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anaesthetic agents and medical gases


Inhalational and volatile anaesthetic agents are used widely for the induction and maintenance of general anaesthesia throughout the world. Since the famous demonstration of an ether anaesthetic by William Morton in 1846, the development of volatile anaesthetic agents paved the way for the introduction of modern surgical practices, procedures and techniques. Early agents such as diethyl ether, chloroform, ethyl chloride, cyclopropane and trichloroethylene, although effective, were either highly flammable or toxic. Halothane, discovered in 1955, had a much improved safety profile and heralded the modern era of fluorinated compounds.

Inhalational agents in current use include the fluorinated ethers (isoflurane, sevoflurane and desflurane), halogenated hydrocarbon (halothane) and nitrous oxide (N 2 O). Xenon is an inert noble gas found in the Earth's atmosphere in trace amounts and has demonstrated impressive anaesthetic properties. It is not currently in widespread use, largely because of significant production costs.

The volatile anaesthetic agents are delivered to the patient via a ‘carrier gas’ mixture. This is most commonly an air/oxygen or oxygen/nitrous oxide combination.

Kinetics of inhaled anaesthetic agents

Inhalational anaesthetic agents exert their effect on the CNS to produce loss of consciousness and loss of response to noxious stimuli. The magnitude of the response is proportional to the partial pressure of the anaesthetic at its effect site. This is not easily measurable, and, therefore, alveolar (end-tidal) anaesthetic partial pressure is used as a surrogate for effect-site concentration. At steady state, the partial pressure of inhaled anaesthetic agent within the alveoli is in equilibrium with that in arterial blood and subsequently the partial pressure in the CNS (the effect site). Steady state, however, is rarely achieved within clinical practice.

Mechanism of action

Despite being widely used in clinical practice for more than 170 years, the exact mechanism by which agents cause a reversible loss of conscious awareness and loss of response to noxious stimuli (antinociceptive effect) is still largely unknown. The inhalation agents are a diverse group and belong to no recognisable or unifying chemical class. This has led to the belief that there is no single distinctive CNS ‘receptor’ upon which these agents exert their effect. The two main theories for their action focus on direct interaction with two components of the cell membrane.

Lipid theory (Meyer–Overton relationship)

In the early 1900s, Meyer and Overton showed a close relationship between the lipid solubility of the inhalational agent and its potency of anaesthetic activity. They noticed that there was a straight line relationship between log minimum alveolar concentration (MAC; i.e. potency) and the lipid solubility; the more lipid soluble the agent (represented by a higher log oil/gas partition coefficient), the greater the potency. This led to the theory that anaesthetic agents could penetrate the cell membrane lipid bilayer and alter the molecular arrangement of the phospholipids and cause disruption of the usual function of membrane-spanning ionic channels. This theory has, however, been largely dismissed in favour of the more popular protein theory.

Protein site of action theory

Throughout the CNS, there are many excitatory and inhibitory ligand-gated ion channels. There is increasing evidence that anaesthetic agents act by inhibiting excitatory (serotonergic, neuronal nicotinic and N -methyl- d -aspartate (NMDA)) channels and activating inhibitory channels (γ-aminobutyric acid A (GABA A ) and glycine). The relationship between lipid solubility and potency can be explained by the lipophilic nature of the specific binding sites.

GABA A is a pentameric ligand-gated ion channel receptor. It comprises two α, two β and one γ subunit which together span the phospholipid bilayer of the cell membrane and surround a chloride ionophore. When activated, the channel permits passage of chloride ions into the cell, resulting in hyperpolarisation and therefore inhibiting postsynaptic neuronal excitability. Volatile anaesthetics are thought to cause activation by binding to the α subunits.

More recently, other similar ion channels have been discovered as potential sites of action of the volatile anaesthetic agents. These include pre- and postsynaptic two-pore domain potassium channels that are responsible for setting the resting membrane potential of a cell. Volatile anaesthetic agents have been found experimentally to enhance the activity of the channels, leading to hyperpolarisation.

Minimum alveolar concentration

The MAC is a measure of the potency of an inhalational anaesthetic agent. It is analogous to the ED50 of a drug; that is, the median effective dose that produces an effect in 50% of the population that receives it. As such, MAC is a misnomer, as median alveolar concentration would be a more accurate term.

One MAC is defined as ‘the minimum concentration (in volumes percent) of inhalational anaesthetic agent in the alveoli, at equilibrium, at one atmosphere pressure, in 100% oxygen, which produces immobility in 50% of unpremedicated adult subjects when exposed to a standard noxious stimulus.’

In clinical practice, MAC correlates with end-tidal anaesthetic agent concentration and is used as a guide to the depth of anaesthesia. Because of the differing potencies between the volatile agents, the end-tidal anaesthetic agent concentration required to achieve 1 MAC varies. For example, in an oxygen–air mixture, sevoflurane has a MAC of 1.8%, whereas desflurane requires an end-tidal concentration of 6.6% to achieve a MAC of 1. Although 1 MAC of sevoflurane is equal in potency to 1 MAC of desflurane, it does not follow that the agents are equipotent at 2 MAC. However, in general terms, 0.5 MAC of one agent, in combination with 0.5 MAC of another, approximates to 1 MAC in total. The MAC values for anaesthetic agents in common use are shown in Table 3.1 . The standard deviation for MAC values is around 10%; this means that MAC plus two standard deviations (i.e. 1.2 MAC) will produce immobility in approximately 95% of patients.

Table 3.1
Comparison of modern volatile anaesthetic agents
Isoflurane Sevoflurane Desflurane Halothane
Molecular mass; Da 184.5 200 168 197
Boiling point; °C 49 58.5 23.5 50
Blood/gas partition coefficient 1.4 0.68 0.42 2.5
Oil/gas partition coefficient 98 47 18.7 224
MAC (40-year-old patient); % 1.17 1.8 6.6 0.75
Preservative None None None Thymol
Stability in carbon dioxide absorbers Stable Unstable Stable Unstable? a
MAC, Minimum alveolar concentration.

a Halothane may be decomposed by soda lime but is still safe to use.

Other MAC concepts have also been described:

  • MAC awake or MAC aw : the alveolar concentration halfway between that allowing a response to verbal command and that preventing it. This is thought to be approximately 0.33 MAC for desflurane, isoflurane and sevoflurane.

  • MAC blocks adrenergic response or MAC bar : the brain concentration sufficient to prevent adrenergic response (i.e. increase in heart rate and/or arterial pressure) to skin incision. This has been found to be 1.3 MAC for isoflurane and desflurane and may be 2.0–3.0 MAC for sevoflurane. However, these values are decreased with the coadministration of opioids (e.g. MAC bar for isoflurane and desflurane falls to 0.40–0.60 MAC when administered with i.v. fentanyl 1.5 µg kg −1 ).

There are many pharmacological and physiological factors that can affect (increase or decrease) MAC ( Box 3.1 ).

Box 3.1
Factors affecting the minimum alveolar concentration (MAC) of inhalational anaesthetic agents

Factors leading to an increase in MAC

  • Decreasing age (peak at 6 months of age)

  • Hyperthermia

  • Hypernatraemia

  • Thyrotoxicosis

  • Elevated CNS catecholamine release: anxiety states, iatrogenic (e.g. hypercapnia), drugs (e.g. ephedrine, acute amphetamine/cocaine use, MAOIs)

  • Chronic alcohol or opioid use

Factors leading to a decrease in MAC

  • Acute intake of sedative or analgesic drugs (e.g. opiates, benzodiazepines, nitrous oxide)

  • Increasing age

  • Pregnancy

  • Hypothermia

  • Hypotension

  • Hypothyroidism

  • Hyponatraemia

  • Acute alcohol ingestion

  • Drugs that reduce CNS catecholamine release (e.g. reserpine, methyl dopa, clonidine, dexmedetomidine, chronic amphetamine/cocaine use).

MAOIs, Monoamine oxidase inhibitors.

Pharmacokinetics of inhaled anaesthetic agents

There are many factors affecting the CNS (effect site) concentration of an anaesthetic agent and therefore speed of onset of volatile anaesthesia.

  • 1.

    Inspired agent concentration. Put simply, the higher the concentration of the inhaled anaesthetic agent, the faster the onset. A high concentration of anaesthetic agent in the alveolus leads to a large concentration gradient between the alveolus and blood, favouring rapid diffusion across the alveolar membrane and therefore faster delivery to, and onset at, the effect site.

  • 2.

    Alveolar ventilation. Increased alveolar ventilation results in a more rapid onset of anaesthesia. Alveolar volatile agent taken up by the pulmonary blood flow is rapidly replaced, thereby maintaining the concentration gradient. Volatile anaesthetic agents such as desflurane and isoflurane which interfere with alveolar ventilation (e.g. because of breath holding or coughing) are therefore unsuitable for gaseous induction of anaesthesia.

  • 3.

    Functional residual capacity (FRC). Patients with a larger FRC will experience a slower onset of anaesthesia, as this will dilute the inspired concentration of gas, thereby reducing the alveolar partial pressure of the volatile agent.

  • 4.

    Cardiac output and pulmonary blood flow. A higher cardiac output results in more rapid alveolar uptake into blood and slower build-up of alveolar concentration; thus equilibration and anaesthesia will occur slowly. A lower cardiac output state will favour faster equilibration between agent in the alveolus and pulmonary blood; in addition, a greater proportion of cardiac output is directed to the cerebral circulation, further increasing the clinical effects. These effects are more pronounced in agents with greater solubility (see next).

  • 5.

    Blood/gas partition coefficient (solubility). The blood/gas partition coefficient is defined as the ratio of the amount of an anaesthetic agent in blood and gas when the two phases are of equal volume and pressure and in equilibrium at 37 o C. Thus the higher the blood/gas coefficient, the more soluble an agent is in blood and the longer it takes for the partial pressure of the agent in blood to rise. As previously alluded to, anaesthesia occurs when the partial pressure, not total amount, of an anaesthetic agent at the effect site reaches a certain value. Consequently, the higher an agent's blood/gas coefficient, the slower its anaesthetic effect ( Fig. 3.1 ). Similarly, the rapidity of recovery from anaesthesia is inversely proportional to the solubility of the anaesthetic ( Fig. 3.2 ).

    Fig. 3.1, Ratio of alveolar ( F A ) to inspired ( F I ) fractional concentration of nitrous oxide, desflurane, sevoflurane, isoflurane and halothane in the first 30 min of anaesthesia. The plot of F A / F I expresses the rapidity with which alveolar concentration equilibrates with inspired concentration. It is most rapid for agents with a low blood/gas partition coefficient.

    Fig. 3.2, Rapidity of recovery from anaesthesia is inversely proportional to the solubility of the anaesthetic: the most rapid recovery is with the least soluble anaesthetic (desflurane). The difference is amplified by duration of anaesthesia. Note that the difference in time of recovery between the least (desflurane) and most soluble anaesthetic (halothane) is greater after 2 h of anaesthesia than after 0.5 h of anaesthesia.

  • 6.

    Second gas effect. This describes the faster onset of anaesthesia that occurs when a volatile agent is coadministered with nitrous oxide and is a direct result of the concentration effect. The second gas effect is used in clinical practice to reduce anaesthetic induction time, particularly in gaseous inductions (see below).

The second gas effect

Nitrous oxide is rapidly absorbed across the alveolar membrane into the pulmonary capillaries. Nitrous oxide is around 20 times more soluble in blood than oxygen or nitrogen. At high concentrations of nitrous oxide, a significantly greater volume of nitrous oxide is entering pulmonary blood than oxygen or nitrogen is entering the alveolus. This results in two phenomena, which together increase the speed of onset of anaesthesia:

  • Concentration of the gases in the alveolus – the concentration effect. As nitrous oxide is rapidly absorbed, the alveolar volume decreases, leading to a fractional concentration of the remaining gases in the alveolus. This results in an increased concentration gradient between the alveolus and pulmonary blood, favouring alveolus to blood transfer of anaesthetic agent.

  • Augmentation of alveolar ventilation. As nitrous oxide is rapidly absorbed, the volume and pressure in the alveolus falls, creating a pressure/volume gradient between the conducting airways and the alveolus. This augments alveolar ventilation by drawing more gas down its pressure gradient into the alveolus, thus increasing speed of onset of anaesthesia. Similarly, use of nitrous oxide will accelerate the offset of anaesthesia. During emergence from anaesthesia, nitrous oxide administration is ceased and an oxygen or oxygen/air mixture is delivered. Nitrous oxide rapidly diffuses from the bloodstream across the alveolar membrane into the alveolus. This dilutes the volatile agent in the alveolus (and therefore the partial pressure), resulting in a faster offset of anaesthesia. This also causes diffusion hypoxia, which is discussed in detail later in the chapter.

The combination of the concentration effect and the augmentation of alveolar ventilation is employed to reduce induction time with the volatile anaesthetics and thus describes the second gas effect ( Fig. 3.3 ).

Fig. 3.3, The concentration and second gas effects. High concentrations of nitrous oxide increase the alveolar ( F A ) to inspired ( F I ) ratio for nitrous oxide (the concentration effect) and for a volatile agent administered with nitrous oxide (the second gas effect).

Individual anaesthetic agents

There is no inhalational anaesthetic agent that fulfils the criteria of the ideal inhalational anaesthetic agent ( Box 3.2 ). Although there are many inhaled anaesthetic agents available, only three are in regular use in economically advantaged countries: isoflurane; sevoflurane; and desflurane. Halothane is still in use in resource-poor environments (see Chapter 45 ); however, its popularity has declined because of its less favourable kinetics and higher incidence of adverse effects. The chemical structures of the volatile agents are shown in Fig. 3.4 .

Box 3.2
Properties of the ideal anaesthetic agent

Physical

  • Stable compound (unaffected by light or heat)

  • Non-flammable/does not support combustion

  • SVP high enough to allow easy vaporisation and production of a clinically relevant concentration

  • Inert when in contact with regularly used equipment e.g. rubber, plastic, glass, soda lime

  • Cheap to manufacture

  • Environmentally friendly

  • Easy to administer

  • Long shelf life without need for preservatives

  • Non-irritant and non-pungent (to allow gaseous induction)

Pharmacological

  • Low blood/gas coefficient (to allow rapid onset/recovery)

  • High oil/gas coefficient (low MAC, high potency; allows delivery with a high F io 2 )

  • Minimal metabolism with pulmonary excretion (i.e. unaffected by renal/hepatic impairment)

  • Non-toxic/non-allergenic, with no trigger for malignant hyperthermia

  • No interactions with other drugs

  • Not teratogenic or carcinogenic

  • CVS:

    • No cardiovascular depression

    • No decrease in coronary blood flow

    • No sensitisation of myocardial tissue to catecholamines

  • RS:

    • No respiratory depression

    • Bronchodilation

  • CNS:

    • Analgesic properties

    • Non-epileptogenic

    • No increase in CBF or ICP

    • No effect on cerebral autoregulation

    • Muscle relaxation

  • GI/GU:

    • Antiemetic properties

    • No effect on uterine tone

CBF, Cerebral blood flow; F io 2 , fraction of inspired oxygen; ICP , intracranial pressure; MAC, minimum alveolar concentration; SVP, saturated vapour pressure.

Fig. 3.4, Structural formulae of inhalational anaesthetic agents.

Isoflurane

Uses

  • 1.

    Maintenance of general anaesthesia.

  • 2.

    Treatment of severe asthma in patients requiring mechanical ventilation in ICU.

Physical properties

Isoflurane is a halogenated ethyl methyl ether (1-chloro-2,2,2-trifluoroethyl difluoromethyl ether) and is a geometric isomer of enflurane. Isoflurane is a clear, colourless, volatile liquid with a pungent odour. It is presented in amber-coloured bottles and requires no preservatives for storage. It is stable, does not react with metal or other substances and is non-flammable in clinical concentrations.

Systemic effects

RS:

  • Dose-dependent depression of ventilation with depression of the ventilatory response to carbon dioxide.

  • Decrease in tidal volume but an increase in ventilatory rate in the absence of opioid drugs.

  • Respiratory tract irritation and laryngospasm, making inhalational induction unfavourable.

  • Inhibition of hypoxic pulmonary vasoconstriction (thereby increasing shunt fraction).

  • Bronchial smooth muscle relaxing properties, particularly in the context of bronchoconstriction caused by histamine and acetylcholine.

CVS:

  • Dose-related reduction in MAP, primarily by reduction in systemic vascular resistance (SVR), although isoflurane also has a negatively inotropic effect.

  • Reflex tachycardia.

  • Arrhythmias are uncommon, and there is little sensitisation of the myocardium to catecholamines.

  • Coronary vasodilatation with the possibility of ‘coronary steal’. Dilatation in normal coronary arteries offers a low resistance to flow and may reduce perfusion through stenosed neighbouring vessels, causing distal ischaemia. However, although this remains a theoretical concern, it does not appear to be of any clinical significance.

CNS:

  • Causes general anaesthesia and reduction in cerebral metabolic rate.

  • At concentrations >1 MAC causes cerebral vasodilatation and increases cerebral blood flow (CBF), leading to raised ICP.

  • Does not cause seizure activity on the EEG.

  • Induces dose-dependent muscle relaxation and depression of neuromuscular transmission with potentiation of non-depolarising neuromuscular blocking agents (NMBAs).

GI/GU:

  • Reduction in renal blood flow, although this is not thought to affect renal function in clinical use.

  • Uterine relaxation.

  • No effect on hepatic function or blood flow.

  • Increased risk of postoperative nausea and vomiting (PONV).

Other:

  • Trigger for malignant hyperthermia (MH).

Pharmacology

Uptake:

  • With its relatively low blood/gas partition coefficient, alveolar and blood partial pressures equilibrate rapidly compared with older agents such as halothane but more slowly than desflurane and sevoflurane.

  • Rate of recovery is slower than that associated with desflurane or sevoflurane because of its greater solubility (higher blood/gas partition coefficient).

Metabolism:

  • Less than 0.2% metabolised by liver (defluorination via cytochrome P450 (CYP2E1) producing hexafluoroisopropanol (HFIP)).

Excretion:

  • Majority of the delivered drug is excreted unchanged through the lungs.

  • Less than 0.2% renal excretion; HFIP is excreted in urine after conjugation with glucuronic acid.

Desflurane

Uses

  • 1.

    Maintenance of general anaesthesia.

Desflurane is the most recent volatile agent to enter mainstream anaesthetic practice. It has been welcomed for surgical techniques where a fast onset and rapid recovery from anaesthesia are particularly desirable, such as major head and neck surgery. In addition, its low solubility (blood/gas coefficient) and subsequent smaller volume of distribution are beneficial to patients undergoing lengthy surgery or bariatric patients, in whom the volume of distribution of lipid-soluble drugs is greater.

Physical properties

Desflurane is a colourless agent which is stored in amber-coloured bottles without preservative. It is non-flammable at commercial concentrations. Desflurane is stable in the presence of soda lime but should be protected from light. Desflurane has an ethereal and pungent odour.

Desflurane has a boiling point close to room temperature (23.5°C) and a vapour pressure of 88.5 kPa at 20°C. A standard vaporiser cannot be used to deliver desflurane as small temperature and/or pressure fluctuations would result in a variable output. A special vaporiser (TEC 6) has been developed which heats the desflurane to 39°C and pressurises it to 2 atmospheres (see Chapter 16 ). The TEC 6 vaporiser therefore requires a source of electricity.

Systemic effects

RS:

  • Dose-dependent respiratory depression, with depression of the ventilatory response to P a co 2 . This exceeds the effect of other volatile agents at concentrations >1 MAC.

  • Irritant to the upper respiratory tract, particularly at concentrations > 6%.

  • Stimulation of coughing, breath holding and laryngospasm precludes its use as an induction agent.

CVS:

  • Dose-related reduction in SVR, myocardial contractility and MAP.

  • Heart rate unchanged at lower steady-state concentrations but increases with higher concentrations.

  • Cardiac output tends to be maintained as per isoflurane.

  • In concentrations >1 MAC, an increase in sympathetic activity, leading to increased HR and MAP.

  • No detectable coronary steal.

  • Does not sensitise the myocardium to catecholamines.

CNS:

  • Causes general anaesthesia and reduction in cerebral metabolic rate.

  • Dose-dependent EEG depression.

  • Does not induce seizure activity at any depth of anaesthesia.

  • Dose-dependent alteration in cerebral autoregulation (vasodilatation) at concentrations > 1 MAC, which can result in an increase in ICP.

  • Dose-dependent muscle relaxation.

  • Potentiation of effects of NMBAs.

GI/GU:

  • Uterine relaxation.

  • Increased risk of PONV.

Other:

  • Malignant hyperthermia trigger.

Pharmacology

Uptake:

  • With a blood/gas partition coefficient of 0.42, equilibration of alveolar with inspired concentrations of desflurane is rapid compared with other available volatile agents. This leads to a rapid onset and recovery from anaesthesia.

Metabolism:

  • Approximately 0.02% of inhaled desflurane is metabolised in the body.

Excretion:

  • Approximately 99.98% is excreted unchanged from the lungs.

Sevoflurane

Uses

  • 1.

    Induction and maintenance of general anaesthesia.

  • 2.

    Sedation on ITU.

  • 3.

    Treatment of severe asthma in patients whose lungs are mechanically ventilated.

Sevoflurane is a polyfluorinated isopropyl methyl ether (fluoromethyl-2,2,2-trifluoro-1-ethyl ether). Unlike the other volatile agents, sevoflurane is achiral.

Physical properties

Sevoflurane is non-flammable and has a pleasant smell. It has a low blood/gas partition coefficient close to those of desflurane and nitrous oxide. During storage, where the concentration of added water is less than 100 ppm, it is susceptible to attack by Lewis acids (defined as any substance that can accept an electron pair) resulting in the release of hydrofluoric acid, which is highly toxic. This can be compounded if sevoflurane is stored in glass bottles as the hydrofluoric acid can corrode glass, formulating further Lewis acids. Consequently, sevoflurane is formulated with 300 ppm water and stored in polyethylene naphtholate or epoxy phenolic resin–lined aluminium bottles to ensure stability.

Systemic effects

RS:

  • Non-irritant to the upper respiratory tract; suitable for gaseous induction.

  • Dose-dependent depression in tidal volume.

  • Reduced respiratory drive in response to hypoxaemia.

  • Reduced respiratory drive in response to raised P a co 2 to a similar degree to other volatile agents.

  • Increased respiratory rate.

  • Inhibits hypoxic pulmonary vasoconstriction.

  • Bronchial smooth muscle relaxation.

CVS:

  • Increased HR (less than that of isoflurane).

  • Not associated with coronary steal.

  • Dose-related reduction in SVR, myocardial contractility and MAP.

  • Does not sensitise the myocardium to exogenous catecholamines.

CNS:

  • Causes general anaesthesia.

  • Dose-dependent reduction in cerebral vascular resistance and cerebral metabolic rate.

  • Preferred volatile agent for neuroanaesthesia. Although ICP is increased at high inspired concentrations (> 1.5 MAC) this effect is minimal over the 0.5–1.0 MAC range. This is thought to be due to preserved cerebral autoregulation of CBF.

  • No excitatory effects on EEG.

  • Potentiation of NMBAs.

  • Dose-dependent muscle relaxation.

GI/GU:

  • No demonstrable renal toxicity clinically despite concerns of fluoride ion exposure.

  • Preservation of renal blood flow.

  • Uterine relaxation.

  • Increased risk of PONV.

Other:

  • Trigger for MH.

  • Production of potentially toxic compounds when in prolonged contact with soda lime (see next section).

Sevoflurane and carbon dioxide absorbers

Sevoflurane is absorbed and degraded by both soda lime and baralyme. When mixed with soda lime in artificial situations, five breakdown products are identified. These are termed compounds A, B, C, D and E and are thought to be toxic in rats, primarily causing renal, hepatic and cerebral injury.

In clinical situations, it is predominantly compound A and, to a lesser extent, compound B, that are produced. Evidence suggests that the concentration of compound A produced is well below the level that is toxic to animals. The use of baralyme is associated with production of higher concentrations of compound A, and this may be related to the higher temperature attained when baralyme is used. The presence of moisture reduces compound A formation. The concentration of compound A is highest during low-flow anaesthesia (<2 L min –1 ) and is reduced by increasing fresh gas flow rate. The toxicity of sevoflurane in combination with carbon dioxide absorbers is probably more a theoretical than clinical concern.

Pharmacology

Uptake:

  • Rapid onset/offset because of a low blood/gas partition coefficient.

Metabolism:

  • Approximately 2%–3% of the absorbed dose is metabolised (by defluorination) in the liver (CYP450 2E1) to HFIP, carbon dioxide and inorganic fluoride. Inorganic fluoride concentrations peak within 2 h of the end of anaesthesia and have a half-life of 15–23 h. There have been no reports of fluoride toxicity in clinical studies investigating sevoflurane.

Excretion:

  • Approximately 98% is excreted unchanged from the lungs. Hexafluoroisopropanol is conjugated with glucuronic acid as excreted as urinary metabolite.

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