DULATINE 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

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.