Doxepin is a tricyclic antidepressant, known under many brand-names such as Aponal®, the original preparation by Boehringer-Ingelheim, now part of the Roche group; Adapine®, Sinquan® and Sinequan® (Pfizer Inc.); and Zonalon®, a cream-based preparation. IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ... CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules . ... DrugBank is a database available at the University of Alberta that provides information about thousands of products. ... A chemical formula (also called molecular formula) is a concise way of expressing information about the atoms that constitute a particular chemical compound. ... The molecular mass of a substance (less accurately called molecular weight and abbreviated as MW) is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of medication that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... Santorio Santorio (1561-1636) in his steelyard balance, from Ars de statica medecina, first published 1614 Metabolism (from μεταβολισμος (metabolismos)) is the biochemical modification of chemical compounds in living organisms anggjgjhnd cell (b). ... The liver is an organ in vertebrates including humans. ... The elimination half-life of a drug (or any xenobiotic agent) refers to the timecourse necessary for the quantity of the xenobiotic agent in the body (or plasma concentration) to be reduced to half of its original level through various elimination processes. ... Excretion is the biological process by which an organism chemically separates waste products from its body. ... Kidneys viewed from behind with spine removed The kidneys are bean-shaped excretory organs in vertebrates. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother. ... The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... Chemical structure of the tricyclic antidepressant amitriptyline Tricyclic antidepressants are a class of antidepressant drugs first used in the 1950s. ... Boehringer Ingelheim is a global pharmaceutical company based in Germany. ... Hoffmann-La Roche, Ltd. ... Pfizer, Incorporated (NYSE: PFE), is a global pharmaceutical company based in New York City. ...

Pharmacology

Doxepin inhibits the reuptake of serotonin and noradrenaline from the synaptic cleft (dual action). The reuptake-inhibition of dopamine is very weak. Serotonin (5-hydroxytryptamine, or 5-HT) is a monoamine neurotransmitter synthesised in serotonergic neurons in the central nervous system and enterochromaffin cells in the gastrointestinal tract. ... Norepinephrine, known as noradrenaline outside the USA, is a catecholamine and a phenethylamine with chemical formula C8H11NO3. ... Illustration of the major elements in a prototypical synapse. ... Dopamine is a chemical naturally produced in the body. ...

It has antagonistic effects (blockade) on a variety of postsynaptic receptors:

• Extremely strong : H1, H2
• Strong : 5-HT2, Alpha1, Muscarinic
• Moderate : 5-HT1
• Weak : D2, Alpha2

These effects account for the actions as well for most side-effects (sedation, hypotension, anticholinergic side-effects, massive weight gain). Doxepin shows strong antagonism against the effects of Reserpin (amine depletion) in the animal model. Like other 'classical' antidepressants it has a sodium channel blocking activity, possibly accounting for its analgesic action. Additionally, Doxepin exerts a strong local-anesthetic action. Sedation is a medical procedure involving administration of sedative drugs, generally to facilitate a medical procedure, such as endoscopy, vasectomy, or minor surgery with local anaesthesia. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... An anticholinergic agent is a member of a class of pharmaceutical compounds which serve to reduce the effects mediated by acetylcholine in the central nervous system and peripheral nervous system. ...

Peak plasma levels are seen 2 to 3 hours after oral dosing.

Toxicology

acute toxicity:

• Mouse : i.v. 15 - 20mg/kg body weight, oral 148 - 178mg/kg body weight
• Rat : i.v. 13 - 19mg/kg body weight, oral 346 - 460mg/kg body weight
• Human : Not exactly known, clinical experience indicates a rather high acute toxicity, as is the case with other tri-/tetracyclics. Fatal dose in sensitive adults may be as low as 500 to 1,000mg oral (7 to 14mg/kg). In children below 12 yrs. of age any oral intake is to be considered as serious.

chronic toxicity

• Dog and Rat : Fat deposits in liver cells and decrease of triglyceride levels in plasma
• Human : Data not available

Triglycerides (also known as triacylglycerols or triacylglycerides) are glycerides in which the glycerol is esterified with three fatty acids. ...

Indications

Approved uses may vary by country. In the United States, the only FDA approved use of doxepin is the treatment of depression. All other uses are considered off-label. The United States Food and Drug Administration is the government agency responsible for regulating food, dietary supplements, drugs, cosmetics, medical devices, biologics and blood products in the United States. ... The term off-label refers to the use of a drug for a medical condition other than for which it was officially approved and marketed. ...

• Depression
• Anxiety disorder, longterm-treatment is possible
• Insomnia, also suitable for longterm-treatment
• Alleviation of the symptoms of alcohol and drug withdrawal (N.B.: Doxepin does not suppress seizure activity in alcoholics ('rum fits'). Cotreatment with benzodiazepines or barbiturates is needed to treat seizures effectively.)
• Gastrointestinal ulceration and other GI-problems (e.g. irritable bowel syndrome), whether part of depression or not. The action is due to strong H2-receptor antagonism. The efficiacy is comparable to H2-Receptor-Inhibitors.
• Chronic pain, particular tension headaches, whether associated with depression or not
• External treatment of itching skin disease with Zonalon®

Clinical depression is a state of sadness or melancholia that has advanced to the point of being disruptive to an individuals social functioning and/or activities of daily living. ... Anxiety disorder is a blanket term covering several different forms of abnormal anxiety, fear, phobia and nervous condition, that come on suddenly and prevent pursuing normal daily routines. ... It has been suggested that Primary insomnia be merged into this article or section. ... Peptic ulcer is usually a non-malignant ulcer of the stomach (called gastric ulcer) or duodenum (called duodenal ulcer). ...

Contraindications

absolute :

• known hypersensitivity to doxepin or other dibenzoxepines or other ingredients of the drug
• acute intoxication with alcohol, sedatives, analgesics and other psychoactive drugs
• acute delirium tremens
• untreated closed angle glaucoma
• hypertrophy of the prostate with urine retention
• paralytic ileus

relative : A sedative is a drug that depresses the central nervous system (CNS), which causes calmness, relaxation, reduction of anxiety, sleepiness, slowed breathing, slurred speech, staggering gait, poor judgment, and slow, uncertain reflexes. ... An analgesic (colloquially known as painkiller) is any member of the diverse group of drugs used to relieve pain and to achieve analgesia. ... Delirium tremens (colloquially, the DTs or, the shakes) is a condition nearly invariably associated with complete alcohol withdrawal, although it also occurs as a complication of benzodiazepine and barbiturate withdrawal. ...

• hypertrophy of the prostate without urine retention
• reduced function of the bone marrow
• organic brain disorders
• increased risk of seizures, preexisting epilepsy
• preexisting cardial damage, particular some arrhythmias (e.g. sinoatrial blockage)

special caution is needed : This article is about the medical term, epileptic seizure, as distinct from psychogenic non-epileptic seizure. ... A cardiac arrhythmia, also called cardiac dysrhythmia, is a disturbance in the regular rhythm of the heartbeat. ...

• other forms of preexisting cardiac damage (other arrhythmias, insufficience)
• MAO-Inhibitors of the irreversible type (tranylcypromine among others) : These drugs should normally be stopped at least 2 weeks before therapy with doxepin is started.

Children under 12 years of age should not be treated, because no sufficient clinical experience exists for this group of age. Tranylcypromine is an antidepressant drug. ...

Precautions

Before initiation of treatment a complete and differentiated blood count should be taken. If any value is pathologic, the blood count should be monitored closely under therapy with doxepin. If values are normal, blood counts should be taken during therapy in regular intervals (recommended: weekly during first month of therapy, monthly during the next 2 months, every 3 months afterwards).

Liver-function studies should be performed periodically.

Pregnancy and Lactation

If Doxepin is used chronically during pregnancy, the newborn may show a withdrawal syndrom with agitation, impaired cardio-respiratory functions, disturbed urination and defecation. Caution should be exerted in treating pregnant women on a regular basis.

Doxepin is found in significant amounts in the milk of lactating women. If therapy is necessary, lactation should be interrupted during treatment.

Side-effects

• Central Nervous System : fatigue, dizziness, drowsiness, lightheadedness, confusion, nightmares, agitation, increased anxiety, insomnia, seizures (infrequently), delirium, rarely induction of hypomania and schizophrenia (stop medication immediately), extrapyramidal side-effects (rarely), abuse in patients with polytoxikomania (rarely)

• Anticholinergic : dry mouth, obstipation, even ileus (rarely), difficulties in urinating, sweating, precepitation of glaucoma

• Antiadrenergic : hypotension, postural collapse (if patient arises too fast from lying/sitting position to standing), arrhythmias (sinus-tachycardia, bradycardia, av-blockade)

• Allergic/toxic : skin rash, photosensitivity, liver damage of the cholostatic type (rarely), hepatitis (extremely rare), leuko- or thrombopenia (rarely), agranulocytosis (very rarely), hypoplastic anemia (rarely)

• Others : frequently increased appetite, massive weight gain, rarely nausea, frequently impaired sexual function in men (impotence, ejaculation-difficulties), rarely hypertension, rarely polyneuropathy, in both sexes breast-enlargement and galactorrhea (rarely)

Fatigue may refer to: Fatigue (physical) - tiredness in humans Fatigue (material) - failure by repeated stress in materials Fatigues (uniform) - military uniform (BDU or ACU) Chronic Fatigue Syndrome - a medical condition Battle fatigue - also known as Post-traumatic stress disorder Readers fatigue - a side-effect of parsing poorly formatted textual... This page is about a type of dream. ... This article is about the medical condition. ... Delirium is a medical term used to describe an acute decline in attention and cognition. ... Hypomania is a state involving combinations of: elevated mood, irritability, racing thoughts, people-seeking, hypersexuality, grandiose thinking, religiosity, and pressured speech. ... In human anatomy, the extrapyramidal system is a neural network located in the brain that is part of the motor system involved in the coordination of movement. ... Intestinal obstruction can be partial or complete blockage of the intestine, either large or small. ... In physiology and medicine, hypotension refers to an abnormally low blood pressure. ... A cardiac arrhythmia, also called cardiac dysrhythmia, is a disturbance in the regular rhythm of the heartbeat. ... Photosensitivity is the amount to which an object reacts upon receiving photons of light. ... Hepatitis is a gastroenterological disease, featuring inflammation of the liver. ... For other forms of hypertension see hypertension (disambiguation) Hypertension or high blood pressure is a medical condition wherein the blood pressure is chronically elevated. ... Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing. ...

Suicidal Patients

Patients with suicidal thoughts, or those with previous suicidal attempts, should be monitored closely under treatment with Doxepin. Perhaps, the decision is made to hospitalize high risk patients until remission or to prescribe an additional sedating drug like a benzodiazepin or chlorprothixene for 2-4 weeks of initial treatment with Doxepin (until significant remission). At least, the smallest amount of Doxepin should be prescribed at one time to minimize the risk of deliberate overdose. Chlorprothixene is a typical antipsychotic drug of the thioxanthine class. ...

Drug Abuse and Dependence

Doxepin has an extremely low potential for abuse and psychological dependence (mostly noted with polytoxicomaniacs, possibly due to the strong anxiolytic action of Doxepin).

Withdrawal symptoms frequently seen when treatment with doxepin is stopped abruptly (agitation, anxiety, insomnia, sometimes activation of mania or rebound depression) are not indicative of addiction and can be avoided by reducing the daily dose of Doxepin gradually by approximately 25% each week. If treatment has to be stopped at once due to medical reasons, the use of a benzodiazepine (e.g. Lorazepam, Clonazepam, or Alprazolam) for a maximum of 4 weeks as needed will usually suppress withdrawal symptoms.

Other remarks

Doxepin may worsen psychotic conditions like schizophrenia and should be given with caution. The antipsychotic treatment should be continued.

With Zonalon® in most countries an external form (cream) is available for the treatment of itching skin disease; the effect is due to strong local-anesthetic properties of Doxepin.

Interactions

• Irreversible MAO-Inhibitors : agitation, delirium, coma, hyperpyrexia (high fever), seizures and severe changes in blood pressure. N.B. Treatment-resistant and hospitalized patients may be treated concomitantly with an MAO-Inhibitor, if they are closely monitored and if the initial dose of the MAO-Inhibitor is low.

• Increased drug actions :
• other antidepressants, barbiturates, narcotics, sedating anthistaminics, anticonvulsive drugs, alcohol - resulting in increased central depression
• anticholinergics (antiparkinsonian agents, tri- and tetracyclic antidepressants) - resulting in increased anticholinergic action (dry mouth, obstipation etc.)
• Cimetidine : impairs the excretion of Doxepin - increased central depression and anticholinergic effects
• Sympathomimetics (also those used in local anesthetics like Noradrenaline) : sympathomimetic effects increased (increased blood pressure, pulse rate, paleness of skin etc)
• Nitrates and Antihypertensives (e.g. Beta-Blockers) - increased antihypertensive action with pronounced fall in blood pressure

• Decreased drug actions :
• Guanethidin, Reserpin, Guanfacin : antihypertensive effects decreased
• Clonidin : antihypertensive effects decreased and risk of (massive) rebound hypertension.

Dosage

• Depending on the disease to be treated, clinical condition, age, weight and liver function :

Initial doses may be as low as 5mg in the evening for treatment of insomnia or as high as 100mg oral as bedtime single dose or in divided doses in severely agitated depressive patients. Patients with severe opioid withdrawal symptoms often even require 3 times 50mg or more in the first few days. Generally, initial doses should be low and increased step by step. Outpatients should not receive more than 150mg daily. Hospitalized patients may receive up to 300mg orally in divided doses. Up to 150mg may be given as single bedtime dose. The dose for i.m.-injections and i.v.-infusions is usually 1/2 or less of the oral dose. Infusions should be given very slowly and the patient should lie during the infusion and for some hours afterwards in order to avoid severe postural hypotension.

It has been shown that Doxepin is able to decrease the risk of relapse of serious depression when given as longterm treatment after the remission is stable. If this applies for you, your physician will determine as well the daily dose and the duration of longterm treatment. The daily dose might be lower than the dose needed for full remission of your depression.

• External use : As directed by physician.

Overdose

If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222.

Canadian residents should call their local poison control center directly. Symptoms of overdose may include flushing, fast or irregular heartbeat, dry mouth, drowsiness, confusion, agitation, enlarged pupils, seizures, and loss of consciousness.

Drugs commonly used to treat overdose are Physostigmin (N.B. increased risk of seizures in Physostigmin treated patients) to counteract central and peripher anticholinergic effects and Diazepam (cautiously, may deepen central depression!) against convulsion. Symptomatic measures are stabilization of blood pressure and correction of water- and electrolyt-deficits. Lidocain can be given i.v. in cautious doses against cardial arrhythmias. The patient should be treated and monitored in an intensive care unit for several days.

History

Doxepin was synthesized by Stach and Spingler from the German drug manufacturer C. F. Boehringer & Söhne GmbH in Mannheim. It was tested from 1963 to 1968 in different German and Swiss psychiatric institutions and was approved in Germany and elsewhere thereafter. The antidepressive effects were found to be excellent. Strong anxiolytic and sedative properties were also demonstrated. Doxepin has been in clinical use for several decades. The drug plays an important role in many indications today, not only in psychiatry/neurology.