Transcript Serotonin and Sedopram

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 blood platelets.
•2% in CNS.
•Neurons in brain make their own;
none from body crosses Blood Brain
Barrier (BBB).
Synthesis:
Tryptophan
5 hydroxytryptophan
5 hydroxytryptophan
5hydroxytryptamine(5HT)
1.Tryptophan hydroxylase (rate 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)
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 Breakdown
• 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).
Receptors
• 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 Brain
Serotonin Pathways in Brain
• Serotonin is released as
neurotransmitter but also released nonsynoptically 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 pathway
(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 pathway
(from Raphe neurons to cerebral cortex and basal 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:
(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 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 depressive
disorders:
1. MAO inhibitors.
2. Tricyclic antidepressants
3. SSRIs “selective serotonin
reuptake inhibitors”
4. Other serotonergic drugs
Sedopram tablets
Product knowledge
Description:
• Sedopram (citalopram HBr)
is an orally administered
selective serotonin reuptake inhibitor (SSRIs) with
a chemical structure
unrelated to that of other
SSRI’s or of tricyclic,
tetracyclic or other
available antidepressant
agent.
Pharmacodynamic
• The mechanism of action of citalopram HBr
as inhibitor of CNS neuronal re-uptake of
serotonin (5HT).
• Citalopram is a highly selective serotonin reuptake 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.
Pharmacokinetics
• 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 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 interactions
• Citalopram has interaction with
ketoconazole, itraconzole,
macrolide antibiotics and
omeprazole.
• Citalopram can be combined with
many other medications as TCAs.
Precaution
• 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:
• 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:
GIT disorders:
Citalopram
Nausea
Diarrhea
Dyspepsia
Vomiting
Abdominal pain
General fatigue
Fever
Placebo
Nausea
Diarrhea
Dyspepsia
Vom iting
Abdom inal pain
General fatigue
Fever
• Comparison of
the GIT adverse
reactions
between the
Citalopram
(n=1063)and the
placebo
(n=446)
Adverse reactions:
Autonomic,central & peripheral
NS
25%
20%
15%
20%
14%
11%
9%
10%
8%
6%
5%
0%
dry mouth
sweating
increse
Citalopram
tremor
Placebo
Adverse reaction:
Psychiatric disorders
20%
Somnolence
18%
16%
14%
Insomnia
12%
10%
8%
Anorexia
Dysmenorrhea
Agitation
Citalopram
Lib
id
o
Placebo
w
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A
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In
so
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So
m
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nc
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2%
0%
ng
Yawning
Libido Decreased
Ya
Anxiety
as
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6%
4%
Re
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sin
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UR
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4%
3%
Ej
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5%
Rh
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6%
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Up
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Adverse reaction:
7%
Ejaculation
disorders
URI Rhinitis
sinusitis
Impotence
2%
Arthralgia Myalgia
1%
0%
Citalopram
Placebo
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:
• 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.