HUMALOG

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

Indications

• Diabetes mellitus type 1
• Diabetes mellitus type 2
• Management of postprandial hyperglycemia

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations for pediatric patients.

Adults: Refer to the BNF for specific dosing recommendations as they may vary based on individual patient needs and blood glucose monitoring.

Mechanism of action

Insulin lispro binds to the insulin receptor (IR), which consists of two extracellular alpha units and two transmembrane beta units. The binding stimulates the tyrosine kinase activity intrinsic to the beta subunit, leading to autophosphorylation of the receptor and phosphorylation of intracellular substrates. This activation cascade affects various downstream signaling molecules, including PI3 kinase and Akt, which play crucial roles in glucose metabolism. Insulin lispro's structure allows for rapid dissociation into monomers after injection, facilitating quick absorption and action.

Pharmacodynamics

Insulin is a hormone produced by the pancreas that regulates glucose homeostasis. It promotes glucose uptake in muscle and adipose tissues, stimulates glycogenesis, and inhibits the breakdown of fats and proteins. Insulin lispro, as a rapid-acting analogue, has a fast onset of action (10-15 minutes) and peaks within 60 minutes, with a duration of action of 4-5 hours. This rapid response is essential for managing blood glucose levels during meals and mimics the physiological insulin response.

Pharmacokinetics

Following subcutaneous administration, insulin lispro is quickly absorbed due to its monomeric form, which enhances its bioavailability. The onset of action occurs within 10-15 minutes, peaking at around 60 minutes, and lasting approximately 4-5 hours. The pharmacokinetic profile allows for effective control of postprandial blood glucose levels in diabetic patients.

Contra-indications

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

Adverse effects

• Hypoglycaemia
• Injection site reactions (e.g. pain, redness, swelling)
• Weight gain
• Allergic reactions (e.g. rash, pruritus)
• Lipodystrophy at the injection site

Interactions

• Sulfonylureas may increase the risk of hypoglycaemia
• Beta-blockers may mask the signs of hypoglycaemia
• Thiazide diuretics may reduce insulin effectiveness
• Corticosteroids may increase insulin requirements

Precautions

• Monitor blood glucose levels regularly
• Adjust dosage in cases of stress, illness, or changes in physical activity
• Assess renal function, as it may affect insulin requirements
• Educate patients on the symptoms of hypoglycaemia

Pregnancy

Insulin lispro is generally considered safe to use during pregnancy. However, careful monitoring of blood glucose levels is essential, and dosage adjustments may be necessary.

Breast-feeding

Insulin lispro is compatible with breastfeeding. Insulin is not expected to be excreted in significant amounts in breast milk.

Storage

Store unopened vials or pens in the refrigerator (2-8°C). Once in use, insulin lispro can be stored at room temperature (up to 25°C) for up to 28 days. Protect from light.

Formulations

• Insulin lispro injection solution (100 units/ml)
• Insulin lispro injection pen (100 units/ml)

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.

Mechanism of action

Insulin lispro 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. Reversal of the proline and lysine residues at positions B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers. Hexamers of insulin lispro are produced in the presence of zinc and <i>m</i>-cresol. These weakly associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting properties.

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. 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 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 lispro is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin lispro is 10-15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 4-5 hours. Compared to regular human insulin, insulin lispro has a more rapid onset of action and a shorter duration of action. Insulin lispro is also shown to be equipotent to human insulin on a molar basis. Insulin lispro has been shown to be equipotent to human insulin on a molar basis. One unit of insulin lispro has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that insulin lispro has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. The pharmacodynamics of a single 20 unit dose of insulin lispro at 200 units/mL (HUMALOG U-200) administered subcutaneously were compared to the pharmacodynamics of a single 20 unit dose of insulin lispro at 100 units/mL (HUMALOG U-100) administered subcutaneously in a euglycemic clamp study enrolling healthy subjects. In this study, the overall, maximum, and time to maximum glucose lowering effect were similar between HUMALOG U-200 and HUMALOG U-100. The mean area under the glucose infusion rate curves (measure of overall pharmacodynamic effect) were 125 g and 126 g for HUMALOG U-200 and HUMALOG U-100, respectively. The maximum glucose infusion rate was 534 mg/min and 559 mg/min and the corresponding median time (min, max) to maximum effect were 2.8 h (0.5 h – 6.3 h) and 2.4 h (0.5 h – 4.7 h) for HUMALOG U-200 and HUMALOG U-100, respectively.