Konorev DSA: Drugs for Diabetes Flashcards
1
Q
Rapid Acting Inulins
A
- aspart
- lispro
- glulisine
2
Q
short acting insulins
A
-regular insulin
3
Q
Intermediate acting insulin
A
NPH
4
Q
Long acting insulin
A
- Detemir
- Glargine
5
Q
Amylin analog
A
-Pramlintide
6
Q
Insulin secretagogues
A
- incretin memetics
- Katp channel blockers
7
Q
Incretin Mimetics
A
- GLP-1 agonists: Exenatide, Liraglutide
- Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, linagliptin, saxagliptin, alogliptin
8
Q
Katp channel blockers
A
- sulfonylureas
- Meglitinides
9
Q
first generation sulfonylureas
A
- Chorpropamide
- tolbutamide
- tolazamide
10
Q
Second generation Sulfonylureas
A
- Glipizide
- Glyburide
- Glimepride
11
Q
Meglitinides
A
- Nateglinide
- Repaglinide
12
Q
Biguanides
A
Metformin
13
Q
Thiazolidinediones
A
- Pioglitazone
- Rosiglitazone
14
Q
Sodium-glucose co transporter 2 (SGLT2) inhibitors
A
- Canagliflozin
- Dapagliflozin
- Empagliflozin
15
Q
Inhibitors of alpha-glycosidases
A
- Acarbose
- Miglitol
16
Q
What are the end effects of insulin?
A
- 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
17
Q
What transcription factor is for cell growth and differentiation and for cell proliferation and increased survival?
A
ELK1
18
Q
Which TF is for cell growth and differentiation and cell proliferation and apoptosis
A
-AP-1
19
Q
Which TF will give of decreased glycogenolysis, decreased gluconeogenesis, and escaped the cell cycle arrest and increases proliferation?
A
FoxO1
20
Q
What happens with GLUT4 when insulin binds IRS?
A
gets translocated to the cell membrane
21
Q
What are the effects on carb metabolism by Insulin?
A
- glucose transport (GLUT4)
- Activation of glycolysis
- Activation of glycogen synthesis
- Inhibition of gluconeogenesis
- Inhibition of glycogenolysis
22
Q
Is cAMP lowered or elevated by insulin binding?
A
lowered
23
Q
Insulin effects on lipid metabolism
A
- inhibition of lipolysis :decreased hormone-sensitive lipase, decreased TG breakdown
- enhanced lipogenesis: increased expression of FA synthase
24
Q
Insulin effects on protein metabolism
A
- increased ptn synth
- increased mTOR,,,, ribosome biogenesis, mRNA translation
25
Why are the rapid acting insulins so rapid?
-mutations fromhuman sequence block assembly of dimers and hexamers... allow for faster absorption
26
Clinical use of rapid-acting insulins
-postprandial hyperglycemia...taken before a meal
27
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
28
What is used for basal insulin maintenance and/or overnight coverage?
NPH, the intermediate acting insulin
| -lasts 4-12 hrs
29
What is used for pretty much only basal insulin maintenance?
Long acting insulin: Detemir or Glargine
| -lasts 24 hrs
30
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
31
Adverse effects of Insulin
- hypoglycemia
- lipodystrophy
- Resistance: they will develop insulin binding antibodies
- Allergic rxns (rare)
- hypokalemia
32
What is the most common complication of insulin therapy?
Hypoglycemia
33
Common causes of hypoglycemia
- delay of a meal or a missed meal
- exercise: exercised muscle consumes more glucose
- overdose of insuin
34
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"
35
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
36
MOA of Glucagon
- Gs coupled GPCR
- activation of AC
- PKA
- phosphorylase.... glycogenolysis
- increased expression of PEPCK and Glu-6-Pase.... gluconeogenesis
37
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)
38
Clinical uses of glucagon
- moderate-to severe hypoglycemia
- beta-blocker overdose
- Radiology of the bowel
39
Amylin analog
Pramlintide
40
What is pramlintide used for?
type 1 or 2 diabetes
| -injected sc before meals as an adjunct to insulin therapy
41
Adverse effects of pramlintide
- GI: nausea, vomiting, diarrhea, anorexia
| - Severe hypoglycemia, especially if used together with insulin... insulin dose should be reduced
42
Drug interactions with Pramlintide
-enhances effects of anticholinergic drugs in GI tract
43
What are the long acting GLP-1 receptor agonists?
- Exenatide
| - Liraglutide
44
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
45
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
46
What are the DPP-4 inhibitors?
- the gliptins
- Sitagliptin
- Linagliptin
- Saxagliptin
- Alogliptin
47
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
48
Averse effects of the DPP-4 inhibitors
- upper respiratory infections and nasopharyngitis
- linked to acute pancreatitis
- hypoglycemia
49
Katp channel blockers
- sulfonylureas 1st and 2nd gen
| - Non-sulfonylureas (meglitinides)
50
What's the difference between 1st and second generation sulfonylureas?
-2nd gen has higher potency
51
Clinical use of sulfonylureas
-type 2 diabetes as a monotherapy or in combo with insulin or other anti-diabetic drugs
52
adverse effects of sulfonylureas
- hypoglycemia
- weight gain
- secondary failure
- Disulfiram-like effect of alcohol-induced flushing
- Dermatological and general hypersensitivity reactions with other sulfonamides
53
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..
54
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.....
55
MOA of Meglitinides
-Katp Channel inhibitiion
56
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
57
Side effects of meglitinides
- hypoglycemia
- secondary failure
- weight gain
58
Biguanides
Metformin!
59
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
60
Clinical use of metformin
-most commonly used oral agent to treat type 2 diabetes*... first line
61
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
62
PK of metformin
- not bound to plasma proteins
- not metabolized
- excreted unchanged by kidneys
63
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
64
Thiazolidinediones
- Pioglitazone
| - Rosiglitazone
65
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
66
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
67
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
68
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
69
clinical use of TZDs?
- type 2 diabetes
- delays progression of prediabetes to type 3 diabetes
- euglycemic drug.... no hypoglycemia when used alone
70
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
71
SGLT2 inhibitors
- Canagliflozin
- Dapagliflozin
- Empagliflozin
72
MOA of SGLT2 inhibitors
-inhibit the SGLT2 transporter, which lets us excrete some glucose into the urine... reduces hyperglycemia
73
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
74
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
75
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
76
Alpha-glycosidase inhibitors
- Acarbose
| - Miglitol
77
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
78
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
79
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
80
Drug interactions
-decrease absorption of digoxin and propranolol and ranitidine
