Diabetes Pharm Flashcards
Rapid acting insulins
- Aspart
- Lispro
- Glulisine
Short acting insulin
Regular insulin
Intermediate acting insulin
-NPH-neutral protamine Hagerdorn
Long acting Insulin
- Detemir
- Glargine
what is the Amylin analog
Pramlintide
What are the categories of insulin secretagogues?
- Incretin mimetics: GLP-1 agonist and Dipeptidyl Peptidase-4 (DDP-4) inhibitors
- K-ATP channel blockers: Sulfonylureas and Meglitinides
What are the GLP-1 agonists
- Exanatide
- Liraglutide
What are the DDP-4 inhibitors
- Sitagliptin
- Linagliptin
- Saxagliptin
- Alogliptin
What are the first gen. Sulfonylureas
- Chlorpropamide
- Tolbutamide
- Tolazamide
What are the second generation Sulfonylureas?
- Glipizide
- Glyburide
- Glimepiride
What are the Meglitinides
- Nateglinide
- Repaglinide
What is the Biguanide
Metformin
What are the Thiazolidinediones?
- Pioglitazone
- Rosiglitazone
What are the sodium-glucose co transporter 2 (SGLT2) inhibitor
- Canagliflozin
- Dapagliflozin
- Empagliflozin
What are the inhibitors of alpha-glycosidases inhibitors?
- Acarbose
- Miglitol
Which insulin pathway has effects on glucose, lipid and protein metabolism, primarily via regulation of enzyme activities
IR-IRS-PI3K-Akt pathway
Which insulin pathway controls regulation of gene transcription and cell proliferation
-IR-IRS-MAP kinases
Describe what the rapid acting insulins are used for
- mutations from human sequence block assembly of dimers and hexamers-allow for faster aborption
- Clinical use: postprandial hyperglycemia - taken before a meal
- onset: 5-10 min
- Duration: 1-3 hrs
- peak: 30min - 1 hour
Describe short acting regular insulins
- Composition: unmodified zinc insulin crystals
- Absorption rate is slow and less predictable - form hexamers, which are too bulky to be transported via endothelium into the bloodstream
- Clinical use: Basal insulin maintenance, overnight coverage, if for postprandial hyperglycemia - inject 45 min before the meal
- onset: 30 min - 1 hr
- Duration: 10 hr
- Peak 3-5 hrs
Describe the intermediate acting NPH preparations
- Composition: complex of protamine with zinc insulin . . protamine has to be digested by tissue proteolytic enzymes before insulin can be absorbed
- Clinical use: basal insulin maintenance and/or overnight coverage . . use is declining and being replaced by long acting insulins
- Onset 1-2 hours
- Duration: 10-12 hours
- Peak: 4-12 hours
Which long acting insulin: Lys 29 in B chain is myristoylated (lipid) rapidly absorbed into blood but binds strongly to albumin
-Detemir
Which long acting insulin: Amino acid substitutions in both A and B chains enhance crystal stability, change pKa of insulin - soluble at low pH (4) but precipitates at Ph 7
Glargine
Which long acting insulin peaks at 3-9 hours?
Which is peakless?
- Detemir
- Glargine
Clinical use of long acting insulins
Basal insulin maintenance: 1-2 injections daily
What are the general clinical indications for insulin
- Types 1 and 2 diabetes
- Gestational diabetes
- Severe Hyperkalemia
Describe the use of insulin in the treatment of severe hyperkalemia?
- Insulin + glucose (to prevent hypoglycemic shock) + furosemide
- Insulin (IV) rapidly activates Na/K ATPase to shift K+ from ECF into cells
- Effect is transient (several hours)
- K+ is eliminated from the body using loop diuretics in the meantime
What are the adverse effects of insulin?
- Hypoglycemia
- Lipodistrophy: localized hypertrophy/atrophy of subcutaneous fat at site of injection . .. prevented by frequently changing the site of injection or by IM injecitons
- Resistance: Pts treated with exogenous insulin commonly develop insulin binding antibodies . . IgG antibodies can neutralize the action
- Allergic reactions: Immediate type hypersensitivity (rare) . . due to histamine release from mast cells sensitized by anti-insulin IgE antibodies
- Hypokalemia
What is the most common complications of insulin therapy
Hypoglycemia
What are the common causes of hypoglycemia from insulin use
- Delay of a meal or missed meal
- Exercise: exercised muscle consumes more glucose and Hyperemic skin leaded to enhanced rate of insulin absorption
- Overdose of insulin
What are the signs of hypoglycemia?
- CNS/Behavioral manifestations: confusion, bizarre behavior, seizures, coma
- Sympathetic hyperactivity: tachycardia, palpitations, sweating, tremor
- Parasympathetic hyperactivity: hunger, nausea
- Patients on tight glycemic control - “hypoglycemic unawareness
What is the treatment of hypoglycemia?
- GLucose: juice, candy (if conscious); IV glucose if unconscious
- Diazoxide: stong hyperglycemic agent - K+ATP channel opener
- Inhibits the release of insulin by beta cells
- Glucagon (1 mg, sc)
Explain the MOA of Glucagon
- Gs-coupled GPCR
- activation of adenylyl cyclase
- Activationg of protein kinase A (PKA)
- Activation of phosphorylase –> glycogenolysis
- increased expression of PEPCK and Glu-6-pase–> gluconeogenesis
Describe what the effects of glucagon are
- Hepatocytes: increase glucose output, glycogen depletion . . No glycogen depletion in the skeletal muscle
- Potent inotropic and chronotropic effect on the heart
- GI smooth muscle relaxation
- increase insulin release by beta cells
- Increase release of catecholamines by chromaffin cells (contraindicated in Pheochromocytoma pts)
Clinical uses of Glucagon
- Moderate to severe hypoglycemia
- beta blocker overdose
- radiology
Pharmacokinetics of Pramlintide
- onset: rapid
- Duration: 3 hr
- peak: 20 min
Clinical use of Pramlintide?
- Type 1 diabetes
- Type 2 diabetes pts who takes mealtime insulin therapy
- Injected sc before meals as an adjunct to insulin
Adverse effects of Pramlintide
- GI: nausea, vomiting, diarrhea, anorexia
- Severe Hypoglycemia: especially if used together with insulin . . insulin dose should be reduced
What is the drug interaction with Pramlintide
enhances effects of anticholinergic drugs in GI tract . . constipation
Describe Exanatide
- recombinant form of exendin-4, proteins from Gila monster saliva
- only 53% homology to GLP-1 but still has agonist activity
- Glycine substitution was made to make it less susceptible to the hydrolysis by DDP-4
- half life: 2.4 hours
Describe liraglutide
- GLP-1 analog with 97% homology to native GLP-1
- Lipid modified-rapidly absorbed, but binds to albumin
- half life: 11-15 hrs
Clinical use of long acting GLP-1 receptor agonists
- The release of GLP-1 is diminished postprandially in type 2 diabetes patients –> inadequate glucagon suppression and excessive hepative glucose output
- approved in type 3 diabetes patients who is not adequately controlled by metformin/sulfonylureas/thiazolidinediones
- doses of other anti-diabetic meds should be reduced to avoid hypoglycemia
- In spite of parenteral route of administration they have been gaining popularity . . improved control of hyperglycemia . . weight loss in some pts
Most insulins are given SQ . .which can also be IV
Regular insulin
What is the MOA of Amylin analog Pramlintide
- inhibits glucagon secretion
- Enhances insulin sensitivity
- Decreases gastric emptying )slow the rate of intestinal glucose absorption)
MOA of GLP-1
- synthesized by intestinal L cells
- Beta cell PROLIFERATION (diff. than amylin)
- Promotes Insulin gene expression
- promotes glucose dependent insulin secretion
- inhibits Glucagon secretion and gastric emptying .. . like amylin
- satiety
What is the disadvantage of GLP-1
very short half life 1-2 min . . its a polypeptide
What is the protease that cleaves GLP-1 leading to its short half life
DDP-4
Describe the K+ATP channel blockers MOA
- The SUR on the outside binds to the sulfonylurea receptor
- Block the K+ current through Kir6.2, inwardly rectifying potassium channel
MAO of metformin (Biguanide)
Activation of AMP-dependent protein kinase
- basically blocks mitochondrial oxidative phosphorylation leading to buildup of AMP
- AMP dependent kinases then phosphorylate a number of targets: inhibition of lipogenesis and gluconeogenesis, increase in glucose uptake, glycolysis, and fatty acid oxidation, lower glucose levels in hyperglycemic (but not normoglycemic states), and increases insulin sensitivity
MOA of Thiazolidinediones
- Ligands of PPARgamma
- this is a nuclear receptor expressed primarily in fat, muscle, liver tissue, and endothelium
- increases GLUT4 in skeletal muscle and adipocytes . . so increases insulin sensitivity
Explain what SGLT2 inhibitors do
decrease reabsorption of glucose so you urinate out the glucose
MOA of alpha glycosidase inhibitors
- only monosaccharides are absorbed from GI into the blood
- Competitive inhibitor of alpha-glycosidases, a family of enzymes on the intestinal epithelium defer digestion and thus absorption of ingested starch and disaccharides
- Lower post prandial hyperglycemia to create an insulin sparing effect
Adverse effects of the long acting GLP-1 receptor analogs
- GI: nausea, vomiting, diarrhea, anorexia
- Lower risk of hypoglycemia vs. Pramlintide
- It exhibits glucose dependent insulinotropism (the ability to stimulate insulin secretion during hyperglycemia but NOT during hypoglycemia)
- Linked to cases of ACUTE PANCREATITIS and PANCREATIC CANCER
- possible like to THYROID CANCER
Clinical used of DDP-4 inhibitors (Gliptins)
- approved as adjunctive therapy to diet and exercise in patients with type 2 diabetes
- Used both as a monotherapy and in combo with metformin/sulfonylureas/TZDs
- taken orally
Adverse effects of DDP-4 inhibitors
- upper respiratory infections and nasopharyngitis
- linked to acute pancreatitis
- Hypoglycemia (if combined with insulin secretagogues - their doses have to be adjusted)
Compare and contrast 1st vs 2nd gen sulfonylureas
First: lower potency so used in high doses; developed in 50s-80s. currently used infrequently for the treatment of diabetes
- Second: higher potency
- developed in 80s and 90s
Clinical use of Sulfonylureas
-type 2 diabetes as a monotherapy or in combination with insulin or other antidiabetic drugs
Adverse effects of Sulfonylureas
- Hypoglycemia
- Weight gain (increased insulin release)
- Secondary failure - patients who respond initially later cease to respond to the sulfonylurea and develop unacceptable hyperglycemia
- Disulfiram-like effect of alcohol induced flushing
- Dermatological and general hypersensitivity reactions: cross reactivity with other sulfonamides (sulfonamide antibiotics, Carbonic anhydrase inhibitors, Diuretics: thiazides and furosemide)
What are the Drug interactions with sulfonylureas that enhance their hypoglycemic effect?
- Displacing from binding with plasma proteins: sulfonamides, clofibrate, and salicylates
- Enhancing the effect on K-ATP channel: ethanol
- Inhibitin CYP enzymes: Azole antifungals, gemfibrozil, cimetidine
What are the drug interctions with sulfonylureas that decrease their glucose lowering effect
- inhibiting insulin secretion: beta-blockers, CCM
- Antagonizing their effect of K-ATP channel: diazoxide
- inducing hepatic CYP enzymes: phenytoin, griseofulvin, rifampin
Clinical use of Meglitinides
- Control of postprandial hyperglycemia in patients with type 2 diabetes
- taken orally before the meal
- Can be used either alone (to control isolated postprandial hyperglycemia) or in combination with other antidiabetic drugs
side effects of Meglitinides
- hypoglycemia
- secondary failure
- weight gain
Clinical use of metformin
-most commonly used oral agent to treat type 2 diabetes and is generally accepted as the first line treatment for this condition
What are the advantages of Metformin use
- superior or equivalent glucose lowering efficacy compared to other oral meds
- Does not cause hypoglycemia
- does not cause weight gain
- taken orally
- can be used either alone or in combination with other oral agents
- In clinical trials decreased the risk of both macro- and microvascular complications in diabetic patients
Pharmacokinetics of metformin
- half life: 1.5-3 hours
- not bound to plasma proteins
- Not metabolized
- Excreted unchanged by kidneys
Adverse effects and contraindications of metformin
- Most common: GI complications - anorexia, vomiting, nausea, diarrhea, abdominal discomfort
- Decreased absorption of vit B12
- Lactic acidosis, especially under conditions of hypoxia, renal and hepatic insufficiency
- Contraindicated in conditions predisposing to tissue hypoxia (HF, COPD), renal failure, chronic alcoholism, and cirrhosis
What CYPs metaboliz pioglitazone?
CYP2C8 and 3A4
What CYPs metabolize Rosiglitazone?
CYP2C8 and 2C9
important pharmacokinetic features of Thiazolidinediones?
- taken orally once daily
- changes gene expression so full effects develop 1 to 3 months later
- metabolized in liver
- safe to administer to pts with renal failure
Clinical use of Thiazolidinediones?
- Type 2 diabetes alone or in combination with other antidiabetic drugs
- Shown to delay progression from prediabetes to type 2 diabetes
- Euglycemic drugs (no hypoglycemia with used alone)
Adverse effects of Thiazolidinediones
- Weight gain (incidence doubles if with insulin)
- Edema (also doubles if with insulin)
- Exacerbation of heart failure: contraindicated in NTHA class III or IV HF
- Link to increased risk of BLADDER CANCER (piogliazone)
- Osteoporosis: bone fractures (especially in post menopausal women
What are the other effects of SGLT2 inhibitors
- cause osmotic diuresis
- induces weight loss
- reduce blood pressure
- reduce plasma levels of uric acid
- Do NOT cause hypoglycemia when used alone
Clinical used of SGLT2 inhibitors?
- Adjunct to diet and exercise in adults with type 2 diabetes
- take orally before the first meal once a da
- in patients with hypovolemia, this condition should be corrected before the start of therapy
Adverse effects of SGLT2 inhibitors
- Hypotension
- hypovolemia: orthostatic hypotension and dizziness, syncope
- Genital (mycotic) and urinary tract infections: can lead to life threatening blood infections (urosepsis) and kidney infections (pyelonephritis)
- Hypoglycemia if combined with insulin or insulin secretegogues
- increased LDL-C
- renal function impairment: induce fall in glomerular filtration rate and increase plasma creatinine
- Hyperkalemia (especially in patients with impaired renal funcitons and those taking ACEIs, ARB, and K+ sparing diuretics
- development of ketoacidosis
Clinical use of alpha-Glycosidase inhibitors
- Type 2 diabetes as monotherapy or in combo with other oral antidiabetic agents or insulin
- Taken orally at mealtime
- Do NOT cause hypoglycemia when used alone
- Do NOT cause weight gain
Adverse effects of alpha Glycosidase inhibitors
- Most common: malabsorption, flatulence, and abdominal bloating
- hypoglycemia has been described when combined with insulin or insulin secretegogues
Drug interactions with Alpha Glycosidase inhibitors
-Decrease absorption of digoxin and propranolol and ranitidine
