Diabetes Drugs - Part 1 Flashcards
Diabetes Mellitus:
insufficiency of insulin signaling relative to the req’s of the tissues for this hormone
Diabetes Mellitus sx’s?
polyuria, polydipsia, polyphagia
elevated fasting blood sugar, ketosis, weight loss etc.
Fasting plasma glucose DM level
> / 7.0
Plasma glucose 2 hours after 75-g glucose load
> / 11.1
T1D
10-20%, (Insulin – Dependent Diabetes Mellitus, IDDM; Juvenile onset diabetes). Autoimmune destruction of beta cells of pancreas.
T2D
10-20%, (Insulin – Dependent Diabetes Mellitus, IDDM; Juvenile onset diabetes). Autoimmune destruction of beta cells of pancreas.
Insulin secretion from the b cells of the pancreas
Resting state (low glucose prior to meal): GLUT2 is a equilibritor transporter b/c driven by [ ] of glucose
- if increased glc outside, glc will enter cell & it’ll equilibrate the [ ]
- ratio of ATP/ADP stays low & Katp channel opens due to hyperpolarization
- VG Ca channel closed & no insulin released
Glucose-stimulated state:
- Post meal (high glc)
- Picked up by metabolism machinery & metabolize glc to increase ATP/ADP ratio
- Katp channel closes & depolarization of mem. & therefore opens Ca channels
- Ca increases & stimulation insulin release
Increased glucose uptake (GLUT4) - insulin dependent glucose transporter - controls insulin dependent reuptake
- skeletal muscle
- cardiac muscle
- smooth muscle
- liver
- adipose tissue
- leucocytes
- pituitary
No effect glucose (GLUT 1/2) 0 equilibrium forms if increased glc outside cell, you’ll see movement of glucose inside the cell (independent of insulin)
- brain
- kidney
- intestinal mucosa
- RBC
- endothelium
- pancreas
What are the insulin actions?
- insulin increase glycogen production
– glc is converted & stored as glycogen - this also inhibits gluconeogenesis (break down of glycogen) to free up glucose
- increase TG storage (esp. in adipose tissue) & throughout tissues it increases protein syn.
Defects in glucose levels in diabetes:
Increase in EXTRACELLULAR glucose
- result of loss of insulin & insulin sensitivity
Decrease in INTRACELLULAR glucose (in tissues with insulin-sensitive glucose transporters)
- skeletal muscle is starved of glucose (why you get muscle wasting in diabetes)
Increase in INTRACELLULAR glucose (in tissues with non-insulin sensitive transporters)
- in tissue (brain, endothelial cells etc. b/c they primarily express GLUT2 or GLUT2, increase external glc –> increase intracellular glucose (toxic to the cell; what drives diabetic complications in multiple organ systems)
How insulin can control insulin dep. glucose uptake (GLUT4) in skeletal muscle for ex
- Insulin triggers association of IRS 1 & 2
- => activation of P13kinase which phosphorylates Akt/PKb
- Interacts directly w/ GLUT4 & moves it to the membrane where it can allow glucose entry
Insulin & glucagon are ______ after a meal
antagonistic
_____ is central for controlling the BG levels & this goes wrong in T2D pts
liver
In T2D the _____ is dysfunctional => increased glucose production contributing to hypoglycaemia => T2D
liver
Complications of diabetes:
- Coma (serious situation)
- BV’s (angiopathy)
- Eyes (retinopathy)
- Kidneys (nephropathy)
- Nerves (neuropathy)
What are the 3 forms in the insulin synthesis pathway?
- Pre-proinsulin
- Proinsulin
- Insulin
Chain C is the segment of peptide cleaved
Insulin LISPRO & ASPART:
Onset: 10-30 min
Peak: 0.5-3
Duration: 3-5
RAPID-ACTING
Regular NOVOLIN R:
Onset: 0.5-1
Peak: 2-5
Duration: 4-12
SHORT-ACTING
NPH/Humulin N:
Onset: 1-2
Peak: 4-8
Duration: 10-20
INTERMEDIATE
NPH/Regular:
Onset: 0.5-1
Peak: 2-12
Duration: 18-24
LONG-ACTING
Insulin Glargine:
Onset: 1-4
Peak: no peak
Duration: 22-24
LONG-ACTING
Insulin Detemir:
Onset: 1-4
Peak: flat
Duration: 12-20
LONG-ACTING
Insulin Lispro Characteristics:
- Analog of human insulin in which amino acids #28 and #29 (lysine and proline) in the beta chain are reversed.
- Pharmacokinetics differ from normal insulin
- Reduces anti-parallel dimer formation
- Monomer > dimer
- Rapid absorption & shorter duration of action (similar to endogenous insulin)
- More closely resembles insulin response to a meal
- Insulin Aspart
Insulin Lispro Use:
- Should be taken 15 mins prior to a meal
- Both TID & T2D pts can use Humalog
- Total daily dose 0.5-1 U/kg
Insulin Lispro Benefits:
- Tighter control of glucose, no AE on HbA1c
- Decreased incidents & risk of hypoglycemia
Regular Novolin R Characteristics:
- Recombinant insulin
- Dimers form hexamers in the vial – stable
- Delays absorption into blood stream – acts as a depot
- Over time hexamers breakdown to release bioactive insulin monomers
- Taken 30-45 min before a meal
- 0.5-1.0 U/kg/day (maintenance dose)
- Regular Humulin R
Insulin Glargine Characteristics:
- Human long acting insulin
- Differs in 3 AA’s in beta chain
- Aspargine replaced by glycine, 2 arginine added at C-terminus
- Soluble & clear in pH 4 solution
- Precipitates at neutral pH in subcutaneous tissue
- One injection per day (but 2 in some cases) – 15-30 U
- Slowly absorbed, duration of action 24 hours
- No peak
- Insulin Determir
Less nocturnal hypoglycemia
Insulin Glargine AE’s:
- Pain at the site of injection
- Other potential effects (tumor growth) – remains to be established
NB it cannot be diluted or mixed w/ any other insulins
New preps & technology:
- Nasal sprays
- Insulin inhalers
- Insulin pumps
Hypoglycemic actions of insulin decreased by:
- Glucocorticoids
- Glucagon
- Epinephrine
- Growth Hormone
- Thyroid Hormone
Hypoglycemic actions of insulin increased by:
- ACE inhibitors
- Alcohol
- Salicylate
- Beta blockers
- MAO inhibitors
(dangerous)
AE’s of Insulin:
- Hypoglycemia - hunger, sweating, blurred vision, headache, fatigue
– coma & death
– unawareness in the elderly
due to insulin overdose, exercise, failure to eat, labile disease
- treat w/ oral or IV glucose, sc glucagon - Lipoatrophy
- Allergy
