Konorev DSA: Drugs for Diabetes Flashcards
Rapid Acting Inulins
- aspart
- lispro
- glulisine
short acting insulins
-regular insulin
Intermediate acting insulin
NPH
Long acting insulin
- Detemir
- Glargine
Amylin analog
-Pramlintide
Insulin secretagogues
- incretin memetics
- Katp channel blockers
Incretin Mimetics
- GLP-1 agonists: Exenatide, Liraglutide
- Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, linagliptin, saxagliptin, alogliptin
Katp channel blockers
- sulfonylureas
- Meglitinides
first generation sulfonylureas
- Chorpropamide
- tolbutamide
- tolazamide
Second generation Sulfonylureas
- Glipizide
- Glyburide
- Glimepride
Meglitinides
- Nateglinide
- Repaglinide
Biguanides
Metformin
Thiazolidinediones
- Pioglitazone
- Rosiglitazone
Sodium-glucose co transporter 2 (SGLT2) inhibitors
- Canagliflozin
- Dapagliflozin
- Empagliflozin
Inhibitors of alpha-glycosidases
- Acarbose
- Miglitol
What are the end effects of insulin?
- increased glycogen/lipid/protein synthesis
- decreased lipolysis
- cell growth and differentiation
- AKT pathway: regulation of enzyme activities
- MAP kinases: regulation of gene trascription and cell proliferation
What transcription factor is for cell growth and differentiation and for cell proliferation and increased survival?
ELK1
Which TF is for cell growth and differentiation and cell proliferation and apoptosis
-AP-1
Which TF will give of decreased glycogenolysis, decreased gluconeogenesis, and escaped the cell cycle arrest and increases proliferation?
FoxO1
What happens with GLUT4 when insulin binds IRS?
gets translocated to the cell membrane
What are the effects on carb metabolism by Insulin?
- glucose transport (GLUT4)
- Activation of glycolysis
- Activation of glycogen synthesis
- Inhibition of gluconeogenesis
- Inhibition of glycogenolysis
Is cAMP lowered or elevated by insulin binding?
lowered
Insulin effects on lipid metabolism
- inhibition of lipolysis :decreased hormone-sensitive lipase, decreased TG breakdown
- enhanced lipogenesis: increased expression of FA synthase
Insulin effects on protein metabolism
- increased ptn synth
- increased mTOR,,,, ribosome biogenesis, mRNA translation
Why are the rapid acting insulins so rapid?
-mutations fromhuman sequence block assembly of dimers and hexamers… allow for faster absorption
Clinical use of rapid-acting insulins
-postprandial hyperglycemia…taken before a meal
What is used for overnight coverage of insulin in the body?
- just regular insulin
- if for postprandial hyperglycemia, inject 45 min before the meal
- lasts 10 hrs
What is used for basal insulin maintenance and/or overnight coverage?
NPH, the intermediate acting insulin
-lasts 4-12 hrs
What is used for pretty much only basal insulin maintenance?
Long acting insulin: Detemir or Glargine
-lasts 24 hrs
Indications for insulin use?
Type 1 or 2 diabetes
- or Severe Hyperkalemia, remember that it also traps all of the K+ in the cell
- use loop diuretics to eliminate K+ from the body
Adverse effects of Insulin
- hypoglycemia
- lipodystrophy
- Resistance: they will develop insulin binding antibodies
- Allergic rxns (rare)
- hypokalemia
What is the most common complication of insulin therapy?
Hypoglycemia
Common causes of hypoglycemia
- delay of a meal or a missed meal
- exercise: exercised muscle consumes more glucose
- overdose of insuin
Signs of hypoglycemia
- confusion,m dizarre behavior, seizures, coma
- sympathetic hyperactivity: tachycardia, palpitations, sweating, tremor
- Parasympathetic hyperactivity: hunger, nausea
- Patients on tight glycemic control: “hypoglycemic unawareness”
Tx for hypoglycemia
- glucose: juice, candy, etc. if consciou; I.V. glucose if unconscious
- Diazoxide: stong hyperglycemic agent- Katp channel opener…. also inhibits the release of insulin by beta cells
- Glucagon
MOA of Glucagon
- Gs coupled GPCR
- activation of AC
- PKA
- phosphorylase…. glycogenolysis
- increased expression of PEPCK and Glu-6-Pase…. gluconeogenesis
Effects of Glucagon
- Hepatocytes: increased glucose output, glycogen depletion (non of this nonsense in skeletal m.)
- Potent inotropic and chronotropic effcet on the heart
- GI smooth muscle relaxation
- Increase insulin release by beta-cells
- increase release of catecholamines by chromaffin cells (contraindicatedin pheochromocytoma patients)
Clinical uses of glucagon
- moderate-to severe hypoglycemia
- beta-blocker overdose
- Radiology of the bowel
Amylin analog
Pramlintide
What is pramlintide used for?
type 1 or 2 diabetes
-injected sc before meals as an adjunct to insulin therapy
Adverse effects of pramlintide
- GI: 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
What are the long acting GLP-1 receptor agonists?
- Exenatide
- Liraglutide
Clinical use of Exenatide or Liraglutide
- release of GLP-1 is diminished post prandially in type 2 diabetes pts
- approved in type 2 diabetics not adequately controlled by metformin/sulfonylureas/thiazolidinediones
- doses of other anti-diabetic meds should be reduced to avoid hypoglycemia
Adverse effects of GLP-1 receptor antagonists
- Nausea, comiting, diarrhea, anorexia
- lower risk of hypoglycemia vs. pramlintide
- linked to cases of acute pancreatitis and pancreatic cancer
- possible link to thyroid cancer
What are the DPP-4 inhibitors?
- the gliptins
- Sitagliptin
- Linagliptin
- Saxagliptin
- Alogliptin
MOA of DPP-4 inhibitors?
- DPP-4 is a serine protease that degrades GLP-1 and other incretins
- so… we stop that shit
- used as adjunctive therapy w/ diet and exercise
Averse effects of the DPP-4 inhibitors
- upper respiratory infections and nasopharyngitis
- linked to acute pancreatitis
- hypoglycemia
Katp channel blockers
- sulfonylureas 1st and 2nd gen
- Non-sulfonylureas (meglitinides)
What’s the difference between 1st and second generation sulfonylureas?
-2nd gen has higher potency
Clinical use of sulfonylureas
-type 2 diabetes as a monotherapy or in combo with insulin or other anti-diabetic drugs
adverse effects of sulfonylureas
- hypoglycemia
- weight gain
- secondary failure
- Disulfiram-like effect of alcohol-induced flushing
- Dermatological and general hypersensitivity reactions with other sulfonamides
Drug interactions with sulfonylureas that enhance their hypoglycemic effect
- displacing from binding with plasma proteins: sulfonamides, clofibrate, and salicylates
- enhancing the effect on Katp channel: ethanol
- inhibiting CYP enzymes: azole antifungals, gemfibrozil, cimetidine, etc..
Drug interactions with sulfonylureas that decrease their glucose-lowering effect
- inhibiting insulin secretion : beta-blockers, CCBs
- antagonizing their effect on Kast channel: diaazoxide
- Inducing hepatic CYP enzymes: phenytoin, griseofulvin, rifampin, etc…..
MOA of Meglitinides
-Katp Channel inhibitiion
clinical use of meglitinides
- control of postprandial hyperglycemia in patients with type 2 diabetes
- taken orally before the meal
- can be used either alone or in combo with other antidiabetic drugs
Side effects of meglitinides
- hypoglycemia
- secondary failure
- weight gain
Biguanides
Metformin!
MOA of metformin
- activation of AMP-dependent ptn kinase
- exact mechanism unclear
- Phophorylates stuff… leads to: inhibition of lipogenesis and gluconeogenesis, increase in glc uptake, glycolysis, and FA oxidation, lower glc levels in hyperglycemic (but not normoglycemic) states, increases insulin sensitivity
Clinical use of metformin
-most commonly used oral agent to treat type 2 diabetes*… first line
Why is metformin so great?
- does better job of lowering glucose
- does not cause hypoglycemia
- no weight gain
- taken orally
- can be used either alone or in combo w/ other oral agents
PK of metformin
- not bound to plasma proteins
- not metabolized
- excreted unchanged by kidneys
Adverse effects and contraindications of metformin
- most common: GI complications like anorexia, vomiting, nausea, diarrhea, abdominal discomfort
- decreased absorption of B12
- lactic acidosis, especially under conditions of hypoxia, renal and hepatic insufficiency
- contraindicated in conditions predisposing to tissue hypoxia, renal failure, chronic alcoholism, and cirrhosis
Thiazolidinediones
- Pioglitazone
- Rosiglitazone
MOA of thiazolidinediones
- Ligands of peroxisome proliferator-activated receptor-gamma (PPARy)
- endogenous ligands: PG and FFAs and their derivatives
- but TZDs have much igher affinity for PPARy
What is PPARy?
a nuclear receptor expressed primarily in fat, muscle, liver tissue, and endothelium
-heterodimeric PPARy/RXR binds to specific DNA PPRE sequences to either increase or decrease gene transcription
What are the effects of PPARy activation on gene expression?
- increased GLUT4 in skeletal m.: enhanced glucose uptake, reduced hyperglycemia
- same for adipocytes
- increased IRS1,2, and PI3K: increased insulin sensitivity
- Increased Adiponectin and other adipiokines: increased insulin sensitivity and decreased inflammation
- decreases gluconeogenesis
- decreases NFKB and AP-1 transactivation: decreased production of IL’s and other cytokines… antiinflammatory
important PK thing for TZDs
- it’s metabolized by the liver, so things that induce CYP will decrease its half life
- safe to administer to patients with renal failure
clinical use of TZDs?
- type 2 diabetes
- delays progression of prediabetes to type 3 diabetes
- euglycemic drug…. no hypoglycemia when used alone
Adverse effects of TZDs
- weight gain, especially if with insulin
- Edema: increased ENaC in kidneys
- Exacerbation of heart failure
- Link to the increased risk of bladder cancer
- Osteoporosis
- Increased TC and LDL-C (rosiglitazone
SGLT2 inhibitors
- Canagliflozin
- Dapagliflozin
- Empagliflozin
MOA of SGLT2 inhibitors
-inhibit the SGLT2 transporter, which lets us excrete some glucose into the urine… reduces hyperglycemia
Other effects of SGLT2 inhibitors
- osmotic iduresis
- induces weight loss
- reduces blood pressure
- reduce plasma levels of uric acid
- do not cause hypoglycemia when used alone
Clinical use of SGLT2 inhibitors
- as an adjunct to diet and exercise in adults with type 2 diabetes
- taken orally before the first meal once a day
- in pts with hypovolemia, this condition should be corrected before the start of therapy
Adverse effects of SGLT2 inhibitors
- hypotension
- hypovolemia: dizziness, syncope
- Genital and urinary tract infections
- hypoglycemia if combined with insulin or insulin secretagogues
- increased LDL-C
- renal function impairment: fall inglomerular filtration rate, increase plasma creatinine
- hyperkalemia
- development of ketoacidosis
Alpha-glycosidase inhibitors
- Acarbose
- Miglitol
MOA of alph-glycosidase inhibitors
- competitive inhibition of a-glycosidases, a family of enzyme located on the brush border of intestinal epithelium
- only monosaccharaides are absorbed from GI into the blood
- Enzyme inhibition defer digestion and thus absorption of ingested starch and disaccharides
- lower postprandial hyperglyemia to creat an insulin-sparing effect
Clinical use of alpha-glycosidase inhibitors
- type 2 diabetes 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
Adverse effects of alpha-glycosidase inhibitors
- most common: malabsorption, flatulence, diarrhea, and abdominal bloating
- hypoglycemia has been described when combined with insulin or insulin secretagogues
Drug interactions
-decrease absorption of digoxin and propranolol and ranitidine
