Serotonin

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					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 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 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 re-
  uptake 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 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.
   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:                       • Comparison of
                  Nausea
                                       the GIT adverse
     Citalopram
                  Diarrhea             reactions
                  Dyspepsia            between the
                  Vomiting             Citalopram
                  Abdominal pain       (n=1063)and the
                  General fatigue      placebo
                  Fever                (n=446)


     Placebo       Nausea
                   Diarrhea
                   Dyspepsia
                   Vom iting
                   Abdom inal pain
                   General fatigue
                   Fever
 Adverse reactions:
      Autonomic,central & peripheral
                   NS
25%
       20%
20%

15%       14%
                  11%
10%                  9%
                             8%
                                  6%
5%

0%
      dry mouth   sweating   tremor
                   increse
             Citalopram        Placebo
       Adverse reaction:
                          Psychiatric disorders
20%
    Somnolence
18%
                      Insomnia
16%
14%
12%
10%
 8%
 6%                               Anxiety
                                            Anorexia
                                                                     Dysmenorrhea
 4%                                                    Agitation                         Yawning
                                                                           Libido Decreased
 2%
 0%



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   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.

				
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posted:11/3/2011
language:English
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