Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Pharmacology 19a – Principles of General Anaesthesia Anil Chopra 1 Explain the clinical objectives of general anaesthesia 2 Describe the pharmacology of inhalational anaesthetics and be able to list examples. 3 Describe the pharmacology of intravenous anaesthetic drugs and be able to name examples. 4 What are the potential neuroanatomical sites of general anaesthetic action? 5 What other drugs are used clinically to facilitate anaesthesia? Why are they used? General anaesthesia (must have the first two): Loss of consciousness (at low concentrations) Relief of pain (analgesia) Muscle relaxation Suppression of reflex responses (at high concentrations) Amnesia They must also cause a reversible physiological change It can be achieved using one drug, e.g. an inhalational anaesthetic or multiple drugs e.g. an hypnotic, analgesic and neuromuscular blocking drug A balanced anaesthetic is where drugs are combined such that the minimum effective dose is used The ideal drug is one with minimum depression of vital functions and no drug interactions Stages of anaesthesia: Stage I – analgesia – consciousness but drowsy, response to painful stimuli reduced Stage II – excitement – loss of consciousness, no response to non-painful stimuli, reflex like response to painful stimuli – a dangerous state eliminated by modern procedures Stage III – surgical anaesthesia – spontaneous movement ceases and respiration becomes regular Stage IV – medullary paralysis – respiration and vasomotor control cease, death in minutes Anaesthetic MOA - anatomical: Loss of consciousness: Depress excitability of thalamocortical neurones Influences on the reticular activating neurons Suppression of reflex responses: Inhibition of spinal motor neuron excitability Analgesia: Opiodergic neurone blockade Amnesia: Reduced synaptic transmission in the hippocampus Anaesthetic MOA – physiological: Either reduced neuronal function: Activation of anaesthetic K current → neuronal hyperpolarisation Or altered synaptic function (main effect): Blocks NMDA type glutamate receptors Inhibition of presynaptic Na and K channels General Anaesthetics Names Intravenous: Propofol, Etomidate Inhaled: Nitrous Oxide, Diethyl Ether, Halothane, Enflurane, Desflurane, Chloroform Usage General anaesthesia is clinically incredibly useful. It causes: Loss of consciousness – Propofol + enflurane Suppression of reflex responses – Propofol + enflurane Relief of pain (analgesia) – IV fentanyl Muscle relaxation - suxamethonium Amnesia – midazolam (barbiturate) The loss of consciousness occurs at low levels of isoflurane (100μM) and suppression of reflex responses occurs at higher levels (300μM). Mode of Action Molecular Targets Intravenous general anaesthetics activate GABAA and glycine receptors which cause inhibition at the postsynaptic neurones. Inhaled general anaesthetics also potentiate GABAA receptors but less potent then intravenous ones. They block NMDA type glutamate receptors which decreases excitation at postsynaptic neurones. They also block nicotinic ACh receptors which causes amnesia and relief of pain. They also facilitate TREK (background leak) potassium channel opening which causes reduced neuronal excitability. Neuroanatomical Targets The loss of consciousness is caused by the depression of thalamocortical neurones and it also has an influence on reticular activating neurons. The suppression of reflexes is caused by the depression of reflex pathways in the spinal cord. The amnesia is caused by the decrease in synaptic transmission in the hippocampus and the amygdala. Side effects and Pharmacokinetics Inhaled Anaesthetics - rapidly eliminated - easy and rapid control of the depth of anaesthesia - Pleasant and not irritant - Low blood/gas solubility – rapidly eliminated allowing for rapid control of depth of anaesthesia - Stable with soda lime - Not explosive or flammable Not metabolised Potent Far less specific than IV Inhalation → lungs → blood → brain (longer than IV drugs to work) If you try and induce unconsciousness with inhalation agents → coughing and excitatory pneumonia At equilibrium is rapidly cleared through the lungs - Metabolism of different inhaled drugs: Halothane 30% Sevoflurane 3% Enflurane 2% Isoflurane 0.2% Desflurane 0.02% Intravenous Anaesthetics - fast induction - less coughing - Rapid onset – fast induction so less coughing and excitatory pneumonia. Cause unconsciousness in secs as go straight to brain (do not rely on alveolar concentration etc) - Rapid recovery - No excitation - No local effects - No histamine release - Formulation stable with a long shelf life - Not as good at controlling depth of anaesthetic as inhaled agents - In light anaesthesia a patient can still be sensitised to pain or be woken up by extreme pain – therefore anaesthetic co-administered with opioid, e.g. IV fentanyl - Co-administration with a benzodiazepine reduces the amount of anaesthesia needed as also bocks GABAA receptors Drug interactions: o Physical – e.g. thiopentone and suxamethonium o Toxic – e.g. soda lime and trichloroethylene o Sensitisation – e.g. halothane and adrenaline