INSULIN INJECTION, REGULAR, INSULIN, ISOPHANE SUSPENSION (NPH), INSULIN, PROTAMINE ZINC SUSPENSION (PZI), INSULIN, ZINC SUSPENSION, EXTENDED (ULTRALENTE)
Note: Insulin preparations available to the practitioner are in a constant state of change. It is highlyrecommended to review current references or sources of information pertaining to insulin therapy for dogs and cats, to maximize efficacy of therapy and reduce chances of errors.
Chemistry - Insulin is a 2 chained hormone linked by disulfide linkages secreted by the beta cellsof the pancreatic islets. It has an approximate molecular weight of 6000 daltons. Insulin ismeasured in Units/ml; one International Unit (IU) is equivalent to 0.04167 mg of the 4th
International Standard (a mixture containing 52% beef insulin and 48% pork insulin). There arespecies variations of insulin, with different amino acids found at positions 8, 9, & 10 of the A chainand position 30 of the B chain. Dog and cat insulin are thought to more closely resemble porcineinsulin, rather than beef insulin. There are two basic purity grades of insulin available from bovineand porcine sources. Single-peak insulins contain not more than 25 parts per million (ppm) ofproinsulin. Purified insulins contain not more than 10 parts per million (ppm) of proinsulin.
Regular insulin, also known as crystalline zinc insulin or unmodified insulin, is obtained forcommercial uses from the pancreases of pigs and/or cat le at slaughter. The insulin is prepared byprecipitating the insulin with zinc chloride, forming zinc insulin crystals. The commercially availablesolutions have a pH of 7 - 7.8.
Isophane insulin, more commonly known as NPH insulin, occurs as a sterile suspension ofzinc insulin crystals and protamine zinc in buffered water for injection. It is a cloudy or milkysuspension with a pH of 7.1-7.4. NPH insulin is an abbreviation for neutral protamine Hagedorninsulin.
Protamine zinc insulin (PZI) occurs as a sterile suspension of insulin modified by the addition of protamine sulfate and zinc chloride in buffered water for injection. It is cloudy or milky suspension with a pH of 7.1-7.4.
IU/liter are used intravenously. Flushing the IV set before administering may allow a more consistent delivery of insulin to the patient. Since IV insulin is given to effect and patients are closelymonitored, the problem may be overstated. Difficulties in determining subsequent SQ doses usingthe quantities of insulin required during intravenous therapy may occur, however.
Regular insulin is reportedly compatible with following drugs/solutions: normal saline, TPNsolutions (4% amino acids, 25% dextrose with electrolytes & vitamins; must occasionally shakebag to prevent separation), bretylium tosylate, cimetidine HCl, lidocaine HCl, oxytetracycline HCland verapamil HCl. Regular insulin may also be mixed with other insulin products (e.g., NPH, PZI, etc.).
Regular insulin is reportedly incompatible with the following drugs/solutions: aminophylline, amobarbital sodium, chlorothiazide sodium, dobutamine HCl, nitrofurantoin sodium, pentobarbitalsodium, phenobarbital sodium, phenytoin sodium, secobarbital sodium, sodium bicarbonate, sulfisoxizole sodium, and thiopental sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references formore specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).
NPH insulin and Protamine zinc insulin (PZI) should be stored in a manner similar to that ofregular insulin (see above). Freezing may cause improper resuspension of the particles with resultant improper dosing; do not use if solution is clear or if the particles appear clumped or granular.
Insulin affects primarily liver, muscle and adipose tissues. In the liver, insulin decreasesglycogenolysis, gluconeogenesis, ketogenesis, and increases glycogen synthesis and fatty acidsynthesis. In muscle, insulin decreases protein catabolism and amino acid output, and increasesamino acid uptake, protein synthesis and glycogen synthesis. In adipose tissue, insulin decreaseslipolysis and increases glycerol and fatty acid synthesis.
Uses, Indications - Insulin preparations have been used for the adjunctive treatment of diabeticketoacidosis, uncomplicated diabetes mellitus and as adjunctive therapy in treating hyperkalemia.
Insulin treatment in veterinary species has been primarily in dogs and cats. Experience in usinginsulin in large animals is rather limited.
In dogs, PZI insulin may take from 1-4 hours for onset of action to take place. The effects of PZIpeak between 5-20 hours after dosing and persist for up to 30 hours. The majority of dogsreceiving PZI injections can be adequately controlled with once daily administration. The onset ofeffect after SQ injection of NPH insulin may be immediate or take up to 3 hours. NPH peaksgenerally 2-10 hours after injection and its effects may persist for up to 24 hours. Most dogs require twice daily injections for optimal control, however.
In cats, PZI insulin will begin to lower blood glucose in about 1-3 hours and has its peak effects in4-10 hours after injection. The duration of action of PZI in cats may be from 12-30 hours.
Because of the variability of PZI's duration in cats, some animals may require twice daily injectionsfor optimal control. NPH insulin peaks sooner (1.5-6 hours) and has a shorter duration of action(4-10 hours) than PZI. Nearly all cats will require twice daily administration of NPH for goodcontrol.
Contraindications/Precautions - Because there are no alternatives for insulin when it is used fordiabetic indications, there are no absolute contraindications to its use. If animals develop hypersensitivity (local or otherwise) or should insulin resistance develop, a change in type or speciesof insulin should be tried. Insulin derived from swine is closest in structure to canine insulin and isthought to be closer to feline insulin, than is insulin derived from bovine sources.
Do not inject insulin at the same site day after day or lipodystrophic reactions can occur.
Overdosage - Overdosage of insulin can lead to various degrees of hypoglycemia. Symptoms mayinclude weakness, shaking, head tilting, lethargy, ataxia, seizures and coma. Prolonged hypoglycemia can result in permanent brain damage or death.
Mild hypoglycemia may be treated by offering the animal its usual food. More serious symptomsshould be treated with oral dextrose solutions (e.g., Karo® syrup) rubbed on the oral mucosa or byintravenous injections of 50% dextrose solutions. Should the animal be convulsing, fluids shouldnot be forced orally nor fingers placed in the animal's mouth. Once the animal's hypoglycemia isalleviated, it should be closely monitored (both by physical observation and serial blood glucoselevels) to prevent a recurrence of hypoglycemia (especially with the slower absorbed products) andalso to prevent hyperglycemia from developing. Future insulin dosages or feeding habits should beadjusted to prevent further occurrences of hypoglycemia.
The following drugs may decrease the hypoglycemic activity of insulin: glucocorticoids, dextrothyroxine, dobutamine, epinephrine, estrogen/progesterone combinations, furosemide and thiazide diuretics. Thyroid hormones can also elevate blood glucose levels in diabetic patients when thyroid hormone therapy is first initiated.
Because insulin can alter serum potassium levels, patients receiving concomitant cardiac glycoside (e.g., digoxin) therapy should be closely monitored. This is especially true in patients alsoreceiving concurrent diuretic therapy.
Chemistry - Insulin is a 2 chained hormone linked by disulfide linkages secreted by the beta cellsof the pancreatic islets. It has an approximate molecular weight of 6000 daltons. Insulin ismeasured in Units/ml; one International Unit (IU) is equivalent to 0.04167 mg of the 4th
International Standard (a mixture containing 52% beef insulin and 48% pork insulin). There arespecies variations of insulin, with different amino acids found at positions 8, 9, & 10 of the A chainand position 30 of the B chain. Dog and cat insulin are thought to more closely resemble porcineinsulin, rather than beef insulin. There are two basic purity grades of insulin available from bovineand porcine sources. Single-peak insulins contain not more than 25 parts per million (ppm) ofproinsulin. Purified insulins contain not more than 10 parts per million (ppm) of proinsulin.
Regular insulin, also known as crystalline zinc insulin or unmodified insulin, is obtained forcommercial uses from the pancreases of pigs and/or cat le at slaughter. The insulin is prepared byprecipitating the insulin with zinc chloride, forming zinc insulin crystals. The commercially availablesolutions have a pH of 7 - 7.8.
Isophane insulin, more commonly known as NPH insulin, occurs as a sterile suspension ofzinc insulin crystals and protamine zinc in buffered water for injection. It is a cloudy or milkysuspension with a pH of 7.1-7.4. NPH insulin is an abbreviation for neutral protamine Hagedorninsulin.
Protamine zinc insulin (PZI) occurs as a sterile suspension of insulin modified by the addition of protamine sulfate and zinc chloride in buffered water for injection. It is cloudy or milky suspension with a pH of 7.1-7.4.
Storage, Stability, Compatibility
Regular insulin is recommended by the manufacturers to bestored in the original container at refrigerated temperatures (2 - 8°C), but the new neutral formulations have been demonstrated to be stable at room temperature for 24-30 months. Temperatureextremes should be avoided; do not freeze. Do not use regular insulin that is turbid, discolored orhas an alteration in viscosity. Regular insulin has been shown to adsorb to the surface of IV bottles/bags and tubing. This may be of greater importance when concentrations of less than 100IU/liter are used intravenously. Flushing the IV set before administering may allow a more consistent delivery of insulin to the patient. Since IV insulin is given to effect and patients are closelymonitored, the problem may be overstated. Difficulties in determining subsequent SQ doses usingthe quantities of insulin required during intravenous therapy may occur, however.
Regular insulin is reportedly compatible with following drugs/solutions: normal saline, TPNsolutions (4% amino acids, 25% dextrose with electrolytes & vitamins; must occasionally shakebag to prevent separation), bretylium tosylate, cimetidine HCl, lidocaine HCl, oxytetracycline HCland verapamil HCl. Regular insulin may also be mixed with other insulin products (e.g., NPH, PZI, etc.).
Regular insulin is reportedly incompatible with the following drugs/solutions: aminophylline, amobarbital sodium, chlorothiazide sodium, dobutamine HCl, nitrofurantoin sodium, pentobarbitalsodium, phenobarbital sodium, phenytoin sodium, secobarbital sodium, sodium bicarbonate, sulfisoxizole sodium, and thiopental sodium. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references formore specific information (e.g., Handbook on Injectable Drugs by Trissel; see bibliography).
NPH insulin and Protamine zinc insulin (PZI) should be stored in a manner similar to that ofregular insulin (see above). Freezing may cause improper resuspension of the particles with resultant improper dosing; do not use if solution is clear or if the particles appear clumped or granular.
Pharmacology - INSULIN INJECTION, REGULAR, INSULIN, ISOPHANE SUSPENSION (NPH), INSULIN, PROTAMINE ZINC SUSPENSION (PZI), INSULIN, ZINC SUSPENSION, EXTENDED (ULTRALENTE)
Insulin is responsible for the proper usage of glucose and other metabolic fuelsby cells in the normal metabolic processes. After binding to specific receptors of target cells, theinsulin-receptor complex is thought to activate a membrane protease that catalyzes a peptidemediator(s) that affects certain intracellular enzymes.Insulin affects primarily liver, muscle and adipose tissues. In the liver, insulin decreasesglycogenolysis, gluconeogenesis, ketogenesis, and increases glycogen synthesis and fatty acidsynthesis. In muscle, insulin decreases protein catabolism and amino acid output, and increasesamino acid uptake, protein synthesis and glycogen synthesis. In adipose tissue, insulin decreaseslipolysis and increases glycerol and fatty acid synthesis.
Uses, Indications - Insulin preparations have been used for the adjunctive treatment of diabeticketoacidosis, uncomplicated diabetes mellitus and as adjunctive therapy in treating hyperkalemia.
Insulin treatment in veterinary species has been primarily in dogs and cats. Experience in usinginsulin in large animals is rather limited.
Pharmacokinetics - INSULIN INJECTION, REGULAR, INSULIN, ISOPHANE SUSPENSION (NPH), INSULIN, PROTAMINE ZINC SUSPENSION (PZI), INSULIN, ZINC SUSPENSION, EXTENDED (ULTRALENTE)
In dogs and cats, regular insulin's effects are continuous when infused at lowdosages intravenously, but effects tend to cease immediately when the infusion is stopped. After IMor IV bolus injection, the duration of action is only 2-4 hours. After subcutaneous injection, regularinsulin's actions may persist for 4-6 hours.In dogs, PZI insulin may take from 1-4 hours for onset of action to take place. The effects of PZIpeak between 5-20 hours after dosing and persist for up to 30 hours. The majority of dogsreceiving PZI injections can be adequately controlled with once daily administration. The onset ofeffect after SQ injection of NPH insulin may be immediate or take up to 3 hours. NPH peaksgenerally 2-10 hours after injection and its effects may persist for up to 24 hours. Most dogs require twice daily injections for optimal control, however.
In cats, PZI insulin will begin to lower blood glucose in about 1-3 hours and has its peak effects in4-10 hours after injection. The duration of action of PZI in cats may be from 12-30 hours.
Because of the variability of PZI's duration in cats, some animals may require twice daily injectionsfor optimal control. NPH insulin peaks sooner (1.5-6 hours) and has a shorter duration of action(4-10 hours) than PZI. Nearly all cats will require twice daily administration of NPH for goodcontrol.
Contraindications/Precautions - Because there are no alternatives for insulin when it is used fordiabetic indications, there are no absolute contraindications to its use. If animals develop hypersensitivity (local or otherwise) or should insulin resistance develop, a change in type or speciesof insulin should be tried. Insulin derived from swine is closest in structure to canine insulin and isthought to be closer to feline insulin, than is insulin derived from bovine sources.
Do not inject insulin at the same site day after day or lipodystrophic reactions can occur.
Adverse Effects, Warnings
Adverse effects of insulin therapy can include, hypoglycemia (seeoverdosage below), insulin-induced hyperglycemia ("Somogyi effect"), insulin antagonism/resistance, rapid insulin metabolism, and local reactions to the "foreign" proteins.Overdosage - Overdosage of insulin can lead to various degrees of hypoglycemia. Symptoms mayinclude weakness, shaking, head tilting, lethargy, ataxia, seizures and coma. Prolonged hypoglycemia can result in permanent brain damage or death.
Mild hypoglycemia may be treated by offering the animal its usual food. More serious symptomsshould be treated with oral dextrose solutions (e.g., Karo® syrup) rubbed on the oral mucosa or byintravenous injections of 50% dextrose solutions. Should the animal be convulsing, fluids shouldnot be forced orally nor fingers placed in the animal's mouth. Once the animal's hypoglycemia isalleviated, it should be closely monitored (both by physical observation and serial blood glucoselevels) to prevent a recurrence of hypoglycemia (especially with the slower absorbed products) andalso to prevent hyperglycemia from developing. Future insulin dosages or feeding habits should beadjusted to prevent further occurrences of hypoglycemia.
Drug Interactions
The following drugs may potentiate the hypoglycemic activity of insulin:alcohol, anabolic steroids (e.g., stanozolol, boldenone, etc.), beta-adrenergic blockers (e.gpropranolol), monoamine oxidase inhibitors, guanethidine, phenylbutazone, sulfinpyrazone, tetracycline, aspirin or other salicylates.The following drugs may decrease the hypoglycemic activity of insulin: glucocorticoids, dextrothyroxine, dobutamine, epinephrine, estrogen/progesterone combinations, furosemide and thiazide diuretics. Thyroid hormones can also elevate blood glucose levels in diabetic patients when thyroid hormone therapy is first initiated.
Because insulin can alter serum potassium levels, patients receiving concomitant cardiac glycoside (e.g., digoxin) therapy should be closely monitored. This is especially true in patients alsoreceiving concurrent diuretic therapy.