Diabetes Drugs Flashcards
What is the main difference between treatment of Type I and Type II diabetes?
Type I diabetes can only be managed via insulin (and adjuvant low carb diet) while Type II diabetes management incorporates diet, exercise, and oral hypoglycemic drugs as well as insulin
What are the three principal types of insulin preparations?
–Short acting: rapid onset of action, short half-life–Intermediate acting: slower onset, longer half-life–Long acting: longest half-life, largest crystals
Describe short-acting insulin. AEs?
These bind quickly (noLAG)to insulin receptors–Soluble, clear, crystalline zinc-insulin–Called Regular Insulin, the only preparation that can be injected IV. All others SC or IM–All other preparations have been modified to provide prolonged action and are dispensed as turbid suspensionscan be used for both Type I AND II diabetesAEs:hypoglycemia, lipodystrophy, rare hypersensitivity
Describe Intermediate-acting insulin
–NPH insulin [Neutral, Protamine, Hagedorn] (Isophane®)–Lente insulins [mixture of 30% semilente (short-acting) and 70% ultralente (long-acting) zinc insulin crystals–Long-acting = large crystals = slow absorption
When is insulin given to a diabetic typically?
Short acting AND a NPH/Lente at breakfast and these two again at dinner
When should BG levels be measured daily?
4 times BEFORE each meal
Blood glucose before lunch reflects the efficacy of what insulin dose?Blood glucose before supper reflects the efficacy of what insulin dose?
morning regular insulin dosethe morning NPH insulin dose
Blood glucose before bedtime reflects the efficacy of what insulin dose?
the evening regular insulin dose
Blood glucose before breakfast reflects the efficacy of what insulin dose?
the evening NPH insulin dose
What are some additional strategies developed to improve insulin replacement regimens?
•Inhaled insulin- Exubera® (human insulin inhalation power) Micronized powder administered into the lungs by an inhaler. (Pfizer stopped marketing this preparation in October 2007. It has not been taken off the market.)•Insulin pump- Mechanical pump administers insulin through a catheter into abdominal fat. These are very useful for young children
How are the recombinant human insulin products made?
–Humulin R® (Lilly) is made using recombinant DNA to produce the hormone in bacteria or yeast.–Novolin R ® (Novo Nordisk) is also made this way.
What does the R in Humulin R mean?
R stands for Regular, not recombinant! R means soluble at room temperature and neutral pHNOTE:Humulin N and Novolin N are NPH treated products to increase crystal size and increase half-life.
How do Human insulin analogs circulate through the body?
Insulin in circulation forms hexamers with Zn2+, but hexamers don’t bind the insulin receptor until dissoc.
What is Insulin lispro (Humalog)?
Insulin lispro (Humalog®) is a rapid actinganalogue of Humulin® in which the normal ProlineB28 and Lysine B29 are switched.Switching is done by mutations of hrDNA.Insulin lispro doesn’t form hexamers. (Exists in circulation as monomer only.)
How are the pharmacokinetics of lispro different than insulin?
Humalog® has a faster onset of action and shorter half-life than Regular Insulin.
How is Insulin aspart (NovoLog) different from insulin?
Insulin aspart (NovoLog®) as another rapid acting insulin analog (Asp substituted for Pro). It also exists only as a monomer.
How is Insulin glulisine (Apidra) different from insulin?
still another rapid-acting insulin analogue that differs from human insulin in that theasparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid. It also does not form hexamers.
NOTE: Insulin lispro, insulin aspart and insulin glulisine all have the same pharmacokinetic properties–faster onset of action and shorter onset of action. Why?
because they exist in the monomeric state
What is Insulin glargine (Lantus)
A long-acting recombinant human insulin analog for use as an injection.•Insulin glargine differs from human insulin - in amino acid Asparagine 21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain.
How do Insulin glargine and insulin detemir work?
•Long-acting (up to 24-hour duration of action)•When injected, the acidic solution is neutralized, causing crystals to precipitate = slow absorption= long-acting.•Can be injected once a day.Low peak insulin concentration decreases chances of nocturnal hypoglycemia
What is insulin degludec?
•(Tresiba®) is a modified human insulin that has one aa deleted and is conjugated to hexadecanedioic acid via gamma-glutamyl spacer at the amino acid lysine at position B29. This modification allows hexamer formation subcutaneously.•No peak concentration; slow absorption.•Can be mixed with other insulins.
What is Exubera?
A short acting human insulin from rDNA in the form of micron-sized particles (dry powder)administered by inhalation into lungs through an inhaler that may be used for either type I or type II diabetics
What are the uses of Exubera?
Not a complete replacement for insulin therapy; could replace meal-time injections•Less difficult but more expensive than injected insulin
Note about hypoglycemia comas. Tx?
–Usually caused by INSULIN OVERDOSE–So common that all comatose patients are given glucose first while blood glucose is being measured.–Treatment: Glucose
What is a main treatment for severe hypoglycemia?
recombinant human glucagon
Describe endogenous glucagon
Glucagon is a 29 a.a. peptide secreted by a-cells of the pancreas that is elevated in times of fasting to liberate glucose and raise BG.
What are some indications that hypoglycemia may be occurring?
Confusion, shakiness, and feeling of light-headedness. This may cause trembling, sweating, anxiety, and tachycardia
What are some signs that hypoglycemia is progressing and becoming more severe?
The development of pounding HA, poor coordination and concentration, numbness in the mouth and tongue, and nightmares
What are some oral drugs available for hyperglycemia?
SulfonylureasMeglitinidesBiguanidesThiazolidinedionesa-Glucosidase InhibitorsSGLT-2 InhibitorsAmylin analogsDDP-4 inhibitors
Describe sulfonylureas
These are developed from ABX having hypoglycemic properties and tonically close the ATP dependent K+ channel in B cells to promote insulin secretion. These initially increase insulin release, may decrease insulin metabolism by the liver, and increase insulin sensitivity by enhancing the effect of insulin on glucose uptake.
How are sulfonylureas metabolized?
These are rapidly absorbed from the GI tract, extensively protein bound,metabolized in liver, and excreted by kidney.NOTE: Second generation drugs are 10-100x more potent
What are the first-gen sulfonylureas? AEs?
Chlorpropamide (long half-life), tolbutaminde, and DiabineseAEs: weight gain, disulfiram-like effects
What are the second-gen sulfonylureas? AEs?
Glyburide (Micronase),Glipizide (Glucotrol),Gliclazide (Diabend), andGlimepiride (Amaryl)AEs: hypoglycemia only
______ enhance the hypoglycemic action of sulfonylureas.
NSAIDsNOTE: Sulfonylureas require some insulin action and thus are useless in Type I diabetes
Describe Meglitinides
Benzoic acid derivatives not related to sulfonylureas that stimulate postprandial insulin secretion by binding to K+ channels on B-cell membranes (not the same site as sulonfylureas)
What are some Meglitinides?
Repaglinide (Prandin)Nateglinide (Starlix)
Describe the pharmokinetics of meglitinides
Very rapid GI absorption and has a short half-life before metabolzied by the liver.
When should be meglitinides be taken? Uses?
Taken before each meal to control post-prandial glucose level.Use: Used as monotherapy in type II diabetes or combined with metformin
How do Biguanides decreaseBG?
Their exact mechanism is unknown but they decrease hepatic gluconeogenesis and enhance peripheral insulin sensitvity(in contrast to the other oral hypoglycemics that increase insulin secretion)
How are Biguanides metabolized?
Absorbed from the GI and have little metabolism
Types of Biguanides?
Metformin (Glucophase)Metformin + glyburide (Glucovance)
How doThiazolidinediones work? Metabolism?
Bind specifically to Peroxisome Proliferator-ActivatedReceptor-g (PPARg) to increase insulin sensitivityand adiponectin levelsLittle metabolism
Types of Thiazolidinediones? Uses?
Rosiglitazone (Avandia)Pioglitazone (Actos)Rosiglitazone+ metformin (Avandamet)Glipizide+ metformin (Metaglip)Uses: Monotherapy in type II diabetes or combined. Safe in renal impairment
How do a-Glucosidase Inhibitors work? Uses?
These reduce intestinal absorption of starch anddisaccharides by inhibitingbrush border a-glucosidase which reduces uptake of carbohydrate and reduces post-prandial glucose rise.•Usually used in combination with other hypoglycemic drugs and/or insulin in Type II diabetes
What are some a-Glucosidase Inhibitors?
Acarbose (Precose)Miglitol (Glyset)
Describe somatostatin and its action
This is a peptide secreted by D cells of pancreatic islets (also some from GI and the brain) that inhibits releaseof TSH and GH from the pitutiary,as well asinhibiting release of insulin AND glucagon
What are some therapeutic uses of somatostatin or its analog drug octreotide (Sandostatin)?
-inhibition of insulin from insulinomas or glucagon release from glucagonomas
What is the half-life of somatostatin?
3-6 min
What is Diazoxide?
AnAntihypertensive antidiuretic that has potent hyperglycemic actions byinhibitinginsulin secretion (but does not inhibit insulin synthesis) causing insulin to buildup in b-cells.Diazoxide (Proglycem®) used to treat various forms of hypoglycemia.Used for inoperable insulinomas.
What arethe effects of GLP-1(and their drug analogs)? AEs?
It increases glucose-dependent insulin secretion/synthesis,inhibits glucagon-stimulatedglycogenolysis in the liver, slows gastric emptying, decreases appetite, and decreases glucagon secretion all in order to decrease postprandial blood gluoseAEs: N/V, pancreatitis, weight loss
How does GLP-1 affect the heart?
provides cardioprotection and increases CO
What are incretins?
The incretins are hormones that canincrease insulin secretion. They were discovered after it was observed that there is more insulin secreted in response to oral glucose versus intravenous glucose.
What are the two main incretin hormones in humans?
GIP (glucose-dependent insulinotropic peptide; also known as gastric inhibitory peptide) and GLP-1(glucagon-like peptide-1). Both hormones are secreted by endocrine cells that are located in the epithelium of the small intestine
What are some exogenous GLP-1 analogs? Uses?
Exanatide (Byetta)Liraglutide (Victoza) (SC)Uses:Type II diabetes
Describe Exenatide
•a synthetic peptide of 39 aa (the natural peptide is exendin-4 isolated from Gila monster venom)inhibits glucagon-stimulated glycogenolysis in the liver. May preserve or increase production of new beta-cells in the pancreas.This is more potent than endogenous GLP-1
How does Sitagliptin phosphate work?
(Januvia ®) is an inhibitor of dipeptidyl peptidase-4 (DPP-4),the enzyme that inactivates incretin hormones.
What are some othersDipeptidyl peptidase-4 inhibitors? Uses? AEs?
Saxagliptin (Onglyza), Linagliptin (Tradjenta)Uses: Type II DiabetesAEs: mild urinary or respiratory infections; weight neutral
What is Pramlintide Symlin?
An analogue of amylin, a peptide hormone released by β-cells of the pancreas along with insulin, after a meal. Like insulin, amylin is deficient in individuals with type 1 diabetes.
What are the effects of Pramlintide Symlin?
By augmenting endogenous amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying andpromoting satiety via hypothalamic receptors (different receptors than for GLP-1), and inhibiting inappropriate secretion of glucagon
What is Symlin approved for?
Approved for use by the FDA by type 1 and type 2 diabetics who use insulin.
What are the effects of Symlin?
Symlin® treatment results in weight loss, allows patients to use less insulin, lowers average blood glucose, and substantially reduces the postprandial glucose rise.
What are SGLTs?
They are a family of glucose transporters found in intestinal mucosal cells (SGLT1) and the proximal tubule of the nephron (SGLT2).
What is the role of SGLT2?
SGLT2 is responsible for renal glucose reabsorption. 100% of filtered glucose (through glomerulus) must be reabsorbed in the tubules.In Type 1 diabetes glucose is excreted in the urine (glucosuria) beause SGLT is saturated.
What is an approved SGLT2 inhibitor? Others?
Canagliflozin (Invokana®) isrecently FDA approved for Type 2 diabetes treatment by decreasing reabsorptionOthers: Dapagliflozin, Empagliflozin
What are the AEs of SGLT2 inhibitors?
UTIs, vaginal yeast infections,hyperkalemia, orthostatic hypotension, hypoglycemia, and elevated LDL levels
What are some contraindications for SGLT2 inhibitors?
–Severe renal impairment–End stage renal disease–Patients on dialysis
Use of Bile Acid sequestrants in diabetes treatment
Colesevelam hydrochloride was developed to lower blood cholesterol and is now approved for Type 2 diabetes patients who are taking other medications. (2 grams/day)•It lowers HbA1c 0.5% and lowers LDL cholesterol 15%.
How is Colesevelam hydrochloride thought to work?
Assumed to interrupt enterohepatic cycling and lower Farnesoid X Receptor activation.
AEs ofbile acid sequestrants?
GI related disturbances
