Reading...
Play button
Play button
Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
126 Cards in this Set
- Front
- Back
|
IOS 9 Quiz one Question break down:
3 questions from Alterie's review 7 questions from Aquilante's lectures: 2 pathophys 2 pathophys complication 3 pharmacology Focus on: * hormones and processes in absorptive and post absorptive states * differences between type I and type II diabetes * hypoglycemia * biochemical pahtyways: adose reductace, AGE, and PKC * Drugs - MOAs * classify and give examples of different insulins |
As you review these notes please let me know if I missed any possible questions/info we need to study.
|
|
|
Processes in the post-absorptive atate are ____________ and include: _____________, ___________, and _________ .
|
catabolic
Glycogenolysis Gluconeogenesis Lipolysis |
|
|
What is the goal of all processes during the post-absorptive state?
|
Maintaining blood glucose levels
|
|
|
Define Glycogenolysis and list the main hormones and enzymes involved.
|
Glycogenolysis – break down of glycogen
Dominant hormone: glucagon Reaction facilitated by: Glycogen Phosphorlyase Glucose-6-Phosphatase |
|
|
What Hormones Control the Transition from Feasting to Fasting?
|
INSULIN
GLUCAGON |
|
|
Define gluconeogenesis. What is the dominant hormone?
|
* Lactate, alanine, glycerol are non-carbohydrate precursors used during gluconeogenesis to from glucose primarily in the liver
* Dominant hormone - glucagon |
|
|
Define lipolysis. What is the dominant hormone?
|
Lipolysis: Triglycerides breakdown to glycerol and fatty acids
* Glycerol breaks down to glucose * Fatty acidsbreak down to ketones Dominant hormone - glucagon |
|
|
Insulin is released by _____________ in response to ____________ causing ____________________
|
Beta Cells
HIGH blood glucose Cells/tissues take up glucose from blood |
|
|
Glucagon is released by _____________ in response to ____________ causing ____________________
|
Alpha Cells
LOW Blood Glucose the liver to release glucose into blood |
|
|
What hormone dominated in the "fed" or absorptive state?/
|
Insulin
|
|
|
Insulin Release from Pancreatic Beta Cells
|
1. Glucose is transported across the cell membrane by facilitated diffusion
2. Glucose is phosphorlyated by glucokinase and then metabolized 3. Glucose is metabolized and results in ATP 4 . ATP binds to ATP-sensitive K+ channels on the beta cells and closes theses K+ channel 5. Because the K+ channels are closed, K+ can no longer flow out of the cell 6. Increased K+ inside the cell causes the cell membrane to depolarize 7. Cell membrane depolarization causes activation of Ca++ channels and Ca++ moves into cell 8. Increased Ca++ in the cell causes insulin granules within the beta cell to move to the cell surface to be release Keep in mind that Insulin secretion from the beta cells is ultimately dependent on the intracellular concentration of Ca++ |
|
|
Insulin’s Action in Liver
|
Stimulates:
* Glycogen synthesis * Fatty Acid Synthesis Inhibits: * Glycogenolysis * Gluconeogenesis * Ketogenesis |
|
|
Insulin’s Action in Fat
|
Stimulates:
* Glucose uptake * Triglyceride synthesis and storage Inhibits: * Lipolysis |
|
|
Insulin’s Action in Muscle
|
Stimulates:
* Glucose uptake * Glycogen synthesis * Amino acid uptake and protein synthesis Inhibits: * Protein breakdown |
|
|
What is Amylin and what is it's function?
|
* Hormone co-secreted with insulin from the pancreatic beta-cells
* Involved in glucose regulation - Neuroendocrine mode of action - Lows rate of gastric emptying - Suppresses postprandial release of glucagon - Improves satiety signals (decreased food intake) |
|
|
Type 1 vs. Type 2 Diabetes: AGE
|
Type 1: < 30 years of age and most often < 20 years of age
Type 2: > 30 years of age or prevalence is increasing in children and young adults |
|
|
Type 1 vs. Type 2 Diabetes: Typical body habitus
|
Type 1: Lean
Type 2: Obese |
|
|
Type 1 vs. Type 2 Diabetes: Insulin secretion
|
Type 1: Absolute deficiency
Type 2: Relative deficiency |
|
|
Type 1 vs. Type 2 Diabetes: Insulin resistance
|
Type 1: Absent
Type 2: Present |
|
|
Type 1 vs. Type 2 Diabetes: Symptoms
|
Type 1: Symptomatic
Type 2:Often asymptomatic |
|
|
Type 1 vs. Type 2 Diabetes: Need for insulin therapy
|
Type 1: Immediate
Type 2: Years after diagnosis |
|
|
Risk Factors for Hypoglycemia
|
* Mismatch between timing and/or dose of insulin and food intake
- Excessive insulin dose - Missed meal - Meal with insufficient carbohydrates * Decreased food intake (e.g., overnight) * Exercise * Alcohol * Intensive insulin regimens * Oral antidiabetic therapy (e.g., sulfonylureas) * Decreased insulin clearance due to kidney failure * Other drugs: e.g., beta blockers mask s/sx of hypoglycemia |
|
|
Treatment of hypoglycemia:
|
* If conscious, consume 15-20 gm of “quick sugar”
- 1/2 cup OJ, 4-5 Lifesavers, 8 oz Gatorade - Glucose Tabs - Instant Glucose Gel * If unconscious, glucagon shot (SQ, IM, IV) |
|
|
Define hypoglycemia
|
* A marked decrease in plasma glucose level
- <60 mg/dL * Hypoglycemia can occur at much higher plasma glucose levels if the rate of decrease is rapid - This is because the patient's body is not used to living at that low of a level |
|
|
Symptoms of hypoglycemia fall into two categories
|
* Neurogenic symptoms - caused by activation of the autonomic nervous system in response to low glucose levels
* Neuroglycopenic symptoms - caused by glucose deprivation of the brain |
|
|
List the Neurogenic symptoms of hypoglycemia
|
* Sympathetic
- Palpitations - Tremor * Parasympathetic - hunger - sweating |
|
|
List the Neuroglycopenic symptoms of hypoglycemia
|
* confusion
* drowsiness * slurred speach * incoordination * diplopia |
|
|
What is hypoglycemic unawareness?
|
- lack of sufficient autonomic response to warn the patient of impending hypoglecemia
- Impaired release of stress hormones to counteract hypoglycemia * Glucagon * Catecholamines |
|
|
Insulin LISPRO
|
Rapid-acting insulin
Onset: 15-30 min Peak: 1-3 hours Duration:3-4 hours Admin: SQ |
|
|
Insulin ASPART
|
Rapid-acting insulin
Onset: 15-30 min Peak: 1-3 hours Duration:3-4 hours Admin: SQ |
|
|
Insulin GLULISINE
|
Rapid-acting insulin
Onset: 15-30 min Peak: 1-3 hours Duration:3-4 hours Admin: SQ |
|
|
Rapid-acting insulins
|
* Designed to mimic physiological post-prandial insulin secretion
* Analogues designed for rapid/immediate dissociation (from hexomers to monomers) - these analogues each differ in 1-2 amino acids |
|
|
Regular insulin
|
Short acting insulin
Onset: 0.5 - 1 hour Peak: 2-4 hours Duration: 3-7 hours Admin: SQ, IV, IM |
|
|
Short-acting insulins
|
Regular insulin
* Timing of administration is more of an issue due to the increased time to onset * No amino acid changes from endogenous * Much less of a peak when compared to rapid-acting insulins |
|
|
NPH
|
* Neutral Protamine Hagedorn
* Suspension of insulin complexed with zinc and protamine in a phosphate buffer (cloudy appearance) * may also be called isophane insulin * Intermediate acting insulin Onset: 1-2 hours Peak: 6-10 hours Duration: 16-20 hours dosed BID |
|
|
Insulin GLARGINE
|
Long-acting insulin
Onset: 1-2 hours Peak: None Duration: 20-24 hours may be dose QD (some pts will still need BID0 ***DO NOT MIX IN SYRYNGE W OTHER INSULINS * Clear soln w/ pH 4.0 * Precipitates at physiological pH |
|
|
How does the precipitation of Insulin Glargine at physiological contribute to it's mechanism of action?
|
It forms a depot that releases insulin slowly over 20-24 hours.
|
|
|
Insulin DETEMIR
|
Long-acting insulin
Onset 1-2 hours Peak: None Duration 20-24 hours * may be administered QD or BID * Duration of action is dose dependant and may be closer to 14 hours with smaller doses * 14-C fatty acid chain added which prolongs effect * Forms a liquid depot at the site of SQ injection - there is no precipitate * Promotes the aggregation of hexamers * 98% reversibly binds to albumin in the plasma so the insulin is distributed more slowly in the tissues |
|
|
ADRs associated with insulin
|
* hypoglycemia
- weight gain (s/t increased glucose utilizatiod? - Lipohypertraphy - Lipoatrophy |
|
|
What is the MOA of sulfonylureas?
|
* Stimulate insulin release from pancreatic beta cells
- Bind to sulfonylurea receptor on pancreatic beta cells - Binding closes K+ channels (K+ cannot get out of cell) - Increased intracellular K+ causes membrane depolarization and activation of calcium channels - Opening of Ca channels results in an inward flux of Ca into cells - Increased intracellular calcium causes translocation of insulin secretory granules to cell surface and insulin is released. |
|
|
Are sulfonylureas appropriate for treatment of type I diabetes?
|
* No, sulfonylureas will only work in the presence of functioning beta cells
* Used in patients with type 2 diabetes when glucose control can not be achieved with diet alone |
|
|
Examples of commonly used sulfonylureas
|
* Glimepiride
* Glipiside * Glyburide |
|
|
General pharmacokinetics of sulfonylureas
|
* Absorption: 90-100%
* Highly protein bound (mainly albumin) * Metabolism: Liver, CYP2C9 * Most SUs have metabolites (active or inactive) that are excreted in urine (this can be problematic in renal dysfunction) |
|
|
List the sulfonylureas in order of least to greatest half-life
|
Glipizide (~3 h) < Glipizide ER and Glyburide (~4-13 h) < Tolbutamide, acetohexamide, and Tolazamide (~7 h) < Glimepiride (~9 h) < Chlorpropamide (~36 h)
|
|
|
What makes Extended Release Glipiside different from the other sulfonylureas?
|
* GITS: Gastrointestinal Therapeutic System
- The tablet consists of a semi-permeable shell surrounding an osmotically active drug core - Water from the GI track diffuses into the shell and helps push the drug out of the shell |
|
|
What are the common adverse events associated with sulfonylureas?
|
* hypoglycemia - the longer the SU half-life and greater the risk of hypoglycemia
* Weight gain (1-3 kg) |
|
|
Drug-drug interactions involving sulfonylureas
|
* Displacement of SU from protein binding sites
- Warfarin, salicylates, sulfonamide antibiotics * Alterations in hepatic metabolism - Rifampin (inducer) -> decreased [SU] - Amiodarone (inhibitor) -> increased [SU] * Alterations in renal excretion - Allopurinol, probenecid |
|
|
What is the MOA of Non-Sulfonylurea Insulin Secretagogues (Meglitinides)?
|
* Stimulate insulin secretion from the beta cells of the pancreas (phase 1 insulin release)
* Binding site is adjacent to the binding site of sulfonylureas * Closes the K+ channel, causing the release of insulin in the same way sulfonylureas do |
|
|
Name the two Meglitinides
|
Repaglinide
Nateglinide |
|
|
Therapuetic uses of Meglitinides?
|
* Used in patients with type II diabetes
* requires functioning beta cells |
|
|
General pharmacokinetic of Meglitinides
|
* Absorption: 0.5-1 hour
* Half-life: 1-1.5 hours * Duration of action: 4 hours * Administered up to 30 min prior to each meal Primarily affect post-prandial concentrations What should a patient do if they skip a meal? Skip the dose |
|
|
Common adverse events of Meglitenides
|
* Hypoglycemia
* Weight gain (1-3 kg) |
|
|
Metabolism of regaglinide
|
hepatic metabolism by CYP 2C8
* inactive metabolites excreted urine |
|
|
What is the MOA of Biguanides?
|
Mechanism of action
* Decreased hepatic glucose production by…. - Increased peripheral muscle glucose uptake - Decreased insulin resistance - Decreased rate of GI glucose absorption * Do NOT stimulate insulin release and do not cause hypoglycemia |
|
|
How is Nateglinide metabolized?
|
Hepatic metabolism by: CYP2C9 and CYP3A4
Weakly active metabolites, primarily renally excreted |
|
|
How is Regaglinide metabolized?
|
Hepatic metabolism by: CYP2C8 and CYP3A4
Inactive metabolites are excreted in feces |
|
|
Meglitinide Drug Interactions
|
* Inhibitors of CYP3A4 may increase plasma concentrations of repaglinide and nateglinide
- Examples: HIV protease inhibitors (e.g., ritonavir), grapefruit juice, azole antifungals (e.g., itraconazole), macrolide antibiotics (e.g., erthyromycin) * Gemfibrozil (CYP2C8 inhibitor)can double the half-life of repaglinide * Rifampin (CYP2C8, 2C9, and 3A4 inducer) may decrease plasma concentrations of repaglinide and nateglinide |
|
|
List the Biguanides currently on the market in the US
|
Metformin (Glucophage), Metformin XR (Glumetza)
|
|
|
Therapeutic uses of Biguanides
|
* Used as monotherapy or as combination therapy (primarily with sulfonylureas) in patients with type 2 diabetes
* Often used in obese patients because it causes minimal weight gain and in some patients causes weight loss |
|
|
Pharmacokinetics of Biguanides
|
* Absorbed mainly from the small intestine
* Metformin is NOT metabolized and does NOT bind to plasma proteins * Half life: 4-6 hours * Duration of action: 6-12 hours * Elimination: renal Drugs that are excreted by renal tubular secretion may increase metformin levels Examples: cimetidine, digoxin, triamterene, trimethoprim |
|
|
Common Adverse Effects of Biguanides
|
* Most common are GI side effects:
- diarrhea - nausea - metallic taste * may cause minimal weight loss in some patients * hypoglycemia when used in combo with SUs or meglitinides |
|
|
What is a rare but serious adverse effect of Biguanides?
|
Rare, but serious side effect (50% mortality)
* Metabolic acidosis that results from lactic acid accumulation * Lactic acid is the end product of: anaerobic glucose metabolism The following conditions predispose individuals to lactic acidosis? - Increased lactic acid production: + CHF + Hypoxia, Shock + Sepsis * Decreased lactic acid removal: + liver dysfunction + cirrhosis + alcoholism |
|
|
Contraindications to Metformin
|
* Renal insufficiency
- SCr ≥ 1.5 mg/dL in men or ≥ 1.4 mg/dL in women * Liver impairment * CHF requiring drug treatment* * Alcohol abuse * Acute or chronic metabolic acidosis * Chronic hypoxic lung disease |
|
|
What is the MOA of Thiazolidinediones (TZDs): PPAR gamma Agonists?
|
Mechanism of Action:
* Stimulate peroxisome proliferator-activated receptor-gamma (PPAR gama) * Activation of PPAR gamma regulates transcription of numerous genes that influence glucose and lipid metabolism - For example: TZDs increase the transcription of GLUT4, a glucose transporter that stimulates glucose uptake * TZDs work at the gene level – turn on or off gene transcription * TZDs are Referred to as Insulin Sensitizers - Increase sensitivity in muscle, liver, and fat - Enhance glucose utilization and improve the ability of insulin to suppress hepatic glucose production and lipolysis * This all leads to improved utilization of endogenous insulin |
|
|
List examples of Thiazolidinediones
|
* Rosiglitazone (Avandia®)
* Pioglitazone (Actos®) * Troglitazone (withdrawn from the market due to cases of fatal hepatotoxicity) |
|
|
What are the therapeutic uses of Thiazolidinediones?
|
* Treatment of type 2 diabetes
* Most often used in combination therapy, but can be used as monotherapy (however, cost is an issue) * Requires functioning beta cells |
|
|
What are the “Non-Glucose” Effects of TZDs?
|
* Lipids Effects: increase HDL, decrease FFA, convert small LDL to large LDL
* Vascular Effects: decrease inflammatory markers, such as C-reactive protein and plasminogen activator inhibitor-1 (PAI-1) * Effect on beta-cells: Decrease glucotoxicity and decrease rate of beta cell loss * Effects on adipose tissue: increase number of small fat cells, increase lipogenesis, increase SQ adipose tissue |
|
|
anterior pituitary gland hormones
|
somatotropin
thyroid stimulating hormone (thyrotropin) adrenocortitropic hormone prolactin gonadotropic hormones -FSH -LH b-lipotorpin and B-endrophin |
|
|
posterior pituitary gland hormones
|
oxytocin
vasopressin (ADH) |
|
|
thymus hormones
|
thymopoietin
|
|
|
thyroid hormones
|
thyroine
triiodothyronine calcitonin |
|
|
hypothalamus hormones
|
hypophysiotropic hormones
-corticotropin-releasing hormone (CRH) -thyrotropin-releasing hormone (TSH) growth hormone releasing hormone somatostatin gonadotropin releasing hormone dopamine |
|
|
Pharmacokinetics of Rosiglitazone
|
* Half-life= 4 h
* Extensively metabolized by CYP2C8 and 2C9 * Metabolites are less potent than parent drug * Excretion: mostly in feces, small amount in urine |
|
|
Pharmacokinetics of Pioglitazone
|
* Half-life (parent)= 3-7 h
* Half-life (active metabolites) = 16-24 h * Extensively metabolized by CYP 2C8 and 3A4 * Excretion: mostly in feces, small amount in urine |
|
|
What is the onset of maximum effect of TZDs and why?
|
* Maximum effects of TZDs typically seen at 8 - 12 weeks of therapy
* Action of the TZDs relies on gene transcription - Onset and duration of action are unrelated to plasma half-life - Onset and duration are related to the time to transcription |
|
|
When used as monotherapy, would you expect TZDs to cause hypoglycemia?
|
No
|
|
|
Adverse Effects of TZDs
|
* Weight gain (dose-dependent)
- Mechanism: due to fluid retention and lipogenesis * Edema and plasma volume - due to increased retention of Na+ and water * Congestive heart failure - Black box warning - ***Contraindicated NYHA Class III/IV heart failure * Macular edema * Fractures (upper arms, hands, feet) in women - May be due to increased osteoblast activity or increased fat content in bone * Anemia - Mechanism: Most likely due to a dilutional anemia – increased plasma volume - Not true anemia and no treatment is needed * Resumption of ovulation in anovulatory women * Hepatotoxicity - Troglitazone was withdrawn from market due to fatal cases of hepatotoxicity - Possibly due to a vitamin E moiety on the troglitazone molecule - Rosiglitazone and pioglitazone do not have this vitamin E moiety - Does not appear to be a “class effect”, however baseline and periodic monitoring of LFTs is still recommended |
|
|
patient education sessions should cover these basic concepts
|
1.Calorie restriction: Shifting the energy balance to net reduction of 500 calories/day to achieve 1 lb/week weight loss
2.Fat restriction: 25% of calories, 3 ways to decrease fat intake 3.Carbohydrates in moderation at each meal: CHO counting, plate method, impact of CHO on glucose 4.Choosing good options in each food group 5.Watching portions 6. Basic healthy eating habits and strategies for success |
|
|
Who is at risk for DM
|
Risk calculator tools for detecting undiagnosed diabetes and those at risk
Age Waist circumference h/o GDM Race/ethnicity HTN Family history Exercise |
|
|
ADA criteria for screening for diabetes
|
All adults who are overweight (BMI ≥ 25) and have additional risk factors
Physical inactivity First degree relative with diabetes Member of high risk ethnic group Women who delivered baby > 9 lbs or with GDM HTN HDL < 35 mg/dL and/or TG > 250 mg/dL Women with PCOS A1C ≥ 5.7%, IGT, or IFG on previous test Other conditions associated with insulin resistance History of CVD |
|
|
Can diabetes be prevented?
|
There is a long period of glucose intolerance that precedes the development of diabetes
Screening tests can identify high risk persons There are safe, potentially effective interventions that can address modifiable risk factors and/or improve insulin resistance Obesity and fat distribution Physical inactivity |
|
|
DPP Primary Goal
|
To prevent or delay the development of type 2 diabetes in persons with impaired glucose tolerance (IGT)
|
|
|
incidence of DM in DPP study
|
Risk reduction
31% by metformin 58% by lifestyle metformin group 7.8% lifestyle group 4.8% placebo group 11% progressed to DM |
|
|
DPP Summary
|
Both interventions were effective at reducing the development of diabetes (by 58% with lifestyle and 31% with metformin)
Both interventions were well accepted and safe. Intensive lifestyle resulted in weight loss and increased activity for the duration of the study Intensive lifestyle was effective in all age groups, including those > 60 years of age |
|
|
Prevention/delay of type 2 diabetes
|
In patients at high risk (ie, pre-diabetes), structured programs emphasizing lifestyle changes can reduce the risk of developing type 2 diabetes.
Weight loss of 5-10% Increased physical activity of at least 150 min/week of moderate activity such as walking Dietary strategies including reduced calories and reduced intake of dietary fat LEVEL A RECOMMENDATION Metformin, in addition to lifestyle counseling, may be considered in those who are at very high risk for developing diabetes. Combined IFG and IGT plus other risk factors such as A1C > 6%, HTN, low HDL, high TG, or family history of diabetes in first degree relative and who are obese and under 60 years of age Monitoring for diabetes in those with pre-diabetes should be performed every year. |
|
|
Tipping the Energy Balance EAT LESS, MOVE MORE
|
1 lb of body fat stores about 3500 calories
1 lb of weight loss per week = 500 calorie deficit per day x 7 days Daily calorie goal Option 1: 500 calories/day less than current intake Option 2: current weight x 12 minus 500 Option 3: Use estimation tables or calculators (Harris-Benedict equation) Option 4: Use guideline/organization standard recommendations |
|
|
daily fatreduction goal
|
<25% of total calories
|
|
|
Three ways to eat less fat
|
Eat high fat foods less often (70% of fat we eat is hidden)
Large french fries = 6 tsp fat (30 fat grams) Eat smaller amounts of high-fat foods Use a spoon for salad dressing instead of the ladle (1 Tbsp versus 4 saves 24 grams of fat) Eat lower-fat foods instead Roast top round, trimmed (4 g fat) vs. roast chuck, untrimmed (22 g fat) |
|
|
What impacts blood glucose values?
|
Carbohydrates (mostly)
1 serving CHO = 15 grams Grains, starchy vegetables, fruits and juices, milk, yogurt, sweets and desserts Limit CHO intake to 3-4 servings per meal for women (45-60 grams CHO) and 4-5 servings per meal for men (60-75 grams CHO) Limit CHO snacks to 15-30 grams |
|
|
Drug Interactions with TZDs
|
* Gemfibrozil significantly increases rosiglitazone and pioglitazone levels
- Due to inhibition of CYP2C8 by Gemfibrozil * Rifampin decreases rosiglitazone and pioglitazone levels - Due to induction of CYP2C8 by Rifampin * Pioglitazone itself may be a weak inducer of CYP3A4 - There is a theoretical risk that coadministering Pioglitazone with a CYP3A4 substrate may decrease the concentration of the substrate |
|
|
CV Risk with TZDs
|
Both Rosiglitazone and Pioglitazone have Black Box Warnings in Heart Failure
Rosiglitazone has an additional Black Box Warning in Myocardial Ischemia |
|
|
What is the MOA of alpha-Glucosidase Inhibitors?
|
* Competitively inhibit glucosidases in the brush border of the small intestine
- Glucosidases are responsible for the breakdown of polysaccharides into monosacharides - So, inhibiting glucosidases inhibits carbohydrate absoption * This leads to a reduction in post-prandial blood glucose concentrations |
|
|
List examples of alpha-Glucosidase Inhibitors
|
* Acarbose (Precose®)
* Miglitol (Glyset®) |
|
|
Therapeutic uses of alpha-Glucosidase Inhibitors
|
Used as monotherapy or in combination therapy, particularly when postprandial glucose concentrations are elevated
|
|
|
Pharmacokinetics of Acarbose
|
* Half life of ~ 2-3 hours
* Minimally absorbed from GI tract * Extensively metabolized by GI amylases to inactive products * 50% excreted unchanged in the feces |
|
|
Pharmacokinetics of Miglitol
|
* Half life of ~ 2-3 hours
* Absorbed * Does not undergo metabolism * Excreted unchanged in the urine |
|
|
Adverse Effects of alpha-Glucosidase inhibitors
|
* GI side effects:
- flatulence - bloating - discomfort - diarrhea * Hepatic - increased LFTS: seen occasionally with high-dose acarbose therapy * Recommended to initiate AGIs at a low-dose and titrate slowly |
|
|
Drug Interactions with alpha-Glucosidase inhibitors
|
* AGIs may decrease bioavailability of digoxin
* Effect of AGIs may be decreased when administered with: - Digestive enzymes (e.g, amylase, pancreatin) - Intestinal adsorbents (e.g., charcoal) |
|
|
What is Amylin
|
* Amylin: peptide hormone co-secreted and located with insulin in the pancreatic beta-cells
* Actions: - Inhibits postprandial rise in glucagon - Decreases hepatic glucose production after meals - Delays gastric emptying - Improves satiety * Deficient amylin secretion is present in type 1 and type 2 diabetes and contributes to abnormal glucose homeostasis |
|
|
What is the MOA of Pramlintide Acetate (Symlin)?
|
* Amylin agonist
* Synthetic analog of human amylin - 37-amino acid peptide - Differs from human amylin by 3 amino acids - Administered as a SQ injection, prior to each major meal |
|
|
Pharmacokinetics of Pramlitidine
|
* Half-life ~ 50 minutes
* Does not extensively bind to blood cells or albumin * Primarily metabolized by the kidneys - The primary metabolite has a half-life and activity similar to parent drug * Pramlintide (pH of 4.0) and insulin should be administered as separate injections |
|
|
Adverse Effects of Pramlitidine
|
* Nausea/vomiting
* Loss of appetite * Headache * Hypoglycemia - Pramlintide alone does NOT cause hypoglycemia - Co-administration of pramlintide with insulin can increase risk of severe hypoglycemia + More frequently seen in type 1 diabetics + Severe hypoglycemia may occur within the first 3 hours following administration + More common during first 3 months of therapy + Less common when mealtime insulin is decreased by 50 % at start of pramlintide therapy |
|
|
Drug Interactions of Pramlitide
|
* Due to pramlintide’s effects on gastric emptying, it may delay the absorption of ingested drugs
* Should not be administered with drugs that alter GI motility or affect absorption of nutrients |
|
|
What are Incretins and what do they do?
|
* Endogenous peptide hormones secreted by cells in small intestine
- Secreted in response to food intake * Biological Actions: - Increased glucose-dependent insulin secretion from pancreatic beta-cells - Suppress glucagon secretion - Slows rate of gastric emptying - Suppress appetite |
|
|
Examples of endogenous incretin hormones:
|
* Glucagon-like Peptide-1 (GLP-1)
* Glucose-dependent insulinotropic polypeptide (GIP) |
|
|
Glucagon-like Peptide 1 (GLP-1)
|
* GLP-1 is derived from proglucagon in mucosal L-cells of the small intestine
* Acts on GLP-1 receptors on pancreatic beta cells * In diabetes, GLP-1 response is defective - Decreased circulating postprandial GLP-1 - Increased postprandial glucagon levels - Blunted insulin secretory response to food intake * Endogenous GLP-1 is rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) |
|
|
Incretin Mimetic Drugs
|
* Mimic the actions of naturally occurring incretins
- Glucose-dependent insulin secretion - Suppress inappropriately elevated glucagon levels - Promote satiety and reduce food intake - Slow rate of gastric emptying |
|
|
Exendin-4
|
* Naturally occurring GLP-1 agonist isolated from the venom of the Gila monster
* Gila monster exendin-4 has 53% amino acid overlap with mammalian GLP-1 * Exendin-4 has some of the same glucose-regulating actions as mammalian GLP-1, and is resistant to DPP-IV degradation |
|
|
Exenatide (Byetta)
|
* Synthetically-derived peptide of exendin-4
* 9 amino acids longer than mammalian GLP-1 * Binds to and stimulates the pancreatic GLP-1 receptor - Also binds to GLP-1 receptors in kidney, stomach, heart, brain * Pharmacodynamic actions in humans: - Promotes glucose-dependent insulin secretion - Restores first-phase insulin response - Decreased glucagon secretion during periods of hyperglycemia - Slows gastric emptying - Decreased food intake * Net Result: decreases fasting and postprandial glucose levels |
|
|
Therapeutic uses of Exenatide (Byetta)
|
* Type 2 diabetes: adjunct therapy in patients who have not achieved adequate glycemic control with metformin, sulfonylurea, and/or TZD therapy
* Administered as a SQ injection twice daily before the morning and evening meals - Given within 60 minutes of meal |
|
|
Pharmacokinetics of Exenatide (Byetta)
|
* Half-life of 2.5 hours
* Eliminated by glomerular filtration and proteolytic degradation * Clearance is significantly reduced in end stage renal disease |
|
|
Drug Interactions with Exanatide
|
* May delay the extent and rate of absorption of oral drugs
* For oral drugs dependent on rate of absorption or threshold concentrations for efficacy, administer those drugs at least 1 hour before exenatide Examples: antibiotics and analgesics |
|
|
Adverse Effects of Exanatide
|
* Nausea and vomiting
* Decreased appetite * Hypoglycemia (mostly when given in conjunction with a sulfonylurea) * Pancreatitis * Formation of anti-exenatide antibodies leading to hypersensitivity reactions or failure to achieve an improvement in glycemic control |
|
|
Liraglutide (Victoza)
|
* Glucagon-like peptide-1 receptor agonist
- 97% amino acid sequence homology to endogenous human GLP-1 - Stable against degradation by peptidases * Mechanism of action: activates GLP-1 receptors on pancreatic beta cells - Increases intracellular cyclic AMP leading to insulin release in the presence of elevated glucose - Decreases glucagon secretion in a glucose-dependent manner - Delays gastric emptying |
|
|
Therapeutic uses of Liraglutide
|
* Indication: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
- Administered as a SQ injection once daily, at any time of day, independent of meals - Weekly dose titration recommended at initiation of therapy: 0.6 mg 1.2 mg 1.6 mg (if needed) + 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce GI intolerance *Not recommended as first-line therapy for patients inadequately controlled on diet and exercise * Has not been studied in combination with insulin * Not indicated for treatment of type 1 diabetes |
|
|
Pharmacokinetics of Liraglutide
|
* Maximum plasma concentrations attained at 8-12 hrs
* Plasma half-life of 13 hours * Endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination |
|
|
Adverse effects, contraindications and orecautions for Liraglutide
|
* Black Box Warning:
- Liraglutide caused dose-dependent and treatment duration-dependent thyroid C-cell tumors at clinically relevant exposures in rodents. Human relevance is unclear. * Adverse effects: - Headache, nausea, diarrhea, anti-liraglutide antibody formation, immunogenicity reactions (e.g., urticaria, angioedema), injection site reactions - Serious hypoglycemia when used in combination with insulin secretagogues, consider reducing liraglutide dose when using it in combination with these agents Pancreatitis * Contraindications: personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 * Precautions: history of pancreatitis |
|
|
Dipeptidyl peptidase-4 (DPP-4) inhibitor
|
* Slows inactivation of endogenous incretin hormones
- E.g., inactivates GLP-1 in circulation * Results in 2- to 3-fold increase in circulating active GLP-1 concentrations * Decreases glucagon concentrations * Increases glucose-dependent insulin secretion * Net result: decreased fasting and postprandial glucose concentrations |
|
|
Examples of Dipeptidyl peptidase-4 (DPP-4) inhibitors
|
Sitagliptin
Saxagliptin |
|
|
Therapeutic uses of Sitagliptin (Januvia)
|
Used in patients with type 2 diabetes as either monotherapy, or in combination with metformin, TZDs, or sulfonylureas (lower sulfonylurea dose may be required)
- Has not been studied in combination with insulin |
|
|
Pharmacokinetics of Sitagliptin
|
* Half-life: 12 hours
* 80% of drug is excreted unchanged by the kidneys - Minimal hepatic metabolism - Recommended dose reductions for renal impairment + CrCl 30 to 50 ml/min = 50 mg QD + CrCl < 30 ml/min = 25 mg QD - Assess renal function prior to beginning sitagliptin |
|
|
Side effects of Sitagliptin
|
- Low incidence of hypoglycemia or weight gain
- Nausea/diarrhea - Small increase in WBC - Allergic and hypersensitivity reactions + Anaphylaxis, angioedema, Stevens-Johnson syndrome - Recent reports of pancreatitis |
|
|
Drug interactions of Sitagliptin
|
* Based on limited studies, does not appear to have significant drug-drug interactions
* Substrate for P-glycoprotein, therefore a theoretical potential exists for interactions with P-glycoprotein inhibitors (e.g., cyclosporine, verapamil) |
|
|
Therapeutic uses of Saxagliptin (Onglyza)
|
Used in patients with type 2 diabetes as either monotherapy, or in combination with metformin, TZDs, or sulfonylureas (lower sulfonylurea dose may be required)
- Has not been studied in combination with insulin |
|
|
Pharmacokinetics of Saxagliptin
|
* Half life: 2.5 hours
* 25% of the drug is excreted in the urine as unchanged drug * Recommended dose reductions for renal impairment CrCl < 50 ml/min = 2.5 mg QD * Assess renal function prior to beginning saxagliptin * Metabolized by CYP3A4/5 * The primary metabolite is also a DPP-4 inhibitor; however the metabolite is ½ as potent as saxagliptin * Dose decrease to 2.5 mg QD needed when administered with strong CYP3A4/5 inhibitors - Examples of strong CYP3A4/5 inhibitors: + Ritonavir + grapefruit juice + Azole antifungals + macrolide antibiotics |
|
|
Adverse Effects of Saxagliptin
|
headache, upper respiratory tract infection, urinary tract infection, hypersensitivity reactions, decrease in absolute lymphocyte count
|
