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Pain
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. (IASP)
Pain is a CNS disease that has to be aggressively treated, regardless it's causeAlan Bussbaum, 2005
What is pain?
Whatever the experiencing person says it is, existing whenever he says it does Margo McCaffrey
TYPES OF PAIN
symptom Pain disease physiologic
Pain
acute Pain pathologic
chronic
TYPES OF PAIN
somatic nociceptive visceral PAIN neuropathic
nonnociceptive
psychogenic R. Kannev, Pain Management Secrets, 1997
TYPES OF PAIN
Nociceptive pain nociceptors A delta fibres C fibres mecanical thermal chemical
Nociceptive Pain
Serotonine Substance Bradikinine
Endogenic stimuli
(algogenic molecules)
PG
Ions: ATP histamine
H+ si K+
TIPURI DE DURERE
DUREREA SOMATIC
Bine localizat Ex:
Durere Durere
postoperatorie musculoscheletica
Durerea Durerea
din artrite
Types of Pain
distension
Visceral Pain
traction torsion
Vague localization Cramps Skin reference (REFERRED PAIN) Autonomic NS symptoms (nausea, vomisments, cardiac rhythm disorders )
particularities:
TYPES OF PAIN
NEUROPATHIC PAIN
Nerve
Exemples:
Pain
in diabetus melitus, zoster Phantom Limb Pain Complex Regional Pain Syndrome CRPS
TIPURI DE DURERE
Psychogenic pain
Unclear mechanism Psychiatric sympthoms Sensitive to psychotropic agents * empathy pain * social pain
PAIN MECHANISMS
FARMACOLOGIA DURERII
PERIFERIC STAGE
PERIFERIC STAGE
PAIN MEDIATORS
CATEGORIA Neurotrasmitori DENUMIREA Neuromodulatori Serotonina (5HT) Histamina Acetilcolina (Ach) Glutamat Factorul de cretere nervoas (NGF) Peptidul legat genetic de calcitonin (CGRP) Tahikinine Substana P (receptor NK1) Neurokinina A (receptor NK2) Neurokinina B (receptor NK3) Bradikinine Bradikinine (receptor B1 i B2) OBERVAII Extrem de activ Mai puin activ, implicat mai ales n senzaia de mncrime Transmitor rapid al durerii Prezent n esuturi lezate, determin hiperalgezie Acioneaz central i periferic
Kinine
Prostaglandine
Puternic algogene, acioneaz i prin eliberare prostaglandine. Se cupleaz cu un receptor specific cuplat cu proteina G. Recent a fost sintetizat un antagonist competitiv icatibant cu proprieti analgezice Nu sunt direct algogene dar poteneaz efectul algogen al serotoninei si kininelor Scderea pH-ului are efect nociceptiv prin deschiderea canalelor ionice activate de protoni (de exemplu canale de calciu). Sunt considerai mediatori poteniali ai durerii ischemice Se pare c n periferie poteneaz stimulii algici iar la nivel central poteneaz analgezia betaendorfinic.
Metabolii
Oxidul Nitric
PERCEPIA DURERII
CORTEX SUBCORTICAL NUCLEI
periphery
sensitizing factors algogene proalgogene Nociceptor
STIMULI
Only
nerve hurts!
PAIN EVALUATION
PAIN EVALUATION
1. Tritium labeled Bradykinine bonding test (RAT ILEON) 2. Tritium labeled substance P bonding test (pig brain) 3. Tritium labeled Naloxone bonding test (rat bran) 4. Tritium labeled Dihydromorphone bonding test (rat brain) 5 Tritium labeled Bromazopcine bonding test (guinea pig brain) 6. Enkephalinaze inhibition test (rat kidney) Compression tail Mechanoalgezic paw Hot plate Thermoalgezic Tail imertion Tail flick Writting test (acetic acid, bradykinine, Chemical benzochinone) Testul la formalin Podolorimetric Electphysiologic Rectodolometric Acute experimental arthritis Subacute experimental arthritis Escape and avoiding Mechanic tests Healthy voluntars Thermic tests Chemical tests Electrophysiologic tests Analogue visual Patients Scales scale Numeric visual scale
IN VITRO IN VIVO
IN HUMANS
IN LAB ANIMAL S
Behavioral analisis
Verbal vicual scale Tones visual scale Pictural scale Visuale mixed scale Simple Movement/posture Enviromental MMPI MPQ DDS Endorphines dosage Algezimey
Questionnaires
PAIN EVALUATION
PAIN EVALUATION
PAIN EVALUATION
PAIN EVALUATION
EVALUAREA DURERII
ENDOGENE OPIOIDS
OPIOIZII ENDOGENI
ProopiomelanocortinE (prehormonE 260 AA) ACTH -lipotropinE 91 AA MSH
ProenkefalinE A
-endorfinE 31 AA
Proenkefaline B (prodynorfine)
dynorfine neoendorfine
rimorfine
ENDOGENE OPIOIDS
PRECURSORs OP
Proopiomelancocortins (POMC) Proenkefalins (proENK)
GENES
3 exons 2 introns 4 exons 5 introns
OPIOPEPTIDES
-endorfins (-LPH61-76) -endorfins (-LPH61-96) Met-enkefaline (5aa) Leu-Enkefaline (5 aa) Heptapeptide (7 aa) Octapeptide (8 aa) Peptide I BAM-12P (Peptid I 15-26) BAM 20 (Peptid I 15-26) -neoendorfine (10 aa) -neoendorfine (9 aa) Dinorfine (32 aa) Dinorfine A (Dinorfina 117) -endorfine (-LPH51-77) -endorfinae (fragmentC) (-LPH51-87) BAM 22P (Peptide I 15-36) Peptide E (Peptide I 15-39) Metorfamide (Peptide E18NH2) Peptide F Peptid B Sinenkefalin (proenkefaline 1-70) Dinorfine B (Dinorfine 2032) Dinorfine 1-8 Levomorfine
4 exons 3 introns
m-ARN
PREPROPEPTIDE
proENK
POMC
proDYN
Postsynaptic stage
Receptors: , ,
Opioid receptors
2nd
OP1
OP2
OP3
OP4
IUPHAR name
disphoric MOR KOR DOR XOR
2nd messengers
- Ca2+
channels blockers
agonists
papaverin a -miorelax
effects
-ANS modifires
Endogene opioids
Analgesia
dynB29>dynA(1-32)>dynA(1-17)>dynB> neoendorfine
Alcohol betaendorfines
Betaendorfines TA Dinorfine A TA
Published results
%MPE (antinociception %). The effect of 1) Tyr-Gly, 0.5 mg/rat i.t., 2) Tyr-Gly-Gly, 0.5 mg/rat i.t., 3) Leu-enkefaline, 0.5 mg/rat i.t. on nociception, evaluated by mechano-algesic test in rats. Throughout the graphs, an asterisk indicates a significant antinociception (p < 0.05) compared with the control group. The horizontal line represents the 30% antinociception level.
Pain therapy
Class
Coanalgezice:
TCA; neuroleptics; anticonvulsivants; miorelaxants; calcitonine; adenozine; metoclopramid; corticoids; nitrits ; antacides; acetazolamide.
Paraanalgezics:
Chronology
1803 1874 1939 1952 1971-1974 1974 -1975 1976-1986
Morphine
is isolated Serturner Heroine semisinteza Petidina sinteze Morphine- complete synthesis Opioid receptors are isolated Enkefalines are isolated Endorfines are isolated The list continues...
OPIOIDES
Morphine Morphine 6 glucuronid 3.7 s.c. 45 i.c.v. Foley 1993 CR Bashford 2001 Roxanol SR (8 ore) MS Contin (12 ore) MST Heroine metabolites: Morfine im 2 - 6 acetyl morphine
ANALGEZICE OPIOIDE
Hydromorfon 5 - avantaje la btrni (t1/2 1.5-2 ore) - analgezie excelent - efecte secundare minime (Brose 1991) Levorfanol 2 - n durerile cronice la cei ce nu tolereaz morfina - afinitate pe receptorii Codeine pentru treapta a II-a n combinaii DH codeina Oxycodone 10 codeina dureri moderate i severe - prezent n combinaii
ANALGEZICE OPIOIDE
Meperidina 75 mg = 10 mg morfina i.m. - normepteridin: metabolit activ convulsivant 2 - analgezic Metadona - 10mg = 10mg morfina - analgezic de linia a II-a - terapia addiciei Propoxifen durerea moderat 1/2 1/3 din codein -metabolit: norpropoxifen (convulsivant) Fentanyl 1:20, 1:30 fa de morfin - dureri intra i post operatorii - numeroase ci de administrare - metabolii inactivi
AGONITI /ANTAGONITI
Pentazocina 35 mg = 10 mg morfina. Receptori , TA disforie, efecte psihotomimetice Nalbufina echivalent cu morfina - pentru dureri postoperatorii - substitut al morfinei (mai puine efecte secundare) - potenial de abuz mai sczut ca morfina - potenial psihotomimetic sczut Butorfanol 2 mg i.m. = 10 mg morfin - potenial slab de dependen fizic - util n durerea acut la pacieni ce nu au mai primit opioide
NSAID`S
NO-NSAID`S
Primul NO-AINS sintetizat a fost nitroaspirina (Wallace i Granger, 1996) NCX 4016, NCX 4215 Tabel 4. Dezvoltarea NO-AINS aflate n stadiul de studii clinice
Non-opioid
MORPHINE IN EUROPE
www.algezio.ro
LEGEA OPIOIDELOR
A.
A1 opioids receptors A2 excitatory aa rec A3 Pg and Lt rec A4 neurokines rec A5 NGF rec) A6 bradikinine rec A7 adenosine rec A8 colecistokinine rec A9 monoamines rec: 5HT1D, alfa2, dopaminergic rec A10 cholinergici rec A11 cannabinoid rec B1 COX 2 inhibitors B2 enkefalinaze inhibitors B3 NO syntase inhibitors
ENZYMATIC LEVEL
RECEPTOR LEVEL
B.
C. Ion channels Inhibitors/Activators Na channel inhibitors starting from local anesthetics or antidepressants; K channels activatorsu; Ca channels inhibitors (SNX-III, N channel bloker in spinal pain modulationl), Gohil, 1993, Malmerg, 1994. D. genetic level
DREAM GENE
DREAM gene (downstream regulatory element antagonist modulator) Transcriptional DNA repressantului. 2 DREAM variants in rats:
ORF 1 ORF 2 (Hammond P.I. et al., 2002) Cuting of prodinorfine exprimation in cell cultures (Campos D. et al., 2003) and at spine level (Costigan M. et al., 2002) Is repressing early c-fos genes (Carrion A.M. et al., 1999)
DREAM:
DREAM GENE
knockout (cu lipsa a genei DREAM) oarecii knockout manifest o reducere semnificativ a sensibilitii acute, a durerii inflamatorii i neuropate dar rspunsuri motorii, cardiace i imunitare normale. (Bradley D., 2002) animalele knockout prezint o atenuare marcat a nocicepiei la toate tipurile de stimuli testai (mecanici, termici, chimici) att pe modele de durere somatic ct i visceral. (Los Santos-Artega M. et al., 2003) rspunsurile la stimularea nociceptiv a oarecilor knockout sunt mediate prin receptorii k-opioizi (norbinaltorphimine dihydrochloride- antagonist selectiv k-opioid). (Brent A. et al., 2002)
GENA DREAM
Modularea funciei genei DREAM poate fi util n alterarea pragului de percepie dureroas direcii viitoare:
substane care ar putea bloca capacitatea de legare a DREAM de ADN; prevenirea producerii proteinei DREAM.
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