Sulfonylureas- include-

First generation - Acetohexamide, Chlorpropamide, Tolazamide, Tobutamide

Second generation - Glipizide, Glyburide ( Glibenclamide ), GlimepIride,Gliclazide

Refer Chlorpropamide

Interacting drugs -summary

Chlorpropamide +

Desmopressin

Chlorpropamide which potentiates ADH, potentiates the effects of desmopressin

+ Sulfonylureas

Androgens/anticoagulants / chloramphenicol/ clofibrate/ fenfuramine/ fluconazole/ gemifibrozil/ histamine H2 antagonist/ magnesium salts / methyldopa/ MAO inhibitors/ phenylbutazone/ propenecid/ salicylates/ sulfinpyrazone/ sulfonamides/ tricyclic antidepressants/  urinary acidifiers

 hypoglycemic effect of the sulfonylureas enhanced  due to various mechanisms (eg decreased hepatic metabolism, inhibition of renal excretion, displacement from protein binding sites,decreased blood glucose or alteration of carbohydrate metabolism)

Betablockers / chlostyramine/ diazoxide/ hydantoins/ rifampicin/ thiazide  diuretics/ urinary alkanisers

 decr the hypoglycemic effect of sulphonylureas decreased due to various mechanisms(eg increased  hepatic metabolism, decreased insulin release,  increased renal excretion) 

Charcoal

 charcoal reduce the absorption of the sulfonylureas depending on the clinical situation, this will reduce their efficacy or toxicity.

Ethanol

 ethanol prolong but not augument glipizide induced reductions in blood glucose. Chronic ethanol use may decrease the half-life of tolbutamide. Ethanol ingestion by patients taking chlorpropamide may result in disulfram-like reaction

Sulfonylureas +  Digitalis glycosides

incr concurrent administration may result in increased digitalis serum levels

Diabetes

Sulfonylureas- include-

First generation - Acetohexamide, Chlorpropamide, Tolazamide, Tobutamide

Second generation - Glipizide, Glyburide ( Glibenclamide ), GlimepIride,Gliclazide

Refer Chlorpropamide

GI- GI disturbances eg. nausea, epigasreic fullness, hrartburn, are the mostvcommon reactions. They tend to dose related and may disapppearwhen dose is reduced. Diarrhea, (glipziode) taste alteration, (tolbutamide) cholestatic jaundice (rare discontinue the drug if this occurs.)

Dermatologic- allergic skin reactions, eczema, pruritus, eryhthema, urticaria, morbilliform, or maculopapular eruptions, lichenoid reactions. These may be transcient and may disaapear despite continued use of the drug, if skin reactions persist,discontinue the drug. Porphyria cutanea tarda, photosentivity reactions

Hematologic- leukopenia, thrombocytopenia, aplastic anemia, agranulocytosis,hemolytic anemia, pancytopenia, hepatic porphyria.

Endocrine-reactions identical to the syndrome of inappropiate secretion of antiuretic hormone (SIDAH)

Miscellaneous- disulram-like reactios , weakness, paresthesia, tinnitus, fatiuge, diziness, verigo, malaise, headache, (infrequent).

Lab test abnormalities- Elevated liver function tests,occassional mild to moderate elevations BUN and creatinine.

Juvenille or brittle diabetes, ketosis & acidosis, diabetic coma,severe trauma, Renal thyroid or hepatic imapairment.

Pregnancy, during surgery & infections. Gangrene, stress. Fluid overload.

Special precautions:

May cause intolerance to alcohol. Hypoglycaemia. Insulin carry over. Elderly.

Monitoring- Keep patients under continous medical supervision. During the initial test period the patient should communicate with the physician daily, and report at least weekly for the firsyt month for physical examination and evaluation of diabetic control. Afdter the first month examine at monthly intervals. Uncooperative individuals may be unsuitable for treatment with oral agents.

Diet and excercise- remain the primary considerations ofdiabetic patient managewment. Calorie restriction and weight loss esential for obese diabetic. These drugs are adjunct to,not a substitute for, dietary regulation.Also loss of blood glucose control ondiet may be transcient, thusrequiring only short term sufonylureas.Identify cardiovasscular risk factors and take corrective measures where possible.

Hypoglycemia- all sulfonylureas may produce hypoglycemia. proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes.

Asymptomatic patients- when patient stabilised on any diabetic regimen is exposed to stress such as fevere, trauma, infection or surgery, a loss of control may occur. Atsuch times. it may be necessary to discontinue drug and give insulin.

The effectiveness of any oral hypoglycemic in lowering blood glucose to a desired level decreases in many patients over time (secondart failure),this may be due progression of te severitry of te disease of the diabetes or to diminished responsiveness. Adequately adjust dose and assess adherence to diet before classifying a patient as secondary failure.

Disulfiram-like syndrome- a sulfonyl -urea induced facial flushing may occur when sulfonylureas are administered with alcohol. This syndrome is characterized by facial flushing and occassional breathlessness but withourt nausea, vomiting and hypertension.seen with a true alcohol-disufiram reaction.

Syndrome of inappropiate secretion of antidiuretic hormone( DIADH)- water retention and dilutional hyponatremia have occured after administration of sulfonylureas to NIDDM patients, especially those with congestive heart failure or hepaticcirhosis.The drugs stimulate antidiuretic hormone(ADH) release,augementing hypothalamic -pituitary release of ADH. The result in excessive water retention ,hyponatremia, low serum osmolality and high osmolality.

Drug/lab interactions- aetabolite of tolbutamide in the urine may give a false positive reaction to albumin ifmeasured by acidification-after-boiling test, which causes the metabolite to precipitate.

Drug/Food interaction Absorption of glipizide is delayed by about 40 minutes when taken with food,the drug is more effective when given approximately 30minutes before a meal. The other sulfonylueas may be taken with food.

Warnings

Administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared with diet alone or diet plus insulin.

Patients treated for 5 to 8 years with diet pllus tolbutamide (1.5g/day) had a rate of cardiovascular mortality approximately 2.5 times greater of patientswith diet alone. Inform patients of the potential risks advantages and alternative methods of therapy.

Bioavailibility- micronized glyburide 3mg tablets provide serum concentration that are not bioequivalent to those from the conventional formulations (nonmicronized ) 5 mg tablets.

Therefore retitrate patients when transferring patients from any hypoglycemic agent to micronizeed glyburide.

Renal/hepatic function- oral hypoglycemic agents are metabloized in the liver. The drugs and most of the metabolites are excreted by the kidneys. Hepatic impairment may rsult in inadequate release of glucose in response to hypoglucemia. Therefore use these agents with acution in NIDDM patients withh remal or hepatic impairement and monitor renal and liver function frequently.

Elderly- Eledrly and debiliated patients are particularly susceptible to hypoglycemia action and of the sulfonylureas. Hypoglycemia may be difficult to recognize in elderly. Use with caution.

Pregnancy- In general avoid sulfonylureas in pregnancy, they will not provide good control in patients who cannot be controlled by diet alone.

Lactation- because of the potential for hypoglycemia in nursing infants, decide whether to discontinue nursing or the drug.

Children- safety and efficacy in children have not been established.

Indications:

 Diabetes

Dosage:

250mg/day in mild to moderate cases. Use 100 to 125mg/day in older patients.

Overdosage- Symptoms

Hypoglycemia- signs and symptoms include- tingling of the lips, and tongue, nausea, diminished cerbral function ( lethargy, yawning, confusion, agitation, nervouseness) increased sympathetic activity, (tachycardia, sweating, tremor, hunger) and ultimately convulsions, stupor and coma.

Treatment

1. Treat mild hypoglycemia without loss of consciuousness or neurologic findings, aggresively with oral glucose and adjustments in dosage or meal patterens.

2. Continue close monitoring until patient is stabilized

3. Severe hypoglycemic reactions infrequently, but require immediate hospitalization.

4. If hypoglycemic coma is suspected rapidly inject concentrated (50% ) dextrose IV. Follow by a continous infusion of more dilute (10% ) dextrose at a rate that will maintain blood glucose at a level of about of 100mg/dl.

5. Closely monitor for a minumum of 24 hours to 48 hours since hypoglycemia may occur after apparent clinical recovery.

 Missed dose

1. If you miss a dose of this medicine, take it as soon as possible.

2. However, if it is almost time for the next dose, skip the missed dose and go back to your regular dosing schedule.

3. Do not double doses.

For Availability/supplies 

Lichenoid eruptions

Drugs causing adverse reactions- 

1. Chlorpropamide

2. Gold stairs.

3. Antimalarials

4. PAS

5. Methyldopa

6. Phenothiazines

Cholestatic jaundice

Obstructive or cholestatic jaundice, by this is meant that clinically and especially biochemically there is little to suggest hepatocellular damage and that the the main features point to interference with or obstruction in, the flow of bile.

Typically one would expect such a patient to show

1. predominantly conjugated hyperbilirubinemia

2. minimal biochemical changes of parenchymal liver damage

3. a moderate to a marked increase in the serum alkaline phophatase level

Drugs causing adverse reactions-

1. Phenothiazine

2. Androgen

3. Anabolic steroids

4. Oral contraceptives

5. Erythromycin

6. Chlorpropamide

7. Gold salts

8. Methimazole

9. Acetohexamide

Retinopathy

The earliest sign of retinal change is an increased capillary peremeability that is evidenced by leakage of dye into vitrous humorafter fluoresin injection. The vascular lesions are acompanied by proliferation of lining endothelial cells and a loss of the pericytes that surrond and support the vessels.

Drugs causing adverse reactions-

1.Chloroquine

2. Phenoithiazine

Refer Chlorpropamide

1. Patients must receive full and complete instructions about the nature of diabetes.

2. Strict adherence to prescribed diet, an excercise program personal hygiene and avoidance of infection are essential

3. It is important to teach patients to self-monitor blood glucose

4. Do not discontinue medication except on advice of a physicain

5. May cause GI upset, may be taken with food. take glipizide 30 minutes before a meal to increse effectiveness.

6. Avoid alcohol (disulfram reaction and interference with blood sugar control ) and salicylates except on professional advice

7. Monitor urine for glcose and ketones as prescribed, monitor blood glucose as prescribed.

8. Notify physician if any of the following occurs-

Hypoglycemia- fatigue, excessive thirst or urination, profuse sweating, numbness of extremities Hypoglycemia- excessive thirst or urination, urinary glucose or ketones Other- sore throat, rash, unusual bruising, or bleeding

9.Allergies- Tell your doctor if you have had any allergic reactions to sulfonylureas or to sulfonamide type medicines incliding thiaziode diuretics. Tell your doctor if you are allergic to any other substances or foods.

10. Pregnancy- sulfonylureas are rarely used during pregnancy. The amount of insulin you need changes during pregnancy and after pregnancy.

11. Breast feeding- Chlorpropamide and tolbutamide pas into breast milk. Chlorpropamide is not recommended but in some cases toulbutamide ahs been used. Check with your doctor if you are thinkinhg of breast feeding

12. Children- little information about the use of sulfonylureas in children. Type II diabetes is unusual in this age group

13. Elderly- elderly patients are more sensitive than younger adults especially when more than one antidiabetic medicine is taken or if other medicines taht afect the blood sugar are also being taken. This may increase the chance of low blood sugar developing during treatment.

14. Other medicines- Tell your doctor if you are taking any other  medicines while you are taking sulfonylureas- Alcohol- when low blood sugar occurs, it may take longer than usual if more than a small amount of alcohol is taken Anticoagulant- the effect of anticoagulant or the antidiabetic medicine is increased.

15. Other medical problems- make sure you tell your doctor if you have any other medical problems- Acid in the blood or acidosis or Diabetic coma or Fever high or Injury severe or Ketones in the blood (diabetic acidosis) or Surgery major or any other conditions in which insulin needs changes rapidly- Insulin may be needed temporarily to control diabetes mellitus in such patients

 16. Missed dose- If you miss a dose take it as soon as possible. However if it is time for the next dose skip the dose and go back to regular schedule. Do not double dose.

17. Storage- Keep out of reach of children Store away from direct sunlight and direct light Do not store in bathroom or damp places Discard outdated medicines

Pregnancy

In general avoid sulfonylureas in pregnancy, they will not provide good control in patients who cannot be controlled by diet alone.

Lactation

Because of the potential for hypoglycemia in nursing infants, decide whether to discontinue nursing or the drug.

Children-

Safety and efficacy in children have not been established.