Pharm E3- Endo

How much glucose does the body require per day?

190 mg

Which type of DM is less common, has an extensive & selective loss of B cells from pancreas, & requires exogenous insulin for survival?

T1DM

Why are patients with liver or kidney failure more prone to hypoglycemia?

Can’t clear insulin as well → sticks around longer → lower blood sugar

What is the T ½ of insulin?

3-9 minutes

What is the mechanism of insulin release?

Pancreas exposed to glucose → binds GLUT-2 on B cells → oxidized to ATP via TCA cycle → closes K channels → K flows outside, cell depolarized & AP triggered → Ca channels open → Ca flows inside & stimulates exocytosis → insulin released

What drugs close the ATP dependent K channels on beta cells to stimulate insulin release?

Sulfonylureas

What is the MOA of insulin?

Stimulate glucose uptake in target tissues (GLUT 4, muscle & adipose), initiates phosphorylation cascade w/in cells, & translocates glucose transporters from inside cell to cell surface

How is the pharmacokinetic profile of insulin altered?

Varing zinc concentration (lente) → prolongs action

Adding protamine (NPH, NPL) → extends T1/2

Change amino acid sequence (insulin analogs) → changes activity

Which insulins are ultra short / rapid acting (used around meals or for quick correction)?

Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra)

Which insulins are short acting?

Regular → Humulin R & Novolin R

Which insulins are intermediate acting?

NPH → Humulin N & Novolin N

Which insulin is long acting?

Ultralente

Which insulin is ultra long acting (used for basal requirements)?

Glargine (Lantus), Determir (Levemir), Degludec (Tresiba)

Which insulin is inhaled?

Afrezza

What products can insulin be made from?

Beef, pork, human, recombinant in E. coli (humulin) & baker’s yeast (novolin)

Which insulin?

• Onset: 15-30 min

• Peak: 1-2 hrs

• Duration: 3-5 hrs (max 5-6)

Lispro (Humalog), Aspart (Novolog), Glulisine (Apidra)

Which insulin?

• Onset: 5-10 min

• Peak: 0.75-1 hr

• Duration: 3 hrs

Afrezza (technosphere)

Which insulin?

• Onset: 0.5-1 hr

• Peak: 2-3 hr

• Duration: 4-6 hr (max 6-8)

Regular

Which insulin?

• Onset: 2-4 hr

• Peak: 4-8 hr

• Duration: 8-12 hr (max 14-18)

NPH

Which insulin?

• Onset: 2 hr

• Duration: 14-24 hr (max 20-24)

Detemir

Which insulin?

• Onset: 2-3 hr

• Duration: 22-24 hr (max 24)

Glargine (U-100)

Which insulin?

• Onset: 2 hr

• Duration: 30-36 hr (max 36)

Degludec

What is the MC comp seen with insulin?

Hypoglycemia (U-100, U-200, U-500)

What complications are seen with insulin?

Hypoglycemia, allergy (IgE), immune resistance (IgG), injection reaction if cold (vasodilation), lipodystrophy at injection sites, & weight gain

Why should insulin be warmed by rolling in between hands before injecting (don’t shake)?

Injection reaction d/t being cold from storage in the fridge

When injecting insulin, why do you need to rotate injection sites around the abdomen?

Lipodystrophy at injection sites

What drugs decrease the hypoglycemic effect of insulin?

OCs, corticosteroids, dobutamine, epinephrine, niacin, smoking, thiazides, thyroid hormone

What drugs increase the hypoglycemic effect of insulin?

Alcohol, alpha blockers, anabolic steroids, beta blocks, MAO inhibitors

What drug can increase the hypoglycemic effect of insulin, but can also block the signs of hypoglycemia?

Beta blockers

What are indications for insulin?

All newly dx T1DM

Pregnancy w/ T2DM or GDM

T2DM not controlled by diet, exercise, & PO meds

DKA

Hyperglycemic hyperosmolar nonketotic syndrome (HHNS) - MC T2

Hyperkalmeia (insulin will push K into cell)

Which T1DM regimen would offer tighter control but is more complex for the patient?

More frequent insulin administrations

Which T1DM regiment has less of a risk for hypoglycemia but offers looser glycemic control?

Less frequent insulin administrations

What factors need to be considered when dosing insulin in T1DM?

Carbohydrate intake & physical activity (decrease dose when exercising)

Why isn’t twice daily dosing sufficient for T1DM?

Timing of insulin onset, peak & duration needs to match meal patterns & exercise schedules, should mimic pancreas

What is an example of an insulin regimen in T1DM?

Long acting in morning & evening (50% as basal), regular or rapid acting taken around meals (50% as bolus; based off sliding scale & carbs)

Which type of DM requires more insulin due to resistance?

T2DM

What are downfalls to insulin pumps?

Extreme attention to detail (doesn’t automatically stop pumping insulin at mealtime), pt needs extensive training (have to input mealtime carbs to calculate bolus dose) & malfunctions can lead to extremes in BG

What BG is considered hypoglycemic?

*educate pt on ssx!

< 65-70 mg/dL

How should hypoglycemia be treated?

Rule of 15 → 15 g of simple carbs (4 oz OJ, milk, 4 glucose tabs), check glucose in 15 min & repeat if BG < 70 mg/dL

How should hypoglycemia be treated in an unconscious patient (unable to take PO meds)?

Glucagon (GlucaGen) & Dextrose IV

What drug might not work to treat long standing hypoglycemia because there are no glycogen stores to work on?

Glucagon (GlucaGen)

What drug stimulates glucogenolysis in the liver to raise BG & causes smooth muscle relaxation in the GI tract (sometimes used to pass foreign bodies in esophagus)?

Glucagon (GlucaGen)

What SEs are associated with Glucagon?

N/V

What can higher concentrations of dextrose IV cause?

Thrombophlebitis

What is the max single dose of IV dextrose?

25 g (100 calories)

What is the approach to treatment in T2DM?

Life style changes → monotherapy → combo therapy (oral drugs only) → combo therapy (oral drugs w/ insulin)

What drugs used to treat T2DM stimulate the pancreas to make more insulin?

Sulfonylureas, meglitinides

What drugs used to treat T2DM sensitize the body to insulin and/or control hepatic glucose production?

Thiazolidinediones, biguanides

What drugs used to treat T2DM slow the absorption of starches?

Alpha glucosidase inhibitors

What drugs used to treat T2DM suppress glucagon, decrease gastric emptying, and decrease food intake?

Incretins (GLPs)

What drugs used to treat T2DM decrease the reabsorption of glucose from renal tubules?

SLGT2 inhibitors

What drugs are 1st generation sulfonylureas?

Chlorpropamide (Diabinese)

Acetohexamide (Dymelor)

Tolazamide (Tolinase)

Tolbutamide (Orinase)

What drugs are 2nd generation sulfonylureas?

Glimepiride (Amaryl)

Glipizide (Glucotrol)

Glyburide (DiaBeta, Glynase)

Which generation of sulfonylureas is 100x more potent & has less SEs?

2nd gen

What is the MOA of sulfonylureas?

Block ATP-dependent K channels on B cells → stimulates depolarization → insulin release (& somatostatin) → dec glucagon levels

Dec basal hepatic glucose production, gluconeogenesis, & glycogenolysis

Inc insulin receptor amount & sensitivity

How are sulfonylureas metabolized?

Mostly in liver (some are active metabolites), excreted in urine, & highly protein bound

*caution in renal or hepatic insufficiency

Why should sulfonylureas not be used in pregnancy?

Crosses placenta & may deplete insulin from fetal pancreas

Which sulfonylureas are most likely to produce hypoglycemia?

Chlorpropamide & glyburide

Which sulfonylurea has the highest SEs, is long acting (48 hrs), has a disulfiram like reaction with alcohol (flushing, hot, N, etc) and should be avoided in elderly?

Chlorpropamide

Which sulfonylurea may enhance peripheral tissues to insulin but mostly causes increased insulin release, & provides more rapid glucose control when used with insulin?

Glimepiride (Amaryl)

What must you do to the dose of glimepiride if using in combination with insulin (may enhance hypoglycemia)?

Decrease

Which sulfonylurea has once daily dosing, is most frequently associated with hypoglycemia & may suppress glucose inhibition in insulin release?

Glyburide

Which sulfonylurea should be given 30 minutes before meals, has a short T ½ & is less likely to cause hypoglycemia?

Glipizide (Glucotrol)

What SEs are seen with sulfonylureas?

*similer to insulin

Hypoglycemia, wt gain, constipation, N, D, rash, pruritus, leukopenia, thrombocytopenia, aplastic anemia, & resistance may develop over time

What are CIs to sulfonylureas?

DKA ± coma, T1DM, pregnancy, breastfeeding

What drug interactions are seen with sulfonylureas?

Protein binding, decreased effectiveness with hyperglycemic drugs, & disulfiram like reactions (chlorpropamide)

What drugs are meglitinides?

Repaglinide (Prandin)

Nateglinide (Starlix)

What is the MOA of meglitinides?

Block ATP dependent K channels in B cells to inc insulin secretions relative to glucose level (won’t work if BG is normal, only when increased related to a meal)

When should meglitinides be taken?

Before meals when carb levels inc → repaglinide 30 min, Nateglinide 1-10 min

If meal missed → skip dose

How are meglitinides metabolized?

Hepatic metabolism, highly protein bound (peaks 1 hr, lasts 3-4 hrs)

What drugs can meglitinides be combined with?

Metformin only

What SEs are seen with meglitinides?

Hypoglycemia, wt gain, HA, N, joint pain, use w/ caution in liver problems

What drugs are biguanides?

Metformin (Glucophage)

Buformin (Europe)

Phenformin (removed d/t fatal lactic acidosis)

What is the MOA of biguanides?

Dec hepatic glucose production & glucose absorption from GI tract

inc peripheral glucose uptake & utilization (inc tissue insulin sensitivity)

**limited hypoglycemia**

How are biguanides metabolized?

Excreted unchanged by kidneys via renal tubular excretion

*monitor renal function

What drug is useful in obese patient with insulin resistance and hyperlipidemia?

Biguanides (does NOT cause wt gain)

What SEs are seen with biguanides?

Unpleasant/metallic taste, anorexia, C, D, heartburn, rash, megaloblastic anemia (dec vit B12 absorption) & lactic acidosis (risk w/ renal impairment, aging & after surgery)

What should a patient taking metformin who is about to have a surgery do?

Stop taking 2 days before & withhold 48 hrs after, use insulin in between

(can become acidotic during surgery → lactic acidosis)

What are CIs to biguanides?

Renal disease (GFR < 30 ml/min), metabolic acidosis, hypoxia, hepatic disease, cationic drugs (compete for tubular excretion) & surgery

What drugs are thiazolidinediones?

Pioglitazone (Actos)

Rosiglitazone (Avandia)

Troglitazone (Rezulin) → removed d/t liver toxicity

What is the MOA of thiazolidinediones?

Selective & potent agonist for PPAR-g → regulate transcription of insulin responsive genes → insulin sensitizers

Inc peripheral glucose uptake & utilization

Dec hepatic glucose production

How are thiazolidinediones metabolized?

Hepatic metabolism & highly protein bound

*monitor LFTs every 2 mos for first year, stop if ALT > 3x

What SEs are seen with thiazolidinediones?

Expanded BV, edema, worsens HF, HA, fatigue, muscle pain, inc HDL, LDL, & TG, weight gain

How long might it take for the maximal effect of thiazolidinediones to be seen?

6-12 wks

What drugs are alpha-glucosidase inhibitors?

Acarbose (Precose)

Miglitol (Glyset)

What is the MOA of alpha-glucosidase inhibitors?

Competitive inhibitor of a-amylase & a-glucosidase → slows starch metabolism → decreases glucose absorption

How are alpha glucosidase inhibitors metabolized?

Acarbose → not absorbed, metabolized by intestinal bacteria

Miglitol → saturable absorption, excreted unchanged by kidney

How should alpha glucosidase inhibitors be taken?

Take w/ first bite of each meal

What do you need to monitor with miglitol?

LFTs

What are SEs of alpha glucosidase inhibitors?

Abd pain, D, flatulence (undigested carbs in colon)

What are CIs to alpha glucosidase inhibitors?

IBD, GI obstruction or ulceration, chronic intestinal disease

What is the MOA of incretins (GLP1)?

Inc GLP secretion & glucose dependent insulin release

Suppress glucagon secretion

Dec gastric emptying → inc satiety→ dec food intake

How is GLP-1 metabolized?

Dipeptidyl peptidase (DPP-IV)

What drug?

• incretin mimetic

• BID SC injection, 1 hr before meals

• T ½: 10-12 hrs

• Indications:

  • T2DM taking metformin & sulfonylureas and not controlled

  • Wt loss

Exenatide (Byetta)

What are SEs of exenatide?

N/V (d/t dec gastric emptying), hypoglycemia w/ sulfonylureas, delayed absorption of PO meds, pancreatitis, weight loss

What drugs are incretins?

Semaglutide

Tirazepatide

Liraglutide (Victoza)

Dulaglutide (Trulicity)

Albiglutide (Tanzeum)

Which incretin is a human GLP-1 analog linked to fatty acid & binds albumin to be released slowly (t ½ - 12 hrs)?

Liraglutide

What drugs are DPP-IV inhibitors?

Alogliptin

Sitagliptin

Saxagliptin

Linagliptin

What SEs are seen with DPP-IV inhibitors?

D, HA, angioedema, anaphylaxis, skin rash, SJS

What is the MOA of DPP-IV inhibitors?

Block the metabolism of GLP-1 & GIP → increases t ½

Also involved in T cell activation (CD26)