Diabetes Drugs DSA Flashcards
drugs used in diabetes
- insulins
- amylin analog
- insulin secretagogues
- biguanides
- thiazolidinediones
- sodium-glucose co-transporter 2
- inhibitors of alpha-glycosidases
Insulins- rapid acting
-Aspart
-Lispro
-Glulisine
(ALG)
Insulins- short-acting
-regular insulin
insulins- intermediate-acting
-NPH
insulins- long-acting
- Detemir
- Glargine
insulin- moa
- IR-IRS-P13K-Akt pathway- effects on glucose, lipid and protein metabolism, primarily via reg of enzyme activities
- IR-IRS-MAP kinases- reg of gene transcription and cell proliferation
effects of insulin- gene expression
- ELK1 (ETS family of TFs)
- AP-1 TF
- FoxO1 (forkhead TFs)
insulin- ELK1
- IR-IRS-Ras-Raf-MEK-ERK-inc ELK1!
- cell growth and diff
- cell prolif and inc survival
insulin- AP-1 TF
- IR-IRS-P1-3K-Rac-inc JNK- inc AP-1
- cell growth and diff
- cell prolif and apoptosis
Insulin- FoxO1
- IR-IRS-Pl-2K- Akt- dec FoxO1
- inc PPAR-y expression and lipogenesis
- dec glycogenolysis
- dec gluconeogenesis
- enhanced cell diff
- escaping cell cycle arrest and inc prolif
insulin- carbohydrate metabolism
- glucose transport- GLUT4 translocation to cell membrane (skeletal m, cardiac myocytes, adipocytes)
- act of glycolysis
- act of glycogen syn
- inhibition of gluconeogenesis
- inhibition of glycogenolysis
Insulin- lipid metabolism
- inhibition of lipolysis
- enhanced lipogenesis
insulin- protein metabolism
-inc prot synthesis
Rapid acting insulins- clinical use
(Aspart, Lispro, Glulisine)
- postprandial hyperglycemia- take before meal
- onset 5-10 min
- duration 1-3 hrs
- peak 30 min -1 hr
short-acting insulin- clinical use
(regular insulin)
- composition- unmodified zinc insulin crystals
- absorption rate is slow and less predictable
- basal insulin maintenace; overnight coverage; postprandial hyperglycemia (45 min b/f meal)
- onset 30 m - 1 hr
- duration 10 hrs
- peak 3-5 hrs
Intermediate acting insulin
(NPH)
- complex of protamine with zinc insulin- protamine has to be digested by tissue proteolytic enzymes b/f insulin can be absorbed
- basal insulin maintenance and/or overnight coverage
- use is declining- replaced by long-acting insulins
- onset 1-2 h
- duration 10-12 h
- peak 4-12 h
long-acting isulin- clinical use
(Detemir, Glargine)
- basal insulin maintenance (1-2 injections dialy)
- onset 3-4 h
- duration 24 h
- peak 3-9 h (detemir); peakless (glargine)
clinical indications for insulin
- type 1 diabetes
- type 2 diabetes (inadequately controlled by diet, exercise, and non-insulin tx)
- gestational diabetes
- severe hyperkalemia- insulin + glucose + furosemide- act Na/K-ATPase- shift K from extracellular fluid into cells
insulin- adverse effects
- hypoglycemia
- lipodystrophy- hypertrophy/atrophy of subcutaneous fat at site of injection- prevented by freq changing the site of injection
- resistance- insulin binding ab’s (IgG)
- allergic rxns (rare- histamine release from mast cells)
- hypokalemia
most common complication of insulin therapy; caused by?
hypoglycemia!!
- delay of a meal/missed meal
- exercise
- overdose of insulin
signs of hypoglycemia
- CNS/behavioral sx- confusion, bizarre behavior, seizures, coma
- symp hyperactivity- tachycardia, palpitations, sweating, tremor
- parasymp hyperactivity- hunger, nausea
- pts on tight glycemic control- “hypoglycemic unawareness”
hypoglycemia- tx
- glucose!- juice, candy (if conscious), IV glucose (if unconscious)
- diazoxide- Katp channel opener- inhibits the release of insulin by B cells
- glucagon
glucagon- moa
Gs-coupled GPCR
- act of AC
- act of PKA
- act of phosphorylase–> glycogenolysis
- inc expression of PEPCK and G6Pase- gluconeogenesis
Glucagon- effects
- hepatocytes- inc glucose output, glycogen depletion
- potent inotropic and chronotropic effect on heart
- GI smooth m relaxation
- inc insulin release by B-cells
- inc release of catecholamines by chromaffin cells (contraindicated in pheochromocytoma pts)
glucagon- clinical uses
- moderate/severe hypoglycemia
- B-blocker overdose
- radiology of bowel
Amylin analog
-pramlintide
amylin analog- clinical use
- type 1 diabetes
- type 2 diabetes who takes mealtime insulin therapy
- injected sc b/f meals as an adjunct to insulin therapy
amylin analog- adverse effects
- GI- N/V, diarrhea, anorexia
- severe hypoglycemia (if used with insulin, insulin dose should be reduced)
amylin analog- drug interactions
-enhances effects of anticholinergic drugs in GI tract (constipation)
insulin secretagogues
- incretin mimetics- GLP-1 agonists, DPP-4 inhibitors
- KATP channel blockers- sulfonylureas, meglitinides
GLP-1 agonists
-exenatide
-liraglutide
(EL)
GLP-1 agonists- clinical use
- release of GLP-1 is diminished postprandially in type 2 diabetes pts- inadequate glucagon suppression and excessive hepatic glucose output
- approved for type 2 diabetes pts who arent controlled by metformin/sulfonylureas/thiazolidinediones
- doses of other anti-diabetic meds should be reduced
- parenteral route- improved control of hyperglycemia, induce weight loss
GLP-1 agonists- adverse effects
- GI- N/V, diarrhea, anorexia
- lower risk of hypoglycemia vs pramlintide
- linked to acute pancreatitis and pancreatic cancer
- linked to thyroid cancer
DPP-4 (dipeptidyl peptidase-4) inhibitors
-Sitagliptin
-Linagliptin
-Saxagliptin
-Alogliptin
(gliptins)
DPP-4 inhibitors- moa
-serine protease that degrades GLP-1 and other incretins
DPP-4 inhibitors- clinical use
- adjunctive tx to diet and exercise in pts with type 2 diabetes
- monotherapy or with metformin/sulfonylureas/TZDs
- orally!
DPP-4 inhibitors- adverse effects
- URIs and nasopharyngitis
- acute pancreatitis
- hypoglycemia (if combined with insulin secretagogues- doses must be adjusted)
Sulfonylureas- first generation
-chlorpropamide
-tolbutamide
-tolazamide
(CTT)
Sulfonylureas- second generation
- glipizide
- glyburide
- glimepiride
Meglitinides
- Nateglinide
- Repaglinide
Sulfonylureas- clinical use
-type 2 diabetes as a monotherapy or in combi with insulin or other anti-diabetic drugs
sulfonylureas- adverse effects
- hypoglycemia
- weight gain
- secondary failure- respond initially, later cease to respond- develop unacceptable hyperglycemia
- disulfiram-like effect of alcohol-induced flushing
- dermatological and general hypersensitivity rxns- cross-reactivity with other sulfonamides (abx, carbonic anhydrase inb, diuretics- thiazides, furosemide)
sulfonylureas- drug interactions- enhancing their hypoglycemic effect
- displacing from binding with plasma proteins- sulfonamides, clofibrate, salicylates
- enhance the effect on KATP channel- ethanol
- inhibit CYP enzymes- azole antifungals, gemfibrozil, cimetidine
sulfonylureas- drug interactions- dec their glucose-lowering effect
- inhibit insulin secretion- B-blockers, CCBs
- antagonist their effect on KATP channel- diazoxide
- induce hepatic CYP enzymes- phenytoin, griseofulvin, rifampin
Meglitinides- moa
-KATP channel inhibition
Meglitinides- clinical use, SE’s
- postprandial hyperglycemia in pts with type 2 diabetes
- orally before meal
- alone or in combo with other antidiabetic drugs
- hypoglycemia, secondary failure, weight gain
Biguanides
-metformin
Metformin- moa
- act of AMP-dep protein kinase
- inhibition of lipogenesis and gluconeogenesis
- inc in glucose uptake, glycolysis, fatty acid oxidation
- lower glucose levels in hyperglycemic state
- inc insulin sensitivity
metformin- clinical use, advantages
most commonly used oral agent to treat type 2 diabetes!!!- first-line tx!!
- superior/equivalent glucose-lowering efficacy compared to other oral meds
- doesnt cause hypoglycemia or weight gain
- taken orally
- dec risk of macro and micro-vascular complications in diabetic pts
metformin- adverse effects, contraindications
- GI
- dec abs of B12
- lactic acidosis- esp under conditions of hypoxia, renal and hepatic insuff
- contraindicated in conditions predisposing to tissue hypoxia (HF, COPD), renal failure, chronic alcoholism, cirrhosis
Thiazolidinediones
- pioglitazone
- rosiglitazone
Thiazolidinediones- moa
- ligands of PPARy (proliferator-activated R-gamma)
- endogenous ligands- prostaglandins and free fa’s
- TZDs have a much higher affinity for PPARy- bind and go to to R and target it to nucleus- gene expression:
- inc GLUT4 in skeletal m- enhances glucose uptake, reduced hyperglycemia
- inc GLUT4 in adipocytes
- inc insulin sensitivity
- inc adiponectin- inc insulin sensitivity and dec infl
- dec PEPCK- inhibit gluconeogenesis
- dec NF-kB and AP-1 transactivation- dec prod of cytokines
Thiazolidinediones- pharmacokinetics
- taken orally once daily
- onset is delayed- full effect after 1-3 months
- metabolized by liver
Thiazolidinediones- clinical use
- type 2 diabetes- alone or in combo
- delay progression from prediabetes to type2 diabetes
- euglycemic drugs (no hypoglycemia when used alone)
Thiazolidinediones- adverse effects
- weight gain
- edema
- linkto inc risk of bladder cancer
- osteoporosis
- inc TC and LDL-C
SGLT2 (sodium-glucose co-transporter 2) inhibitors
- Canagliflozin
- Dapagliflozin
- Empagliflozin
SGLT2 inhibitors- moa
- kidneys filter 160-180 g of glucose/day- glucose reabs in proximal tubule by SGLT2
- inhibit SGLT2 to inc glucose excretion and to reduce hyperglycemia
SGLT2 inhibitors- other effects
- osmotic diuresis
- weight loss
- reduce BP
- reduce plasma levels of uric acid
- doesnt cause hypoglycemia when used alone
SGLT2 inhibitors- clinical use
- adjunct to diet and exercise in type 2 diabetic pts
- taken orally b/f first meal once a day
- in pts with hypovolemia- should be corrected first b/f start of therapy
SGLT2 inhibitors- adverse effects
-hypotension
-hypovolemia
-genital and UTIs- can lead to life-threatening blood and kidney infections
-hypoglycemia
-inc LDL-C
renal fxn impairment
-hyperkalemia
-ketoacidosis
Inhibitors of alpha-glycosidases
- acarbose
- miglitol
Inhibitors of alpha-glycosidases- moa
- inhibition of alpha-glycosidases (located on brush border of intestinal epit)
- only monosaccharides are absorbed from GI into the blood
- inhibition defer digestion and thus abs of ingested starch and disaccharides
- lower postprandial hyperglycemia to create an insulin-sparing effect
Inhibitors of alpha-glycosidases- clinical use
- type 2 diabetes- monotherapy or combo
- taken orally at mealtime
- dont cause hypoglycemia when used alone
- dont cause weight gain
Inhibitors of alpha-glycosidases- adverse effects
- malabs, flatulence, diarrhea, abd bloating
- hypoglycemia when combined
Inhibitors of alpha-glycosidases- drug interactions
-dec abs of digoxin and propranolol and ranitidine
