diabeties Flashcards

Question

What is the MOA for the Incretin mimetics (GLP-1)

Answer 1

• Improve glucose-dependent insulin secretion • Slow gastric emptying time, • Reduce food intake by enhancing satiety (a feeling of fullness), • Decrease postprandial glucagon secretion, • and promote -cell proliferation. • Consequently, postprandial hyperglycemia is reduced, A1C levels decrease, and weight loss may occur.

Answer 2

Dulaglutide, exenatide ,liraglutide , lixisenatide , semaglutide All injectable for type 2 Semaglutide is also available in an oral formulation.] • Dulaglutide, liraglutide, and semaglutide are also approved to reduce the risk of cardiovascular mortality in patients with type 2 diabetes and cardiovascular disease. • Two premixed preparations of long-acting insulins and GLP-1 receptor agonists are available: • insulin glargine plus lixisenatide and insulin deglude plus liraglutide. • Use of these combinations may decrease daily insulin requirements and the number of daily injections. Higher dosages of injectable semaglutide and liraglutide are approved for the treatment of obesity

Answer 3

Dulaglutide, semaglutide and ,liraglutide , are considered long- acting • Dulaglutide, semaglutide are dosed once weekly • Liraglutide is dosed once-daily injection • Oral formulation of semaglutide once daily • Lixisenatide is short acting dosed once daily • Exenatide is available as both short-acting (BID) and extended- release preparation( once weekly) • Exenatide should be avoided in patients with severe renal impairment.

Answer 4

- Main : nausea, vomiting, & diarrhea. - Associated with pancreatitis, should be avoided in patients with chronic pancreatitis - Exenatide has caused serious and sometimes fatal pancreatitis - Hypoglycemia when exenatide is combined with sulfonylureas. - Long- acting agents have been associated with certain thyroid tumors in rodents .

Answer 5

Sulfonylureas & Meglitinides (glinides) increase insulin secretion

Answer 6

• Secretagogues. • Mainly tolbutamide & the second-generation drugs, glyburide, glipizide, & glimepiride. • MOA: • 1) Stimulation of insulin release from the β cells of the pancreas by blocking the ATP-sensitive K+ channels, resulting in depolarization, Ca2+ influx, and insulin exocytosis. 2) Reduction in hepatic glucose production 3) Increase in peripheral insulin sensitivity. • Pharmacokinetics: bind to serum proteins, metabolized by liver, & excreted in the urine and feces. • Give with meals-single dose with breakfast, or divided doses for ones with shorter durations • The duration of action ranges from 12 to 24 hours. • Adverse effects: • weight gain, hyperinsulinemia, and hypoglycemia. • They should be used with caution in hepatic or renal insufficiency, since accumulation may cause hypoglycemia. • Renal impairment is a particular problem for glyburide, as it may increase the duration of action and increase the risk of hypoglycemia significantly • Glipizide or glimepiride are safer options in renal dysfunction and in elderly patients because they are metabolized to inactive metabolites. • Glyburide has minimal transfer across the placenta and may be a reasonably safe alternative to insulin therapy for diabetes in pregnancy. • Pregnancy category C, while Insulin is Pregnancy Category B. • Sulfonylureas shouldn’t be used during breast-feeding.

Answer 7

Meglitinides, Short-acting insulin secretagogues • Repaglinide & nateglinide • They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators. • MOA: • they bind to a distinct site on the β cell, closing ATP-sensitive K+ channels, thereby initiating a series of reactions that results in the release of insulin. • In contrast to the sulfonylureas, the glinides have a rapid onset and a short duration of action. • Combined with metformin or the glitazones. • Should not be combined with sulfonylureas due to overlapping mechanisms of action. This would increase the risk of serious hypoglycemia. • Pharmacokinetics: • Glinides should be taken prior to a meal and are well absorbed after oral administration. • Both glinides are metabolized to inactive products by CYP3A4 in the liver and are excreted through the bile. • Adverse effects: • can cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas. • Drugs that inhibit CYP3A4, such as: • itraconazole, fluconazole, erythromycin, and clarithromycin, may enhance the glucose-lowering effect of repaglinide. • Drugs that induce CYP3A4, such as: • barbiturates, carbamazepine, and rifampin, may have the opposite effect. • Repaglinide has been reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil (enzyme inhibition) and concurrent use is contraindicated.. • Caution in patients with hepatic impairment. • C/I in pregnancy & lactation.

Answer 8

• Biguanides and thiazolidinediones : • lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion. • It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance.

Answer 9

• MOA: 1) Main:↓ Hepatic glucose output by inhibiting hepatic gluconeogenesis (accounting for the high fasting blood glucose in type 2 DM) 2) Slows intestinal absorption of sugars 3) Improves peripheral glucose uptake and utilization (decreasing insulin resistance). 4) Causes loss of appetite→ weight loss. 5) ↓ Hyperlipidemia (↓ LDL & ↑ HDL): these effects may not be apparent until 4 to 6 weeks of use. The ADA treatment algorithm recommends metformin as the drug of choice for newly diagnosed Type 2 diabetics. Metformin may be used alone or in combination with one of the other oral agents or insulin. Combination with insulin has the advantage of reducing weight gain that results from insulin • Pharmacokinetics: • Metformin is well absorbed orally, • not bound to serum proteins, not metabolized. • Excretion is via the urine.?? • Given 3 times a day with meals. • Maximum dose: 850 mg x 3 (gradual titration).

Answer 10

• These are largely gastrointestinal.?? • Does not promote insulin secretion →the risk of hypoglycemia is far less than that with sulfonylurea agents, and it may only occur if caloric intake is not adequate or exercise is not compensated for calorically. →If used with insulin, the dose of insulin may require adjustment, because metformin decreases the production of glucose by the liver. Metformin is contraindicated in renal dysfunction due to the risk of lactic acidosis. • Most dangerous A/E is lactic acidosis (rarely)→ • Contraindicated in diabetics with : • renal dysfunction, hepatic disease, exacerbation of HF, acute MI (because of hypoperfusion), diabetic ketoacidosis, severe infection, sepsis, dehydration, • other disorders that may cause acute renal failure . • In severe infection and other acute stresses, oral hypoglycemics are stopped and insulin is initiated). • Should be temporarily discontinued in patients undergoing diagnosis requiring IV radiographic contrast agents, because use of such products may result in acute alteration of renal function. • Should be used with caution in patients greater than 80 years of age (check renal function) or in those with HF or alcohol abuse. • Long-term use may interfere with vitamin B12 absorption.

Answer 11

1) metformin is effective in the treatment of polycystic ovary disease. Its ability to lower insulin resistance in these women can result in ovulation and, possibly, pregnancy. Polycystic ovary syndrome (PCOS), also called hyperandrogenic anovulation (HA) is a set of symptoms due to a hormone imbalance in women. Symptoms include: irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, & trouble getting pregnant, obesity , higher risk of prediabetes • 2) Recent clinical trials suggest that metformin decreases the risk of diabetes in high risk patients (prediabetic persons).

Answer 12

• Pioglitazone & rosiglitazone. • MOA: lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ)—a nuclear hormone receptor. • Activation of PPARγ regulates the transcription of several insulin responsive genes( that affect glucose and lipid homeostasis) → increase insulin sensitivity in adipose tissue, liver, and skeletal muscle. → In DM the major site is adipocytes: ↓adipocyte production and secretion of fatty acids & ↑ glucose metabolism • They lead to a favorable redistribution of fat from visceral to subcutaneous tissues. • Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases triglycerides. Both drugs increase HDL cholesterol. • TZDs can be used as monotherapy or in combination with other hypoglycemics or with insulin. • The ADA recommends pioglitazone as a second- or third-line agent for type 2 diabetes. • Rosiglitazone is less utilized due to concerns regarding cardiac adverse effects. • Pharmacokinetics: • Pioglitazone and rosiglitazone are well absorbed after oral administration • extensively bound to serum albumin. • Both undergo extensive metabolism by different CYP450 isozymes. Some metabolites of pioglitazone have activity. • Pioglitazone and metabolites excreted in the bile and eliminated in the feces. • Metabolites of rosiglitazone are primarily excreted in the urine. • Caution with rosiglitazone if creatinine clearance < 30 mL/min.

Answer 13

• Measure liver enzyme initially and periodically thereafter. • Weight gain, possibly through the ability of TZDs to increase subcutaneous fat & cause fluid retention (can worsen HF). • Osteopenia and increased fracture risk in females. • Several meta-analyses identified a potential increased risk of MI and death from cardiovascular causes with rosiglitazone. • TZDs reduce plasma concentrations of the estrogen-containing contraceptives. • These agents should be avoided in patients with severe heart failure and in nursing mothers.

Answer 14

• TZDs can cause ovulation to resume in premenopausal women with polycystic ovary syndrome. • Recent clinical trials suggest that TZDs decrease the risk of diabetes in high risk patients. • Have fallen out of favor in recent years

Answer 15

Orally active. For type 2 diabetes. • MOA: • Located in the intestinal brush border, α-glucosidase enzymes break down carbohydrates into glucose and other simple sugars that can be absorbed. • Acarbose and miglitol reversibly inhibit α-glucosidase enzymes. • Taken at the beginning of meals → Inhibit: a) Membrane-bound α-glucosidase in the intestinal brush border (the enzyme responsible for the hydrolysis of oligosaccharides to glucose and other sugars) b) Pancreatic α-amylase, thus interfering with the breakdown of starch to oligosaccharides. → delay the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels. • Do not stimulate insulin release or tissue sensitivity. • Like metformin & TZDs, α-glucosidase inhibitors have been shown to prevent diabetes in prediabetic persons. • Pharmacokinetics: • Given 3 times daily. • Acarbose is poorly absorbed. • It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine → avoid if creatinine cl < 25 mL/min. • Miglitol is very well absorbed but has no systemic effects. • It is excreted unchanged by the kidney • Adverse effects: • Flatulence , diarrhea, & abdominal cramping. • C/I in patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction. • As monotherapy, they do not cause hypoglycemia. However, when used in combination with sulfonylureas or insulin,… • It is important that hypoglycemia in this context be treated with glucose rather than sucrose, because sucrose is also inhibited by these drugs

Answer 16

are orally active DPP-4 inhibitors used for the treatment of type 2 diabetes. • MOA: • These drugs inhibit the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as GLP-1. • Prolonging the activity of incretin hormones increases insulin release in response to meals and reduces inappropriate secretion of glucagon. • They may be used as monotherapy or in combination with a sulfonylurea, metformin, TZDs or insulin. • Unlike GLP-1 agonist , these drugs do not cause satiety of fullness and so are weight neutral • Pharmacokinetics: • The DPP-4 inhibitors are well absorbed after oral administration. • Alogliptin and sitagliptin are mostly excreted unchanged in the urine. • Saxagliptin is metabolized via CYP450 3A4/5 to an active metabolite. • The primary route of elimination for saxagliptin and the metabolite is renal. • Linagliptin is primarily eliminated via the enterohepatic system. • All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction (↓ Dose). • Adverse effects: • Nasopharyngitis, and headache are the most common • pancreatitis. ( infrequent) • No significant incidence of hypoglycemia. • Hepatic enzyme inhibitors (like clarithromycin) can cause significant increase in levels of saxagliptin→ reduce dose.

Answer 17

for treating of type 2 diabetes ✓ MOA: are oral Sodium Glucose cotransporter 2 inhibitors ➢ SGLT2 is responsible for reabsorbing filtered glucose in the tubular lumen of the kidney. ➢ So SGLT2 inhibitors ↓ reabsorption of glucose, ↑ urinary glucose excretion, and ↓ blood glucose. ➢ Also, ↓ reabsorption of Na+ → osmotic diuresis. Figure next slide ➢ So they ↓ BP, but they are not used as a treatment for HTN ✓ Monotherapy or in combination with insulin or other antidiabetics. ✓ Some of these drugs are indicated to reduce CVS death in patients with type 2 DM and CVS diseases • Pharmacokinetics: • These agents are given orally once daily in the morning. • Canagliflozin should be taken before the first meal of the day. • All drugs are mainly metabolized by glucuronidation to inactive metabolites. • While the primary route of excretion for canagliflozin is via the feces, about one-third of a dose is renally eliminated. • These agents should be avoided in patients with severe renal dysfunction. ✓ Adverse effects: ✓ The most common are: ✓ female genital mycotic infections, UTIs, urinary frequency. ✓ Others : ✓ Hypotension in elderly or patients on diuretics. ✓ Ketoacidosis ✓ Increased bone fractions