Brain

The human brain weighs about 1400 g and is estimated to contain around 100 billion neurons (see Figure 11-3), each of which connects with around 10,000 others (on average) in branching networks. The brain is suspended in cerebrospinal fluid (CSF), and surrounded and protected by membranes called the meninges. CSF helps keep the brain in a very stable environment, acts as a fluid shockabsorber and circulates compounds such as neurotransmitters and other mediators. The parts of the brain can be divided and discussed in various ways; a simplified approach is to consider the major component areas (see Figure 14-2):

Figure 14-2 The human brain, left lateral view.

In the following sections, the major areas of the brain are described briefly, especially those areas affected by drug therapies. The ‘special senses’ (sight, hearing, smell) and drugs affecting the eye or the ear are discussed in Chapters 31 and 32.

CNS functional systems

Specific types of signals are processed in particular brain regions, described not so much by anatomical boundaries as by overall functional aspects. Generally, sensory areas receive and interpret information from receptors for touch, temperature, pain and proprioception; motor areas integrate all voluntary movements, including speech; and association areas have complex integrative functions in memory, emotions, willpower, intelligence and personality. Four major CNS functional systems affected by CNS-active drugs include the reticular activating system, the limbic system, the extrapyramidal system and the basal ganglia.

Spinal cord

The spinal cord is a thick band of nerve fibres surrounded by the three meningeal membranes (dura mater, arachnoid mater, pia mater) that surround the entire CNS; it lies within the spinal canal formed by the protective vertebrae. It functions in the transmission of impulses to and from all parts of the brain and is also a centre for reflex activity. Ascending tracts of afferent nerves conduct impulses up from peripheral receptors and nerves to the brain, and descending tracts conduct efferent impulses down from the brain to synapse with peripheral motor and autonomic nerves.

A cross-section of the spinal cord (Figure 14-3) reveals an internal mass of grey matter (cell bodies, dendrites, axon terminals, unmyelinated axons and neuroglia) enclosed by white matter (tracts or columns of myelinated nerve fibres). The butterfly-shaped grey matter is divided into horns; the afferent (sensory) nerve fibres are located in the dorsal (posterior) horns, while the efferent (motor and autonomic) nerve fibres exit from the ventral (anterior) horns. When a pain impulse reaches the dorsal horn, for example, the impulse will be transmitted towards the brain along specialised tracts (lateral spinothalamic tracts) to the thalamus, and thence to other areas of the brain. The brain responds by means of the descending efferent fibre pathways to inhibit or modify other incoming pain stimuli (see the discussion of the gate theory of pain in Chapter 15). Through this pathway, the perception of pain can be blunted by stress, stoic determination, the ‘heat of battle’ or analgesic drugs. Small doses of spinal stimulants may increase reflex excitability; larger doses may cause convulsions.

Figure 14-3 Transverse section of the spinal cord; neural components of a spinal reflex are shown in darker blue on the right-hand side.

Some sensory afferent neurons synapse with motor efferents in the grey matter of the spinal column, forming reflex arcs. An example is the flexor (withdrawal) reflex, which is important in preventing injury. If the hand touches a hot object, for example, then even before the ascending impulse reaches the brain and allows conscious thought about dangers, synapses between sensory neurons onto ipsilateral motor efferents within the spinal dorsal horn (via interneurons) relay signals back to the appropriate muscle groups, initiating movement to pull the hand away.

Blood–brain barrier

The blood–brain barrier is a selectively permeable filter between the blood circulation and the cells of the brain and spinal cord, which tends to exclude from the CNS large water-soluble molecules, microorganisms and other toxins. The existence of a barrier between the blood and the brain, preventing easy passage of molecules from the systemic circulation into the CNS, was first postulated to account for the fact that acidic dyes (after being injected IV into animals to stain tissues for histological studies) did not stain the brain cells. Other clinical evidence was that many antimicrobial drugs useful in peripheral infections were ineffective in treating infections of the CNS.

The blood–brain barrier is now attributed to tight junctions between endothelial cells in the cerebral capillaries, a covering formed from the foot-like processes of the glial cells (astrocytes) that encircle the brain’s capillary walls, and the almost complete absence of pinocytotic vesicles in the capillary endothelial cells (see Figure 14-4).

Figure 14-4 The blood–brain barrier, showing tight junctions between capillary endothelial cells and astrocyte foot processes.

Source: netterimages.com; used with permission.

The barrier presumably evolved for protective functions, as it prevents passage of many potentially toxic large molecules into the CNS and keeps the brain and spinal cord in a remarkably stable internal environment. This barrier function is not absolute but is selectively permeable, as it will allow small molecules (such as water, alcohol, oxygen and carbon dioxide), lipid-soluble substances and gases to penetrate but excludes water-soluble and large molecules. There is also active transport and secretion of compounds between the brain and blood: nutrients such as D-glucose and precursors to neurotransmitter substances (such as choline and the amino acids phenylalanine, tyrosine and L-dopa) pass across or are actively transported. Such selective processing allows the brain a degree of security against the toxic effects of some ingested poisons or drugs on the CNS, while substances essential to energy supply or metabolic pathways are permitted. The barrier also effectively prevents active compounds such as neurotransmitters released in one site in the CNS or in the periphery from being taken up into the bloodstream, transported to other CNS sites and acting inappropriately. Some of the important clinical implications of the existence of the blood–brain barrier are summarised in Clinical Interest Box 14-4.

Nerve cells and synaptic transmission in the CNS

The two major cell types in the CNS are neurons, or nerve cells, and glial cells (neuroglia). The functions of the glial cells are not fully understood: they do not conduct action potentials, but may express a range of receptors and transporters, serve to nurture, support and assist neurons in the transfer and integration of information in the CNS and assist in maintaining nutrients, forming myelin, protecting against disease and helping form the blood–brain barrier. Recent studies indicate that glial cells play a role in neural plasticity, in protection from or recovery after injury (by taking up excitatory amino acids), and may also be crucial to memory formation.

Neurons in the CNS have the same basic structure as those in the PNS: dendrites, cell body, axon and nerve terminals (see Figure 11-3). However there are two major differences:

The CNS can be envisioned as an incredibly complex series of wired connections among neurons, with an estimated 100 billion neurons in a human brain. The connections, however, are incomplete: between each nerve terminal and the next cell is a gap, or synapse, and electrical impulses cannot jump directly across. Instead, chemical messengers are released from the terminal end of the first neuron (the presynaptic side) and cross the gap to receptors in the membrane of the cell on the post-synaptic side, which may be a neuron or (in the PNS) another cell that carries out some function stimulated by the nerve (an effector cell). This process is known as synaptic transmission and the chemical messenger is termed a neurotransmitter. Neurotransmission is described in more detail in Chapter 11 and Figures 11-6 and 11-7 in the context of transmission in the PNS. Neurotransmission in the CNS is a similar process but there are many more connections: each CNS neuron may synapse directly or indirectly with around 10,000 others.

Action potentials and ion channels

Most information transmitted in the CNS is due to alterations in electrical currents. The electrical properties of nerve cells are generated by various ions, pumps and channels located in the cell membrane (see Chapter 11 and Figure 11-4 for more detail). The pumps maintain an electrical difference or potential across the cell membrane by maintaining imbalances in the ionic concentrations of sodium, potassium and chloride across the membrane. They are capable of actively moving charged ions from one side of the membrane to the other side through ion channels (membrane pores) that allow the passage of specific ions. Channels are described as voltage-gated if they open in response to changes in membrane potential (voltage), e.g. during the generation and conductance of action potentials. By comparison, a ligand-gated channel opens and closes in response to a specific chemical stimulus (a ligand is something that binds, e.g. a neurotransmitter, hormone or drug that binds to a specific receptor or channel).

The movement and concentration of ions in and around the cell are the primary determinants affecting the membrane potential of the nerve cells. In the resting state, sodium and chloride are found in large amounts outside the cell, while potassium is in high concentration within the cell. The concentration gradients are stabilised by the sodium–potassium adenosine triphosphatase (ATPase) pump, which trades three sodium ions from the intracellular fluid for two potassium ions from the extracellular fluid. Overall, there is a small build-up of negative ions (phosphate and proteins) in the cytosol inside the cell membrane, and an equal build-up of positive ions (mainly sodium) just outside the membrane. This helps to maintain the resting membrane potential, i.e. the voltage difference across the membrane, normally at about −70 mV, as the inside of the cell is negative compared with the extra cellular fluid.

An important property of a nerve cell therefore is that it is polarised (electrically charged) in the resting state. However, a depolarising potential or other stimulus may reduce the membrane potential, i.e. depolarise the cell, to a critical level. This depolarisation will result in the rapid opening of voltage-gated sodium channels, allowing sodium to flow into the cell, which causes further depolarisation of the nerve cell along its length; this reduction in membrane potential generates an action potential (see Figure 11-5). Voltage-gated potassium channels open slightly later, allowing potassium ions to rush out of the cell, producing repolarisation. As the action potential moves very rapidly along the membrane of an axon, the nerve impulse is propagated along the nerve towards the terminals. The ATPase pump then restores the resting potential.

Many drugs act either directly on the ion channels or via receptors that affect ion channels; for example, local anaesthetics enter nerve cells and physically block sodium channels. This effectively reduces sodium influx, preventing generation of the action potentials and conduction of nerve impulses, especially in neurons that carry messages from pain receptors. Sedative drugs such as benzodiazepines and barbiturates modulate the binding of the inhibitory transmitter GABA to the GABA_A receptor and thus enhance opening of the chloride channel, producing inhibitory postsynaptic potentials and synaptic inhibition.

CNS neurotransmitters

There are about 40 different types of CNS neurons (classified by neurotransmitter) that use chemical transmitters for rapid communication across synapses. Some of the chemicals that have been identified as acting as CNS neurotransmitters are:

• amino acids—excitatory: glutamate, aspartate; inhibitory: glycine, γ-aminobutyric acid (GABA); also possibly alanine, taurine, serine

• monoamines—noradrenaline (NA), adrenaline, dopamine (DA), serotonin (5-HT [5-hydroxytryptamine]) and histamine

• acetylcholine (ACh)

• neuroactive peptides—opioids such as enkephalins and endorphins; gastrointestinal peptides such as substance P and cholecystokinin (CCK); hypothalamic releasing factors, including somatostatin and thyrotropin-releasing hormone; and other hormones and peptides including oxytocin,⁵ calcitonin, bradykinin, galanin and neuropeptide Y.

Pathways (tracts) of neurons containing a particular transmitter have been identified and tracked through brain areas (see Figure 14-5). For example, there are dopaminergic pathways (neurons that use DA as a transmitter) from the substantia nigra to the striatum, involved in motor control; from the ventral tegmental area to the limbic system and the frontal cortex, involved in cognition and emotion; and from the hypothalamus to the pituitary, controlling release of pituitary hormones. Drugs that affect DA transmission will therefore have major actions and/or side effects on motor control, thought processes and emotions, and endocrine functions.

Figure 14-5 Sagittal sections of the brain, indicating major pathways of central neurons utilising important neurotransmitters: A noradrenaline; B 5-HT (serotonin); C dopamine; D acetylcholine.

Source: Boron & Boulpaep 2005; used with permission.

Acetylcholine

Acetylcholine (ACh) was the first identified and is the best known chemical transmitter of nerve impulses. In the PNS, ACh is the neurotransmitter at all autonomic ganglia, at parasympathetic (and sympathetic cholinergic) neuroeffector junctions and at the neuromuscular junction. However, not all parts of the CNS contain ACh; CNS areas with high concentrations of cholinergic neurons are the reticular formation, the basal forebrain, basal ganglia and anterior spinal roots (Figure 14-5D). In the CNS, ACh is mainly excitatory and is involved in cognition, memory, consciousness and motor control. Levels appear to be low in Huntington’s disease and in dementias such as Alzheimer’s disease.

Monoamines

The monoamine transmitters are NA, DA, adrenaline,⁶ 5-HT and histamine. DA is particularly involved in motor control, behaviour, reward systems and endocrine control and is present in high concentrations in the ventral tegmental area, the substantia nigra and the caudate nucleus (Figure 14-5C). In the CNS, NA is mainly inhibitory; cell bodies for noradrenergic neurons are found in the pons and medulla. NA is present in central autonomic pathways, particularly in the hypothalamus and medullary centres, and is involved in central autonomic control, arousal, mood and reward systems (Figure 14-5A).

Important 5-HT pathways run between the midbrain and cortex, with extensive innervation of virtually all parts of the CNS. Cell bodies are especially prevalent in the raphe nuclei of the brainstem (Figure 14-5B). 5-HT actions are mediated through a wide range of receptor types and may be excitatory or inhibitory; 5-HT is involved in cognition, behaviour, sleep–wake cycles, mood, vomiting and pain (especially in the aetiology of migraine).

Although the effects of catecholamines (NA, DA and adrenaline) injected into the CNS are slight in comparison with their effects in the ANS, rises in levels of catecholamines and 5-HT do cause cerebral stimulation. Drugs such as reserpine and methyldopa that deplete the 5-HT and NA levels in the brain have a cerebral depressing effect. Centrally acting α₂-adrenoceptor stimulants such as clonidine paradoxically reduce blood pressure by inhibiting peripheral sympathetic stimulation. The roles of monoamine transmitters in psychiatric disorders (schizophrenia and depression) and the effects of psychotropic drugs on monoaminergic transmission are discussed in greater detail in Chapter 18, and DA’s role in Parkinson’s disease in Chapter 20.

Amino acid transmitters

Amino acids are probably the most ancient (from an evolutionary viewpoint) type of neurotransmitter, being particularly prevalent in the spinal cord. For example, GABA is an important inhibitory transmitter in many interneurons in the spinal cord and in the cerebellum and hippocampus. GABA is involved particularly in motor control, in spasticity and in sleep/wakefulness. Inhibitory control is necessary to avoid such excessive excitation as occurs during seizures and epilepsy.

The excitatory amino acids (EAA)—glutamate, aspartate, cysteic acid and homocysteic acid—are present in virtually all regions and are thought to be implicated in the neuronal injury involved in many neurological disorders. Overactivation of receptors for L-glutamate, the major excitatory transmitter, mediates excitotoxicity leading to neuronal death in both acute brain injury such as stroke and chronic disorders such as motor neurone disease. Monosodium glutamate (MSG), a flavour enhancer present in many Asian foods and meals, causes in susceptible people the ‘Chinese restaurant syndrome’, with CNS stimulation, flushing and nausea. Other excitotoxins may be involved in chronic degenerative diseases such as Huntington’s chorea, in dysfunction after CNS viral infections and in neurological syndromes linked to plant neurotoxins.

Neuropeptides

Neuroactive peptides are derived from secretory proteins formed in the cell body; they may be considered as neuromodulators, neurohormones or neurotransmitters. Peptides may cause excitation or inhibition of target neurons. The parenteral or intracerebral injection of these chemicals causes potent behavioural effects. Some of these peptides also exist in tissues other than the CNS, primarily in the gastrointestinal tract cells or in the pituitary gland.

There are several families of neuropeptides: peptides in the same family contain long stretches of identical amino acid chains. Examples are vasopressin and oxytocin, the secretins, the tachykinins, the somatostatins and the opioid peptides. (The opioids, including enkephalins and endorphins, are considered in greater detail in Chapter 16, in the context of pain and analgesic drugs.) Many of the neuropeptides that have been demonstrated to be present in the brain have currently no specific pharmacological antagonists, so it is difficult to identify their functions. In the process of co-transmission, classic neurotransmitters and several neuroactive peptides may be released simultaneously from the same neuron, e.g. ACh and vasoactive intestinal peptide (VIP), enkephalin, substance P or galanin.

Other CNS neurotransmitters

Other chemicals that may act as neurotransmitters or neuromodulators include eicosanoids, such as prostaglandins, and purine nucleotides, such as adenosine and ATP. Nitric oxide undoubtedly has neurotransmitter-like functions in the CNS, but it does not classify as a typical transmitter by the ‘classical’ criteria listed above. There may indeed be many other chemicals with neurotransmitter functions in the CNS but these are as yet unidentified.

Receptors for neurotransmitters

The effect of a transmitter at any synapse is determined by the nature of the receptor to which it binds; thus ACh may have fast excitatory effects at nicotinic receptors and slower effects via G-proteins and second messengers at muscarinic receptors. Some transmitters may have inhibitory effects, e.g. by hyperpolarising postsynaptic membranes or by inhibiting further release of transmitter from the pre synaptic terminal by actions on autoreceptors (see below).

The field of CNS neurotransmitter receptor types is one of the most active and rapidly developing in all pharmacology: a bewildering number of types and subtypes of receptors for many CNS transmitters have been discovered, cloned and, for many, the amino acid sequence identified, and chemicals acting as specific agonists or antagonists synthesised. The pharmacological significance and clinical importance of these discoveries are still being elucidated. Table 14-1 summarises some of the better-known receptors and pharmacologically relevant data in this field.

Table 14-1 Summary of types of receptors for CNS neurotransmitters, emphasising those involved in pharmacological activity of clinically-important CNS-active drugs^*

Several types of receptors for EAA such as glutamate have been identified, including receptors for NMDA (N-methyl-D-aspartate) and kainate (a constituent of seaweed); these may be involved in the aetiology of epilepsy (see Chapter 17). The GABA_A receptor has sites for bind ing GABA and also sites that bind benzodiazepines, barbiturates, neurosteroids and picrotoxin, a GABA antagonist. Dopamine receptors have been classified into several subtypes (D_1–5); development of agonists or antagonists specific for the different receptor types will be beneficial clinically and assist research into dopaminergic mechanisms. There are at least seven main types of 5-HT receptors, involved in functions as diverse as sleep and wakefulness, mood, feeding, behaviour and hallucinations.

Autoreceptors

Release of some transmitters can be modulated by the transmitter acting back on autoreceptors located on the presynaptic side of the nerve ending and on the dendrites and axons (analogous to α₂-adrenoreceptors in the sympathetic nervous system; see Figure 12-2). The mechanisms by which a transmitter inhibits its own release have not been fully elucidated and may be different from postsynaptic transduction mechanisms. Presynaptic receptors may also be involved in modulating the release of other transmitters; for example, NA release can be inhibited by agonists acting on muscarinic, opioid and DA receptors and can be facilitated by agonists on β₂-adrenergic, ACh-nicotinic and angiotensin II receptors. There are also presynaptic DA auto receptors that inhibit DA synthesis and release and thus slow the firing of dopaminergic neurons; these may be involved in the on–off effects in levodopa therapy for Parkinson’s disease. The presynaptic inhibitory and facilitatory receptors on the same nerve terminals are thought to allow for fine-tuning of transmitter release in various physiological (and pharmacological) situations.

Neurotransmitter imbalances in disease states

In many disorders of the CNS, it appears there are imbalances between levels of different neurotransmitters in particular parts of the brain. In some conditions, chemical analysis of the brains of patients who have died from a disease has shown that tracts or neurons had degenerated in particular areas. In a (simplistic) attempt to describe an overview of these conditions, the following scheme can be proposed (see Figure 14-6): the effects of monoamines (NA, DA, adrenaline, 5-HT) are envisaged to ‘balance’ (as on a see-saw; not in strict molecular equivalents) the effects of ACh, particularly on motor control, mood and thought processes. Thus in depression there is a relative deficiency of NA and 5-HT in areas of the brain related to mood (affect) and an excess of ACh. The depressed mood can be improved by antidepressant drugs such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), all of which, by differing mechanisms, increase the levels of monoamines at synapses in the CNS. By contrast, in Parkinson’s disease there appears to be damage to DA-containing neurons and a relative deficiency of DA or excess of ACh. The main drugs used in treatment of Parkinson’s disease either raise the levels of DA or block the actions of ACh (atropinic drugs). This concept (and Figure 14-6) will be referred to again in later chapters on clinical use of drugs in neurological and psychiatric disorders.

Figure 14-6 Neurotransmitter balances in CNS disorders. In the normal state, effects of monoamine transmitters are ‘balanced’ by those of acetylcholine. In various CNS disorders, imbalances occur and drugs are used in attempts to bring the levels back into balance. 5-HT = 5-hydroxytryptamine (serotonin); ACh = acetylcholine; DA = dopamine; Glu = gluta mate; NA = noradrenaline.

Stages of general anaesthesia

The four stages of CNS depression during general anaesthesia were first described in detail by American anaesthetist Dr Arthur Guedel,⁷ who observed the effects on the eyes of slowly deepening unconsciousness induced with early anaesthetics such as ether and chloroform. However, the stages of anaesthesia vary with the choice of anaesthetic, speed of induction and skill of the anaesthetist. Stages 1 and 2 constitute induction of anaesthesia. It is now recognised that stage 2 (excitation) can be dangerous, so the current practice is to induce general anaesthesia rapidly with an intravenously administered anaesthetic, then maintain the stage of surgical anaesthesia (stage 3) by inhalation of an anaesthetic gas.

Mechanisms of action of general anaesthetics

Administration

Most patients will be administered an anaesthetic by inhalation, so the first rule of anaesthesiology is to keep a clear airway. Airway obstruction will lead to anoxia and impaired gas intake, and hence to decreased absorption of anaesthetic drugs and the risk of the patient regaining consciousness too early. A typical set-up of equipment for administration of gas and volatile liquid anaesthetics via the mouth and larynx is shown diagrammatically in Figure 14-8.

Figure 14-8 Diagrammatic representation of the arrangement of a typical general anaesthetic machine. Gases from the cylinders are admitted by opening the cylinder keys (CK), and the pressures are measured with gauges (PG) and lowered by reduction valves (RV). The flows of gases are controlled by flow control valves (FCV) and monitored by flowmeters (FM). Gases other than those shown may be available (e.g. 5% CO₂ in O₂), and there may be additional volatilisers for generating anaesthetic vapour in the replenishment line or in the circuit.

Source: Bowman & Rand 1980; used with permission.

Methoxyflurane is available in an inhaler, to facilitate easy administration in an emergency situation. It is now used only as an analgesic, not for full anaesthesia, due to nephrotoxicity associated with higher doses.

Endotracheal intubation

Airways obstruction can be caused by the tongue falling back, laryngeal spasm, airways disease or mechanical faults. For these reasons, most patients will be intubated, i.e. have an endotracheal tube passed via the larynx into the upper part of the trachea (see Figure 28-6), to maintain a reliable airway. The tube is usually cuffed to help prevent inhalation of secretions or vomit. A dose of a skeletal muscle relaxant (see below, ‘Adjuncts to anaesthesia’) is normally administered to facilitate intubation.

Balanced anaesthesia

Maintaining the surgery patient insensible to pain, while supporting life functions and balancing mechanisms for fluid, electrolyte and metabolic homeostasis, requires the administration of many drugs concurrently by non-oral routes. No single anaesthetic drug can produce analgesia, relief of anxiety, muscle relaxation, amnesic effects, suppression of reflexes, physiological stability and rapid, maintained, reversible anaesthesia. The induction of anaesthesia by using a combination of drugs, each for its specific effect, rather than by using a single drug with multiple effects, is termed balanced anaesthesia (see Clinical Interest Box 14-6).

The specific drugs and dosages used depend on the procedure to be carried out, the physical condition of the patient and the patient’s responses to the medications. The advantages of balanced anaesthesia include a safer induction, quicker recovery and lower reported incidence of postoperative nausea, vomiting and pain.

Neuroleptanalgesia and day surgery procedures

An anaesthetic technique formerly frequently used, but now dropping out of favour, is neuroleptanalgesia, or neuroleptanaesthesia. This is a state of deep sedation, analgesia and amnesia produced by a combination of a neuroleptic agent (i.e. an antipsychotic, see Chapter 18), such as droperidol, and a narcotic analgesic, most commonly fentanyl. Neuroleptanalgesia was used for minor surgical procedures requiring the patient’s cooperation, such as endoscopies. However, there was a high incidence of postoperative sedation and restlessness, so newer anaesthetic, anxiolytic and analgesic agents are considered to provide better pain relief and recovery. A typical current IV sedative/analgesic regimen for minor day procedures such as colonoscopy, and those in which the patient needs to remain conscious, is propofol and midazolam (for induction/sedation) and fentanyl (for analgesia). There is a potential for synergistic effects on respiratory depression, and patients must be warned not to drive, sign important documents or operate machinery for at least 24 hours.

Adverse effects and toxicity of general anaesthetics

Although each individual drug has its particular adverse effects, there are adverse effects that are common to all GAs as depressants of the cardiovascular and respiratory systems and reflexes. GAs may also cause postoperative convulsions, headache, nausea and vomiting, kidney or liver toxicity (hepatotoxicity especially with chloroform and halothane), malignant hyperthermia (see Clinical Interest Box 14-7) and hypersensitivity reactions. They are relatively contraindicated during pregnancy (see Drugs at a Glance 14); however, they may be carefully administered when required as maintenance of the mother’s health is important to the wellbeing of the fetus.

Drugs at a glance 14 Anaesthetics

Studies on chemical series of halogenated hydrocarbon compounds have shown that, overall, fluorinated compounds are more potent and less toxic than others. Two recently introduced drugs, sevoflurane and desflurane, appear to have optimal properties as anaesthetics, compared with earlier agents such as ether, chloroform and halothane (Figure 14-7).

Other surgery-related problems

Many other problems unrelated to the anaesthetics used can occur during surgical procedures, such as:

Significant drug interactions

Among the dangers facing a surgical patient are the adverse effects of, and interactions between, all the many drugs likely to be used during surgery, plus any drugs the patient has been taking for concurrent illness, whether prescribed, over-the-counter or complementary therapies, or for social rather than medical purposes. Anaesthetists need to be familiar with the significant interactions between anaesthetics and the maintenance drug therapies used in a wide range of illnesses.

As a general guideline, if a drug is needed for treatment preoperatively, it should be continued through surgery. Unnecessary drugs are discontinued for a period at least five times the half-life of the drug before surgery. Drugs having significant interactions with anaesthetic agents are replaced, where possible, with an alternative medication before surgery. An overview of potentially significant drug interactions during anaesthesia is given in Drug Interactions 14-1; reference texts (e.g. the Australian Medicines Handbook) should be consulted for likely effects of specific combinations. Not all drug interactions are adverse: the additive CNS-depressant effects of opioid analgesics and GAs can be useful in allowing lower doses of the GA, provided the interaction is anticipated and monitored. Multiple drug interactions are also possible with the many other drugs likely to be used during general anaesthesia, in particular between anticholinesterases or aminoglycoside antibiotics and neuromuscular blocking agents.

Special anaesthesia considerations

Many disease states and risk factors can alter a person’s response to anaesthesia. The preoperative assessment of the patient’s health status should consider acute and chronic medical conditions.

Preoperative management

The preoperative visit to the patient by the anaesthetist and care of the patient by other health-care professionals should include taking a thorough medical history and ascertaining any relevant information such as drug allergies and concurrent disease. Questions (in words the patient can understand) are asked about:

Adjuncts to anaesthesia: muscle relaxants

Many surgical procedures, especially those on the abdomen, require inhibition of voluntary muscle tone and reflexes to stop muscles contracting when stimulated, to provide surgeons with easier access or to aid intubation. This can be achieved with deep general anaesthesia or with nerve block regional anaesthesia, but both these techniques carry risks. More simply, selective skeletal muscle relaxants can be administered once the patient is lightly anaesthetised and adequate analgesia provided. Artificial mechanical ventilation must be administered as the respiratory muscles are paralysed by neuromuscular blocking agents. The pharmacology of these drugs is considered in detail in Chapter 13; the two main groups of drugs used are summarised below.

Postoperative aspects

There are many potential complications following surgical operations. Nausea and vomiting can be induced by pain, drugs (especially opioids), suggestion, irritation, ketosis or dehydration. Refraining from food is sometimes helpful; if nausea and vomiting are severe, antiemetics (metoclopramide, ondansetron) can be given. Postoperative pain is common, particularly after procedures involving the thorax or abdomen, episiotomy after childbirth and haemorrhoidectomy. Adequate pain relief must be maintained to facilitate recovery and ease of coughing and defecation; remifentanil (an opioid analgesic) and nonsteroidal anti-inflammatory agents (such as parecoxib) are useful.

Respiratory depression often follows the use of narcotic analgesics (opioids); treatment may be with the opioid antagonist naloxone. Chest complications are exacerbated in smokers and patients with chronic airways diseases and by sputum retention, dehydration, ongoing use of opioids and pain that inhibits coughing. Physiotherapy and rehydration are helpful. The inactivity caused by long surgical procedures and prolonged bed-rest predisposes to thrombosis; early ambulation and antithrombotic drugs (aspirin) or anticoagulants help prevent thrombosis and embolism. Clonidine and dexmedetomidine are sometimes administered for their sedative and cardiovascular stabilising actions.

More general aspects of postoperative care include monitoring of cardiovascular and respiratory functions and fluid balance, supportive nursing and provision of adequate information. Doses of concurrent drugs may need to be lower than usual in the postoperative period, until the patient’s functioning returns to normal.

Inhalation anaesthetics

Inhalation anaesthetics are gases or volatile liquids that can be administered by inhalation when mixed with oxygen. These rapidly reach a concentration in the blood and brain sufficient to depress the CNS and cause anaesthesia. This is expressed as the minimum alveolar concentration (MAC) for anaesthesia and is inversely related to potency as an anaesthetic (Figure 14-7). Inhalation anaesthetics have the following characteristics:

Volatile liquid anaesthetics

When volatile liquid anaesthetics such as ether or chloroform were first used, they were administered by placing a pad soaked in the liquid over the patient’s mouth and nose, so that the fumes of the liquid were inhaled. This unpleasant procedure caused struggling, skin reactions, uncertain levels of dosage and absorption and a slow progression through the stages of anaesthesia. The more civilised technique used now involves controlled vaporisation of the volatile liquid into a flow of gas (oxygen with or without nitrous oxide), so that a known concentration of volatile agent in oxygen is administered via a mask or endotracheal tube.

Chloroform is hepatotoxic and ether and cyclopropane are highly flammable; these agents have now generally been replaced by safer anaesthetics. In 1956 halothane, a non-flammable chemical, largely replaced the older volatile liquids. However, halothane has been associated with hepatic dysfunction and failure, so safer analogues of the halogenated hydrocarbon series have been developed: methoxyflurane, desflurane, enflurane, isoflurane and sevoflurane (see Table 14-3). Sevoflurane has become the drug of choice for most procedures owing to its fast action and low toxicity (see Drug Monograph 14-2). Metho xyflurane is an effective analgesic and is used during acute trauma, patient transport and wound dressing; however, renal toxicity limits its regular use.

Table 14-3 Volatile liquid anaesthetic agents

Drug monograph 14-2 Sevoflurane

Sevoflurane is non-irritant and has a pleasant smell and a rapid onset of action and recovery, so it is suitable for inhalation anaesthesia, particularly in children and in day surgery.

INDICATIONS Sevoflurane is indicated for induction and maintenance of general anaesthesia during surgery.

PHARMACOKINETICS Sevoflurane has a faster uptake, distribution and rate of elimination than isoflurane and halothane (but slightly slower than desflurane). About 5% is metabolised in the liver to an inactive derivative that is rapidly eliminated. Inorganic fluoride, released during metabolism of sevoflurane, has an elimination half-life in the range 15–23 hours.

ADVERSE EFFECTS Cardiac and respiratory depression and shivering and salivation can occur, as well as postoperative nausea and vomiting.

DRUG INTERACTIONS Few significant interactions have been reported. Concurrent administration of other CNS depressants (opioid analgesics, benzodiazepines, inhaled anaesthetics) allows reduction in sevoflurane dosage.

WARNINGS AND CONTRAINDICATIONS Sevoflurane is contraindicated in patients with susceptibility to malignant hyperthermia and used with caution in those with renal failure. A fluoro-ether derivative of sevoflurane (known as compound A), formed after passage of the exhaust gas over lime absorbers for carbon dioxide, is potentially toxic. Levels can be minimised by using high gas flow rates.

DOSAGE AND ADMINISTRATION Sevoflurane is administered from a vaporiser in a stream of oxygen, with or without nitrous oxide. While the induction dose is individualised, the usual inhalation dose for maintenance is up to 5% in adults and 7% in children; surgical anaesthesia is achieved in less than 2 minutes.

Intravenous anaesthetics

Intravenous anaesthetic agents are used for induction or maintenance of general anaesthesia, to induce amnesia and as adjuncts to inhalation-type anaesthetics. The major groups include ultrashort-acting barbiturates (thiopentone) and non-barbiturates (propofol and ketamine). The benzodiazepine midazolam is mainly a sedative–antianxiety agent, but is considered here as it is frequently used as an adjunct to IV anaesthesia. Intravenous anaesthetics are valuable in allaying emotional distress (because many patients fear having a tight mask placed over the face while they are fully conscious) and in reducing the amount of inhalation anaesthetic required. Clinical Interest Box 14-9 lists the advantages and disadvantages of intravenous anaesthetics.

Chemistry and dissociation of LA drugs

Chemically, LA drugs are closely related compounds: they generally have at one end an aromatic (phenyl) group, joined through an intermediate chain of carbons to an amine (nitrogen-containing) group. The aromatic group helps make that end of the molecule lipid-soluble (lipophilic) and the amine group makes the other end water-soluble (hydrophilic). This property appears to be essential, as it allows the LA molecules to align and act within nerve cell membranes (which can be considered as phospholipid bilayers).

The intermediate carbon chains contain either an ester link (CO–O) or an amide link (CO–N), which has some important clinical implications. The ester-type LAs (cocaine, procaine, amethocaine and benzocaine) are metabolised rapidly by plasma esterase enzymes to p-aminobenzoic acid (PABA) metabolites, which are mainly responsible for allergic reactions in some patients; ester LAs are not often used now. The amide anaesthetics (such as lignocaine, prilocaine, bupivacaine and ropivacaine) are not metabolised to PABA derivatives, and allergic reactions induced by these anaesthetics are rare. Articaine is interesting in that it has both an amide link and is presented as a methyl ester derivative, hence is metabolised both in the plasma by esterases and in the liver.

As the LAs are all amines (except benzocaine), they can exist in solution as the uncharged amine form (analogous to ammonia, NH₃) or as the charged quaternary amine form (like the ammonium ion, N⁺H₄). The forms are in equilibrium, as shown in the dissociation reaction below:

The proportion of each form depends on the chemistry of the individual LA molecule and the pH of the solution or tissue it is in. Clinically this is important for the following reasons:

Mechanism of action

Local anaesthetics reversibly prevent the generation and conduction of impulses in excitable membranes and thus decrease sensitivity to pain. The basic mechanism of action of these drugs has been studied in detail: they enter the cell by diffusion through membranes, bind to a modulatory site in the voltage-dependent sodium channel (see Figure 11-4), block the sodium channel and interfere with the transient opening of these channels, thus preventing the transient inrush of sodium. Hence threshold potential is not reached, the cell membrane is not depolarised, the development of the action potential and its propagation are prevented and the nerve is blocked.

It is important to remember that all potentially excitable membranes are affected, so LAs have actions not only on sensory nerve cells but also on autonomic and motor nerves, muscle cells (cardiac, smooth, skeletal), secretory cells and neurons in the CNS.

The susceptibility of a nerve to LA action depends on the fibre diameter, myelination, tissue pH and length of nerve fibre exposed to LA solution. Local anaesthetics are capable of abolishing all sensation, but autonomic and sensory fibres are blocked preferentially because they are thinner, unmyelinated and more easily penetrated by these drugs. Loss of pain is followed in sequence by loss of response to temperature, proprioception (position of body parts), touch and pressure. Most motor fibres may also be anaesthetised if an adequate concentration of the drug is present over sufficient time.⁹

The LA drugs are said to be ion channel modulators or membrane stabilisers. Other drug groups with similar actions are the anti-arrhythmic agents and anticonvulsants (lignocaine is in fact used for these effects). Natural toxins, such as those of the puffer fish (tetrodotoxin), blue-ringed octopus (maculotoxin) and marine organisms (saxitoxin), also block nerve transmission, particularly in skeletal muscle, often causing fatal paralysis (see Figure 13-3).

Pharmacokinetics

The purpose of giving an LA is to localise its analgesic action in the tissue or nerve pathway into which it is injected. It is only later that the drug is absorbed from the tissues into the bloodstream and distributed around the body, where it may have effects in other systems and be metabolised and excreted (see Figure 14-9). This is in contrast to the more usual situation of an orally administered drug, which is absorbed from the gastrointestinal tract and passes through the liver before being distributed via the bloodstream to the tissues where it acts.

Figure 14-9 Pharmacokinetics of local anaesthetics.

An injected LA will first undergo local dispersion (i.e. moving around) in the tissue. The onset of action is determined by the speed with which it diffuses into nerve cells, which depends largely on its lipid solubility, which depends in turn on the pH of the tissue and the degree of ionisation of the LA molecules (a function of the pK_a [negative logarithm of ionisation constant] of the drug). Binding of the LA to tissue proteins and the presence of a vasoconstrictor in the solution help retain the drug in the tissues for longer action. Other potential factors include the volume and concentration of solution injected, speed of injection and local blood flow.

Local action is terminated by diffusion away, dilution and uptake into the vasculature (i.e. systemic absorption from the tissue). Lipid solubility is again the major determining factor and a vasoconstrictor, by decreasing blood flow in the area, will decrease the rate of absorption into the general circulation. Studies have shown that the peak plasma concentration of lignocaine (plain, i.e. without adrenaline) is reached about 20 minutes after injection; at this time systemic adverse effects are most likely to occur. During distribution around the body, effects may occur in other tissues, the drug may bind in tissues and it may be transferred across the blood–brain barrier or the placenta. Ester LAs (procaine and benzocaine) are rapidly metabolised by esterase enzymes in the plasma, red cells and liver and have few systemic adverse effects. Rapid metabolism of amide LAs occurs on first pass through the liver; this explains why LAs are inactive if taken orally (besides which, oral administration does not allow for localised actions except in the mouth). Inactive metabolites are excreted via the kidneys.

Overall, the onset and duration of action of an injected LA depends on all the above factors and on the patient’s cardiovascular and liver functions. The half-lives of LAs are generally short (1–2 hours); however, the bupivacaine type LAs have high lipid solubility and are more highly proteinbound, so have longer durations of action. The choice of LA for a particular procedure depends largely on the duration of drug action desired; Table 14-4 summarises the properties of several commonly used short-, intermediate- and long-acting LAs. Another, proxymetacine, is available in eye-drop formulations for use as an ocular local anaesthetic (see Chapter 31).

Table 14-4 Properties of commonly used local anaesthetics

Indications and contraindications for use of local anaesthetics

Local anaesthetics are indicated for surgical procedures when the patient’s cooperation and consciousness are required or desired, for minor superficial and body surface procedures when general anaesthesia would be unnecessary or hazardous and for sympathetic blockade or postoperative analgesia.

Contraindications to the use of local anaesthesia include extensive surgery that would require potentially toxic doses, known allergy or hyper sensitivity to the LA agent, lack of cooperation from the patient and local inflammation, infection or ischaemia at the injection site. As usual, precautions may be required in paediatric, elderly or pregnant patients and in patients with liver disease.

Dosage

The lowest effective dose should be used, noting that maximum safe doses are only guides (see Clinical Interest Box 14-11). Because a dose that is safe when injected SC may be toxic if injected IV, the dose should be injected slowly, with frequent aspirations (applying suction to syringe) to avoid intravascular injection.

Use of a vasoconstrictor

Most LAs produce vasodilation by direct action on blood vessels and by anaesthetising sympathetic vasoconstrictor fibres. This can cause rapid absorption of the drug into the systemic circulation; when the rate of absorption exceeds the rate of elimination, toxic effects can occur. Hence vasoconstrictors, such as adrenaline or felypressin, are sometimes formulated in with the LA solution to decrease systemic absorption and hence prolong the contact of the drug with local tissue, prolong the anaesthetic’s duration of action and reduce risk of systemic toxicity. Another example is the combination of phenylephrine, an α-adrenoceptor agonist, with lignocaine in a nasal spray for use in nasal/pharyngeal anaesthesia.

Vasoconstrictors are not used for nerve blocks in areas where there are end-arteries (fingers, toes, ears, nose or penis) because ischaemia may develop, resulting in gangrene. The dose of vasoconstrictor must be carefully determined to prevent ischaemic necrosis at the injection site. Other potential risks include cardiovascular stimulation (from stimulation of cardiac β₁-adrenoceptors by adrenaline), so caution is required in patients with cardiovascular or thyroid disease or those taking antidepressants.

Some LAs do not require the use of a vasoconstrictor: cocaine itself has vasoconstrictor actions (due to its sympathomimetic effects) and bupivacaine and related drugs inherently have long contact times in tissues, allowing tissue binding and prolonging their actions.

Formulations of local anaesthetics

Interestingly, there are no formulations for oral administration and systemic absorption (although there are topical formulations for mouth and gastric ulcers). This is because LAs are rapidly metabolised in the circulation or first-pass effect and because it would be impossible to localise their effects once absorbed into the systemic circulation.

Adverse drug reactions and drug interactions

Reversal of local anaesthesia

Recovery of sensation after local anaesthesia (administered plus a vasoconstrictor) can be accelerated by administration of phentolamine. This is particularly important in dental practice, in order to reduce the number of soft tissue injuries in children from biting their lips or tongue, and to reduce difficulties eating, drinking and speaking. Phentolamine, an α-adrenoceptor antagonist (α-blocker), injected by infiltration into the same site as the LA overcomes the vasoconstriction, enhances the clearance of lignocaine from oral tissues and markedly reduces the time to recovery of full lip sensation (see Moore et al [2008]).

Topical or surface anaesthesia

The use of surface, or topical, anaesthesia is restricted to mucous membranes, damaged skin surfaces, wounds and burns. Topical local anaesthesia is used to relieve pain and itching; to anaesthetise mucous membranes of the eye, nose, throat or urethra for minor surgical procedures; to facilitate instrumentation; and before venepuncture or split skin grafting. Many dose forms are available, including eye- and ear-drops, solutions, ointments, gels, creams, sprays or powders.

Topical anaesthetics do not effectively penetrate unbroken skin, except for the combination cream EMLA (eutectic mixture for local anaesthesia), which contains 25 mg/g each of lignocaine and prilocaine. Cocaine in a 4%–10% solution is still used topically for nasal anaesthesia.

A number of local anaesthetic agents cannot be injected because they are too insoluble (benzocaine) or too toxic (cocaine, amethocaine). However, because they are only slowly absorbed, they can usually be used safely on open wounds, ulcers and mucous membranes. They occasionally cause dermatitis and allergic sensitisation, which necessitates their discontinuance. Absorption is increased from mucous membranes and broken skin (e.g. abrasions, trauma and ulcers), leading to the possibility of systemic effects; deaths have occurred from absorption via the urethra. When they are used in the oral cavity (mouth and pharynx), interference with swallowing may occur and aspiration is a risk. The patient is assessed for a returning gag reflex by gentle touching of the back of the pharynx with a tongue blade. All food and fluids are withheld until the reflex returns.

Infiltration anaesthesia

Infiltration anaesthesia is the use of LAs in a small area that circles the operative field; it is produced by injecting dilute solutions (0.1%) of the agent into the skin and then subcutaneously into the region to be anaesthetised. Adrenaline is often added to the solution as a vasoconstrictor to intensify the anaesthesia in a limited region and to prevent excessive bleeding and systemic effects. Repeated injection extends the anaesthesia as long as needed. The sensory nerve endings are anaesthetised, but not motor nerves. This method of administration is used for minor surgery such as for skin lesions, skin incision and drainage or excision of a cyst, and sometimes for more major procedures including dental extractions.

Intravenous regional anaesthesia (Bier’s block)

Intravenous regional anaesthesia (IVRA) is a specialised technique for anaesthesia of the upper limb; the technique is as follows (see Figure 14-11):

The tourniquet is kept tight during the operation (and for a minimum of 20 minutes) to reduce blood flow to and from the area, which localises the LA and facilitates tissue binding. It is proposed that the injected LA diffuses from the vein into adjacent arteries and thence into the tissues, causing rapid analgesia and muscle relaxation within 10–15 minutes; the whole limb distal to the cuff is anaesthetised, allowing major surgery. This technique is considered safer than a major nerve block of the upper limb. It is not used in children, who do not tolerate well the discomfort of the tourniquet, but is very useful in emergency situations, e.g. treatment of Colles’ fracture, and in developing countries.

In theory, Bier’s block can also be used for the lower limb, but the large muscle masses in the leg make the method unsatisfactory in practice.

Nerve (conduction) block anaesthesia

For a nerve block, the LA is injected into the vicinity of a nerve trunk and inhibits the conduction of impulses to and from the area supplied by that nerve, the region of the operative site. The injection can be made at some distance from the surgical site. A single nerve may be blocked, or the anaesthetic may be injected where several nerve trunks emerge from the spinal cord (paravertebral block). During peripheral nerve block, motor nerves are usually blocked as well as sensory pathways. A concentrated solution is required because of the thickness of nerve trunk fibres; overall less LA is needed than for infiltration technique. This method of anaesthesia is often used for foot and hand surgery, eye surgery, pudendal block for obstetric procedures and postoperative pain relief.

Central nerve block: epidural and spinal anaesthesia

Two specialised types of central nerve blocks are the epidural and spinal blocks, in which spinal roots are blocked where they emerge from the spinal canal. These techniques are used for abdominal, pelvic and lower limb surgery. Autonomic nerves may also be blocked, so there is a risk of autonomic adverse effects. To increase analgesia, an opioid such as morphine, pethidine or fentanyl is often also administered by these techniques. Central nerve block is contraindicated if there is systemic anticoagulation or coagulation abnormality or if there is raised intracranial pressure.