SEROTONIN. Serotonin Serotonin is used throughout the body in multiple physiological roles. 90% of all serotonin in human body in the GI tract. 8% in.

SEROTONIN

SerotoninSerotonin•Serotonin is used throughout the body in multiple physiological roles.•90% of all serotonin in human body in the GI tract.•8% in blood platelets.•2% in CNS.•Neurons in brain make their own; none from body crosses Blood Brain Barrier (BBB).

Synthesis:Synthesis:

Tryptophan 5 hydroxytryptophan5 hydroxytryptophan 5hydroxytryptamine(5HT)

1.Tryptophan hydroxylase (rate 1.Tryptophan hydroxylase (rate limiting step)limiting step)

High serotonin levels within neuron do not inhibit enzyme synthesis-serotonin just builds up.

Rate of enzyme activity can be modulated by second messengers involving cAMP.

Also, can be modulated by Oxygen levels in blood; more oxygen, more synthesis of serotonin.

2.5-hydroxytryptophan( 5HTP) 2.5-hydroxytryptophan( 5HTP) decarboxylase:decarboxylase:

• Production of enzyme and use to make serotonin very rapid.

• Can't manipulate serotonin by manipulating this enzyme.

• N.B. Release of serotonin is Ca++ dependant, Ca++ must come into trigger release.

Deactivation and Deactivation and BreakdownBreakdown

• Action terminated by active re-uptake process into neurons and ganglia.

• Then broken down by MAO.

• MAO breaks down 5HT into several things.

• 5-hydrozindoleacetic acid (5HIAA) is a metabolite that is often used to index activity in system; measured in CSF( cerebrospinal fluid).

ReceptorsReceptors• 7 major types;3 of relevance to

current set of medications:

• 5HT1 “slow inhibition”: through G proteins, reduce adenylyl cyclase activity; exists as postsynaptic and presynaptic receptors.

• 5HT2 “slow excitation": through G proteins, increase K+ & Ca++ influx.CNS has mostly 5HT1A (found in prefrontal cortex).

• 5HT3 “Fast excitation”: ion-coupled to Na+;some modulation also of Ca++ channels in the area of postrema,trigger vomiting.

Serotonin Pathways in Serotonin Pathways in BrainBrain

Serotonin Pathways in Serotonin Pathways in BrainBrain• Serotonin is released as

neurotransmitter but also released non-synoptically through some axon terminals.

• Neurotransmitter pathways can be consolidated into 3 major paths.

• All paths emerge from same set of neurons in the Raphe region of the brainstem, a group of nuclei along midline of midbrain,pons and medulla.

1.Caudal pathway1.Caudal pathway(from Raphe nuclei to medulla and spinal cord)(from Raphe nuclei to medulla and spinal cord)

• Uses mainly 5HT1 receptors " slow excitation”.

• Causes contraction or uterine muscles cramps.

• Causes some contraction of blood vessel walls" blood pressure”.

• Causes mild motor neuron excitation.

• Stimulates release of endorphins that then inhibit pain messages.

• 5HT3 receptors in area postrema trigger vomiting.

2.Middle pathway2.Middle pathway(from Raphe neurons to cerebral cortex and basal (from Raphe neurons to cerebral cortex and basal ganglia)ganglia)

• Goes to cortex along with NE axons.

• Goes to basal ganglia along with DA & ACh neurons.

• 5HT2 “slow excitation” receptors.

• Serotonin induces positive mood and affect cortex.

• “This is the system where SSRIs work by inhibiting the transporter protein necessary for serotonin reuptake”.

3.Rostral pathway:3.Rostral pathway:(from Raphe nuclei to 5 areas)(from Raphe nuclei to 5 areas)

• Uses 5HT1 “slow inhibition” &5HT2 “slow excitation”• A. Raphe nuclei within):

within Raphe,there are autoreceptors(5HT1-self inhibit)

• B. Raphe to sensory cortex:Sensory cortex-particularly visual perception-5HT2 relevant to hallucinogens(LSD,psilocybin mushrooms)

• C. Raphe to limbic system:Limbic system “Pleasure & anxiety” slow inhibition at 5HT1 receptors.

• D. Raphe to hypothalamus and thalamus:Uses 5HT1 receptors in thermoregulation.Ecstasy causes hyperthermia through here.

• E. Raphe to suprachiasmatic nucleus:Uses 5 HT1.Important in sleep/wakefulness.Serotonin induces sleep-inject into brain-sleep occurs.Inhibit serotonin (by PCPA,inhibits Tryptophan hydroxylase and production of serotonin); no sleep and there is an increase in activity.But other neurotransmitter are also important in sleep.

CNS Relevant diseasesCNS Relevant diseases• Depression

• Anxiety

• Possible some interactive role in Schizophrenia

• Ecstasy “empathogen”

• High levels of Amphetamine

• LSD and psilocybin mushroom hallucinogens

• Migraine headache(5HT1 agonists cause constriction of intracranial blood vessels; may block endogenous inflammatory agents)

Drugs used to treat Drugs used to treat depressive disorders:depressive disorders:

1. MAO inhibitors.

2. Tricyclic antidepressants

3. SSRIs “selective serotonin reuptake inhibitors”

4. Other serotonergic drugs

SedopramSedopram tabletstablets

Product knowledgeProduct knowledge

Description:Description:

• Sedopram (citalopram HBr) is an orally administered selective serotonin re-uptake inhibitor (SSRIs) with a chemical structure unrelated to that of other SSRI’s or of tricyclic, tetracyclic or other available antidepressant agent.

PharmacodynamicPharmacodynamic• The mechanism of action of citalopram

HBr as inhibitor of CNS neuronal re-uptake of serotonin (5HT).

• Citalopram is a highly selective serotonin re-uptake inhibitor (SSRI) with minimal effects on norepinephrine(NE) and dopamine (DA) neuronal re-uptake.

• Citalopram has no or very low affinity for 5HT 1A,5HT 2A,dopamine D1& D2,alpha 1;alpha 2 & beta adrenergic, histamine H1,gamma amino-butyric acid (GABA), muscarinic cholinergic and benzodiazepine receptors.

PharmacokineticsPharmacokinetics

• Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram(DDCT), citalopram-N-oxide & deaminated propionic acid derivative.

• Citalopram is at least 8 times more potent than its metabolites.

• Biotransformation of citalopram is mainly hepatic.

• Approximately 20 % is excreted by renal clearance.

Population and SubgroupsPopulation and Subgroups

• 20 mg is the recommended dose for most elderly patients.

• No sex difference and no adjustment of dose on the basis of gender is recommended.

• In hepatic patients;20 mg is the recommended dose for most hepatically impaired patients.

• No adjustment of dosage for mild to moderate renal function impairment patients is recommended.

Drug-Drug interactionsDrug-Drug interactions

• Citalopram has interaction with ketoconazole, itraconzole, macrolide antibiotics and omeprazole.

• Citalopram can be combined with many other medications as TCAs.

PrecautionPrecaution• Hyponatremia:

In few cases of hyponatremia & inappropriate antidiuretic hormone secretion may occur.

• Activation of Mania/Hypomania was reported in 0.2% in one trial; so citalopram should be used cautiously in patients with a history of mania.

• Seizures occurred in 0.3% of patients treated with citalopram. Like other antidepressants; citalopram should be introduced with care to patients with history of seizure disorder.

• Patients should be advised to notify their physician if they become pregnant or intended to become pregnant during therapy.

• Patients should be advised to notify their physician if they are breast feeling an infant.

Precautions:Precautions:• The product dose not interfere with

cognitive and motor performance as Sedopram in doses of 40 mg/day did not produce impairment of intellectual function or psychomotor performance.

• Sedopram is not associated with the development of clinically significant ECG abnormalities or with orthostatic changes or weight changes.

• There was no evidence for carcinogenicity of citalopram in mice receiving up to 240 mg/kg/day, which equivalent to 20 times the maximum recommended human daily dose.

• When citalopram was administered orally to male & female rats fertility was decreased at doses>/=32mg/kg/day,approximately 5 times the maximum recommended human dose.

Adverse reactions:Adverse reactions:GIT disorders:GIT disorders:

Citalopram Nausea

Diarrhea

Dyspepsia

Vomiting

Abdominal pain

General fatigue

Fever

• Comparison of the GIT adverse reactions between the Citalopram (n=1063)and the placebo (n=446)

Placebo Nausea

Diarrhea

Dyspepsia

Vomiting

Abdominal pain

General fatigue

Fever

Adverse reactions:Adverse reactions:Autonomic,central & peripheral

NS

20%

11%

8%

14%

9%

6%

0%

5%

10%

15%

20%

25%

dry mouth sweatingincrese

tremor

Citalopram Placebo

Adverse reaction:Adverse reaction:

Psychiatric disordersSomnolence

Insomnia

AnxietyAnorexia

AgitationDysmenorrhea

Libido DecreasedYawning

0%

2%

4%

6%

8%

10%

12%

14%

16%

18%

20%

Somno

lenc

e

Inso

mnia

Anxiety

Anorexia

Agita

tion

Dysm

enor

rhea

Libido De

crea

sed

Yawni

ng

Citalopram Placebo

Adverse reaction:Adverse reaction:

URI Rhinitis

sinusitis Impotence

Arthralgia Myalgia

Ejaculation disorders

0%

1%

2%

3%

4%

5%

6%

7%

Uppe

r Res

pira

tory trac

tUR

I

Rhini

tis

sinus

itis

Urog

enita

l

Ejacu

latio

n diso

rders

Impo

tenc

e

Mus

cular s

ystem d

isorder

Arthra

lgia

Mya

lgia

Citalopram Placebo

Dose and administration:Dose and administration:• Initial treatment:• Should be administered at an initial

dose of 20 mg once daily, generally with an increase to a dose of 40 mg/day.

Dose increases should usually occur in increments of 20 mg at intervals of no less than one week up to 60 mg.

• Sedopram should be administered once daily, in the morning or evening with or without food.

Dose and administration:Dose and administration:• Maintenance treatment:

in two studies show that its antidepressant efficacy is maintained for periods of up to 24 weeks following 6 or 8 weeks of initial treatment(32 weeks total).

• In dose of citalopram (20-40 mg/day) during maintenance treatment and if adverse reactions are bothersome; a decrease in dose to 20 mg/day can be considered.