Antidiabetics II Flashcards
Insulin Secretagogues
Sulfonylureas & Meglitinides
Sulfonylureas are effective at reducing ___ and ___
Sulfonylureas are effective at reducing fasting plasma glucose and HbA1C
Sulfonylureas bind to ____ subunit and block the ATP-sensitive ___ channel in the B cell membrane stimulating ___ release
Sulfonylureas bind to SUR1 subunit and block the ATP-sensitive K+ channel in the B cell membrane stimulating insulin release
sulfonylureas end in “__”
“ide”
1st generation Sulfonylurea
Chlorpropamide
Chlorpropamide has a ___ half life
AE’s?
- Long half-life
-
Hypoglycemia, particularly in elderly
- Contraindicated in elderly patients
-
Hyperemic flush with alcohol
- d/t inhibition of aldehyde dehydrogenase
- may potentiate vasopressin
- elicit an apparent SIADH
- hyponatremia
list 2nd generation Sulfonylureas
compare them to Chlorpropamide
- Glyburide (Glibenclamide)
- Glipizide
- Glimepiride
- much more potent than 1st gen drugs
- lack some of the adverse effects and drug interactions of 1st gen drugs
- replaced 1st gen drugs
compare hypoglycemic actions between 2nd gen sulfonylureas
Glimepiride < Glipizide < Glyburide
Sulfonylurea & Meglitinide AEs
- Hypoglycemia
- Weight gain
list Meglitinides
Glinides have the same MOA as ___
- Repaglinide, Nateglinide
- same MOA as Sulfonylureas
- stimulate insulin release by binding to SUR1 and inhibiting ATP-sensitive K+ channel
Sulfonylureas vs. Meglitinides
- effect
- onset and duration of action
Sulfonylureas = more effective in reducing FPG and HbA1C levels
Meglitinides = more rapid onset and shorter DOA
Glinides are ____ glucose regulators.
Must be taken ____; if the meal is missed the drug must be omitted
Glinides are postprandial glucose regulators
Must be taken before each meal; if the meal is missed the drug must be omitted
Comparing the Meglitinides, ___ has a less risk of hypoglycemia than ___
Comparing the Meglitinides, Nateglinide has a less risk of hypoglycemia than Repaglinide
Biguanides
Metformin
Metformin does not cause ____
does not cause ___ (even in large doses)
___ efficacy to sulfonylureas in reducing FPG and HbA1C levels
Metformin does not cause insulin secretion
does not cause hypoglycemia (even in large doses)
Equal efficacy to sulfonylureas in reducing FPG and HbA1C levels
Metformin reduces glucose levels primarily by inhibiting ___ by reducing ____ of gluconeogenic enzymes
Metformin reduces glucose levels primarily by inhibiting gluconeogenesis by reducing gene expression of gluconeogenic enzymes
- increases insulin-mediated glucose utilization in muscle and liver
- As a result of the improvement in glycemic control, serum insulin concentrations decline slightly
Metformin actions are mediated by activation of ____
Metformin actions are mediated by activation of AMPK
other effects of metformin
- Reduces plasma TG by 15-20%
- weight LOSS
(sulfonylureas / glinides = weight gain)
1st line agent for treating T2 DM
Metformin
- high insulin sensitivity
- associated w/ weight loss
- rarely causes hypoglycemia
- does not depend on B-cells
Metformin AE and contraindications
- Largely GI: anorexia, nausea, vomiting, abdominal discomfort, diarrhea
- Long term use: B12 deficiency
- Fatal lactic acidosis
- Contraindicated: renal disease, hepatic disease, hypoxia, alcoholism
list the TZDs
- Pioglitazone
- Rosiglitazone
Pioglitazone and Rosiglitazone decrease insulin ____
___ agonist found in muscle, fat and liver
Pioglitazone and Rosiglitazone decrease insulin resistance
Peroxisome proliferator-activated receptor-y (PPAR-y) agonist found in muscle, fat and liver
Glitazones promote glucose uptake and utilization in adipose tissue by ___
__ effective than Sulfonylureas/Metformin in decreasing FPG and HbA1C
MOA involves ___
Glitazones promote glucose uptake and utilization in adipose tissue by increasing insulin sensitization
Less effective than Sulfonylureas/Metformin in decreasing FPG and HbA1C
MOA involves gene regulation
Glitazones have a slow onset and offset of activity taking ____
Glitazones have a slow onset and offset of activity taking weeks to months
____ effects on lipids are more favourable than ___
associated with significant improvements in:
pioglitazone effects on lipids are more favourable than rosiglitazone
pioglitazone is associated with significant improvements in: HDL, TG, LDL particle concentration, LDL particle size
TZD AE’s
- fluid retention, weight gain, edema
- cause or exacerbate CHF
- contraindicated: Class III or IV heart failure
-
Troglitazone: 1st TZD approved, caused severe hepatotoxicity → withdrawn
- FDA requires monitoring of liver function with TZD
- so far pioglitazone or rosiglitazone have not been associated with hepatotoxicity
a-Glucosidase Inhibitors
Acarbose
Acarbose: MOA
- competitive inhibitor of intestinal a-glucosidases
- reduces postprandial digestion of starch and disaccharides
- minimizes upper intestinal carb absorption and defers absorption to distal SI
- decreases postprandial hyperglycemia and hyperinsulinemia
- modest drop in HbA1C and FPG levels
Acarbose AEs
- Flatulence, diarrhea, abdominal pain
- Contraindicated in IBS or any intestinal condition worsened by gas and distension
- associated with reversible hepatic enzyme elevation
- Periodical liver function monitoring is required with acarbose therapy
Incretin Analog: ____
DDP-4 inhibitor: ____
both ___ insulin secretion
GLP-1 analog: Exenatide
DDP-4 inhibitor: Sitagliptin (oral)
both increase insulin secretion
Incretin secretion & action on the B cell
Exenatide effects
- Resistant to dipeptidyl peptidase IV (DPP-IV)
- increases insulin secretion
- Suppresses postprandial glucagon release
- Slows gastric emptying
- Decreases appetite
- May stimulate β-cell proliferation
Exenatide and Sitagliptin AEs
- Both: Pancreatitis
- Exenatide
- GI: Nausea, vomiting and diarrhea
- not used in patients w/ gastroparesis
- Sitagliptin
- urticaria, angioedema, anaphylaxis, skin reactions (Stevens-Johnson syndrome)
Amylin Analog
- Pramlintide
- Peptide co-secreted with insulin from pancreatic β-cells
- Inhibits food intake, gastric emptying, and glucagon secretion
Bile-acid Sequestrants and Use
Colesevelam
used to lower LDL cholesterol
Approved for treatment of type 2 DM
Mechanism unclear.
Given orally
SGLT2 Inhibitor
- “-Gliflozin” (canagliflozin)
- blocked SGLT2 leads to decreased glucose reabsorption in proximal tubule, increased glucose excretion, and decreased blood glucose levels
- Given orally
-gliflozin AE
- Increased risk of genital and urinary tract infections
- osmotic diuresis: volume depletion, increased serum creatinine levels, hyperkalemia, hypermagnesemia, hyperphosphatemia and hypotension
- Contraindicated in patients with renal insufficiency
INITIAL DRUG THERAPY FOR T2 DM
____ is the preferred first agent if lifestyle intervention does not achieve HbA1c goals
INITIAL DRUG THERAPY FOR T2 DM
Metformin is the preferred first agent if lifestyle intervention does not achieve HbA1c goals
Patients with HbA1c ≥9.0% are unlikely to achieve HbA1c goals with ____
what do we give them?
Patients with HbA1c ≥9.0% are unlikely to achieve HbA1c goals with monotherapy
combination of 2 noninsulin agents or with insulin itself
If monotherapy does not achieve HbA1C goal over∼3 months, the next step is to add a second agent:
oral agent, exenatide or insulin (the higher the HbA1C, the more likely insulin will be required)
If 2-drug combination fails to achieve the glycemic target a third agent can be added - many patients will eventually need to be on ___
when HbA1c ≥ 8.5% we should transition to ___
If 2-drug combination fails to achieve the glycemic target a third agent can be added - many patients will eventually need to be on insulin
when HbA1c ≥ 8.5% we should transition to insulin
Describe Insulin Therapy
- Begins with a single low dose injection of basal insulin
- NPH, Glargine, Detemir
- Dose is then uptitrated
- If there is postprandial hyperglycemia, add prandial insulin
- lispro, aspart, glulisine
___ is the most effective of diabetes medications in lowering glycemia
Insulin is the most effective of diabetes medications in lowering glycemia
- decreases any level of elevated HbA1C to therapeutic goal
- no maximum dose of insulin beyond which a therapeutic effect will not occur
- Large doses of insulin may be necessary to overcome the insulin resistance of type 2 diabetes
when is insulin warranted as initial therapy for patients with type 2 diabetes?
-
severe hyperglycemia
- Significant hyperglycemic symptoms
- Ketonuria
- HbA1c > 10%
- random glucose > 300 mg/dL
what is the preferred drug for Gestational DM?
Insulin (does not cross the placenta)
- start with a single dose of bedtime NPH insulin
- If postprandial glucose control is required injections of lispro or aspart can be added
which insulin drugs should not be given in Pregnancy
Glulisine, Glargine, Degludec (Category C)
DM + HTN should be given:
ACEi (pril) or ARB (sartan)
what should be monitored in a patient on an ACEi?
K+ and creatinine
DM + Dyslipidemia should be given…
Potential AE of this drug?
Statins
AE: AST/ALT elevations, rhabdomyolysis
- With overt CVD
- Aged < 40 yr with CVD risk factors
- Aged > 40 yr with or without CVD risk factors
DM + increased CV risk should be given…
Aspirin (antiplatelet agent) - 1° prevention strategy
DM + Albuminuria patients should be given….
ACE inhibitors or ARBs
Drugs used for neuropathic pain
- Imipramine
- Amitriptyline
- Pregabalin
- Gabapentin
- Duloxetine
- Venlafaxine
- Valproate
- Opioids
Diabetic gastroparesis (2)
Metoclopramide or Erythromycin (prokinetic agents)
Potential AE of Metoclopramide: Parkinsonism
Contraindicated in a patient with gastroparesis?
Exenatide, Sitagliptin, Pramlintide
DM neuropathy + erectile dysfunction
Phosphodiesterase-5 inhibitor: Sildenafil
____ is used to treat severe hypoglycemia in diabetic patients treated with insulin
Glucagon is used to treat severe hypoglycemia in diabetic patients treated with insulin
Also used for:
- Radiology of bowel (relaxes intestine)
- B-blocker overdose
- Glucagon C-peptide Test (tests for residual β-cell function in diabetes)
