Antidiabetics: p. 1 of 1Antidiabetic Agents

Overview: InsulinStimulants: oral glucose load > IV glucose; fatty acids; amino acids; GI hormones; glucagon; -AR; vagal stimulation; GH, ACTHInhibitors: insulin; -AR; 5-HT; hypoxiaInsulin release:1) Glucose taken up by -cell GLUT transporter & broken down by glucokinase to ATP 2) ATP inhibits ATP-sensitive K+-channels, which depolarizes the -cell3) Depolarization triggers voltage-sensitive Ca2+-channels: influx of Ca2+ causes release of insulin Insulin effects: Overall, promotion of an anabolic state

Treatment for Diabetes Mellitus, type I (DM-I) DrugsActionPharmacokineticsIndicationsOther

Rapid Acting Insulin Lispro [Humalog], Aspart [NovoLog], GlulisineRecombinant human insulin analogues

All insulin preparations:Parenteral (s.c.) administration; C= 100 U/mL; contain Zn to slow absorption

Onset: 10-30 mins.Duration: 3-6 hrs. DM-IGiven before a meal, faster onset Mix before use

Short Acting InsulinInsulinOnset: 30-60 mins. Duration: 5-10 hrs.

- Can be given IV when managing DKA DM-I, DKA Risk of hypokalemia when treating DKA (by IV)

Intermediate ActingNeutral Protamine Hagedorn, NPH [Isophane]Onset: 1-2 hrs.Duration: 16-24 hrs. DM-IPremixed (70% NPH, 30% Insulin) - Protamine & insulin titrated, neither in excess- Protamine delays absorption

Long Acting InsulinDetemir [Levemir], Glargine [Lantus]Onset: ~1 hr.Duration: 24 hrs. DM-IUsed for basal levels

A/E, ToxicityHypoglycemia: SNS: HR, palpitations, sweating; in elderly, neurological impairment [repeated episodes cause tolerance]; if severe- coma; can reverse with glucose (p.o. or IV) or glucagon (IM)- Caution with juveniles; hypoglycemia impairs CNS developmentLipodystrophy & hypertrophy at site of injectionInsulin resistance: formation of Ab (rare for human insulins); also associated with obesityAllergy: local & systemic (rare with human insulins)

Optimal RegimenGlargine + Rapid Acting

Treatment for Diabetes Mellitus, type II (DM-II)DrugsActionPharmacokineticsIndicationsOther

1st Generation Sulfonylureas (SU)Mimic effect of ATP on -cells (secretagogue) Inhibition of ATP-sensitive K+-chan.Acute: Insulin releaseChronic: Glucagon release to hepatic glucose outflow

With improved glycemic control, less glucose toxicity & less impairment of insulin release- Given p.o. - Highly bound by plasma proteins DM-II(15% lose initial good response) Contraindications: DM-I, pregnancy, stress, surgery, infection, renal or hepatic impairment, **Sulfa allergies**- Least risk of hypoglycemia in elderly - Diuretic- Tolbutamide: 2.5x risk of CV death

Tolbutamide, Tolazamide

2nd Generation SU- Given qd, p.o. - Highly bound by plasma proteins - Potency: 100x 1st generation SU- Liver metabolism- Mild diuretic

Glyburide [Diabeta], Glipizide [Glucotrol], Glimepiride

A/E, ToxicityHypoglycemia, GI upset, rashes (Sulfa allergies!)- Poor control of post-prandial hyperglycemia

Rx-Rx InteractionsAntagonized by agents that impair release/action of insulinPotentiated by agents that displace from plasma protein, prolong t1/2, decrease excretion or enhance hypoglycemic effect

Treatment for Diabetes Mellitus, type II (DM-II), suiteDrugsActionPharmacokineticsIndicationsA/E, Toxicity, Other

MeglitinidesAllosteric modulation of ATP effects (secretagogue)-cell selective - Insulin release is still glucose-dependentRapid onset (15-20 min) but short duration (~4 hrs.)- Liver metabolism- Given p.o., before meals DM-II

ContraindicationsLiver problems Hypoglycemia (Not combined with SU)- Nateglinide, less risk

Repaglinide, Nateglinide

BiguanidesEuglycemic agent- Targets insulin resistance (sensitizes)

- Activation of AMP-K, hepatic glucose output

- Renal excretion, unmetabolized- Onset: 2-3 days- Insulin sensitivity- Delays glucose absorption- Glucose uptake- FA oxidationFirst line Tx for DM-IIOff-label: fertility in PCOD

ContraindicationsRenal impairment, EtOH abuse, cardiac & respiratory insufficiency/hypoxia (lactic acidosis?)Other effects: TG, Cholesterol, HDL& weight

A/E: GI upset (titration of Rx ; dissipates with time)

Metformin [Glucophage]

ThiazolidinedionesPPAR-R agonist Euglycemic agent - Insulin sensitivity- Adipokines: favorable effects on muscle

- Slow onset: 2-3 wks.- Insulin-R kinase- Hepatic GNG & muscle glucose uptake

Pioglitazone: also -agonist ( TGs)DM-II

Contraindications: CHF, osteoporosis, liver damageWeight gain, fluid retention, risk of fractures in women, lipodystrophy, risk: liver damage

Rosiglitazone [Avandia], Pioglitazone

-Glucosidase InhibitorsInhibition of Glucosidase & breakdown of sugarsPrevents absorption in SI (blunts in glucose postprandially)2nd line Tx DM-II: added to Metformin

Contraindications:IBDA/E: flatulence, diarrhea & abdominal pain [some tolerance develops]

Acarbose, Miglitol

DrugsActionPharmacokineticsIndicationsA/E, Toxicity, Other

Amylin AnalogueAmylinSlows gastric emptying, promotes satiety & inhibits glucagon- Parenteral (s.c.) admin., postprandial- Short duration (2.5 hrs.)DM-II

Combined with Insulin, Metformin or a SUHypoglycemia

Pramlintide

Incretins

Exenatide [Byetta]Reptilian analogue of GLP-1 Insulin release, Glucagon release, body weight

- Renal elimination- Parenteral admin.DM-IIPancreatitis, GI discomfort

Sitagliptin, SaxagliptinInhibitor of DPP-4- Given p.o.- Effects like Exenatide (GLP-1), but weakerDM-II- Can be combined with Metformin Minimal toxicity (pancreatitis?)

Incretins: Glucagon-like peptide (GLP) and Gastric Inhibitory peptide (GIP) are incretins; rapidly inactivated by DPP-4