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Serotonin (5-HT)
& itsAgonists & Antagonists
Dr. Addis A.
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Serotonin(5-HT)
Serotonin (pronounced or5-Hydroxytryptamine(5-HT) is amonoamine neurotransmitter Biochemically derived from tryptophan
Primarily found in the GIT, platelets,
and CNS of humans and animals
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Serotonin(5-HT)
Also found in fungi and plants Presence in insect venoms and plant
spines causes pain, which is a sideeffect of serotonin injection
Produced by pathogenic amoebas
effects gut causes diarrhea
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Serotonin(5-HT)
Well-known contributor to feelingsof well-being; therefore it is alsoknown as a "happiness hormone"despite not being a hormone.
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The Serotonergic system is known tomodulate mood, emotion, sleep and
appetite and is implicated in thecontrol of behavioral andphysiological functions.
Serotonin(5-HT)
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Serotonin(5-HT)
Approximately90 percent located in theenterochromaffin cells in the gut -- used toregulate intestinal movements
Remainder synthesized in serotonergic neurons inthe CNS -- has various functions includingregulation of mood, appetite, sleep, perception ofpain, regulation of BP, vomiting, as well as muscle
contractionAlso has some cognitive functions,including in memory and learning
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Serotonin(5-HT)
Appears to be involved in clinical conditionssuch as depression, anxiety, and migraine
Modulation of serotonin at synapses isthought to be a major action of several
classes of pharmacological antidepressants
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Synthesis & Degradation
Tryptophan
Hydroxylase
5-hydroxytryptophanDecarboxylase
5-HT
MAO
5HIAA(hydroxyindole acetic acid)
Dehydrogenase
5-Hydroxy Tryptophol
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Synthesis & Degradation
After synthesis the free amine is stored or israpidly inactivated mainly by metabolism to5-HIAA, chiefly by the liver
Metabolism involves first oxidation by monoamineoxidase ( MAO ) to the corresponding aldehyde.This is followed by oxidation by aldehydedehydrogenase to5-HIAA, the indole acetic acidderivative .
The latter is then excreted by the kidneys
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In the pineal gland, serotonin servesas a precursor of melatonin, a
melanocyte stimulating hormone
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Pharmacodynamics - MOA
Multiple actions - Mediated by large number of cellmembrane receptors
Seven families of 5-HT receptor subtypes (1 through 7) Six involving GPCR(G protein coupled receptors( of the usual 7-
transmembrane serpentine type
One ligand-gated ion channel type (5-HT3) is a member of
the nicotinic/GABAA family of Na+, K+ channel proteins
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Serotonin receptors
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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 inmemory and learning
Appears to be involved in clinical conditions such asdepression, anxiety, and migraine
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Tissue & Organ System Effects
Respiratory system Direct stimulant effect on bronchiolar smooth
muscles (5-HT2A
)
Facilitate ACh release from bronchial vagalnerve endings
May also cause hyperventilation result of
chemoreceptor reflex or stimulation ofbronchial sensory nerve endings
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Tissue & Organ System Effects
CVS Venoconstriction with subsequent increased capillary
filling causes flushing following serotoninadministration
Small direct positive inotropic and chronotropiccardiac effects No clinical significance
Subendocardial fibroplasia associated with prolongedelevation of serotonin in the blood (e.g. in carcinoid
syndrome) -- may result in myocardial space forelectrical or valve malfunction
Serotonin: induces platelet aggregation byactivation of platelet surface 5-HT2 receptors
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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
GIT
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Tissue & Organ System Effects
Skeletal muscle 5-HT2 receptors - role unknown
Serotonin syndrome
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Serotonin syndrome
Potentially life-threatening adverse drug reaction thatmay occur following therapeutic drug use,inadvertent interactions between drugs, overdoseof particular drugs, or the recreational use of certaindrugs
Not an idiosyncratic drug reaction; it is a predictableconsequence of excess serotonergic activity at centralnervous system and peripheral serotonin receptors
For this reason, some experts strongly prefer the
terms serotonin toxicity or serotonin toxidromebecause these more accurately reflect the fact that itis a form of poisoning. It may also be called serotoninstorm, hyperserotonemia, or serotonergic syndrome.
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Serotonin syndrome
The symptoms are often described as a clinicaltriad 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
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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
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Serotonin syndrome
Management is based primarily on stopping the usage ofthe precipitating drugs
Administration of serotonin antagonists such ascyproheptadine
Supportive care including the control of agitation, thecontrol of autonomic instability, and the control ofhyperthermia.
Additionally, those who ingest large doses serotonergicagents may benefit from gastrointestinal decontamination
with activated charcoal if it can be administered within anhour of overdose.
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Serotonin syndrome
The intensity of therapy depends on theseverity of symptoms
For mild symptoms, treatment may onlyconsist of discontinuation of the offendingmedication or medications, offering supportivemeasures, giving benzodiazepines for myoclonus,
and waiting for the symptoms to resolve.
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Pathophysiological roles - Serotonin
Neurotransmitter Precursor of melatonin Neuroendocrine function Nausea & vomitting Migraine Haemostasis Raynauds phenomenon Variant angina
Hypertension Intestinal motility Carcinoid syndrome
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Drugs acting on SerotonergicNeurotransmission
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Drugs acting on Serotonergic Neurotransmission
MAO inhibitorsMonoamine oxidase is a key enzyme for serotonin, dopamine andnorepinephrine inactivation. MAO inhibitors prevent inactivation ofmonoamines within a neuron, causing excess neurotransmitter todiffuse into the synaptic space. This class of agents is used in the
treatment of depression (phenelzine, tranylcypromine, selegiline) andParkinsons disease (selegiline). Dietary restrictions (because oftyramine toxicity) limit their widespread use.
Inhibitors of serotonin storageThey interfere withe the ability of synaptic vesicles to storemonoamines; displace serotonin, dopamine and norepinephrine from
their storage in presynaptic nerve terminals. Agents that share thismechanism of action include amphetamine, methylphenidate andmodafinil.
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Drugs acting on Serotonergic Neurotransmission
SNRISNRIs mechanism involves blockade of 5-HT and norepinephrinereuptake in a concentration-dependent manner. Agents in this classinclude venlafaxine and duloxetine, they may be effective for thetreatment of depression in patients in whom SSRIs are ineffective.
SSRIs block the reuptake of serotonin, leading to increasedconcentrations of the neurotransmitter in the synaptic cleft and toan enhanced postsynaptic neuronal activity.
TCAsTricyclic antidepressantsact by inhibiting reuptake of 5-HT andnorepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters, thereby causingenhancement of postsynaptic response.
http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/http://pharmacologycorner.com/differences-between-tricyclic-antidepressants-and-selective-serotonin-norepinephrine-reuptake-inhibitors-mechanism-of-action/8/1/2019 Serotonin (5-HT)
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Serotonin agonists
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Serotonin agonists
Have wide clinical applications, from treatment of depression toabortive medications for migraine headache
5-HT1A agonistsBuspirone is a partial 5-HT1A agonist used clinically for thetreatment of anxiety and depression.
5-HT1B and 5-HT1D agonistsThe triptans are a drug class useful as abortive medication forthe treatment of acute migraine headaches. They are veryeffective medications that bind to 5-HT1B and 5-HT1D receptorsin cranial vessels, which leads to vasoconstriction and decreasedrelease of neuropeptides involved in sterile inflammation.
5-HT2C agonistTrazodone behave as a 5-HT2C agonist. This drug is used generallyas somnorific.Head lines with examples
like 5HT1A agonist exampleBuspirone
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Serotonin agonists
5-HT4 agonistsCisapride is a serotonin and cholinergic agonist used asa prokinetic drug, it was withdrawn from the U.S.market because of cardiovascular toxicity.
Non-selective agonistsErgotamine activates a more than one subtype of 5-HTreceptor, it binds to 5-HT1A, 5-HT1D, 5-HT1B, D2 andnorepinephrine receptors. Its vasoconstrictor effectmakes it a suitable treatment for migraine attacks.
LSD is a 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, 5-HT5, 5-HT6 agonist that has psychedelic properties.
Head lines with exampleslike 5HT1A agonist exampleBuspirone
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Serotonin Antagonists
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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 as5-HT2A/2C receptor antagonist with high affinityfor dopamine receptors.
Agomelatine is a new antidepressant with agonistaction at the melatonin receptor and antagonism atthe 5-HT2C receptor.
Head lines with exampleslike 5HT1A agonist
example Buspirone
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Serotonin Antagonists
5-HT3 antagonistsThis class includes drugs such as
ondansetron , palonosetron and others.These agents are particularly useful in thetreatment of chemotherapy inducednausea and vomiting (CINV)
Head lines with exampleslike 5HT1A agonist example
Buspirone
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