Mechanism of general anaesthesia at molecular level.

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Mechanism of general anaesthesia at molecular level.

  1. 1. MECHANISM OF GENERAL ANAESTHESIA AT MOLECULAR LEVEL DR.P. NARASIMHA REDDY PROFESSOR OF ANAESTHESIA, NARAYANA MEDICAL COLLEGE, NELLORE.
  2. 2. INTRODUCTION General anaesthetics have been in use since mid 19th century, ether and chloroform were the first two agents to come, later in mid 20 th century the Halothane was synthesized. GA’s are most useful, most dangerous, and least specific & least understood drugs. GA’s comprise one of the most important and dangerous groups of drugs in medicine because of which surgery flourished and flourishing
  3. 3. Since 160 years scientists are trying to explain how GA drugs work in the midst of an era of molecular neurology. It has been stated that mystery of anaesthesia like that of consciousness has not yielded to molecularity. How and where anaesthetics act remains a mystery, and that has instigated and frustrated many physicians for many decades.
  4. 4. ONE OF THE UNSOLVED MYSTERIES OF PHARMACOLOGY
  5. 5. WHY CHANGE IN THE RESPONSE NO STRUCTURE ACTIVITY RELATIONSHIP AMONG ANAESTHETICS WORKS AT VERY HIGH CONCENTRATION ONLY
  6. 6. AIM WHAT IS ANAESTHESIA? HOW IS ANAESTHESIA MEASURED? WHAT ARE THE ANATOMICAL SITES OF ANAESTHETIC ACTION IN THE CNS? WHAT ARE THE MOLECULAR TARGETS OF ANAESTHESIA?
  7. 7. ANAESTHESIA DEFINITION UNCONSCIOUS AMNESIA ANALGESIA IMMOBILITY ATTENUATION OF AUTONOMIC RESPONSE TO NOXIOUS STIMULI
  8. 8. SLEEP- there are two main pathways in determining the sleep & wakefulness state. Ascending arousal pathway includes penduculo-pontine and lateral dorsal tegmental nuclei which send projections to thalamus and cortex. This pathway also includes ascending projections from locus coeruleus, raphe and tubero mamillary nucleus. The descending pathways includes projections from the ventrolateral preoptic nucleus and lateral hypothalamic orixinergic neurons to the TMN, raphe, LC & PP, Lateral hypothalamic nucleus.
  9. 9. ANAESTHESIA MEASUREMENT AIM IS TO RANK THE ORDER OF POTENCY
  10. 10. ANAESTHESIA MEASUREMENT MAC- MINIMAL ALVEOLAR CONCENTRATION THE ALVEOLAR PARTIAL PRESSURE OF A GAS AT WHICH 50% OF HUMANS DO NOT RESPOND TO A SURGICAL INCISION
  11. 11. SITE OF ACTION PLAUSIBLE TARGETS ARE PERIPHERAL RECEPTORS, SPINAL CORD, BRAINSTEM, CEREBRAL CORTEX SPINAL CORD > DIRECT EFFECT ON THE SPINAL MOTOR NEURONS > ENDPOINT FOR ANAESTHETIC POTENCY CONT….
  12. 12. SITE OF ACTION BRAINSTEM > RETICULAR ACTIVATING SYSTEM > INVOLVED IN AROUSAL BEHAVIOUR CEREBRAL CORTEX > MAJOR SITE FOR INTEGRATION, STORAGE, RETRIEVAL > INTERFERE WITH COMPLEX FUNCTIONS CONT….
  13. 13. SITE OF ACTION BOTH PRESYNAPTIC & POSTSYNAPTIC EFFECTS GLUTAMATE- MAIN EXCITATORY NEUROTRANSMITTER IN CNS GABA- MAIN INHIBITIORY NEUROTRANSMITTER IN THE CNS GLYCINE- MAIN INHIBITORY NEUROTRANSMITTER IN THE SPINAL CORD
  14. 14. MOLECULAR TARGETS MEYER-OVERTON HYPOTHESIS ACTION ON ION CHANNELS 1. EFFECT ON VOLTAGE GATED ION CHANNELS 2. EFFECT ON LIGAND GATED ION CHANNELS
  15. 15. MEYER-OVERTON HYPOTHESIS HYDROPHOBIC TARGET POTENCY OF ANAESTHETICS AND LIPID SOLUBILITY PRODUCE ANAESTHESIA WHEN THEY REACH A CRITICAL CONCENTRATION IN THE MEMBRANE
  16. 16. MEYER-OVERTON HYPOTHESIS UNITARY THEORY OF ANAESTHESIA > STRUCTURALLY UNRELATED COMPOUND ARE LIKELY TO ACT AT THE SAME MOLECULAR SITE > ANAESTHESIA IS PRODUCED BY DISTURBANCE OF THE PHYSICAL PROPERTIES OF CELL MEMBRANES
  17. 17. MEYER-OVERTON HYPOTHESIS LIMITATIONS > Applies to gases and volatile mixture > Olive oil is a poor mixture of oil Theory fails to explain how the proposed disturbance of the lipid bilayer would result in a dysfunctional membrane protein
  18. 18. MEYER-OVERTON HYPOTHESIS EXCEPTIONS > HALOGENATED COMPOUNDS > NONIMMOBILIZERS > CUTOFF EFFECT
  19. 19. PRESSUREREVERSALTHEORY GA can be reversed by applying pressure on to the tissues. All these theories conclude that there is no chemical reaction but physiological perturbation occurring during anaesthesia, like changes in phase separation, changes in bilayer thickness, changes in order parameters, changes in elasticity.  
  20. 20. Modern lipid hypothesis Modern version of hypothesis states that anesthetic effect happens if solubulisation of GA in bilayer causes re distribution of lateral pressures. Each layer has distinct profile of distribution of lateral pressure in it. Ion channels are sensitive to changes in this lateral pressure distribution profile. Changes in membrane lateral pressure profile shifts the conformational equilibrium of certain membrane proteins known to be affected by GA drugs such as Ligand gated ion channels, this is also non
  21. 21. According to modern lipid hypothesis GA drugs do not act directly on their membrane protein targets, but rather perturbs specialized lipid matrices at the protein lipid interface which acts as mediators. Oleamied is an endogenous anaesthetic found in vivo and it is known to potentiate sleep and lower the temperature of the body through the closing gap junction channel connection.
  22. 22. PROTEIN THEORIES OF ANAESTHESIA HYDROPHOBIC SITES OF PROTEINS > CORE OF WATER SOLUBLE PROTEINS > LINING OF BINDING SITES FOR HYDROPHOBIC LIGANDS FIREFLY LUCIFERASE
  23. 23. ACTION ON ION CHANNELS LIKELY TARGET FOR ANAESTHETICS PATCH CLAMP TECHNIQUE
  24. 24. VOLTAGE GATED ION CHANNELS INCLUDES > VOLTAGE DEPENDENT SODIUM CHANNELS > VOLTAGE DEPENDENT POTASSIUM CHANNELS > VOLTAGE DEPENDENT CALCIUM CHANNELS
  25. 25. SODIUM CHANNELS INSENSITIVE TO VOLATILE ANAESTHETICS 50% INHIBITION OF SODIUM CHANNEL CURRENT REQUIRED HALOTHANE CONCENTRATION 8 TIMES THOSE REQUIRED TO PRODUCE ANAESTHESIA FEW SUBTYPES ARE SENSITIVE RESULTS IN SIGNIFICANT REDUCTION IN SYNAPTIC FUNCTION
  26. 26. CALCIUM CHANNELS LOCATED AT PRESYNAPTIC TERMINAL RESPOND TO ACTION POTENTIAL BY OPENING RELEASE OF CALCIUM INTO THE CELL RELEASE OF NEUROTRANSMITTER IN THE SYNAPTIC CLEFT CONT….
  27. 27. CALCIUM CHANNELS SIX TYPES L, N, P, Q, R, T N, P, Q, R- MAJOR ROLE IN SYNAPTIC TRANSMISSION L, T- MAJOR ROLE IN CARDIAC, SKELETAL AND SMOOTH MUSCLE CONT….
  28. 28. CALCIUM CHANNELS VOLATILE SUBSTANCE INHIBIT VOLTAGE DEPENDENT CALCIUM CHANNELS (50% REDUCTION OF CURRENT) AT CONCENTRATION 2 TIMES THOSE REQUIRED TO PRODUCE ANAESTHESIA IN HUMANS
  29. 29. BACKGROUND(LEAK) POTASSIUM ION CHANNELS ACTIVATED BY BOTH VOLATILE AND GASEOUS ANAESTHETICS TEND TO BE OPEN AT ALL VOLTAGES PRODUCE A LEAK CURRENT
  30. 30. LIGAND GATED ION CHANNELS WHICH OPENS WHEN THERE IS ALTERATION IN THE MEMBRANE POTENTIAL MEDIATES EXCITATORY AND INHIBITORY NEUROTRANSMISSION LOGICAL TARGET FOR ANAESTHETIC ACTION
  31. 31. GABA-ACTIVATED ION CHANNELS MOST IMPORTANT INHIBITORY NEUROTRANSMITTER RESPONSE TO MANY DRUGS BARBITURATES, BENZODIAZEPINES, PROPOFOL & VOLATILE ANAESTHETICS MODULATE GABAA RECEPTOR FUNCTION CONT….
  32. 32. GABA-ACTIVATED ION CHANNELS ANAESTHETICS BIND TO THIS RECEPTOR CLORIDE ION CONDUCTANCE INCRAESES HYPERPOLARIZATION OF THE POSTSYNAPTIC CELL MEMBRANE INHIBITION OF POSTSYNAPTIC NEURON
  33. 33. GABA-ACTIVATED ION CHANNELS 3 TYPES OF EFFET ON THE RECEPTOR 1. POTENTIATION 2. DIRECT GATING 3. INHIBITION
  34. 34. GABA-ACTIVATED ION CHANNELS POTENTIATION ABILITY OF THE ANAESTHETICS TO INCREASE THE CURRENT ELICITED BY LOW CONCENTRATION OF GABA DIRECT GATING ABILITY OF THE ANAESTHETICS TO ACTIVATE GABAA CHANNELS IN THE ABSENCE OF GABA
  35. 35. GABA-ACTIVATED ION CHANNELS INHIBITION ABILITY OF THE ANAESTHETICS TO PREVENT GABA FROM INITIATING CURRENT FLOW THROUGH GABAA CHANNELS
  36. 36. GLUTAMATE ION CHANNELS MAIN EXCITATORY NEOROTRANSMITTER IN THE CNS 3 CATEGORIES > AMPA RECEPTORS > KAINATE RECEPTORS > NMDA RECEPTORS
  37. 37. GLUTAMATE ION CHANNELS AMPA & KAINATE RECEPTORS INVOLVED IN FAST EXCITATORY SYNAPTIC TRANSMISSION(Na & K) NMDA RECEPTORS LONG TERM MODULATION KETAMINE & NITROUS OXIDE
  38. 38. GLYCINE-ACTIVATED ION CHANNELS INHIBITORY NEUROTRANSMITTER IN SPINAL CORD & BRAINSTEM VOLATILE ANAESTHETICS PRODUCE EFFECT BY INCREASING AFFINITY OF THE RECEPTOR PROPOFOL, PHENTOBARBITAL ALSO POTENTIATE GLYCINE-ACTIVATED CURRENT
  39. 39. O2PATHWAY PERTURBATION THEORY This theory tries to explain how membranes are not simply permeable to O2 but actually a complex O2 transportation structure.it is postulated that all the receptors interactions seen under the effect of anaesthetics are as a result of a kind of cellular cascade initiated by O2.O2 is needed in neurons,anaesthetics may disrupt O2 pathway causing less energy production. Anaesthetics acting on membrane lipid-protein disrupt O2 transport initiating a cellular cascade via triggered o2 sensing mechanisms.mitochondria have
  40. 40. CONCLUSIONS. Observations favor the membrane has the site of action & anaesthetic receptors seems to be of finite size & anaesthetic molecules of limited size. It is suggested that narcosis occurs when a critical fraction of membrane is occupied by anaesthetic agent. It is clear that all anaesthetic action cannot be localized to a specific site in the
  41. 41. Some Evidence Suggest That different components of anaesthetic state may be mediated by actions disparate anaesthetic site Actions of anaesthetics cannot be localized by specific physiological process. Some assume that anaesthetic ultimately effects synaptic function as opposed to intrinsic neuronal excitability
  42. 42. The effects of anaesthetics depend on the agent and pre and post synaptic receptors. At molecular level volatile anaesthetic agents show some selectivity but still effect multiple ion channels and synaptic proteins. IV anaesthetics are more specific with GABA a receptors, but there are more proteins directly interact with anaesthetics.
  43. 43. is agreed that narcosis is due to physical rather han chemical action of the molecule & relatively wea orces are involved. here is a good correlation between anaesthetic otency & molar refraction polarisability of the naesthetic agent, molal volume & solubility in olive l. Developments in molecular biology, genetics, and ell physiology make it possible that next generation an find some answers to the 160 yrs old harmacological puzzle of mechanism of naesthesia.
  44. 44. CURRENT NEWS March 30, 2007 The Wall Street Journal: “FDA Wants More Research on Anesthesia Risk to Kids” Anesthesia can be harmful to the developing brain, studies on animals suggest, raising concerns about potential risks in putting young children under for surgery Prolonged changes in behavior; memory and learning impairments Relevance of the animal findings to pediatric patients is unknown
  45. 45. REFERENCES CLINICAL ANAESTHESIA BY PAUL G. BARASH SIXTH EDITION A PRACTICE OF ANAESTHESIA BY WYLIE & CHURCHILL-DAVIDSON’S SEVENTH EDITION INTERNET
  46. 46. THANK YOU

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