Anaesthetics - Pharmacology of anaesthesia

Question 1

What patients are intravenous induction agents used on and what are its advantages?

Answer 1

Intravenous anaesthesia is the most common method of inducing anaesthesia (adults > children).

Advantages:

• pleasant for patients
• rapid loss of consciousness under the control of the anaesthetist
• Loss and recovery of consciousness are determined by passive pharmacokinetics and so more predictable

Question 2

Why do people recover consciousness after induction with intravenous anaesthesia?

Answer 2

If the concentration of drug is plotted against time, there is a rapid rise in the plasma concentration after injection to its maximal concentration. This is followed by a rapid fall in concentration due to redistribution predominantly into fat.

Fat has a relatively poor blood supply, so the fat that the drug redistributes into first is the fat present in muscle. So it is the fat in the muscle that IV agents redistribute into. This is followed by a prolonged clearance of drug from the body by the kidney or liver and a combination of the two.

So the fall in concentration to the wake up concentration is due to distribution not clearance, which takes place over a longer period of time.

Question 3

What are the important properties of propofol?

Answer 3

Propofol is the most common IV induction agent. It is a hindered phenol and is insoluble in water (because it is completely fat soluble).

It is suspended in a soya bean, egg phosphatide emulsion. Like most IV agents it is a vasodilator and causes myocardial depression.

It has a rapid wake up, with little accumulation and is white.

Question 4

What is Etomidate? What are its important features?

Answer 4

This is another IV induction agent that is less commonly used than propofol. It does have a role in cardiac anaesthesia though because it causes less CVS effects.

Etomidate is a carboxylated imidazole. It is short acting, and potent with no accumulation. Infusion can cause adrenal suppression.

It is dissolved in propylene glycol.

Question 5

What is thiopentone? What are its adverse effects?

Answer 5

Thiopentone is a barbiturate that produces rapid loss of consciousness after IV injection. It is not suitable for day case surgery due to its “hangover effect” (has a prolonged terminal half life of several days). It is widely used in obstetrics.

It is a potent myocardial depressant and causes dose dependent histamine release. It is contraindicated in porphyria.

Question 6

What is ketamine?

Answer 6

Ketamine is a phencyclidine derivative which acts as an NMDA receptor antagonist. It is highly lipid soluble with a rapid onset of action.

It causes “dissociative anaesthesia” with loss of consciousness and profound analgesia (it has the potential for abuse). It is also associated with terrible nightmares in adults.

It can be given IV or IM (although large doses are required).

Question 7

In what groups of patients is Ketamine particularly useful?

Answer 7

Ketamine is relatively CVS stable - HR and BP increase while cardiac output is maintained unlike with other agents, this is due to direct myocardial stimulation and central sympathetic effect - this makes it a useful drug for anaesthetic induction of shocked patients.

It also has less airway effect that other agents, which makes it suitable for radiological interventions, radiotherapy, burns and plastics.

Question 8

What benzodiazepine can be considered an induction agent?

Answer 8

Midazolam, in sufficient quantities, can induce anaesthesia. The effects of benzodiazepines are anxiolytic, hypnotic, anticonvulsant, and sedative.

It works by binding to the GABA(A) receptor complex and increasing chloride ion influx resulting in neuronal hyperpolarization.

Question 9

What are the adverse effects of Midazolam?

Answer 9

Benzodiazepines in general can cause mild respiratory depression but this can be marked and lead to apnoea in the elderly, with associated respiratory disease or with concurrent use of other respiratory depressant drugs (e.g. opiates).

Question 10

What are the properties of Midazolam that make it particularly useful as an induction agent?

Answer 10

Midazolam is water soluble (unlike diazepam) due to a cyclic imidazole group that is attached to the diazepine ring.

This structure gives it a unique physiochemical characteristic:

• at pH < 4.0 the ring opens and it is water soluble so it can be dissolved
• at pH > 4.0 the ring closes making it lipid soluble and allowing it to cross the BBB

Question 11

When is inhalation induction used?

Answer 11

Inhalation induction takes longer but is useful in paediatrics (due to the difficulty cannulating) and in adults when the patient has difficult veins or is needle phobic.

The main disadvantages to inhalation induction is that it is a skilled task and there are many things that can influence the speed of onset particularly solubility*, respiratory rate and depth and cardiac output.

• the more insoluble a drug is, the quicker the onset of action - not the other way round!

Question 12

When are inhalation agents most commonly used?

Answer 12

They are used less for induction and more often for maintenance of anaesthesia. This is usually as part of a circle system and because they are insoluble they are relatively short acting (and have a rapid speed of onset).

Question 13

What are the main volatile agents used for induction and what are there key features?

Answer 13

Main agents currently in use are: isoflurane, sevoflurane, and desflurane. All of then are halogenated ethers.

The mechanism of action of the volatile agents are still not fully understood, but the key features include:

• action at pre/ postsynaptic ligand gated ion channels
• interruption of information processing and memory establishment
• potentiation of GABA activity at GABA(A) receptors
• inhibition of NMDA transmission

Question 14

What determines the potency of a volatile agent?

Answer 14

The potency of an inhalational anaesthetic is related to its lipid solubility - the more lipophilic, the greater its potency. Th is expressed as the oil/gas solubility coefficient.

Question 15

What is the blood/gas solubility coefficient?

Answer 15

This describes the rate of uptake of the agent and the speed with which adequate partial pressure of the agent is exerted within brain tissues to induce and or maintain anaesthesia.

The lower the coefficient, the quicker the steady state is achieved. The greater the coefficient the longer it takes the reach equilibrium of partial pressures between alveoli and brain tissue to be met, and hence a slower speed of on and offset.

Question 16

What is MAC?

Answer 16

Each volatile inhalational agent has a specific minimum alveolar concentration (MAC), defined as the amount of vapour (%) needed to render 50% of spontaneously breathing patients unresponsive to standard painful surgical stimulus.

MAC is inversely related to potency, i.e. the higher the MAC the less potent the agent.

Question 17

What factors decrease the MAC?

Answer 17

• age (peak at 6 months)
• premedication (e.g. benzodiazepines)
• opioids
• pregnancy
• acute alcohol intoxication
• other volatiles (MACs are additive)

Question 18

What factors increase MAC?

Answer 18

• chronic alcohol consumption (upregulates liver enzymes)
• increased sympathetic activity
• hypermetabolic states (e.g. thyrotoxicosis, pyrexia)
• anxiety
• some antidepressants (e.g. tricyclics, MAOis)

Question 19

What is nitric oxide used for?

Answer 19

Nitric oxide (NOT nitrous) is a colourless gas that has a low molecular weight. It is relatively non polar and highly lipid soluble (although it has a low oil/gas solubility coefficient).

Its low potency means it cannot be used as a sole anaesthetic agent. Also, with a predicted MAC of 105% it would cause death as there would be no oxygen present.

It has a low blood/gas solubility coefficient which means that it rapidly equilibrates between brain and inhaled concentrations.

Question 20

What problems are associated with nitric oxide?

Answer 20

The problem with nitric oxide is that it is more soluble than nitrogen, diffusing into air filled spaces quicker than nitrogen can diffuse out. Situations where this might be a problem:

• endotracheal cuff expansion
• bowel expansion
• a simple pneumothorax might become a tension pneumothorax
• air emboli (a small insignificant embolus might enlarge)
• tympanic membrane bulging

Question 21

What side effects are associated with nitrous oxide?

Answer 21

Its main side effect is post operative nausea and vomiting (PNOV). It also inhibits methionine synthetase, involved in vitamin B12 production - megaloblastic anaemia is a theoretical complication with prolonged use.

Question 22

What is diffusional hypoxia?

Answer 22

At the end of an anaesthetic, when nitrous oxide is stopped, it diffuses out of the tissues and blood into the alveolar gas, down its concentration gradient at a rate greater than nitrogen uptake. This will dilute the oxygen present in the alveoli, resulting in potential hypoxia because the capillary blood is now exposed to a low oxygen concentration. This is avoided by giving the patient 100% oxygen at emergence.

Question 23

What is entonox and when is it used?

Answer 23

Entonox is an equal mixture of nitrous oxide and oxygen.

It is used as an inhaled analgesic in labour, trauma and often in children.

Question 24

What is halothane?

Answer 24

Halothane is a halogenated hydrocarbon that is still used in some parts of the world but has largely been replaced because of its side effects. It has a low MAC making it a potent inhalation agent.

It is chemically unstable in light, and increases vagal tone. One of the major side effects of halothane is the so called halothane hepatitis. The exact mechanism behind this is unknown but is believed to due to repeat exposure. It carries a high mortality and is less common in children.

Question 25

What are the important properties of enflurane and isoflurane?

Answer 25

These are fluorinated ethers and are in fact isomers of one another. They are both highly irritant and potent vasodilators.

The risk of hepatitis is much rarer (compared with halothane) but enflurane has been associated with epilepsy. The MAC of both agents is quite low.

Isoflurane causes a drop in BP, systemic vascular resistance and tachycardia.

Question 26

Why is Sevoflurane a useful agent?

Answer 26

Sevoflurane has a low blood/gas solubility (meaning it equilibrates quickly) and is non-irritant. It is therefore useful for inhalational induction. It causes bradycardia, blood pressure and SVR but cardiac output is maintained.

Question 27

What are the important properties of Desflurane?

Answer 27

Desflurane is a respiratory irritant and cannot be used for the induction of anaesthesia. It increases salivary and respiratory secretions; CVS effects are similar to isoflurane. R

Recovery is rapid due to a low blood/gas solubility coefficient. Its boiling point is close to room temperature and therefore it is used in a special vaporiser.

Question 28

What are the stages of ACh release at the neuromuscular junction?

Answer 28

An action potential arriving at the presynaptic terminal opens voltage gated calcium channels causing calcium influx. ACh is sorted in vesicles which are held in an actin network during the resting state. Calcium influx releases vesicles from the actin network causing them to fuse with the presynaptic active zone (axonal membrane), thus releasing ACh into the synaptic cleft.

An action potential causes 200-300 vesicles to release their quanta into the synaptic cleft.

ACh binds to the two alpha subunits on the nAChR causing its ionophore to briefly open and allow ion influx to occur (Na)*. Spread of depolarisation at the motor end plate causes mobilisation of calcium from the sarcoplasmic reticulum and subsequent muscle contraction.

• K+ efflux occurs through the receptor so sux can cause hyperkalaemia

Question 29

When are neuromuscular blocking drugs used?

Answer 29

Neuromuscular blocking drugs (NMBDs) bind to post synaptic acetylcholine receptors on the motor end plate, and block onward propagation of the action potential which inhibits muscle contraction.

They affect skeletal muscle only.

They are used to facilitate endotracheal intubation and to provide muscle relaxation during surgery.

Question 30

What can prolong the effects of NMBDs?

Answer 30

• electrolyte disturbance (decr. K, Ca, Mg)
• acidosis
• volatile anaesthetics
• hypothermia
• old age
• myasthenia gravis: postsynaptic receptor autoantibodies cause increased sensitivity to non depolarising NMBDs. Increased sensitivity to suxamethonium may occur

Question 31

What type of NMBD is suxamethonium? Describe its mechanism of action

Answer 31

Suxamethonium is a depolarising neuromuscular blocking drug. It consists of 2 ACh molecules connected by their acyl groups. It binds to postsynaptic ACh receptor causing depolarisation. In order for the ionophore to be reset for the next depolarisation, ACh is metabolised in the cleft by acetylcholinesterase. However, suxamethonium is not metabolised by acetylcholinesterase and so produces initial fasciculation followed by a block as no further action potential can be propagated whilst suxamethonium remains bound to the ACh receptor.

It is subsequently metabolised by plasma cholinesterase.

Question 32

When is suxamethonium used?

Answer 32

It has the fastest onset and offset of all the NMBDs. Its main use is in endotracheal intubation when rapid intubating conditions are required (i.e. rapid sequence induction).

Question 33

What are the side effects of suxamethonium?

Answer 33

Suxamethonium has many side effects, some important ones are:

• malignant hyperpyrexia
• anaphylaxis
• hyperkalaemia: care must be taken in patients with renal failure
• histamine release
• bradycardia
• suxamethonium apnoea: less plasma cholinesterase results in prolongation of effect due to inherited or acquired causes (e.g. liver disease, malignancy, starvation, cardiac failure, renal failure)

Question 34

What is the mechanism of action of non depolarising neuromuscular blocking drugs?

Answer 34

Non-depolarising NMBDs have a slower onset of action than suxamethonium and provide reversible competitive antagonism at the neuromuscular junction with ACh.

Blockade starts when 70-80% of receptors at the junction are blocked and is complete with 90% blockade.

These drugs are poorly lipid soluble, highly ionized and protein bound at physiological pH.

Question 35

What are the 2 types of non depolarising NMBDs?

Answer 35

1) Benzylisoquinoliniums:
- atracurium: metabolised spontaneously by Hoffman degradation, causes histamine release
- cisatracurium: atrocurium isomer causing less histamine release
- mivacurium

2) Aminosteroids:
- pancuronium: long acting cardiovascular stability
- vecuronium: CVS stable, minimal histamine release
- rocuronium: fastest onset of non depolarising NMBDs, minimal histamine release and is CVS stable, long duration of action

Question 36

How are NMBDs reversed?

Answer 36

Reversal of residual NMBDs is nearly always required at the end of surgery. Residual weakness is very unpleasant for patients and puts them at risk postoperatively of inadequate breathing and airway protection.

Anticholinesterases inhibit acetylcholinesterase, increasing synaptic ACh concentrations. The most commonly used reversal agent is neostigmine.

Question 37

What is neostigmine given with and why?

Answer 37

Neostigmine increases ACh levels at nicotinic and muscarinic receptors. This produces the desired effect of reversing a NMBD but also causes bradycardia, bronchospasm, increased bronchial secretions, salivation and GI upset. Therefore neostigmine is always administered with an antimuscarinic drug (e.g. glycopyronium or atropine).

Question 38

What is sugammadex?

Answer 38

Sugammadex binds irreversibly to rocuronium and vecuronium rendering them inactive. It has a role in failed intubation/ ventilation scenarios by reversing muscle relaxation when rapid resumption of airway reflexes and respiratory function is required.

Question 39

How can the degree of muscle paralysis be monitored during anaesthesia?

Answer 39

1) neuromuscular blockade monitoring
2) fade
3) facilitation
4) double burst stimulation

Question 40

How is neuromuscular blockade monitoring performed?

Answer 40

For this, a nerve stimulator applies a current to a peripheral nerve and the motor response is observed. Common sites include the facial nerve (facial twitch) and ulnar nerve (thumb abduction). A current of uniform amplitude is applied; a supramaximal stimulus ensures all the nerves within a fibre are depolarised.

Assessment is usually tactile based on observing muscle twitch.

Question 41

What is the fade technique for monitoring muscle paralysis?

Answer 41

This is the progressive diminuation of muscle twitch when 4 stimuli (at 2Hz) are applied. The ratio of the 4th to the 1st twitch amplitude is called the train of four (TOF). As the degree of block increases the twitches disappear from the 4th to the 1st with recovery in the opposite order.

Question 42

What is facilitation?

Answer 42

This is used to assess profound block. After a tetanic stimulus there is enhanced response to single twitches, thought to be due to presynaptic mobilisation of ACh. The number of single twitches elicited is the post tetanic count, which can be used to determine recovery time and can be used when TOF is undetectable.

Question 43

What is double burst stimulation?

Answer 43

This is two 50Hz stimuli separated by 750ms. It is though to be a more accurate visual assessment of fade than TOF.