Insulin and Oral Sulfonylureas in the Treatment of Diabetes Mellitus These agents are important for those patients who cannot manage their diabetes by diet and exercise alone. by John R. White, .Jr., PharmD
Introduction Approximately 13 million people in the United States suffer from diabetes mellitus, and about one-half of these people don 't know they have the disease. It is estimated that 10%-15% of patients with diabetes mellitus have Type I or insulin-dependent diabetes mellitus (IDDM) , while 85%-90% have Type II or non-insulin-dependent diabetes mellitus (NIDDM).1
The pharmacologic management of diabetes mellitus in the United States uses either insulin or oral sulfonylurea agents or, on rare occasions, both insulin and sulfonylurea agents. All patients with Type I disease require COUNSELING PATIENTS insulin to sustain life. About WIT H one-third of patients with Type II disease are treated with insulin, a third are treated with oral agents, and the remainder are treated with diet and exercise or receive no treatment. Patients with diabetes see their pharmacist six times more frequently than they see their physicians. Pharmacists are in an excellent position to counsel, monitor, teach, refer, and in some situations treat patients with diabetes.
DIABETES
Insulin The isolation of insulin from animal pancreas glands in 1922 by Best and Banting was the fIrst major advancement in Vol. NS32, No.8 August 1992/643
the pharmacologic management of diabetes. 2 Before the discovery of insulin, no effective treatment was available for Type I disease. The discovery of insulin was one of the greatest advances of modem medicine, and its effects were at that time considered miraculous. Administration of insulin causes an attenuation of hyperglycemia and the symptoms of polydipsia, polyuria, and polyphagia; reverses diabetic coma; and causes weight gain in direly emaciated patients because it affects carbohydrate, fat, and protein metabolism. Insulin is required for the uptake of glucose into many cell types such as muscle cells. ' In the presence of insulin, free fatty acids are stored as triglycerides. Insulin also promotes the production of structural proteins. Currently, many forms of insulin are available (Table 1). Factors to consider when selecting insulins include source (beef, pork, or human), type (short-acting, intermediate-acting, or long-acting), cost, strength, mixing compatibility, and purity.
Structure and Source Insulin is a large proteinaceous molecule (51 amino acids) formed from the cleavage of proinsulin. Normal pancreatic reserves of insulin are about 200 units, with daily secretions ranging from 30 to 75 units/day in the adult. 1 Insulins available commercially in the United States include pork, beef, beef and pork mixture, and biosynthetic human. Pork and beef insulins differ from human insulin by one and three amino acids respectively. These various chemical structures result in solubility and immunologic differences. The incidence of immunologic side effects such as lipoatrophy and antibody formation is greatest with beef AMERICAN PHARMACY
- - - - - - - - - - - --- - - -- - - - -- ---
- - - - -- - - - - - - - -
--------
-
- --
Table 1
Insulin Products Available Type
Manufacturer
Strength
lIetin II Regular
Lilly
U-100
Semilente
Novo Nordisk
U-100
Brand Name
Short-ActinQ1nsulins Beef
Pork
BeefIPork
Human
lIetin II Regular
Lilly
U-100, -500
Regular
Novo Nordisk
U-100
Purified Pork Regular
Novo Nordisk
U-100
Velosulin
Novo Nordisk
U-100
lIetin I Regular
Lilly
U-100
lIetin I Semilente
Lilly
U-100
Humulin Regular
Lilly
U-100
Humulin BR
Lilly
U-100
Novolin R
Novo Nordisk
U-100
Velosulin Human R
Novo Nordisk
U-100
Int~t,.I!'~diate-Acting
19sulin
Beef
lIetin II Lente
Lilly
U-100
lIetin II NPH
Lilly
U-100
Lente
Novo Nordisk
U-100
NPH
Novo Nordisk
U-100
lIetin II Lente
Lilly
U-100
lIetin II NPH
Lilly
U-100
Purified Pork Lente
Novo Nordisk
U-100
Purified Pork NPH
Novo Nordisk
U-100
Insulatard NPH
Novo Nordisk
U-100
Pork
BeefIPork
.~
lIetin I NPH
Lilly
U-100
lIetin I Lente
Lilly
U-100
insulin and least with human insulin. 3 Human insulin is more soluble than animalderived insulin and hence has a more rapid onset and a shorter duration of action than animal-source insulin. 4
Type Insulins may be subdivided into several categories based on time-action profiles (Table 1): short-acting insulins (regular and semilente) , intermediate-acting insulins (NPH and lente), long-acting insulins (ultralente and PZI) , and insulin combinations (mixtures of NPH and regular) (Table 2). The onset of action, time to peak activity, and duration of action differ not only between the above-mentioned categories, but vary from product to product within a category. These differences underline the importance of not switching the insulin type or brand on which a patient has been stabilized. Time-action profiles of one product may vary in the same patient from day to day depending on such factors as injection site , exercise , and ambient 3 temperature.
Humulin L (Lente)
Lilly
U-100
Humulin N (NPH)
Lilly
U-100
Novolin L (Lente)
Novo Nordisk
U-100
Novolin (NPH)
Novo Nordisk
U-100
Insulatard NPH Human
Novo Nordisk
U-100
lIetin II PZI
Lilly
U-100
Ultralente
Novo Nordisk
U-100
Cost
Pork
lIetin II PZI
Lilly
U-100
BeefIPork
lIetin I PZI
Lilly
U-100
lIetin I Ultralente
Lilly
U-100
Humulin U (Ultralente)
Lilly
U-100
Novo Nordisk
U-100
The price discrepancy between human insulin and animal-source insulins is becoming less of a factor in the choice of insulins as the co st of human insulin declines in relation to animalsourc e insulins. In many instances, human insulin is less expensive than purified pork insulin. Human insulin m ay in fact be le ss costly
Human
Beef
Human
Fi~ed:Coml!!i!!!i~n I,!!!!Uns Pork
Mixtard 70/30
Human
Humulin 70/30
Lilly
U-100
Novolin 70/30
Novo Nordisk
U-100
Mixtard Human 70/30
Novo Nordisk
U-100
AMERICAN PHARMACY
August 1992/644 Vol. NS32, No . 8
than its animal-derived counterparts, because often less insulin is required. It also causes fewer immunologic side effects, w hich are expensive to diagnose and treat. 4
Purity Insulins are purified by multiple chromatographic processes. Purity of insulin is quantified by measuring proinsulin concentration. Conventional modern animal-source insulins contain less than 10 ppm of proinsulin. Semisynthetic insulin contains 1 ppm, and biosynthetic insulin contains less than 1 ppm. 1
Strength Originally, 1 unit of insulin was the amount needed to induce hypoglycemic coma in a fasting I-kg rabbit. Today, of course, insulin strength is a much more tightly controlled and regulated entity. Currently there are two strengths of insulin available in the United States- U-I00 and U-500 , which contain 100 and 500 units/mL, respectively. U-40 insulins , containing 40 units/mL, were discontinued in December 1991. This reduction in the number of insulin strengths should reduce the number of medication errors involving insulin. U-500 is available by prescription only and must be special ordered from Eli Lilly and Company. The use of U-500 insulin is reserved for patients with insulin resistance and is usually used only in patients requiring greater than 200 units/day of insulin.
Many patients are treated with two daily injections of a mixture of NPH and regular insulin. Patients being treated with this regimen typically take two-thirds of the total daily dose in the morning and one-third in the evening. The ratio of NPH/regular varies based on the patients' needs, but it usually ranges from 70/30 to 50/50. Patients being treated with an intensive insulin regimen inject doses of regular insulin before meals and take single daily doses of either NPH or ultralente to provide nocturnal glycemic control. Another insulin regimen uses an external insulin p ump . The pump provides a continuous basal amount of insulin (0.5-1.0 units/hour) in addition to bolus doses with meals and snacks. The insulin of choice for external insulin pumps is a buffered insulin such as Humulin BR (Lilly), or Velosulin (Nordisk-USA). These insulins are less likely to precipitate in the insulin pump and cause blockage of insulin flow.
Table 2
Insulin Pharmacokinetics Time (hours) Insulin Type
Onset
Peak
Duration
Short-acting
0.5- 1 1- 4 4- 6
2- 4
6-8 16-24
Intermediate-acting Long-acting
6-10 18
24-36
- - - - - - - - ---_ ._--- _._----- -_.
Mixing Compatibility The insulin mixture of choice is NPH and regular. These two insulins may be mixed in any ratio with the retention of the time-action profiles of the individual constituents. Lente insulins may be mixed with other lente-type insulins with a resultant stable mixture. Lente causes a diminution of the activity of regular insulin when the two are mixed, and the combination should be consistently either injected immediately or allowed to stabilize for 24 hours before injection. Other insulin mixtures are normally not recommended. 5
~,. _,
o
2
4
6
8
"" "
-:'~~ -;-: , ~ :_;.
r-
,
10 12 14 16 18 20 22 24 Time (hours)
.Long-acting
o
Short-acting
0
Intermediate-acting
Table 3
Regimens The Americah Diabetes Association has established guidelines for glycemic control that should be followed by all practitioners (Table 3). To attain glycemic control, normal total daily insulin doses in the Type I patient range from 0.5 to 1.0 units/kg/day. A common regimen is the single daily injection of intermediate-acting insulin. This regimen probably will prevent the development of diabetic ketoacidosis, but does not offer sufficient glycemic control to prevent complications in most patients. Vol. NS32, No.8 August 1992/ 64 5
ADA Guidelines for Glycemic Control Specimen
Normal
Ranges (mgldL) Acceptable Fair
Fasting
< 115
115-140
140- 200
> 200
Postprandial
< 140
140-175
175-235
> 235
Glycosylated hemoglobin
6
8
10
> 10
Poor
AMERICANPHARMACY
Travel Precautions Patients who require insulin therapy should understand several precautions concerning travel. The availability of insulin varies from country to country. For instance, many developing countries do not have access to U-I00 insulin. Patients traveling to these areas should carry extra insulin and should understand the difference in the insulin strengths. It is also prudent for patients to carry prescription orders for insulin and insulin syringes to avoid problems in procuring these items in countries where they are more tightly controlled. Patients should be instructed to protect their insulin from extreme temperatures. Insulin may be protected from heat by placing the vial in a cooled wide-mouth thermos or in a commercially available insulin storage kit. Insulin should be transported in carry-on luggage if the patient is flying.
glyburide. They differ from the first-generation agents in potency and plasma protein binding. 8 The first-generation agents are usually administered in daily doses of 250-1,500 mg while the second-generation agents are administered in daily doses of from 2 to 40 mg. First-generation agents bind to plasma proteins ionically while second-generation agents bind nonionically. The reduced plasma concentrations and the nonionic plasma protein binding result in a lower incidence of drug interactions with the second-generation agents.
Monitoring Patients Pharmacists monitor patients for the signs and symptoms of hyperglycemia and hypoglycemia.
Oral Sulfonylureas Hyperglycemia Six sulfonylurea agents are currently available in the United States (Table 4). These agents are indicated for patients who cannot maintain acceptable glycemic control with exercise and dietary modification alone. The oral agents are contraindicated in patients with Type I diabetes, patients with a history of allergy to sulfonylureas, and patients who are pregnant or breast feeding.6 The sulfonylureas may be used in combination with insulin in the treatment of Type II patients who are refractory to treatment with insulin or sulfonylureas alone. The mechanisms of action of the sulfonylureas include improved binding of insulin to receptor sites, improved postreceptor activity, an increase in insulin secretion, and other minor mechanisms.7 These agents are generally divided into two categories: frrst and second generation. First-generation agents include tolbutamide , tolazamide , acetohexamide , and chlorpropamide. The second-generation agents are glipizide and
Table 4
Oral Sulfonylurea Agents Available in the United States • Tolbutamide-Orinase (Upjohn) and generics • Tolazamide-Tolinase (Upjohn) and generics • Chlorpropamide-Diabinese (Pfizer) and generics • Acetohexamide-Dymelor (Lilly) and generics • Glyburide-Micronase (Upjohn) and DiaBeta (Hoechst-Roussel) • Glipizide-Glucotrol (Roerig)
AMERICAN PHARMACY
The classic signs of hyperglycemia, a consequence of the disease, are polydipsia, polyuria, and polyphagia. Other signs and symptoms of hyperglycemia include blurred vision, itching, and fatigue. Hyperglycemia not only causes these acute symptoms but may lead to diabetic ketoacidosis in patients with Type I disease or hyperosmolar coma in patients with Type II disease. Chronic hyperglycemia has been linked to the complications of diabetes.
Hypoglycemia Side effects of sulfonylureas include rash, blood dyscrasias, hyponatremia, disulfiram-like reaction, and diuretic effect, but hypoglycemia is the most frequently observed side effect. Untreated hypoglycemia can result in coma, central nervous system damage, and even death. Hypoglycemia occurs every six months in about 20% of all patients being treated with these agents. Patients with multiple risk factors (for example, the elderly, patients taking multiple medications, and patients with poor eating habits) for developing hypoglycemia may experience hypoglycemia more frequently than every six months. 9 Hypoglycemia is also the most frequently observed side effect of insulin therapy. Hypoglycemia is present when a patient's blood glucose level is less than 60 mg/dL and the patient is symptomatic (Table 5). The pharmacist is in an excellent position to train the patient to recognize and treat hypoglycemia. The pharmacist can recommend glucagon emergency kits to those patients for whom they are indicated and can instruct the patient and his/her family in the treatment of hypoglycemia. Virtually every patient treated with insulin will experience hypoglycemia at some point in time. It is estimated that Au gust 199 2/646 Vol. NS32, No. 8
annually 10% of patients treated with insulin will experience severe hypoglycemia.lO Patients who have had diabetes for five or more years may lose their ability to mount a counterregulatory response (via glucagon) to hypoglycemia and are more prone to prolonged hypoglycemia (hypoglycemic unresponsiveness). Patients who have had the disease for more than 10 years may lose their ability to recognize hypoglycemia because of an inability to secrete epinephrine and cortisol in response to hypoglycemia (hypoglycemic unawareness). More frequent blood glucose monitoring is essential to the safety of patients who have lost their ability to mount a counterregulatory response. Patients treated with sulfonylurea agents who are more prone to develop hypoglycemia include the elderly, patients who consume ethanol, individuals who suffer from renal or hepatic failure, patients who miss meals, and patients requiring multiple medications. Hypoglycemic patients who are conscious should be treated with oral glucose. An initial dose of glucose of 10-15 g is effective for most patients. Examples of food sources that provide 10 g of carbohydrates are: 6 Lifesavers, 2 teaspoons of sugar, 2 BID glucose tablets, ~ cup of orange juice, or 1/3 cup of apple juice. If the patient's blood glucose level remains depressed after 15 minutes, an additional dose should be administered. If a meal is not anticipated in the following two hours, the patient should consume a snack of complex carbohydrates and protein to provide sufficient glucose until the next meal. Patients should be instructed against overtreating hypoglycemia by consuming inordinate amounts of carbohydrates. The unconscious hypoglycemic patient may be treated with either intravenous glucose or glucagon. Intravenous glucose is not practical in the home setting. Glucagon is simple to prepare and may be administered at home by the patient's
Table 5
Hypoglycemia Symptoms and T reatment Symptoms • Pale, moist skin • Nervous, excited, irritable, confused • Hunger • Headache
spouse or care giver. Glucagon is administered in doses of 0.5 mg to 1 mg. One of the major side effects of glucagon is nausea and vomiting; hence patients should be placed with their faces toward the floor to prevent aspiration in the event of emesis. Patients should be fed oral glucose as soon as they awaken. All patients who are treated with insulin and patients treated with oral agents who are prone to hypoglycemia should own a glucagon emergency kit. Unfortunately, it is estimated that only one out of 90 patients who should own these emergency kits actually do.
Conclusion Patients with diabetes can lead a normal life with careful monitoring and control of blood glucose. Insulin and sulfonylureas are valuable in the pharmacologic management of diabetes. Pharmacists playa role in ensuring optimum care by counseling and monitoring patients using these agents to manage their disease. John R. White, Jr., PharmD, is assistant professor ofpharmacy practice, College of Pharmacy, Washington State University, Spokane, Wash.
References 1. Galloway JA, Potvin JH, Shuman CR, eds. Diabetes Mellitus. 9th ed. Indianapolis: Lilly Research Laboratories, 1988. 2. Bliss M. The Discovery of Insulin. Chicago: The University of Chicago Press, 1982. 3. Koda-Kimble MA, Rotblatt MD. Diabetes mellitus. In: Young LY, KodaKimble MA, eds. Applied Therapeutics, 4th ed. Vancouver, Wash: Applied Therapeutics Inc, 1988. 4. Campbel l RK. Human insulin. Practical Diabetology. August 1988; 7:22-3. 5. Anderson JH, Campbell RK. Mixing insulins in 1990. Diabet Educator. 1990;16:380-7. 6. Campbell RK, Steil CF. Diabetes. In: Gourley DR, Hart LL, eds. Clinical Pharmacy and Therapeutics, 4th ed. Baltimore: Williams and Wilkins, 1988. 7. Marble A, Krall L, Bradley R, et al. Joslin's Diabetes Mellitus. 12th ed. Philadelphia: Lea and Febiger, 1985. 8. Gerich J. Oral hypoglycemic agents. N Engl J Med. 1989;321(18): 1231-45. 9. White JR, Campbell RK. Hypoglycemic drugs. Clin Podiatr Med Surg. 1992;9(2):239-55. 10. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989;321:1231-45.
• Breathing-normal to rapid • Tongue-moist, numb, tingling
Treatment • If patient is conscious-oral glucose . • If patient is unconscious-glucagon or intravenous glucose
Vol. NS32, No.8 August 1992/647
AMERICAN PHARMACY
Introduction Approximately 13 million people in the United States suffer from diabetes mellitus, and about one-half of these people don 't know they have the disease. It is estimated that 10%-15% of patients with diabetes mellitus have Type I or insulin-dependent diabetes mellitus (IDDM) , while 85%-90% have Type II or non-insulin-dependent diabetes mellitus (NIDDM).1
The pharmacologic management of diabetes mellitus in the United States uses either insulin or oral sulfonylurea agents or, on rare occasions, both insulin and sulfonylurea agents. All patients with Type I disease require COUNSELING PATIENTS insulin to sustain life. About WIT H one-third of patients with Type II disease are treated with insulin, a third are treated with oral agents, and the remainder are treated with diet and exercise or receive no treatment. Patients with diabetes see their pharmacist six times more frequently than they see their physicians. Pharmacists are in an excellent position to counsel, monitor, teach, refer, and in some situations treat patients with diabetes.
DIABETES
Insulin The isolation of insulin from animal pancreas glands in 1922 by Best and Banting was the fIrst major advancement in Vol. NS32, No.8 August 1992/643
the pharmacologic management of diabetes. 2 Before the discovery of insulin, no effective treatment was available for Type I disease. The discovery of insulin was one of the greatest advances of modem medicine, and its effects were at that time considered miraculous. Administration of insulin causes an attenuation of hyperglycemia and the symptoms of polydipsia, polyuria, and polyphagia; reverses diabetic coma; and causes weight gain in direly emaciated patients because it affects carbohydrate, fat, and protein metabolism. Insulin is required for the uptake of glucose into many cell types such as muscle cells. ' In the presence of insulin, free fatty acids are stored as triglycerides. Insulin also promotes the production of structural proteins. Currently, many forms of insulin are available (Table 1). Factors to consider when selecting insulins include source (beef, pork, or human), type (short-acting, intermediate-acting, or long-acting), cost, strength, mixing compatibility, and purity.
Structure and Source Insulin is a large proteinaceous molecule (51 amino acids) formed from the cleavage of proinsulin. Normal pancreatic reserves of insulin are about 200 units, with daily secretions ranging from 30 to 75 units/day in the adult. 1 Insulins available commercially in the United States include pork, beef, beef and pork mixture, and biosynthetic human. Pork and beef insulins differ from human insulin by one and three amino acids respectively. These various chemical structures result in solubility and immunologic differences. The incidence of immunologic side effects such as lipoatrophy and antibody formation is greatest with beef AMERICAN PHARMACY
- - - - - - - - - - - --- - - -- - - - -- ---
- - - - -- - - - - - - - -
--------
-
- --
Table 1
Insulin Products Available Type
Manufacturer
Strength
lIetin II Regular
Lilly
U-100
Semilente
Novo Nordisk
U-100
Brand Name
Short-ActinQ1nsulins Beef
Pork
BeefIPork
Human
lIetin II Regular
Lilly
U-100, -500
Regular
Novo Nordisk
U-100
Purified Pork Regular
Novo Nordisk
U-100
Velosulin
Novo Nordisk
U-100
lIetin I Regular
Lilly
U-100
lIetin I Semilente
Lilly
U-100
Humulin Regular
Lilly
U-100
Humulin BR
Lilly
U-100
Novolin R
Novo Nordisk
U-100
Velosulin Human R
Novo Nordisk
U-100
Int~t,.I!'~diate-Acting
19sulin
Beef
lIetin II Lente
Lilly
U-100
lIetin II NPH
Lilly
U-100
Lente
Novo Nordisk
U-100
NPH
Novo Nordisk
U-100
lIetin II Lente
Lilly
U-100
lIetin II NPH
Lilly
U-100
Purified Pork Lente
Novo Nordisk
U-100
Purified Pork NPH
Novo Nordisk
U-100
Insulatard NPH
Novo Nordisk
U-100
Pork
BeefIPork
.~
lIetin I NPH
Lilly
U-100
lIetin I Lente
Lilly
U-100
insulin and least with human insulin. 3 Human insulin is more soluble than animalderived insulin and hence has a more rapid onset and a shorter duration of action than animal-source insulin. 4
Type Insulins may be subdivided into several categories based on time-action profiles (Table 1): short-acting insulins (regular and semilente) , intermediate-acting insulins (NPH and lente), long-acting insulins (ultralente and PZI) , and insulin combinations (mixtures of NPH and regular) (Table 2). The onset of action, time to peak activity, and duration of action differ not only between the above-mentioned categories, but vary from product to product within a category. These differences underline the importance of not switching the insulin type or brand on which a patient has been stabilized. Time-action profiles of one product may vary in the same patient from day to day depending on such factors as injection site , exercise , and ambient 3 temperature.
Humulin L (Lente)
Lilly
U-100
Humulin N (NPH)
Lilly
U-100
Novolin L (Lente)
Novo Nordisk
U-100
Novolin (NPH)
Novo Nordisk
U-100
Insulatard NPH Human
Novo Nordisk
U-100
lIetin II PZI
Lilly
U-100
Ultralente
Novo Nordisk
U-100
Cost
Pork
lIetin II PZI
Lilly
U-100
BeefIPork
lIetin I PZI
Lilly
U-100
lIetin I Ultralente
Lilly
U-100
Humulin U (Ultralente)
Lilly
U-100
Novo Nordisk
U-100
The price discrepancy between human insulin and animal-source insulins is becoming less of a factor in the choice of insulins as the co st of human insulin declines in relation to animalsourc e insulins. In many instances, human insulin is less expensive than purified pork insulin. Human insulin m ay in fact be le ss costly
Human
Beef
Human
Fi~ed:Coml!!i!!!i~n I,!!!!Uns Pork
Mixtard 70/30
Human
Humulin 70/30
Lilly
U-100
Novolin 70/30
Novo Nordisk
U-100
Mixtard Human 70/30
Novo Nordisk
U-100
AMERICAN PHARMACY
August 1992/644 Vol. NS32, No . 8
than its animal-derived counterparts, because often less insulin is required. It also causes fewer immunologic side effects, w hich are expensive to diagnose and treat. 4
Purity Insulins are purified by multiple chromatographic processes. Purity of insulin is quantified by measuring proinsulin concentration. Conventional modern animal-source insulins contain less than 10 ppm of proinsulin. Semisynthetic insulin contains 1 ppm, and biosynthetic insulin contains less than 1 ppm. 1
Strength Originally, 1 unit of insulin was the amount needed to induce hypoglycemic coma in a fasting I-kg rabbit. Today, of course, insulin strength is a much more tightly controlled and regulated entity. Currently there are two strengths of insulin available in the United States- U-I00 and U-500 , which contain 100 and 500 units/mL, respectively. U-40 insulins , containing 40 units/mL, were discontinued in December 1991. This reduction in the number of insulin strengths should reduce the number of medication errors involving insulin. U-500 is available by prescription only and must be special ordered from Eli Lilly and Company. The use of U-500 insulin is reserved for patients with insulin resistance and is usually used only in patients requiring greater than 200 units/day of insulin.
Many patients are treated with two daily injections of a mixture of NPH and regular insulin. Patients being treated with this regimen typically take two-thirds of the total daily dose in the morning and one-third in the evening. The ratio of NPH/regular varies based on the patients' needs, but it usually ranges from 70/30 to 50/50. Patients being treated with an intensive insulin regimen inject doses of regular insulin before meals and take single daily doses of either NPH or ultralente to provide nocturnal glycemic control. Another insulin regimen uses an external insulin p ump . The pump provides a continuous basal amount of insulin (0.5-1.0 units/hour) in addition to bolus doses with meals and snacks. The insulin of choice for external insulin pumps is a buffered insulin such as Humulin BR (Lilly), or Velosulin (Nordisk-USA). These insulins are less likely to precipitate in the insulin pump and cause blockage of insulin flow.
Table 2
Insulin Pharmacokinetics Time (hours) Insulin Type
Onset
Peak
Duration
Short-acting
0.5- 1 1- 4 4- 6
2- 4
6-8 16-24
Intermediate-acting Long-acting
6-10 18
24-36
- - - - - - - - ---_ ._--- _._----- -_.
Mixing Compatibility The insulin mixture of choice is NPH and regular. These two insulins may be mixed in any ratio with the retention of the time-action profiles of the individual constituents. Lente insulins may be mixed with other lente-type insulins with a resultant stable mixture. Lente causes a diminution of the activity of regular insulin when the two are mixed, and the combination should be consistently either injected immediately or allowed to stabilize for 24 hours before injection. Other insulin mixtures are normally not recommended. 5
~,. _,
o
2
4
6
8
"" "
-:'~~ -;-: , ~ :_;.
r-
,
10 12 14 16 18 20 22 24 Time (hours)
.Long-acting
o
Short-acting
0
Intermediate-acting
Table 3
Regimens The Americah Diabetes Association has established guidelines for glycemic control that should be followed by all practitioners (Table 3). To attain glycemic control, normal total daily insulin doses in the Type I patient range from 0.5 to 1.0 units/kg/day. A common regimen is the single daily injection of intermediate-acting insulin. This regimen probably will prevent the development of diabetic ketoacidosis, but does not offer sufficient glycemic control to prevent complications in most patients. Vol. NS32, No.8 August 1992/ 64 5
ADA Guidelines for Glycemic Control Specimen
Normal
Ranges (mgldL) Acceptable Fair
Fasting
< 115
115-140
140- 200
> 200
Postprandial
< 140
140-175
175-235
> 235
Glycosylated hemoglobin
6
8
10
> 10
Poor
AMERICANPHARMACY
Travel Precautions Patients who require insulin therapy should understand several precautions concerning travel. The availability of insulin varies from country to country. For instance, many developing countries do not have access to U-I00 insulin. Patients traveling to these areas should carry extra insulin and should understand the difference in the insulin strengths. It is also prudent for patients to carry prescription orders for insulin and insulin syringes to avoid problems in procuring these items in countries where they are more tightly controlled. Patients should be instructed to protect their insulin from extreme temperatures. Insulin may be protected from heat by placing the vial in a cooled wide-mouth thermos or in a commercially available insulin storage kit. Insulin should be transported in carry-on luggage if the patient is flying.
glyburide. They differ from the first-generation agents in potency and plasma protein binding. 8 The first-generation agents are usually administered in daily doses of 250-1,500 mg while the second-generation agents are administered in daily doses of from 2 to 40 mg. First-generation agents bind to plasma proteins ionically while second-generation agents bind nonionically. The reduced plasma concentrations and the nonionic plasma protein binding result in a lower incidence of drug interactions with the second-generation agents.
Monitoring Patients Pharmacists monitor patients for the signs and symptoms of hyperglycemia and hypoglycemia.
Oral Sulfonylureas Hyperglycemia Six sulfonylurea agents are currently available in the United States (Table 4). These agents are indicated for patients who cannot maintain acceptable glycemic control with exercise and dietary modification alone. The oral agents are contraindicated in patients with Type I diabetes, patients with a history of allergy to sulfonylureas, and patients who are pregnant or breast feeding.6 The sulfonylureas may be used in combination with insulin in the treatment of Type II patients who are refractory to treatment with insulin or sulfonylureas alone. The mechanisms of action of the sulfonylureas include improved binding of insulin to receptor sites, improved postreceptor activity, an increase in insulin secretion, and other minor mechanisms.7 These agents are generally divided into two categories: frrst and second generation. First-generation agents include tolbutamide , tolazamide , acetohexamide , and chlorpropamide. The second-generation agents are glipizide and
Table 4
Oral Sulfonylurea Agents Available in the United States • Tolbutamide-Orinase (Upjohn) and generics • Tolazamide-Tolinase (Upjohn) and generics • Chlorpropamide-Diabinese (Pfizer) and generics • Acetohexamide-Dymelor (Lilly) and generics • Glyburide-Micronase (Upjohn) and DiaBeta (Hoechst-Roussel) • Glipizide-Glucotrol (Roerig)
AMERICAN PHARMACY
The classic signs of hyperglycemia, a consequence of the disease, are polydipsia, polyuria, and polyphagia. Other signs and symptoms of hyperglycemia include blurred vision, itching, and fatigue. Hyperglycemia not only causes these acute symptoms but may lead to diabetic ketoacidosis in patients with Type I disease or hyperosmolar coma in patients with Type II disease. Chronic hyperglycemia has been linked to the complications of diabetes.
Hypoglycemia Side effects of sulfonylureas include rash, blood dyscrasias, hyponatremia, disulfiram-like reaction, and diuretic effect, but hypoglycemia is the most frequently observed side effect. Untreated hypoglycemia can result in coma, central nervous system damage, and even death. Hypoglycemia occurs every six months in about 20% of all patients being treated with these agents. Patients with multiple risk factors (for example, the elderly, patients taking multiple medications, and patients with poor eating habits) for developing hypoglycemia may experience hypoglycemia more frequently than every six months. 9 Hypoglycemia is also the most frequently observed side effect of insulin therapy. Hypoglycemia is present when a patient's blood glucose level is less than 60 mg/dL and the patient is symptomatic (Table 5). The pharmacist is in an excellent position to train the patient to recognize and treat hypoglycemia. The pharmacist can recommend glucagon emergency kits to those patients for whom they are indicated and can instruct the patient and his/her family in the treatment of hypoglycemia. Virtually every patient treated with insulin will experience hypoglycemia at some point in time. It is estimated that Au gust 199 2/646 Vol. NS32, No. 8
annually 10% of patients treated with insulin will experience severe hypoglycemia.lO Patients who have had diabetes for five or more years may lose their ability to mount a counterregulatory response (via glucagon) to hypoglycemia and are more prone to prolonged hypoglycemia (hypoglycemic unresponsiveness). Patients who have had the disease for more than 10 years may lose their ability to recognize hypoglycemia because of an inability to secrete epinephrine and cortisol in response to hypoglycemia (hypoglycemic unawareness). More frequent blood glucose monitoring is essential to the safety of patients who have lost their ability to mount a counterregulatory response. Patients treated with sulfonylurea agents who are more prone to develop hypoglycemia include the elderly, patients who consume ethanol, individuals who suffer from renal or hepatic failure, patients who miss meals, and patients requiring multiple medications. Hypoglycemic patients who are conscious should be treated with oral glucose. An initial dose of glucose of 10-15 g is effective for most patients. Examples of food sources that provide 10 g of carbohydrates are: 6 Lifesavers, 2 teaspoons of sugar, 2 BID glucose tablets, ~ cup of orange juice, or 1/3 cup of apple juice. If the patient's blood glucose level remains depressed after 15 minutes, an additional dose should be administered. If a meal is not anticipated in the following two hours, the patient should consume a snack of complex carbohydrates and protein to provide sufficient glucose until the next meal. Patients should be instructed against overtreating hypoglycemia by consuming inordinate amounts of carbohydrates. The unconscious hypoglycemic patient may be treated with either intravenous glucose or glucagon. Intravenous glucose is not practical in the home setting. Glucagon is simple to prepare and may be administered at home by the patient's
Table 5
Hypoglycemia Symptoms and T reatment Symptoms • Pale, moist skin • Nervous, excited, irritable, confused • Hunger • Headache
spouse or care giver. Glucagon is administered in doses of 0.5 mg to 1 mg. One of the major side effects of glucagon is nausea and vomiting; hence patients should be placed with their faces toward the floor to prevent aspiration in the event of emesis. Patients should be fed oral glucose as soon as they awaken. All patients who are treated with insulin and patients treated with oral agents who are prone to hypoglycemia should own a glucagon emergency kit. Unfortunately, it is estimated that only one out of 90 patients who should own these emergency kits actually do.
Conclusion Patients with diabetes can lead a normal life with careful monitoring and control of blood glucose. Insulin and sulfonylureas are valuable in the pharmacologic management of diabetes. Pharmacists playa role in ensuring optimum care by counseling and monitoring patients using these agents to manage their disease. John R. White, Jr., PharmD, is assistant professor ofpharmacy practice, College of Pharmacy, Washington State University, Spokane, Wash.
References 1. Galloway JA, Potvin JH, Shuman CR, eds. Diabetes Mellitus. 9th ed. Indianapolis: Lilly Research Laboratories, 1988. 2. Bliss M. The Discovery of Insulin. Chicago: The University of Chicago Press, 1982. 3. Koda-Kimble MA, Rotblatt MD. Diabetes mellitus. In: Young LY, KodaKimble MA, eds. Applied Therapeutics, 4th ed. Vancouver, Wash: Applied Therapeutics Inc, 1988. 4. Campbel l RK. Human insulin. Practical Diabetology. August 1988; 7:22-3. 5. Anderson JH, Campbell RK. Mixing insulins in 1990. Diabet Educator. 1990;16:380-7. 6. Campbell RK, Steil CF. Diabetes. In: Gourley DR, Hart LL, eds. Clinical Pharmacy and Therapeutics, 4th ed. Baltimore: Williams and Wilkins, 1988. 7. Marble A, Krall L, Bradley R, et al. Joslin's Diabetes Mellitus. 12th ed. Philadelphia: Lea and Febiger, 1985. 8. Gerich J. Oral hypoglycemic agents. N Engl J Med. 1989;321(18): 1231-45. 9. White JR, Campbell RK. Hypoglycemic drugs. Clin Podiatr Med Surg. 1992;9(2):239-55. 10. Gerich JE. Oral hypoglycemic agents. N Engl J Med. 1989;321:1231-45.
• Breathing-normal to rapid • Tongue-moist, numb, tingling
Treatment • If patient is conscious-oral glucose . • If patient is unconscious-glucagon or intravenous glucose
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