Mechanism of general anaesthesia at molecular level.
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Transcript of Mechanism of general anaesthesia at molecular level.
MECHANISM OF GENERAL
ANAESTHESIA AT MOLECULAR LEVEL
DR.P. NARASIMHA REDDY
PROFESSOR OF ANAESTHESIA,NARAYANA MEDICAL COLLEGE,
NELLORE.
INTRODUCTIONGeneral anaesthetics have been in use since
mid 19th century, ether and chloroform were the first two agents to come, later in mid 20th 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
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.
ONE OF THE UNSOLVED MYSTERIES OF
PHARMACOLOGY
WHY
CHANGE IN THE RESPONSE
NO STRUCTURE ACTIVITY RELATIONSHIP AMONG ANAESTHETICS
WORKS AT VERY HIGH CONCENTRATION ONLY
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?
ANAESTHESIA DEFINITION
UNCONSCIOUS
AMNESIA
ANALGESIA
IMMOBILITY
ATTENUATION OF AUTONOMIC RESPONSE TO NOXIOUS STIMULI
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.
ANAESTHESIA MEASUREMENT
AIM IS TO RANK THE ORDER OF POTENCY
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
SITE OF ACTION
PLAUSIBLE TARGETS ARE PERIPHERAL RECEPTORS, SPINAL CORD, BRAINSTEM, CEREBRAL CORTEXSPINAL CORD
> DIRECT EFFECT ON THE SPINAL MOTOR NEURONS
> ENDPOINT FOR ANAESTHETIC POTENCY CONT….
SITE OF ACTION
BRAINSTEM > RETICULAR ACTIVATING SYSTEM > INVOLVED IN AROUSAL BEHAVIOUR
CEREBRAL CORTEX > MAJOR SITE FOR INTEGRATION, STORAGE, RETRIEVAL > INTERFERE WITH COMPLEX FUNCTIONS CONT….
SITE OF ACTIONBOTH PRESYNAPTIC & POSTSYNAPTIC EFFECTS
GLUTAMATE- MAIN EXCITATORY NEUROTRANSMITTER IN CNS
GABA- MAIN INHIBITIORY NEUROTRANSMITTER IN THE CNS
GLYCINE- MAIN INHIBITORY NEUROTRANSMITTER IN THE SPINAL CORD
MOLECULAR TARGETS
MEYER-OVERTON HYPOTHESIS
ACTION ON ION CHANNELS
1. EFFECT ON VOLTAGE GATED
ION CHANNELS
2. EFFECT ON LIGAND GATED
ION CHANNELS
MEYER-OVERTON HYPOTHESIS
HYDROPHOBIC TARGET
POTENCY OF ANAESTHETICS AND LIPID SOLUBILITY
PRODUCE ANAESTHESIA WHEN THEY REACH A CRITICAL CONCENTRATION IN THE MEMBRANE
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
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
MEYER-OVERTON HYPOTHESIS
EXCEPTIONS
> HALOGENATED COMPOUNDS
> NONIMMOBILIZERS
> CUTOFF EFFECT
PRESSUREREVERSALTHEORYGA 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.
Modern lipid hypothesisModern 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 specific. Experiments showed that GA drugs likely involve inhibition of opening of the ion channel in post synoptic ligand gated membrane protein.
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.
PROTEIN THEORIES OF ANAESTHESIA
HYDROPHOBIC SITES OF PROTEINS
> CORE OF WATER SOLUBLE
PROTEINS
> LINING OF BINDING SITES FOR
HYDROPHOBIC LIGANDS
FIREFLY LUCIFERASE
ACTION ON ION CHANNELS
LIKELY TARGET FOR ANAESTHETICS
PATCH CLAMP TECHNIQUE
VOLTAGE GATED ION CHANNELS
INCLUDES
> VOLTAGE DEPENDENT SODIUM
CHANNELS
> VOLTAGE DEPENDENT POTASSIUM
CHANNELS
> VOLTAGE DEPENDENT CALCIUM
CHANNELS
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
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….
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….
CALCIUM CHANNELS
VOLATILE SUBSTANCE INHIBIT VOLTAGE DEPENDENT CALCIUM CHANNELS (50% REDUCTION OF CURRENT) AT CONCENTRATION 2 TIMES THOSE REQUIRED TO PRODUCE ANAESTHESIA IN HUMANS
BACKGROUND(LEAK) POTASSIUM
ION CHANNELS
ACTIVATED BY BOTH VOLATILE AND GASEOUS ANAESTHETICS
TEND TO BE OPEN AT ALL VOLTAGES PRODUCE A LEAK CURRENT
LIGAND GATED ION CHANNELS
WHICH OPENS WHEN THERE IS ALTERATION IN THE MEMBRANE POTENTIAL
MEDIATES EXCITATORY AND INHIBITORY NEUROTRANSMISSION
LOGICAL TARGET FOR ANAESTHETIC ACTION
GABA-ACTIVATED ION CHANNELS
MOST IMPORTANT INHIBITORY NEUROTRANSMITTER
RESPONSE TO MANY DRUGS
BARBITURATES, BENZODIAZEPINES, PROPOFOL & VOLATILE ANAESTHETICS MODULATE GABAA RECEPTOR FUNCTION
CONT….
GABA-ACTIVATED ION CHANNELS
ANAESTHETICS BIND TO THIS RECEPTOR
CLORIDE ION CONDUCTANCE INCRAESES
HYPERPOLARIZATION OF THE POSTSYNAPTIC CELL MEMBRANE
INHIBITION OF POSTSYNAPTIC NEURON
GABA-ACTIVATED ION CHANNELS
3 TYPES OF EFFET ON THE RECEPTOR
1. POTENTIATION
2. DIRECT GATING
3. INHIBITION
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
GABA-ACTIVATED ION CHANNELS
INHIBITION
ABILITY OF THE ANAESTHETICS TO
PREVENT GABA FROM INITIATING CURRENT FLOW THROUGH GABAA
CHANNELS
GLUTAMATE ION CHANNELS
MAIN EXCITATORY NEOROTRANSMITTER IN THE CNS
3 CATEGORIES
> AMPA RECEPTORS
> KAINATE RECEPTORS
> NMDA RECEPTORS
GLUTAMATE ION CHANNELS
AMPA & KAINATE RECEPTORS INVOLVED IN FAST EXCITATORY SYNAPTIC TRANSMISSION(Na & K)
NMDA RECEPTORS LONG TERM MODULATION KETAMINE & NITROUS OXIDE
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
O2PATHWAY PERTURBATION THEORYThis 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 been implicated in this proposed mode of action.
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 CNS.
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
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
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.
It is agreed that narcosis is due to physical rather than chemical action of the molecule & relatively weak forces are involved.
There is a good correlation between anaesthetic potency & molar refraction polarisability of the anaesthetic agent, molal volume & solubility in olive oil.
Developments in molecular biology, genetics, and cell physiology make it possible that next generation can find some answers to the 160 yrs old pharmacological puzzle of mechanism of anaesthesia.
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
REFERENCES
CLINICAL ANAESTHESIA BY PAUL G. BARASH SIXTH EDITION
A PRACTICE OF ANAESTHESIA BY
WYLIE & CHURCHILL-DAVIDSON’S SEVENTH EDITION
INTERNET
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