Monoamine oxidase inhibitors (MAOIs)

are a class of medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.

Indications
MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder. There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports used in the treatment of clinical depression and anxiety. MAOIs appear to be particularly indicated for outpatients with "neurotic depression" complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected

Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenylethylamine and trace amines. Dopamine is equally deaminated by both types. Many formulations have forms of fluoride attached to assist in permeating the bloodbrain barrier, which is suspected as a factor in pineal gland effects.

Reversibility
The early MAOIs inhibited monoamine oxidase irreversibly. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.

Selectivity
MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B.

Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. Tyramine is broken down by MAO-A (and MAO-B), therefore inhibiting its action may result in excessive build-up of it, so diet must be monitored for tyramine intake. MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine so there are no dietary restrictions associated with this. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine.

Dangers
MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese effect"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result. MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine,[15] tramadol, and dextromethorphan Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.

Withdrawal
Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome which may be severe especially if MAOIs are discontinued abruptly or over-rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. For example, antidepressants have significantly less abuse potential than benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.

Interactions
The MAOIs are infamous for their numerous drug interactions. Unless the interaction is desired, any drug that falls within the following classifications should be avoided:

Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold. Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.

Such substances include:

Phenethylamines: 2C-B, Mescaline, Phenethylamine (PEA), etc.

Amphetamines: Amphetamine, MDMA ("Ecstasy"), Dextroamphetamine, Methampheta mine, DOM, etc.

Tryptamines: DMT, Psilocin/Psilocybin ("Magic Mushrooms"), etc.

Lysergamides: Ergolines/LSA, LSD ("Acid"), etc. Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, Par oxetine, Sertraline.

Serotonin, Norepinephrine, and/or Dopamine Reuptake Inhibitors:

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Desvenlafaxine, Duloxetine, Milnacipran, Venlafaxine. Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs): Amineptine, Bupropion, Methylphenidate, Nomifensine. Norepinephrine Reuptake Inhibitors (NRIs): Atomoxetine, Mazindol, Reboxetine. Tricyclic Antidepressants (TCAs): Amitriptyline, Butriptyline, Clomipramine, Desipramine, Dosule pin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Protriptyline, Trimipramine.

Tetracyclic Antidepressants (TeCAs): Amoxapine, Maprotiline. Phenylpiperidine derivative Opioids: Meperidine/Pethidine, Tramadol, Methadone, Fentanyl, Dextropropo xyphene, Propoxyphene.

Others: Brompheniramine, Chlorpheniramine, Cocaine, Cyclobenzaprine, Dextromethor phan (DXM), Ketamine, MDPV, Nefazodone, Phencyclidine (PCP), Pheniramine, Sibutr amine,Trazodone.

Serotonin, Norepinephrine, and/or Dopamine Releasers: 4-Methylaminorex (4MAR), Amphetamine, Benzphetamine, Cathine, Cathinone, Diethylcathinone, Ephedrine, Le vmetamfetamine,Lisdexamfetamine, MDMA ("Ecstasy"), Methamphetamine, Pemoline, Phe ndimetrazine, Phenethylamine (PEA), Phentermine, Propylhexedrine, Pseudoephedrine, Ph enylephrine, Tyramine.

Serotonin, Norepinephrine, and/or Dopamine Supplemental Precursors: 5-HTP, L-DOPA, LPhenylalanine, L-Tryptophan, L-Tyrosine. Local and General anesthetic in surgery and dentistry in particular those containing Epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as Phenelzine and it is, therefore, vital to inform all clinicians especially dentists of the potential effect of MAOIs and Local Anesthesia. In preparation for dental work, withdrawal from Phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using Local Anesthesia are advised to use a non-epinephrine anesthetic such as Carbocaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure and the level of the anesthetic should be regularly and appropriately topped up since nonepinephrine anestetics take longer to come into effect and wear off faster. Patients taking Phenelzine are advised to notify their Psychiatrist prior to any dental treatment. Certain Other Supplements: Hypericum perforatum ("St John's Wort"), Inositol, Rhodiola rosea, S-Adenosyl-L-Methionine (SAMe), L-Theanine. Other Monoamine Oxidase Inhibitors.

It is recommended by the FDA to contact a physician or pharmacist before taking any drug while on an MAOI.

List of MAOIs

Herbal Drugs

Selective MAO-A Inhibitors

Harmala alkaloids (found in Coffee,[27] Syrian rue,[28] Passion flower, Ayahuasca,Tribulus terrestris and Tobacco)

Harmine, Harmaline, Tetrahydroharmine, Harmalol, Harman, Norharman, etc.

Piperine[29] (found in Pepper has a 1.85 fold selectivity for MAOA over MAOB) Resveratrol[30] (found in Japanese knotweed and skin of red grapes) Curcumin[31] (found in Turmeric) Rhodiola rosea[32] (active constituent(s) unknown) Ruta graveolens[33] (active constituent(s) unknown) Ginkgo biloba[34] Anthocyanins[35] Proanthocyanidin[36]

Nonselective MAO-A/MAO-B Inhibitors

Selective MAO-B inhibitors

Catechin (found in the Tea plant, Cocoa, and Cat's claw)

Desmethoxyyangonin (found in Kava) Epicatechin[37] (also found in the Tea plant, Cocoa, and Cat's claw) Emodin[29] (found in Fo-Ti) Hydroxytyrosol (found in Olive oil) Gentiana lutea[38] (active constituent(s) unknown)

Unknown Selectivity

Liquorice (active constituent(s) unknown) Myristicin (found in Nutmeg, Parsley, and Dill) Siberian Ginseng (active constituent(s) unknown) Yerba Mate (active constituent(s) unknown) Yohimbe (active constituent(s) unknown)

Pharmaceutical Drugs

Nonselective MAO-A/MAO-B Inhibitors

Hydrazines

Benmoxin (Nerusil, Neuralex) Hydralazine (Apresoline) Iproclozide (Sursum) Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida) Isocarboxazid (Marplan) Isoniazid (Laniazid, Nydrazid) Mebanazine (Actomol) Nialamide (Niamid) Octamoxin (Ximaol, Nimaol) Phenelzine (Nardil, Nardelzine) Pheniprazine (Catron) Phenoxypropazine (Drazine) Pivalylbenzhydrazine (Tersavid) Procarbazine (Matulane, Natulan, Indicarb) Safrazine (Safra)

Non-Hydrazines

Caroxazone (Surodil, Timostenil) Echinopsidine (Adepren) Furazolidone (Furoxone, Dependal-M)

Linezolid (Zyvox, Zyvoxam, Zyvoxid) Tranylcypromine (Parnate, Jatrosom)

Selective MAO-A Inhibitors

Brofaromine (Consonar) Metralindole (Inkazan) Minaprine (Cantor) Moclobemide (Aurorix, Manerix) Pirlindole (Pirazidol) Toloxatone (Humoryl)

Selective MAO-B Inhibitors

Lazabemide (Pakio, Tempium) Pargyline (Eutonyl) Rasagiline (Azilect) Selegiline (Deprenyl, Eldepryl, Emsam)

Research Compounds

Nonselective MAO-A/MAO-B Inhibitors

Hydrazines

Metfendrazine

Selective MAO-A Inhibitors

Amiflamine Bazinaprine Befloxatone Cimoxatone Clorgyline Esuprone Eprobemide (Befol) Methylene Blue Pirlindole Sercloremine Tetrindole Thesputiaint CX157 (Tyrima)

Selective MAO-B Inhibitors

D-Deprenyl Ladostigil Milacemide Mofegiline

Antiparasitic

Invertebrate MAO Inhibitors

Amitraz antiparasitic used in animals for ticks, mites (sarcoptes, demodex) and lice. Used on plants as an insecticide against mites, aphids, etc.

Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor[1] (SSRIs) are a class of compounds typically used asantidepressants in the
treatment of depression, anxiety disorders, and some personality disorders. SSRIs are believed to increase the extracellular level of the neurotransmitter serotonin by inhibiting its reuptake into the presynaptic cell, increasing the level of serotonin in the synaptic cleft available to bind to the postsynaptic receptor. They have varying degrees of selectivity for the othermonoamine transporters, with pure SSRIs having only weak affinity for the noradrenaline and dopamine transporter.

Medical uses
The main indication for SSRIs is clinical depression. SSRIs are frequently prescribed for anxiety disorders, such as social anxiety, panic disorders, obsessivecompulsive disorder (OCD), eating disorders, chronic pain and occasionally, for posttraumatic stress disorder (PTSD). They are also frequently used to treat depersonalization disorder, although generally with poor results.

List of agents
Drugs in this class include (trade names in parentheses):

citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital) dapoxetine (Priligy) escitalopram (Lexapro, Cipralex, Seroplex, Esertia) fluoxetine (Depex, Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (IND)) fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox, Floxyfral) indalpine (Upstene) (discontinued)

paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc) sertraline (Zoloft, Lustral, Serlain, Asentra) zimelidine (Zelmid, Normud) (discontinued)

Adverse effects
General side effects are mostly present during the first 14 weeks while the body adapts to the drug (with the exception of sexual side effects, which tend to occur later in treatment). In fact, it often takes 68 weeks for the drug to begin reaching its full potential (the slow onset is considered a downside to treatment with SSRIs). Almost all SSRIs are known to cause one or more of these symptoms:

anhedonia apathy nausea/vomiting drowsiness or somnolence headache (very common as a short-term side effect) bruxism tinnitus extremely vivid or strange dreams dizziness fatigue mydriasis (pupil dilation) urinary retention changes in appetite insomnia and/or changes in sleep excessive diarrhea weight loss/gain (measured by a change in bodyweight of 7 pounds) increased risk of bone fractures and injuries changes in sexual behaviour (see the next section) increased feelings of depression and anxiety (which may sometimes provoke panic attacks) mania and psychotic disorders tremors (and other symptoms of Parkinsonism in vulnerable elderly patients)[16] autonomic dysfunction including orthostatic hypotension, increased or reduced sweating akathisia renal impairment Restless legs syndrome

suicidal ideation (thoughts of suicide) photosensitivity[17] Paresthesia dissociative disorders, cognitive disorders and loss of contact with reality Syndrome of inappropriate antidiuretic hormone hypersecretion

Bleeding tendencies
SSRIs appear to increase the risk of bleeding.[74] This includes an increased risk of GI bleeding, post operative bleeding,[74], and intracranial bleeding.[75] SSRIs are known to cause platelet dysfunction

Contraindications and drug interaction

One major contraindication of SSRIs is the concomitant use of MAOIs (monoamine oxidase inhibitors). This is likely to cause severe serotonin syndrome/toxidrome. People taking SSRIs should also avoid taking pimozide (an antipsychotic diphenylbutylpiperidine derivative). Tramadol hydrochloride (or Ultram, Ultracet) can, in rare cases, produce seizures when taken in conjunction with an SSRI or tricyclic antidepressant. Liver impairment is another contraindication for medications of this type. SSRIs may increase blood levels and risk of toxicities of certain medications: 1. highly protein-bound medications like warfarin (coumadin) and digoxin 2. antiarrhythmic agents like propafenone (Rythmol) or flecainide (Tambocor) 3. beta blockers like metoprolol (Toprol xl) or propranolol (Inderal) 4. Tricyclic antidepressants like amitriptyline (Elavil, Endep) etc. 5. triptans like sumatriptan (Imitrex, Imigran) etc. 6. benzodiazepines like alprazolam (Xanax) or diazepam (Valium)[citation needed] 7. carbamazepine (Tegretol) 8. cisapride (Propulsid) 9. clozapine (Clozaril) 10.ciclosporin (Neoral) 11.haloperidol (Haldol) 12.phenytoin (Dilantin) 13.pimozide (Orap) 14.theophylline (Theo-dur) Certain drugs may increase toxicities of SSRIs: 1. alcohol and other CNS depressants

2. methylene blue dye 3. diuretics (water pills) 4. MAOIs possibly fatal serotonin syndrome/toxidrome 5. sympathomimetic drugs like pseudoephedrine (Sudafed) 6. lithium 7. sibutramine (Meridia) 8. MDMA (ecstasy) 9. zolpidem (ambien)[82] 10.dextromethorphan (cough suppressant) increased risk of serotonin syndrome/toxidrome 11.tramadol (synergistic serotoninergic effect said to increase risk of seizure or serotonin syndrome/toxidrome) 12.pethidine/meperidine increased risk of serotonin syndrome/toxidrome 13.herbal Saint John's wort or yohimbe increased risk of serotonin syndrome/toxidrome Painkillers of the NSAIDs drug family may interfere and reduce efficiency of SSRIs: [83][84] 1. Aspirin 2. Ibuprofen (Advil,Nurofen) 3. Naproxen (Aleve)

Tricyclic antidepressants (TCAs) are heterocyclic chemical compounds used primarily as antidepressants.

Tricyclic antidepressant
From Wikipedia, the free encyclopedia
Tricyclic antidepressants (TCAs) are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; [1] they are named after their chemical structure, which contains three rings of atoms. Thetetracyclic antidepressants (TeCAs), which contain four rings of atoms, are a closely related group of antidepressant compounds. In recent times, the TCAs have been largely replaced in clinical use in most parts of the world by newer antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), which typically have more favorable side-effects profiles, though they are still sometimes prescribed for certain indications.[edit]

List of TCAs
The TCAs include the following agents which are predominantly serotonin and/or norepinephrine reuptake inhibitors:

and

Amitriptyline (Tryptomer, Elavil) Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin) Butriptyline (Evadyne) Clomipramine (Anafranil) Demexiptiline (Deparon, Tinoran) Desipramine (Norpramin, Pertofrane) Dibenzepin (Noveril, Victoril) Dimetacrine (Istonil, Istonyl, Miroistonil) Dosulepin/Dothiepin (Prothiaden) Doxepin (Adapin, Sinequan) Imipramine (Tofranil, Janimine, Praminil) Imipraminoxide (Imiprex, Elepsin) Lofepramine (Lomont, Gamanil) Melitracen (Deanxit, Dixeran, Melixeran, Trausabun) Metapramine (Timaxel) Nitroxazepine (Sintamil) Nortriptyline (Pamelor, Aventyl, Norpress) Noxiptiline (Agedal, Elronon, Nogedal) Pipofezine (Azafen/Azaphen) Propizepine (Depressin, Vagran) Protriptyline (Vivactil) Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine)

Amineptine (Survector, Maneon, Directim) - Norepinephrine-dopamine reuptake inhibitor Iprindole (Prondol, Galatur, Tetran) - 5-HT2 receptor antagonist Opipramol (Insidon, Pramolan, Ensidon, Oprimol) - receptor agonist Tianeptine (Stablon, Coaxil, Tatinol) - Selective serotonin reuptake enhancer Trimipramine (Surmontil) - 5-HT2 receptor antagonist

[edit]Indications
The TCAs are used primarily in the clinical treatment of mood disorders such as major depressive disorder (MDD), dysthymia, and treatment-resistant variants. They are also used in the treatment of a number of other medical disorders, including anxiety disorders such as generalized anxiety disorder (GAD), social phobia (SP) also known as social anxiety disorder, obsessive-compulsive disorder (OCD), and panic disorder (PD), post-traumatic stress disorder (PTSD), body dysmorphic disorder (BDD), eating disorders like anorexia nervosa and bulimia nervosa, certain personality disorders such as borderline personality disorder (BPD), attention-deficit hyperactivity disorder (ADHD), as well as chronic pain, neuralgia or neuropathic pain, and fibromyalgia, headache, ormigraine, smoking cessation, tourette syndrome, trichotillomania, irritable bowel syndrome (IBS), interstitial cystitis (IC), nocturnal enuresis (NE),[4] narcolepsy, insomnia, pathological cryingand/or laughing, chronic hiccups, ciguatera p oisoning, and as an adjunct in schizophrenia.

Pharmacology
The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.[16][17] Notably, the TCAs have negligible affinity for thedopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).[16] Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.[18] In addition to their reuptake inhibition, many TCAs also have high affinity as antagonists at the 5-HT2[19] (5HT2A[20] and 5-HT2C[20]), 5-HT6,[21] 5-HT7,[22] 1-adrenergic,[19] and NMDAreceptors,[23] and as agonists at the sigma receptors[24] (1[24] and 2[25]), some of which may contribute to their therapeutic efficacy, as well as their side effects.[26] The TCAs also have varying but typically high affinity for antagonising the H1[19] and H2[27][28] histamine receptors, as well as the muscarinic acetylcholine receptors.[19] As a result, they also act as potent antihistaminesand anticholinergics. These properties are generally undesirable in antidepressants, however, and likely contribute to their large side effect profiles.[26]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[29][30]The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[31]

Side effects
Many side effects may be related to the antimuscarinic properties of the TCAs. Such side effects are relatively common and may include dry mouth, dry nose, blurry vision, lowered gastrointestinal motility or

constipation, urinary retention, cognitive and/or memory impairment, and increased body temperature.
Other side effects may include drowsiness, anxiety, emotional blunting (apathy/anhedonia),

confusion, restlessness, dizziness, akathisia, hypersensitivity, changes in appetite and weight, sweating, sexual dysfunction, muscle twitches, weakness, nausea and vomiting, hypotension, tachycardia, and rarely, irregular heart rhythms. Twitching, hallucinations, delirium and coma are also some of the toxic effects caused by overdose. [34] Rhabdomyolysis or muscle breakdown has been rarely reported with this class of drugs as well.[35].

[edit]Discontinuation
Antidepressants in general may produce a discontinuation syndrome. Since the term "withdrawal" has been linked to addiction to recreational drugs like opioids the medical profession and pharmaceutical public relations prefer that a different term be used, hence "discontinuation syndrome."[36] Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms.[37] In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.[38]

[edit]Interactions
The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes. Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, andcalcium channel blockers) may produce decreases in the TCAs' metabolism, leading to increases in their blood concentrations and accompanying toxicity.[39] Drugs that prolong the QT intervalincluding antiarrhythmics such as quinidine, the antihistamines astemizole and terfenadine, and some antipsychotics may increase the chance of ventricular dysrhythmias. TCAs may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Side effects may also be enhanced by other drugs that have antimuscarinic properties.

[edit]Overdose
Main article: Tricyclic antidepressant overdose

TCA overdose is a significant cause of fatal drug poisoning. The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurologicaltoxicity. Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[40] and the availability of these in the home when prescribed for bed wetting and depression. A number of treatments are effective in a TCA overdose. An overdose on TCA is especially fatal as they are rapidly absorbed from GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose. However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting). Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose [41]: 1. Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever 2. Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals) 3. CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia 4. Pulmonary effects: hypoventilation resulting from CNS depression 5. Gastrointestinal effects: decreased or absent bowel sounds Treatment depends on severity of symptoms. If there is a metabolic acidosis, infusion of sodium bicarbonate is recommended by Toxbase (UK poisons advice website). Two mechanisms are postulated for its therapeutic effect. Tricyclics are protein bound and become less bound in more acidic conditions. By reversing the acidosis, protein binding increases and bioavailability thus decreases. An alternative explanation is that the sodium load helps to reverse the Na+ channel blocking effects of the TCA. Treatment is otherwise supportive.