Exam Review Diabetes Winter 2024-1-1.pdf

Pancreatic Hormones & Diabetes Mellitus CLASSIFICATION NAME OF DRUG Ultra-Rapid Onset Short DOA 1. Insulin lispro (Humalog) 2. Insulin aspart (Novolog) 3. Insulin glulisine (Apidra) Rapid Onset Short DOA 1.Regular (crystalline zinc) Insulin (Humulin R, Velosulin BR, Regular Iletin II) IMPORTANT NOTE...

Pancreatic Hormones & Diabetes Mellitus CLASSIFICATION NAME OF DRUG Ultra-Rapid Onset Short DOA 1. Insulin lispro (Humalog) 2. Insulin aspart (Novolog) 3. Insulin glulisine (Apidra) Rapid Onset Short DOA 1.Regular (crystalline zinc) Insulin (Humulin R, Velosulin BR, Regular Iletin II) IMPORTANT NOTE(S) Onset: 15 min (quickest) DOA: 2-5 hr Can dose on sliding scale Soluble (Clear) – can be used I.V. Use approx. 15 min. before start of meal Onset: 30 min DOA: 5-7hr Can dose on sliding scale Soluble (Clear) – can be used I.V. Used IV in emergencies (ketoacidois) Inject S.C. 30-60 min before meal Intermediate Onset Intermediate DOA 1. Neutral Protamine Hagedorn (Humulin N, NPH Insulin, NPH IletinII) (“Isophane Insulin Susp.”) (Phosphate buffer) Intermediate Onset Extended DOA 1. Insulin glargine (Lantus) 100 IU/mL Onset: 2-4 hr DOA: 10-16 hr Suspension (crystalline insulin/zinc/protamine) Not used IV (S.C. only) Phosphate buffer Used to maintain fasting blood glucose levels Onset: 1.1hr DOA: 24hr (peakless) Clear soln. in vial at pH 4 (micro-precipitates upon injection.) Concentrated insulin glargine (Toujeo) 300 IU/mL 2. Insulin detemir (Levemir) Dose 1x daily at bedtime Onset: 2hr DOA: 22hr (peakless) Soluble (in vial and upon injection) Regular insulin bound to fatty acid to extend action In contrast to glargine and Ultra long-acting 2nd Generation Sulfonylureas Longer DOAs than 1st generation agents Hypoglycemic agents (100 x more potent than 1st generation agents (bad in overdose) Same side effects as 1st generation Weight gain Potent hypoglycemic agents! MOA: Bind to and close K+ATP channel on pancreatic β-cell → depolarization of β-cell opens Ca2+ channel → Insulin release. Release of insulin in response to glucose is also increased Potentiate insulin effects in adipose and muscle tissue Reduction in serum glucagon Side effects: Hypoglycemia Weight gain Rare dematological (sulfa?) allergies (rash, puritis) Nausea/ vomiting Blood dyscresias Insulin degludec (Tresiba) Glyburide (Micronase) QD dosing Liver metabolism/ renal excretion of metabolites Don’t use in renal or liver failure Weakly active metabolites that are excreted by the kidney → higher incidence of hypoglycemia mainly in eldery patients with kidney disease. Also the original (nonmicronized) formulation has the longest plasma half-life (10 hrs) amongst the 2nd generation agents Glipizide (Glucotrol) Glipizide XL(Glucotrol XL) Glimepiride (Amaryl) Meglitinides Repaglinide (Prandin) Hypoglycemic agents MOA: Close K+ATP channel→ depolarization of β-cell → open Ca+ channel → insulin release Weght gain detemir insulins, degludec may be mixed with rapid-acting insulins without altering the kinetics of the degludec or the rapid-acting insulins DOA > 42 hours (peakless) Ryzodeg 70/30® = degludec + aspart Nateglinide (Starlix) Shortest DOA =use BID Extended length (XL) = QD Liver Metabolism DOC in renal failure QD dosing Administered before meals to reduce post-prandial glucose levels Short half-lives No sulfa allergy S.E. = Weight gain, GI upset, headache, hypoglycemia Biguanides Not a hypoglycemic agent MOA: Decreases hepatic glucose production by INHIBITING GLUCONEOGENESIS: metformin indirectly activates AMP-dependent kinase (AMPK) which is normally activated when cellular energy ATP/AMP ratio is low(i.e.,decreased energy reserves). Activated AMPK phosphorylates and activates transcription factors which inhibit the expression of hepatic gluconeogenic genes. The ability of metformin to indirectly activate AMPK may result from it ability to inhibit Complex I of the mitochondrial oxidative phosphorylation process thereby decreasing the ATP/AMP ratio Increases sensitivity of muscle, adipose to insulin Does not stimulate insulin secretion Decreases intestinal glucose absorption Metformin (Glucophage) Can be used in combinations with sulfonylureas, TZD’s,DPP-4 inhibitors, insulin Not a hypoglycemic agent “Anti-hyperglycemic” “Gold standard” for Type-2 diabetes Weight Neutral (Loss?) ↑HDL, ↓serum triglyceride, ↓total cholesterol Possible Lactic acidosis (very rare, but 50% fatality in severe cases ): don’t use metformin in patients with kidney or liver disease , or those with CHF; avoid excessive acute/ chronic ethanol use N/V, GI disturbances including diarrhea → releases 5-HT in gut ↓ Vitamin B12 / folic acid; suggest patient take PO B12 1000 mcg/day Metallic taste Taken TID with 1st bite of each meal (these agents are used to reduce post-prandial glycemia) Alpha Glucosidase Inhibitors Not hypoglycemic agent MOA: Competitive, reversible inhibition of alpha-glucosidase in the brush border of the small intestine to prevent breakdown of carbohydrates into glucose. This delays digestion of carbs and therefore delays glucose absorption Also inhibits pancreatic α-amylase. Delays rise in blood glucose concentrations after a meal (i.e., the amplitude of post postprandial blood spike is reduced) Do not affect glucose, lactose, or fructose absorption Acarbose (Precose) Miglitol (Glyset) As monotherapy can lower HbA1c approx. 0.8% Prevents sucrose breakdown into glucose (only glucose or dextrose can be used if patient is experiencing a hypoglygemic episode ) S.E. = flatulence (gas) Poorly tolerated ! (gas) Contraindicated in IBS and obstruction Increases effectiveness of insulin and reduces amount of external insulin required by 30% Thiazolidinediones (TZD’s) “glitazones” Not hypoglycemic agent Rosiglitazone (Avandia) MOA: increases tissue insulin sensitivity → enhances the insulindependent uptake of fatty acids and glucose from plasma into fat/muscle Pioglitazone (Actos) Liver Function Tests are required at baseline, and at 2-3 month intervals for first year Slow onset ~ 2 months for max. effect Action is dependent on presence of circulating endogenous or exogenous insulin S.E. = weight gain (2-10 lbs) Does not increase insulin release from the pancreas Fluid retention (↑ plasma volume, Activates PPAR-γ, a nuclear transcription factor which increases transcription of LPL, GLUT-4, & other factors involved in adipose storage of TG’s By “forcing” TG (fat) storage, cells can’t utilize fatty acids as an energy source; cells must catabolize (utilize) glucose to produce energy → this decreases serum glucose levels Reduces transcription of leptin (may increase appetite) Indirectly produces a mild inhibition of gluconeogenesis ↑ extravasular fluid (Bad in CHF pt)) Increase subcutaneous fat but not visceral fat Increased incidence of CHF 83% increased risk of bladder cancer w/ pioglitazone ??? ↑HDL ↓TG with pioglitazone GI disturbances, fatique, headache, contradicted in pregnancy & breast-feeding Increased risk of bone fractures in women: decreases bone mineral density Macular edema GLP-1 Agonists (Incretinmimetics) Not hypoglycemic agents MOA: Enhance secretion of insulin in the presence of glucose Slow the rate of absorption of glucose and other nutrients by delaying gastric emptying Reduce appetite (increase satiety) Inhibit glucagon release (reduces hepatic glucose output) Stimulates beta cell differentiation and proliferation?? Elimination and/or metabolism of these GLP-1 agonist drugs occurs in the kidney where they are degraded by various proteinases to small fragments (DPP-4 does not play a significant role in their degradation) Exception is liraglutide which is eliminated hepatically Weight Loss Exenatide (Byetta) (GLP-1 agonist) (S.C. injection BID) Extended release formulation used once weekly = Bydureon® Liraglutide (Victoza) (GLP-1 agonist) (S.C. injection once a day) Dulaglutide (Trulicity) (GLP-1 agonist) (S.C. injection once weekly) Lixisenatide (Adlyxin) (GLP-1 agonist) (S.C. injection once a day) Semaglutide (Ozempic) (GLP-1 agonist) (S.C injection once weekly) (Rybelsus) (once daily oral formulation) Antihypertensive (↑ cardiac ANP secretion) Antiatherogenic (suppress macrophage foam cell formation to ↓ inflammatory cytokine secretion) Tirzepatide (Mounjaro) (GIP and GLP-1 receptor agonist) (S.C.injection once weekly) Cause weight loss → Liraglutide(Saxenda®) and Semaglutide Wegovy®) are marketed as treatments for obesity) Common S.E.= Nausea, vomiting, diarrhea, Acute pancreatitis potentially fatal: tell patients to report any upper abdominal pain and vomiting) Medullary (C-cell) carcinoma / thyroid C-cell hyperplasia: Black box warning for all of these agents: contraindicated in patients with a family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type2 Acute renal failure (these agents are not recommended in ESRD; caution combining with other agents that can impair renal functioning: NSAIDS, ACEI, diuretics, MTX) No dose adjustment is required for liraglutide, albiglutide, and dulaglutide in CKD stages 2 and 3, although all GLP-1 receptor agonists are currently contraindicated in stages 4 and 5 CKD. All 4 agents are used orally QD Dipeptidyl-peptidase-4 (DPP4) Inhibitors Sitagliptin (Januvia) Inhibit the metabolism of endogenous GLP-1 and GIP, thereby increasing their duration of effectiveness DPP-4 is a serine protease widely distributed throughout the body on endothelial cells, on the surface of Tlymphocytes, and in a circulating form Saxagliptin( Onglyza) Usually used as add on therapy; considered inappropriate for initial therapy. Type-2 diabetics ONLY. NOT indicated for use with insulin Weight Linagliptin (Tradjenta) neutral. Delay gastric emptying (decreases the rate and extent of absorption of other drugs; take other drugs at least 1 hour before or 2hours after administration of the DPP4 inhibitor ( especially important for antibiotics and contraceptives) DPP-4 may be important enzyme involved in proper immune system functioning: SE’s of inhibitors = angioedema, urticaria, localized skin exfoliation, bronchial hyperreactivity, runny nose, headache Severe joint pain (b/c Alogliptin (Nesina) DPP-4 normally breaks down substrates involved in inflammation and inhibitors of DPP-4 would prevent this) Acute pancreatitis (rare) DPP-4 inhibitors can be used in all stages of renal impairment, with appropriate dose reduction, with the exception of linagliptin, which can be used without dose adjustment. Increased risk of heart failure: with saxagliptin and alogliptin (especially in patients who already have heart or kidney disease) SGLT2 Inhibitors Inhibit the sodium-glucose transporter type 2 (SGLT2), a membrane protein expressed mainly in the early proximal tubule (S1 segment) of the kidney where 90% of renal glucose reabsorption occurs Canagliflozin (Invokana) Inhibition of SGLT2 inhibits Ertugliflozin (Steglatro) transport of glucose from the renal tubule back into the bloodstream → glucose remains in the urine until it is excreted by urination Adverse side effects: Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Bexagliflozin (Brenzavvy) Weight loss (2-5 kg) Genital yeast (mycotic) infections in both men and women Urinary tract infections Volume depletion due to diuretic effect arising from increased osmolality of the urine → Hypotension, dehydration, thirst Hyperkalemia ↑ LDL cholesterol (doserelated) Bone fractures (TZDs are also associated with fractures) Amylin agonist Pramlintide (Symlin) MOA: Acts on amylin receptors to: : Slow gastric emptying Suppress post-prandial glucagon concentration Increase Satiety (CNS action) Weight loss Renal impairment (↑Scr) Ketoacidosis At stage 3 CKD or greater, either require dose adjustment or are contraindicated Use: Type-1/Type-2 diabetics who use insulin at mealtime and have failed to achieve diabetic control Injected S.C. before meals (reduces post-prandial glycemia) Weight loss Nausea !(28-48%) → titrate dose to avoid Vomiting, anorexia, headache Caution in patients with diabetic gastroparesis Drug interactions because it slows gastric emptying → Take other drugs at least 1 hour before or at least 2 hours after, injection. Don’t co-administer anticholinergics or other agents that can slow gastic motility ). Avoid using acarbose or miglitol