Serotonin (5-HT)

8/1/2019 Serotonin (5-HT)

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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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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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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


GIT


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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/


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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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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
http://pharmacologycorner.com/serotonin-5-ht3-receptor-antagonists/http://pharmacologycorner.com/serotonin-5-ht3-receptor-antagonists/


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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
http://pharmacologycorner.com/serotonin-5-ht3-receptor-antagonists/http://pharmacologycorner.com/serotonin-5-ht3-receptor-antagonists/


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Serotonin (5-HT)

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