Oral Hypoglycemic + I. Preps

Question 1

Sulfonylurea

Answer 1

1- insulin secretagogues, The sulfonylureas in current use are the second-generation drugs glyburide , glipizide , and glimepiride ,
2- block ATP-sensitive K + channels , reduce hepatic glucose production and increase peripheral insulin sensitivity.
3- taken 1 hrs before meal + at bedtime (decrease hepatic glu during)
& loss efficacy overtime and 20% of DM pts won’t be effective enough

S.E. :
1- weight gain, hyperinsulinemia, and hypoglycemia.
2- They should be used with caution in hepatic or renal insufficiency (also older)
- Renal impairment is a particular problem for glyburide, as it may increase the duration of action and increase the risk (Glipizide or glimepiride are safer options in renal dysfunction and in elderly patients)
3- Glyburide has minimal transfer across the placenta and may be an alternative to insulin for diabetes in pregnancy
4-glimepiride is more rapid onset+longer action(+may be DOC in this group in pt ē CAD

Question 2

Glinides

Answer 2

1-insulin secretagogues, In contrast sulfonylureas, the glinides have a rapid onset and a short duration of action(ē meals only) , categorized as postprandial glucose regulators. Glinides should not be used in combination with sulfonylureas ,
2-metabolized by liver enzymes and secreted into bile (CBU renal failure)
nateglinide >more rapid ēs shorter action than repaglinide, indicated ē metformin combination
S.E. :
- hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas.
- but the drugs that induce or inhibit liver enzyme may affect its level and action .
- lipid-lowering drug gemfibrozil may significantly increase the effects of repaglinide, and concurrent use is contraindicated.
- should be used with caution in patients with hepatic impairment.

Question 3

Metformin (biguanides)

Answer 3

1-insulin sensitizer. It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance,
2-hyperinsulinemia is not a problem, and the risk of hypoglycemia is far , decrease appetite(wt neutral or loss , unlike TZDs+I. Secretagogues {also due to increase l. Levels})
Improve lipids + endothelial function (dec CVD, dec mortality )
3-main mechanism of action of metformin is reduction of hepatic gluconeogenesis ( but also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization)
- used alone or in combination with other oral agents or insulin. Hypoglycemia may occur when metformin is taken in combination with insulin or insulin secretagogues, so adjustment in dosage may be required.
S.E. :
1-largely gastrointestinal (N & D)
2-Metformin is contraindicated in renal dysfunction (>=1.5mg/dl Cr)&raquo_space; risk of lactic acidosis. (It should be discontinued in cases of acute myocardial infarction, exacerbation of heart failure, sepsis, or other disorders that can cause acute renal failure , but in caution ē >80 pts, heart failure or alcohol abuse.)
3- should be temporarily discontinued in patients undergoing procedures requiring IV radiographic contrast.
4- Long-term use may interfere with vitamin B 12 absorption.
* metformin is effective in the treatment of polycystic ovary syndrome + metabolic syndrome (to delay DM onset)

Question 4

The thiazolidinediones (TZDs)

Answer 4

1-insulin sensitizers. The two members of this class are pioglitazone and rosiglitazone , insulin is required for their action, hyper-insulinemia is not a risk , increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. 
2-Rosiglitazone increases LDL cholesterol and triglycerides, whereas pioglitazone decreases triglycerides. Both drugs increase HDL cholesterol.

3-can be used as monotherapy or in combination with other glucose-lowering agents or insulin, No dosage adjustment is required in renal impairment.??
S.E. :
-few cases of liver toxicity(the older >troglitazone,but the 2 new not serious effect has been recorded) (periodic monitoring of liver function is recommended)
-have been associated with osteopenia and increased fracture risk.(in females)
-Pioglitazone may also increase the risk of bladder cancer.
- meta-analyses identified a potential increased risk of myocardial infarction and death from cardiovascular causes with rosiglitazone.
- Rosiglitazone is less utilized due to concerns regarding cardiac adverse effects
#As with metformin, the relief of insulin resistance with the TZDs can cause ovulation to resume in premenopausal women with polycystic ovary syndrome.

Question 5

α-Glucosidase inhibitors

Answer 5

Acarbose and miglitol , do not cause hypoglycemia when used as monotherapy , [Hypoglycemia induced by themtreated with glucose(dextrose) or lactose ,not sucrase]
S.E.:-
1-flatulence, diarrhea, and abdominal cramping. Adverse effects limit the use of these agents in clinical practice.(should ad slowly rising dose )
2- Can’t be used in pt ē GI disorders (Ex IBD, colonic ulceration, or intestinal obstruction) ,cirrhosis or >2 mg/dl Cr
3- Liver enzymes should be followed q3m in 1st yr
*has been shown to prevent (delay) Type 2 DM in prediabetics (also metformin , TZD)

Question 6

DPP-4 inhibitors

Answer 6

1-Alogliptin ,linagliptin , saxagliptin , and sitagliptin are orally active(1qd (DPP-4) inhibitors , may be used as monotherapy or in combination with sulfonylureas, metformin, TZDs, or insulin, stimulate insulin release ,inhibit glucagon R + gastric emptying
2-Unlike incretin mimetics, these drugs do not cause satiety, or fullness, and are weight neutral ,
3-Linagliptin is primarily eliminated via the enterohepatic system. All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction ,
S.E.:-
-nasopharyngitis and headache, N + V . Although infrequent, pancreatitis has occurred with use of all DPP-4 inhibitors.
- must decrease dose in renal impairment .

Question 7

NGLT-2

Answer 7

Canagliflozin and dapagliflozin , inhibiting SGLT2, these agents decrease reabsorption of glucose ,Inhibition of SGLT2 also decreases reabsorption of sodium and causes osmotic diure- sis. Therefore, SGLT2 inhibitors may reduce systolic blood pressure.(but not used in HTN Tx) , given once daily, primary route of excretion for canagliflozin is via the feces, about one-third of a dose is renally eliminated. should be avoided in patients with renal dysfunction.
S.E.:-
-female genital mycotic infections (for example, vul- vovaginal candidiasis),UTI , polyuria ,hoptension , (volume status should be evaluated prior to starting these agents)

Question 8

Incretin mimetics

Answer 8

Exenatide: GLP-1 analog derived from Gila monster saliva ,used as SC injection prior(injected twice daily within 60 minutes prior) to morning/evening meals , once-weekly extended-release preparation(maybe more efficient if given 1qw&raquo_space;Long acting dose )

-Liraglutide is highly protein bound and has a long half-life, allowing for once-daily dosing without regard to meals.
- Early satiety + wt loss (both
S.E. :-
1-N ,V,D ,C&raquo_space;GI , hypoglycemia(eps. ē Sulfonylurea ) , exenatide»hemorrhagic/necrotizing pancreatitis
2- Exenatide should be avoided in patients with severe renal impairment.

Question 9

bromocriptine , colesevelam

Answer 9

Both the dopamine agonist bromocriptine and the bile acid sequestrant colesevelam produce modest reductions in HbA 1c . The mecha- nism of action of glucose lowering is unknown for both of these drugs. Although bromocriptine and colesevelam are indicated for the treatment of type 2 diabetes

Question 10

Pramlintide

Answer 10

SYNTHETIC AMYLIN ANALOG,
-delays gastric emptying, decreases postprandial glucagon secretion, and improves satiety,
- subcutaneous injection immediately prior to meals ,
S.E.:-
-dose of mealtime insulin should be decreased by 50% to avoid a risk of severe hypoglycemia. Other adverse effects include nau- sea, anorexia, and vomiting,
-avoided in patients with diabetic gastroparesis (delayed stomach emptying), cresol hypersensitivity, or hypoglycemic unawareness.