Docstoc

SEROTONERG FARMAKOLOGI

Document Sample
SEROTONERG FARMAKOLOGI Powered By Docstoc
					       AARHUS
       UNIVERSITET          9 FEBRUARY, 2009




SEROTONERG FARMAKOLOGI
[Kapitel 10, 38]




     Edgaras Stankevicius



                      TATION
                     pRÆSEN
       AARHUS


      SEROTONERG FARMAKOLOGI
       UNIVERSITET




I.    Serotonin
›     Distribution, Biosynthesis and Degradation
›     Serotonin receptors
›     Drugs acting on 5-HT receptors
›     Pharmacological effects

II.   Migraine
›     Epidemiology
›     Symptoms
›     Pathophysiology
›     Treatment strategies
›     Prophylaxis
Serotonin (5-HT)
    AARHUS
    UNIVERSITET




› named to an unknown vasoconstrictor substance in
  serum in 1976 (Page et al.)
› Widely distributed in mammals, plants and insects
› Chemically – 5-hydroxytryptamine (5-HT)


                               CH 2    CH 2    NH 2
                  HO


                              N
                              H
    AARHUS

 Serotonin plays a role in multiple states
    UNIVERSITET




› Aggression, pain, sleep, appetite
› Anxiety, depression
› Obesitis
› Migraine
› Alcoholism
› Vomiting
› Gastro-intestinal hypomobility
› Hemostasis
› Carcinoide tumor
    AARHUS

 •Carcinoide tumor
    UNIVERSITET




› Release of chemical mediators:
 › Serotonine
› Neuropeptides:
 › Substance P
 › Prostaglandins
 › Bradykinin
› SYMPTOMS:
 › Flushing
 › Diarrhoea
 › Bronchoconstriction
 › Hypotension
Distribution of Serotonin
    AARHUS
    UNIVERSITET




› Central Nervous System   › Periphery
  (Raphe nuclei)
                           1. Blood (platelets)

                           2. Intestine wall (90 %):
                              - enterochromaffin cells
                              - interneurones:
 AARHUS

Biosynthesis and Degradation
 UNIVERSITET




                                  (5-HT)
               (5-HIAA)   Urine
Serotonin receptors
    AARHUS
    UNIVERSITET




› Receptors are of seven types (5-HT1 ... 5-HT7)
› 15 subtypes are known:
› 5-HT1 has A to F subtype
› 5-HT2 has A, B, C subtypes
› 5-HT5-7 the function is not clear
  AARHUS

Serotonin receptors
  UNIVERSITET




   5-HT                           5-HT      5HT2A, B, C
                 5-HT1

                                          a b         PLC
                                                      PL
            b
          a g   AC                          g
                                                      C
         cAMP                    5-HT5?         IP3
                                                      Ca2+

  5-HT           5-HT 4, 6 & 7
                                 5-HT     Na+/K+
                                                          5-HT3
         a b    AC
           g
        cAMP
Serotonin receptors:
  AARHUS
  UNIVERSITET
 Drugs affecting on tryptaminergic
     AARHUS
     UNIVERSITET


 system
› 5-HT Precursor – Tryptophan in diet increases 5-HT production

› Synthesis inhibitors – p-chloro-phenylalanine (PCPA) inhibits tryptophan
  hydroxylase

› Storage inhibitors – selectively release the 5-HT (Fenfluramine)

› Uptake inhibitors – selective 5-HT reuptake inhibitors (Fluoxetine, Paroxetine)

› Neuronal degradation – selectively destroys tryptaminergic neurons (5-6 di-
  hydroxytryptamine

› Inhibit metabolism – MAO inhibitors (Clorgyline, Selegiline)

› Promote release – depletes the storage (p-chloroamphetamine)
    Drugs affecting on tryptaminergic
       AARHUS
       UNIVERSITET


    system

                                tryptofan

             p-klorfenylalanin -
 Hypertension
                                5-HTP
                                       --MAO-A hæmmer
                     Reserpin      5-HT                      5-HIAA
     Autoreceptor                                      Na+
                                                          SSRI (citalopram, fluoxetin)
Anorexia                                                  TCA (amitryptilin)
           fenfluramin -
                                   5-HT                                     Antipsychotic
                                            receptorligander

              Postsynaptiske receptorer (5-HT2, 5-HT3, 5-HT4)
  AARHUS

Ergot Alkaloids
  UNIVERSITET




                › Ergot is the dried sclerotium of a fungus,
                 Claviceps purpurea
                › Consumption of flour contaminated with
                  Ergot led to many serious intoxications known
                  as (Ergotism- Ignis Fire) in Europe leading to:
                 - Mental disturbancies
                 - Peripheral vasoconstriction leading to
                 gangrene:
   AARHUS

Main sites of action:
   UNIVERSITET




› 5-HT receptors
› Dopamine receptors
› Adrenoreceptors
Classification of Ergot Alkaloids:
   AARHUS
   UNIVERSITET




A- Clavine Type Alkaloids:
Simple water soluble bases with little medicinal value. All
end with “clavine: e.g. Agroclavine.
B- Lysergic acid Amides:
They are all derivatives of (l)-Lysergic acid and
subclassified into:
       1 - Simple lysergic acid amides:
       Composed of Lysergic acid and simple amines.
     2 - Polypeptide Alkaloids:
     Composed of Lysergic acid and at least 3 amino
acids.
    Simple Lysergic acid amides
          AARHUS
          UNIVERSITET




› Characters:
 1- Composed of Lysergic acid and simple amines.
 2- Low molecular weight.
 3- Water Soluble.


                           Ergometrine
                                                        OH    CH3

                                                       H2C   HC HN     CO

 Composed of (l)-lysergic acid and 2-aminopropanol.                      8
 Its (d) isomer is called Ergometrinine.                                           N     CH3
                                                                     10



› Uses:
 It causes vigorous contraction of the uterus.                                N
                                                                              H
 It is mainly used as an oxytocic in order to aid
 delivery or to prevent postpartum hemorrhage.          =      Ergonovine (l) (Ergometrine)
                                                        =      Ergonovinine (d) (Ergometrinine)
     AARHUS

 Lysergic acid diethylamide (LSD)
     UNIVERSITET




› It is a semisynthetic product.

› LSD has potent CNS stimulant effect.                C2H5
                                          CON
› LSD is one of the abused drugs.                     C2H5
                                              8
                                                        N    CH3
                                         10




                                                  N
                                                  H
          AARHUS

    Polypeptide Alkaloids
          UNIVERSITET



› Characters:

 Its (d) isomer is called Ergotaminine.
 The peptide moiety is composed of 3 amino acids:
           α-Hydroxyalanine
           Proline
           Phenylalanine

                                Ergotamine
› Uses:
                                                        OH
                                                  N          O CH3
 Treatment of migraine as it constricts
                                                                     CO
 the peripheral blood vessels.                O         N
 Has some oxytocic (ecobolic) activity.                     O            8
                                                      CH2       9                N   CH3
                                                                    10




                                                                             N
                                                                             H
   AARHUS

 Summary:
   UNIVERSITET



 The most important Ergot compouds:

›The most important compouds:
› Ergotamine – migraine treatment
› Ergometrine – used in obstetrics
› Methysergide – carcinoid syndrom, migraine
                  prophylaxis
› Bromocriptine – parkinsonism and endocrine
                  disorders
    AARHUS

 Pharmacological effects:
    UNIVERSITET


                    Role in brain
› Neurotransmitter in tryptaminergic nerves
› Regulates appetite, body temperature
› Pain perception (Headache, Migraine)
› Sleep/Wakefulness
› Various behaviors/mood normal/abnormal, depression,
  schizophrenia, etc.
› Neuro-endocrine regulation – controls release of several
  anterior pituitary hormones, prolactine
› Serotonin stimulates adrenal gland for release of
  catecholamine
    AARHUS

 Pharmacological effects:
    UNIVERSITET


                    Cardiovascular system

› Direct vasoconstriction (large arteries) and
› Indirect vasodilatation in small blood vessels due to:
 - release of relaxing factors (NO and PGI2)
 - inhibition of EN/NE release from sympathetic nerve
 terminals
› Heart:
› direct ionotropic and chronotropic effects
› Bradycardia and Hypotension
    AARHUS

 Pharmacological effects:
    UNIVERSITET


                    Cardiovascular system
› Triphasic response:
 Rapid intravenous injection of serotonin causes:
 - Initial rise in systemic arterial blood pressure
 - Short period of pressor effect
 - Prolong fall in systemic blood pressure due to
 vasodilatation
 Pharmacological effects:
     AARHUS
     UNIVERSITET


                 Gastrointestinal tract
› Increases motility of the gastrointestinal tract (GIT)
  › Entero-chromaffin cells in the mucosa main 5-HT in body
    › Release of 5-HT                   5-HT3
    › Inhibition of 5-HT                5-HT4

   › Ganglia cells (presynaptic)
     › Release of ACh                   5-HT4
     › Inhibition of ACh release        5-HT1P & 1A

   › Ganglia cells (postsynaptic)
     › Fast depolarization              5-HT3
     › Slow depolarization              5-HT1P

   › Smooth muscle contraction
     › Bowels, stomach and esophagus 5-HT2A, 2B & 4
Pharmacological effects:
    AARHUS
    UNIVERSITET


                Gastrointestinal tract

› Stimulates vomiting      5-HT3
› Serotonin inhibits gastric acid and pepsin secretion,
  however increase mucus production thus it has ulcer
  protective property
Pharmacological effects:
    AARHUS
    UNIVERSITET


                Platelets

› The main function is to prevent leakage
› Platelets have 5-HT2 receptors in the memrane. On
  interaction:
        - it increases the platelet aggregation and
        - vasoconstriction to leakage site promoting
  hemostasis
 Pharmacological effects:
    AARHUS
    UNIVERSITET


                 respiratory system

› Bronchoconstriction
› Stimulation of aortic and carotid chemo-receptors result in
  increase in respiration rate and minute volume
 Pharmacological effects:
    AARHUS
    UNIVERSITET


                 Other systems
› Serotonin produces:
› vasoconstriction in:
       - renal and splanchic beds,
       - placental
       - uterine
       - umbilical
       - pulmonary vessels
› Vasodilatation of:
      - skeletal muscle beds
Lægemiddelgrupper med virkning på
    AARHUS
    UNIVERSITET


serotonins dannelse eller signalveje
› Antidepressiva
  › Selektive serotonin uptake inhibitors (SSRI) fx citalopram
  › Tricykliske antidepressiva (TCA) fx amitryptiline

› Appetithæmmende mod obesitas
  › Sibutramin hæmmer uptake af 5-HT (og NA)

› Anxiolytika
  › Partielle 5-HT1A agonister (fx buspiron)
› Antiemetika
  › 5-HT3 antagonister, virker centralt og på neuroner i mave-tarm kanalen (fx
    odansetron). Metoklopramid blokerer også D2 receptorer (kap. 20)

› Lægemidler til behandling af migræne
AARHUS
UNIVERSITET




    MIGRAINE
   AARHUS

 Migraine - Definition
   UNIVERSITET




“Migraine is a familial disorder characterized by
 recurrent attacks of headache widely variable in
 intensity, frequency and duration. Attacks are
 commonly unilateral and are usually associated
 with anorexia, nausea and vomiting”


                  -World Federation of Neurology
 World prevalence of migraine
          AARHUS
          UNIVERSITET



                                                         Switzerland 13%
                                        Denmark 10%

                                  France 8%†




USA 13%
                                                                                    Japan 8%
                                        Italy 16%




                                                          1-year prevalence rates
                                                          Population-based studies
                Chile 7%                                  IHS criteria (or modified)

                                                Rasmussen and Olesen (1994); Rasmussen (1995);
                                                 Lipton et al (1994); Lavados and Tenhamm (1997);
†Prevalence measured over a few years                                      Sakai and Igarashi (1997)
Epidemiology
    AARHUS
    UNIVERSITET




› Migraine is one of the common causes of recurrent headaches
› Migraine affects 10-20% of the general population
› A family history of migraine increases patients chance of
  having it
        - Family history positive in 60% of patients

›Woman are effected 3 times more than man
 - In childhood migraine, boys and girls are affected equally
until puberty, when the predominance shifts to girls.
  Prevalence of migraine by
       AARHUS
       UNIVERSITET


  sex and age
                Migraine prevalence (%)                 Females
                30                                      Males
                25

                20
                15

                10
                 5
                 0
                     20   30    40    50     60    70     80      100
                                     Age (years)



The American Migraine Study (n=2479 migraine sufferers)    Lipton and Stewart (1993)
Migraine - PATHOPHYSIOLOGY
     AARHUS
     UNIVERSITET




› VASCULAR THEORY
› Intracerebral blood vessel vasoconstriction – aura
› Intracranial/Extracranial blood vessel vasodilatation – headache


› BRAIN THEORY
› Cortical spreading depression (associated with aura):
  - In the depressed area signal transduction is slow - 2 mm/min.
  - High extracellular K+ concentration
  - Reduced blood flow


› NEUROGENIC INFLAMMATION
› Perivascular inflammation stimulating sensory nerve – migraine attack
  - activation of trigeminal nerve terminals
Serotonin is involved:
    AARHUS
    UNIVERSITET




› Decreased serotonin levels linked to migraine
       - Increased urinary excretion of the 5-HT metabolite,
  5-HIAA, during attack
       - Blood concentration of 5-HT falls

› Specific serotonin receptors found in blood vessels of
 brain
       - 5-HT agonists and antagonists are effective for
 treatment
Migraine classification
    AARHUS
    UNIVERSITET




    According to Headache Classification Committee of the
    International Headache Society, Migraine has been
    classified as:

›   Migraine without aura (common migraine (80%))
›   Migraine with aura (classic migraine)
›   Complicated migraine
Phases of Acute Migraine
    AARHUS
    UNIVERSITET




› Prodrome
› Aura
› Headache
› Postdrome
Phases of Acute Migraine
    AARHUS
    UNIVERSITET




› Prodrome


› Vague premonitory symptoms that begin from 12 to 36
  hours before the aura and headache
› Symptoms include
  › Yawning
  › Excitation
  › Depression
  › Lethargy
  › Craving or distaste for various foods
  Duration – 15 to 20 min
Phases of Acute Migraine
    AARHUS
    UNIVERSITET




› Aura
Aura is a warning or signal before
onset of headache

Symptoms
› Flashing of lights
› Zig-zag lines
› Difficulty in focussing
Duration : 15-30 min
Phases of Acute Migraine
    AARHUS
    UNIVERSITET




› Headache


› Headache is generally unilateral and is associated with
  symptoms like:
  Anorexia
  Nausea
  Vomiting
  Photophobia
  Phonophobia
  Tinnitus

› Duration is 4-72 hrs
Phases of Acute Migraine
    AARHUS
    UNIVERSITET




› Postdrome


Following headache, patient complains of
› Fatigue
› Depression
› Severe exhaustion
› Some patients feel unusually fresh

Duration: Few hours or up to 2 days
 AARHUS
 UNIVERSITET   MIGRAINE MANAGEMENT

› Non-pharmacological treatment

      ›        Identification of triggers
      ›        Meditation
      ›        Relaxation training
      ›        Psychotherapy

› Pharmacotherapy
                                            non-specific
      ›        Acute therapy
                                            specific
      ›        Prophylaxis
Migraine Triggers:
    AARHUS
    UNIVERSITET




› Food                      › Non-pharmacological
                              treatment
› Disturbed sleep pattern
› Hormonal changes           ›   Identification of triggers
                             ›   Meditation
› Drugs                      ›   Relaxation training
› Physical exertion          ›   Psychotherapy
› Visual stimuli
› Auditory stimuli
› Olfactory stimuli
› Weather changes
› Hunger
› Psychological factors
Migraine:
    AARHUS
    UNIVERSITET


         Acute Therapy

Non-specific treatment:

          Drug        Dose       Route
Aspirin             500-650 mg    Oral
Paracetamol        500 mg-4 g     Oral
Ibuprofen          200- 300 mg    Oral
Diclofenac          50-100 mg    Oral/IM
Naproxen            500-750 mg    Oral
Migraine:
    AARHUS
    UNIVERSITET


         Acute Therapy

Specific treatment:
         Drug                    Receptor          Route
5-HT receptor agonists
Sumatriptan              5-HT1D             Oral
                                            SC
Rizatriptan              5-HT1              Oral
Ergot alkaloids
Ergotamine               5-HT1D             Oral


Dihydroergotamine        5-HT1D             SC
Anfaldskuperende behandling ved migræne
      AARHUS
      UNIVERSITET

Triptanerne (fx sumatriptan)
 › Virkningsmekanisme
   › 5-HT1B/1D agonist, vasokonstriktion, hæmmer sensoriske nerver

 › Administrationsform
   › s.c., supp., p.o., næsespray (aldrig i.v.)

 › Bivirkninger
   › Kvalme og opkastning (ikke i så høj grad som ved ergotamin)
   › Svimmelhed, svaghedsfølelse og tyngdefornemmelse
   › Brystsmerter
   › Påvirkning af blodtryk og hjerterytme ses

 › Kontraindikationer
   › Iskæmisk hjertesygdom, MI, variant angina, hypertension, samtidig
     med ergotalkaloider
Ergotamin
     AARHUS
     UNIVERSITET




› Virkningsmekanisme
  › 5-HT1B/D agonist, α-adrenoceptor agonist, 5-HT2 receptor antagonist
  › Mindre effekt end triptaner
› Administrationsform
  › Suppositorie, peroralt
› Bivirkninger
  › Kvalme og opkastning
  › Kramper i ben, paræstesier
  › Abdominalsmerter
  › Ergotisme
  › Angina pectoris (medfører seponering)
› Kontraindikationer
  › Graviditet, perifer vaskulær sygdom, hypertension, Isk. hjertesygdom,
    nedsat lever og nyrefunktion
WHY THE NEED FOR PROPHYLAXIS ?
    AARHUS
    UNIVERSITET




› Abortive drugs should not be used more than 2-3 times a
  week

› Long-term prophylaxis improves quality of life by reducing
  frequency and severity of attacks

› 80% of migraine patients may require prophylaxis
Profylaktisk behandling
    AARHUS
    UNIVERSITET




› Kriterier
 › Svær hoved pine, optræder > 2-3 gange per måned
 › Invaliderende
 › Kvalme / opkast
 › Varighed: Ofte > 12 timer

› Profylaktisk behandling – virkning ukendt
 › ß-adrenoceptor antagonist (fx propranolol, timolol)
 › Calcium kanal-blokker (fx flunarizin)
 › 5-HT-receptor antagonister: Pizotifen, (cyproheptadin)
 › Prostaglandinsyntese hæmning: Tolfenamsyre
 › Antiepileptika: Valproat

				
DOCUMENT INFO
Shared By:
Categories:
Stats:
views:64
posted:4/2/2011
language:Danish
pages:49