HENKA 60

Indications

• Major depressive disorder
• Generalized anxiety disorder
• Diabetic peripheral neuropathic pain
• Fibromyalgia
• Chronic pain (e.g., osteoarthritis)
• Stress urinary incontinence

Dosage

Adults: Initially 60 mg once daily, with adjustments made based on clinical response. The maximum recommended dose is

Mechanism of action

Duloxetine acts as a potent inhibitor of neuronal serotonin and norepinephrine reuptake, with less potent effects on dopamine reuptake. It increases serotonin and norepinephrine concentrations in various brain regions, particularly Onuf's nucleus, leading to enhanced activation of 5-HT2, 5-HT3, and α1 adrenergic receptors. This activation enhances neuronal excitability by facilitating calcium release and sodium influx, contributing to improved muscle contraction in the external urethral sphincter and pain modulation in the spinal cord.

Pharmacodynamics

Duloxetine increases serotonin and norepinephrine concentrations, enhancing glutamatergic activation of the pudendal motor nerve, which innervates the external urethral sphincter, thus improving urinary control and reducing incontinence episodes. Additionally, it modulates pain pathways by strengthening serotonergic and adrenergic pathways in the spinal cord, resulting in an increased threshold for pain transmission and effective pain relief in conditions like diabetic neuropathy and fibromyalgia.

Pharmacokinetics

Duloxetine is well absorbed after oral administration, with peak plasma concentrations achieved within 6 hours. It has a half-life of approximately 12 hours and is metabolized primarily in the liver via the cytochrome P450 system. The drug is excreted largely in urine, with both unchanged drug and metabolites present. Its pharmacokinetics can be influenced by factors such as age, hepatic function, and concurrent medications.

Contra-indications

• Hypersensitivity to duloxetine or any of its excipients
• Concurrent use with monoamine oxidase inhibitors (MAOIs)
• Uncontrolled narrow-angle glaucoma

Adverse effects

• Nausea
• Dry mouth
• Dizziness
• Somnolence
• Fatigue
• Constipation
• Decreased appetite
• Sweating
• Increased blood pressure
• Sexual dysfunction

Interactions

• Duloxetine + eliglustat: Moderate (increases exposure)
• Givosiran + duloxetine: Moderate (increases exposure)
• Duloxetine + pitolisant: Moderate (increases exposure)
• Rucaparib + duloxetine: Moderate (increases exposure)
• Vemurafenib + duloxetine: Moderate (increases exposure)
• Axitinib + duloxetine: Unknown (increases exposure)
• Duloxetine + beta-blockers, selective: Unknown (increases exposure)
• Duloxetine + metoprolol: Unknown (increases exposure)
• Leflunomide + duloxetine: Unknown (decreases exposure)
• Mexiletine + duloxetine: Unknown (increases exposure)

Precautions

• Monitor blood pressure in patients with hypertension
• Caution in patients with a history of seizures
• Assess risk of serotonin syndrome, particularly when used with other serotonergic agents
• Use with caution in patients with hepatic impairment

Pregnancy

Duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is limited data on the use of duloxetine during pregnancy.

Breast-feeding

Duloxetine is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Duloxetine 30 mg capsules
• Duloxetine 60 mg capsules

Indications

• Chronic pain management
• Gastroesophageal reflux disease (GERD)
• Irritable bowel syndrome
• Attention-deficit hyperactivity disorder (ADHD) management
• Chronic respiratory conditions requiring bronchodilation

Dosage

Children: Refer to specific product labeling or clinical guidelines for paediatric dosing information.

Adults: Refer to specific product labeling or clinical guidelines for adult dosing information.

Mechanism of action

The mechanism of action varies depending on the specific drug formulation. Generally, delayed-release formulations are designed to dissolve at a specific site in the gastrointestinal tract, allowing for a slower absorption process. This can enhance the drug's therapeutic effects while minimizing side effects associated with peak plasma concentrations.

Pharmacodynamics

The pharmacodynamics of delayed-release medications involve the interaction between the drug and its target receptors or enzymes over a prolonged period. This can lead to sustained therapeutic effects, reduced frequency of dosing, and improved patient adherence to treatment regimens. The slow release mechanism also helps in maintaining more stable plasma drug concentrations, potentially reducing the occurrence of adverse effects.

Pharmacokinetics

Pharmacokinetics of delayed-release drugs typically include altered absorption rates due to the formulation's design. The onset of action may be delayed compared to immediate-release formulations. The distribution, metabolism, and excretion of the drug will depend on its chemical properties, but generally, the half-life may be extended due to prolonged absorption. Many delayed-release formulations utilize polymers or other excipients that control the release rate of the active ingredient.

Pregnancy

The safety of delayed-release formulations during pregnancy has not been well established. Consultation with a healthcare provider is recommended.

Breast-feeding

Caution is advised when using delayed-release medications while breastfeeding, as effects on the infant are unknown.

Storage

Store at room temperature, away from moisture and direct sunlight. Keep out of reach of children.

Indications

• Bacterial infections
• Infections caused by susceptible organisms
• Prophylaxis in certain surgical procedures

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations based on age, weight, and condition.

Adults: Refer to the BNF for specific dosages based on the condition being treated, severity of infection, and patient factors.

Mechanism of action

Release exerts its effects by inhibiting bacterial cell wall synthesis, leading to cell lysis and death. This mechanism is primarily mediated through the disruption of peptidoglycan cross-linking, which is essential for maintaining the structural integrity of bacterial cell walls.

Pharmacodynamics

The pharmacodynamics of Release involves its bactericidal action against a wide range of gram-positive and some gram-negative bacteria. The drug displays a time-dependent killing effect, meaning that its efficacy is related to the duration of exposure rather than the peak concentration achieved. Resistance to Release can develop through various mechanisms, including alterations in target sites or enzymatic degradation.

Pharmacokinetics

Release is absorbed and distributed throughout the body following administration. Peak plasma concentrations are typically achieved within a few hours. The drug is metabolized primarily in the liver, with metabolites excreted via the kidneys. The half-life of Release can vary depending on individual patient factors, including age, liver function, and concurrent medications.

Mechanism of action

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors. Action on the external urinary sphincter is mediated via duloxetine's CNS effects. Increased serotonin and norepinephrine concentrations in Onuf's nucleus leads to increased activation of 5-HT₂, 5-HT₃, and α₁ adrenergic receptors. 5-HT₂ and α₁ are both G_q coupled and their activation increases the activity of the inositol trisphosphate/phospholipase C (IP₃/PLC) pathway. This pathway leads to release of intracellular calcium stores, increasing intracellular calcium concentrations, and facilitating neuronal excitability. 5-HT₃ functions as a ligand-gated sodium channel which allows sodium to flow into the neuron when activated. Increased flow of sodium into the neuron contributes to depolarization and activation of voltage gated channels involved in action potential generation. The combined action of these three receptors contributes to increased excitability of the pudendal motor nerve in response to glutamate. Also related to duloxetine's action at the spinal cord is its modulation of pain. Increasing the concentration of serotonin and norepinephrine in the dorsal horn of the spinal cord increases descending inhibition of pain through activation of 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT₂, 5-HT₃, α₁-adrenergic, and α₂-adrenergic receptors. 5-HT₂, 5-HT₃, and α₁-adrenergic mediate neuronal activation as described above. The activated neuron in this case is the GABAergic inhibitory interneuron which synapses onto the nociceptive projection neuron to inhibit the transmission of painful stimuli to the brain. The 5-HT₁ and α₂ receptors are G_i/G_o coupled and their activation leads to increased potassium current through inward rectifier channels and decreased adenylyl cyclase/protein kinase A signaling which contributes to neuronal inhibition. These inhibitory receptors are present on the projection neuron itself as well as the dorsal root ganglion which precedes it and serves to directly suppress the transmission of painful stimuli. The mechanisms involved in duloxetine's benefits in depression and anxiety have not been fully elucidated. Dysfunctional serotonin and norepinephrine signaling are thought to be involved and increases in the availability of these neurotransmitters at the synaptic cleft thought to mediate a therapeutic effect. It is postulated that the involvement of serotonin and norepinephrine in area responsible for emotional modulation such as the limbic system contributes to the effects in mood disorders specifically but this has yet to be confirmed. Duloxetine's hypertensive effect is related to its intended pharmacological effect. Increased availability of norepinephrine leads to activation of adrenergic receptors on the vascular endothelium. Since the action of α₁ receptors predominates, vasoconstriction results as the G_q coupled receptor mediates calcium release from the sarcoplasmic reticulum to facilitate smooth muscle contraction. Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase (MAO). CYMBALTA is in a class of drugs known to affect urethral resistance. If symptoms of urinary hesitation develop during treatment with CYMBALTA, consideration should be given to the possibility that they might

Pharmacodynamics

Duloxetine, through increasing serotonin and norepinephrine concentrations in Onuf's nucleus, enhances glutamatergic activation of the pudendal motor nerve which innervates the external urethral sphinter. This enhanced signaling allows for stronger contraction. Increased contraction of this sphincter increases the pressure needed to produce an incontinence episode in stress urinary incontinence. Duloxetine has been shown to improve Patient Global Impression of Improvement and Incontinence Quality of Life scores. It has also been shown to reduce the median incontinence episode frequency at doses of 40 and 80 mg. Action at the dorsal horn of the spinal cord allows duloxetine to strengthen the the serotonergic and adrenergic pathways involved in descending inhibition of pain. This results in an increased threshold of activation necessary to transmit painful stimuli to the brain and effective relief of pain, particularly in neuropathic pain. Pain relief has been noted in a variety of painful conditions including diabetic peripheral neuropathy, fibromyalgia, and osteoarthritis using a range of pain assessment surveys. While duloxetine has been shown to be effective in both animal models of mood disorders and in clinical trials for the treatment of these disorders in humans, the broad scope of its pharmacodynamic effects on mood regulation in the brain has yet to be explained. Increased blood pressure is a common side effect with duloxetine due to vasoconstriction mediated by the intended increase in norepinephrine signaling.