Chemical structure of the tricyclic antidepressant amitriptyline. Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil Tryptanol Endep Elatrol Tryptizol Trepiline Laroxyl Saroten is a Tricyclic antidepressant

Tricyclic antidepressants (abbreviation TCA) are a class of antidepressant drugs first used in the 1950s. An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease The 1950s Decade refers to the years of 1950 to 1959 inclusive They are named after the drugs' molecular structure, which contains three rings of atoms (compare tetracyclic antidepressant). There are also several chemically unrelated tetracyclic Antibiotics based on Tetracycline.

Example compounds

The first tricyclic antidepressant discovered was imipramine, which was discovered accidentally in a search for a new antipsychotic in the late 1950s. Imipramine (sold as Antideprin, Deprenil, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia.

Antidepressant drugs in the tricyclic drug group (along with their actions as listed in MeSH) include:

Note: Other sources suggest that most of the tricyclics combine adrenergic and serotonergic effects to some degree. Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books Norepinephrine reuptake inhibitors ( NRIs) also known as noradrenaline reuptake inhibitors ( NARIs) are compounds that elevate the extracellular level of Selective serotonin reuptake inhibitors ( SSRIs) are a class of Antidepressants used in the treatment of depression, Anxiety disorders A dopamine antagonist is a drug which blocks Dopamine receptors by Receptor antagonism. A histamine antagonist is an agent which serves to inhibit the release or action of Histamine. Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil Tryptanol Endep Elatrol Tryptizol Trepiline Laroxyl Saroten is a Tricyclic antidepressant Butriptyline (Dl-1011-Dihydro-NNbeta-trimethyl-5H-dibenzocycloheptene-5-propylamine is a Tricyclic antidepressant with sedative properties and uses similar to that of Amoxapine (brand-names Asendin, Asendis, Defanyl, Demolox, Moxadil) is a Clomipramine (brand-name Anafranil) is a Tricyclic antidepressant. Desipramine is a Tricyclic antidepressant (TCA that inhibits the reuptake of Norepinephrine. Dosulepin hydrochloride ( INN) (formerly the BAN dothiepin hydrochloride) is an Antidepressant of the tricyclic family Dosulepin hydrochloride ( INN) (formerly the BAN dothiepin hydrochloride) is an Antidepressant of the tricyclic family Doxepin is a psychotropic agent with Tricyclic antidepressant and Anxiolytic properties known under many brand-names such as Aponal Imipramine (sold as Antideprin, Deprenil, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil Dibenzepin (Noveril is a Noradrenaline reuptake inhibitor, an H1 receptor antagonist and a muscarinic antagonist. Iprindole (C19H28N2 a 5-HT2 antagonist is a Tricyclic antidepressant that can be fatal when combined with MDMA Lofepramine (trademarked Gamanil Tymelyt generic Lomont is a third generation Tricyclic antidepressant used in the treatment of depressive disorders Nortriptyline is a second generation Tricyclic antidepressant marketed as the Hydrochloride under the trade names Sensoval, Aventyl, Pamelor Opipramol (Opipramol-neuraxpharm Insidon is an Anxiolytic primarily used in Germany Protriptyline (Vivactil is a Tricyclic antidepressant (TCA specifically a Secondary amine, indicated for depression and ADHD Trimipramine is an Tricyclic antidepressant with Sedative and Anxiolytic properties and available as Stangyl Surmontil Rhotrimine and generic forms This is often reported as selectivity ratios. Some of the above, in order from most selective for nor-epinephrine to most selective for serotonin: lofepramine, nortriptyline, amitriptyline, imipramine, clomipramine^[1].

Amine classification

Tricyclics are sometimes classified as tertiary amines and secondary amines. Amines are Organic compounds and Functional groups that contain a basic Nitrogen Atom with a Lone pair. In general, the tertiary amines boost serotonin as well as nor-epinephrine (adrenergic) and produce more sedation, anticholinergic effects, and orthostatic hypotension. ^[2] The secondary amines act primarily on nor-epinephrine and tend to have a lower side-effect profile^[3].

Tertiary amines include: amitriptyline, imipramine, trimipramine, doxepin, clomipramine, and lofepramine.

Secondary amines include: nortriptyline, desipramine, protriptyline, and amoxapine.

Mechanism of action

The exact mechanism of action is not well understood, however it is generally thought that tricyclic antidepressants work by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by neurons. In Pharmacology, the term mechanism of action (MOA refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect Reuptake, or re-uptake, is the reabsorption of a Neurotransmitter by the Neurotransmitter transporter of a pre-synaptic Neuron after See Chemical synapse for an introduction to concepts and terminology used in this article Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Serotonin (ˌsɛrəˈtoʊnən ( 5-hydroxytryptamine, or 5-HT) is a Monoamine Neurotransmitter synthesized in serotonergic Neurons Tricyclics may also possess an affinity for muscarinic and histamine H1 receptors to varying degrees. Although the pharmacologic effect occurs immediately, often the patient's symptoms do not respond for 2 to 4 weeks. Pharmacology (from Greek grc φάρμακον pharmakon, "drug" and grc -λογία -logia) is the study of how Drugs ^[4] Although norepinephrine and dopamine are generally considered stimulatory neurotransmitters, tricyclic antidepressants also increase the effects H1 histamine, and thus most have sedative effects. Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates Histamine is a Biogenic amine involved in local immune responses as well as regulating physiological function in the gut and acting as a Neurotransmitter A sedative, or more specifically a sedative-hypnotic, is a substance that depresses the Central nervous system (CNS resulting in calmness relaxation sleepiness ^[5]

Chemistry of re-uptake inhibitors

The chemical action of re-uptake inhibitors in general was unknown for a long time. In August 2007, two research groups independently reported that the tricyclic molecule docks to the transporter protein in a cavity adjacent to where the neurotransmitter substrate binds, locking the substrate in place and thereby obstructing re-uptake transport. ^[6]

Clinical use

Tricyclic antidepressants are used in numerous applications; mainly indicated for the treatment of clinical depression, neuropathic pain, nocturnal enuresis, and ADHD, but they have also been used successfully for headache (including migraine headache), anxiety, insomnia, smoking cessation, bulimia nervosa, irritable bowel syndrome, narcolepsy, pathological crying or laughing, persistent hiccups, interstitial cystitis, and ciguatera poisoning, and as an adjunct in schizophrenia. Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Neuropathy is a medical term usually short for Peripheral neuropathy. Pain, in the sense of physical pain, is a typical sensory experience that may be described as the unpleasant awareness of a noxious stimulus or bodily harm Bedwetting is involuntary Urination while asleep after the age at which bladder control would normally be anticipated Attention-Deficit Hyperactivity Disorder (ADHD is a neurobehavioral developmental disorder affecting about 3-5% of the world's population A headache ( cephalalgia in medical terminology is a condition of pain in the Head; sometimes Neck or upper back pain may also be interpreted Migraine is a neurological Syndrome characterized by altered bodily experiences painful headaches and nausea Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity Smoking cessation is the effort to stop smoking Tobacco products Bulimia nervosa is an Eating disorder characterized by recurrent Binge eating, followed by compensatory behaviors referred to as "purging" In Gastroenterology, irritable bowel syndrome ( IBS) is a Functional bowel disorder characterized by mild to severe Abdominal pain, discomfort Narcolepsy is a Neurological condition most characterized by Excessive Daytime Sleepiness (EDS in which a person falls asleep during the day at inappropriate A hiccup or hiccough (normally pronounced "HICK-up" ˈhɪkʌp also known as a condition of singulitis is the Spasmodic contraction of the diaphragm Interstitial cystitis (commonly abbreviated to "IC" is a Urinary bladder Disease of unknown cause characterised by urinary frequency (as often as every Ciguatera is a Foodborne illness poisoning in humans caused by eating Marine species whose flesh is contaminated with a toxin known as Ciguatoxin, Schizophrenia ( from the Greek roots schizein (σχίζειν "to split" and phrēn ^[4]

Depression

For many years they were the first choice for pharmacological treatment of depression. Although still considered effective, they have been increasingly replaced by SSRIs and other newer drugs. Selective serotonin reuptake inhibitors ( SSRIs) are a class of Antidepressants used in the treatment of depression, Anxiety disorders Newer antidepressants are thought to have fewer side effects and are also thought to be less effective if used in a suicide attempt, as the treatment and lethal doses (see therapeutic index) are farther apart than with the tricyclic antidepressants. An adverse drug reaction (abbreviated ADR) or adverse drug event (abbreviated ADE) is an expression that describes the unwanted negative consequences The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic Tricyclic antidepressants are sometimes still used to treat refractory depression that has failed to respond to standard SSRI therapy. ^[7] They are not considered addictive and are preferable to the MAOIs. Monoamine oxidase inhibitors ( MAOIs) are a class of powerful antidepressant drugs prescribed for the treatment of depression. Side effects usually occur before depression is effectively suppressed; for this reason and via other mechanisms they can be dangerous, as volition may be increased, giving the patient greater ability to attempt suicide. Volition or will is the cognitive process by which an individual decides on and commits to a particular course of action ^[8]

ADHD

Tricyclic antidepressants have been shown to be effective in treating attention-deficit hyperactivity disorder. Attention-Deficit Hyperactivity Disorder (ADHD is a neurobehavioral developmental disorder affecting about 3-5% of the world's population ^[9] ADHD is thought to be caused by dopamine and norepinephrine shortages in the brain's prefrontal cortex. Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Tricyclic antidepressants block the reuptake of these neurotransmitters. ^[10] They are commonly used in patients for whom psychostimulants (the primary medication for ADHD) are ineffective or contraindicted. TCAs are more effective in treating the behavioral aspects of ADHD than the cognitive deficits; they help limit hyperactivity and impulsivity but have little effect on attention. ^[11]

Analgesia

Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain (like back pain in radiculitis). Neuropathy is a medical term usually short for Peripheral neuropathy. Radicular Pain, or Radiculitis, is pain "radiated" along the dermatome (sensory distribution of a Nerve due to inflammation or other irritation ^[12][13] A precise mechanism for their analgesic action is unknown, but it is thought that they modulate opioid systems in the CNS via an indirect serotonergic route. An opioid is a chemical Substance that has a Morphine -like action in the body In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. ^[14] Typically pain modification requires lower dosages than for treating depression (e. g. Amitriptyline at 10 to 30 mg rather than 75 to 150 mg). They are also effective in migraine prophylaxis, but not in relief of an acute migraine attack. Migraine is a neurological Syndrome characterized by altered bodily experiences painful headaches and nausea This is also believed to be related to serotonergic effects. There is, however, little evidence for an analgesic effect in acute pain. ^[4]

Nocturnal enuresis

Tricyclics with greater anti-muscarinic action (i. A muscarinic receptor antagonist is an agent that reduces the activity of the Muscarinic acetylcholine receptor. e. , amitriptyline, imipramine and nortriptyline) may prove useful in helping to treat nocturnal enuresis (bedwetting) in children over the age of 7 years. Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil Tryptanol Endep Elatrol Tryptizol Trepiline Laroxyl Saroten is a Tricyclic antidepressant Imipramine (sold as Antideprin, Deprenil, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil Nortriptyline is a second generation Tricyclic antidepressant marketed as the Hydrochloride under the trade names Sensoval, Aventyl, Pamelor Bedwetting is involuntary Urination while asleep after the age at which bladder control would normally be anticipated The drug needs to be gradually withdrawn and the total treatment period is advised to be no greater than 3 months at a time. It is thought that the anticholinergic effects of tricyclics may inhibit urination, and/or the CNS stimulant effect may lead to easier arousal when the stimulus of a full bladder occurs. ^[15] However, one robust review of tricyclics for the treatment of enuresis found the benefits of tricyclics were relatively small and transient and due to potentially serious adverse effects suggested more research into other methods (bedwetting alarms, behavioural methods, desmopressin) which may be better suited for treatment of this condition. A bedwetting alarm is an electronic device used as a treatment option for Nocturnal Enuresis. Desmopressin (trade names DDAVP, Stimate, Minirin) is a Synthetic replacement for antidiuretic hormone, the Hormone that ^[16]

Side effects

Many side effects are related to tricyclics antimuscarinic actions. A muscarinic receptor antagonist is an agent that reduces the activity of the Muscarinic acetylcholine receptor. The antimuscarinic side effects are relatively common and include:

• Dry mouth (salivary secretion is affected)
• Dry nose
• Blurred vision (accommodation in the eye is affected)
• Decreased gastro-intestinal motility and secretion. This may lead to constipation
• Urinary retention or difficulty with urination
• Hyperthermia

Tolerance to these adverse effects often develops if treatment is continued, side effects may also be less troublesome if treatment is initiated with low dose and then gradually increased, although this may delay the clinical effect. Constipation, costiveness, or irregularity, is a condition of the Digestive system in which a person (or animal experiences hard Feces that Hyperthermia, in its advanced state referred to as heat stroke or sunstroke, is an acute condition which occurs when the Body produces or absorbs more

Other side effects may include drowsiness, anxiety, restlessness, cognitive and memory difficulties, confusion, dizziness, akathisia, hypersensitivity reactions, increased appetite with weight gain, sweating, decrease in sexual ability and desire, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components In Psychology, memory is an organism's ability to store retain and subsequently retrieve information Confusion, of a Pathological degree usually refers to loss of orientation (ability to place oneself correctly in the world by time location and personal identity and Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain Hypersensitivity (also called hypersensitivity reaction refers to undesirable (damaging discomfort-producing and sometimes fatal reactions produced by the normal immune system Muscle (from Latin musculus, diminutive of mus "mouse" is contractile tissue of the body and is derived from the In Physiology and Medicine, hypotension refers to an abnormally low Blood pressure. Dysrhythmia redirects here For the American band see Dysrhythmia (band. ^[4] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs. [1]

Interactions

TCAs are highly metabolized by the cytochrome P450 hepatic enzymes. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, antipsychotics, and calcium channel blockers) may produce decreases in the tricyclic's metabolism leading to increases in tricyclic blood concentrations and accompanying toxicity. Cytochrome P450 (abbreviated CYP, P450, infrequently CYP450) is a very large and diverse superfamily of Hemoproteins found in all Domains Cimetidine ( INN) (sɨˈmɛtɨdiːn/ /saɪ- is a histamine H2-receptor antagonist that inhibits the production of acid in the Stomach. Calcium channel blockers are a class of drugs and natural substances with effects on many excitable cells of the body like the muscle of the Heart, smooth muscles Drugs which prolong the QT interval including antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. In medicine specifically Cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's Quinidine is a Pharmaceutical agent that acts as a Class I antiarrhythmic agent in the Heart. Astemizole (marketed under the brand name Hismanal) is a second generation Antihistamine drug which has a long duration of action Terfenadine is an Antihistamine formerly used for the treatment of allergic conditions Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. In Chemistry, an alcohol is any Organic compound in which a Hydroxyl group ( - O[[hydrogen H]]) is bound to a Carbon Barbiturates are drugs that act as central nervous system Depressants and by virtue of this they produce a wide spectrum of effects from mild Sedation Side effects may also be enhanced by other drugs which have antimuscarinic properties. ^[4]

Overdose

Tricyclic antidepressant overdose is a significant cause of fatal drug poisoning. In the context of Biology, poisons are substances that can cause damage, Illness, or Death to Organisms usually by The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity. In Medicine, Epidemiology and Actuarial science, the term morbidity can refer to the state of poor health (from Latin This is an article about the rock music band "Circulatory System" Additionally, they are a serious problem in the pediatric population due to their inherent toxicity^[17] and the availability of these in the home when prescribed for bed wetting and depression.

Symptoms

The central nervous system and heart are the two main systems that are affected. In Vertebrates the central nervous system ( CNS) is the part of the Nervous system which is enclosed in the Meninges. The heart is a muscular organ in all Vertebrates responsible for pumping Blood through the Blood vessels by repeated rhythmic Initial or mild symptoms include drowsiness, a dry mouth, nausea, and vomiting. Somnolence (or " drowsiness " is a state of near- Sleep, a strong desire for sleep or sleeping for unusually long periods (c Nausea ( Latin: Nausea, Greek:, " Sea-sickness " also called wamble) is the sensation of unease and discomfort Vomiting (also called throwing up, emesis) is the forceful expulsion of the contents of one's Stomach through the Mouth and sometimes the More severe complications, include hypotension, cardiac rhythm disturbances, hallucinations, and seizures. In Physiology and Medicine, hypotension refers to an abnormally low Blood pressure. A hallucination, in the broadest sense is a Perception in the absence of a stimulus. An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting Electrocardiogram (ECG) abnormalities are frequent and a wide variety of cardiac dysrhythmias can occur, the most common being sinus tachycardia and intraventricular conduction delay (QRS prolongation). Dysrhythmia redirects here For the American band see Dysrhythmia (band. ^[18] Seizures and cardiac dysrhythmias are the most important life threatening complications.

Toxicity

Tricyclics have a narrow therapeutic index, i. The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic e. the therapeutic dose is close to the toxic dose. In the medical literature the lowest reported toxic dose is 6. 7 mg per kg body weight, ingestions of 10 to 20 mg per kilogram of body weight are a risk for moderate to severe poisoning, although doses ranging from 1. 5 to 5 mg/kg may even present a risk. Most poison control centers refer any case of TCA poisoning (especially in children) to a hospital for monitoring. A poison control center ( PCC) or poison information center ( PIC) is a Medical facility that is able to provide immediate free and expert treatment ^[19] Factors that increase the risk of toxicity include advancing age, cardiac status, and concomitant use of other drugs. ^[20] However, serum drug levels are not useful for evaluating risk of arrhythmia or seizure in tricyclic overdose. ^[21]

Toxic mechanism

Most of the toxic effects of TCAs are caused by four major pharmacological effects. TCAs have anticholinergic effects, cause excessive blockade of norepinephrine reuptake at the postganglionic synapse, direct alpha adrenergic blockade, and importantly they block sodium membrane channels with slowing of membrane depolarization, thus having quinidine like effects on the myocardium. An anticholinergic agent is a substance that blocks the Neurotransmitter acetylcholine in the central and the Peripheral nervous system. Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Chemical synapses are specialized junctions through which Neurons signal to each other and to non-neuronal cells such as those in Muscles or Glands Quinidine is a Pharmaceutical agent that acts as a Class I antiarrhythmic agent in the Heart. Myocardium is the muscular tissue of the Heart. Relationship to other layers The other tissues of the heart are the Endocardium ^[22]

Treatment

Initial treatment of an acute overdose includes gastric decontamination of the patient. This is achieved by administering activated charcoal which adsorbs the drug in the gastrointestinal tract either orally or via a nasogastric tube. Activated carbon, also called activated charcoal or activated coal, is a form of Carbon that has been processed to make it extremely porous and thus to Adsorption is a process that occurs when a gas or liquid Solute accumulates on the surface of a solid or a liquid (adsorbent forming a film of molecules or atoms (the Nasogastric intubation is a medical process involving the insertion of a plastic tube ( nasogastric tube NG tube) through the Nose, past the Throat Other decontamination methods such as stomach pumps, ipecac induced emesis, or whole bowel irrigation are not recommended in TCA poisoning. Gastric Lavage, also commonly called Stomach pump or Gastric irrigation, is the process of cleaning out the contents of the Stomach. Syrup of ipecac commonly referred to as simply Ipecac is derived from the dried Rhizome and Roots of the Ipecacuanha plant and is a well-known Whole bowel irrigation ( WBI) is a medical process involving the rapid administration of large volumes of an osmotically balanced Polyethylene glycol solution ^[23][24]

Symptomatic patients are usually monitored in an intensive care unit for a minimum of 12 hours, with close attention paid to maintenance of the airways, along with monitoring of blood pressure, arterial pH, and continuous ECG monitoring. ^[22] Supportive therapy is given if necessary, including respiratory assistance, maintenance of body temperature, and administration of sodium bicarbonate as an antidote. Sodium bicarbonate or sodium hydrogen carbonate is the Chemical compound with the formula NaHCO3 An antidote or counterdose is a substance which can counteract a form of Poisoning. Sodium bicarbonate is given intravenously and it has been shown to be an effective treatment for resolving the metabolic acidosis and cardiovascular complications of TCA poisoning. Intravenous therapy or IV therapy is the giving of Liquid substances directly into a Vein. In Medicine, metabolic acidosis is a process which if unchecked leads to acidemia (i If sodium bicarbonate therapy fails to improve cardiac symptoms, conventional antidysrhythmic drugs such as phenytoin and magnesium can be used to reverse any cardiac abnormalities. Phenytoin sodium is a commonly used Antiepileptic. Phenytoin acts to dampen the unwanted runaway brain activity seen in seizure by reducing electrical conductance among brain Magnesium (mægˈniːziəm is a Chemical element with the symbol Mg, Atomic number 12 Atomic weight 24 However, no benefit has been shown from lidocaine or other class 1a and 1c antiarrhythmic drugs; it appears they worsen the sodium channel blockade, slow conduction velocity, and depress contractility and should be avoided in TCA poisoning. Lidocaine ( INN) (ˈlaɪdoʊkeɪn or lignocaine (former BAN) (/ˈlɪgnoʊkeɪn/ is a common Local anesthetic and antiarrhythmic drug ^[25] Hypotension is initially treated with fluids along with bicarbonate to reverse metabolic acidosis (if present), if the patient remains hypotensive despite fluids then further measures such as the administration of epinephrine, norepinephrine, or dopamine can be used to increase blood pressure. In Medicine, metabolic acidosis is a process which if unchecked leads to acidemia (i Norepinephrine ( INN) (abbreviated norepi or NE) or noradrenaline ( BAN) (abbreviated NA or NAd) is a Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates ^[25] Another potentially severe symptom is seizures; often seizures resolve without treatment but administration of a benzodiazepine or other anticonvulsive may be required for persistent muscular overactivity. The benzodiazepines (pronounced, often abbreviated to "benzos") are a class of Psychoactive drugs with varying Hypnotic There is no role for physostigmine in the treatment of tricyclic toxicity as it may increase cardiac toxicity and cause seizures. Physostigmine (also known as eserine from éséré West African name for the Calabar bean is a Parasympathomimetic, specifically a reversible Cholinesterase ^[22]

Tricyclic antidepressants are highly protein bound and have a large volume of distribution; therefore removal of these compounds from the blood with hemodialysis, hemoperfusion or other techniques are unlikely to be of any significant benefit. The volume of distribution (VD, also known as apparent volume of distribution, is a pharmacological term used to quantify the distribution In Medicine, hemodialysis (also haemodialysis) is a method for removing waste products such as Potassium and Urea, as well as free water Hemoperfusion (British English haemoperfusion) is a Medical process used to remove toxic substances from a patients Blood. ^[24]

Epidemiology

Studies in the 1990s in Australia and the United Kingdom showed that between 8 and 12% of drug overdoses were following TCA ingestion. For a topic outline on this subject see List of basic Australia topics. The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom, the UK or Britain,is a Sovereign state located TCAs may be involved in up to 33% of all fatal poisonings, second only to analgesics. ^[26][27]

Development history

Tricyclic antidepressants were developed amid the "explosive birth" of psychopharmacology in the early 1950s. The story begins with the synthesis of Chlorpromazine in December 1950 by Rhône-Poulenc's chief chemist, Paul Charpentier, from synthetic antihistamines developed by Rhône-Poulenc in the 1940s. Chlorpromazine (as chlorpromazine Hydrochloride, abbreviated CPZ, marketed in the US as Thorazine) is a Phenothiazine Antipsychotic Rhône-Poulenc was a French chemical and pharmaceutical company founded in 1928 through the merger of Société des Usines Chimiques du Rhône (Rhône Chemical Plant Company A histamine antagonist is an agent which serves to inhibit the release or action of Histamine. ^[28] Its psychiatric effects were first noticed at a hospital in Paris in 1952. The first widely-used psychiatric drug, by 1955 it was already generating significant revenue as an antipsychotic. Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia. ^[29] Research chemists quickly began to explore other derivatives of chlorpromazine.

The first TCA reported for the treatment of depression was imipramine, an imino-dibenzyl analogue of chlorpromazine code-named G22355. Imipramine (sold as Antideprin, Deprenil, Deprimin, Deprinol, Depsonil, Dynaprin, Eupramin, Imipramil It was not originally targeted for the treatment of depression. The drug's tendency to induce manic effects was "later described as 'in some patients, quite disastrous'". The paradoxical observation of a sedative inducing mania lead to testing with depressed patients. The first trial of imipramine took place in 1955 and the first report of antidepressant effects was published by Swiss psychiatrist Ronald Kuhn in 1957. ^[30] Some testing of Geigy’s imipramine, then known as Tofranil, took place at the Münsterlingen Hospital near Konstanz. ^[31] Geigy later became Ciba-Geigy and eventually Novartis. Novartis International AG is a multinational Pharmaceutical company based in Basel Switzerland that manufactures drugs such as Clozapine

Many patents were filed in the 1950s and 1960s concerning variations on these three-ring structures with applications to psychiatric conditions.

• Phenothiazine derivatives are described in U. Phenothiazine is the Organic compound with the formula S(C6H42NH S. patent 2,591,679 issued 1952-04-08 to John W. Year 1952 ( MCMLII) was a Leap year starting on Tuesday (link will display full calendar of the Gregorian calendar. Events 217 - Roman Emperor Caracalla is Assassinated (and succeeded by his Praetorian Cusic. The compounds described contain a sulfur group on the central carbon ring, and a nitrogen atom in the cental ring to which the side chain attaches, in the manner of chlorpromazine. Most of the illustrated side chains contain an amine group.

• Dibenzazepine derivatives are described in U. Benzazepines are Heterocyclic compounds consisting of a Benzene ring fused to an Azepine ring S. patent 3,074,931 issued 1963-01-22 by assignment to Smith Kline & French Laboratories. Year 1963 ( MCMLXIII) was a Common year starting on Tuesday (link will display full calendar of the Gregorian calendar. Events 565 - Eutychius is deposed as Patriarch of Constantinople by John Scholasticus. GlaxoSmithKline plc () is a United Kingdom -based pharmaceutical, biological and Healthcare Company. The compounds described share a tricyclic backbone identical to the backbone of the TCA amitriptyline and family of side chains typical of early TCA drugs. Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil Tryptanol Endep Elatrol Tryptizol Trepiline Laroxyl Saroten is a Tricyclic antidepressant

Merck introduced the second member of the TCA family, amitriptyline (Elavil), in 1961. Merck & Co Inc ( also known as Merck Sharp & Dohme or MSD outside the USA and Canada, is one of the largest Pharmaceutical companies ^[32]

These patents cover the structures of the compounds and their mode of chemical synthesis. Understanding of their mode of action as re-uptake inhibitors and development of the serotonin theory of depression came in the years to follow.

References

See also

• Antidepressant
• Clinical depression
• Tetracyclic antidepressant

External links

• MeSH Tricyclic+Antidepressive+Agents