Serotonin (5-HT)

Serotonin OR 5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Well-known contributor to feelings of well-being; therefore it is also known as a "happiness hormone" despite not being a hormone. Biochemically derived from tryptophan Primarily found in the GIT, platelets, and CNS of humans and animals

5% CNS

OH

NH2

NH

95% GI tract 90% EC s 10% Neurons

5-Hydroxytryptamine

CMOA 3

Serotonin (5-HT)

Helps in regulation of smooth muscles, function of CVS and GI systems and in platelet function. In the CNS -- has various functions including regulation of mood, appetite, sleep, perception of pain, regulation of BP, and vomiting.
Also has some cognitive functions, including in memory and learning. Appears to be involved in clinical conditions such as depression, anxiety, and migraine.

Synthesis & Degradation

Tryptophan
Hydroxylase

5-hydroxytryptophan
Decarboxylase

5-HT
MAO

5- hydrxyoxyindoleacetaldehyde
reductase dehydrogenase 5-Hydroxy Tryptophol aldehyde

Serotonin receptors

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 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

Tissue & Organ System Effects

CNS

Sleep: 5HT favours NREM sleep. Depletion of 5HT cause insomnia Aggressive behaviour: is enhanced in low 5HT conc. Mood: 5HT mediates mood changes and anxiety. Appetite : 5HT stimulates satiety centre. Bezold jarisch reflex: activation of 5HT3 receptors in afferent vagal nerve endings. pain perception: 5HT3 receptors on peripheral sensory nerves, dorsal horn of spinal cord & autonomic nerve endings. Vomiting: mediated by 5HT3 receptors in CTZ and NTS

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

Smooth muscle-- direct effects: contraction, 5-HT2 receptors. Serotonin-induced vasoconstriction: strong effects on pulmonary and renal vasculature Serotonin: vasoconstriction except: skeletal muscle vasculature } vasodilation heart } vascular endothelial cell-dependent vasodilation Serotonin: reflex bradycardia (5-HT3 activation of chemoreceptor nerve endings)

Tissue & Organ System Effects

CVS

Effect on BP on IV is a triphasic response:

Initial reduced BP- chemoreceptor response Increased BP- peripheral vasoconstriction Lastly reduced BP- vasodilation in skeletal muscle vasculature

Subendocardial fibroplasia associated with prolonged 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

Tissue & Organ System Effects

GITContraction 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

Neurotransmitter Precursor of melatonin Psychosis Depression Anxiety Nausea & vomitting Migraine Haemostasis Raynauds phenomenon Variant angina Hypertension Intestinal motility Carcinoid syndrome

INCREASING THE CONC. 5HT

DECREASING THE CONC 5HT

ACTING THROUGH 5HT RECEPTORS

Degradation inhibitors

Releasing 5HT

Agonist

Antagonist

Reuptake inhibitors

SSRI = selective serotonin reuptake inhibitor blocks reuptake of 5-HT, so concentration increases and more receptors are activated SSRIs are the most common drug treatment for major depressive illnesses, and are also used to treat anxiety disorders

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.

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.

This class of agents is used in the treatment of depression (phenelzine, tranylcypromine, selegiline) and Parkinsons disease (selegiline). Dietary restrictions (tyramine toxicity) limit their widespread use.

Inhibitors of serotonin storage

They interfere with 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,

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 conc. of the neurotransmitter in the synaptic cleft & enhanced postsynaptic neuronal activity. Agents in this class are: sertraline, Fluoxetine, Fluoxamine, citalopram. Mostly common prescribed anti-depressant.
TCAs

They act by inhibiting reuptake of 5-HT and norepinephrine from the synaptic cleft by respectively blocking 5-HT and norepinephrine reuptake transporters.

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.
Trazodone behave as a 5-HT2C agonist. This drug is used generally as somnorific.

5-HT2C agonist

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. Renzapride is more selective for 5HT4 receptors.

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.

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 5HT2A/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.

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)

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