block 3- 7. local and general anaesthetics

made by chat and not double checked

What is the aim of general anaesthetic (GA) drugs?

To provide ‘balanced anaesthesia’ – amnesia, analgesia & relaxation – suitable for medical procedures.

Why are GAs rarely used in isolation?

They are typically combined with neuromuscular blockers, sedatives & anxiolytics, and/or analgesics.

Where do general and local anaesthetics act?

GAs are administered systemically but exert effects on the CNS; LAs act on the PNS.

What paved the way for modern surgery?

The introduction of general anaesthetics.

What are the two main types of general anaesthesia?

Inhalational and intravenous.

What are the four stages of general anaesthesia?

Stage I – analgesia; Stage II – euphoria; Stage III – surgical anaesthesia; Stage IV – medullary paralysis (overdose).

How do patients progress through the stages of general anaesthesia?

Patients pass through these stages in turn as the dose of GA increases; this varies from patient to patient.

How do the stages of anaesthesia vary?

The extent and duration of each stage varies from drug to drug; some produce little analgesia or euphoria.

What was surgery like before inhalational GAs?

Most surgeries were performed on struggling patients at high speed, often amputations.

What effects did nitrous oxide have in 1800?

Euphoria, analgesia and loss of consciousness.

What led to diethyl ether being used in surgery?

“Ether frolics” in 1846 led to diethyl ether being used for tooth extraction and amputation.

Who used chloroform to relieve childbirth pain in 1846?

James Simpson.

How was chloroform initially regarded, and when did acceptance increase?

The church denounced it as “the decoy of Satan”; it was accepted after 1853, when Queen Victoria used it for her seventh child.

What happened in 1659 in the history of intravenous anaesthesia?

A warm intravenous solution of opium and sherry “stupefied a dog”.

Who invented the hypodermic syringe, and when?

Alexander Wood, in 1853.

What developments occurred in intravenous anaesthesia in 1875, 1920 and 1934?

1875: chloral hydrate (Pierre Oré); 1920: first anaesthetic barbiturates introduced; 1934: introduction of thiopental.

What was oral anaesthesia used for in 1804?

Mastectomy was performed using oral tsūsensan, a herbal mixture containing scopolamine and atropine.

What is unusual about the chemical structures of GAs?

They are structurally diverse and belong to no recognisable chemical class.

What is an extreme example of a simple compound producing general anaesthesia?

The inert gas xenon.

What did the Overton–Meyer theory propose?

Anaesthetic potency is closely correlated with lipid solubility, not chemical structure.

What is the lipid theory of general anaesthesia?

Efficacy is determined by interaction of the drug with lipids in neuronal cell membranes.

What has superseded the lipid theory?

The protein theory, which proposes that efficacy is determined by interaction with membrane-bound ion channels.

What did Overton and Meyer demonstrate at the turn of the 20th century?

A close correlation between lipid solubility and the potency of GAs in tadpoles.

What was the original explanation for the lipid theory?

Interaction with lipids in cell membranes, possibly affecting volume expansion or membrane fluidity.

What evidence challenges the lipid theory?

Two stereoisomers of isoflurane have the same lipid solubility but different potency.

What might the relationship between lipid solubility and anaesthetic potency reflect instead?

Binding of GAs to hydrophobic pockets on membrane proteins.

What is minimal alveolar concentration (MAC)?

The concentration (or partial pressure) at which 50% of patients become insensitive to surgical incision.

What does the protein theory propose about GA binding?

GAs bind to a variety of ion channels expressed in neuronal cell membranes.

Has a single site of action been identified for any GA?

No single site of action has been identified for any GA.

Why is identifying selective binding sites difficult?

There is a lack of competitive antagonists.

When are laboratory effects of GAs considered relevant?

Only if they occur at therapeutically relevant concentrations.

What are the main targets of GAs?

Ligand-gated ion channels (LGICs).

What should you include for ligand-gated ion channel families?

Include diagram on slide 12.

What is the major target of almost all GAs?

The GABAA receptor.

Which GAs are exceptions to the major GABAA receptor target?

Cyclopropane, ketamine and xenon.

How do many GAs act at GABAA receptors?

As positive allosteric modulators.

Which subunits comprise GABAA receptors?

Combinations of α, β, γ, δ and other subunits; commonly 2α + 2β + 1γ.

Where do GAs bind on GABAA receptors?

To hydrophobic pockets within different GABAA receptor subunits.

Which antagonist can reverse some cellular effects of GAs?

Bicuculline, a GABA antagonist.

How do α-subunit mutations affect GAs?

They inhibit the actions of inhalational GAs but not intravenous GAs.

How do β-subunit mutations affect GAs?

They affect both inhalational and intravenous GAs.

Where might inhalational and intravenous GAs bind on GABAA receptors?

Inhalational GAs bind at the interface between α- and β-subunits; intravenous GAs may bind to the β-subunit alone.

How does GABAA receptor heterogeneity complicate GA pharmacology?

Some evidence suggests preferential effects at extrasynaptic GABAA receptors containing α4-, α6- and δ-subunits.

What diagram should you include for propofol binding?

Include diagram on slide 13.

What does the propofol righting-reflex experiment illustrate?

Propofol effects on the righting reflex in wild-type mice and mice with a point mutation in the β3 subunit of the GABAA receptor. Include diagram on slide 14.

Which other ligand-gated ion channels are affected by GAs?

Nicotinic acetylcholine receptors, glycine receptors, 5-HT3 receptors and glutamate receptors (AMPA, kainate and NMDA).

How do ketamine and xenon act at NMDA receptors?

Ketamine blocks the channel pore; xenon competes at the glycine site.

How do GAs affect inhibitory receptors?

They act as positive allosteric modulators at inhibitory receptors, e.g. GABA and glycine receptors.

How do GAs affect excitatory receptors?

They act as negative allosteric modulators at excitatory receptors, e.g. acetylcholine, serotonin and glutamate receptors.

What should you include for the spectrum of GA effects on LGICs?

Include diagram on slide 16, showing potentiation and inhibition.

What three major neurophysiological changes occur during anaesthesia?

Unconsciousness; loss of response to painful stimuli; loss of reflexes (motor & autonomic).

What can happen at supra-therapeutic GA concentrations?

Death due to loss of cardiovascular reflexes and respiratory paralysis.

Which GAs differ from the typical effects of most GAs?

Xenon, ketamine and nitrous oxide.

How do most GAs affect the cardiovascular system?

They cause cardiovascular depression via effects on the myocardium and blood vessels.

Which GAs can cause cardiac dysrhythmias?

Halogenated GAs.

Where does GA-induced amnesia occur?

Hippocampus.

Where does GA-induced analgesia occur?

Suppression of nociceptive inputs at spinal level (substantia gelatinosa).

Where does GA-induced unconsciousness occur?

Reticular activating system (brainstem) and thalamocortical tracts.

Where does muscle reflex suppression occur?

Spinal interneurons.

Why are GAs combined with other drugs?

There is no perfect GA that possesses all these attributes; more selective drugs are combined to provide ‘balanced anaesthesia’.

How quickly do principal intravenous GAs act after IV administration?

Within 20–30 seconds.

What should you include for the principal intravenous GAs?

Include diagram on slide 19.

Why is the relationship between inspired gas and blood concentration important?

Blood concentration should follow changes in the partial pressure of drug in the inspired gas mixture closely, allowing depth of anaesthesia to be controlled easily.

Why should blood levels of inhalational GAs fall rapidly after withdrawal?

To facilitate recovery; prolonged semi-consciousness with impaired respiratory reflexes and risk of vomiting is hazardous.

How do inhalational GAs enter and leave the body?

Through the lungs; metabolic degradation in the liver or other tissues is negligible.

What are the characteristics of inhalational GAs?

Small, lipid-soluble molecules that freely cross the blood–brain barrier (BBB).

What determines the overall behaviour of an inhalational GA?

The rate of delivery to and from the lungs.

Which two chemical properties determine the rate of equilibration between lungs and blood?

Blood-gas partition coefficient (solubility in blood) and oil-gas partition coefficient (solubility in fat and phospholipid membranes).

What does a low blood-gas partition coefficient mean?

Rapid induction and recovery.

What can high lipid solubility cause?

GAs accumulate in adipose tissue and may produce a prolonged hangover after a long operation.

What other factors affect induction and recovery?

Alveolar ventilation rate and cardiac output.

Why is the initial alveolar partial pressure lower than the inspired partial pressure?

Initial breaths are diluted in residual gas in the lungs.

How does alveolar partial pressure change with subsequent breaths?

It rises towards equilibrium.

Why does a low blood-gas partition coefficient allow alveolar partial pressure to rise faster?

Absorption of drug into the blood is initially slower.

Why does lower blood solubility allow faster equilibration?

A smaller number of breaths is required to reach equilibrium.

How does transfer of GA between blood and tissues affect equilibration?

Body fat has low blood flow but high capacity to take up GAs.

Why can higher oil-gas partition coefficients delay recovery?

GAs with higher oil-gas partition coefficients accumulate more in fat, prolonging recovery, particularly in fatter patients.

What proportion of body fat is given for a lean person in the lecture?

20% body fat.

How soluble is halothane in fat compared with water?

100 times more soluble in fat than water.

Where is halothane found after equilibration?

95% is found in adipose tissue.

Why does it take a long time to clear GAs from fat?

Low blood flow means that GAs take a long time to clear from fat.

What should you include for inhalational GA pharmacokinetics?

Include diagrams on slides 22 and 23.

Which inhalational GAs are listed in the principal inhalational GAs slide?

Include diagram on slide 24 and review the drug names shown on the slide.

What are intravenous GAs used for?

Induction of anaesthesia (e.g. propofol or thiopental) and maintenance throughout surgery using total intravenous anaesthesia.

What is typically used for total intravenous anaesthesia?

Propofol in combination with muscle relaxants and analgesics.

What are inhalational GAs used for?

Maintenance of anaesthesia.

How are volatile GAs delivered?

In air, oxygen or oxygen–nitrous oxide mixtures as the carrier gas. Examples include isoflurane and sevoflurane.

What must always accompany nitrous oxide?

Oxygen.

Why was halothane replaced by isoflurane?

Due to hepatotoxicity.

What serious reaction can all inhalational GAs cause in susceptible individuals?

Malignant hyperpyrexia.

When are GAs used alone?

Only in simple, short procedures.

Which drugs may be used as pre-medication?

Sedatives or anxiolytics, e.g. benzodiazepines.

Which drug may be used for rapid induction?

Intravenous GA, e.g. propofol.

Which opioid may be used peri-operatively?

Alfentanil.

Which GAs may be used for maintenance?

Inhalational GA, e.g. N2O plus isoflurane.

Which drug may be used for muscle relaxation?

A neuromuscular blocker, e.g. vercuronium (as written in the slides).

Which drug may prevent peri-operative vomiting?

An anti-emetic, e.g. ondansetron.

Which drug may prevent bradycardia and reduce secretions?

A muscarinic antagonist, e.g. atropine.

Which drug may reverse neuromuscular block?

An anticholinesterase, e.g. neostigmine.

Which drug may be used for post-operative pain?

An analgesic, e.g. morphine.