NovoRapid Flexpen

Indications

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus

Dosage

Adults: The dosage of insulin aspart must be

Mechanism of action

Insulin aspart binds to the insulin receptor (IR), a heterotetrameric protein composed of two extracellular alpha units and two transmembrane beta units. This binding stimulates the intrinsic tyrosine kinase activity of the beta subunit, leading to autophosphorylation and subsequent phosphorylation of various intracellular substrates, including insulin receptor substrates (IRS) and others. This cascade activates downstream signaling molecules such as PI3 kinase and Akt, which play critical roles in glucose metabolism and cellular uptake. The modification of the proline residue at B28 to aspartic acid reduces hexamer formation, resulting in a quicker absorption rate and faster action onset.

Pharmacodynamics

Insulin is a natural hormone secreted by pancreatic beta cells, responsible for maintaining glucose homeostasis. In non-diabetic individuals, insulin is released in a basal pattern with spikes post-meal. It facilitates glucose uptake in muscle and adipose tissues, promotes glycogen storage, inhibits the breakdown of energy stores, and stimulates protein synthesis and DNA replication. Insulin is also essential for the anabolic effects of growth hormone. Insulin aspart serves to replicate these physiological insulin responses, particularly postprandially, with a rapid onset of action and a peak effect occurring 60-90 minutes after administration.

Pharmacokinetics

Insulin aspart demonstrates a rapid onset of action, typically within 10-15 minutes after subcutaneous injection. Its peak effect occurs 60-90 minutes post-injection, with a duration of action lasting approximately 4-5 hours. The pharmacokinetics are influenced by factors such as the injection site and blood flow to the area. As a rapid-acting insulin analogue, it is designed for immediate use around mealtime, allowing for flexible dosing according to meal times.

Contra-indications

• Hypersensitivity to insulin aspart or any of its excipients
• Severe hypoglycaemia
• Diabetic ketoacidosis

Adverse effects

• Hypoglycaemia
• Weight gain
• Injection site reactions
• Allergic reactions
• Lipodystrophy

Interactions

• Beta-blockers may mask the symptoms of hypoglycaemia
• Thiazide diuretics may increase blood glucose levels
• Corticosteroids may increase insulin requirements
• Alcohol may potentiate or diminish the hypoglycaemic effect

Precautions

• Monitor blood glucose levels regularly
• Adjust dose carefully in patients with renal or hepatic impairment
• Use with caution in patients with a history of allergic reactions to insulin
• Educate patients regarding signs and symptoms of hypoglycaemia

Pregnancy

Insulin aspart can be used during pregnancy, but careful monitoring of blood glucose levels is essential. The dosage may need adjustment.

Breast-feeding

Insulin aspart is compatible with breastfeeding. Insulin does not pass into breast milk in significant amounts.

Storage

Store in a refrigerator (2-8°C). Do not freeze. Once in use, can be kept at room temperature (below 30°C) for up to 28 days.

Formulations

• Injection solution
• Pen fill cartridges
• Pre-filled pens

Indications

• Diabetes mellitus (type 1 and type 2)
• Diabetic ketoacidosis
• Hyperglycemia due to other conditions
• Management of blood glucose levels during surgery
• Continuous subcutaneous insulin infusion therapy

Dosage

Children: For children aged 1-17 years, insulin is administered immediately before meals or when necessary shortly after meals, according to individual requirements. Specific dosing should be determined based on blood glucose monitoring and should be referred to the BNF for Children for precise guidance.

Adults: The dosage of insulin varies based on individual needs and is typically guided by blood glucose monitoring. It is recommended to consult local protocols for specific dosing instructions.

Mechanism of action

Insulin has a direct inhibitory effect on lipase, which is involved in the mobilization of fatty acids. In the absence of insulin, there is an abnormally high rate of conversion of protein to glucose, primarily in the liver. Insulin stimulates glycogen synthesis and enhances facilitated diffusion of glucose and the active transport of amino acids, although the exact mechanisms for these actions are not fully understood.

Pharmacodynamics

Insulin's primary pharmacodynamic effect is the reduction of blood glucose levels. It promotes the uptake of glucose by cells, increases glycogen synthesis in the liver, and inhibits gluconeogenesis. Insulin also influences lipid metabolism by inhibiting lipolysis and encouraging fat storage. Additionally, insulin enhances protein synthesis by promoting amino acid uptake into cells.

Pharmacokinetics

Insulin is administered by injection and is rapidly absorbed into the bloodstream. Its onset, peak, and duration of action depend on the formulation used (e.g., rapid-acting, short-acting). The half-life of insulin is typically around 5 to 10 minutes, but its effects can last several hours depending on the formulation. It is metabolized primarily in the liver and kidneys.

Contra-indications

• Hypersensitivity to insulin or any of its excipients
• Hypoglycemia

Adverse effects

• Hypoglycemia
• Injection site reactions
• Weight gain
• Allergic reactions
• Edema
• Lipodystrophy

Interactions

• Metreleptin may increase the risk of hypoglycemia when used with insulin
• Fibrates may increase the risk of hypoglycemia when used with insulin
• Macrolides may increase the risk of severe hypoglycemia when used with insulin
• Clarithromycin may increase the risk of severe hypoglycemia when used with insulin

Precautions

• Monitor blood glucose levels regularly, especially when changing insulin preparations
• Use caution in patients with renal impairment, as insulin clearance may be reduced
• Patients should be advised about the risks of hypoglycemia and how to manage it
• Should be used with caution in patients with cardiovascular disease

Pregnancy

Insulin is generally considered safe for use during pregnancy, but dosages may need to be adjusted.

Breast-feeding

Insulin is compatible with breastfeeding; insulin does not pass into breast milk in significant amounts.

Storage

Store unopened vials or pens in a refrigerator (2-8°C). Once opened, insulin can be stored at room temperature (below 25°C) for up to 28 days, depending on the formulation.

Formulations

• Insulin human 500 units/ml solution for injection
• Insulin human 100 units/ml solution for injection
• Insulin porcine 100 units/ml solution for injection

Mechanism of action

Insulin aspart binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Substitution of the proline residue at B28 with aspartic acid reduces the tendency to form hexamers and results in a faster rate of absorption and onset of action and shorter duration of action.

Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Postprandial insulin spikes are responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin aspart is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin aspart is 10-15 minutes. Its activity peaks 60-90 minutes following subcutaneous injection and its duration of action is 4-5 hours.

Mechanism of action

INSULIN HAS DIRECT INHIBITORY EFFECT ON LIPASE CONCERNED WITH MOBILIZATION OF FATTY ACIDS, WHILE GROWTH HORMONE, GLUCOCORTICOIDS, THYROID HORMONES & CATECHOLAMINES ENHANCE LIPOLYSIS. IN ABSENCE OF INSULIN THERE IS ABNORMALLY HIGH RATE OF CONVERSION OF PROTEIN TO GLUCOSE. ... PROTEINS & AMINO ACIDS ARE CONVERTED TO GLUCOSE @ ABNORMALLY HIGH RATE IN INSULIN DEFICIENCY. THE LIVER IS SITE OF CONVERSION. PROTEIN & AMINO ACIDS ARE MOBILIZED FROM PERIPHERAL TISSUES. INSULIN ACTS TO.../STIMULATE/ GLYCOGEN SYNTHESIS. MECHANISM OF IMPORTANT ACTIONS OF INSULIN TO ENHANCE FACILITATED DIFFUSION OF GLUCOSE & ACTIVE TRANSPORT OF AMINO ACIDS ARE NOT KNOWN.