Med Chem of Antidiabetics Flashcards
1
Q
Human Insulin
A
- 51 amino acids
- A and B chain linked by two disulfide bonds
- Additional disulfide bond within the A chain
- Degrades by insulinase that cleaves disulfides
- T1/2 = ~5-10 minutes
2
Q
Hexamer-Monomer Conversion
A
- Stored as a hexamer
- Active form is a monomer
- Hexamer is inactive but stable long-term
- The conversion from hexamer to monomer is cenral to insulin formulations
3
Q
Factors Increasing Hexamers
A
- Zinc ions
- High insulin formations
- Hexamers are too large to permeate capillary walls
4
Q
Aggregation Equilibrium Shifting
A
- Point mutations
- Chemical Modifications
- Utilizes these methods in fast or slow acting insulin formulations
5
Q
Hexamer Modifications
A
- Proline 28 that normally interacts between B chains in dimer forms is replaces
- Fast-acting insulin lispro: proline B28 is replaces by lysine, destabilizes the two monomers
- Fast-acting insulin aspart: proline B28 is replaces by aspartic acid which also disturbs the reaction
6
Q
Insulin Analog
A
- Altered insulin
- Utilize genetic engineering (aka recombinant DNA technology) to alter amino acid sequences and therefore alter ADME characteristics
7
Q
Types of Insulin Analogs
A
- Faster acing: more readily absorbed from injection site and intended to supply prandial insulin needs
- Slow Insulin: releases over a period of 8-24 hours to supply basal insulin needs
- Rapid acting: substitute aa at beginning or end of B chain, peak fast and short durations
- Long-acting: form depot reservoirs upon administration
8
Q
Long-Acting Insulin Examples
A
- Glargine: replace A21 Asn by Gly and add two Args to C-terminus of the B chain
- Detemir: removing B30 Thr and adding a C14 fatty acid to the B29 Lys
9
Q
Insulin Lispro
A
- Humalog
- Lysine and proline exchanged at B28 and B29
- Equilibrium shifts away from hexamer formation
- Increases rate of monomer formation and therefore the rate of absorption
10
Q
Insulin Aspart
A
- Novolog
- Aspartate substitutued for proline at B28
- Shifts equilibrium away from hexamer formation
- Increasing rate of absorption
11
Q
Fiasp
A
- Fast-acting insulin aspart
- Flexibility in administration time for meals due to faster onset and offset
- Niacinamide (vitamin B3) used to increase its absorption from SC tissue
- Arginine is added to enhance its stability
12
Q
Insulin Glulisine
A
- Apidra
- Lysine is substituted for asparagine at B3 and glutamate for lysine at B29
- Short-acting nature is related to insulin stabilizer used in formation that takes the place of zinc
- Hexamer is never formed
13
Q
Insulin Glargine
A
- Lantus
- Long-acting insulin by adding two arginines to C-terminus
- Shifts isoelectric point from 5.4 to 6.7
- Slowly dissolves into bloodstream over 24 hours
14
Q
Isoelectric point
A
- pH when protein net charge is zero
- Lowest solubility
- Once determined, back off by one or two pH units to attain solubility and avoid protein aggregation
15
Q
Insulin Detemir
A
- Acylated derivative
- Binds to albumin through a fatty-acid chain attached to lysin at B29
- Reduces free detemir levels
