L28- Antidiabetic Drugs I

Question 1

_____ is the generally the main treatment for DM type I

Answer 1

exogenous insulin injection (SQ) to control blood glucose and avoid ketoacidosis

Question 2

why is DKA less apparent in DM type II

Answer 2

insulin secretion is sufficient enough to restrain ketogenesis but not enough to overcome hyperglycemia

Question 3

generally describe DM type II treatment

Answer 3

-noninsulin hypoglycemic agents

• 20% require exogenous insulin for optimum health
• insulin is NOT for survival

Question 4

Insulin:

• (1) MW
• (2) AAs
• (3) arrangement

Answer 4

• MW = 5808

- 51 AAs arranged on 2 polypeptides connected via 2 disulfide bonds

Question 5

β-cells are stimulated to release insulin by….

Answer 5

Glucose*, most important

AAs

GI hormones- Incretins (responds to ingestion of food)

Question 6

describe the effect of Incretins

Answer 6

• respond to ingestion of food / glucose
• enhances secretion of insulin

Note- compared to IV glucose administration, about 4x more insulin is released upon ingestion / oral administration due to Integrins

Question 7

describe the mechanism of Insulin secretion

Answer 7

1) β-cell: glucose influx via GLUT2
2) inc glycolysis + citric acid cycle
3) inc ATP
4) closes K(ATP) channel
5) dec K+ efflux
6) cell depolarization
7) Ca++ channels open
8) Ca++ triggers exocytosis and insulin is secreted

Question 8

describe the structure and function of Insulin receptor

Answer 8

2 covalently linked heterodimers: α and β subunits bind their counterpart

α- extracellular, insulin recognition
β- transmembrane, contains TK

Insulin binds α-subunit –> β subunit activated –> Tyr residue phosphorylation (β subunit) –> cytoplasmic protein phosphorylation

Question 9

list the general cellular effects of Insulin

Answer 9

• upregulates GLUT4 to membrane
• metabolic actions (anabolism)
• cell growth / differentiation
• gene expression

Question 10

describe the production of exogenous Insulin

Answer 10

recombinant human DNA: proinsulin gene placed w/in a plasma –> insulin is generated by E. coli or yeast

Ex:
mammilian proinsulin mRNA –> proinsulin cDNA –> plasmid –> infect`s E. coil

Question 11

list the insulin preparation types

Answer 11

Rapid Acting
*Short Acting (normal human insulin)
Intermediate Acting
Long Acting

Question 12

list the rapid-acting insulin analogs

Answer 12

Insulin Lispro
Insulin Aspart
Insulin Glulisine

Question 13

how is rapid-acting insulin different from normal insulin (short-acting)

Answer 13

Native insulin (short-acting) is usually in hexamer form –> slows down absorption

Rapid-acting insulin only provides monomers for absorption for a much faster onset of action— as a result from changing AAs in insulin B chain

Question 14

Rapid Acting insulin:

• given via (1) route, at (2) time of day
• given to mimic (3)
• usually associated with (4) administration

Answer 14

1- SQ (can be given IV)
2- 15 mins before meals
3- prandial release of insulin
4- long acting insulin (for basal insulin levels)

Question 15

Short Acting insulin, aka (1):

• (2) formulation
• given via (3) route, at (4) time of day

Answer 15

1- regular insulin
2- soluble crystalline zinc insulin

3- SQ (IV in emergencies)
4- 30 mins before meals

Question 16

Intermediate Acting insulin, aka (1):

• (2) formulation
• given via (3) route
• (4) uses

Answer 16

1- NPH (neutral protamine Hagedorn), Isophane insulin
2- suspension of cystralline zinc insulin + protamine

3- SQ
4- basal insulin control (usually combined with rapid/short acting insulin for mealtime control)

Question 17

list the long-acting insulin analogs

Answer 17

• Insulin Glargine
• Insulin Detemir
• Insulin Degludec* (longest duration of action)

Question 18

how is long-acting insulin different from normal insulin (short-acting)

Answer 18

Normal- monomers form hexamers

Long-Acting- precipitation of multiple hexamers –> slow dissociation into insulin monomers (once a day SQ injections)

Question 19

describe the appearance of all the insulins

Answer 19

all are clear

ONLY NPH is cloudy due to protamine addition

Question 20

what is the main insulin formulation combination prescribed

Answer 20

Rapid Acting Insulin (mealtime) + Long Acting Insulin (basal)

much more effective than regular (short-acting) insulin + NPH

Question 21

IV insulin:

• predominately in (1) form
• (2) are indications for use

Answer 21

1- IV infusion

2- ketoacidosis, preoperative period, labor / delivery, ICU situations
always IV insulin in hospitals

Question 22

Inhaled Insulin:

• (1) formulation
• levels peak at (2)

Answer 22

1- regular human insulin in dry powder formulation

2- 12-15 mins (returns to baseline at 3hrs)

Question 23

Inhaled Insulin:

• (1) AEs
• (2) must be monitored
• (3) contraindications

Answer 23

1- cough, throat pain, hypoglycemia

2- pulmonary function

3- asthma, COPD, smokers

Question 24

list the types of insulin regimens

Answer 24

Basal-Bolus Insulin Regimens:

• long acting at night or in morning
• mealtime insulin (before)

-Insulin Pump Therapy: releases rapid acting (glulisine, lispro) or insulin (short-acting)

Question 25

describe the main AE of insulin

Answer 25

Hypoglycemia- most serious and common AE

• rapid acting is LOWER risk than short acting insulin
• long acting is LOWER risk than NPH

Question 26

how is Hypoglycemic episodes managed (insulin OD)

Answer 26

Mild Hypoglycemia: give OJ, glucose, sugary beverage/food

Severe Hypoglycemia = unconciousness / stupor: IV glucose infusion

*if IV is not available –> give glucagon SC or IM

Question 27

list some drugs that cause hypoglycemia

Answer 27

• ethanol (inhibits gluconeogenesis)
• β-blockers (inhibits SNS => glucose mobilization)
• Salicylates (inhibits sensitivity to blood glucose)

Question 28

list some drugs that cause hyperglycemia

Answer 28

• epinephrine
• glucocorticoids
• atypical antipsychotics
• HIV protease inhibitors
• phenytoin
• clonidine
• Ca++ channel blockers
• diuretics

Question 29

describe DM management of hospitalized patients

Answer 29

Illness => inc insulin resistance

-oral antidiabetics replaced with insulin –> restarted on discharge