Phar 430 - Diabetes

Front 1

What was the original plant that Metformin wa derived from?

Back 1

Galega officinalis

Front 2

What was Galega officinalis used for? (3)

Back 2

1) Promote persipration during plague epidemics

2) Stimulate lactation in cows

3) Relieve intense urination associated with diabetes

Front 3

What was the main pharmacophere of G.officinalis?

Back 3

Galegine

Front 4

What are examples of Biguanides? (3)

Back 4

1) Metformin

2) Buformin

3) Phenformin

Front 5

What is the MOA of Biguanides? (5)

Back 5

1) Inhibits gluconeogenesis in the liver

2) Increasing glycolysis

3) Reducing Glucose Oxidation

4) Decreasing intestinal glucose absorption

5) Contributes to the translocation of glucose transporters to the cell surface for insulin independent glucose uptake

Front 6

What is the target of Metformin?

Back 6

AMP-Activated Protein Kinase (AMPK)- A central metabolic regulator

Front 7

How do Buformin & Phenformin compare to Metformin?

Back 7

Buformin & Phenformin are more lipophilic than Metformin.

Comes with a 10-20 fold greater risk of lactic acidosis from decreased gluconeogenesis, as well as increased incidence of cardiac mortality

Front 8

What is the role of Insulin?

Back 8

It activates insulin receptors to regulate the metabolism of carbohydrate, fat & protein.

Also facilitates the removal of glucose from the blood stream.

Front 9

How is Insulin activated?

Back 9

It is secreted as a 93-amino acid pro-peptide whose intervening C-peptide is proteolytically removed to yield an active insulin hormone comprised of a 30-amine acid B chain linked through two disulfide bridges to a 21 amino acid A chain.

Front 10

What stabilizes the Insulin Hexameric form?

Back 10

Zinc and Phenolic compounds that sit between insulin monomers

Front 11

What is the physical structure of Insulin?

Back 11

A-chain consists of two α helices orthogonally packed against the α helix of the B chain.

The C-terminal portion of the B chain forms an anti-parallel β sheet with an adjacent B-chain monomer to provide additional stability of the hexamer.

Front 12

Which residue of Insulin both interacts with the receptor and gets modified as well?

Back 12

Asn - A21 (changes into Gly-A21)

Front 13

How do Bolus and Basal Insulins compare?

Back 13

Bolus: Faster onset and shorter duration of action

Basal: Longer oonset and much longer duration of action

Front 14

Why do Insulin Detemir and Degludec have the longest Duration of actions?

Back 14

The fatty acid groups on Detemir and Degludec complexes with plasma albumin to produce a depot longer duration of action.

Front 15

What are insulin fibrils?

Back 15

Partially unfolded insulin that forms a viscous solution or insoluble precipitate.

Interactions between exposed aliphatic residues and normally buried residues in the hexameric structure form fibrils.

Front 16

How do you overcome insulin fibrils?

Back 16

By preparing the insulin in the phosphate buffer or other additives

Front 17

How do you overcome insulin adsorbing to tubing and other surfaces?

Back 17

By adding albumin to the dose

Front 18

How do both Sulfonylureas & Meglitinides stimulate insulin secretion?

Back 18

By binding to the SUR of the ATP sensitive K channel on pancreatic Beta cells

Front 19

Describe the structure of the ATP sensitive K channel?

Back 19

An octameric hetero-complex consisting of 4 pore forming inwardly rectifying K channel subunits & 4 regulatory sulfonylurea subunits

Front 20

What does ATP bind to close the K channel?

Back 20

ATP binds to Kir6.2.

Sulfonylureas and Meglitinide bind to SUR1

Front 21

How do 1st generation Sulfonylureas compare to the Pharmacophere?

Back 21

They have a small lipophilic substituent on the R1 position & an alkyl or cyclic lipophilic substituent at the R2 position

Front 22

What are examples of 1st gen Sulfonylureas? (3)

Back 22

1) Chlorpropramide

2) Tolbutamide

3) Gliclazide

Front 23

What are examples of 2nd gen Sulfonylureas? (2)

Back 23

1) Glyburide

2) Glimepiride

Front 24

Why are 1st generation Sulfonylureas not used anymore?

Back 24

Because relatively high doses are required to achieve effectiveness coupled with long half-life increasing potential for side effects

Front 25

Why are 2nd generation Sulfonylureas used more often than 1st generation Sulfonylureas?

Back 25

Have increased potency (50-100 fold) shorter onset, shorter plasma half-lives (1-4h) & longer duration of action

Front 26

Why is SUR1 selectivity desired over SUR2?

Back 26

Is desired because Inhibition of SUR2 subtypes is determinetal to the heart. The ATP-sensitive K channels are not only found on the plasma membrane of the pancreatic Beta cells, but also in cardiac myocytes (SUR2A) & vascular smooth muscles (SUR2B)

Front 27

Which groups of the Sulfonylureas are key to binding to all 3 subtypes?

Back 27

Anionic groups

Front 28

What are examples of Meglitinides? (3)

Back 28

1) Glyburide

2) Repaglinide

3) Nateglinide

Front 29

Why does Repaglinide have minimal cardiac and smooth muscle side effects even though they bind well to SUR1, SUR2A and SUR2B?

Back 29

Its rapid onset (~20min) & short duration of action helps to minimize cardiac and smooth muscle effects

Front 30

Why is Nateglinide preferable over Meglitinides?

Back 30

Nateglinide binds selectively to SUR1 on Beta cells

Front 31

What is Stereochemistry important for Meglitinides?

Back 31

It is important for the U-shape conformation of Meflitinides to bind to SUR1 on Beta cells

Front 32

What are Incretins?

Back 32

Insulinotropic hormones originating from the GI tract -ultimately resulting in a lowering of Blood Glucose

Front 33

Where does GLP-1 come from?

Back 33

Secreted by the Intestinal L cells in response to food/glucose

Front 34

Where does GIP come from?

Back 34

Secreted by the intestinal K cells

Front 35

"GLP-1 also inhibits ______ release" (Not Insulin!)

Back 35

Glucagon

Front 36

What is the role of the Enzyme Dipeptidyl Dipeptidase IV (DPP-IV) and how does it function?

Back 36

Rapidly activates GLP-1 & GIP by removing their first two N-terminal amino acids.

Additionally these peptides are rapidly cleared by the kidneys

Front 37

How are GLP-1 analougues formed?

Back 37

By replacing Ala at residue 8 with different AAs we get more effective analougues

Front 38

Useful GLP-1 analogues require..? (2)

Back 38

1)DPP-IV resistance

2) Decreased renal elimination

Front 39

What is the original Incretin and where was it derived from?

Back 39

Exenatide that was originally isolated from the saliva of the Gila monster

Front 40

What is an example of a GLP-1 analogue with two amino acid substitutions?

Back 40

Liraglutide

Front 41

What are the two amino acid substitutions in Liraglutide?

Back 41

1) Lys-26 contains an α-L-glutamoyl-(N-α-Hexadecanoyl) group that increases albumin binding

2) Lys-to Arg substitution at position 34 & substitution/modification at position 26

Front 42

Why is selectivity for DPP-IV important?

Back 42

Selectivity for DPP-IV is important to avoid toxcity (DPP-VIII & DPP-IX cases severe toxcity in animals)

Front 43

What are examples of DPP-IV inhibitors? (4)

Back 43

1) Vildegliptin

2) Saxagliptin

3) Sitagliptin

4) Linagliptin

Front 44

"Most DDP-IV inhibitors are peptide derivatives from ____"

Back 44

α-aminoacylpyrrolidines

Front 45

What is the selectivity of Vildegliptin for DPP?

Back 45

Vildegliptin exhibits 32 fold greater selectivity toward DPP-IV over DPP-VIII & 250-fold over DPP-IX

Front 46

What are the pharmacokinetics for Vildegliptin?

Back 46

Bioavailability: 67%

>10% Protein bound

t(1/2)=2.5hr

Front 47

What is the selectivity of Saxagliptin for DPP?

Back 47

Saxaglipitin exhibits 400-fold selectivity of DPP-IV over DPP-VIII & 75-fold over DPP-IX

Front 48

What is the pharmacokinetics for Saxagliptin?

Back 48

Bioavailability: 67%

>10% Protein bound

t(1/2)=2.5hr

Front 49

What does Sitagliptin's structure lack that Saxagliptin and Vildegliptin have?

Back 49

No Cyano Group

Front 50

Which DPP-IV inhibitors are Competitive Inhibitors?

Back 50

Sitagliptin and Linagliptin

Front 51

What is the selectivity of Sitagliptin for DPP?

Back 51

Sitaglipitin exhibits 2600-fold selectivity of DPP-IV over DPP-VIII & DPP-IX

Front 52

What are the pharmacokinetics for Sitagliptin?

Back 52

Bioavailability: 87%

38% Protein bound

t(1/2)=12.4hr

Front 53

What is the selectivity of Linaglipitin for DPP?

Back 53

Linagliptin exhibits 40,000 fold greater selectivity toward DPP-IV over DPP-VIII & greater than 10,000 fold over DPP-IX

Front 54

What is the pharmacokinetics for Linagliptin?

Back 54

Bioavailability: 30%

70-80% Protein bound

t(1/2)=12hr

Front 55

How does Vildegliptin bind to DPP?

Back 55

Forms a covalent imidate adduct with Ser630; stabilized by Tyr547

Front 56

How does Saxagliptin bind to DPP?

Back 56

Forms the same imidate adduct as seen between Vildagliptin & DPP-IV

Front 57

How does Sitaglipitin bind to DPP?

Back 57

Contains Beta amino amide that H-bonds with active site residues

Front 58

How does Linagliptin bind to DPP?

Back 58

Linagliptins planar aromatic group participate in pi-pi stacking interactions. The amino group on the piperidine moiety engages in H-bonding to Glu205, Glu206 & Tyr662 whereas the butynyl group occupies the hydrophobic group

Front 59

What are is the other name for Thiazolidinediones?

Back 59

Glitazones

Front 60

What is the MOA for Thiazolideniediones?

Back 60

PPAR(gamma) agonists such as the glitazones act as anti-hyperglycemic by increasing the sensitivity of cells to insulin and its other actions.

Front 61

Which region of the PPAR(gamma) agonist is reponsible for its activity?

Back 61

Thiazolidinedionine Moiety

Front 62

"The benzyl group of the PPAR agonist is essential for its activity" True or False?

Back 62

TRUE

Front 63

Why was Troligitazone withdrawn in 2000?

Back 63

Due to the risk of drug induced hepatotoxcity & CV effects

Front 64

What is the pharmacokinetics for Rosiglitazone?

Back 64

Rapidly & Well absorbed;

99.8% protein bound;

t(1/2)=3-4hours

Front 65

What is the pharmacokinetics for Pioglitazone?

Back 65

Rapidly & Well absorbed;

>99% protein bound;

t(1/2)=3-7hours

Front 66

Where is the SGLT2 transport protein found?

Back 66

Is found in the proximal renal tubules and is responsible for reabsorbing glucose that has been filtered

Front 67

What is the MOA of Canagliflozin?

Back 67

Inhibits SGLT2, it reduces reabsorption of filtered glucose and lowers the renal threshold for glucose, which increases urinary glucose excretion

Front 68

Which SGLT is the low affinity and which is the high affinity?

Back 68

SGLT2 is a low affinity co-transporter. SGLT1 is a high affinity co-transporter

Front 69

What is the selectivity of Canagliflozin toward SGLT2?

Back 69

Canagliflozin has been shown to exhibit a 250-fold selectivity toward SGLT2 over SGLT1

Front 70

What is the hydrophilic portion of Canagliflozin?

Back 70

β-D-Glucose

Front 71

What is the pharmacokinetics for Canagliflozin?

Back 71

Bioavailability: 65%

>99% Protein bound;

UGT substrate;

t(1/2)=10.6-13.1hr;

renal elimination

Front 72

What is the MOA for α-Glucosidase Inhibitors?

Back 72

Prevents the breakdown of complex carbohydrates into glucose so that it is not absorbed in the small intestine.

Front 73

What compounds are the result of the breakdown for Amylose? (3)

Back 73

1)α-Maltose

2) α-D-Glucose

3) Sucrose

Front 74

Why doesn’t Acarbose cross the lumen of the intestine?

Back 74

Because the TPSA>140

Front 75

What is the role of α-Glucosidae?

Back 75

It is a membrane bound enzyme present on the brush border cells of the small intestine, catalzyes the conversion of the disaccharide maltose & sucrose into glucose, which is then absorbed.

Front 76

What is the structural difference between Acarbose and Amylose?

Back 76

The addition of N-glycosidic bond

Front 77

What is the pharmacokinetics for Acarbose?

Back 77

Bioavailability: Extremely low; t(1/2)=2 hr; renal elimination of metabolites

Front 78

What are examples of α-Glucosidase Inhibitors? (3)

Back 78

1) Acarbose

2) Miglitol

3) Voglibose