Diabetes Drugs Flashcards
(25 cards)
Normal Insulin Profile
- Low basal rate + higher stimulated Rate
- Insulin T1/2 = 3-5 hrs, degraded by kidney + liver
- Endogenous Insulin: 60% liver metab, 40% kidney Metab. (prox. tubules)
- Exogenous Insulin: 60% kidney metab, 40% liver Metab
Regular Insulin- SubQ
- Short Acting
- Soluble crystalline Zn2+ form of recombinant human insulin
- Hexamerizes at injection site
- Effects in 30 min; Peak @ 2-3 hrs; T1/2 = 5-8 hrs
Regular Insulin- IV
- Short Acting
- Diluted, phosphate buffered, no Zn2+
- Forms monomers instantly following IV
Key in crisis situations i.e. DKA
Neutral Protamine Hagedorn (Isophane) Insulin (NPH)
- Intermediate Acting
- Combines insulin (-) and protamine (+) s/t neither is uncomplexed (isophane)
- Protamine degrades to release insulin after SubQ injection
- Onset 2-5 hrs; Duration 4-12 hrs
- Highly unpredictable action
Rapid Acting Insulin Analogs (drugs + properties)
- Human insulin analogs
- Onset 5-15 min; Peak @ 1 hr; Duration
Glargine
- long acting human insulin analog
- Crystallization into slowly dissolving hexamers upon injection
- Slow onset: 1-1.5 hrs, Max. effect 4-6 hrs.
- Maintained 11-24 hrs or longer; 1x daily injection
- Provides background (basal) insulin activity
- Asn at alpha 21 replaced w/ gly; 2 arg added to c-terminus of beta chain
Detemir
- long acting human insulin analog
- Most reproducible effects of the int. and long acting insulins
- Onset: 1-2 hrs; Duration > 12 hrs
- 2x daily dosing for smooth background insulin activity
- Thr at B30 omitted; C14 fatty acid attached to B29
Degludec
- Ultra long lasting human insulin analog
- Onset 1-1.5 hrs; Duration up to 42 hrs; 1x daily dosing
- 1 AA deleted from human insulin and conjugated to hexadecandeioic acid via. y-L-glutamyl spacer at the AA Lys at B29
Afrezza (inhalable Insulin)
- Rapid acting insulin
- Peak ~15 min.
- Adv. Effects: couch, throat pain/irritation, hypoglycemia
Insulin Adverse Effects
Weight gain: Type 2
Lipodystrophy: injection site fatty tissue hypertrophy
Hypoglycemia: Type 1
Abs: very rare allergy or resistance
- Insulin efficacy may be changed by glucocorticoids, OCPS, B-agonists/antagonists
Metformin
- Biguanide, 1st line Type 2 DM drugs
- Targets liver, activates AMPK, Mechanisms not fully understood
- Decreases hepatic glucose output & lowers fasting glucose
- Anti-Hyperglycemic BUT NOT Hypoglycemic
- Doesn’t cause weight gain, may help w/ weight loss in obese pt.
- T1/2: 1.5-3 hrs; excreted unchanged in urine
- 1st line monotherapy for DM2 + lifestyle changes or in combo with nearly every other DM2 med.
Adverse Effects: - N/V, diarrhea, abdominal discomfort
- Decreased B12 absorption (screen annually)
- Severe lactic acidosis: very rare, dose related w/ heaptic or renal insufficiency
Contraindications: Renal disease, Alcoholism or liver disease, predisposition to tissue anoxia (cardiopulm) – b/c increase risk of lactic acidosis
Insulin Secretagogues
- Sulfonylureas, Meglitinide, Nateglinide
- Target ATP sensitive K+ channels
- Action depends on having functional beta- cells
Sulfonylureas
Stimulate insulin release from beta-cells
1st gen: Tolbutamide, Chloropromide, Tolazamide (not used)
2nd gen: Glyburide, Glimepiride, Glipizide
2nd Gen. Sulonylureas
- well absorbed, protein-bound in plasma
- Increased hypoglycemia risk w/ longer half life
Glyburide: widely prescribed
Glipizide: Short T1/2, extended release formula widely uesd
Glimepiride: Longest T1/2, 1x daily dose
Adverse Effects: - Weight gain + hypoglycemia
- Glyburide + Glipizide: liver + kidney inactivation, contraindicated w/ hepatic and renal dysfunction
- Glimepiride: liver inactivation, not indicated w/ hepatic disease
Drug interactions: - Decreased efficacy w/ CYP3A4 activators (barbituates, rifampin)
- Decreased efficacy w/ OCPs, Glucocorticoids, Phenytoin, thiazides & beta-agonists
- Tolerance: decreased efficacy w/ years of tx, secondary failure
Repaglinide
Meglinitide
- structurally unrelated to sulfonylureas but same mech- stimulate insulin release form beta-cells
- Rapid abs, short T1/2, fast/brief insulin stimulation
- Take before meals to decrease post-prandial hyperglycemia
- T1/2: 1 hr, peak: 30-60 min
- Caution w/ heapatic/renal impairment
Nateglinide
- D- Phe derivative
- Even faster and shorter duration
- Liver inactivation- caution w/ liver disease, safe w/ very reduced renal function
- May cause weight gain
Thiazolidinediones (glitazones)
Pioglitazone & Rostiglitazone
- PPARy agonists: PPARy is a nuclear factor that increases transcription of genes encoding proteins that mediate insulin action
- Increase glucose uptake in adipose (primary target), muscle and liver in response to insulin
- Decrease visceral fat deposits, increase FA uptake at other sites
- Benefits take weeks-months
Adverse Effects:
- modest weight gain w/ some fluid retention
- Changes in HDL, LDL and TGs
- Mild anemia
- Risk of fatal liver damage- contraindicated w/ hepatic disease, do liver function test w/ initial tx
Drug interactions: - metab by CYP3A4, may induce enz. that degrade OCPs
Rostiglitazone: BLACK BOX WARNING
- May induce CHF w/ acute MI
- Limit to pt. already on Rostiglitazone or whose sugar can’t be controlled any other way
GLP-1 & DPP-4
GLP-1: Glucagon- like peptide, incretin
- Released after meals to stimulate insulin secretion
- Stim. glucose dependent insulin secretion and inhibits glucagon release
- Delays gastric emptying, normalizes fasting/post-prandial insulin
DPP-4: Dipeptidyl Peptidase IV
- Rapidly inactivates GLP-1; T1/2= 1-2 min
- Increases insulin and speeds up gastric emptying by inhibiting GLP-1 action
GLP-1 Receptor Agonists
Exenatide, Liraglutide, Dulaglutide, Albiglutide
- Peptide agonists of GLP-1, DPP-4 resistant
- SubQ, monotherapy or in combo w/ other drugs
- Don’t cause weight gain, may cause weight loss
Exenatide: 2x/daily
Liraglutide: 1x/daily
Dulaglutide: 1x/weekly
Albiglutide: 1x/weekly, T1/2= 5-8 days
Adverse Effects:
- N/V, Diarrhea
- may increase hypglycemic episodes when used w/ sulfonylureas (increase insulin release/activity)
- Cleared by kidney- contraindicaed w/ renal insufficiency
DPP-4 Inhibitors
Sitagliptin, Saxagliptin, Linaglipitin, Alogliptin
- Small molecule DPP-4 inhibitors: increase GLP-1 and GIP levels which stimulates insulin secretion, suppresses glucagon production and slows gastric emptying
Sitagliptin & Saxagliptin: Renally excreted; dose adjust for renal dysfunction
- Saxagliptin = CYP3A4/5 metab.; Sitagliptin not CYP metab
SGLT-2 Inhibitors
Canaglifozin, Dapaglifozin, Empagliflozin
- Inhibitors of SGLT-2: kidney Na/Glucose co-transporter
- Decreases glucose reabs and increases glucose excretion
Contraindications: Type 1 DM or DKA
- Severe renal impairment, ESRD, Dialysis
Adv. Effects: - UTIs and vag. yeast infections
- Diuretic effect – orthostatic hypotension, dizziness, fainting (most common in 1st 3 mo.)
alpha- glucosidase Inhibitors
Acarbose + Miglitol
Acarbose: complex oligosacch. or microbial origin
Miglitol: simple sugar analog
- competitively inhibit alpha-glucosidases in intestines which digest dietary starches into absorbable monosacch
- Decreases upper intestinal digestion of starch and disaccharides, defers to SI
- Decreases post-prandial glucose spike
- No hypoglycemia when used alone, little effect on weight
- Decreases Hb1AC but not as well as metformin or sulfonylureas
Adverse Effects:
- Abdominal pain, diarrhea
- Gass b/c of carb. fermentation
- Contraindicated w/ GI disease
Pramlintide
Amylin: secreted by beta-cells, slows gastric emptying and decreases glucagon production
Amylin Agonist: slows gastric emptying, increases satiety, suppresses post-prandial plasma glucagon and hepatic glucose output
- Adjucnt tx of DM Type 1 & 2
- SubQ; may cause weight loss
Adverse Effects: Nausea, Hypoglycemia
- Contraindicated in patients w/ gastroparesis or other GI motility disorders; caution w/ drugs affecting GI motility
Colsevelelam
Bile Acid Resin: Cholesterol drug repurposed for DM Type 2
- Modest efficacy, unclear mech.
- Oral admin, no systemic abs, distributed in GI tract
Adverse Effects:
- Contipation, dyspepsia, Abdominal pain, nausea
- Can increase TGs and interfere w/ absorption of commonly used drugs
