LEVEMIR FLEXPEN

Indications

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus
• Diabetes management requiring basal insulin therapy

Mechanism of action

Insulin detemir binds to the insulin receptor (IR), which consists 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 of the receptor and phosphorylation of intracellular substrates such as insulin receptor substrates (IRS) proteins. This activation cascade influences downstream signalling molecules like PI3 kinase and Akt. Akt plays a crucial role in regulating glucose transporter 4 (GLUT4), thus facilitating glucose uptake by tissues and promoting energy storage. The long duration of action of insulin detemir is attributed to its slow absorption from the injection site and high binding affinity to serum albumin, which prolongs its distribution to target tissues.

Pharmacodynamics

Insulin detemir functions as a synthetic analogue of human insulin, facilitating the cellular uptake of glucose in muscle and adipose tissues. It promotes glycogenesis, opposes catabolism of energy stores, and enhances protein synthesis by stimulating amino acid uptake in various tissues. The drug also plays a role in growth promotion and is essential for the metabolic actions of growth hormone. Insulin detemir provides a flat and predictable action profile, with an onset of action within 1 to 2 hours and a duration of up to 24 hours, making it effective for maintaining basal insulin levels in diabetic patients.

Pharmacokinetics

Insulin detemir exhibits slow absorption following subcutaneous administration, with a prolonged duration of action due to its high affinity for serum albumin. The drug's pharmacokinetic profile supports a sustained release of insulin into the bloodstream, achieving steady-state levels that can last up to 24 hours. The myristic acid side chain enhances self-association and binding to albumin, further contributing to its extended action compared to regular insulin formulations.

Contra-indications

• Hypoglycaemia
• Hypersensitivity to insulin detemir or any of its excipients

Adverse effects

• Hypoglycaemia
• Injection site reactions (e.g. redness, swelling, itching)
• Weight gain
• Lipodystrophy (abnormal distribution of fat)
• Allergic reactions (rare)

Interactions

• Certain medications (e.g. corticosteroids, diuretics, thyroid hormones) may affect insulin requirements
• Alcohol can enhance the risk of hypoglycaemia

Precautions

• Monitor blood glucose levels regularly
• Adjust doses during periods of stress, illness, or changes in activity
• Caution in patients with renal or hepatic impairment

Pregnancy

Insulin detemir may be used during pregnancy if needed, as insulin is the preferred treatment for diabetes in pregnancy.

Breast-feeding

Insulin detemir can be used during breastfeeding, as it is not expected to harm a nursing infant.

Storage

Store at 2 to 8 degrees Celsius. Do not freeze. Once in use, it may be stored at room temperature (up to 25 degrees Celsius) for up to 6 weeks.

Formulations

• Injection solution in vials
• Pre-filled pen devices

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 detemir 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 signalling 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. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slow its distribution into target tissues and prolong its duration of action.

Pharmacodynamics

Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin following meals. Increased insulin secretion following meals is 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 the 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 detemir is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin.

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.