52. General anaesthetics

General anaesthetics are drugs that are used to put the patient into a state of general anaesthesia for the purpose of performing surgical procedures. A state of general anaesthesia is characterised by:

• Reversible loss of consciousness
• Amnesia
• Analgesia
• Loss of arousability
• Immobility

We usually need multiple drugs to reach general anaesthesia. Many different drugs are used as general anaesthetics. They’re either inhalation anaesthetics or intravenous anaesthetics, according to the method of delivery. These two types are often combined to exploit the favourable properties of each type while minimizing the unfavourable properties.

Mechanism of action

General anaesthetics cause CNS depression by hyperpolarizing neurons, which inhibits the synaptic transmission.

The exact mechanism of how this is achieved depends on the exact general anaesthetic. Generally, these drugs either stimulate inhibitory receptors like the GABAA and glycine receptors or they inhibit excitatory receptors like neuronal acetylcholine and NMDA glutamate receptors.

The inhibitory receptors GABAA and glycine receptors are ligand-gated Cl– channels. When these are activated by the general anaesthetics, chloride ions enter the neurons, which hyperpolarizes the membrane.

The excitatory receptors neuronal acetylcholine receptor and NMDA glutamate receptors are ligand-gated Na+ channels. When these are inhibited by general anaesthetics the neurons are hyperpolarized.

By hyperpolarizing neurons in the thalamus, hypothalamus, cortex, spinal cord and hippocampus these drugs achieve loss of consciousness, immobility, analgesia and amnesia.

Overdose

All anaesthetic agents can cause death at doses higher than those used to induce anaesthesia. These agents depress the heart and/or lungs, and at high doses death occurs by circulatory or respiratory failure.

Inhalation anaesthetics

The inhalation anaesthetics are lipophilic molecules to different degree. The lipophilicity of the inhalation anaesthetics determines several properties, like:

Property	More lipophilic anaesthetics	Less lipophilic anaesthetics
Potency	More potent	Less potent
Induction of anaesthesia	More slowly	More rapidly
Recovery from anaesthesia	More slowly	More rapidly
Minimal alveolar concentration (MAC)	Lower	Higher

However, even the fastest-acting inhalation anaesthetics take a few minutes before anaesthesia is induced.

The important inhalation anaesthetics are:

• Halogenated hydrocarbons
  • Halothane
• Halogenated ethers
  • Sevoflurane
  • Desflurane
  • Isoflurane
• Gases
  • Nitrous oxide (N2O)

When talking about inhalation anaesthetics, the minimal alveolar concentration (MAC) is important. The MAC is the concentration of anaesthetic in the alveolar space that is enough to cause anaesthesia in 50% of patients. Each drug has a characteristic MAC value. Typically, concentrations of 1.3 times the MAC are used during surgical procedures.

A potent inhalation anaesthetic will have a low MAC while less potent one will have a higher MAC. Drugs that are more lipophilic are more potent (and therefore have lower MAC) than drugs that are less lipophilic.

Pharmacokinetics

These drugs are rapidly absorbed by diffusion across the alveolar membrane.

More lipophilic drugs will immediately dissolve in lipids in the blood. This causes them to enter the brain more slowly, which is why more lipophilic inhalation anaesthetics induce anaesthesia more slowly and vice versa.

These drugs are mainly eliminated by exhalation. More lipophilic drugs are more retained in the CNS and adipose tissue and are therefore eliminated more slowly. More lipophilic drugs therefore cause the patient to recover from the general anaesthesia more slowly and vice versa.

Adverse effects

Inhaled anaesthetics can cause cardiac depression and respiratory depression.

Halogenated inhaled anaesthetics can induce malignant hyperthermia in people who have a mutation in the ryanodine receptor. The ryanodine receptor is a calcium channel in the muscle, and in susceptible people halogenated inhaled anaesthetics or depolarizing muscle relaxants like succinylcholine will cause calcium to enter skeletal muscles. This causes hyperthermia and potentially rhabdomyolysis. Treatment is with dantrolene, which blocks the ryanodine receptor.

Halogenated hydrocarbons

The only important drug in this class is halothane, and it isn’t widened used anymore in the developed world. Halothane induces a massive hepatic necrosis called halothane hepatitis in 1 out of 10 000 cases. It has a mortality rate of 80%. This development of halothane hepatitis was very unpredictable, so the use of halothane has been mostly discontinued where possible.

Halothane is metabolized into a compound called TFA in the liver. TFA acts as a hapten, so it binds to surface proteins on hepatocytes and make them immunogenic. The immune system will then attack the hepatocytes.

Halogenated ethers

• Isoflurane
• Desflurane
• Sevoflurane

Enflurane also belongs to this category but isn’t used anymore due to being seizure-inducing and nephrotoxic.

These drugs are favourable because they don’t have significant cardiodepressive effect, nor do they cause hepatotoxicity or nephrotoxicity. They do cause respiratory depression, though.

Halogenated ethers also increase the cerebral blood flow, which increases the intracranial pressure. This is an undesirable effect, especially during brain surgery.

Gases

The only important gas currently used in general anaesthesia is nitrous oxide, also known as laughing gas or N2O. Nitrous oxide is the least potent inhalation anaesthetic. It’s more useful for smaller procedures where complete loss of consciousness is not necessary, like dental procedures. It can also be combined with other anaesthetics.

It’s the only inhaled anaesthetics that doesn’t depress respiration, and it can’t cause malignant hyperthermia. It does not induce muscle relaxation, so it should be used with a muscle relaxant.

Special considerations

After the surgical procedure is finished and the nitrous oxide anaesthetic is removed, N2O will rapidly diffuse back into the alveolar space. This causes it to displace oxygen, which causes so-called “diffusional hypoxia”. This effect is counteracted by giving the patient pure O2 for a few minutes after the procedure.

Repeated use of N2O causes vitamin B12 deficiency, because N2O can oxidize the vitamin. This is mostly only a problem in medical personnel who abuse the gas repeatedly.

Intravenous anaesthetics

The important IV anaesthetics are:

• Propofol
• Etomidate
• Ketamine
• Barbiturates
  • Thiopental
  • Methohexital

While inhalational anaesthetics can be “fast-acting”, they’re still relatively slow and need a few minutes to kick in. Intravenous anaesthetics can cause anaesthesia in as little as 20 second.

IV anaesthetics can be given in doses or as continuous infusion via IV.

Mechanism of action

All intravenous anaesthetics (except ketamine) activate the GABAA receptor. They may also inhibit receptors like neuronal acetylcholine receptor and NMDA glutamate receptor.

Ketamine blocks NMDA glutamate receptors in the CNS.

Pharmacokinetics

IV anaesthetics are lipophilic drugs that distribute rapidly to well-perfused organs like the brain immediately after IV injection. This rapid distribution is what causes anaesthesia to kick in so quickly.

Later the anaesthetic will redistribute to poorly perfused organs like muscles, skin and adipose tissue. When this happens the level of anaesthetic in the CNS will drop, causing the patient to recover from anaesthesia. In people with decreased perfusion or muscle and adipose tissue mass, this redistribution will take longer, and the anaesthesia will last longer as well.

To reiterate: the anaesthetic action of IV anaesthetics is terminated by redistribution and not by elimination. Because all IV anaesthetics follow the same pattern of redistribution, they all cause similar duration of action, 5 – 10 minutes.

All IV anaesthetics are eliminated by biotransformation. All IV anaesthetics have similar half-life of around 1 – 4 hours, except thiopental, which has a half-life of 12 hours. Because thiopental has such a long elimination half-life it would accumulate in the body if given as a continuous infusion. Thiopental is instead given in doses. All other IV anaesthetics have short half-lives and will not accumulate in the body, so they can be given as continuous infusion.

Indications

All IV anaesthetics can be given in single IV doses for:

• Induction of anaesthesia, which is later maintained by an inhalation anaesthetic
• Induction of a short (5 – 10 minute) anaesthesia, for short surgeries or painful interventions

Some IV anaesthetics (especially propofol) can be given in continuous infusion for:

• Production of long-lasting anaesthesia (total intravenous anaesthesia (TIVA))
• Sedation of patients (in low doses)

Propofol

Propofol is the standard drug for inducing anaesthesia. It can also be used to maintain anaesthesia.

Advantages:

• Induces anaesthesia rapidly, within 20s
• Decreases cerebral blood flow and ICP

Disadvantages:

• Cardiodepressive effects
• Vasodilator effect
• Propofol infusion syndrome may occur

Propofol infusion syndrome (PRIS) is a rare but potentially lethal side effect of propofol. The drug can uncouple the oxidative phosphorylation in the mitochondria, which can cause lactic acidosis, rhabdomyolysis and acute renal failure.

Etomidate

Etomidate is also used for inducing anaesthesia. It cannot be used in prolonged infusion as it inhibits the synthesis of cortisol.

Indications:

Etomidate is preferred in patients with haemodynamic instability.

Advantages:

Etomidate preserves cardiovascular stability by not affecting vascular tone or the heart. This is especially useful for patients with impaired myocardial contractility.

Ketamine

Ketamine can also be used to induce anaesthesia.

Mechanism of action:

Unlike the other IV anaesthetics ketamine acts by blocking NMDA glutamate receptors in the CNS.

• Ketamine induces a state called dissociative anaesthesia, a form of anesthesia characterized by catalepsy, catatonia, analgesia, and amnesia. The patient may remain conscious

Indications:

Ketamine is especially useful in emergency medicine due to its stimulatory effects on the cardiovascular system.

Advantages:

• Ketamine stimulates the cardiovascular system

Disadvantages:

• Ketamine causes unpleasant experiences like weird dreams and hallucinations when recovering from the anaesthesia

Benzodiazepines in anaesthesia

Benzodiazepines can be used to induce a state of conscious sedation, which can be useful if the patient should be awake during the procedure. They can’t induce general anaesthesia alone.

Indications:

• Minor procedures like colonoscopy

Barbiturates in anaesthesia

The important barbiturates used as IV anaesthetics are thiopental and methohexital.

Indications:

Barbiturates are especially useful in cases where there is increased intracranial pressure.

Advantages:

• Barbiturates decrease the intracranial pressure

Opioids in anaesthesia

Certain opioids like fentanyl can be used in combination with benzodiazepines to induce general anaesthesia. This is especially useful in cardiac surgery as this combination does no affect cardiac function.

The combination of fentanyl and a certain antpsychotic called droperidol was previously used to induce neuroleptanalgesia, a state where the patient is conscious but indifferent to pain. This is rarely used nowadays but has been asked on the exam.