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Amitriptyline is a derivative of dibenzocycloheptadiene and a tricyclic antidepressant. Amitriptyline inhibits the re-uptake of norepinephrine and serotonin by the presynaptic neuronal membrane in the central nervous system (CNS), thereby increasing the synaptic concentration of norepinephrine and serotonin. Due to constant stimulation to these receptors, amitriptyline may produce a downregulation of adrenergic and serotonin receptors, which may contribute to the antidepressant activity.
Amitriptyline hydrochloride is a medicine used to treat a number of mental illnesses. These include major depressive disorder and anxiety disorder, and less commonly attention deficit hyperactivity disorder and bipolar disorder. Other uses include prevention of migraines, treatment of neuropathic pain such as fibromyalgia and postherpetic neuralgia, and less commonly insomnia , its basically dibenzocycloheptene-derivative tricyclic antidepressant (TCA). TCAs are structurally similar to phenothiazines. They contain a tricyclic ring system with an alkyl amine substituent on the central ring. In non-depressed individuals, amitriptyline does not affect mood or arousal but may cause sedation. In depressed individuals, amitriptyline exerts a positive effect on mood. TCAs are potent inhibitors of serotonin and norepinephrine reuptake.
Mechanism of Action of Amitriptyline
Amitriptyline, a tertiary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is extremely sedating, and thus improvement of sleep patterns can be the first benefit of treatment. Amitriptyline exhibits strong anticholinergic activity. Amitriptyline is metabolized to nortriptyline which inhibits the reuptake of norepinephrine and serotonin almost equally. Amitriptyline inhibits the membrane pump mechanism responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neurons. Pharmacologically this action may potentiate or prolong neuronal activity since reuptake of these biogenic amines is important physiologically in terminating transmitting activity. This interference with the reuptake of norepinephrine and/or serotonin is believed by some to underlie the antidepressant activity of amitriptyline.
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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 AMPin the astrocytes. Chronic exposure to amitriptyline or tranylcypromine led to a decrease in the isoproterenol-induced accumulation of cyclic AMP, and the time course for the development of this phenomenon was similar to that reported for the whole brain in vivo. These findings suggest that these antidepressant drugs act as 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.
Indications of Amitriptyline
- Acute depression
- Anorexia nervosa
- Bulimia
- Depression
- Diabetic neuropathies
- Migraines
- Sleep disorders and disturbances
- Sleeplessness
- Chronic pain
- Paresthesia ,itching ,numbness
- Anxiety and stress
- Insomnia
- Cyclic vomiting syndrome
- Dysautonomia
- Fibromyalgia
- Hyperhidrosis
- Interstitial cystitis
- Irritable bowel syndrome
- Neurotic depression
- Persistent depressive disorder
- Post traumatic stress disorder
- Pudendal neuralgia
- Reflex sympathetic dystrophy syndrome
- Somatoform pain disorder
- Urinary incontinence
- Urge incontinence
- Chronic cough
- Preventive treatment for patients with recurring biliary dyskinesia (sphincter of Oddi dysfunction)
- Attention deficit/hyperactivity disorder (in addition to, or sometimes in place of ADHD stimulant drugs)
- the treatment of major depressive disorder in adults
- the treatment of neuropathic pain in adults
- the prophylactic treatment of chronic tension type headache (CTTH) in adults
- the prophylactic treatment of migraine in adults
- the treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, has been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This medicinal product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis.
Indicated for the treatment of major depressive disorder in adults – Indicated for the management of neuropathic pain in adults – Indicated for the prophylactic treatment of chronic tension-type headache (CTTH) in adults – Indicated for the prophylactic treatment of nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।" data-rx-term="migraine" data-rx-definition="Migraine is a recurring headache disorder often with throbbing pain, nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।">migraine in adults – Indicated for the the treatment of nocturnal enuresis in children aged 6 years and above when organic pathology, including spina bifida and related disorders, has been excluded and no response has been achieved to all other non-drug and drug treatments, including antispasmodics and vasopressin-related products. This medicinal product should only be prescribed by a healthcare professional with expertise in the management of persistent enuresis. -Other off-label uses include irritable bowel syndrome, sleep disorders, diabetic numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।" data-rx-term="neuropathy" data-rx-definition="Neuropathy means nerve damage or irritation causing pain, numbness, tingling, or weakness. সহজ বাংলা: স্নায়ুর ক্ষতি/সমস্যা।">neuropathy, agitation and insomnia
Contraindications of Amitriptyline
- Hypersensitivity to TCAs or to any of its excipients
- History of myocardial infarction
- History of arrhythmias, particularly heart block to any degree
- Congestive heart failure
- Coronary artery insufficiency
- Mania
- Severe liver disease
- Being under 7 years of age
- Breast feeding
- Patients who are taking monoamine oxidase inhibitors (MAOIs) or have taken them within the last 14 days.
Dosages of Amitriptyline
Strengths: 10 mg; 25 mg; 50 mg; 75 mg; 100 mg; 150 mg;
Depression
Outpatients
- Usual dose: 75 mg orally per day in divided doses; this may be increased to a total of 150 mg per day if needed
- Alternate dose: 40 to 100 mg orally as a single dose at bedtime; this may be increased by 25 or 50 mg as needed at bedtime to a total of 150 mg per day
- Maximum dose: 150 mg orally per day
Inpatients
- Initial dose: 100 mg orally per day
- Maintenance dose: 40 to 100 mg orally as a single dose at bedtime
- Maximum dose: 300 mg orally per day
Geriatric Dose for Depression
- 10 mg orally 3 times a day with 20 mg at bedtime
Pediatric Dose for Depression
12 years or older
- 10 mg orally 3 times a day with 20 mg at bedtime
Neuropathic pain,tension headache, nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।" data-rx-term="migraine" data-rx-definition="Migraine is a recurring headache disorder often with throbbing pain, nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।">migraine
Adults
- Recommended doses are 25 mg – 75 mg daily in the evening. Doses above 100 mg should be used with caution.
- The initial dose should be 10 mg – 25 mg in the evening. Doses can be increased with 10 mg – 25 mg every 3 – 7 days as tolerated.
- The dose can be taken once daily, or be divided into two doses. A single dose above 75 mg is not recommended.
- The pain-relieving medicine. সহজ বাংলা: ব্যথানাশক ওষুধ।" data-rx-term="analgesic" data-rx-definition="An analgesic is a pain-relieving medicine. সহজ বাংলা: ব্যথানাশক ওষুধ।">analgesic effect is normally seen after 2 – 4 weeks of dosing.
- Elderly patients over 65 years of age and patients with cardiovascular disease
- A starting dose of 10 mg – 25 mg in the evening is recommended.
- Doses above 75 mg should be used with caution.
Neuropathic pain
Treatment is symptomatic and should, therefore, be continued for an appropriate length of time. In many patients, therapy may be needed for several years. Regular reassessment is recommended to confirm that the continuation of the treatment remains appropriate for the patient.
Prophylactic treatment of chronic tension-type pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।" data-rx-term="headache" data-rx-definition="Headache means pain in the head or upper neck. সহজ বাংলা: মাথাব্যথা।">headache and prophylactic treatment of nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।" data-rx-term="migraine" data-rx-definition="Migraine is a recurring headache disorder often with throbbing pain, nausea, or light sensitivity. সহজ বাংলা: বারবার হওয়া বিশেষ ধরনের মাথাব্যথা।">migraine in adults
Treatment must be continued for an appropriate length of time. Regular reassessment is recommended to confirm that the continuation of the treatment remains appropriate for the patient.
Nocturnal enuresis
Pediatric population
The recommended doses for
- Children aged 6 to 10 years: 10 mg – 20 mg. A suitable dosage form should be used for this age group.
- Children aged 11 years and above: 25 mg – 50 mg daily
- The dose should be increased gradually.
- Dose to be administered 1-1½ hours before bedtime.
- The maximum period of treatment course should not exceed 3 months. If repeated courses of
amitriptyline is needed, a medical review should be conducted every 3 months.
Postherpetic Neuralgia (Off-label)
- 65-100 mg PO qDay for at least 3 weeks
Eating Disorder (Off-label)
- 150 mg PO qHS for 8 weeks
Side Effects of Amitriptyline
The most common
- nausea, vomiting, loss of appetite;
- anxiety, sleep problems (insomnia);
- dry mouth, unusual taste;
- little or no urinating;
- constipation;
- vision changes;
- breast swelling (in men or women); or
- decreased sex drive, impotence, or difficulty having an orgasm.
- blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- restless muscle movements in your eyes, tongue, jaw, or neck;
- a light-headed feeling, like you might pass out;
- seizure (convulsions);
- new or worsening chest pain, pounding heartbeats or fluttering in your chest;
- sudden numbness or weakness, problems with vision, speech, or balance;
- fever, sore throat, easy bruising, unusual bleeding;
- painful or difficult urination;
Common
- Abdominal or stomach pain
- agitation
- black, tarry stools
- bleeding gums
- blood in urine or stools
- blurred vision
- burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings
- change in consciousness
- changes in patterns and rhythms of speech
- chest pain or discomfort
- cold sweats
- coma
- confusion
Rare
- Abdominal or stomach pain
- agitation or irritability
- blurred vision
- change in urination
- chest pain or discomfort
- confusion about identity, place, and time
- convulsions
- cool, pale skin
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or
- Anxiety
- change in vision
- seizures
- weight loss
- chest pain or tightness
- confusion
- cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- hallucinations
- headache
- irritability
- muscle pain or cramps
- pale or yellowed skin, dark colored urine, fever, confusion or weakness;
- sore throat, and headache with a severe blistering, peeling, and red skin rash;
- swelling, rapid weight gain, feeling short of breath (even with mild exertion); or
- increased thirst, loss of appetite, urinating less than usual or not at all.
Drug Interaction of Amitriptyline
Amitriptyline may interact with the following drugs, supplements, & may change the mode of action of drugs.
- anticholinergic medications (e.g., atropine, benztropine, pinaverium, scopolamine)
- antihistamines (e.g., diphenhydramine, hydroxyzine)
- antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine, quetiapine, risperidone)
- barbiturates (e.g., phenobarbital, secobarbital)
- beta-2 agonists (e.g., formoterol, salbutamol, salmeterol)
- bupropion
- carbamazepine
- celecoxib
- certain antiarrhythmic medications (e.g., amiodarone, propafenone, sotalol)
- chloroquine
- cimetidine
- clobazam
- clonidine
- clozapine
- imatinib
- ipratropium
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- methyldopa
- other antidepressants especially MAO inhibitors (e.g., linezolid, moclobemide, phenelzine, selegiline, tranylcypromine)
- protease inhibitors (e.g., darunavir, lopinavir, ritonavir)
- quinolone antibiotics (e.g., levofloxacin, moxifloxacin
- selective serotonin reuptake inhibitors (SSRIs) such as citalopram, fluoxetine, fluvoxamine , paroxetine and sertraline
- 5-HT3 antagonists (e.g., granisetron, ondansetron)
- sodium phosphates
- sotalol
- tizanidine
- tolterodine
- topical decongestants (eye drops and nasal sprays; naphazoline, oxymetazoline, xylometazoline)
- tramadol
- other tricyclic antidepressants (e.g., amitriptyline, clomipramine, trimipramine)
- “triptan” migraine medications (e.g., eletriptan, sumatriptan)
- warfarin
Pregnancy & Lactation of Amitriptyline
FDA Pregnancy Category C
Pregnancy
For amitriptyline, only limited clinical data are available regarding exposed pregnancies.
Animal studies have shown reproductive toxicity.
Amitriptyline is not recommended during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit.
During chronic use and after administration in the final weeks of pregnancy, neonatal withdrawal symptoms can occur. This may include irritability, hypertonia, tremor, irregular breathing, poor drinking, and loud crying and possibly anticholinergic symptoms (urinary retention, constipation).
Lactation
Amitriptyline and its metabolites are excreted into breast milk (corresponding to 0.6 % – 1 % of the maternal dose). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from the therapy of this medicinal product taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
References
