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Drug Action II > Block 3: T2DM Med Chem > Flashcards

Block 3: T2DM Med Chem Flashcards

1
Q

How does insulin differ from other hormones?

A
  1. Preprohormone that is synthesized in the b-cells and transported to the rough ER
  2. Upon transport to the rough ER, 24 aa are cleaved from N-terminus to yield proinsulin
  3. In rough ER, protein folds and three critical disulfide bonds form
  4. In the golgi complex, proinsulin is cleaved to insulin
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2
Q

What are the strorage structure of insulin?

A

Exists as a monomer, dimer, or hexamer

  1. Dimers occur in higher concentrations
  2. Hexamer are stored in pancreas with coordination to zinc
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3
Q

**T/F: **In the case of insulin, onset is dependent on size of the structure.

A

True

Monomers form quicker and faster onset of action

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4
Q

Types of rapid acting insulin?

A
  1. Lispro (Humalog)
  2. Aspart (Novolog)
  3. Glulisin (Apidra)
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5
Q

What are the characteristics of insulin analogs?

A

Small changes in Chain B

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6
Q

Lispro

Brand, Structure, DOA

A

Humalog
Structure:
* No changes in chain A
* B28 Pro -> B28 Lys
* B29 Lys -> B29 Pro

DOA: Decrease the dimerization, monomers have quicker the faster onset

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7
Q

Aspart

Brand, Forms, Structure, DOA

A

Novolog
Forms: 100% Aspart, 70/30 mix of aspart protamine suspension and aspart insulin
Structure:
* No changes in chain A
* B28 Pro -> B28 Asp

DOA:
* Decreases the dimerization…thus monomers form quicker and faster onset of action
* 70/30 formulation give some intermediate DOA

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8
Q

Glulisine

Brand, Structure, DOA

A

Apidra
Structure:
* No changes in A
* B3 Asn -> B3 Lys
* B20 Lys -> B29 Glu

DOA: Fast onset

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9
Q

What are the short acting insulins?

A

Humulin U-100 & U-500 (Concentrated insulins for injections and pumps)

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10
Q

Types of intermediate insulins?

A
  1. NPH (Humulin N, Novolin N)
  2. Aspart (NovoLog)
  3. Lente (Humulin L, Novolin L)
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11
Q

NPH

Brand, Structure, DOA

A

Humulin N, Novolin N
Neutral Protamine Hagedorn insulin

Structure:
* Insulin + stoichiometric amounts of protamine
* Fine precipitate

DOA:
* Decreased H2O solubility slow
* 1st intermediate-acting insulin analogue (18-26 hr, wanes after 12 hr)

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12
Q

Types of long term insulins?

A
  1. Glargine (Lantus)
  2. Determir (Levemir)
  3. UltraLente (Humulin U)
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13
Q

Glargine

Brand, Structure, DOA

A

Lantus
Structure:
* A21 Asn -> A21 Gly
* Addition of B31 Arg and B32 Arg

DOA: Isoelectric point (5.35) is similar to physiological (6.7), leads to microcrystal precipitation on SC injections (slow dissolves)
* Soluble in more acidic pH in the bottle
* 24 hr

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14
Q

Detemir

Brand, Structure, DOA

A

Levemir
Structure:
* No changes in A
* Remove B30 Thr
* Add C14 fatty acid to B29 Lys

DOA:
* Binds to plasma albumin and slowly dissociate the insulin analogue (true 20-24hr unlike NPH)

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15
Q

Types of UltraLong-acting insulin?

A

Degludec (Tresiba)

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16
Q

Degludec

Brand, Structure, DOA

A

Tresiba
Structure:
* No changes in A
* Remove B30 Thr
* Acylate B29 Lys with hexadecandioc acid

DOA:
* Binds to plasma albumin and slowly dissociate the insulin analogue AND increases hexamer formation
* >48 hr

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17
Q

What is Ryzodeg?

A

70/30 degludec/aspart

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18
Q

What is amylin?

A
  1. Co secreted with insulin
  2. Promote satiety
  3. Suppress glucagon secretion
  4. Administered with insulin before meal
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19
Q

What is the MOA of GLP-1 and DPP-4?

A
20
Q

What is the function of GLP1?

A
  1. Prepare the body for insulin surge upon ingestion of meal
  2. Stimulate the first response of insulin from B cell
  3. Slow stomach emptying: fuller feeling
  • Impaired in T2DM
21
Q

Exenatide

Brand, Structure, Forms

A

Byetta
Structure: Exendin-4 binds to GLP-1 receptor
Forms: Bydureon Pen, Bydureon BCise

Admin with metformin or sulfonylurea

22
Q

Liraglutide

Brand, Structure

A

Victoza
Structure:
* GLP-1 analogue with fatty acid chain
* promotes binding to albumin – leads to controlled release (QD)

23
Q

Albuglutide

Brand, Structure

A

Tanzeum
Structure: GLP-1 analogue dimer coupled with human albumin
* CR, QW

24
Q

Dulaglutide

Brand, Structure

A

Trulicity
Structure: GLP-1 analogue dimer coupled with a portion of a modified IgG4 heavy chain
* CR, QW

25
Q

Lixisenatide

Brand, Structure, DOA

A

Adlyxin
Structure: Byetta analogue
* Deletion of Pro38
* Addition of 6 Lys residues to the end

DOA: 4-5 hr more than Byetta

Not a better drug

26
Q

Semaglutide

Brand, Strucutre, DOA

A

Ozempic
Structure: GLP-1 analogue with a C18 fatty acid attached
DOA: Injection QW, PO QD

27
Q

Types of GLP1 agonist

A

Exenatide (Byetta®)
Liraglutide (Victoza®)
Albiglutide (Tanzeum®)
Dulaglutide (Trulicity®)
Lixisenatide (Adlyxin®)
Semaglutide (Ozempic®)

28
Q

Types of DPP-4 inhibitor? MOA?

A

Sitagliptin (Januvia®)
Saxagliptin (Onglyza®)
Linagliptin (Tradjenta®)
Alogliptin (Nesina®)

Inhibits the metabolism of endogenous GLP-1
QD dosing

29
Q

Types of biguanides?

A

Metformin (Glucophage)

30
Q

Describe the SAR of metformin

A

Biguanide and methyl group

31
Q

MOA of metformin?

A
  1. increases glucose uptake into fat and muscle cells, reduces steatosis, and inhibits gluconeogenesis
  2. Does not stimulate insulin secretion
    * No hypoglycemic effet (antihyperglycemic)
    * Combination with sulfonylurea has a synergistic effect
    * No metabolism
32
Q

ADR of metformin?

A

GI disturbances

33
Q

Describe the MOA of sulfonylurea? Indications>

A

Stimulate insulin release from B-cells of pancreas:
1. Interaction with pancreatic b-cell receptors to block ATP-sensitive K+-channels
2. Opens a voltage sensitive Ca channels producing influx of Ca
3. Influx of Ca results in b-cell secretion of insulin

T2DM

34
Q

SAR of sulfonylureas?

A
  1. Acidic
  2. Benzene ring must contain one p-substituent
    non-selective (-CH3, NH2, Cl, etc.)
  3. R = lipophilic moiety; R> Et, usually
    3-6 carbons (>12 destroys activity) - R=Me or Et
    not active
35
Q

Types of 2nd gen sulfonylureas?

A

Glimepiride (Amaryl)
Glipizide (Glucotrol)
Glyburide (Glynase)

36
Q

Additional MOA of 3rd gen sulfonylureas?

A
  1. May bind to different protein in the putative sulfonylurea receptor than 1st/2nd gen
  2. direct translocation of GLUT-4 glucose transporter from cytoplasm to cell membrane
  3. Quick onset, longer duration of action
37
Q

Types of meglitinides?

A

Repaglinide (Prandin)
Nateglinide (Starlix)

38
Q

MOA of meglitinides?

A
  1. Modulate b-cell insulin release by regulating K+-efflux through K-channels
  2. closes K-channels which deploarizes b-cells leading to an opening of Ca2+ channels
  3. Ca2+ influx which induces insulin secretion
  4. Have two binding sites in common with sulfonylureas and one additional unique site
39
Q

Types of PPARa/g Agonists?

A

Pioglitazone (Actos)
Rosiglitazone (Avadia)

40
Q

Function of SGLT2?

A

Sodium-glucose co-transporter type 2

41
Q

Types of SGLT2 inhibitors?

A

Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
Ertugliflozin (Steglatro)

42
Q

SAR of SGLT2 inhibitor?

A

Must mimic the structure of glucose

Reduced HbA1c better
Improved weight loss

43
Q

ADRs of SGLT2 inhibitors?

A
  1. Increased UTI
  2. Dehydration/thirst
  3. Fatigue
  4. Diabetic ketoacidosis (DKA)
44
Q

Types of a-glucosidase inhibitors?

A

Miglitol (Glyset)
Acarbose (Precose)

45
Q

MOA of a-Glucosidase Inhibitors? ADR?

A

Inhibts a-glucosidases (key enzyme for carb digestion) -> carbohydrate mal-absorption thus decreasing blood glucose levels

ADR: Flatluence and diarrhea

Drug Action II (28 decks)

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