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Medicinal Chemistry - Winter > 20, 21 - Diabetes > Flashcards

20, 21 - Diabetes Flashcards

1
Q

What are the 3 types of diabetes?

A
  • Type 1 – autoimmune destruction of insulin-producing beta cells
  • Type 2 – metabolic disorder characterized by hyperglycemia
  • Gestational diabetes – development of DM during pregnancy
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2
Q

What are the causes of type 1 DM?

A

Genetic and environmental (autoimmune, viral, exposure to toxic chemicals)

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3
Q

What is insulin?

A
  • Peptide hormone produced by beta cells in pancreas
  • Central for regulating carbohydrate and fat metabolism
  • Causes skeletal muscles and fat tissue to absorb glucose from blood, lowering blood glucose levels
  • Stops use of fat as an energy source and inhibits release of glucagon
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4
Q

What is glucagon?

A

Peptide hormone produced by alpha cells in pancreas, raising blood glucose levels

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5
Q

What is the insulin receptor?

A
  • Transmembrane receptor

- Tyrosine kinase mediates activity by phosphorylation of tyrosine that starts many protein activation cascades

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6
Q

What happens when insulin binds to insulin receptor?

A

1) Protein activation
2) Translocation of glut-4 transporter to plasma membrane and glucose influx
3) Glycogen synthesis
4) Glycolysis
5) Fatty acid synthesis

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7
Q

What are the problems w/ insulin binding in type 1 and type 2 DM?

A
  • Type 1 = ineffective activation of glut-4, resulting in diminished glucose uptake
  • Type 2 = defective activation/signaling to glut-4, resulting in diminished glucose uptake
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8
Q

What are the 3 tests for diabetes?

A
  • Fasting plasma glucose (normal = 80-100 mg/dL)
  • A1C - reflects average plasma glucose over 3 months (normal = 5%)
  • 2h fasting plasma glucose (normal = below 200 mg/dL)
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9
Q

Diabetes is the most common cause of _____

A

Blindness

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10
Q

What is the target organ of each diabetes drug class?

A
  • Pancreas = sulfonylureas, DPP-4 inhibitors and meglitinides
  • Muscle and fat = thiazolidinediones, biguanides, and insulin
  • Gut = alpha-glucosidase inhibitors
  • Liver = biguanides, thiazolidinediones, DPP-4 inhibitors, GLP-1 inhibitors, and insulin
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11
Q

How is insulin produced (as what)?

A
  • Produced and stored as hexamer
  • Inactive, giving long-term stability
  • Contains 2 polypeptide chains, A and B linked together by disulfide bonds
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12
Q

What is important about insulin monomer?

A

Fast-reacting, higher diffusion rate

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13
Q

What happens with lantus (insulin glargine)?

A
  • Precipitation on injection

- Slow release (18-26 h)

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14
Q

What substitutions occur in lantus (insulin glargine)? Why are these beneficial? What is the benefit to the parent compound?

A
  • Substitute glycine for asparagine w/ two arginines added to carboxy terminal B chain
  • Arginine shifts isoelectric point from 5.4 to 6.7, making it more soluble at acidic pH
  • Glycine substitution avoids deamidization at pH 4
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15
Q

What substitution occurs in NovoRapid (insulin aspart)? What effect does this have on release rate?

A
  • Aspartic acid substituted for proline, which increases charge repulsion and prevents formation of hexamers
  • Modification allows quick absorption into bloodstream, onset in 15 min
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16
Q

What modification occurs in Humalog (insulin lispro)? What effect does this have? What is the onset?

A
  • Penultimate lysine and proline residues on C-terminal end of B-chain are reversed
  • Blocks formation of insulin dimers and hexamers; doesn’t alter receptor binding
  • Faster onset than regular insulin
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17
Q

What is the modification in Levemir (insulin detemir)? What effect does this have?

A
  • Fatty acid (myristic acid) bound to lysine aa at position B29
  • Quickly absorbed and binds to albumin in blood
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18
Q

What is the modification in Apidra (insulin glulisine)? What effect does this have? Is this a short or long acting form?

A
  • Asparagine at B3 replaced w/ lysine and lysine at B29 replaced w/ glutamic acid
  • Decreases zinc-free self-association (decreased dimers)
  • Since it decreases dimers, it is a short acting form (taken before meals)
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19
Q

Which drugs are first gen sulphonylureas?

A
  • Acetohexamide
  • Chlopropamide
  • Tolbutamide
  • Tolazamide
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20
Q

Which drugs are second gen sulphonylureas?

A
  • Glipizide
  • Gliclazide
  • Glibenclamide
  • Gliquidone
  • Glyclopyramide
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21
Q

Which drug is a third gen sulphonylurea?

A

Glimepiride

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22
Q

What is the MOA of sulphonylureas?

A
  • Binds to ATP-dependent K+ channels on cell membranes of pancreatic beta-cells, preventing K+ efflux
  • Potential over cell becomes positive and opens voltage gated Ca2+ channels
  • Increased Ca2+ causes increased fusion of insulin granulae w/ cell membrane, increasing secretion of insulin
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23
Q

Which 2 sulphonylureas are used most often?

A

Glibenclamide (glyburide) and glimepiride

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24
Q

What is a severe side effect of sulphonylureas?

A

Hypoglycemia

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25
Q

What is the MOA of meglitinides?

A
  • Bind to ATP-dependent K+ channel on cell membrane of pancreatic beta cells; have weaker affinity and faster dissociation from SUR1 binding site than sulphonylureas
  • Increased intracellular K+ causes positive potential to develop across membrane, depolarizing voltage-gated Ca2+ channels, increasing fusion of insulin
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26
Q

What is the main meglitinide?

A

Repaglinide

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27
Q

Which drug is a biguanide?

A

Metformin

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28
Q

What is a difference between metformin and sulphonylureas?

A

Metformin doesn’t affect ouput of insulin; sulphonylureas do

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29
Q

What is the MOA of metformin?

A
  • Suppresses hepatic gluconeogenesis (generation of glucose from non-carbohydrates)
  • Increases insulin sensitivity and fatty acid oxidation
  • Decreases absorption of glucose in GI tract
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30
Q

How does metformin increase insulin sensitivity?

A
  • Reduces hepatic glucose production and artificially lowers plasma glucose levels
  • So less insulin is needed to keep plasma glucose levels normal, resulting in increased insulin sensitivity and decreased insulin resistance
31
Q

What occurs in obese people w/ type 2 DM w/ respect to insulin?

A
  • Failure to activate postreceptor tyrosine kinase, causing insulin resistance and hyperglycemia, meaning higher amounts of insulin needed to reduce plasma glucose
  • This is insulin resistance/sensitivity (needing more insulin to keep plasma glucose low or normal)
32
Q

Which anti-diabetic drug is shown to prevent CV complications of diabetes?

A

Metformin

33
Q

What is a contraindication to metformin?

A

Those who may develop lactic acidosis, such as those w/ kidney disorders

34
Q

What effect does metformin have on lactate?

A
  • Metformin reduces gluconeogenesis, so less lactate is taken up by the liver, so must be excreted through kidneys
  • Those w/ kidney disorders can have a build-up of lactic acid
35
Q

Which other drugs can metformin be combined w/?

A
  • Thiazolidinediones
  • Sulfonylureas
  • DPP-4 inhibitors
36
Q

What is the effect and MOA of alpha-glucosidase inhibitors?

A
  • Prevent digestion of carbohydrates (starch and sugars)
  • Long-term effects include small decrease in hemoglogin A1C levels (post-prandial), so increased control of type 2 DM
  • MOA = competitive inhibition of digestive enzyme alpha-glucosidase, reducing rate of hydrolysis of oligosaccharides to glucose
37
Q

What is the MOA of acarbose? What is its short-term and long-term effects? What are some SE?

A
  • Inhibits both alpha-glucosidase and pancreatic alpha-amylase
  • Short-term lowers blood glucose levels
  • Long-term lowers Hb A1C levels
  • SE = flatulence and diarrhea
38
Q

What is the main use of alpha-glucosidase inhibitors?

A

Lower blood glucose after a meal

39
Q

What is the MOA of miglitol and voglibose? When are they taken? What are the main differences?

A
  • Inhibits glycoside hydrolysis of alpha-glucosidase, lowering degree of post-prandial hyperglycemia
  • Taken at start of meal
  • Voglibose has better SE profile, but reduced efficacy on fasting plasma glucose than acarbose
40
Q

Which drugs are sodium-glucose cotransporter 2 inhibitors?

A
  • Canagliflozin
  • Dapagliflozin
  • Empagliflozin
  • Can be used in combination w/ metformin
41
Q

What is the effect of SGLT2 inhibitors?

A

Lower blood sugar by causing the kidneys to remove sugar from the body (urination)

42
Q

Are SGLT2 inhibitors safe for type 1 DM?

A

Unknown

43
Q

What is the MOA of SGLT2 inhibitors?

A
  • SGLT2 = protein that facilitates glucose reabsorption in kidneys; located in proximal tubule
  • SGLT2 inhibitors block reabsorption of glucose in kidneys, increasing glucose excretion
44
Q

What is phlorizin?

A
  • Potent and non-selective inhibitor of SGLT1 and SGLT2

- Beta-glucoside

45
Q

What is the MOA of thiazolidinediones?

A
  • Activate peroxisome proliferator-activated receptor gamma (PPAR-gamma), a nuclear receptor which regulates fatty acid and glucose metabolism
  • PPAR-gamma receptor agonists
  • When activated, receptor binds to DNA in complex w/ retinoid X receptor (RXR), increasing and decreasing transcription of specific genes
  • Process is called PPAR-gamma transactivation and PPAR-gamma transrepression
46
Q

What is another name for thiazolidinediones?

A

Glitazones

47
Q

What occurs in PPAR-gamma transactivation?

A

On DNA strand, PPAR/RXR heterodimer binds to peroxisome proliferator hormone response elements upstream of target genes, in complex w/ cofactors, causing upregulation of genes via transcription

48
Q

What occurs in PPAR-gamma transrepression?

A

1) Binding of PPAR-gamma to coactivators reduces levels of coactivators available for binding to pro-inflammatory transcription factors, causing a decrease in transcription of specific genes
- PPAR/RXR/ligand complexes block signaling cascades
2) Can also physically bind directly w/ transcription factors to decrease transcription
3) PPAR/RXR complex can inhibit activation of MAPK to block transcription factors and decrease transcription

49
Q

What is the benefit to thiazolidinediones causing PPAR-gamma transactivation?

A
  • Decreases insulin resistance

- Decrease leptin levels, increasing appetite

50
Q

What else do thiazolidinediones do?

A

Increase synthesis of specific proteins involved in fat and glucose metabolism

51
Q

What is insulin resistance?

A
  • Reduced responsiveness to normal circulating insulin levels => hyperinsulinemia
  • Pancreas unable to keep up w/ increased insulin requirements, so hyperglycemia occurs
52
Q

What tissues do thiazolidinediones act on and what do they do?

A
  • Liver and skeletal muscle

- Sensitize them to insulin action, increasing glucose uptake and decreasing glucose hepatic output

53
Q

Are thiazolidinediones used alone or in combination?

A

Can be used alone or in combination w/ metformin or a sulfonylurea

54
Q

What is a thiazolidinedione?

A

5-membered thiazole-diketone

55
Q

Which drugs are thiazolidinediones?

A
  • Troglitazone (not used anymore b/c drug-induced hepatitis)
  • Pioglitazone (not used anymore b/c associated w/ bladder cancer)
  • Rosiglitazone
56
Q

What are incretins?

A
  • Hormones produced by GI tract in response to incoming nutrients
  • Contribute to glucose homeostasis
  • 2 hormones = gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)
57
Q

What secretes GLP-1 and what are the effects of GLP-1?

A
  • Intestinal L-cells; produced by cleavage of proglucagon
  • Increases insulin secretion in glucose-dependent manner, decreases glucagon secretion, promotes insulin sensitivity, and increases satiety in brain
58
Q

What are the therapeutic options targeting GLP-1 since GLP-1 itself can’t be used therapeutically (very short half life b/c of metabolism by DPP-4)?

A
  • Incretin mimics acting as GLP-1 agonists

- Dipeptidyl peptidase-4 (DPP-4) antagonists that inhibit breakdown of GLP-1?

59
Q

What is exenatide?

A
  • GLP-1 receptor agonist
  • Resistant to DPP-4 inactivation
  • Measurably present in plasma for 10 h (BID dosing)
60
Q

What is the difference between exenatide and liraglutide?

A
  • Both are GLP-1 agonists, but liraglutide has much longer half life so only requires once daily dosing while exenatide requires twice daily
  • Liraglutide has longer half life b/c attached fatty acid molecule enables albumin binding, decreasing elimination
61
Q

What is the effect of liraglutide for diabetes?

A
  • Improves control of blood glucose
  • Reduces meal-related hyperglycemia by increasing insulin secretion, delaying gastric emptying and suppressing glucagon secretion
  • Works in glucose-dependent manner, so only stimulates insulin secretion when blood glucose is high
62
Q

What is budyreon?

A

Microspheres of exenatide which require once weekly dosing

63
Q

What is pramlinitide? When is it used? What does it do?

A
  • Amylin analogue (proline substitution on pramlinitide allows for better protein properties)
  • Used as an adjunct therapy
  • Aids in absorption of glucose by slowing gastric emptying and promoting satiety
64
Q

What is amylin?

A

Small peptide hormone released into bloodstream by beta cells along w/ insulin

65
Q

What is dipeptidyl peptidase-4?

A
  • Glycoprotein expressed on surface of most cells
  • Cleaves dipeptide proline units from N-terminus (forms an imidate intermediate)
  • Degrades incretins
66
Q

What do DPP-4 inhibitors do and what effect do they have on diabetes?

A
  • Increase incretin levels of GLP-1 and GIP by preventing inactivating cleavage
  • Inhibit glucagon release, increase glucose-dependent insulin secretion, decrease gastric emptying, and decrease plasma glucose levels
67
Q

Which drugs are DPP-4 inhibitors?

A
  • Sitagliptin
  • Saxagliptin
  • Linagliptin
  • Alogliptin
68
Q

What kind of inhibitors are DPP-4 inhibitors?

A
  • “Substrate-like inhibitors”, so bind either covalently or non-covalently
  • “Analog inhibitors” so mimic transition state of protease/peptidase
69
Q

How do DPP-4 inhibitors bind in the pockets of a protease?

A
  • P1 (proline mimetic) occupies S1 pocket
  • P2 occupies S2 pocket
  • P1 and P2 connected via amino-carbonyl linker
70
Q

What is an imidate group?

A
  • Carbon attached to proline is double bonded to N which is attached to remainder of peptide and carbon is single bonded to O which is attached to serine of DPP-4
  • Imidate = Serine-O-C=N-peptide (carbon is also attached to proline)
71
Q

What is important about the proline mimetic group of a DPP-4 inhibitor?

A

Act as covalent inhibitors

72
Q

What is the MOA of DPP-4 inhibitors (model 1)?

A

Electrophilic group (-CN or C=N) interacts w/ hydroxyl group of catalytic serine in active binding site

73
Q

What is the difference between the 2 models of DPP-4 inhibitors?

A
  • Model 1 (proline mimetics) are covalent inhibitors

- Model 2 are non-covalent and non-substrate-like inhibitors

Medicinal Chemistry - Winter (15 decks)

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