Serotonin (5-HT) & its Agonists & Antagonists Dr. Addis A.

Serotonin (5-HT)
Serotonin (pronounced or 5Hydroxytryptamine (5-HT) is a monoamine neurotransmitter Biochemically derived from tryptophan Primarily found in the GIT, platelets, and CNS of humans and animals

Serotonin (5-HT)
Also found in fungi and plants Presence in insect venoms and plant spines causes pain, which is a side effect of serotonin injection Produced by pathogenic amoebas effects gut causes diarrhea

Serotonin (5-HT)
Well-known contributor to feelings of well-being; therefore it is also known as a "happiness hormone" despite not being a hormone.

Serotonin (5-HT)
The Serotonergic system is known to modulate mood, emotion, sleep and appetite and is implicated in the control of behavioral and physiological functions.

Serotonin (5-HT)
Approximately 90 percent located in the enterochromaffin cells in the gut -- used to regulate intestinal movements Remainder synthesized in serotonergic neurons in the CNS -- has various functions including regulation of mood, appetite, sleep, perception of pain, regulation of BP, vomiting, as well as muscle contraction Also has some cognitive functions, including in memory and learning

Serotonin (5-HT)
Appears to be involved in clinical conditions such as depression, anxiety, and migraine Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants

Synthesis & Degradation

Tryptophan
Hydroxylase

5-hydroxytryptophan
Decarboxylase
Dehydrogenase

5-HT
MAO
5HIAA(hydroxyindole acetic acid)

5-Hydroxy Tryptophol

Synthesis & Degradation

After synthesis the free amine is stored or is rapidly inactivated mainly by metabolism to 5HIAA, chiefly by the liver Metabolism involves first oxidation by monoamine oxidase ( MAO ) to the corresponding aldehyde. This is followed by oxidation by aldehyde dehydrogenase to 5-HIAA, the indole acetic acid derivative . The latter is then excreted by the kidneys

 In the pineal gland, serotonin serves as a precursor of melatonin, a melanocyte stimulating hormone

Pharmacodynamics - MOA
Multiple actions - Mediated by large number of cell membrane receptors Seven families of 5-HT receptor subtypes (1 through 7) Six involving GPCR(G protein coupled receptors( of the usual 7transmembrane serpentine type One ligand-gated ion channel type (5-HT3) is a member of the nicotinic/GABAA family of Na+, K+ channel proteins

Serotonin receptors

Tissue & Organ System Effects

CNS
Present in various sites Role as a NT( neurotransmitter) These include the regulation of mood, appetite, sleep, perception of pain, regulation of BP, vomiting, as well as muscle contraction Has some role in cognitive functions, including in memory and learning Appears to be involved in clinical conditions such as depression, anxiety, and migraine

Tissue & Organ System Effects Respiratory system

Direct stimulant effect on bronchiolar smooth muscles (5-HT2A) Facilitate ACh release from bronchial vagal nerve endings May also cause hyperventilation result of chemoreceptor reflex or stimulation of bronchial sensory nerve endings

Tissue & Organ System Effects

CVS
Venoconstriction with subsequent increased capillary filling causes flushing following serotonin administration Small direct positive inotropic and chronotropic cardiac effects No clinical significance Subendocardial fibroplasia associated with prolonged elevation of serotonin in the blood (e.g. in carcinoid syndrome) -- may result in myocardial space for electrical or valve malfunction Serotonin: induces platelet aggregation by activation of platelet surface 5-HT2 receptors

GIT

Tissue & Organ System Effects

Contraction of gastrointestinal smooth muscle

increased tone, increased peristalsis 5-HT2 receptor mediated: direct effect on smooth muscle receptors stimulation of enteric ganglia cells Serotonin: -- activation of 5-HT4 receptor increased acetylcholine release (increased motility, prokinetic) Example: Serotonin over production (carcinoid tumor) -- severe diarrhea

Tissue & Organ System Effects

Skeletal muscle
5-HT2 receptors - role unknown Serotonin syndrome

Serotonin syndrome
Potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs Not an idiosyncratic drug reaction; it is a predictable consequence of excess serotonergic activity at central nervous system and peripheral serotonin receptors For this reason, some experts strongly prefer the terms serotonin toxicity or serotonin toxidrome because these more accurately reflect the fact that it is a form of poisoning. It may also be called serotonin storm, hyperserotonemia, or serotonergic syndrome.

Serotonin syndrome
The symptoms are often described as a clinical triad of abnormalities Cognitive effects: headache, agitation, hypomania,
mental confusion, hallucinations, coma Autonomic effects: shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor

Serotonin syndrome
Drugs Causing A large number of medications either alone or in combination can produce serotonin syndrome. Antidepressants: Monoamine Oxidase Inhibitors (MAOIs), TCAs, SSRIs, SNRIs, bupropion, nefazodone, trazodone Opioids: tramadol, pethidine, fentanyl, pentazocine, buprenorphine, CNS: stimulants phentermine, amphetamine, methamphetamine, cocaine 5-HT1 agonists triptans

Serotonin syndrome
Management is based primarily on stopping the usage of the precipitating drugs Administration of serotonin antagonists such as cyproheptadine Supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia. Additionally, those who ingest large doses serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within an hour of overdose.

Serotonin syndrome
The intensity of therapy depends on the severity of symptoms
For mild symptoms, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines for myoclonus, and waiting for the symptoms to resolve.

Pathophysiological roles - Serotonin

Neurotransmitter Precursor of melatonin Neuroendocrine function Nausea & vomitting Migraine Haemostasis Raynauds phenomenon Variant angina Hypertension Intestinal motility Carcinoid syndrome

Drugs acting on Serotonergic Neurotransmission

Drugs acting on Serotonergic Neurotransmission

MAO inhibitors Monoamine oxidase is a key enzyme for serotonin, dopamine and norepinephrine inactivation. MAO inhibitors prevent inactivation of monoamines within a neuron, causing excess neurotransmitter to diffuse into the synaptic space. This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinsons disease (selegiline). Dietary restrictions (because of tyramine toxicity) limit their widespread use. Inhibitors of serotonin storage They interfere withe the ability of synaptic vesicles to store monoamines; displace serotonin, dopamine and norepinephrine from their storage in presynaptic nerve terminals. Agents that share this mechanism of action include amphetamine, methylphenidate and modafinil.

Drugs acting on Serotonergic Neurotransmission

SNRI SNRIs mechanism involves blockade of 5-HT and norepinephrine reuptake in a concentration-dependent manner. Agents in this class include venlafaxine and duloxetine, they may be effective for the treatment of depression in patients in whom SSRIs are ineffective. SSRIs block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft and to an enhanced postsynaptic neuronal activity. TCAs Tricyclic antidepressants act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5HT and norepinephrine reuptake transporters, thereby causing enhancement of postsynaptic response.

Serotonin agonists

Serotonin agonists
Have wide clinical applications, from treatment of depression to abortive medications for migraine headache 5-HT1A agonists Buspirone is a partial 5-HT1A agonist used clinically for the treatment of anxiety and depression. 5-HT1B and 5-HT1D agonists The triptans are a drug class useful as abortive medication for the treatment of acute migraine headaches. They are very effective medications that bind to 5-HT1B and 5-HT1D receptors in cranial vessels, which leads to vasoconstriction and decreased release of neuropeptides involved in sterile inflammation. 5-HT2C agonist Trazodone behave as a 5-HT2C agonist. This drug is used generally as somnorific. Head lines with examples

like 5HT1A agonist example Buspirone

Serotonin agonists
5-HT4 agonists Cisapride is a serotonin and cholinergic agonist used as a prokinetic drug, it was withdrawn from the U.S. market because of cardiovascular toxicity. Non-selective agonists Ergotamine activates a more than one subtype of 5-HT receptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 and norepinephrine receptors. Its vasoconstrictor effect makes it a suitable treatment for migraine attacks. LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5HT6 agonist that has psychedelic properties.

Head lines with examples like 5HT1A agonist example Buspirone

Serotonin Antagonists

Serotonin Antagonists
5-HT2 antagonists
Ketanserin is a 5-HT2A/2C antagonist used for the treatment of hypertension. Also possesses alpha-1 agonistic effect Clozapine - atypical antipsychotic drug that acts as 5-HT2A/2C receptor antagonist with high affinity for dopamine receptors. Agomelatine is a new antidepressant with agonist action at the melatonin receptor and antagonism at the 5-HT2C receptor.

Head lines with examples like 5HT1A agonist example Buspirone

Serotonin Antagonists

5-HT3 antagonists
This class includes drugs such as ondansetron , palonosetron and others. These agents are particularly useful in the treatment of chemotherapy induced nausea and vomiting (CINV) Head lines with examples like 5HT1A agonist example Buspirone

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