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.

Inhaled anaesthetics

Inhaled anaesthetics, also called volatile or inhalation anaesthetics, are drugs used to induce and maintain general anaesthesia which are administered by inhalation (as opposed to intravenous anaesthetics). These are lipid-soluble, hydrophobic drugs. The more lipid-soluble the drug, the:

• Higher the potency (the lower the minimal alveolar concentration (MAC))
• Slower the induction of anaesthesia
• Slower the recovery from anaesthesia

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

In addition to their medical effects, the climate effects of these drugs must be considered. Desflurane and nitrous oxide are potent greenhouse gases. Sevoflurane is the inhaled anaesthetic with the least greenhouse potency.

Compounds

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

Halothane is no longer used in the developed world due to the risk of halothane hepatitis, which has a very high mortality.

The halogenated ethers, mostly sevoflurane, are widely used anaesthetic drugs. Sevoflurane is usually the first choice, while desfluran can be used if faster recovery is necessary.

Indications

Halogenated hydrocarbons can either be used for induction of general anaesthesia alone (and using an intravenous anaesthetic for maintainance), or be used for both induction and maintainance. Sevoflurane is often used for induction of anaesthesia, especially in children and in short interventions.

Nitrous oxide (N2O) is the least potent inhaled anaesthetic. It’s used for smaller procedures where complete loss of consciousness is not necessary, like during labour or dental procedures. It may be self-administered by the patient. It’s necessary to give pure O2 for a few minutes after the operation to prevent diffusional hypoxia. N2O is 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.

Dosage

MAC is the concentration of drug in the alveolar space which prevents a motor response to pain in 50% of patients. It’s inversely proportional to the potency. During general anaesthesia, the anaesthetic machine measures the amount of anaesthetic in the exhaled air (the end-tidal sevoflurane, for example), and the dose of anaesthetic is adjusted so that an end-tidal concentration of 1,0 – 1,3 x MAC is reached.

Mechanism of action

The specific mechanism of action of halogenated inhaled anaesthetics is not known. However, it is known that 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.

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. The halogenated ethers vasodilate cerebral vessels, which increases the CBF and therefore the ICP, generally making them unsuitable for brain surgery. They all also have a cardiodepressive and bronchodilatory effects, the latter of which may be useful in an ICU setting. They also cause vasodilation in systemic vessels, causing hypotension. Isoflurane has the least cardiodepressive effect of the three.

All of them cause airway irritation, except for sevoflurane, so only sevoflurane can be used for induction of anaesthesia.

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. 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.

Halothane hepatitis

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.

Malignant hyperthermia

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.

Intravenous anaesthetics

Intravenous anaesthetics (IV anaesthetics) are drugs used to induce and maintain general anaesthesia which are administered intravenously (as opposed to inhaled anaesthetics).

While inhaled 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. The anaesthetic effect stops when the drug redistributes from the CNS to other tissues. The duration of action is 5 – 10 minutes.

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

Compounds

The important IV anaesthetics are:

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

Although not technically anaesthetic agents, benzodiazepines and opioids can be combined with intravenous anaesthetics or used alone for conscious sedation:

• Benzodiazepines
  • Midazolam
  • Diazepam
  • Lorazepam
• Opioids
  • Fentanyl
  • Remifentanil
  • Alfentanil

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)

Intravenous anaesthetics can either be used for induction of general anaesthesia alone (and using an inhaled anaesthetic for maintainance), or be used for both induction and maintainance. The latter is called total intravenous anaesthesia (TIVA). Propofol is the most commonly anaesthetic used for TIVA, usually combined with remifentanil.

• Propofol is perhaps the most widely used IV anaesthetic as it has a rapid onset of action, within 20 seconds. It’s the standard drug for induction of anaesthesia, it can be used for TIVA, or for sedation of patients in the ICU.

• Etomidate has the least depressive effect on the cardiovascular system, so it’s the preferred anaesthetic for induction of patients with haemodynamic instability or heart conditions. It cannot be used for maintainance as it inhibits the synthesis of cortisol.

• Ketamine induces a state of dissociative anaesthesia, a form of anesthesia characterized by catalepsy, catatonia, analgesia, and amnesia. It has a stimulatory effect on the cardiovascular system. It’s especially used in emergency situations with polytrauma, shock, severe asthma. In low doses it can be used for pain management, in moderate doses it can cause conscious sedation, and in high doses it causes anaesthesia. Some believe it may be used to treat depression.

• Benzodiazepines like midazolam, diazepam, lorazepam are used for conscious sedation during procedures like colonoscopies. They can be combined with opioids for general anaesthesia.
• Opioids like remifentanil can be combined with propofol to provide TIVA.

• Barbiturates are used for patients who have increased intracranial pressure.

The combination of fentanyl and a certain antipsychotic 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.

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.

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.

Adverse effects

• Propofol has depressive and vasodilatory effects on the cardiovascular system. Administration of propofol can be painful at the infusion site
• Etomidate inhibits cortisol synthesis.
• Ketamine causes unpleasant experiences like weird dreams and hallucinations when recovering from the anaesthesia.

Propofol infusion syndrome

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.