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Clinical Experience with Purinergic Analgesia 1992 – 2004.
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Transcript of Clinical Experience with Purinergic Analgesia 1992 – 2004.
Clinical Experience Clinical Experience
with with
Purinergic AnalgesiaPurinergic Analgesia1992 – 2001992 – 20044
ADENOSINEADENOSINE
• PurinePurine nucleotidenucleotide
• Natural metaboliteNatural metabolite
• Metasympathetic Metasympathetic autonomous mediatorautonomous mediator
• Interacts with Interacts with adenosine (purinergic) adenosine (purinergic) receptorsreceptors А А11, А, А2 2 , А, А33
Adenosine MedicinesAdenosine Medicines
• AdenosineAdenosine ( (purepure nucleosidenucleoside))
• Adenosine MonophosphateAdenosine Monophosphate (АМ (АМPP, , AdenocardAdenocard®®))
• Diadenosine TetraphosphateDiadenosine Tetraphosphate (2А (2АTPTP))
• Sodium AdenosinetriphosphateSodium Adenosinetriphosphate (АТ (АТPP))
• R-phenylisopropyladenosineR-phenylisopropyladenosine (R-PIA(R-PIA))
ATP ATP
АТPАТP
NucleotidaseNucleotidase
ADPADP PhosphatePhosphate
NucleotidaseNucleotidase
АМPАМP PhosphatePhosphate
NucleotidaseNucleotidase
ADENOSINEADENOSINE PhosphatePhosphate
Adenosine Derivatives MetabolismAdenosine Derivatives Metabolism
Adenosine: Main EffectsAdenosine: Main Effects
• VasodilationVasodilation, , especiallyespecially PulmonaryPulmonary
• NegativeNegative chronochrono-, -, dromodromo-, -, batmobatmo- - && inotropicinotropic actionaction
• GI Motility InhibitionGI Motility Inhibition
• Bronchial ConstrictionBronchial Constriction
• Central AnalgesiaCentral Analgesia
• Anti-Inflammatory actionAnti-Inflammatory action
• SedationSedation ? ?????
Influences on InflammationInfluences on Inflammation::
• SuppressesSuppresses free free O-O-radical effluxradical efflux from from
neutrophils (A2)neutrophils (A2)
• DecreasesDecreases TNFTNF-- productionproduction in in
reperfusionreperfusion//reoxygenationreoxygenation
• ReducesReduces IL-6 releaseIL-6 release
• ButBut:: maymay lead to direct histaminelead to direct histamine
releaserelease (А (А33)!)!
ADENOSINEADENOSINE
NucleosidaseNucleosidase
ADENINEADENINE RiboseRibose
AdenindeaminaseAdenindeaminase
HYPOXANTHINEHYPOXANTHINE AmmoniaAmmonia
XanthinoxidaseXanthinoxidase
XANTHINEXANTHINE АmmoniaАmmonia
XanthinoxidaseXanthinoxidase
URIC ACIDURIC ACID
Adenosine CatabolismAdenosine Catabolism
TT1/21/2<10 <10 s!s!
N.B.! N.B.! Any Adenosine drug acts Any Adenosine drug acts only as a direct agonist at only as a direct agonist at
specific cell membrane specific cell membrane receptors, receptors,
butbutdoes not deliver does not deliver
any energy supply!any energy supply!
Adenosine EffectsAdenosine EffectsModulationModulation
+ + POTENTIATIONPOTENTIATION
• DipyridamoleDipyridamole
– – BLOCKINGBLOCKING
• TheophyllineTheophylline
• PentoxiphyllinePentoxiphylline
• CaffeineCaffeine
Adenosine: Routine Clinical UseAdenosine: Routine Clinical Use
• Supraventricular Antiarrhythmic
• Vasodilator, esp. Pulmonary
• Test Bronchoconstrictor
Marta SegerdahlMarta Segerdahl
Alf Sollevi Alf Sollevi
Karolinska Institutet, Karolinska Institutet, StockholmStockholm1992 - 19951992 - 1995
Alf Sollevi:Alf Sollevi:Adenosine infusion during Adenosine infusion during isoflurane-nitrous oxide isoflurane-nitrous oxide anaesthesia: indications of anaesthesia: indications of perioperative analgesic effect // perioperative analgesic effect // AnesthesiaAnesthesia & Analgesia. – & Analgesia. – 1992. – Vol. 80. – P. 595-599.1992. – Vol. 80. – P. 595-599.
Gomaa AA:Gomaa AA:Characteristics of analgesia induced Characteristics of analgesia induced by adenosine triphosphate // by adenosine triphosphate // Pharmacology and Toxicology. – 1987. Pharmacology and Toxicology. – 1987. – V. 61. – P. 199-202.– V. 61. – P. 199-202.
Zarate E, Sa Rego MM, White PF et al.:Zarate E, Sa Rego MM, White PF et al.: Comparison of adenosine and remifentanil Comparison of adenosine and remifentanil infusions as adjuvants to desflurane infusions as adjuvants to desflurane anesthesia // Anesthesiology. – 1999. – anesthesia // Anesthesiology. – 1999. – Vol. 90. – P. 956-963.Vol. 90. – P. 956-963.
Fukunaga AF, Alexander GE, Stark CW:Fukunaga AF, Alexander GE, Stark CW: Characterization of the analgesic actions of Characterization of the analgesic actions of adenosine: comparison of adenosine and adenosine: comparison of adenosine and remifentanil infusions in patients remifentanil infusions in patients undergoing major surgical procedures // undergoing major surgical procedures // Pain. – 2003. – Vol. 101. – P. 129-138.Pain. – 2003. – Vol. 101. – P. 129-138.
AdenosineAdenosine::analgetic per se,analgetic per se,
analgetic adjuvant analgetic adjuvant or or
just direct autonomous just direct autonomous corrector?corrector?
ComparativeComparative Study IStudy I
BBiiiillrrootthh--IIII SSttoommaacchh RReesseeccttiioonn
HHaallootthhaannee uupp ttoo 11%% iinn NN22OO++OO22 ffllooww 22::11
FFeennttaannyyll 00,,0099--00,,4455
mmkkgg··kkgg--11··mmiinn--11
5500%% FFeennttaannyyll ++ 5500%% AAddeennoossiinnee
AAddeennoossiinnee 00,,1177--00,,55
mmkkgg··kkgg--11··mmiinn--11
NN == 1155 NN == 1122 NN == 1122
((FF)) ((FFAA)) ((АА))
Surgery and AnaesthesiaSurgery and AnaesthesiaControl PointsControl Points
1. 1. Starting Point before InductionStarting Point before Induction
2. 2. On Anaesthesia InductionOn Anaesthesia Induction
3. 3. On Skin CuttingOn Skin Cutting
4. 4. During MobilizationDuring Mobilization
5. 5. Restorative Phase (Anastomosis)Restorative Phase (Anastomosis)
6. 6. Recovery from AnaesthesiaRecovery from Anaesthesia
CARDIAC INDEXCARDIAC INDEX
12
34
5
6
Р1
Р2
Р3
0
1
2
3
4
Ряд1
Ряд2
Ряд3
CI
FENTANYL
АDENOSINE
F+А
l / ml / m2 2 · min· min
SVR INDEXSVR INDEX
12
34
5
6
Р1
Р2
Р3
2000
2500
Ряд1
Ряд2
Ряд3
SVRI
FENTANYL
ADENOSINE
F+А
dyn · s · cmdyn · s · cm-5-5 · m · m2 2
Two-component ModelTwo-component Modelof Respiratory of Respiratory
MechanicsMechanics• P – full Circuit PressureP – full Circuit Pressure, , kPkPаа
• R – Airways aerodynamicR – Airways aerodynamic ResistanceResistance, , kPkPаа·s·s//ll
• С - «С - «ThoraxThorax--LungsLungs»» System System ComplianceCompliance, , ll//kPkPаа
P = R·dV/dt + V/C,P = R·dV/dt + V/C,
wherewhere V - VolumeV - Volume, , t - Timet - Time..
AIRWAYS RESISTANCEAIRWAYS RESISTANCE
1
3
5Р1
Р2
Р300,050,10,150,20,250,3
Ряд1
Ряд2
Ряд3
R
FENTANYL
АDENOSINE
F+А
kPkPа·а·ss//ll
THORAXTHORAX & LUNGS COMPLIANCE& LUNGS COMPLIANCE
12
34
56
Р1
Р2
Р30
0,2
0,4
0,6
0,8
1
Ряд1
Ряд2
Ряд3
C
FENTANYL
АDENOSINE
F+А
l/kPаl/kPа
DEAD VOLUME (VDСОDEAD VOLUME (VDСО22 ) )
12
34
5
6Р1
Р2
Р3
0
0,5
1
1,5
2
2,5
Ряд1
Ряд2
Ряд3
VDCO2
FENTANYL
АDENOSINEF+А
ml/kgml/kg
METABOLIC RATEMETABOLIC RATE(Indirect Calorimetry)(Indirect Calorimetry)
12
34
56
Р1
Р2
Р30
100200300400500600700800
Ряд1
Ряд2
Ряд3
MR
FENTANYL
АDENOSINE
F+А
calcal//mm2 2 ··minmin
ComparativeComparative Study IIStudy II
EElleeccttiivvee LLaappaarroossccooppiicc CChhoolleeccyysstteeccttoommyy
IInnhhaallaattiioonn NN22OO++OO22 ffllooww 22::11
FFeennttaannyyll 00,,0099--00,,4455
mmkkgg··kkgg--11··mmiinn--11
AAddeennoossiinnee 00,,1177--00,,55
mmkkgg··kkgg--11··mmiinn--11
NN == 5500 NN == 5500
((FF)) ((АА))
Surgery and AnaesthesiaSurgery and AnaesthesiaControl PointsControl Points
1. 1. Starting Point before InductionStarting Point before Induction
2. 2. On BladderOn Bladder SeparationSeparation
3. 3. Just beforeJust before RecoveryRecovery
Surgery Spectrum Surgery Spectrum
CChhoolleeccyysstteeccttoommyy 112266 GGaassttrreeccttoommyy && ssttoommaacchh rreesseeccttiioonn 3355 EEssoopphhaagguuss rreesseeccttiioonn ((oonnee--ssttaaggeedd)) 11 CCoolloorreeccttaall rreesseeccttiioonnss 1100 AAddrreennaalleeccttoommyy 1199 PPuullmmoonnaarryy rreesseeccttiioonn 11 HHyysstteerreeccttoommyy 1133 TThhyymmeeccttoommyy 55 OOtthheerr ssuurrggeerryy aanndd pprroocceedduurreess 8833 TToottaall 229933
Specific Cases of Specific Cases of Adenosine UseAdenosine Use
• Surgery in Surgery in Myasthenia GravisMyasthenia Gravis – 6 – 6
• Fast Opiate Detoxification under General Fast Opiate Detoxification under General Anaesthesia with Naloxone – 49Anaesthesia with Naloxone – 49
• Anaesthesia in Opiate Addicts – 12Anaesthesia in Opiate Addicts – 12
• Test in Full Consciousness – 1Test in Full Consciousness – 1
Adenosine InfusionAdenosine Infusion
Precision Syringe PumpPrecision Syringe Pump!!!!!!
ECG MonitoringECG Monitoring!!!!!!!!
Official 1% Sodium-ATP solution:
Infusion Rate = 1…5 mg/kg per hour
No Bolus Infusion!
DETAILS &… COMPLICATIONSDETAILS &… COMPLICATIONS
• BradycardiaBradycardia
• BronchospasmBronchospasm
• SSА- А- oror А АVV--block exacerbationblock exacerbation
• SpOSpO2 2 decrease (vasodilation, V/Q decrease (vasodilation, V/Q mismatch)mismatch)
• Hyperuremic metabolic acidosisHyperuremic metabolic acidosis
!!
CONTRAINDICATIONCONTRAINDICATIONSS
• AllAll cases of bronchial obstructioncases of bronchial obstruction
• SSА- А- oror А АVV--conduction conduction disturbancesdisturbances
• Weak sinus syndromeWeak sinus syndrome
• HyperuricemiaHyperuricemia??
ADVANTAGESADVANTAGES• GoodGood AnalgesiaAnalgesia withoutwithout SedationSedation
• Excellent ControllabilityExcellent Controllability
• Stimulates BreathingStimulates Breathing
• Mild Hemodynamic EffectsMild Hemodynamic Effects
• No Postoperative HyperalgesiaNo Postoperative Hyperalgesia
• Treats Pulmonary HypertensionTreats Pulmonary Hypertension
• May be used in Opiate AddictsMay be used in Opiate Addicts
• No Law RestrictionsNo Law Restrictions
ANALGESIC SPECTRUM:ANALGESIC SPECTRUM:BETWEEN HYSTORY & BETWEEN HYSTORY &
FUTURE…FUTURE…
• OPIATESOPIATES
22-ADRENOPOSITIVE AGENTS-ADRENOPOSITIVE AGENTS
• PURINE DERIVATIVESPURINE DERIVATIVES
• SEROTONINE (5-HT) AGONISTSSEROTONINE (5-HT) AGONISTS
FUTURE ANALGESIC FUTURE ANALGESIC SETSET
• PREEMPTIVE (ANTI-INFLAMMATORY) PREEMPTIVE (ANTI-INFLAMMATORY) ANALGESICS:ANALGESICS: NSAIDs, PROTEINASE INHIBITORS, NSAIDs, PROTEINASE INHIBITORS, GLUCOCORTICOIDSGLUCOCORTICOIDS
• INTRAOPERATIVE ANALGESICS – DIRECT INTRAOPERATIVE ANALGESICS – DIRECT AUTONOMOUS CORRECTORS: AUTONOMOUS CORRECTORS: 22--ADRENOPOSITIVE AGENTS, PURINE DERIVATIVES, ADRENOPOSITIVE AGENTS, PURINE DERIVATIVES, -BLOCKERS, Ca-BLOCKERS, Ca++++-CHANNEL BLOCKERS, etc.-CHANNEL BLOCKERS, etc.
• ““FULL-CONSCIOUSNESS” ANALGESICS:FULL-CONSCIOUSNESS” ANALGESICS: OPIATES, OPIATES, NMDA-ANTAGONISTSNMDA-ANTAGONISTS