general anasthetic Flashcards
Aims of general anaesthesia
Loss of consciousness (=hypnosis) linked to amnesia
Analgesia
Muscle relaxation (immobility)
These changes are achieved by combination of drugs and, at a physiological level, are used remove sensation (anaesthesia = “without sensation”) i.e loss of consciousness, response to pain stimuli and reflex responses.
Anasthesia methods benefitted from introduction of syringes to deliver drugs IV and control of the airways with the use of tubes placed into the trachea.
Actions of general anaesthetics
General anaesthetics represent a range of drug classes from gases (e.g. nitrous oxide), halogenated hydrocarbons (e.g. isoflurane) and barbiturates (e.g. thiopental).
General anaesthetics were initially proposed to act by integrating into the plasma membrane (lipid theory):
However, the lipid theory is a little too simplistic to account for General anaesthetic effects and molecular drug targets (ion channels and receptors) are now known and accepted
Measuring anaesthetic action:
Anaesthetic effect is measured in terms of :
Minimum alveolar concentration (MAC) is defined as:
the concentration of the vapour in the lungs that is needed to prevent movement in 50% of subjects in response to pain stimulus
MAC is inversely proportional to potency; thus, a lower MAC value represents a more potent volatile anesthetic
Actions of general anaesthetics
- CNS
At a cellular level, general anaesthetics act mainly to inhibit synaptic transmission (rather than affect axonal conductance)
CNS
General anaesthetics act to:
inhibit excitatory ion channels such as glutamate and acetylcholine ionotropic receptors
Activate inhibitory ion channels such as GABAA (and glycine) ionotropic receptors and two-pore potassium channels
i.e general anaesthetics act to reduce excitation or increase inhibition
CNS
At a higher level, general anaesthetics act at:
(i) Midbrain reticular formation (unconsciousness) and thalamic sensory relay nuclei (analgesia).
NB. some general anaesthetics e.g. flunitrazepam (Rohypnol) may also act on hippocampus to affect short-term memory (amnesia)
(ii) Spinal level to cause loss of reflexes (contributes to control of motor function = muscle relaxation)
- Peripheral
Cardiovascular
In general, general anaesthetics cause circulatory depression by decreasing cardiac contractility. However, due to the range of drug classes that are used some general anaesthetics also act on autonomic sympathetic nervous system and/or vascular smooth muscle to affect cardiac output, blood pressure etc.
Respiratory
In general, general anaesthetics cause profound respiratory depression.
Muscular
General anaesthetic action at the neuromuscular junction (NMJ) causes muscle relaxation
Stages of general anaesthesia
Premedication
Induction
Maintenance
Pain relief
Muscle relaxation
pre medication
stage
purpose
drug class
Stage: combined drug treatment, typically 1-3 hours prior to anaesthesia
Purpose:
Reduction of anxiety and pain
Promotion of amnesia
Reduction of secretions
Enhancing the hypnotic effects of general anaesthesia
Reduction of vagal reflexes to intubation
Reduction of postoperative nausea and vomiting
Drug classes:
Benzodiazepine e.g. diazepam - increases inhibitory GABA release for sedative and anxiolytic effect
mAChR antagonist e.g. atropine - prevents secretion and vagal reflexes
opioid receptor agonist e.g. morphine - reduce pain and sedative
Proton pump inhibitors e.g. metoclopramide limits nausea and vomiting
Some patients prefer not to have premed and potential benefits may be outweighed by risk of drugs used. May be replaced by day-case surgery. Cochrane review found no evidence of a difference in time to discharge from hospital following adult day surgery compared to use of anxiolytics.
induction
stage
drugs
Stage: IV bolus agents which induce loss of consciousness and amnesia
Drugs:
Propofol or barbiturate e.g. sodium thiopental, activate GABAA receptors and promote inhibition
Induction drug properties:
small, highly lipophilic compounds with rapid distribution.
very fast onset (loss of consciousness typically ~20 s time for blood circulation to reach the brain)
action terminated by distribution into large compartments (including muscle)
given in preference to inhalation agents which are slower (mins) and therefore prone to more dangerous induction
INDUCTION DRUGS
Propofol
Favoured due to rapid metabolism and lack of hangover effect
Thiopental
Only remaining widely used barbiturate potent agent acts within ~20 s and lasts 5-10 mins due to rapid metabolism; however can accumulate in fat which may lead to ‘hangover’ effect. Associated with profound respiratory depression
Etomidate
Favoured due to high therapeutic index and therefore lack of respiratory and cardiovascular side effects
Whilst thiopental, etomidate and propofol work, at least in part, by activating inhibitory GABAA receptors, in theory block of excitatory glutamate receptors can also induce anaesthesia. The only major drug in this class is ketamine a NMDA glutamate receptor antagonist.
Ketamine
Relatively slow onset (2-5 mins)
Produces ‘dissociative’ anaesthesia i.e patient experiences sensory loss and analgesia but remains conscious. Can cause dysphoria and hallucination, these are less pronounced in children so ketamine is typically used in pediatric medicine.
maintenance
stage
drugs
Stage: volatile, inhalation agents used to maintain loss of consciousness and amnesia
Drugs:
Isoflurane, nitrous oxide, halothane
Maintenance drug properties:
inhaled gases with fast onset and offset of action, allowing control of depth of anaesthesia
inhaled general anaesthetics freely cross blood-brain barrier so kinetics are determined by rate of transfer from inspired air into blood
better for maintenance than IV induction agents due to rapid elimination
fewer side-effects than strongly sedative drugs, eg morphine and hyoscine
Halothane
Introduced in 1950’s and now a widely used, potent agent, but which can lead to adverse cardiovasular and respiratory effects. Can also sensitise cardiac tissue to adrenaline, leading to dysrhythmia. May also cause hepatotoxicity. Hangover effects linked to high accumulation in fat.
Nitrous oxide (laughing gas)
Low potency so typically used in combination. Use to reduce pain in childbirth
Isoflurane
Halogenated ether which replaced flammable ether, together with other members of the flurane drug class are now most commonly used inhalation anaesthetics
pain relief
drugs
IV opioids agents used to provide analgesia
Drugs:
Opioids e.g. morphine, fentanyl
Analgesic drug properties:
see Pain and Analgesic lecture
opioids also useful to cause sedation and cardiorespiratory depression.
side-effects include nausea and vomiting and may also precipitate bronchospasm or anaphylaxis which may outweigh any beneficial effects
muscle relaxations
Agents acting at the nicotinic acetylcholine receptors at neuromuscular junctions to cause immobility during surgery
Neuromuscular blocking agents work by:
Competitive antagonists of nAChRs = competitive blockers
Agonists which cause a depolarizing block of the muscle endplate = depolarizing blockers
- Uses of competitive nAChR blockers
Examples: atracurium, pancuronium, vecuronium
Act as competitive antagonists at nAChRs
Na+ entry:
depolarizes the postsynaptic membrane
causes an excitatory postsynaptic potential
generates an action potential (if threshold is reached)
Widely used as muscle relaxants as an adjunct to anaesthesia; in particular, obstetrics as these drugs do not cross placenta.
Given IV and vary in duration of action according to surgery:
atracurium, vecuronium, rocuronium (< 60 mins)
pancuronium (> 60 mins)
- Uses of depolarizing nAChRs blockers
Continually stimulation of the NMJ by agonists causes muscle paralysis: muscle contracts due to maintained depolarization, but cannot repolarize (relax) causing loss of excitability (Na+ channels cannot inactivate)
Na+ entry:
depolarizes the postsynaptic membrane
causes an excitatory postsynaptic potential
generates an action potential (if threshold is reached)
Example: suxamethonium (succinylcholine)
Used to cause paralysis during anaesthesia:
Suxamethonium is short-acting ~ 10 mins (compared to competitive, non-depolarizing blockers) because it is rapidly hydrolysed by cholinesterases.
summary :
General anaesthesia represents delivery of a combination of drugs. Following pre-medication (predominantly with sedative and anxiolytic benzodiazepines), unconsciousness is induced using IV proprofol or thiopental. This state and analgesia is maintained using inhalation agents (such as isoflurane), pain relief may be supplemented with an IV opioid. Muscle relaxation is produced using a neuromuscular blocking agents (such as atracurium).
This procedure ensures a rapid onset and recovery, avoids long, potential dangerous, periods of semi-consciousness without undue disruption of homeostasis.
