Definition
Tricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the re-uptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines.
Description
Amitriptyline hydrochloride is a 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. Tertiary amine TCAs, such as amitriptyline, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline. TCAs also down-regulate cerebral cortical β-adrenergic receptors and sensitize post-synaptic serotonergic receptors with chronic use. The antidepressant effects of TCAs are thought to be due to an overall increase in serotonergic neurotransmission. TCAs also block histamine-H1 receptors, α1-adrenergic receptors and muscarinic receptors, which accounts for their sedative, hypotensive and anticholinergic effects (e.g. blurred vision, dry mouth, constipation, urinary retention), respectively. See toxicity section below for a complete listing of side effects. Amitriptyline may be used to treat depression, chronic pain (unlabeled use), irritable bowel syndrome (unlabeled use), diabetic neuropathy (unlabeled use), post-traumatic stress disorder (unlabeled use), and for migraine prophylaxis (unlabeled use).
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Amitriptyline is rapidly and well absorbed following oral administration. Exclusively hepatic, with first pass effect. Amitriptyline is demethylated in the liver to its primary active metabolite, nortriptyline. Route of Elimination: Virtually the entire dose is excreted as glucuronide or sulfate conjugate of metabolites, with little unchanged drug appearing in the urine. 25-50% of a single orally administered dose is excreted in urine as inactive metabolites within 24 hours. Small amounts are excreted in feces via biliary elimination. Half Life: 10 to 50 hours, with an average of 15 hours
- Uses/Sources: For the treatment of depression, chronic pain, irritable bowel syndrome, sleep disorders, diabetic neuropathy, agitation and insomnia, and migraine prophylaxis.
- Health Effects: Some rare side effects include tinnitus, hypotension, mania, psychosis, heart block, arrhythmias, lip and mouth ulcers, extrapyramidal symptoms, depression, and hepatic toxicity.Amitriptyline exhibits strong anticholinergic activity, cardiovascular effects including orthostatic hypotension, changes in heart rhythm and conduction, and a lowering of the seizure threshold (A308, L1032).
- Symptoms: Symptoms of overdose include abnormally low blood pressure, confusion, convulsions, dilated pupils and other eye problems, disturbed concentration, drowsiness, hallucinations, impaired heart function, rapid or irregular heartbeat, reduced body temperature, stupor, and unresponsiveness or coma. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia.
- Treatment: Consider gastric lavage only if within one hour of a potentially fatal overdose. Give 50 grams of charcoal if within one hour of ingestion. Prolonged resuscitation may be successful in case of cardiac arrest. Give sodium bicarbonate in case of arrhythmias. (A311)
- Route of Exposure: Oral (A308) Rapidly and well absorbed following oral administration (bioavailability is 30-60% due to first pass metabolism). Peak plasma concentrations occur 2-12 hours following oral or intramuscular administration.
Toxicity
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: LD50: 350 mg/kg (Oral, Mouse) (A308)
Mechanism of Action
| Target Name | Mechanism of Action | References |
|---|---|---|
|
Potassium voltage-gated channel subfamily H member 2 Sodium channel protein type 2 subunit alpha Sodium channel protein type 5 subunit alpha Sodium channel protein type 9 subunit alpha Potassium voltage-gated channel subfamily KQT member 3 Muscarinic acetylcholine receptor M1 Muscarinic acetylcholine receptor M2 Muscarinic acetylcholine receptor M3 Muscarinic acetylcholine receptor M4 Muscarinic acetylcholine receptor M5 Potassium voltage-gated channel subfamily D member 2 Potassium voltage-gated channel subfamily D member 3 Potassium voltage-gated channel subfamily A member 1 5-hydroxytryptamine receptor 2A 5-hydroxytryptamine receptor 2C 5-hydroxytryptamine receptor 1A Alpha-1A adrenergic receptor Sodium-dependent dopamine transporter Mu-type opioid receptor Kappa-type opioid receptor 5-hydroxytryptamine receptor 7 D(2) dopamine receptor D(3) dopamine receptor 5-hydroxytryptamine receptor 1B Delta-type opioid receptor 5-hydroxytryptamine receptor 1D D(1A) dopamine receptor Histamine H1 receptor Alpha-1B adrenergic receptor Histamine H4 receptor Alpha-1D adrenergic receptor Histamine H2 receptor Sigma non-opioid intracellular receptor 1 D(1B) dopamine receptor 5-hydroxytryptamine receptor 6 Solute carrier family 22 member 1 High affinity nerve growth factor receptor BDNF/NT-3 growth factors receptor Beta adrenergic receptor Histamine H3 receptor |
18788725 18448342 22770500 12190308 11339973 6146381 7696602 19110341 10997731 11179435 7855217 14744476 17456683 8100134 9537821 10447960 20363235 19828880 6103762 19549602 21427517 3037421 12873512 19091563 9781919 18083778 17689532 10227113 7971731 14645659 15745831 8522988 15911273 |
|
|
Potassium voltage-gated channel subfamily KQT member 2 Sodium-dependent serotonin transporter Alpha-2A adrenergic receptor Sodium-dependent noradrenaline transporter |
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. |
16140280 14744476 7855217 16032412 17456683 9400006 9537821 14757140 16079297 15877309 |
Amitriptyline Interacts with Diseases
| Disease | Inference Score | References/Inference Genes |
| Lipidoses | 58.3 |
|
| Liver Cirrhosis, Experimental | 31.73 |
|
| Prostatic Neoplasms | 17.61 |
|
| Autism | 17.05 |
|
| Diabetes Mellitus, Type 2 | 16.01 |
|
| Alzheimer's Disease | 13.74 |
|
| Gliosarcoma | 11.47 |
|
| Asthma | 11.43 |
|
| Diabetes Mellitus, Experimental | 10.32 |
|
| Endometriosis | 9.81 |
|
| Breast carcinoma | 9.6 |
|
| Amphetamine-Related Disorders | 9.25 | |
| Kidney Failure, Chronic | 9.17 |
|
| Ureteral Calculi | 8.86 |
|
| Carcinoma | 8.67 |
|
| Disease Progression | 8.45 |
|
| Nephrosis | 8.42 |
|
| Genetic Predisposition to Disease | 8.37 |
|
| Parkinson's disease | 8.13 |
|
| Protein Deficiency | 7.77 |
|