Drugs used in Diabetes Flashcards
Rapid, short, intermediate, and long-acting insulins used in tx of diabetes
Rapid acting: Aspart, Lispro, Glulisine
Short-acting: regular insulin
Intermediate acting: Neutral protamine hagerdorn (NPH)
Long-acting: detemir, glargine
Amylin analog used in tx of diabetes
Pramlintide
Of the insulin secretagogues used to treat diabetes, there are incretin mimetics and K(ATP) blockers. Of the Incretin mimetics, what drugs fall into the GLP-1 agonist category?
Exanatide
Liraglutide
Of the insulin secretagogues used to treat diabetes, there are incretin mimetics and K(ATP) blockers. Of the Incretin mimetics, what drugs fall into the Dipeptidyl peptidase-4 (DPP-4) category?
Sitagliptin
Linagliptin
Saxagliptin
Alogliptin
Of the insulin secretagogues used to treat diabetes, there are incretin mimetics and K(ATP) blockers. Of the K(ATP) blockers, what drugs fall into the Sulfonylurea category?
First generation:
Chlorpropamide
Tolbutamide
Tolazamide
Second generation:
Glipizide
Glyburide
Glimepiride
Of the insulin secretagogues used to treat diabetes, there are incretin mimetics and K(ATP) blockers. Of the K(ATP) blockers, what drugs fall into the Meglitinide category?
Nateglinide
Repaglinide
Biguanide used to tx diabetes
Metformin
Thiazolidinediones used to tx diabetes
Pioglitazone
Rosiglitazone
Sodium-glucose co-transporter 2 (SGLT2) inhibitors used to tx diabetes
Canagliflozin
Dapagliflozin
Empagliflozin
Inhibitors of alpha-glycosidases used to tx diabetes
Acarbose
Miglitol
To maintain a state of normoglycemia, insulin helps to decrease blood glucose. What hormones operate in the opposite direction, increasing blood glucose?
T3/T4
Glucagon
Epinephrine
Glucocorticoids
Rapid acting insulin is insulin with mutations from human sequence that block assembly of dimers and hexamers, allowing for faster absorption. Onset is within 5-10 mins with duration of 1-3 hrs, with a peak at 30 min to 1 hours. What is the clinical use for rapid acting insulin?
Postprandial hyperglycemia — taken before the meal as a SC injection
Short acting and regular insulin consists of unmodified ____ insulin crystals. Absorption rate is _____ and less predictable d/t formation of hexamers that are too bulky to be transported via endothelium into the bloodstream
Zinc; slow
Short acting and regular insulin have onset within 30 min-1hr with a duration of 10 hours and peak at 3-5 hours. What are the clinical uses for short acting or regular insulin?
Basal insulin maintenance
Overnight coverage
If for prostprandial hyperglycemia, inject 45 min before meal
Can be injected IV in urgent situations
Composition of intermediate acting insulin NPH
Complex of protamine with zinc insulin
[protamine has to be digested by tissue proteolytic enzymes before insulin can be absorbed]
NPH is an intermediate-acting insulin with onset in 1-2 hrs, duration 10-12 hrs, and peaks at 4-12 hrs. What are the clinical uses of intermediate acting insulin?
Basal insulin maintenance and/or overnight coverage
Use is declining because it is being replaced by long-acting insulin
Difference in composition between long acting insulins: Detemir and Glargine
Detemir = Lys 29 in B chain is myristoylated (lipid) — rapidly absorbed into blood but binds strongly to albumin; Detemir peaks at 3-9 hrs.
Glargine = amino acid substitutions in both A and B chains enhance crystal stability, change pKa of insulin — soluble at low pH (4) but precipitates at pH 7; Glargine is “peakless”
Both are used for basal insulin maintenance (1-2 SC injections/day) with onset 3-4 hrs, duration 24 hrs
How is insulin used in the tx of severe hyperkalemia?
Insulin + glucose (to prevent hypoglycemic shock) + furosemide
Insulin rapidly activates Na/K ATPase to shift K+ into cells
Effect is transient (several hours); in the meantime K+ is eliminated from the body using loop diuretic
AEs of insulin
Hypoglycemia (most common)
Lipodistrophy (localized hypertrophy of subcutaneous fat at site of injection — can be prevented by changing injection site, or using IM injection)
Resistance (pts treated with exogenous insulin commonly develop insulin binding Abs — IgG can neutralize its actions)
Allergic reactions (immediate type HSR)
Hypokalemia
Common causes of hypoglycemia in the setting of insulin therapy
Delay of meal or missed meal
Exercise — exercising skeletal muscle consumes more glucose; hyperemic skin —> enhanced rate of insulin absorption
Overdose of insulin
Signs of hypoglycemia
Confusion, bizarre behavior, seizures, coma
Sympathetic hyperactivity: tachycardia, palpitations, sweating, tremor
Parasympathetic hyperactivity: hunger, nausea
Tx for hypoglycemia resulting from insulin therapy
Glucose (juice, candy, etc. if conscious — if unconscious use IV glucose)
Diazoxide — strong hyperglycemic agent (K+ATP channel opener); inhibits release of insulin by beta cells
Glucagon
Amylin is a pancreatic hormone synthesized by beta cells. Its analog Pramlintide can be used as an adjunct to treat diabetes. What is the MOA?
Inhibits glucagon secretion
Enhances insulin sensitivity
Decreases gastric emptying (slows rate of intestinal glucose absorption)
Causes satiety
[rapid onset, 3 hr duration, peak at 20 mins]
Adverse effects of pramlintide
Nausea, vomiting, diarrhea, anorexia
Severe hypoglycemia — especially if used together with insulin — insulin dose should be reduced
Drug interactions with pramlintide
Enhances effects of anticholinergic drugs in GI tract (i.e., constipation)
Endogenous factors regulating insulin secretion
Glucose and other energy substrates
GPCR-G(s) ligands — beta2-AR agonists, GLP-1 receptor agonists (incretins)
GPCR-G(i) ligands — somatostatin, alpha2-AR agonists
_____ are a group of gastrointestinal hormones that cause a decrease in blood glucose levels
Incretins
Hormone synthesized by intestinal L-cells that promotes beta-cell proliferation, insulin gene expression, glucose-dependent insulin secretion, and inhibits glucagon secretion; causes sateity and inhibits gastric emptying but is NOT an effective drug d/t short half life
GLP-1
Recombinant form of exendin-4, protein from Gila monster saliva with glycine substitution to make it less susceptible to hydrolysis by DPP-4
Exenatide
GLP-1 analog with 97% homology to native GLP-1, lipid-modified to be rapidly absorbed but binds to albumin
Liraglutide
Clinical use of GLP-1 receptor agonists
The release of GLP-1 is diminished postprandially in T2DM pts —> inadequate glucagon suppression and excess hepatic glucose output
GLP-1 receptor agonists are approved in T2DM pts who are not adequately controlled by metformin/sulfonylureas/thiazolidinediones
Doses of other anti-diabetic meds should be reduced to avoid hypoglycemia
AEs of GLP-1 receptor agonists
N/V, diarrhea, anorexia
Hypoglycemia (although lower risk than Pramlintide bc exhibits glucose-dependent insulinotropism)
Linked to cases of acute pancreatitis and pancreatic cancer
MOA of DPP-4 inhibitors (gliptins)
DPP-4 is a serine protease that degrades GLP-1 and other incretins
Increase levels of GLP-1 to enhance its interactions with the cognate receptor — effects are similar to those of GLP-1 agonists
Clinical use of DPP-4 inhibitors (gliptins)
Approved as adjunctive therapy to diet and exercise in pts with T2DM
Used both as monotherapy and in combo with metformin/sulfonylureas/TZDs
AEs of DPP-4 inhibitors (gliptins)
URIs and nasopharyngitis
Linked to acute pancreatitis
Hypoglycemia (if combined with insulin secretagogues — their doses have to be adjusted)
MOA of K(ATP) channel blockers
Binding to SUR — sulfonylurea receptor
Blocking K+ current through Kir6.2 inwardly rectifying potassium channel
Clinical use of sulfonylureas
T2DM as a monotherapy or in combo with insulin or other anti-diabetic drugs
AEs of sulfonylureas
Hypoglycemia
Weight gain (increased insulin release)
Secondary failure — pts who respond initially later cease to respond to sulfonylureas and develop unacceptable hyperglycemia
Dermatological and general hypersensitivity reactions — cross-reactivity with other sulfonamidees (sulfonamide abx, carbonic anhydrase inhibitors, diuretics — thiazides, furosemide)
Drug interactions of sulfonylureas that enhance their hypoglycemic effect
Displacing from binding with plasma proteins: sulfonamides, clofibrate, salicylates
Enhancing the effect on K(ATP) channel: ethanol
Inhibiting CYP enzymes: azole antifungals, gemfibrozil, cimetidine, etc.
Drug interactings with sulfonylureas that decrease their glucose-lowering effect
Inhibiting insulin secretion: beta blockers, CCBs
Antagonizing their effect on K(ATP) channel: diazoxide
Inducing hepatic CYP enzymes: phenytoin, griseofulvin, rifampin, etc.
MOA of meglitinides (repaglinide and nateglinide)
K(ATP) channel inhibition —similar to sulfonylureas
Clinical use of meglitinides
Control of postprandial hyperglycemia in pts with T2DM
Taken orally before the meal; can be used alone (to control postprandial hyperglycemia) or in combo with other antidiabetic drugs
AEs of meglitinides
Hypoglycemia
Secondary failure
Weight gain
MOA of metformin (biguanide)
Activation of AMP-dependent protein kinase
AMP-dependent protein kinase phosphorylates a number of targets —> inhibition of lipogenesis and gluconeogenesis, increase in glucose uptake, glycolysis, and FA oxidation, lower glucose levels in hyperglycemic (but not normoglycemic) states, increases insulin sensitivity
[Exact MOA is unclear — may be indirect—inhibition of respiratory complex I in mitochondria]
Clinical use for metformin
The most commonly used oral agent to tx T2DM and generally accepted as first-line tx
Advantages: superior or equivalent glucose-lowering efficacy compared to other oral meds, does not cause hypoglycemia, does not cause weight gain, taken orally, can be used either alone or in combo with other oral agents, in clinical trials decreased the risk of both macro-and microvascular complications in diabetic pts
Pharmacokinetics of metformin
Half life 1.5-3 h
Not bound to plasma proteins
Not metabolized; excreted unchanged by kidneys
AEs of metformin
Most common are GI complications — anorexia, vomiting, nausea, diarrhea, and abdominal discomfort
Decreased absorption of Vit B12
Lactic acidosis, especially under conditions of hypoxia, renal, and hepatic insufficiency
Contraindications to metformin
Contraindicated in conditions predisposing to tissue hypoxia (HF, COPD), renal failure, chronic alcoholism and cirrhosis
MOA of thiazolidinediones (pioglitazone, rosiglitazone)
Ligands of peroxisome proliferator-activated receptor-gamma (PPARy)
PPARy is a nuclear receptor expressed primarily in fat, muscle, liver tissue, and endothelium
Leads to increased GLUT4 in skeletal m. and adipocytes; increased IRS1, IRS2, and PI3K; decreased PEPCK, NF-kB, and AP-1
Thiazolidinediones are taken orally once daily, and since their effects are d/t changes in gene expression their onset is delayed 1-3 months. How are they metabolized? Are they safe in renal failure pts?
Metabolized by the liver — half life is reduced by CYP inducers (rifampin) and prolonged by CYP inhibitors (gemfibrozil)
YES safe to administer in renal failure
Clinical use of thiazolidinediones
T2DM, alone or in combo with other antidiabetic drugs
Shown to delay progression from prediabetes to T2DM
Euglycemic drugs (no hypoglycemia when used alone)
AEs of thiazolidinediones
Weight gain and edema (increased risk if administered with insulin)
[edema may be d/t increase in vascular permeability and/or increase in ENaC expression — thus increasing sodium and water reabsorption in collecting duct]
Exacerbation of heart failure (contraindicated in class III or IV HF pts)
Increased TC and LDL-C (rosiglitazone)
Osteoporosis (direct MSCs to adipocyte differentiation so less osteoblast lineage)
MOA of sodium-glucose co-transporter2 inhibitors
Glucose is reabsorbed in proximal tubule primarily by SGLT2
Gliflozins inhibit this transporter to increase glucose excretion and reduce hyperglycemia
Other effects: causes osmotic diuresis, induces weight loss, reduces BP, reduces plasma uric acid levels, does not cause hypoglycemia when used alone
Clinical use of SGLT2 inhibitors
As an adjunct to diet and exercise in adults with T2DM
Taken orally before first meal once/day
In pts with hypovolemia, this condition should be correct prior to starting therapy
AEs of SGLT2 inhibitors
Hypotension
Hypovolemia
Genital (mycotic) and urinary tract infections
Hypoglycemia if combined with insulin or insulin secretagogues
Renal function impairment — induce fall in GFR
Hyperkalemia (esp in pts with impaired renal function and those taking ACEIs, ARBs, and K-sparing drugs)
MOA of alpha-glycosidase inhibitors (acarbose, miglitol)
Only monosaccharides are absorbed from GI into blood
Competitive inhibition of alpha-glycosidases (family of enzymes on intestinal epithelium) defer digestion and thus absorption of ingested starch and disaccharides
Lower postprandial hyperglycemia to create an insulin-sparing effect
Clinical use of alpha-glycosidase inhibitors
T2DM as monotherapy or in combo with other oral antidiabetic agents or insulin
Taken orally at mealtime, do not cause hypoglycemia when used alone, do not cause weight gain
AEs of alpha-glycosidase inhibitors
Most common are malabsorption, flatulence, diarrhea, and abdominal bloating
Hypoglycemia has been described when combined with insulin or insulin secretagogues
Drug interactions with alpha glycosidase inhibitors
Decrease absorption of digoxin (acarbose) and propranalol and ranitidine (miglitol)
A 24 y/o woman wishes to try tight control of her diabetes to improve her long-term prognosis. Which of the following regimens is most appropriate?
A. Morning injections of mixed insulin lispro and insulin aspart
B. Evening injections of mixed regular insulin and insulin glargine
C. Morning and evening injections of regular insulin, supplemented by small amounts of NPH insulin at mealtimes
D. Morning injections of insulin glargine, supplemented by insulin lispro at mealtimes
D. Morning injections of insulin glargine, supplemented by insulin lispro at mealtimes
Insulin glargine covers long-term release, lispro (short-acting) covers postprandial hyperglycemia
Which sequence correctly describes the cell mechanism of glucose-induced insulin release from pancreatic beta cells?
A. Glucose binds GLUT transporter; depolarization; increase in cell ATP, calcium channel closes
B. Glucose binds to the GLUT transporter; increase in cell ATP; potassium channel closes, depolarization
C. Glucose binds GLUT transporter; potassium channel opens, increase in intracellular calcium
D. Glucose binds GLUT transporter; potassium channel closes; depolarization; decrease in intracellular calcium
E. Glucose binds GLUT transporter; potassium channel closes; hyperpolarization; increase in intracellular calcium
B. Glucose binds GLUT transporter; increase in cell ATP; potassium channel closes; depolarization
Which of the following will increase the release of insulin by islet beta cells?
A. Clonidine B. Verapamil C. Isoproterenol D. Somatostatin E. Atenolol
C. Isoproterenol
[beta1 and beta 2 mimetic — increases release of insulin]
Clonidine is an alpha2 agonist — will decrease insulin release
Verapamil is calcium channel blocker — will decrease insulin release
Which of the following drugs stimulates the secretion of insulin from intact pancreatic beta cells?
A. Metformin
B. Insulin
C. Pramlintide
D. Repaglinide
D. Repaglinide
All these will decrease hypoglycemia but only one that does so via stimulating insulin secretion is Repaglinide (a meglitinide in the K[ATP] channel blocking class)
18 y/o patient presents with signs and symptoms that suggest T1DM. What is the tx plan?
A. Metformin B. Glyburide C. Lifestyle adjustments only D. Insulin E. Reosiglitazone
D. Insulin
Type 1 diabetic patient is started on insulin. Which of the following is appropriate regimen?
A. Pre-meal detamir and lispro at bedtime
B. Pre-meal lispro and glulisine after daily exercise
C. Pre-meal aspart and glargine at bedtime
D. Lispro QD before bed
E. Glulisine QD in the morning
C. Pre-meal aspart and glargine at bedtime
Which of the following sets glargine apart from other formulations?
A. Blood levels and hypoglycemic effects more accurately described as plateau rather than definite spike or peak
B. Disulfiram-like effect more common and severe
C. Fast onset of action and useful for postprandial hyperglycemia
D. Poses little or no risk of hypoglycemia if pt skips meals
E. Sensitizes parenchymal cells to insulin
A. Blood levels and hypoglycemic effects more accurately described as plateau rather than definite spike or peak
Which of the following is most appropriate in a pt who presents with lethargy, moderate ketonemia, and BG of 450?
A. Glyburide B. Metformin C. Insulin aspart D. Insulin regular E. Insulin glargine
D. Insulin regular
This is urgent situation that requires IV insulin, and the only insulin formulation that can be given IV is regular insulin
Which of the following does not cause increased risk of weight gain?
A. Canagliflozin B. Insulin C. Glipizide D. Pioglitazone E. Repaglinide
A. Canagliflozin
[an SGLT2 inhibitor]
T2D pts who are obese should avoid insulin, TZDs, sulfonylureas, and meglitinides. They tend to lose weight on biguanides, SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors
Which of the following is associated with increased risk of lactic acidosis?
A. Acarbose B. Glyburide C. Metformin D. Insulin E. Liraglutide
C. Metformin
[increased risk of lactic acidosis especially under conditions of hypoxia, renal, and hepatic insufficiency]
How would a type 1 diabetic’s insulin therapy regimen be adjusted if pt is placed on prednisolone therapy?
A. Add glyburide B. Add glucagon C. Cancel insulin and start metformin D. Decrease insulin dose E. Increase insulin dose
E. Increase insulin dose
How should glyburide dose be adjusted in a pt that has been prescribed sulfa abx for a UTI?
A. Increase glyburide dose
B. Decrease glyburide dose
C. No change in glyburide dose
B. Decrease glyburide dose
