187. DM Pharmacology

Question 1

Types of Insulin and how long they last

Insulin Regimens

Insulin pump: what it is, problems

Limitations of Insulin administration

SE of ins (tx of biggest one)

Answer 1

Short acting: lispro, aspart, glulisine (3hrs, take before a meal)
Regular insulin (5-8 hr)
Intermediate acting: NPH (12-16 hr)
Long acting: Gargine, Detemir (16-24 hr) peakless

Basal/Bolus: glargine/detemir before breakfast or at bedtime with preprandial injections of short acting ins
Split-mixed: pre-breakfast and pre-dinner injection of mix of short and long acting insulin (less # shots)

Pump: Continuous Sc Ins Injection - basal rate and mealtime injections, but can lead to abscess, cellulitis, pump failure

Limitations: amount + type of food influence ins requirement, regional blood flow affected by exercise, temperature, smoking (changes ins absorption), counterregulatory hormones, injury, infection, other drugs alter ins requirement

SE: HYPOGLYCEMIA (highest risk in children - seizure, coma, permanent cognitive impairment; tx: glucose (oral, iv), glucagon - increase hepatic glu production, SE: N/v, diazoxide - interacts with B-cell K channel to decrease ins secretion, SE: N/V, Na/fluid retention, thrombocytopenia, leukopenia)
- weight gain, enlargement of sc fat depots, allergic rxns

Question 2

Sulfonylureas

• name
• primary effect
• kinetics/metabolism
• SE
• drug interactions

Answer 2

GLYBURIDE
Increases ins secretion from B cell (T2DM tx only), binds to and blocks K channel = b cell depolarize = ca influx = ins release
Kinetics: rapid absorption, ORAL, absorption reduced by food/hyperglycemia, highly protein bound, 24 hr hypoglycemic effect, hepatic (CYP2C9) and renal metabolism
SE: hypoglycemia, WEIGHT GAIN, interferes with alcohol metabolism (accumulation of acetaldehyde/hangover), some adverse CV effects possible
Drug interaction: competition for binding proteins may increase SU concentration, Alcohol increases hypoglycemic effect!!, interactions at metabolism (CYP2C9) and renal excretion

Question 3

Meglitinides

• name
• mechanism
• kinetics/metabolism
• SE
• drug interactions

Answer 3

REPAGLINIDE
Acts on B cell K-ATP channel, overlap with SU but both do not compete
kinetics: rapid onset ORALLY (stim ins secretion over meal digestion), CYP3A4 hepatic metabolism
SE: hypoglycemia
Drug interactions: none with alcohol, some with gemfibrozil (anti-lipid drug)

Question 4

GLP-1 Agonists

• name
• mechanism
• other effects
• kinetics
• SE
• drug interactions

Answer 4

EXENATIDE + LIRAGLUTIDE (DULAGLUTIDE, SEMAGLUTIDE)
Main mechanism: promote glu-dependent ins secretion (only good for T2 DM); act through GPCRs = cAMP/PKA = close K channels = Ca release = ins release
Other: lower hepatic glu production, lower glu secretion, lower gastric emptying, increase satiety, increase beta cell mass and increase ins synthesis/secretion
kinetics: SC INJECTION, variable peaks from 2 hrs to 5 days (1x/week dose for dulaglutide), semaglutide is ORAL
SE: WEIGHT LOSS
GI - N/V, abd pain, pancreatitis
Contraindicated in MTC pts
Drug interactions: ABx, EtOh, OCPs

Question 5

DPP4-inhibitors

• name
• mechanism
• kinetics
• SE
• drug interaction

Answer 5

SITAGLIPTIN
inhibit DPP4 = blocks GLP1 breakdown = increase glu-mediated ins secretion, decreases glucagon
kinetics: ORAL, renal excretion, hepatic metabolism
SE: headache, allergy, nasopharyngitis
Drug interaction: some competition with CYP3A4 (do not use with meglutanide)

Question 6

Biguanides

• name
• mechanism
• actions
• kinetics
• SE
• drug interaction

Answer 6

METFORMIN
Activates AMPK and complex I inhibition
Action: decreases hepatic glu production, decreases gluconeogenesis, increase glycogen storage in muscle, LESS LIKELY TO CAUSE HYPOGLYCEMIA than other agents
Kinetics: not metabolized, renal excretion
SE: Weight NEUTRAL, indigestion, cramps, diarrhea, less vit B12 absorption (watch for anemia), lactic acidosis
Drugs: cationic drugs compete for proximal tubule secretory system = raises circulating metformin

Question 7

Thiazoldinediones (TZDs)

• name
• mechanism
• kinetics
• SE
• drug interaction

Answer 7

PIOGLITAZONE
Mech: binds and activates nuclear receptor PPAR-gamma (complexes with RXR); promotes transcription of ins-sensitive genes in liver, muscle, adipose tissue
Kinetics: ORAL, liver metabolism (several CYPs)
SE: weight GAIN, edema, macular edema, bone fracture, high CHF risk (contraindicated in HF pts)
Drug interactions: liver metabolism (esp rifampin - anti-TB tx)

Question 8

alpha-glucosidase inhibitor

• name
• mechanism
• kinetics
• SE
• drug interaction

Answer 8

ACARBOSE
high affinity for a-glucosidase on brush border of epithelial cells delays glu absorption by interfering with disaccharide hydrolysis
Kinetics: minimal absorption, renal excretion
sx: ABD PAIN, FLATULENCE (due to bacterial metabolism of disaccharides), weak effect
Drug interactions: can decrease absorption of some drugs (ex: digoxin)

Question 9

Amylin analogs

• Name
• mechanism
• action
• use
• kinetics
• SE

Answer 9

PRAMLINTIDE
Mech: binds amylin receptor (peptide hormone secreted from pancreatic B cells) in hindbrain, mimics amylin effects
Actions: delays gastric emptying = decrease post-prandial glu conc., anoretic effect (decrease appetite), inhibits glucagon release
Use: adjunct in T1 + T2 DM
Kinetics: Sc injection (pre-prandially), renal metabolism/excretion
SE: nausea, HYPOGLYCEMIA risk, contraindicated in pts with GI motility disorder (delays gastric emptying)

Question 10

Bile-binding resins

• Name
• mechanism
• kinetics
• use
• SE
• drug interaction

Answer 10

COLESEVELAM
primary use in tx of hypercholesterolemia
kinetics: minimal oral absorption
actions: lowers BG in T2DM, lowers HbA1c
SE: GI - constipation, dyspepsia, abd pain, nausea
raises plasma TGs
Drug interaction: interferes with absorption of many commonly-used drugs and fat soluble vitamins

Question 11

SGLT2-inhibitors

• name
• mechanism
• kinetics
• SE

Answer 11

CANAGLIFLOZIN
mech: increase glucose excretion
kinetics: ORALLY effective, metabolized - fecal/renal excretion
SE: genital mycotic/UTIs (glycosuria), higher risk amputations, diuresis/volume depletion, WEIGHT LOSS, renal fx abnormalities (high serum Cr, hyperK, hyperMg, hyperPO4)

Question 12

DA Agonists

• name
• mechanism
• kinetics
• SE

Answer 12

BROMOCRYPTINE
Mechanism: increase DA activity in hypothalamus, decrease post-prandial glu without increasing ins
kinetics: oral
SE: N/V, headaches, fatigue, orthostatic hypotension, weak effect, not widely used

Question 13

What is the T2 DM tx sequence

Answer 13

1. Metformin monotx
2. if A1c not at target (<7% at 3-4mo), add 2nd drug
3. if A1c not at target after 3-4 more mo, add 3rd drug

Best adjuncts: SGLT2-i, GLP-1 agonist, DPP4-i