A vial of NPH insulin with insulin syringe
|Trade names||Novolin N, Humulin N, others|
|Synonyms||Neutral protamine Hagedorn insulin,|
protamine zinc insulin (slightly different),
compound insulin zinc suspension (slightly different),
|Onset of action||90 minutes|
|Duration of action||24 hours|
NPH insulin, also known as isophane insulin, is an intermediate–acting insulin given to help control blood sugar levels in people with diabetes. It is used by injection under the skin once to twice a day. Onset of effects is typically in 90 minutes and they last for 24 hours. Versions are available that come premixed with a short–acting insulin, such as regular insulin.
The common side effect is low blood sugar. Other side effects may include pain or skin changes at the sites of injection, low blood potassium, and allergic reactions. Use during pregnancy is relatively safe for the baby. NPH insulin is made by mixing regular insulin and protamine in exact proportions with zinc and phenol such that a neutral-pH is maintained and crystals form. There are human and pig insulin based versions.
Protamine insulin was first created in 1936 and NPH insulin in 1946. It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system. The wholesale cost in the developing world is about US$2.23–10.35 per 1,000 iu of NPH insulin. In the United Kingdom 1,000 iu of NPH insulin costs the NHS 7.48 pounds while in the United States this amount costs about US$134.00.
NPH insulin is cloudy and has an onset of 1–4 hours. Its peak is 6–10 hours and its duration is about 10–16 hours.
Hans Christian Hagedorn (1888–1971) and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in Toronto, Canada. In 1923 they formed Nordisk Insulin laboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charter as a non-profit foundation.
In 1936, Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or semen of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection. University of Toronto, Canada later licensed protamine zinc insulin (PZI), to several manufacturers. This mixture only needed to be shaken before injection. The effects of PZI lasted for 24–36 h.
In 1946, Nordisk was able to form crystals of protamine and insulin and marketed it in 1950 as NPH insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to complement its longer lasting action, which is the primary reason NPH remains on the market today, because manufacturers sell a variety of premixed insulin formulations.
Eventually all animal insulins made by Novo Nordisk were replaced by synthetic, recombinant 'human' insulin. Synthetic 'human' insulin is also complexed with protamine to form NPH.
NPH insulin may be combined with faster acting insulin to allow more accurate dosing and better blood sugar level control. When administered this way, the two insulin types will normally be combined in the same syringe. NPH and fast-acting insulin bind when mixed, so they should not be combined until it is time to inject. People are instructed on the proper procedure to prepare this type of injection to minimize the likelihood of combining two types of insulin in the same vial. The proper order for withdrawing NPH insulin and fast-acting insulin into the same syringe can be remembered by the mnemonic "clear before cloudy", or fast acting clear insulin first, followed by NPH (cloudy). Aspiration, or pulling back on the plunger of the syringe after the needle has been injected to check for blood, is not appropriate for subcutaneous injections.
- 1926 Nordisk receives Danish charter to produce insulin
- 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
- 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to Novo
- 1946 Nordisk crystallizes a protamine and insulin mixture
- 1950 Nordisk markets NPH insulin
- 1953 Nordisk markets "Lente" zinc insulin mixtures.
NPH stands for neutral protamine Hagedorn, and the words refer to neutral pH (pH = 7), protamine (a protein), and Hans Christian Hagedorn (an insulin researcher).
Brand names include Humulin N, Novolin N, Novolin NPH, Gensulin N, SciLin N, Insulatard, and NPH Iletin II.
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