A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

146 ANAESTHETICS AND MUSCLE RELAXANTS
• Pulmonary blood flow – an increase in cardiac output results
in an increase in pulmonary blood flow and more agent is
removed from the alveoli, thereby slowing the rate of
increase in arterial tension and slowing induction. A fall in
pulmonary blood flow, as occurs in shock, hastens
induction.
• Pulmonary ventilation – changes in minute ventilation have
little influence on induction with insoluble agents, as the
alveolar concentration is always high. However, soluble
agents show significant increases in alveolar tension with
increased minute ventilation.
• Arteriovenous concentration gradient – the amount of
anaesthetic in venous blood returning to the lungs is
dependent on the rate and extent of tissue uptake. The
greater the difference in tension between venous and
arterial blood, the more slowly equilibrium will be
achieved.
PHARMACODYNAMICS
MECHANISM OF ACTION AND MEASURE OF
POTENCY
The molecular mechanism of action of anaesthetics is still
incompletely understood. All general anaesthetics depress
spontaneous and evoked activity of neurones, especially synaptic
transmission in the central nervous system. They cause
hyperpolarization of neurones by activating potassium and
chloride channels, and this leads to an increase in action
potential threshold and decreased firing. Progressive depression
of ascending pathways in the reticular activating system
produces complete but reversible loss of consciousness. The
probable principal site of action is a hydrophobic site on
specific neuronal membrane protein channels, rather than
bulk perturbations in the neuronal lipid plasma membrane.
This is consistent with classical observations that anaesthetic
potency is strongly correlated with lipid solubility which were
originally interpreted as evidence that general anaesthetics
act on lipid rather than on proteins.
The relative potencies of different anaesthetics are
expressed in terms of their minimum alveolar concentration
(MAC), expressed as a percentage of alveolar gas mixture at
atmospheric pressure. The MAC of an anaesthetic is defined as
the minimum alveolar concentration that prevents reflex
response to a standard noxious stimulus in 50% of the population.
MAC represents one point on the dose– response curve,
but the curve for anaesthetic agents is steep, and 95% of
patients will not respond to a surgical stimulus at 1.2 times
MAC. Nitrous oxide has an MAC of 105% (MAC of 52.5% at 2
atmospheres, calculated using volunteers in a hyperbaric
chamber) and is a weak anaesthetic agent, whereas halothane
is a potent anaesthetic with an MAC of 0.75%. If nitrous oxide
is used with halothane, it will have an addi-tive effect on the
MAC of halothane, 60% nitrous oxide reducing the MAC of
halothane by 60%. Opioids also reduce MAC. MAC is reduced
in the elderly and is increased in neonates.
HALOTHANE
Use
Halothane is a potent inhalational anaesthetic. It is a clear,
colourless liquid. It is a poor analgesic, but when co-administered
with nitrous oxide and oxygen, it is effective and convenient.
It is inexpensive and used world-wide, although only
infrequently in the UK. Although apparently simple to use, its
therapeutic index is relatively low and overdose is easily produced.
Warning signs of overdose are bradycardia, hypotension
and tachypnoea. Halothane produces moderate muscular
relaxation, but this is rarely sufficient for major abdominal
surgery. It potentiates most non-depolarizing muscle relaxants,
as do other volatile anaesthetics.
Adverse effects
• Cardiovascular:
• ventricular dysrhythmias;
• bradycardia mediated by the vagus;
• hypotension;
• cerebral blood flow is increased, which contraindicates
its use where reduction of intracranial pressure is
desired (e.g. head injury, intracranial tumours).
• Respiratory: respiratory depression commonly occurs,
resulting in decreased alveolar ventilation due to a
reduction in tidal volume, although the rate of breathing
increases.
• Hepatic. There are two types of hepatic dysfunction
following halothane anaesthesia: mild, transient
subclinical hepatitis due to the reaction of halothane with
hepatic macromolecules, and (very rare) massive hepatic
necrosis due to formation of a hapten–protein complex
and with a mortality of 30–70%. Patients most at risk are
middle-aged, obese women who have previously (within
the last 28 days) had halothane anaesthesia. Halothane
anaesthesia is contraindicated in those who have had
jaundice or unexplained pyrexia following halothane
anaesthesia, and repeat exposure is not advised within
three months.
• Uterus: halothane can cause uterine atony and postpartum
haemorrhage.
Pharmacokinetics
Because of the relatively low blood:gas solubility, induction of
anaesthesia is rapid but slower than that with isoflurane,
sevoflurane and desflurane. Excretion is predominantly by
exhalation, but approximately 20% is metabolized by the liver.
Metabolites can be detected in the urine for up to three weeks
following anaesthesia.
ISOFLURANE
Isoflurane has a pungent smell and the vapour is irritant,
making gas induction difficult. Compared with halothane, it
has a lower myocardial depressant effect and reduces systemic
vascular resistance through vasodilation. It is popular in
hypotensive anaesthesia and cardiac patients, although there