AMITRYP-25

Indications

• Major depressive disorder
• Anxiety disorders
• Chronic pain syndromes
• Post-herpetic neuralgia
• Diabetic neuropathic pain
• Fibromyalgia (off-label use)

Dosage

Adults: Refer to BNF for specific dosing guidelines based on the condition being

Mechanism of action

The exact mechanism of action of amitriptyline is not fully understood. It is believed to inhibit the membrane pump mechanism responsible for the re-uptake of norepinephrine and serotonin, leading to increased concentrations of these neurotransmitters in the synaptic clefts. This action is thought to counteract depressive symptoms, as deficiencies in these neurotransmitters are associated with mood disorders. Amitriptyline may also have effects on ion channels, such as hERG channels, which could influence cardiac function.

Pharmacodynamics

Amitriptyline has demonstrated efficacy in managing pain related to conditions such as post-herpetic neuralgia and diabetic neuropathic pain, achieving a good to moderate response in a significant proportion of patients. Its strong anticholinergic properties can lead to side effects like orthostatic hypotension and tachycardia, particularly in elderly patients. The drug's sedative effects may also contribute to its effectiveness in treating anxiety and sleep disturbances associated with depression.

Pharmacokinetics

Amitriptyline is well absorbed from the gastrointestinal tract, with an extensive first-pass metabolism in the liver. Its bioavailability is variable, leading to differing plasma concentrations among individuals. The drug is primarily metabolized by cytochrome P450 enzymes, producing active metabolites like nortriptyline. Amitriptyline has a long half-life, allowing for once-daily dosing. It is highly protein-bound and is distributed widely throughout the body, including the central nervous system.

Adverse effects

• Sedation
• Dry mouth
• Constipation
• Blurred vision
• Weight gain
• Orthostatic hypotension
• Cardiac arrhythmias

Interactions

• metyrapone: Severe (decreases effects)
• fluvoxamine: Moderate (increases exposure)

Precautions

• Use with caution in elderly patients due to the risk of orthostatic hypotension and tachycardia
• Monitor for cardiac arrhythmias due to potential effects on cardiac repolarization
• Consider anticholinergic properties, particularly in patients with glaucoma or urinary retention

Pregnancy

Amitriptyline should only be used in pregnancy if the potential benefit justifies the potential risk to the fetus. Caution is advised.

Breast-feeding

Amitriptyline is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Tablets
• Oral solution

Indications

• Depression
• Neuropathic pain
• Chronic pain syndromes

Dosage

Children: For children aged 1-11 years: Initially 200–500 micrograms/kg once daily (max. per dose 10 mg), taken at night. For children aged 12-17 years: Initially 10 mg once daily, increased if necessary to 75 mg once daily, taken at night.

Adults: Initially, 25-50 mg once daily at night; may be increased to a maximum of 150 mg per day based on response and tolerability.

Mechanism of action

Amitriptyline works by inhibiting the reuptake of norepinephrine and serotonin, thereby increasing their levels in the synaptic cleft. It also has anticholinergic properties, which contribute to its side effect profile.

Pharmacodynamics

Amitriptyline enhances neurotransmitter activity in the central nervous system, leading to improved mood and reduced perception of pain. It has a sedative effect due to its antagonistic action on histamine H1 receptors.

Pharmacokinetics

Amitriptyline is well absorbed after oral administration, with a significant first-pass metabolism. It has a half-life of approximately 10-28 hours, and it is metabolized in the liver, primarily by cytochrome P450 enzymes. Excretion is mainly through urine as metabolites.

Contra-indications

• Hypersensitivity to amitriptyline or any of its excipients
• Recent myocardial infarction
• Concurrent use of monoamine oxidase inhibitors (MAOIs)
• Severe hepatic impairment
• Angle-closure glaucoma

Adverse effects

• Drowsiness
• Dry mouth
• Constipation
• Urinary retention
• Dizziness
• Weight gain
• QT interval prolongation
• Anticholinergic syndrome
• Agranulocytosis
• Alopecia
• Anxiety

Interactions

• Increased risk of arrhythmias with other drugs that prolong the QT interval
• Serotonin syndrome risk when used with other serotonergic agents
• Increased sedation with alcohol, benzodiazepines, and other CNS depressants
• MAOIs can cause severe interactions if used concurrently

Precautions

• Use with caution in patients with a history of seizures
• Caution in patients with a history of mania or bipolar disorder
• Regular monitoring of cardiac function is advised
• Gradual withdrawal recommended to avoid withdrawal symptoms

Pregnancy

Use only if potential benefit outweighs risk.

Breast-feeding

The amount secreted into breast milk is too small to be harmful.

Storage

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

Formulations

• Tablets
• Oral suspension
• Oral solution

Mechanism of action

The mechanism of action of this drug is not fully elucidated. It is suggested that amitriptyline inhibits the membrane pump mechanism responsible for the re-uptake of transmitter amines, such as norepinephrine and serotonin, thereby increasing their concentration at the synaptic clefts of the brain,. These amines are important in regulating mood. The monoamine hypothesis in depression, one of the oldest hypotheses, postulates that deficiencies of serotonin (5-HT) and/or norepinephrine (NE) neurotransmission in the brain lead to depressive effects. This drug counteracts these mechanisms, and this may be the mechanism of amitriptyline in improving depressive symptoms. Whether its analgesic effects are related to its mood-altering activities or attributable to a different, less obvious pharmacological action (or a combination of both) is unknown. Acute and chronic effects of the antidepressant drugs tranylcypromine, a monoamine oxidase inhibitor, and amitriptyline, a monoamine uptake inhibitor, were studied on beta-adrenergic receptor function in mouse astrocytes in primary cultures. In clinically relevant concentrations, acute administration of either antidepressant drug had a direct inhibitory effect on the binding of the beta-adrenergic ligand dihydroalprenolol and on the isoproterenol-induced accumulation of cyclic AMP. However, in the absence of isoproterenol, these drugs enhanced the formation of cyclic AMP in the astrocytes. Chronic exposure to amitriptyline or tranylcypromine led to a decrease in isoproterenol-induced accumulation of cyclic AMP, and the time course for the development of this phenomenon was similar to that reported for whole brain in vivo. These findings suggest that these antidepressant drugs act as a partial agonists at beta-adrenergic receptors on astrocytes, and that the down-regulation of beta-adrenergic activity that occurs in vivo after chronic administration of antidepressant drugs may, to a large extent, take place in astrocytes and may result from the partial beta-agonist nature of the drugs. Astrocytes play important roles in guiding the construction of the nervous system, controlling extracellular ions and neurotransmitters, and regulating CNS synaptogenesis. Egr-1 is a transcription factor involved in neuronal differentiation and astrocyte cell proliferation. In this study, we investigated whether the tricyclic antidepressant (TCA) amitriptyline induces Egr-1 expression in astrocytes using rat C6 glioma cells as a model. We found that amitriptyline increased the expression of Egr-1 in a dose- and time-dependent manner. The amitriptyline-induced Egr-1 expression was mediated through serum response elements (SREs) in the Egr-1 promoter. SREs were activated by the Ets-domain transcription factor Elk-1 through the ERK and JNK mitogen-activated protein (MAP) kinase pathways. The inhibition of the ERK and JNK MAP kinase signals attenuated amitriptyline-induced transactivation of Gal4-Elk-1 and Egr-1 promoter activity. Our findings suggest that the induction of Egr-1 expression in astrocytes may be required to attain the therapeutic effects of antidepressant drugs. Antidepressants such as serotonin-noradrenaline reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) are frequently used for the management of neuropathic pain. Noradrenaline (NA) and serotonin (5-HT) increase in the spinal cord by reuptake inhibition is considered to be main mechanism of the therapeutic effect of antidepressants in neuropathic pain. In the present study, we examined the analgesic effects of duloxetine (SNRI) and amitriptyline (TCA) in a rat model of neuropathic pain induced by spinal nerve ligation (SNL). Intraperitoneal administration of duloxetine and amitriptyline dose-dependently (3,10 and 30 mg/kg) suppressed hyperalgesia induced by SNL. In vivo microdialysis in the lumbar spinal dorsal horn revealed that NA and 5-HT concentrations increased after intraperitoneal administration of duloxetine and am

Pharmacodynamics

**Effects in pain and depression** Amitriptyline is a tricyclic antidepressant and an analgesic. It has anticholinergic and sedative properties. Clinical studies have shown that oral amitriptyline achieves, at a minimum, good to moderate response in up to 2/3 of patients diagnosed with post-herpetic neuralgia and 3/4 of patients diagnosed with diabetic neuropathic pain, and neurogenic pain syndromes that are frequently unresponsive to narcotic analgesics. Amitriptyline has also shown efficacy in diverse groups of patients with chronic non-malignant pain. There have also been some studies showing efficacy in managing fibromyalgia (an off-label use of this drug),. **Cardiovascular and Anticholinergic Effects** Amitriptyline has strong anticholinergic properties and may cause ECG changes and quinidine-like effects on the heart. Amitriptyline may inhibit ion channels, which are necessary for cardiac repolarization (hERG channels), in the upper micromolar range of therapeutic plasma concentrations. Therefore, amitriptyline may increase the risk for cardiac arrhythmia. Orthostatic hypotension and tachycardia can be a problem in elderly patients receiving this drug at normal doses for depression. There is evidence in the literature that these effects may occur, rarely, at the lower dosages utilized in the treatment of pain. As with any other tricyclic antidepressant agent, increased glucose levels can occur with amitriptyline. **Effects on seizure threshold** This drug also decreases the convulsive threshold and causes alterations in EEG and sleep patterns.