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

АТP

Nucleotidase

ADP Phosphate

Nucleotidase

АМP Phosphate

Nucleotidase

ADENOSINE Phosphate

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)!)!

ADENOSINE

Nucleosidase

ADENINE Ribose

Adenindeaminase

HYPOXANTHINE Ammonia

Xanthinoxidase

XANTHINE Аmmonia

Xanthinoxidase

URIC 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

56

Р1

Р2

Р3

0

1

2

3

4

Ряд1

Ряд2

Ряд3

CI

FENTANYL

АDENOSINEF+А

l / ml / m2 2 · min· min

SVR INDEXSVR INDEX

12

34

56

Р1

Р2

Р3

2000

2500

Ряд1

Ряд2

Ряд3

SVRI

FENTANYL

ADENOSINEF+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

АDENOSINEF+А

kPkPа·а·ss//ll

THORAXTHORAX & LUNGS COMPLIANCE& LUNGS COMPLIANCE

12

34

56

Р1

Р2

Р30

0,20,40,60,8

1

Ряд1

Ряд2

Ряд3

C

FENTANYL

АDENOSINE

F+А

l/kPаl/kPа

DEAD VOLUME (VDСОDEAD VOLUME (VDСО22 ) )

12

34

56

Р1

Р2

Р3

00,511,52

2,5

Ряд1

Ряд2

Ряд3

VDCO2

FENTANYL

АDENOSINEF+А

ml/kgml/kg

METABOLIC RATEMETABOLIC RATE(Indirect Calorimetry)(Indirect Calorimetry)

12

34

56

Р1

Р2

Р30100200300400500600700800

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) ANALGESICS:PREEMPTIVE (ANTI-INFLAMMATORY) 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