Date post: | 16-Jul-2015 |
Category: |
Health & Medicine |
Upload: | lollan-daran |
View: | 78 times |
Download: | 0 times |
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