© 2003-17 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D. Published by
Elephant Care International
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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 highly recommended 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 cells of the pancreatic islets. It has an approximate molecular weight of 6000 daltons. Insulin is measured 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 are species variations of insulin, with different amino acids found at positions 8, 9, & 10 of the A chain and position 30 of the B chain. Dog and cat insulin are thought to more closely resemble porcine insulin, rather than beef insulin. There are two basic purity grades of insulin available from bovine and porcine sources. Single-peak insulins contain not more than 25 parts per million (ppm) of proinsulin. 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 for commercial uses from the pancreases of pigs and/or cattle at slaughter. The insulin is prepared by precipitating the insulin with zinc chloride, forming zinc insulin crystals. The commercially available solutions have a pH of 7 – 7.8.
Isophane insulin , more commonly known as NPH insulin , occurs as a sterile suspension of zinc insulin crystals and protamine zinc in buffered water for injection. It is a cloudy or milky suspension with a pH of 7.1-7.4. NPH insulin is an abbreviation for neutral protamine Hagedorn insulin .
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 be stored 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. Temperature extremes should be avoided; do not freeze. Do not use regular insulin that is turbid, discolored or has 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 100 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 closely monitored, the problem may be overstated. Difficulties in determining subsequent SQ doses using the quantities of insulin required during intravenous therapy may occur, however.
Regular insulin is reportedly compatible with following drugs/solutions: normal saline, TPN solutions (4% amino acids, 25% dextrose with electrolytes & vitamins; must occasionally shake bag to prevent separation), bretylium tosylate, cimetidine HCl, lidocaine HCl, oxytetracycline HCl and 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, pentobarbital sodium, 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 for more 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 of regular 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 is responsible for the proper usage of glucose and other metabolic fuels by cells in the normal metabolic processes. After binding to specific receptors of target cells, the insulin-receptor complex is thought to activate a membrane protease that catalyzes a peptide mediator(s) that affects certain intracellular enzymes.
Insulin affects primarily liver, muscle and adipose tissues. In the liver, insulin decreases glycogenolysis, gluconeogenesis, ketogenesis, and increases glycogen synthesis and fatty acid synthesis. In muscle, insulin decreases protein catabolism and amino acid output, and increases amino acid uptake, protein synthesis and glycogen synthesis. In adipose tissue, insulin decreases lipolysis and increases glycerol and fatty acid synthesis.
Uses/Indications – Insulin preparations have been used for the adjunctive treatment of diabetic ketoacidosis, uncomplicated diabetes mellitus and as adjunctive therapy in treating hyperkalemia. Insulin treatment in veterinary species has been primarily in dogs and cats. Experience in using insulin in large animals is rather limited.
Pharmacokinetics – In dogs and cats, regular insulin’s effects are continuous when infused at low dosages intravenously, but effects tend to cease immediately when the infusion is stopped. After IM or IV bolus injection, the duration of action is only 2-4 hours. After subcutaneous injection, regular insulin’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 PZI peak between 5-20 hours after dosing and persist for up to 30 hours. The majority of dogs receiving PZI injections can be adequately controlled with once daily administration. The onset of effect after SQ injection of NPH insulin may be immediate or take up to 3 hours. NPH peaks generally 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 in 4-10 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 injections for 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 good control.
Contraindications/Precautions – Because there are no alternatives for insulin when it is used for diabetic 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 species of insulin should be tried. Insulin derived from swine is closest in structure to canine insulin and is thought 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 (see overdosage 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 may include 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 symptoms should be treated with oral dextrose solutions (e.g., Karo® syrup) rubbed on the oral mucosa or by intravenous injections of 50% dextrose solutions. Should the animal be convulsing, fluids should not be forced orally nor fingers placed in the animal’s mouth. Once the animal’s hypoglycemia is alleviated, it should be closely monitored (both by physical observation and serial blood glucose levels) to prevent a recurrence of hypoglycemia (especially with the slower absorbed products) and also to prevent hyperglycemia from developing. Future insulin dosages or feeding habits should be adjusted 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.g propranolol), 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 also receiving concurrent diuretic therapy.
Note: The reader is strongly encouraged to refer to the original referenced materials for the doses below, for more thorough discussions on the treatment of diabetes.
For diabetes mellitus:
a) True diabetes mellitus rarely occurs in horses. Most cases are a result of pituitary tumors that cause hyperglycemia secondary to excessive ACTH or Growth Hormone. A case is cited where an animal received 0.5 – 1.0 Unit/kg of PZI insulin and the hyperglycemia was controlled. Patients with hyperglycemia secondary to a pituitary tumor are apparently insulin-resistant. (Merritt 1987)
b) PZI insulin 0.15 U/kg IM or SQ bid (Robinson 1987)
Monitoring Parameters – 1) Blood glucose; 2) Patient weight, appetite, fluid intake/output; 3) Blood, urine ketones (if warranted); 4) Glycosylated hemoglobin (if available and warranted)
Client Information – Keep insulin products away from temperature extremes. If stored in the refrigerator, allow to come to room temperature in syringe before injecting.
Clients must be instructed in proper techniques for withdrawing insulin into the syringe, including rolling the vial, not shaking before withdrawing into syringe, and to use the proper syringe size with insulin concentration (e.g., don’t use U-40 insulin with U-100 syringes). Proper injection techniques should be taught and practiced with the client before the animal’s discharge. The symptoms of hypoglycemia should be thoroughly reviewed with the owner. A written protocol outlining monitoring procedures and treatment steps for hypoglycemia should be also be sent home with the owner.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times – All products except 500 U/ml insulin are available without prescription.
Veterinary-Approved Products: None
Human-Approved Products (partial listing):
Insulin Injection, Regular
From pork sources; 100 Units/ml
Regular Insulin (Novo-Nordisk)
Regular Purified Pork insulin (Novo-Nordisk); Pork Regular Iletin II (Lilly)
Human (either rDNA or semi-synthetic) insulin:
Humulin® R (Lilly); Novolin® R (Novo-Nordisk), Velosulin® Human (Novo-Nordisk)
Insulin, Isophane Suspension (NPH)
From beef sources; 100 Units/ml
Insulin, NPH (Novo-Nordisk)
From pork sources (purified); 100 Units/ml
Iletin® II, NPH Purified Pork (Lilly), NPH-N® (Novo-Nordisk)
Human (either rDNA or semi-synthetic) insulin:
Humulin® N, (Lilly); Novolin® N (Novo-Nordisk),
Insulin, Zinc Suspension, Extended (Ultralente)
From rDNA Human sources; 100 Units/ml
Humulin® U Ultralente (Lilly)
Other insulins that are commercially available, but have not been used extensively in veterinary patients, include: Insulin Zinc (Lente) , and fixed dose combination products containing regular insulin and isophane insulin (NPH).