186. Diabetic Pharmacology Flashcards
2 arginines at C terminus of B chain
Aspragine at position 21 of A chain
Acidic - forms microprecipitates at physiologic pH
- does not readily go into circulation
When injected subcutaneously, aggregation results in slower absorption
Onset: 1-4 hours
Duration: 20-24 hours
Duration = Peakless
Glargine insulin
Adverse effects:
- genetical mycotic and urinary tract infections (d/t increased sugars in urine)
- Increased risk of amputations
- diuresis and volume depletion –> CHF
- abnormalities in renal function
Interacts with gatifloxacin
SGLT-2 inhibitors
Increases dopaminergic activity in the hypothalamus
- mechanism for effects on blood glucose is unknown
- decreases post-prandial glucose without increasing insulin
Orally effective
Adverse effects:
- nausea and vomiting
- HAs, fatigue, orthostatic hypotension
- weak effect
Dopaminergic agonist
Structurally related to sulfonamide antibiotics
Primary effect is to increase secretion of insulin from pancreatic beta-cells
- used for type 2 DM
- block K+ channel => Ca2+ channels opening => insulin secretion
Rapidly absorbed after oral administration
- absorption can be reduced by food
Plasma half life of 3-5 hours, but 24 hours duration of hypoglycemic action
Hepatic metabolism - CYP2C9
Renal excretion
Sulfonylureas
Natural molecule that associates as hexamers in solution at neutral pH
Onset: 30-60 min
Peak: 2-3 hours
Duration: 5-8 hours
Regular insulin
Coleseyelam
Primary use is in the treatment of hypercholesterolemia
- lowers plasma glucose in patients with Type 2 DM
- lowers A1c
Minimally orally absorbed
Adverse effects:
- constipation, dyspepsia, abdominal pain, nausea
- increased plasma TGs
Interferes with absorption of many commonly used drugs and fat-soluble vitamins
Bile-binding resin
Glargine or determir before breakfast or bedtime with preprandial injections of short-acting insulin
Basal/bolus
Act on beta-cell potassium channels
- some overlap in binding sites with sulfonylureas
Very rapid onset with oral administration; stimulate insulin over the period of meal digestion
Metabolized in the liver - CYP3A4
- some renal metabolism
Drug interactions with gemfibrozil
Meglitinides
Lysine and proline are reverse which results in a rapid dissociation upon injection (aggregates less)
Onset: 5-15 min
Peak: 30-90 min
Duration: 3-5 hours
Lispro insulin
Bind to PPAR-gamma, which interacts with retinoid X receptors
- promotes transcription of insulin-sensitive genes in liver, muscle, and adipose tissue
Orally effective
Metabolized in liver by several CYPs
Thiazolidinediones
Pre-breakfast and pre-supper injection of a mixture of short- and long-acting insulins
Split-mixed
If A1c is not at target (<7% after 3-4 months) what do you do? (first time)
Add another drug to metformin
Biguanide
Metformin
Neutral protamine hagedorn (isophane)
- protamine slows absorption in circulation
Onset: 1-4 hours
Peak: 6-10 hours
Duration: 10-16 hours
NPH insulin
Acts on a receptor in the proximal tubule
- functions in reabsorption of glucose which is then returned to the circulation via GLUT-1 and GLUT-2
- causes glucosuria when the transporter is mutated
Orally effective, peak at 1-2 hours
Metabolized, undergoes fecal and renal excretion
SGLT-2 inhibitors
Most commonly used oral agent
- first line for type 2 DM
Activates AMP kinase
- decreases hepatic glucose production
- suppresses gluconeogenesis
- increases glycogen storage in muscle
- less likely to cause hypoglycemia than other agents
Metformin
2 short-acting insulins used in pumps for continuous subcutaneous insulin infusion
Aspart and glulisine
Glimepiride
Glipizide
Glyburide
Sulfonylureas
A thiazide drug but has no diuretic effects
Interacts with beta cell K+ channels - opens it (active)
- decreases insulin secretion
Adverse effects:
- nausea
- vomiting
- Na+ and fluid retention
- thrombocytopenia
- leukopenia
Diazoxide
Inhibit DPP-4 that inactivates GLP-1
Increase glucose-mediated insulin secretion
- decrease glucagon
Orally effective, renally excreted
Adverse effects:
- HAs
- allergy
- nasopharyngitis
CYP3A4 metabolism
DPP-4 Inhibitors
High affinity for alpha-glucosidases on the brush border of epithelial cells
Delays absorption of glucose, interfering with hydrolysis of disaccharides
Minimally absored, renally excreted
Adverse effects:
- abdominal pain
- flatulence
- weak effects
Interacts with digoxin
Alpha-glucosidase inhibitors
__ injection is used for patients undergoing diabetic ketoacidosis
IV
Adverse effects:
- weight gain, edema
- macular edema
- bone fractures
- possibly bladder cancer
- increase in CHF
Interacts with rifampin
Thiazolidinediones
Side effect of insulin that is not hypoglycemia
Weight gain (enlargement of subcutaneous fat depots)
Binds to the amylin receptor in the hindbrain
- mimics physiological effects of amylin
Slows gastric emptying, decreases post-prandial glucose concentrations
- anoretic effect
- inhibits glucagon release
Used as an adjunct in Type 1 or Type 2 DM
Amylin analog
Risk of hypoglycemia d/t insulin injection is higher in __
Children
Example of a SGLT-2 inhbitor
Canagliflozin
Act through GPCRs –> cAMP/PKA activity
Promote glucose-dependent insulin secretion
- only effective in Type 2 DM
Also decrease hepatic glucose production, decrease glucagon secretion, delay gastric emptying, and promote satiety
Can result in weight loss
GLP-1 mimetics
Regular insulin
Lispro
Aspart
Glulisine
Short-acting insulins
Example of a meglitinide
Repaglinide
Aspartic acid replaces proline at B28 which results in a rapid dissociation upon injection (aggregates less)
Onset: 5-15 min
Peak: 30-90 min
Duration 3-5 hours
Aspart insulin
Pump provides a continuous basal rate, with mealtime bolus injections based on the size and nature of meals
Problems include abscesses, cellulitis, pump failures
CSII
Example of a dopaminergic agonist
Bromocryptine
Example of an amylin analog
Pramlintide
GLP-1 mimetics (2 of them)
Exenatide, liraglutide
Example of a thiazolidinedione
Pioglitazone
Acts through GPCRs and cAMP
Increases hepatic glucose production
Adverse effects:
- nausea
- vomiting
Glucagon
Adverse effects:
- hypoglycemia - elderly and pts w/ renal and hepatic impairments
- weight gain
- nausea, vomiting
- cholestatic jaundice
- agranulocytosis, aplastic and hemolytic anemia
- allergic reaction
- interference with alcohol metabolism (disulfiram-like)
- Possible CV effects
Sulfonylureas
NPH insulin
Glargine
Detemir
Longer-acting insulins
Rapidly absorbed after sc injection
- exenatide: peaks at 2 hours, not significantly metabolized, excreted by kidneys
- liraglutide: peaks at 8-12 hours
Adverse effects:
- nausea, vomiting, abdominal pain, pancreatitis
- contraindicated in patients with thyroid medullary carcinoma
Drug interactions:
- antibiotics
- alcohol
- oral contraceptives (exenatide)
GLP-1 mimetics
If A1c is still not at target after an additional 3-4 months then ..
Add 2 oral agents or insulin to metformin regimen
Regional blood flow, which affects insulin absorption, is affected by (3 things)
Exercise
Temperature
Smoking
Not metabolized, renal excretion
Adverse effects:
- indigestion, cramps, diarrhea
- decreased Vit B12 absorption
- lactic acidosis
Cationic drugs can increase bioavailability
Metformin
Administered subcutaneously, prior to meals
Renal metabolism and excretion
Adverse effects:
- nausea
- increases insulin hypoglycemic risk
- contraindicated in patients with disorder of GI motility
Amylin analog
Example of alpha-glucosidase inhibitor
Acarbose
DPP-4 inhibitor
Sitagliptin
Myristoyl fatty acid side chain on B29
Aggregates and binds to albumin (slows down kinetics)
Onset: 1-4 hours
Duration: 20-24 hours
Duration = Peakless
Detemir insulin
Glutamic acid at B29, lysine at B23 which results in a rapid dissociation upon injection (aggregates less)
Onset: 5-15 min
Peak: 30-90 min
Duration 3-5 hours
Glulisine insulin
