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Neuropharmacology

Neuropharmacology. Presentors: Dr. Shalini Kalyanaraman Dr. Bikram Moderator: Dr. Vimi Rewari. www.anaesthesia.co.in anaesthesia.co.in@gmail.com. Effect of Anaesthetic Agents. Inhalation Agents Intravenous induction agents Muscle Relaxants Opioids. CBF CMRO 2 ICP CO 2 Reactivity

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Neuropharmacology

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  1. Neuropharmacology Presentors: Dr. Shalini Kalyanaraman Dr. Bikram Moderator: Dr. Vimi Rewari www.anaesthesia.co.inanaesthesia.co.in@gmail.com

  2. Effect of Anaesthetic Agents • Inhalation Agents • Intravenous induction agents • Muscle Relaxants • Opioids

  3. CBF • CMRO2 • ICP • CO2 Reactivity • CSF dynamics

  4. Inhalation Agents: • ↓ CMRO2 • Alter ( ↑ ) Flow metabolism coupling • Direct vasodilatory effect Factors affecting effect: • MAC multiples • PaCo2 • Hemodynamic status • Airway pressures • Simultaneous administration of other CNS active drugs • Control state – awake, sedated, anaesthetised • Animal vs human studies • Method of measurement

  5. N2O N2O alone • CBF: ↑ • CMRO2 : ↑ • ICP : ↑ N2O + volatile anaesthetic CBF(0.5 MAC N2O+0.5MAC volatile)>CBF (1 MAC volatile) CBF ↑ caused by N2O is exaggerated at higher conc. of volatile agent ( Lam et al, Anesth Analg 1994; 78:462-8) (Strebel, Kaufmann et al, Acta Anesth Scand 1995;39:653-8)

  6. N2O + iv anaesthetic Barbiturates,benzodiazepines,Propofol, & narcotic attenuate the effect of N2O on CBF CO2 Reactivity : Preserved CSF Dynamics: Vf & Ra unchanged Pneumaceohalus,VAE At the least, it would seem clinically prudent in the event of a tight brain…the efforts to reduce brain mass should include discontinuation of N2O whenever possible - Mitchenfelder

  7. Halothane • CBF: ↑ by 191% • CMRO2 : ↓ by 10% • ↓ MAP → ↓ CBF • ↓ PaCO2 → ↓ CBF • EtHalo > 2.3% → Direct toxicity by progressive disruption of mitochondrial transport • Isoelectric EEG @4 MAC

  8. Distribution of CBF/CMRO2 changes Halothane – global Iso/Sevo/Des – CBF ↑ greater in the subcortex CMRO2 ↓ greater in the neocortex

  9. Anesthetics & the brain (ACNA,20(2002):265-92) • Effect of desfluane on cerebral autoregulation (Bedforth, Mahajan et al,BJA;87(2):193-7(2001) • Direct cerebral vasodilatory effects of sevoflurane & isoflurane (Matta et al;Anesthesiology;91;677-80:1999) • Effect of Sevoflurane on ICP,CBF &CMR (Bundgard et al,Acta Anesth Scand:1998;42;621-7)

  10. Intravenous Induction Agents • Barbiturates ( Thiopentone, Methohexital, Pentobarbital) • Cerebral vasoconstrictors • ↓ CMRO2 → ↓CBF • Doses beyond maximal CMR reduction may produce vasodilatation • Thiopentone • First study in humans –Pierce et al, 1962 • 50 – 60 % ↓ in CMRO2 • Flow metabolism coupling • CO2 reactivity retained • Autoregulation: Preserved • CO2 Reactivity : Preserved

  11. CSF Dynamics (LD/HD) Vf : (0/0) Ra: (-/0) • ICP : ↓ • Tolerance > 24 hours • Cerebral protection: Endpoint of EEG is Burst suppression that provides near maximal metabolic suppression • Modes of action : • GABA agonism • Free Radical Scavenging • Membrane stabilisation • Calcium channel blockade

  12. No improvement in outcome if instituted after global/complete ischemia • In focal ischemia: 3-5 mg/kg q 5 – 10 min (upto 15 – 20 mg/kg) • Pentobabital : Similar (t1/2 : 30 hrs) • Methohexital : Can precipitate seizures

  13. Propofol • CBF : ↓ by 52 % • CMRO2 : ↓ by 36% • Autoregulation : Preserved • CO2 Reactiviy : Preserved • CSf Dynamics : Vf & Ra unchanged • ICP : ↓ • MAP : ↓ • Prompt awakening • ↓ PONV

  14. Etomidate • CBF : ↓ by 34% ( vasoconstrictor) • CMRO2 : ↓ by 45% • Depression in metabolism not uniform- major effect in the forebrain • Autoregulation: Not evaluated • CO2 Reactivity : maintained • CSF Dynamics: (LD/HD) Vf : (0/ ↓) Ra: (0/0) • ICP: ↓, without ↓ing CPP No e/o brain toxicity , normal brain metabolites

  15. Myoclonus • Adrenocortical suppession • Renal toxicity on prolonged use due to propylene glycol in preparation

  16. Ketamine • Early reports < 1971 , considered to be the ideal anaesthetic for neuroradiologic procedures in children • CBF : ↑ by upto 60% • CMRO2 :0 / ↑ • Regional neuroexcitation • Respiratory depression with mild hypercapnia • Direct vasodilation with no change in metabolism

  17. Autoregulation: Maintained • CO2 Reactivity: Maintained • CSF Dynamics: Vf - 0; Ra - ↑ • ICP: ↑ • Diazepam, Midazolam, Iso/N2O, propofol shown to blunt or eliminate ↑ ICP/CBF with ketamine • Unsuitable for neuroanaesthesia

  18. Benzodiazepines • Effect intermediate between narcotics & barbiturates • CBF : ↓ by 25% • CMRO2 : ↓ by 30% • ↓ CBF mainly in areas associated with arousal, attention & memory • Ceiling effect • Cerebral autoregulation & CO2 responsiveness : Maintained • CSF Dynamics • Vf : (0/ ↓) • Ra : (0/0) • ICP: ↓

  19. Flumazenil: • No effect in unanaesthetised volunteers • Reversal of CBF, CMRO2,ICP lowering effects of benzodiazepines • Substantial though short lived overshoot of CBF(44-56%) & ICP(180 – 217%). No rise in CMR • Probably an arousal phenomenon ( Fleischer, Mitchenfelder et al, Anesthesiology, 68;234-42,1988)

  20. Sevofurane VS Propofol • Cerebral hemodynamic changes during Propofol – remifentanil or sevoflurane anaesthesia (Conti et al;BJA;97(3);333-9:2006)

  21. Muscle Relaxants • Muscle relaxants do not cross the blood brain barrier • Cerebral effects due to: • Histamine release • Systemic hemodynamic changes • Action of metabolites • Altered cerebral afferent input • ↓ ICP by preventing coughing & straining, thus lowering CVP & concomitant reduction in cerebral venous outflow impedence

  22. Non Depolarising Muscle Relaxants • Atracurium • Causes histamine release when given in large rapid boluses • The metabolite laudanosine crosses the blood brain barrier & may be epileptogenic • Large doses (3.5 mg/kg) in dogs consistently showed EEG arousal but no change in CBF,CMRO2,ICP • Highly unlikely that epileptoid activity will occur in humans in clinically relevant doses of atracurium (Lanier, Mitchenfelder et al, Anesthesiology,63,589,1985) (Cardiovascular & neurovascular effects of laudanosine,BJA, 59;218-225;1987)

  23. Vecuronium Popular choice in neuroanaes due to its hemodynamic stability & lack of cerebral effects • Pancuronium Large bolus doses → ↑MAP → ↑ICP ,in impaired autoregulation • Rocuronium Rapid onset of action makes it an excellent choice for intubation in neurosurgical patients

  24. Depolarising Muscle Relaxant • Succinylcholine • ↑ ICP 2° to ↑ muscle spindle activity ↑ by 5 mm Hg in 1-3 min & lasts 8 – 10 min (Minton, Grosslight et al, Anesthesiology,65;165-9,1986) • ↑ K+ release in closed head trauma, CVA, hemiparesis, spinal cord trauma, neuromuscular disorders Sch continues to be a valuable drug in neurosurgical anaes with benefit outweighing it risk when rapid & reliable control of airway is necessary

  25. Opioids • CBF & CMRO2: • Low dose: No effect • High dose: ↓ both • Baseline anaesthetic : vasodilator - ↓ both • vasoconstrictor – no effect • Burst suppression never achieved • Cerebral autoregulation & CO2 reactivity: Preserved • ICP: No change

  26. Thank You www.anaesthesia.co.inanaesthesia.co.in@gmail.com

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