2 Antidiabetic Drugs Flashcards
Name the rapid-acting insulins
Insulin lispro (Humalog)
Insulin as part (Novolog)
Insulin glulisine (Apidra)
Insulin, inhaled (Afrezza)
Name the short-acting insulin
Regular Insulin (Novolin R, Humulin R0
Name the intermediate-acting insulin
NPH or Isophane Insulin (Humulin N, Novolin N)
Name the long-acting insulins
Insulin glargine (Lantus) Insulin detemir (Levemir) Insulin degludec (Tresiba)
Ocular signs of chronic DM
Cataract and refractory changes in the lens
Retinopathy (—>blindness)
CV signs of chronic DM
Occlusive vascular disease of the lower extremity (gangrene)
Atherosclerosis
HTN
Coronary and cerebral atherosclerosis
Neurobiological signs of chronic DM
PERIPHERAL NEUROPATHY
Postural hypotension
Alternativing bouts of diarrhea and constipation
Inability to empty the bladder
Skin and mucous membrane signs of chronic DM
Chronic polygenic infection
Eruptive xanthomas
Shin spots
Candida infections, vulvo-vaginitis, pruritis
Diagnostic criteria for DM
Random blood glucose ≥200 mg/dL
Fasting blood glucose ≥126 mg/dL
Oral glucose challenge ≥200 mg/dL at 2 hr
HbA1C ≥ 6.5%
HbA1C is proportional to…
Long term blood glucose concentration
Used as an integrated index or marker of glycemic control
HbA1C of _____ indicates poorly controlled DM
> 10%
Release of insulin is activated by…
Glucose and other sugars Amino acids Fatty acids Ketone bodies B2 adrenergic agonists GLP-1 agonists Vagal activation
Insulin release is inhibited by…
Alpha2 agonists
Conditions that activate the sympathetic nervous system
Insulin promotes entry of glucose into _______, _________, ________, and __________
Skeletal muscle, Heart muscle, Fat tissue, and leukocytes
Insulin NOT required for glucose transport into the brain, liver, or RBCs
What are the main treatment modalities for DM?
Insulin in Type 1 and Type 2
Antidiabetic agents in Type 2 ONLY • Insulin secretagogues • Insulin sensitizers • Glucose uptake inhibitors • Central modulators
What is the most important adverse effect of exogenous insulin?
HYPOGLYCEMIA
Causes tachycardia, confusion, vertigo, sweating
Repetitive hypoglycemic events —> cognitive dysfunction
Other adverse effects of insulin treatment
Weight gain Cough (inhaled only) Local reactions (allergy) Lipodystrophy and liphohypertrophy Insulin resistance Interactions with other drugs
What is the treatment for hypoglycemia
Give 50-100 ml of 50% glucose solution IV
0.5-1 mg glucagon (much less common)
Local allergic reactions are _______ more common than systemic allergic reactions to insulin
10x
Inflammation may persist for several days
Factors that increase insulin requirement
Fever, thyrotoxicosis, pregnancy, states of stress, surgery, trauma, infection, or any increased metabolic activity
Which type of insulin is first line in Type 2 DM?
Long-acting (basal)
What kind of insulin is used in insulin pumps?
Rapid-acting insulins
What type of insulin is preferred for less hypoglycemia?
Rapid acting over regular insulin
Hormone produced by alpha cells of the pancreas?
Glucagon
Regulates glucose, amino acids, and possibly free fatty acid homeostasis
Increases blood glucose levels by mobilizing hepatic glycogen when available
What are the therapeutic effects of glucagon?
Juveniles respond less favorably than adults with stable diabetes
Not very effective in patients with reduced glycogen stores
Potent inotropic and chronotropic effects on the heart (used in beta blocker overdose)
Produces profound relaxation of the intestine (used in radiology)
Non-diuretic thiazides, vasodilator, and hyperglycemic agent
Diazoxide (Proglycem)
MOA of Diazoxide (Proglycem)
Hyperglycemia by:
- Directly inhibiting insulin secretion
- Or decreasing peripheral glucose utilization
- Or stimulating hepatic glucose production
Used in patients with INSULINOMA
Fairly long duration, oral administration
MOA for Metformin
Reduces glucose levels in a predominantly insulin-independent manner
Increases glucose removal from blood Increases secretion of glucagon-like peptide (GLP-1) Decreases glucose absorption from the GI Decreases glucagon levels Decreases gluconeogenesis
Initial drug of choice for Type 2 DM if A1C is <10%
Metformin
Glycemic effects of Metformin
HIGH - A1C decrease ~1-1.5%
Promotes a EUGLYCEMIC STATE
Cardiovascular effects of Metformin
15-20% reduction of plasma triglycerides
Decreased macrovascular events
Other benefits of metformin
Weight neutral
Decreases all-cause mortality events
Best pharmacological therapy for diabetes prevention (use in prediabetics)
What are the pharmacokinetics of Metformin?
Oral admin
Renal excretion
Extended release available
Adverse effects of Metformin
Hypoglycemia is rare
LACTIC ACIDOSIS** (dose dependent)
Diarrhea (53%)***
Contraindications for Metformin
Lactic acidosis conditions
• Kidney disease (esp renal failure with GFR <30)
• Hepatic disease
• Alcoholism
• Diseases predisposing to tissue hypoxia (CHF, COPD)
Name the GLP-1 agonists
Exenatide (Byetta, Bydureon) Liraglutide (Victoza) Dulaglutide (Trulicity) Albiglutide (Tanzeum) Lixisenatide (Adlyxin)
GULP DOWN THOSE TIDE PODS
MOA for GLP-1 agonists
GLP-1 agonists resistant to DPP-4 degradation —> increase the release of insulin
How are GLP-1 agonists administered?
S.C. Injections 2x/day —> 1x/week
Glycemic effects of GLP-1 agonists
High A1C decrease (1-1.5%)
Cardiovascular effects of GLP-1 agonists
LIRAGLUTIDE (Victoza) decreases macrovascular events
Potential decrease in BP
Benefits of GLP-1 agonists
Slows gastric emptying —> patient eats less
WEIGHT LOSS, or at worst weight neutral (Liraglutide is the only one approved for weight loss)
Potential increased beta cell number and function
Adverse effects of GLP-1 agonists
Hypoglycemia (low risk)
GI disturbance, N/V, diarrhea
Hypersensitivity
Associated with acute pancreatitis***
Contraindications for GLP-1 agonists
Slow GI problems/GI disease
Other oral meds that cannot be exposed to stomach acid to long
Renal impairment
History of, or acute, PANCREATITIS
Thyroid cancer
What drugs are the Dipeptidyl-peptidase-4 (DPP-4) inhibitors?
The “gliptins”
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Alogliptin (Nesina)
MOA for DPP-4 inhibitors
Potentiates the effects of endogenous incretin hormones by inhibiting their breakdown by DPP-4
How are DPP-4 inhibitors administered?
Oral, once/day
Glycemic effects of DPP-4 inhibitors
Medium A1C decrease (0.5-1%) - not huge but nice addition to their treatments
CV effects of DPP-4 inhibitors
Neutral CVD effects
Also weight neutral
Adverse effects of DPP-4 inhibitors
Low hypoglycemia risk
Hypersensitivity reactions
Associated with ACUTE PANCREATITIS***
Joint pain
Contraindications for DPP-4 inhibitors
Slow GI problems
Renal impairment
History of, or acute, PANCREATITIS
Which drugs are SGLT-2 inhibitors?
Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
Ertugliflozin (Steglatro)
MOA for SGLT-2 inhibitors
Inhibits the sodium-glucose co-transporter 2 in the kidney
How are SGLT-2 inhibitors administered?
Oral
Glycemic effects of SGLT-2 inhibitors?
Medium A1C decrease (0.5-1%)
CV effects of SGLT-2 inhibitors
Empagliflozin decreases CV events (FDA approved, like Liraglutide) - probably due to WEIGHT LOSS
Canagliflozin similar but not FDA approved
Reduced BP
Adverse effects of SGLT-2 inhibitors
Hypoglycemia rare
Female genital mycotic infections, UTI and increased urinary frequency***
Increased urinary Na+ excretion and OSMOTIC DIURESIS
Increases in serum Cr, decreases in eGFR, and rarely renal impairment and AKI
Increased LDL-C
Increased incidence of bone fractures
Contraindications of SGLT-2 inhibitors
Severe renal impairment or dialysis
Prone to UTIs or other genitourinary infections
What are the Thiazolidinediones?
Pioglitazone (Actos), Rosiglitazone (Avenida)
“Insulin sensitizers” —> specifically targets insulin resistance
MOA for thiazolidinediones
Ligand of the nuclear PPAR-gamma receptor which can cause post-receptor insulin-mimetic action
—> increased glucose transporter synthesis in adipose
—> decreased hepatic glucose production
Pharmacokinetics of thiazolidinediones
Oral
Plasma half-life long (takes awhile to take effect)
Metabolized to the liver
Onset and offset of action can take weeks to months
Glycemic effects of thiazolidinediones
High A1C decrease (1-1.5%)
CV effects of thiazolidinediones
Decreased TGs in long-term use
Slight increase in HDL
Also lower insulin resistance
Adverse effects of thiazolidinediones
Low risk hypoglycemia Weight GAIN (possible edema) EDEMA —> increased risk of HF in patients with CHF*** Increased risk of bone fracture Back pain, fatigue, H/A
Contraindications for thiazolidinediones
HEPATIC DISEASE (troglitazone —> hepatotoxicity, taken off the market)
Heart Failure
What drugs are the Alpha-glucosidase inhibitors?
Acarbose (Precose), Miglitol (Glyset)
Used in both Type 1 (off label) and Type 2 DM
MOA for alpha-glucosidase inhibitors
Inhibit alpha-glucosidase in small intestine —> delayed carbohydrate digestion and absorption
Addresses the diet issues but not the glucose issue***
How are alpha-glucosidase inhibitors taken?
Orally, pre-prandially
Glycemic effects of alpha-glucosidase inhibitors
LOW A1C decrease (0.5-1%) —> decreased postprandial glucose ONLY
Also weight neutral
Adverse effects of alpha-glucosidase inhibitors
NEVER causes hypoglycemia
Frequent GI effects - esp FLATULENCE
Elevated hepatic enzymes, jaundice
Contraindications for Alpha-Glucosidase inhibitors
GI disease, GI obstruction, ileum, IBD, hiatal hernia
Hepatic disease
Renal impairment
MOA for sulfonylureas
Bind to and block ATP-sensitive K+ channel to cause membrane depolarization and increase Ca2+ influx on beta cells
Basically, squeeze the last bit of insulin out of the beta cells
Glycemic effects of sulfonylureas
High A1C decrease (1-1.5%)
CV effects of sulfonylureas
Short term: neutral
Long term: decreased risk of MI and microvascular disease (better than placebo but not metformin)
Which noninsulin therapy has the highest risk of hypoglycemia?
Sulfonylureas
Adverse effects of sulfonylureas
HYPOGLYCEMIA
- highly dependent on their half-life
- typically less of a problem with 2nd gen agents
- why we don’t use these much anymore
Weight gain
GI side effects
Contraindications for sulfonylureas
Severe renal disease or hepatic dysfunction
Allergies to SULFA DRUGS
Which are the first gen sulfonylureas?
Tolbutamide (short acting)
Chlorpropamide (long acting - worst hypoglycemia***)
Tolazamide
What are the second gen sulfonylureas?
Glyburide (worst hypoglycemia of the 2nd’s)
Glipizide (least hypoglycemia of the 2nd’s)
Glimepiride
Which drugs are Meglitinides?
Repaglinide (Prandin)
Nateglinide (Starlix)
They are not sulfas so can be used in sulfa allergic patients
MOA for meglitinides
Same as sulfonylureas (bind to and block ATP-sensitive K+ channels —> membrane depolarization and increased Ca2+ influx on beta cells)
Mimic insulin***
Glycemic effects of Meglitinides
Low A1C decrease —> decrease postprandial glucose only
MOA for Colesevelam
Bile acid binding resin - unknown glycemic effect but good for combo with other antidiabetic agents to reduce basal plasma glucose
Most common toxic effect of Colesevelam
Constipation and bloating
MOA for Bromocriptine (Cycloset)
Dopamine agonist - quick release
Augments low hypothalamic dopamine levels —> inhibits excessive sympathetic tone within the CNS —> decreased postmeal plasma glucose levels due to enhanced suppression of hepatic glucose production
Glycemic effects of Bromocriptine
Low A1C decrease (but decreased postprandial glucose levels)
CV effects of Bromocriptine
Decreased free fatty acid and TG levels
Decreased CV end point problems
What is Pramlintide (Symlin)?
Amylin-like peptide - a hormone co-secreted with insulin
Only an adjunct to insulin therapy in type 1 and 2 DM
Works with insulin to regulate postprandial glucose by delaying gastric emptying, suppression of postprandial glucagon secretion, and centrally-mediated modulation of appetite (dec caloric intake)
How is Pramlintide (Symlin) administered?
SC injection 3x/day (with meal bolus of insulin)
