Serotonin Reuptake Inhibitors and Similar Antidepressants
Serotonin Reuptake Inhibitors and Similar Antidepressants
Antidepressants encompass several drug classes and are used to treat individuals with depression, anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder, and psychiatric conditions, as well as those with chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways and symptoms of menopauseMenopauseMenopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause. Antidepressants include selective serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Antidepressants are indicated as the 1st-line treatment for anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorders and major depressive disorderMajor depressive disorderMajor 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) and are contraindicated in cases of current or recent use of monoamine oxidase inhibitorsMonoamine oxidase inhibitorsMonoamine 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. Therapeutic response to antidepressants takes 2–4 weeks and complete benefit is not seen until up to 8 weeks, which is attributed to downstream cellular responses necessary for eliciting a physiologic response. In general, serotonin-affecting antidepressants are well tolerated, but caution must be taken while prescribing them in combination with other drugs that inhibit or induce the same hepatic cytochrome P450Cytochrome P450A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism.Drug-Induced Liver InjuryenzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes to prevent increased levels of both drugs. An overdose can be life-threatening. It is important to recognize the signs and symptoms of SSRI/SNRI overdose to enable prompt treatment in an emergency setting.
Selective serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake inhibitors (SSRIs):
Vary considerably in their chemical structures
Have similar mechanisms of action, which result in increased synaptic serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS (also known as 5-hydroxytryptamine5-hydroxytryptamineA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS (5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS))
Serotonin-norepinephrine reuptake inhibitors (SNRIs) have a similar mechanism of action to SSRIs:
Chemical structures of duloxetine, milnacipran, and venlafaxine are dissimilar.
Desvenlafaxine and venlafaxine are bicyclic phenylethylamines with a similar structure.
Duloxetine is a naphthalene derivative.
SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS antagonist and reuptake inhibitors (SARIs): trazodone and nefazodone
Inhibit reuptake of serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS by blocking the 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS2AreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors (antagonist)
Induce significant changes in the 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS presynaptic receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors adrenoreceptors
Block histamine (H₁) and α-1 adrenergic receptorsAdrenergic receptorsCell-surface proteins that bind epinephrine and/or norepinephrine with high affinity and trigger intracellular changes. The two major classes of adrenergic receptors, alpha and beta, were originally discriminated based on their cellular actions but now are distinguished by their relative affinity for characteristic synthetic ligands. Adrenergic receptors may also be classified according to the subtypes of g-proteins with which they bind; this scheme does not respect the alpha-beta distinction.Autonomic Nervous System: Anatomy
5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS1AreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors partial agonist: vilazodone
Inhibits CNS neuron serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS uptake
No significant effect on the reuptake of norepinephrineNorepinephrinePrecursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus.Receptors and Neurotransmitters of the CNS (NE) or dopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS
SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS modulator and stimulator(SMS): vortioxetine
Inhibits serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake
Has agonist activity at the 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS1AreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors and antagonist activity at the 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS3receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
Mechanisms of antidepressants: The basic mechanisms of action of commonly prescribed antidepressants are listed. These medications include monoamine oxidase (MAO) inhibitors, the α-2 antagonist mirtazapine, the selective serotonin reuptake inhibitor fluoxetine, the serotonin antagonist and reuptake inhibitor trazodone, the tricyclic antidepressant desipramine, and the tetracyclic drug maprotiline.
Image by Lecturio.
PharmacodynamicsPharmacodynamicsPharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is “what the body does to the drug,” whereas pharmacodynamics is “what the drug does to the body.”Pharmacokinetics and Pharmacodynamics
SSRIs:
“Selective”: have affinity for the serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNSreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors and very little affinity for other receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
Many types of pre- and postsynaptic serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNSreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors exist (e.g., 5-HT2A and 5-HT2C).
SSRIs decrease the action of the presynaptic serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake pumpPumpACES and RUSH: Resuscitation Ultrasound Protocols by 60%–80% → increased 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS levels in the synaptic cleftSynaptic cleftSynapses and Neurotransmission
Increased levels of serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS are not sufficient to treat depression. The beneficial effect on mood takes several weeks and occurs due to:
Increased production of neuroprotective proteinsProteinsLinear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.Energy Homeostasis
Vary in their affinity for the serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS and NE transporters → ↑ NE and 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS levels in the synaptic cleftSynaptic cleftSynapses and Neurotransmission
The degree to which serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS and NE reuptake is inhibited depends on the dose and drug.
SARIs:
Relatively targeted at the 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS2A and 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS2CreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS2A and 5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS2C are G-protein-mediated receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors located in the neocortexNeocortexThe largest portion of the cerebral cortex in which the neurons are arranged in six layers in the mammalian brain: molecular, external granular, external pyramidal, internal granular, internal pyramidal and multiform layers.Cerebral Cortex: Anatomy → antidepressant action
Also block H₁ receptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
Physiologic effects:
Physical symptoms may improve in the 1st 1–2 weeks (energy, sleepSleepA readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility.Physiology of Sleep, appetite).
Affective symptoms improve after physical symptoms (mood, concentration, self-esteem).
Secondary serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS reuptake inhibitors
AbsorptionAbsorptionAbsorption 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:
Well-absorbed in the GI tract, not affected by food
Reach peak plasmaPlasmaThe residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation.Transfusion Products levels in a few hours
Distribution:
Lipophilic
Widely distributed throughout the body (including the brainBrainThe part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem.Nervous System: Anatomy, Structure, and Classification)
Metabolism:
Via cytochrome P450Cytochrome P450A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism.Drug-Induced Liver Injury (CYP)2D6, CYP3A4CYP3A4Class 3 Antiarrhythmic Drugs (Potassium Channel Blockers), and CYP2C19 pathways: significant for drug interactions
Half-lives vary from 21 hours (paroxetine) to 5 days (fluoxetine after long-term use).
Fluoxetine may be dosed every other day owing to its very long half-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics.
All SSRIs except fluvoxamine produce pharmacologically active metabolites.
Fluoxetine is the only drug with an active metabolite that has antidepressant activity.
Excreted in the urine and feces
Serotonin-norepinephrine reuptake inhibitors
AbsorptionAbsorptionAbsorption 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:
Food decreases the rate but not the degree of absorptionAbsorptionAbsorption 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.
Taking with meals may reduce nauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics, which is generally the most common side effect of SNRIs.
Distribution:
Duloxetine is highly protein bound and primarily undergoes hepatic clearance.
Other SNRIs are not as highly protein bound as duloxetine. Renal excretion plays a significant role in their clearance.
Metabolism:
Significant interindividual differences in the clearance of SNRIs
Doses may vary substantially among individuals.
Excretion:
Partially metabolized by the kidneysKidneysThe kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine.Kidneys: Anatomy and excreted in the urine
DosageDosageDosage Calculation adjustments may be required in individuals with CKDCKDChronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities.Chronic Kidney Disease.
SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS antagonist and reuptake inhibitor = trazodone (nefazodone is not currently available in the US)
Short-acting drug with a half-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics of 7 hours
SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS modulator and stimulator = vortioxetine
Protein binding: 98%
Hepatic metabolism mainly via oxidation by CYP450 isoenzymesIsoenzymesStructurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Basics of Enzymes, primarily CYP2D6, and subsequent glucuronic acid conjugationConjugationA parasexual process in bacteria; algae; fungi; and ciliate eukaryota for achieving exchange of chromosome material during fusion of two cells. In bacteria, this is a unidirectional transfer of genetic material; in protozoa it is a bi-directional exchange. In algae and fungi, it is a form of sexual reproduction, with the union of male and female gametes.Bacteriology to an inactive carboxylic acid metabolite
Long eliminationEliminationThe initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapyhalf-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics: approximately 66 hours (causes fewer withdrawal symptoms if doses are missed)
Excreted in the urine and feces
5-Hydroxytryptamine5-hydroxytryptamineA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS1AreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors partial agonist = vilazodone
EliminationEliminationThe initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapyhalf-lifeHalf-LifeThe time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity.Pharmacokinetics and Pharmacodynamics: approximately 25 hours
Classification and Indications
Antidepressant medications that affect serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS levels in the brainBrainThe part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem.Nervous System: Anatomy, Structure, and Classification to treat depression, anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder, and other conditions are classified into several groups. The most commonly prescribed antidepressants are SSRIs. Other important classes of antidepressants include monoamine oxidase inhibitorsMonoamine oxidase inhibitorsMonoamine 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 (MAOIsMAOIsMonoamine 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), tricyclic antidepressantsTricyclic antidepressantsTricyclic 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.Tricyclic Antidepressants (TCAsTCAsTricyclic 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.Tricyclic Antidepressants), and the NE/dopamineDopamineOne of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement.Receptors and Neurotransmitters of the CNS reuptake inhibitor (NDRI) bupropionBupropionA propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of dopamine.Other Antidepressants.
Classification
The brand names of commonly used medications are listed in parentheses for further understanding.
SSRIs:
Citalopram (Celexa)
Escitalopram (Lexapro)
Fluoxetine (Prozac)
Fluvoxamine (Luvox)
Paroxetine (Paxil)
Sertraline (Zoloft)
SNRIs:
Duloxetine (Cymbalta)
Venlafaxine (Effexor)
Desvenlafaxine (Pristiq)
Milnacipran (Savella)
SARIs:
Trazodone (generic)
Nefazodone: not currently available in the US (August 2021), but may soon be made available
SMS: vortioxetine (Trintellix)
Indications
Antidepressants are used to treat several psychiatric conditions, and SSRIs/SNRIs/SARIs/SMS are most commonly used to treat major depressive disorderMajor depressive disorderMajor 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) such as unipolarUnipolarNervous System: Histology depression and anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorders, and also to treat chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways.
General indications for antidepressant medications:
MDD:
SSRIs are usually the preferred 1st-line agents (except fluvoxamine).
Concomitant therapy with psychosocial/behavioral therapy should be considered.
AnxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorders:
Generalized anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorder
Social anxietyAnxietyFeelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders.Generalized Anxiety Disorder disorder
Panic disorderPanic disorderPanic disorder is a condition marked by recurrent and episodic panic attacks that occur abruptly and without a trigger. These episodes are time-limited and present with cardiorespiratory (palpitations, shortness of breath, choking), GI (nausea, abdominal distress), and neurologic (paresthesias, lightheadedness) symptoms.Panic Disorder
OCDOCDObsessive-compulsive disorder (OCD) is a condition characterized by obsessions (recurring and intrusive thoughts, urges, or images) and/or compulsions (repetitive actions the person is compelled to perform) that are time-consuming and associated with functional impairment.Obsessive-compulsive Disorder (OCD): SSRIs and SNRIs are effective.
Chronic painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways:
Chronic musculoskeletal painPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways
FibromyalgiaFibromyalgiaFibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia:
Duloxetine
Milnacipran (Savella) indicated for fibromyalgiaFibromyalgiaFibromyalgia is a chronic pain syndrome characterized by widespread body pain, chronic fatigue, mood disturbance, and cognitive disturbance. It also presents with other comorbid symptoms such as migraine headaches, depression, sleep disturbance, and irritable bowel syndrome. Fibromyalgia, not depression
Unique uses for some medications that may be preferred over other similar drugs:
PrematurePrematureChildbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization).Necrotizing Enterocolitis ejaculation: sertraline
Vasomotor symptoms of menopauseMenopauseMenopause is a physiologic process in women characterized by the permanent cessation of menstruation that occurs after the loss of ovarian activity. Menopause can only be diagnosed retrospectively, after 12 months without menstrual bleeding. Menopause: paroxetine, venlafaxine, escitalopram
Vulvodynia may respond to SNRIs.
MigraineMigraineMigraine 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 HeadacheprophylaxisProphylaxisCephalosporins in individuals without depression: escitalopram, venlafaxine
PTSDPTSDPosttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD): venlafaxine, paroxetine
BulimiaBulimiaEating an excess amount of food in a short period of time, as seen in the disorder of bulimia nervosa. It is caused by an abnormal craving for food, or insatiable hunger also known as ‘ox hunger’.Bulimia Nervosa nervosa: fluoxetine
Premenstrual dysphoric disorderPremenstrual Dysphoric DisorderPremenstrual dysphoric disorder (PMDD) refers to a group of mood, somatic, and behavioral symptoms that follow a cyclical pattern experienced by some women prior to menstruation. Unlike premenstrual syndrome (PMS), PMDD is characterized by significant distress and/or functional impairment. Premenstrual Dysphoric Disorder (PMDDPMDDPremenstrual dysphoric disorder (PMDD) refers to a group of mood, somatic, and behavioral symptoms that follow a cyclical pattern experienced by some women prior to menstruation. Unlike premenstrual syndrome (PMS), pmdd is characterized by significant distress and/or functional impairment.Premenstrual Dysphoric Disorder): fluoxetine, sertraline
InsomniaInsomniaInsomnia 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: Trazodone is used more as a sleepSleepA readily reversible suspension of sensorimotor interaction with the environment, usually associated with recumbency and immobility.Physiology of Sleep aid than to treat depression.
Atomoxetine (Strattera) is used for ADHDADHDAttention deficit hyperactivity disorder is a neurodevelopmental disorder characterized by a pattern of inattention and/or hyperactivity-impulsivity that occurs in at least 2 different settings for more than 6 months. Although the patient has normal intelligence, the disease causes functional decline.Attention Deficit Hyperactivity Disorder and narcolepsyNarcolepsyNarcolepsy is a neurological sleep disorder marked by daytime sleepiness and associated with cataplexy, hypnagogic hallucinations, and sleep paralysis. There are 2 types of narcolepsy: type 1 is associated with cataplexy and type 2 has no association with cataplexy. Narcolepsy:
The exact mechanism of action is unknown; however, it selectively inhibits NE reuptake.
None of the SSRIs significantly affect the α-adrenergic, histaminic, or cholinergic receptorsCholinergic receptorsCell surface proteins that bind acetylcholine with high affinity and trigger intracellular changes influencing the behavior of cells. Cholinergic receptors are divided into two major classes, muscarinic and nicotinic, based originally on their affinity for nicotine and muscarine. Each group is further subdivided based on pharmacology, location, mode of action, and/or molecular biology.Autonomic Nervous System: Anatomy, except for paroxetine, which has a weak antagonistic effect on the cholinergic receptorsCholinergic receptorsCell surface proteins that bind acetylcholine with high affinity and trigger intracellular changes influencing the behavior of cells. Cholinergic receptors are divided into two major classes, muscarinic and nicotinic, based originally on their affinity for nicotine and muscarine. Each group is further subdivided based on pharmacology, location, mode of action, and/or molecular biology.Autonomic Nervous System: Anatomy. The side effects of all SSRIs are due to their effects on the serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNSreceptorsReceptorsReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors.
Adverse effects
SSRIs:
GI:
NauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics
DiarrheaDiarrheaDiarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea (most common with sertraline)
Sexual dysfunctionSexual dysfunctionPhysiological disturbances in normal sexual performance in either the male or the female.Sexual Physiology:
Anorgasmia in women or delayed orgasm in men (sertraline may be used as a treatment for prematurePrematureChildbirth before 37 weeks of pregnancy (259 days from the first day of the mother’s last menstrual period, or 245 days after fertilization).Necrotizing Enterocolitis ejaculation)
Decreased libido
Erectile dysfunctionErectile DysfunctionErectile 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
Weight changes: also may be due to depression itself
HeadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain Abscess
CNS depression
InsomniaInsomniaInsomnia 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
Increased risk of bleeding due to inhibition of platelet serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS uptake (and drug interaction with clopidogrelClopidogrelA ticlopidine analog and platelet purinergic p2y receptor antagonist that inhibits adenosine diphosphate-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive diseases; myocardial infarction; stroke; or atrial fibrillation.Antiplatelet Drugs)
HyponatremiaHyponatremiaHyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism.Hyponatremia
Cardiovascular: Citalopram may cause QT prolongation.
SNRIs, vilazodone, and vortioxetine:
Similar side effects as SSRIs
SNRIs may cause a slight increase in blood pressure.
Trazodone (SARI):
GI:
ConstipationConstipationConstipation 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
NauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics
HeadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain Abscess
FatigueFatigueThe state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli.Fibromyalgia
HeadacheHeadacheThe symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders.Brain Abscess
NauseaNauseaAn unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses.Antiemetics
InsomniaInsomniaInsomnia 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
Irritability
ParesthesiasParesthesiasSubjective cutaneous sensations (e.g., cold, warmth, tingling, pressure, etc.) that are experienced spontaneously in the absence of stimulation.Posterior Cord Syndrome: including a feeling of “electric-like” shocks
SerotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS syndrome (a potentially life-threatening side effect):
Usually caused by > 1 medication affecting the serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNSreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors
Was 1st described as a reaction between SSRIs and MAOIsMAOIsMonoamine 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
Drug combinations with SSRIs/SNRIs/other serotonergic antidepressants:
To treat migraineMigraineMigraine 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: triptansTriptansTriptans and ergot alkaloids are agents used mainly for the management of acute migraines. The therapeutic effect is induced by binding to serotonin receptors, which causes reduced vasoactive neuropeptide release, pain conduction, and intracranial vasoconstriction.Triptans and Ergot Alkaloids and ergots
Antidepressants: TCAsTCAsTricyclic 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.Tricyclic Antidepressants, MAOIsMAOIsMonoamine 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, antipsychotics
Anticonvulsants: carbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs, valproic acidValproic acidA fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels.First-Generation Anticonvulsant Drugs
Antianxiety drug: buspirone
OpioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation analgesics: tramadolTramadolA narcotic analgesic proposed for severe pain. It may be habituating.Opioid Analgesics, methadoneMethadoneA synthetic opioid that is used as the hydrochloride. It is an opioid analgesic that is primarily a mu-opioid agonist.Opioid Analgesics, codeineCodeineAn opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.Opioid Analgesics
Herbal supplements for depression: St. John’s Wort, 5-HTP
Antibiotic: linezolidLinezolidAn oxazolidinone and acetamide derived anti-bacterial agent and protein synthesis inhibitor that is used in the treatment of gram-positive bacterial infections of the skin and respiratory tract.Oxazolidinones
Street drugs: cocaineCocaineAn alkaloid ester extracted from the leaves of plants including coca. It is a local anesthetic and vasoconstrictor and is clinically used for that purpose, particularly in the eye, ear, nose, and throat. It also has powerful central nervous system effects similar to the amphetamines and is a drug of abuse. Cocaine, like amphetamines, acts by multiple mechanisms on brain catecholaminergic neurons; the mechanism of its reinforcing effects is thought to involve inhibition of dopamine uptake.Local Anesthetics, methamphetamineMethamphetamineA central nervous system stimulant and sympathomimetic with actions and uses similar to dextroamphetamine. The smokable form is a drug of abuse and is referred to as crank, crystal, crystal meth, ice, and speed.Stimulants
Symptoms include CNS stimulation, cardiovascular stimulation, and GI stimulation:
Severe muscle rigidityRigidityContinuous involuntary sustained muscle contraction which is often a manifestation of basal ganglia diseases. When an affected muscle is passively stretched, the degree of resistance remains constant regardless of the rate at which the muscle is stretched. This feature helps to distinguish rigidity from muscle spasticity.Megacolon
MydriasisMydriasisDilation of pupils to greater than 6 mm combined with failure of the pupils to constrict when stimulated with light. This condition may occur due to injury of the pupillary fibers in the oculomotor nerve, in acute angle-closure glaucoma, and in adie syndrome.Glaucoma
MyoclonusMyoclonusInvoluntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome.Neurological Examination
Hyperreflexia
Hyperthermia
SeizuresSeizuresA 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
TachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children
Unstable blood pressure
DiarrheaDiarrheaDiarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
Mnemonic to recall serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS syndrome manifestations: “Madam’s tips”
M = mental status changes
A = agitationAgitationA feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions.St. Louis Encephalitis Virus
D = diarrheaDiarrheaDiarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
A = ataxiaAtaxiaImpairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions.Ataxia-telangiectasia
M = myoclonusMyoclonusInvoluntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome.Neurological Examination
S = shiveringShiveringInvoluntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals.Body Temperature Regulation
T = tachycardiaTachycardiaAbnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia.Sepsis in Children
I = increased reflexes
P = pyrexia
S = sweating
Drug interactions
Both drug factors and patient factors can contribute to the toxicityToxicityDosage Calculation of SSRIs/SNRIs in some individuals.
Drug factors: Some SSRIs and SNRIs are moderate-to-potent inhibitors of hepatic cytochrome P450Cytochrome P450A superfamily of hundreds of closely related hemeproteins found throughout the phylogenetic spectrum, from animals, plants, fungi, to bacteria. They include numerous complex monooxygenases (mixed function oxygenases). In animals, these p450 enzymes serve two major functions: (1) biosynthesis of steroids, fatty acids, and bile acids; (2) metabolism of endogenous and a wide variety of exogenous substrates, such as toxins and drugs (biotransformation). They are classified, according to their sequence similarities rather than functions, into cyp gene families (>40% homology) and subfamilies (>59% homology). For example, enzymes from the cyp1, cyp2, and cyp3 gene families are responsible for most drug metabolism.Drug-Induced Liver Injury → drug-drug interactions by altering blood levels of other medications that depend on these enzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for clearance or activation
Patient factors: Enzyme may function differently in individuals with significant variations in the CYP2D6 geneGeneA category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms.Basic Terms of Genetics.
“Slow metabolizers”
“Extensive metabolizers”
CYPs are hepatic enzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes that metabolize several drugs:
Render the drug either more or less active
Combinations of drugs using the same metabolic pathway can cause serious adverse effects.
Examples of the CYP450 family of proteinsProteinsLinear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein.Energy Homeostasis used by antidepressants:
CYP2C9CYP2C9A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics.Anticoagulants
CYP1A2
SSRI drug interactions with other drugs that are metabolized by CYP450 enzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes:
Citalopram and escitalopram inhibit liverLiverThe 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: AnatomyenzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes much less than other SSRIs.
Fluoxetine and paroxetine are potent inhibitors of CYP2D6 causing ↑ 2D6 substrateSubstrateA substance upon which the enzyme acts.Basics of Enzymes levels
Other CYP2D6 inhibitors that can interact with SSRIs and should be used with caution:
Antiarrhythmic agents: amiodaroneAmiodaroneAn antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting potassium channels and voltage-gated sodium channels. There is a resulting decrease in heart rate and in vascular resistance.Pulmonary Fibrosis, quinidineQuinidineAn optical isomer of quinine, extracted from the bark of the cinchona tree and similar plant species. This alkaloid dampens the excitability of cardiac and skeletal muscles by blocking sodium and potassium currents across cellular membranes. It prolongs cellular action potentials, and decreases automaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission.Class 1 Antiarrhythmic Drugs (Sodium Channel Blockers)
H₂ histamine receptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors antagonist: ranitidine
BupropionBupropionA propiophenone-derived antidepressant and antismoking agent that inhibits the uptake of dopamine.Other Antidepressants (an antidepressant in its own class)
CinacalcetCinacalcetCalcimimetics (used for hyperparathyroidismHyperparathyroidismHyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism)
Other CYP2D6 substrates (SSRIs can interact with other drugs and lead to increased drug levels and adverse effects):
β-blockers:
Used for hypertensionHypertensionHypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension or cardiac conditions: propranololPropranololA widely used non-cardioselective beta-adrenergic antagonist. Propranolol has been used for myocardial infarction; arrhythmia; angina pectoris; hypertension; hyperthyroidism; migraine; pheochromocytoma; and anxiety but adverse effects instigate replacement by newer drugs.Antiadrenergic Drugs, metoprololMetoprololA selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias.Antiadrenergic Drugs, atenololAtenololA cardioselective beta-1 adrenergic blocker possessing properties and potency similar to propranolol, but without a negative inotropic effect.Class 2 Antiarrhythmic Drugs (Beta Blockers), bisoprololBisoprololA cardioselective beta-1 adrenergic blocker. It is effective in the management of hypertension and angina pectoris.Class 2 Antiarrhythmic Drugs (Beta Blockers)
Combination with SSRIs can ↑ drug levels and cause hypotensionHypotensionHypotension 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
TamoxifenTamoxifenOne of the selective estrogen receptor modulators with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the endometrium.Antiestrogens: used to treat breast cancerBreast cancerBreast cancer is a disease characterized by malignant transformation of the epithelial cells of the breast. Breast cancer is the most common form of cancer and 2nd most common cause of cancer-related death among women. Breast Cancer
Antinausea medications: ondansetronOndansetronA competitive serotonin type 3 receptor antagonist. It is effective in the treatment of nausea and vomiting caused by cytotoxic chemotherapy drugs, including cisplatin, and has reported anxiolytic and neuroleptic properties.Antiemetics, metoclopramideMetoclopramideA dopamine d2 antagonist that is used as an antiemetic.Antiemetics
Other antidepressantsOther antidepressantsAntidepressants encompass several classes of medications and are used to treat individuals with depression, anxiety, and other psychiatric conditions, as well as to manage chronic pain and menopausal symptoms.Other Antidepressants:
Tricyclic (amitriptylineAmitriptylineTricyclic antidepressant with anticholinergic and sedative properties. It appears to prevent the reuptake of norepinephrine and serotonin at nerve terminals, thus potentiating the action of these neurotransmitters. Amitriptyline also appears to antagonize cholinergic and alpha-1 adrenergic responses to bioactive amines.Tricyclic Antidepressants, imipramineImipramineThe prototypical tricyclic antidepressant. It has been used in major depression, dysthymia, bipolar depression, attention-deficit disorders, agoraphobia, and panic disorders. It has less sedative effect than some other members of this therapeutic group.Tricyclic Antidepressants, nortriptylineNortriptylineA metabolite of amitriptyline that is also used as an antidepressant agent. Nortriptyline is used in major depression, dysthymia, and atypical depressions.Tricyclic Antidepressants)
Combination with SSRIs can ↑ drug levels and lead to serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS syndrome
Antipsychotics:
AripiprazoleAripiprazoleA piperazine and quinolone derivative that is used primarily as an antipsychotic agent. It is a partial agonist of serotonin receptor, 5-HT1a and dopamine D2 receptors, where it also functions as a postsynaptic antagonist, and an antagonist of serotonin receptor, 5-HT2a. It is used for the treatment of schizophrenia and bipolar disorder, and as an adjunct therapy for the treatment of depression.Second-Generation Antipsychotics, haloperidolHaloperidolA phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in intellectual disability and the chorea of huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups.First-Generation Antipsychotics, olanzapineOlanzapineA benzodiazepine derivative that binds serotonin receptors; muscarinic receptors; histamine h1 receptors; adrenergic alpha-1 receptors; and dopamine receptors. It is an antipsychotic agent used in the treatment of schizophrenia; bipolar disorder; and major depressive disorder; it may also reduce nausea and vomiting in patients undergoing chemotherapy.Second-Generation Antipsychotics, quetiapineQuetiapineA dibenzothiazepine and antipsychotic agent that targets the serotonin 5-HT2 receptor; histamine h1 receptor, adrenergic alpha1 and alpha2 receptors, as well as the dopamine d1 receptor and dopamine D2 receptor. It is used in the treatment of schizophrenia; bipolar disorder and depressive disorder.Second-Generation Antipsychotics, risperidoneRisperidoneA selective blocker of dopamine D2 receptors and serotonin 5-HT2 receptors that acts as an atypical antipsychotic agent. It has been shown to improve both positive and negative symptoms in the treatment of schizophrenia.Second-Generation Antipsychotics
Combination with SSRIs can ↑ drug levels and lead to serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS syndrome
1st-generation antihistaminesAntihistaminesAntihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines/H₁-receptor antagonists: chlorpheniramineChlorpheniramineA histamine h1 antagonist used in allergic reactions, hay fever, rhinitis, urticaria, and asthma. It has also been used in veterinary applications. One of the most widely used of the classical antihistaminics, it generally causes less drowsiness and sedation than promethazine.Antihistamines, diphenhydramineDiphenhydramineA histamine h1 antagonist used as an antiemetic, antitussive, for dermatoses and pruritus, for hypersensitivity reactions, as a hypnotic, an antiparkinson, and as an ingredient in common cold preparations. It has some undesired antimuscarinic and sedative effects.Antihistamines
PainPainAn unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons.Pain: Types and Pathways medications/opioidOpioidCompounds with activity like opiate alkaloids, acting at opioid receptors. Properties include induction of analgesia or narcosis.Constipation analgesics: codeineCodeineAn opioid analgesic related to morphine but with less potent analgesic properties and mild sedative effects. It also acts centrally to suppress cough.Opioid Analgesics or tramadolTramadolA narcotic analgesic proposed for severe pain. It may be habituating.Opioid Analgesics
Some calciumCalciumA basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Electrolytes channel blockers
StatinsStatinsStatins are competitive inhibitors of HMG-CoA reductase in the liver. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis. Inhibition results in lowered intrahepatocytic cholesterol formation, resulting in up-regulation of LDL receptors and, ultimately, lowering levels of serum LDL and triglycerides.Statins
BenzodiazepinesBenzodiazepinesBenzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
Hypnotics: zopiclone and zolpidem
Macrolide antibiotics: clarithromycinClarithromycinA semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50s ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation.Macrolides and Ketolides and azithromycinAzithromycinA semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis.Macrolides and Ketolides
Psychiatric medications: haloperidolHaloperidolA phenyl-piperidinyl-butyrophenone that is used primarily to treat schizophrenia and other psychoses. It is also used in schizoaffective disorder, delusional disorders, ballism, and tourette syndrome (a drug of choice) and occasionally as adjunctive therapy in intellectual disability and the chorea of huntington disease. It is a potent antiemetic and is used in the treatment of intractable hiccups.First-Generation Antipsychotics, mirtazapine
Antifungals: ketoconazoleKetoconazoleBroad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.Azoles
CalciumCalciumA basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Electrolytes channel blockers: specifically diltiazemDiltiazemA benzothiazepine derivative with vasodilating action due to its antagonism of the actions of calcium ion on membrane functions.Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers) and verapamilVerapamilA calcium channel blocker that is a class IV anti-arrhythmia agent.Pulmonary Hypertension Drugs
Grapefruit juice
Antivirals used in the management of HIVHIVAnti-HIV Drugs (note that they are also CYP34 substrates, as listed above)
Anticonvulsants: carbamazepineCarbamazepineA dibenzazepine that acts as a sodium channel blocker. It is used as an anticonvulsant for the treatment of grand mal and psychomotor or focal seizures. It may also be used in the management of bipolar disorder, and has analgesic properties.First-Generation Anticonvulsant Drugs, phenytoinPhenytoinAn anticonvulsant that is used to treat a wide variety of seizures. The mechanism of therapeutic action is not clear, although several cellular actions have been described including effects on ion channels, active transport, and general membrane stabilization. Phenytoin has been proposed for several other therapeutic uses, but its use has been limited by its many adverse effects and interactions with other drugs.First-Generation Anticonvulsant Drugs, barbituratesBarbituratesA class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants.Intravenous Anesthetics
RifampinRifampinA semisynthetic antibiotic produced from streptomyces mediterranei. It has a broad antibacterial spectrum, including activity against several forms of Mycobacterium. In susceptible organisms it inhibits dna-dependent RNA polymerase activity by forming a stable complex with the enzyme. It thus suppresses the initiation of RNA synthesis. Rifampin is bactericidal, and acts on both intracellular and extracellular organisms.Epiglottitis
St. John’s wort
CYP2C9CYP2C9A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics.Anticoagulants pathway: fluoxetine can also interact with:
Antifungals: voriconazoleVoriconazoleA triazole antifungal agent that specifically inhibits sterol 14-alpha-demethylase and cytochrome p-450 cyp3a.Azoles
Some TCAsTCAsTricyclic 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.Tricyclic Antidepressants
BenzodiazepinesBenzodiazepinesBenzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
Proton pump inhibitorsProton Pump InhibitorsCompounds that inhibit h(+)-k(+)-exchanging ATPase. They are used as anti-ulcer agents and sometimes in place of histamine h2 antagonists for gastroesophageal reflux.Gastric Acid Drugs: omeprazoleOmeprazoleA 4-methoxy-3, 5-dimethylpyridyl, 5-methoxybenzimidazole derivative of timoprazole that is used in the therapy of stomach ulcers and zollinger-ellison syndrome. The drug inhibits an h(+)-k(+)-exchanging ATPase which is found in gastric parietal cells.Gastric Acid Drugs
Fluvoxamine (a different SSRI) is a potent CYP2C9CYP2C9A cytochrome p-450 subtype that has specificity for acidic xenobiotics. It oxidizes a broad range of important clinical drugs that fall under the categories of nonsteroidal anti-inflammatory agents; hypoglycemic agents; anticoagulants; and diuretics.Anticoagulants inhibitor:
↑ Levels of the antipsychotics clozapineClozapineA tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors, and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2a/2c receptor subtype. It also displays strong affinity to several dopaminergic receptors, but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with administration of this agent.Second-Generation Antipsychotics, thioridazineThioridazineA phenothiazine antipsychotic used in the management of psychosis, including schizophrenia.First-Generation Antipsychotics, and olanzapineOlanzapineA benzodiazepine derivative that binds serotonin receptors; muscarinic receptors; histamine h1 receptors; adrenergic alpha-1 receptors; and dopamine receptors. It is an antipsychotic agent used in the treatment of schizophrenia; bipolar disorder; and major depressive disorder; it may also reduce nausea and vomiting in patients undergoing chemotherapy.Second-Generation Antipsychotics
Contraindicated with the hypnotic drug ramelteon (Rozerem), melatonin, and the muscle relaxant tizanidineTizanidineSpasmolytics (Zanaflex) due to the risk of causing increased drug levels and CNS depression
SNRI drug interactions:
Duloxetine is a moderately potent inhibitor of CYP2D6 and may interact with other drugs:
↑ MetoprololMetoprololA selective adrenergic beta-1 blocking agent that is commonly used to treat angina pectoris; hypertension; and cardiac arrhythmias.Antiadrenergic Drugs levels
↑ ThioridazineThioridazineA phenothiazine antipsychotic used in the management of psychosis, including schizophrenia.First-Generation Antipsychotics levels and risk of QT prolongation
Other SNRIs (venlafaxine, desvenlafaxine, and milnacipran) do not have significant effects on CYP enzymesEnzymesEnzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body’s constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
SARI (trazodone) drug interactions:
Some sedatives or CNS depressants can cause increased sedation:
OpioidsOpioidsOpiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics
BenzodiazepinesBenzodiazepinesBenzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
BarbituratesBarbituratesA class of chemicals derived from barbituric acid or thiobarbituric acid. Many of these are gaba modulators used as hypnotics and sedatives, as anesthetics, or as anticonvulsants.Intravenous Anesthetics
EthanolEthanolA clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages.Ethanol Metabolism
Potent CYP2D6 inhibitors (paroxetine, tamsulosinTamsulosinA sulfonamide derivative and adrenergic alpha-1 receptor antagonist that is used to relieve symptoms of urinary obstruction caused by benign prostatic hyperplasia.Antiadrenergic Drugs): ↑ trazodone levels
5-HT5-HTA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS1AreceptorReceptorReceptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell.Receptors partial agonist (vilazodone) drug interactions:
Similar adverse effects and contraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation as with SSRIs
Antibiotics: clarithromycinClarithromycinA semisynthetic macrolide antibiotic derived from erythromycin that is active against a variety of microorganisms. It can inhibit protein synthesis in bacteria by reversibly binding to the 50s ribosomal subunits. This inhibits the translocation of aminoacyl transfer-RNA and prevents peptide chain elongation.Macrolides and Ketolides, azithromycinAzithromycinA semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis.Macrolides and Ketolides
Antifungals: itraconazoleItraconazoleA triazole antifungal agent that inhibits cytochrome p-450-dependent enzymes required for ergosterol synthesis.Azoles, ketoconazoleKetoconazoleBroad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.Azoles
Antivirals: indinavirIndinavirA potent and specific HIV protease inhibitor that appears to have good oral bioavailability.Anti-HIV Drugs, nelfinavirNelfinavirA potent HIV protease inhibitor. It is used in combination with other antiviral drugs in the treatment of HIV in both adults and children.Anti-HIV Drugs, ritonavirRitonavirAn HIV protease inhibitor that works by interfering with the reproductive cycle of HIV. It also inhibits cytochrome p-450 cyp3a.Anti-HIV Drugs, saquinavirSaquinavirAn HIV protease inhibitor which acts as an analog of an HIV protease cleavage site. It is a highly specific inhibitor of HIV-1 and HIV-2 proteases, and also inhibits cytochrome p-450 cyp3a.Anti-HIV Drugs used in the management of HIVHIVAnti-HIV Drugs infection
Vortioxetine drug interactions: Use with other CYP2D6 inhibitors can ↑ vortioxetine levels
ContraindicationsContraindicationsA condition or factor associated with a recipient that makes the use of a drug, procedure, or physical agent improper or inadvisable. Contraindications may be absolute (life threatening) or relative (higher risk of complications in which benefits may outweigh risks).Noninvasive Ventilation
All SSRIs are contraindicated in individuals currently takingMAOIsMAOIsMonoamine 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 to treat depression.
The combination may increase the risk of serotoninSerotoninA biochemical messenger and regulator, synthesized from the essential amino acid l-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis, and cardiovascular integrity.Receptors and Neurotransmitters of the CNS syndrome.
Additive risks of CNS depression and psychomotor impairment
SSRIs/SNRIs/SARIs/SMS are not recommended for individuals with bipolarBipolarNervous System: Histology depression as these drugs may induce maniaManiaA state of elevated excitement with over-activity sometimes accompanied with psychotic symptoms (e.g., psychomotor agitation, inflated self esteem and flight of ideas). It is often associated with mental disorders (e.g., cyclothymic disorder; and bipolar diseases).Bipolar Disorder (except for fluoxetine).
SNRIs:
Contraindicated with MAOIsMAOIsMonoamine 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
Duloxetine is contraindicated in individuals with narrow-angle glaucomaGlaucomaGlaucoma 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.
Overdose
Generally, an overdose of SSRI/SNRI/similar drugs can cause signs and symptoms of neuromuscular excitation and autonomic stimulation.
AgitationAgitationA feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions.St. Louis Encephalitis Virus
Diaphoresis
Tremors
Hyperreflexia
Hyperthermia
Treatment:
Supportive care:
Discontinue serotonergic therapies.
BenzodiazepinesBenzodiazepinesBenzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines may be needed for severe agitationAgitationA feeling of restlessness associated with increased motor activity. This may occur as a manifestation of nervous system drug toxicity or other conditions.St. Louis Encephalitis Virus.
Individuals exhibiting refractory symptoms can be treated with cyproheptadineCyproheptadineA serotonin antagonist and a histamine h1 blocker used as antipruritic, appetite stimulant, antiallergic, and for the post-gastrectomy dumping syndrome, etc.Serotonin Syndrome.
Clinical characteristics of serotonin syndrome
Image by Lecturio.
References
O’Donnell, J.M., Bies, R.R., Shelton, R.C. (2018). Drug Therapy of Depression and Anxiety Disorders. In: Brunton LL, Hilal-Dandan R, Knollmann BC.(Eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics [Internet], 13th ed. New York, NY: McGraw-Hill.
Schatzberg, A.F., Nemeroff, C.B. (Eds.) (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology [Internet], 5e. Arlington, VA: American Psychiatric Association Publishing. https://doi.org/10.1176/appi.books.9781615371624
Stahl, S.M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications [Internet], 4th de. Cambridge University Press.
Neurotransmitters and Neuromodulators. (2019). In: Nelson, L.S., et al. Goldfrank’s Toxicologic Emergencies [Internet], 11th ed. New York, NY: McGraw-Hill.
Smink, F.R., van Hoeken, D., Hoek, H.W. (2013). Epidemiology, course, and outcome of eating disorders. Curr Opin Psychiatry. 26(6):543-8. https://doi.org/10.1097/yco.0b013e328365a24f
American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. https://doi.org/10.1111/jgs.15767