INSULIN GLARGINE

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

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus
• Diabetes management in adults and children

Dosage

Adults: The initial dose of insulin glargine is usually individualized based on the patient's blood glucose levels and metabolic needs. Typical starting doses may range from 10 to 20 units once daily, adjusted

Mechanism of action

Insulin glargine binds to the insulin receptor (IR), stimulating the intrinsic tyrosine kinase activity of the receptor's beta subunit. This leads to autophosphorylation of the receptor and phosphorylation of intracellular substrates, activating downstream signaling molecules such as PI3 kinase and Akt. These pathways promote glucose uptake via glucose transporter 4 (GLUT4), enhance glycogenesis, and inhibit catabolism, thereby regulating glucose metabolism. Upon subcutaneous injection, insulin glargine forms microprecipitates, allowing for a sustained release and a stable insulin concentration over 24 hours with no pronounced peak.

Pharmacodynamics

Insulin is a hormone synthesized by pancreatic beta cells, essential for glucose homeostasis. It facilitates the uptake of glucose in muscle and adipose tissues, promotes glycogenesis, and inhibits the breakdown of fat and glycogen. Insulin also stimulates protein synthesis and DNA replication, playing a crucial role in growth and metabolism. Insulin glargine's long-acting properties provide a stable insulin level, which is vital for managing blood glucose levels in diabetic patients.

Pharmacokinetics

Insulin glargine is formulated to be soluble at pH 4, with low solubility at physiological pH 7.4. After subcutaneous injection, it forms microprecipitates that release small amounts of insulin gradually, ensuring a constant concentration of the drug in the bloodstream over a 24-hour period. This results in a prolonged duration of action without peaks, contrasting with regular insulin which has a more rapid onset and shorter duration.

Contra-indications

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

Adverse effects

• Hypoglycaemia
• Injection site reactions
• Weight gain
• Allergic reactions
• Lipodystrophy at injection sites

Interactions

• Certain medications may affect blood glucose levels, including corticosteroids, oral contraceptives, and thyroid hormones
• Beta-blockers may mask the signs of hypoglycaemia
• Alcohol may potentiate or reduce the hypoglycaemic effect of insulin

Precautions

• Caution in patients with renal or hepatic impairment
• Monitor blood glucose levels regularly
• Adjust dose during periods of stress, illness, or changes in activity
• Educate patients on recognizing and treating hypoglycaemia

Pregnancy

Insulin glargine is generally regarded as safe for use during pregnancy, but blood glucose levels must be carefully monitored.

Breast-feeding

Insulin glargine can be used during breastfeeding, but blood glucose levels should be monitored closely.

Storage

Store in a refrigerator (2-8°C). Do not freeze. Once in use, can be stored at room temperature (up to 25°C) for up to 28 days.

Formulations

• Insulin glargine 100 units/mL solution for injection

Indications

• Major depressive disorder
• Generalized anxiety disorder
• Panic disorder
• Obsessive-compulsive disorder
• Post-traumatic stress disorder

Dosage

Children: Refer to the BNF for Children for appropriate dosing guidelines in paediatric patients.

Adults: Refer to the BNF for specific dosing recommendations based on the condition being treated.

Mechanism of action

Impact works by modulating neurotransmitter pathways in the brain, particularly affecting serotonin and norepinephrine levels. This modulation helps to alleviate symptoms of depression and anxiety.

Pharmacodynamics

Impact demonstrates dose-dependent effects on neurotransmitter reuptake, leading to increased availability of serotonin and norepinephrine in the synaptic cleft. This results in improved mood and reduction of anxiety symptoms. The onset of therapeutic effects may take several weeks, requiring careful monitoring during treatment initiation.

Pharmacokinetics

Impact is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations occurring within a few hours of administration. It is extensively metabolized in the liver, primarily by cytochrome P450 enzymes, and its metabolites are excreted via the kidneys. The elimination half-life is variable, necessitating consideration of patient-specific factors such as age and liver function.

Pregnancy

Consult relevant guidelines, as risk factors must be evaluated based on clinical context.

Breast-feeding

Consult relevant guidelines, as the effects on breastfed infants should be considered.

Storage

Store in a cool, dry place away from light.

Dosage

Children: Refer to specific drug guidelines as dosing in units varies based on the drug and its clinical application.

Adults: Refer to specific drug guidelines as dosing in units varies based on the drug and its clinical application.

Mechanism of action

The mechanism of action of drugs measured in units depends on the specific substance. For example, insulin (measured in units) facilitates glucose uptake in cells by binding to insulin receptors, activating a signaling pathway that enhances glucose transporter translocation to the cell membrane. This results in a decrease in blood glucose levels. Similarly, other drugs measured in units may exert their effects through receptor binding, enzyme catalysis, or other biochemical interactions.

Pharmacodynamics

Pharmacodynamics describes the effects of the drug on the body and includes the relationship between drug concentration and effect. For substances measured in units, the pharmacodynamic response may be variable and is often dependent on the individual’s sensitivity to the drug, receptor availability, and other pharmacological factors. For instance, the effect of 1 unit of insulin can vary significantly among individuals based on their insulin sensitivity and metabolic state.

Pharmacokinetics

Pharmacokinetics refers to the absorption, distribution, metabolism, and excretion of drugs. For substances measured in units, the pharmacokinetic profile can differ widely. For instance, insulin is rapidly absorbed when administered subcutaneously, distributed throughout the body, metabolized by the liver and kidneys, and its effects can be observed within minutes. Other drugs may have different absorption rates, half-lives, and routes of elimination.

Pregnancy

Consult a healthcare professional. The safety of this drug during pregnancy has not been established.

Breast-feeding

Consult a healthcare professional. The safety of this drug during breastfeeding has not been established.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

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 glargine 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. Insulin glargine is completely soluble at pH 4, the pH of administered solution, and has low solubility at physiological pH 7.4. Upon subcuteous injection, the solution is neutralized resulting in the formation of microprecipitates. Small amounts of insulin glargine are released from microprecipitates giving the drug a relatively constant concentration over time profile over 24 hours with no pronounced peak. This release mechanism allows the drug to mimic basal insulin levels within the body.

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 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 glargine 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.