Hawler Medical UniversityCollege of MedicineDepartment of Pharmacology

SEROTONIN

Pharmacist: Asma A. Abdulqader

INTRODUCTION

Serotonin /ˌsɛrəˈtoʊnɨn/ or

5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Biochemically derived from tryptophan.

Serotonin is primarily found in the gastrointestinal tract (GI tract), blood platelets, and the central nervous system (CNS).

It is popularly thought to be a contributor to feelings of well-being and happiness

Biosynthesis and metabolism of 5-hydroxytryptamine

Serotonin pathways in the Brain

Serotonin pathways that are located in the brainstem area “the Raphe nuclei” these neurons control muscle activity, 5-HT receptors trigger vomiting.

The serotonin neurons in frontal cortex, regulate cognition and memory.

The serotonin neurons in the hippocampus regulate memory.

The serotonin neurons in the other limbic areas regulate mood. ( basal ganglia and cerebral cortex). SSRI’s work in this pathway.

Actions and functions of serotonin

• Important actions:

Increased GI motility (direct excitation of smooth muscle and indirect action via enteric neurons.

Contraction of the other smooth muscles (bronchi and uterus).

Mixture of vascular constriction (direct via sympathetic innervation) and dilation (endothelium dependant.

Continue…

Platelet aggregation

Stimulation of peripheral nociceptive nerve endings

Excitation/inhibition of CNS neurons.

Continue…

• Postulated physiological and pathophysiological roles include:

In periphery: peristalsis, vomiting, platelet aggregation and haemostasis, inflammatory mediator, sensitization of nociceptors and microvascular control.

In CNS, control of appetite, sleep, mood, hallucinations, steriotyped behavior, pain perception and vomiting.

Clinical conditions associated with 5-hydroxytryptamine function include migraine, carcinoid syndrome, mood disorders and anxiety.

Receptors

Classical signal transduction Type of receptor Subtype Family

Inhibit AC, reduce cAMP, inhibit PKA

Gi/G0- protein coupled

1A,1B,1D,1E,1F5-HT1

Increase IP3, increase intracellular Ca ion, activate PKC

Gq- Protiencoupled

2A,2B,2C5-HT2

Membrane depolarizationLigand-gated Na and K ion ch.

5-HT3

Activate AC, increase cAMP, activate PKA

Gs-protein coupled5-HT4

Activate AC, increase cAMP, activate PKA

Gs- protein coupled

5A,5B5-HT5

Activate AC, increase cAMP, activate PKA

Gs- protein coupled

5-HT65-HT7

Drugs acting on 5-HT receptors

antagonistagonistfunctionlocationreceptor

Ergotamine(PA), methiothepin

Buspirone(PA), triptans

Neuronal inhibition, sleep, behavior, feeding, anxiety

CNS, vascular smooth muscle

5-HT1

Ketanserin,ciproheptadine, pizotifen, ketotifen

LSDNeuronal excitation, smooth muscle contraction, plateletaggrigation

CNS, PNS, smooth muscle, platelets

5-HT2

Ondansetron, granisetron, palonosetron

-------Neuronal excitation(nociceptive,autonomicneurons,emesis, anxiety

PNS, CNS5-HT3

Metoclopromide, cisapride

Neuronal excitation, GI motility

PNS (GIT) , CNS

5-HT4

----------Modulationof behavior?

PNS, CNS5-HT5

--------Learning and memory??

CNS, Leukocytes

5-HT6

LSDThermoregulation?

CNS, GIT, Blood vessels

5-HT7

Clinical utility

Sumatriptan, ergotaminemigraine

buspironeanxiety

ondansetronControl of vomiting

cisaprideGastric stasis , GERD

Methisergide, cyproheptadinesCitalopram, flouxetine

Carcinoid tumordepression

Pathogenesis of migriane

Carcinoid syndrome

• Rare disorder associated with malignant tumors of enterochromaffin cells, which usually arise from small intestine and metastasize to the liver.

• Tumors secrete a variety of mediators, 5-HT is the most important.

• the release of these substances into the bloodstream leads to symptoms, include flushing, diarrhea, bronchoconstriction and hypotension that causes dizziness and fainting.

• 5-HT2 antagonists, such as cyproheptadine given for controlling some symptoms.

Role of serotonin in emesis

Selective serotonin reuptake inhibitors

SSRI are currently first choice of medication for depression.

Work by blocking reabsorption of serotonin by nerve cells in the brain. Leaving more serotonin available in the brain.

This increase will enhance sending of nerve impulses and improves mood.

They only affect serotonin and not others NTs.

SSRI’s

Indications of SSRI’s

Depression: all SSRI except fluvoxamine.Anxiety disorders like social anxiety: safer

than MAOI and BDZ.Panic disorders: paroxetine and sertraline.Obsessive-compulsive disorder (OCD):

fluoxetine, sertraline, and fluvoxamine.Eating disorders: Fluoxetine.Premenstrual dysphoric disorder (PMDD):

sertraline, paroxetine and fluoxetine.

Common side effects of SSRI

Nausea

Sexual dysfunction

Dry mouth

Headache

Diarrhea

Nervousness

Rash

Weight gain

Insomnia

Agitation, restlessness

Serotonin syndrome

Rare life-threatening side effect of SSRI characterized by dangerously high levels of serotonin in the brain.

Can occur when SSRI taken together with MAOIs

Serotonin syndrome

Can occur when SRRI are taken with other medications:

Pain relief medications such as tramadol.

Migraine medication such as sumatriptan.

Supplemnets that affect serotonin levels, such as St. Johns Wort.

Symptoms: Confusion

Anxiety

Extreme agitation

Fluctuation in blood pressure

Increased heart rate

Nausea and vomiting

Fever

Seizure

Flu like symptoms

Lethargy

Coma

Drugs used to treat serotonin syndrome

Non-specific blocking agents: methysergide, cyproheptadine.

Beta –adrenoceptor blockers: propranolol, pindolol.

benzodiazepines: lorazepam, diazepam

Neuroleptics: chlorpromazine, haloperidol