Acids (arginine most potent) Deep sleep exercise Dopamine agonists (DA normally stimulates GH release by inhibiting SST release, but in acromegaly DA inhibits GH release) ```

What recombinant hGH form causes mild allergies in 50% of patients?

Somatrem

Growth hormone therapy for hypopituitary dwarfism

Dose 0.3mg/kg/wk, three IM or subcut. injections of 0.1 mg/kg Start treatment ASAP require T3 and T4 for GH to increase growth will need to increase dose over time because there is a decrease in response.

What is Hypersomatotrophic dwarfism?

"Laron Syndrome" Defect in GH receptor (GH cannot stimulate IGF-1 synthesis and release. Occurs in: jews of oriental origin, african pygmies, toy poodles.

Whats another name for Somatomedin C?

IGF-1

Laron Syndrome: GH high or low? IGF-1 high or low?

GH high | IGF-1 Low

Mecasermin: What is it? What does it treat?

Recombinant human IGF-1 combined with rhIGF-BP-3 to increase IGF-1 stability. Increasing drowth in Laron Dwarfs.

What is the usual cause of acromegaly?

Adenoma of somatotroph

Features of acromegaly

Broadening of nose, elongation of mandible, severe narrowing of joints, carpal tunnel syndrome, glucose intolerance, hypertension, hypertrophy of organs (heart -> congestive failure)

How can you treat a GH secreting adenoma of the anterior pituitary?

``` Surgical removal Bromocriptine Cabergoline Ocreotide Pegvisomant ```

Dopamine agonists work best in patients whose tumors secrete what two things?

GH and Prolactin

Somatotroph and Lactotroph stem from the same progenitor cell. What receptors are expressed on the progenitor cell?

GHRH, SST, Dopamine 2

Which drug is a dopamine agonist?

Bromocriptine | Cabergoline is also a very long acting D2 agonist (t1/2 = 65 hr)

Octreotide: | Description

Long acting somatostatin agonist. | Peptide so it MUST be injected.

Pegvisomant: Gen:

Gen: GH receptor antagonist has PEG polymers attached to it and decreases antigenicity -> causes GH receptors to dimerize but not activate Effective but costs a SHIATTTT ton (50000-100K a year!)

``` Pasireotide General: Use: MOA: SE: ```

Gen:Somatostatin analog Use: Treat's Cushing's Disease that persists after surgical removal of an ACTH-secreting pituitary tumor. MOA: Binds to somatostatin receptor, esp subtype 5 which is often overexpressed on corticotroph adenomas that secret ACTH SE: diarrhea, nausea, cholelithiasis, ab pain, fatigue, hyperglycemia

Pasireotide inhibits insulin release from the pancreas (SST receptors) which will cause what in patients who are being treated for Cushing Disease? How can you fix this issue?

hyperglycemia | Co-treat with sitagliptin, drug that prolongs activity of endogenous insulin secretagogue (GLP-1)

Where is prolactin produced?

Lactotrophs in anterior pituitary. | Stimulates milk production in women who have given birth.

What are four causes of hyperprolactinemia?

Lack of sufficient dopamine Adenoma of lactrotrophs Hypothyroidism (excess TRH stimulates lactrotrophs) Antipsychotic (most antipsychotics block D2 dopamine receptors)

Treatment of hyperprolactinemia

Bromocriptine (long acting D2 dopamine agonist) Cabergoline (long acting D2 dopamine agonist) both reduce prolactin levels and shrink adenomas.

Side effect of cabergoline?

Can cause valvular heart disease