Tricyclic Antidepressants

Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. In effect, there is an increased concentration of neurotransmitters in the synapse Synapse The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. Synapses and Neurotransmission. Histaminic, muscarinic, and adrenergic receptors are also blocked, leading to a wide array of side effects. For decades, TCAs have been utilized for depression and are considered alternative antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications options to selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs). Full effects take a latent period of around 2–3 weeks. Overdose can lead to cardiac toxicity, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma. Other uses include treatment for anxiety disorders, chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain syndrome, and nocturnal enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders.

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Table of Contents

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Overview

Tricyclics antidepressants (TCAs)

  • Antidepressant medications are named based on the characteristic 3-ring chemical structure.
  • Used mainly for depression, a unipolar mood disorder characterized by persistent low mood, loss of interest, and somatic symptoms for ≥ 2 weeks
  • 2nd-line management for depression after selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs)

Chemistry

  • Related to phenothiazines structurally 
  • Consists of 3-ring structure with a side chain
Chemical structure of imipramine, the first tca

Chemical structure of imipramine, the 1st tricyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (TCA)

Image: “2D structure of TCA imipramine (Tofranil)” by Harbin. License: Public Domain

Classification

  • Tertiary amines:
    • Have 2 methyl groups on the nitrogen atom of the side chain
    • Have more potency inhibiting reuptake of serotonin
    • Medications:
      • Amitriptyline 
      • Clomipramine
      • Doxepin 
      • Imipramine 
      • Trimipramine 
  • Secondary amines:
    • Have 1 methyl group at the side chain end 
    • Have more potency inhibiting reuptake of norepinephrine
    • Medications:
      • Desipramine
      • Nortriptyline 
      • Protriptyline

Pharmacodynamics and Pharmacokinetics

Mechanism of action

  • ↑ Number of neurotransmitters in the CNS:
    • Blocks the serotonin transporter and norepinephrine transporter (NET)  
    • ↑ Concentration of neurotransmitters in the synapse Synapse The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. Synapses and Neurotransmission 
  • Additional receptors blocked: 
    • 5-hydroxytryptamine receptor 2 (5-HT2)
    • Histaminergic H1 receptors
    • Alpha-1 adrenergic receptors
    • Muscarinic cholinergic receptors
Mechanisms antidepressants

Mechanisms of antidepressants:
Top center: Monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs) inhibit the activity of monoamine oxidase (MAO), thereby increasing the number of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). Mirtazapine, an alpha-2 adrenergic antagonist, results in increased release of norepinephrine and serotonin.
Right: The selective serotonin reuptake inhibitor (SSRI), fluoxetine, inhibits CNS serotonin or 5-hydroxytryptamine (5-HT) reuptake. Trazodone is a serotonin antagonist and reuptake inhibitor (SARI).
Left: Desipramine, a secondary amine tricyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (TCA), and maprotiline, a heterocyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications, have potency of inhibiting reuptake of norepinephrine.

Image by Lecturio.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: rapid oral absorption 
  • Distribution: 
    • Lipophilic property allows wide distribution, including the brain.
    • Extensive plasma albumin binding 
    • Half-life: average of 24 hours (thus, generally taken once a day)
  • Metabolism: 
    • Undergoes 1st-pass metabolism 
    • Metabolized in liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver via N-demethylation and ring hydroxylation 
  • Excreted via kidney 

Indications and Side Effects

Indications

  • Psychiatric: 
    • Major depressive disorder Major depressive disorder Major depressive disorder (MDD), commonly called depression, is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of ≥ 2 weeks. Major depressive disorder has the highest lifetime prevalence among all psychiatric disorders. Major Depressive Disorder (MDD) 
    • Anxiety disorders
    • Obsessive compulsive disorder 
  • Neurological: 
    • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache prophylaxis 
    • Chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain syndrome 
  • Nocturnal enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders 
  • Eating disorders 

Adverse effects

With a narrow therapeutic index and capability to block multiple neurotransmitter receptors, TCAs are associated with multiple side effects (e.g., cardiac, anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs).

  • H1 blockade:
    • Sedation
    • Confusion
    • Weight gain
  • Anticholinergic effect: 
    • Dry mouth (xerostomia)
    • Blurred vision 
    • Urinary retention and constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation 
    • Cognitive impairment 
    • Tachycardia
    • Glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma
  • Antiadrenergic Antiadrenergic Antiadrenergic agents are drugs that block the activity of catecholamines, primarily norepinephrine (NE). There are 2 major types of adrenergic receptors-alpha and beta receptors, and there are several subtypes of each. Antiadrenergic Drugs effect (vasodilation): 
    • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Priapism 
    • Erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction (ED)
  • Serotonergic effect: sexual dysfunction (more common with SSRIs)
  • QT prolongation and other cardiac arrhythmias
  • ↓ Seizure threshold
  • Bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones fractures
  • Antidepressants are associated with ↑ suicidal thinking

Overdose

  • Clinical features:
    • Cardiovascular:
      • Hypotension
      • Tachycardia 
      • Arrhythmias
      • Prolonged QT interval 
    • Central nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System:
      • Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
      • Seizure 
      • Coma 
    • Anticholinergic toxicity (e.g., flushing, dilated pupils, ↑ temperature) 
  • 3 Cs of toxicity: 
    • Convulsions 
    • Cardiotoxicity 
    • Coma 
  • Management:
    • Supportive care with timely management of airway, breathing, and circulation (ABC)
    • Decontamination with activated charcoal within 2 hours of ingestion
    • IV infusion of sodium bicarbonate if metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis occurs 

Contraindications and Drug Interactions

Contraindications and precautions

  • Hypersensitivity to the drug
  • Angle closure glaucoma 
  • Enlarged prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. Prostate and other Male Reproductive Glands 
  • Urinary retention 
  • Heart disease 
  • Liver impairment
  • Thyroid disorders

Drug interactions

  • Potentiates the action of sympathomimetic drugs Sympathomimetic drugs Sympathomimetic drugs, also known as adrenergic agonists, mimic the action of the stimulators (α, β, or dopamine receptors) of the sympathetic autonomic nervous system. Sympathomimetic drugs are classified based on the type of receptors the drugs act on (some agents act on several receptors but 1 is predominate). Sympathomimetic Drugs and alcohol 
  • Should not be used concurrently with MAOIs and requires 14-day washout period (may lead to serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome
  • Antipsychotic Antipsychotic Antipsychotics, also called neuroleptics, are used to treat psychotic disorders and alleviate agitation, mania, and aggression. Antipsychotics are notable for their use in treating schizophrenia and bipolar disorder and are divided into 1st-generation antipsychotics (FGAs) and atypical or 2nd-generation antipsychotics. First-Generation Antipsychotics agents can increase the concentration of TCAs. 
  • Strong CYP2D6 inducers: ↓ TCA levels
  • Strong CYP2D6 inhibitors: ↑ TCA levels 

Comparison of TCAs

Table: Comparison of the characteristics of different medications in the TCA drug class
Medication Characteristics Indications Adverse effects
Amitriptyline
  • Tertiary amine (↑ blocking of serotonin reuptake)
  • High affinity to H1 and muscarinic receptors
  • MDD
  • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache prophylaxis
  • Neuropathic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain syndromes
  • Functional GI disorders
  • Highly sedating
  • Anticholinergic side effects
  • Cardiac conduction abnormalities
  • Acute angle closure glaucoma
Amoxapine
  • ↑ Blocking of norepinephrine reuptake
  • Also blocks dopamine receptor (antipsychotic)
MDD Well tolerated in relation to other medications
Clomipramine
  • Tertiary amine (↑ blocking of serotonin reuptake)
  • High affinity for H1 and muscarinic receptors
Obsessive compulsive disorder
  • Highly sedating
  • Weight gain
  • Anticholinergic side effects
Desipramine
  • Secondary amine (↑ blocking of norepinephrine reuptake)
  • Active metabolite of imipramine
  • Less affinity to H1 and muscarinic receptors
MDD Less anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs
Doxepin
  • Tertiary amine (↑ blocking of serotonin reuptake)
  • Strongest affinity for H1 receptors
  • MDD
  • Sleep Sleep Sleep is a reversible phase of diminished responsiveness, motor activity, and metabolism. This process is a complex and dynamic phenomenon, occurring in 4-5 cycles a night, and generally divided into non-rapid eye movement (NREM) sleep and REM sleep stages. Physiology of Sleep maintenance insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • ↑ Weight gain
  • Highly sedating
Imipramine
  • Tertiary amine (↑ blocking of serotonin reuptake)
  • High affinity for alpha-adrenergic, H1, and muscarinic receptors
  • MDD
  • Nocturnal enuresis Enuresis The elimination disorders that most commonly occur in childhood are enuresis (urinary incontinence) and encopresis (fecal incontinence in inappropriate situations). Enuresis is usually diagnosed when children > 5 years of age continue to wet the bed. Enuresis can occur both in the daytime (diurnal) and at night (nocturnal). Elimination Disorders
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Sedation
  • Weight gain
  • Anticholinergic side effects
Maprotiline
  • Tetra- or heterocyclic
  • Side chain similar to that of the secondary amines
  • ↑ Blocking of norepinephrine reuptake
  • Affinity for H1 receptor
  • MDD
  • Anxiety with depression
Highly sedating
Nortriptyline
  • Secondary amine (↑ blocking of norepinephrine reuptake)
  • Therapeutic window of efficacy (50 to 150 ng/mL)
  • Less affinity to H1 and muscarinic receptors
MDD Well tolerated in relation to other medications
Protriptyline
  • Secondary amine (↑ blocking of norepinephrine reuptake)
  • Most potent cyclic antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications
  • Less affinity to H1 and muscarinic receptors
MDD Well tolerated in relation to other medications
MDD: major depressive disorder

References

  1. Brunton, L. L., et al. (Eds.). (2017). Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed., McGraw Hill Medical.
  2. Doroudgar, S. (2018). Antidepressants. DeckerMed Medicine.
  3. Doroudgar, S. (2018). General psychopharmacology. DeckerMed Medicine.
  4. Hirsch, M., & Birnbaum, R. J. (2020). Tricyclic and tetracyclic drugs: Pharmacology, administration, and side effects. In Solomon, D. (Ed.). UpToDate. Retrieved Oct 14, 2021, from https://www.uptodate.com/contents/tricyclic-and-tetracyclic-drugs-pharmacology-administration-and-side-effects
  5. Khalid, M. M., & Waseem, M. (2021). Tricyclic antidepressant toxicity. In StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved October 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK430931/
  6. Moraczewski, J., & Aedma, K. K. (2020). Tricyclic antidepressants. In StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved October 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK557791/
  7. O’Donnell, J. M., Bies, R. R., & Shelton, R. C. (2017). Drug therapy of depression and anxiety disorders. In Brunton, L. L., Hilal-Dandan R., & Knollmann, B. C. (Eds.). Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed., McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=169518711
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  10. Mayo Clinic. (2019). Tricyclic antidepressants (TCAs). Retrieved August 9, 2021, from https://www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046983

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