Anaesthetics inhalation

General anaesthesia usually involves administration of several drugs with different actions for premedication, induction and maintenance of anaesthesia. 

Premedication is intended to prevent the parasympathetic effects of anaesthesia (excessive salivation and bronchial secretion and a reduction in heart rate) and to reduce anxiety or pain. Premedication and adjuncts to general anaesthesia are discussed further on page 234. 

Induction is most likely to be achieved using an intravenous anaesthetic, which produces unconsciousness within seconds. 

Maintenance of anaesthesia is then usually by administration of an inhalation anaesthetic in a mixture of air or oxygen. 

Inhalation anaesthetics are either gases or volatile liquids. Apart from nitrous oxide, which is still widely used, earlier inhalation anaesthetics are no longer used. Ether is not suitable because it is explosive and irritant to the respiratory tract. Chloroform cannot be used because it is toxic to the liver. Inhalation anaesthetics currently in use are the volatile liquids halothane (since 1956) and more recently isoflurane, desflurane and sevoflurane and nitrous oxide gas. 

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A nonconventional synthesis of the known inhalation anaesthetic, 2-bromo-2 chloro-l,l,l-trifluoroethane (Halothane), based on the reaction of ethyl 1,2 di bromo-1,2-dicliloroethyl ether with anhydrous hydrogen fluoride and sulfur tetrafluoride, has been patented The reaction presumably involves cleavage of the ether linkage, followed by fluorination of the intermediate bromochloroacetyl halide with sulfur tetrafluoride, ethyl halides are the by-products [2] (equation 2)... 

Cyclic ethylene carbonate and its halogeno derivatives are converted into 2 2 difluoro 1,3 dioxolanes, which are useful as inhalation anaesthetics by treatment with sulfur tetrafluonde m an anhydrous hydrogen fluoride solution at 100-150 °C [239] (equation 126)... 

Baden JM, Kelley M, Mazze Rl, et al. 1979. Mutagenicity of inhalation anaesthetics Trichloroethylene, divinyl ether, nitrous oxide, and cyclopropane. Br J Anaesth 51 417-421. 

Feingold A, Holaday DA. 1977. The pharmacokinetics of metabolism of inhalation anaesthetics. BrJ Anaesth 49 155-162. 

The phenomenon by which the speed of onset of inhalational anaesthetic agents is increased when they are administered with N20 as a carrier gas. 

Dale O, Brown BRJ (1987) Clinical pharmacokinetics of the inhalation anaesthetics. Clin Pharmacokinet 12 145-167. 

While ionophore-stimulated 5-LO product release from neutrophils is often used as an indication of 5-LO inhibition, one must interpret these results cautiously. For example, halothane, an inhalation anaesthetic which may cause membrane perturbation [26], and colchicine, a microtubule disrupter [27], both were active, but presumably not because of 5-LO inhibition. A23187 is assumed to stimulate 5-LO by raising the intracellular calcium level, but this agent causes many other effects which may or may not be related to 5-LO activation, including changes in membrane potential, protein phosphorylation, phospholipid turnover, cyclic nucleotide levels, and DNA and protein synthesis [28]. Also, the effects of some putative 5-LO inhibitors on product release from neutrophils has been shown to vary with the stimulant used [29]. 

Diethyl ether has been used widely as an inhalation anaesthetic. But due to its slow effect and an unpleasant recovery period, it has been replaced, as an anaesthetic, by other compounds. 

Most of the anticholinergic drugs which cause delirium have prominently antimuscarinic actions. However, nicotinic receptors are also present in the brain. Mecamylamine, a nicotinic receptor antagonist which penetrates the brain to some extent, has produced delirium (Paykel et al., 1982). Furthermore, general (inhalational) anaesthetics, which by definition decrease arousal, target nicotinic receptors among others (Chapter 9). Conversely, nicotine itself increases arousal and selective attention (Ashton, 1992b). 

It is a clear, colourless liquid with a sweet and fruity odour. It is noninflammable and non-explosive in air or oxygen in anaesthetic concentrations. It is the most potent inhalational anaesthetic which has a good analgesic and muscle relaxant properties. Renal blood flow, glomerular filtration rate and urine flow are reduced as with the halothane. 

The alveolar-capillary membrane is normally very thin, has a huge surface area, and a large blood supply. Drugs given by this route, such as bronchodilators and pulmonary steroids, are rapidly absorbed into the bloodstream. This is also the route for administering the inhalational anaesthetics. DRUG METABOLISM AND EXCRETION... 

All inhaled anaesthetic drugs must be soluble in blood and brain in order to pass across the alveolar-capillary membrane and the blood-brain barrier. The term used to quantify solubility is partition coefficient. For anaesthetic purposes this is defined as the ratio of the concentration of dissolved gas/vapour in the blood to the concentration in the alveoli at... 

Figure 3.1 Graph showing the ratio between inspired (FJ) and alveolar (FA) end-tidal concentrations of the agents shown. The least soluble agents approach equilibrium (FA/FI=1) the most rapidly. Also, since both inhalation and intravenous anaesthetic drugs tend to reduce cardiac output, they facilitate the uptake of volatile agents. It follows that any inhaled anaesthetic drug must be given with great caution to patients in shocked states, e.g. hypovolaemia, arrhythmias, myocardial infarction.

The tensions of inhaled anaesthetics in tissues with a high blood flow—brain, heart, kidney (vessel rich group)—equilibrate quickly with the tensions in blood. The converse is true in tissues having low blood flows, e.g. fat, bone. Muscle occupies an intermediate position. 

In order to compare the anaesthetic, haemo-dynamic, and other effects of these agents, it is necessary to have a measure of potency so that equivalent doses of the agents may be administered. Eger in 1974 coined the term minimum aiveolar ventilation (MAC) to describe the potency of inhaled anaesthetics. MAC is defined as ... 

Rare, familial hyperthermia (41 °C) associated with inhalation anaesthetics, muscle relaxants, tricyclic antidepressants, phenothiazine neuroleptics (particularly chlorpromazine) monoamine oxidase inhibitors and haloperidol. 

The ethers are also an homologous series. We will only use the common compound simply called ether as a further example. It is really diethyl ether or ethoxy ethane, C2H5 O C2H5. Ether was one of the earliest inhaled anaesthetics and it has a sweet sickly smell. Diethyl ether has a low boiling point (no hydrogen bonding unlike ethanol) and is easily evaporated at room temperatures. If you leave the bottle open it will soon evaporate into a heavy vapour which is extremely flammable. Never use ether near flames or sparks because fire and explosions are possible. 

It was William Morton, in 1846, who first noted that ether could be used as an anaesthetic for dentistry and surgery. Before that all surgery was conducted on conscious patients. Chloroform, CHCI3, was developed later and Queen Victoria gave the process of anaesthesia credence when she gave birth to a child in 1853 and suffered little or no pain. More recent inhaled anaesthetics include isofluorane , CF3 CH(C1) O CHF2. Draw its structure (hint it is also an ether). 

More recent inhaled anaesthetics include isofluorane CF3 CH(Cl) O CHF2. Draw its structure (from p. 51). 

Shulman, M., and M.S. Sadove. 1967. 1,1,1,2-Tetrafluoroethane An inhalation anaesthetic agent of intermediate potency. Anesth. Analg. 46(5) 629-633. 

AMIODARONE ANAESTHETICS - GENERAL Amiodarone may t the myocardial depressant effects of inhalational anaesthetics Additive effect Monitor PR, BP and ECG closely... 

DIRECT ANAESTHETICS-GENERAL 1. Risk of arrhythmias when inhalational anaesthetics are coadministered with epinephrine or norepinephrine 2. Case report of marked t BP when phenylephrine eye drops given during general anaesthesia... 

INHALATIONAL -HALOTHANE OXYTOCICS Report of arrhythmias and cardiovascular collapse when halothane was given to patients taking oxytocin Uncertain possibly additive effect. High-dose oxytocin may cause hypotension and arrhythmias Monitor PR, BP and ECG closely give oxytocin in the lowest possible dose. Otherwise consider using an alternative inhalational anaesthetic... 

ANAESTHETICS-GENERAL INDIRECTLY ACTING SYMPATHOMIMETICS (e.g. methylphenidate) 1. Risk of arrhythmias when inhalational anaesthetics are co-administered with methylphenidate 2. Case report of 1 sedative effect of midazolam and ketamine by methylphenidate 1. Uncertain attributed by some to sensitization of the myocardium to sympathomimetics by inhalational anaesthetics 2. Uncertain at present possibly due to CNS stimulation caused by methylphenidate (hence its use in narcolepsy) Avoid giving methylphenidate on the day of elective surgery... 

Inhalational anaesthetics seem to sensitize the myocardium to beta-adrenoceptor stimulation... 

Membranes Inhalation anaesthetics (diethylether, chloroform, and their more modem replacements). The mode of action of these was enshrouded in mystery for a long time, but accumulating evidence now supports direct interaction with several ion channels. Nevertheless, there is a remarkably close correlation between the ability of these agents to partition into lipid membranes, as measured by their oil-water partition coefficients, and their narcotic activity so, in a sense, cell membranes may be considered the targets of these agents. 

Drug interactions. Addition of 50% nitrous oxide/ oxygen mixture to another inhalational anaesthetic... 

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