General Anesthetics

Chapter -27 

General Anesthetics

General an aesthetics (GAs) are drugs which produce reversible loss of all sensation and consciousness. The cardinal features of general an aesthesia are:

• Loss of all sensation, especially pain 

• Sleep (unconsciousness) and amnesia 

• Immobility and muscle relaxation 

• Abolition of somatic and autonomic reflexes.

In the modern practice of balanced an aesthesia, these modalities are achieved by using combination of inhaled and i.e. drugs, each drug for a specific purpose; an aesthesia has developed as a highly specialized science in itself.

History Before the middle of 19th century a number of agents like alcohol, opium, cannabis, or even concussion and asphyxia were used to obtund surgical pain, but operations were horrible ordeals. Horace Wells, a dentist, picked up the idea of using nitrous oxide (N2O) from a demonstration of laughing gas in 1844. However, he often failed to relieve dental pain completely and the use of N2O had to wait till other advances were made. Morton, a dentist and medical student at Boston, after experimenting on animals, gave a demonstration of ether anesthesia in 1846, and it soon became very popular. Chloroform was used by Simpson in Britain for obstetrical purpose in 1847, and despite its toxic potential, it became a very popular surgical anesthetic. Cyclopropane was introduced in 1929, but the new generation of anesthetics was heralded by halothane in 1956. The first i.v. anesthetic thiopentone was introduced in 1935.

MECHANISM OF GENERAL ANAESTHESIA

• The mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs. Mayer and Overton (1901) pointed out a direct parallelism between lipid/water partition coefficient of the GAs and their anesthetic potency.

• Minimal alveolar concentration (MAC) is the lowest concentration of the anesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision) in 50% individuals. It is accepted as a valid measure of potency of inhalational GAs because it remains fairly constant for a given species even under varying conditions.

• The MAC of a number of GAs shows excellent correlation with their oil/gas partition coefficient. However, this only reflects capacity of the anesthetic to enter into CNS and attain sufficient concentration in the neuronal membrane, but not the mechanism by which anesthesia is produced

• Recent evidence Favours a direct interaction of the GA molecules with hydrophobic domains of membrane proteins or the lipid-protein interface.

• It has now been realized that different anesthetics may be acting through different molecular mechanisms, and various components of the anesthetic state involve action at discrete loci in the cerebrospinal axis. The principal locus of causation of unconsciousness appears to be in the thalamus or reticular activating system, amnesia may result from action in hippocampus, while spinal cord is the likely seat of immobility on surgical stimulation.

• Recent findings show that ligand gated ion channels (but not voltage sensitive ion channels) are the major targets of inaesthetic action. The GABAA receptor gated Cl¯ channel is the most important of these. Many inhalational anesthetic's, barbiturates, benzodiazepines and propofol potentiate the action of inhibitory transmitter GABA to open Cl¯ channels. Each of the above anesthetics appears to interact with its own specific binding site on the GABAA receptor-Cl¯ channel complex, but none binds to the GABA binding site as such; though some inhaled anesthetics and barbiturates (but not benzodiazepines) can directly activate Cl– channels. Action of glycine (another inhibitory transmitter which also activates Cl¯ channels) in the spinal cord and medulla is augmented by barbiturates, propofol and many inhalational anesthetics. This action may block responsiveness to painful stimuli resulting in immobility of the anesthetic state. Certain fluorinated anesthetics and barbiturates, in addition, inhibit the neuronal cation channel gated by nicotinic cholinergic receptor which may mediate analgesia and amnesia.

• On the other hand, N2O and ketamine do not affect GABA or glycine gated Cl¯ channels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor. This receptor gates mainly Ca2+ selective cation channels in the neurons, inhibition of which appears to be the primary mechanism of anesthetic action of ketamine as well as N2O. The volatile anesthetics have little action on this receptor

• Neuronal hyperpolarization caused by GAs has been ascribed to activation of a specific type

• of K+ channels, while inhibition of transmitter release from presynaptic neurons has been related to interaction with certain critical synaptic proteins. Thus, different facets of anesthetic action may have distinct neuronal basis, as opposed to the earlier belief of a global neuronal depression.

• Unlike local anesthetics which act primarily by blocking axonal conduction, the GAs appears to act by depressing synaptic transmission.

STAGES OF ANAESTHESIA

GAs causes an irregularly descending depression of the CNS, i.e., the higher functions are lost first, and progressively lower areas of the brain are involved, but in the spinal cord lower segments are affected somewhat earlier than the higher segments. The vital centers located in the medulla are paralyzed the last as the depth of anesthesia increases. Guedel (1920) described four stages with ether anesthesia, dividing the III stage into 4 planes. These clear-cut stages are not seen now-a-days with the use of faster acting GAs, premedication and employment of many drugs together. The precise sequence of events differs somewhat with anesthetics other than ether. However, ether continues to be used in India and description of these stages still serves to define the effects of light and deep anesthesia. Important features of different stages are depicted in

• I. Stage of analgesia Starts from beginning of anesthetic inhalation and lasts up to the loss of consciousness. Pain is progressively abolished. Patient remains conscious, can hear and see, and feels a dream like state; amnesia develops by the end of this stage. Reflexes and respiration remain normal.

• Though some minor operations can be carried out during this stage, it is rather difficult to maintain—use is limited to short procedures.

• II. Stage of delirium from loss of consciousness to beginning of regular respiration. App

• rent excitement is seen patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, involuntary micturition or defecation may occur. Heart rate and BP may rise, and pupils dilate due to sympathetic stimulation.

• No stimulus should be applied, or operative procedure carried out during this stage. This stage is inconspicuous in modern anesthesia.

III. Surgical anesthesia Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes which may be distinguished as:

IV. Medullary paralysis Cessation of breathing to failure of circulation and death. Pupil is widely dilated, muscles are totally flabby, pulse is thready or imperceptible and BP is very low.

Many of the above indices have been robbed by the use of atropine (pupillary, heart rate), morphine (respiration, pupillary), muscle relaxants (muscle tone, respiration, eye movements, reflexes) etc. and the modern anesthetist has to depend on several other observations to gauge the depth of anesthesia.

• If eyelash reflex is present and patient is making swallowing movements—stage II has not been reached. 

• Loss of response to painful stimulus (e.g., pressure on the upper nasal border of orbit) — stage III has been reached. 

• Incision of the skin causes reflex increase in respiration, BP rise or other effects; insertion of endotracheal tube is resisted and induces coughing, vomiting, laryngospasm; tears appear in eye; passive inflation of lungs is resisted anesthesia is light. 

• Fall in BP, cardiac and respiratory depression are signs of deep anesthesia.

In the present-day practice anesthesia is generally kept light; adequate analgesia, amnesia and muscle relaxation are produced by the use of intravenous drugs. Premedication with CNS depressants and opioids or their concurrent use lowers MAC of the inhaled anesthetic. When a combination of two inhalational anesthetics (e.g. N2O + isoflurane) is used, their MACs are additive: lower concentration of each is required. The dose-response relationship of inhaled anesthetics is very steep; just 10% higher concentration (1.1 MAC) immobilizes >90% subjects. Concentrations of inhalational anesthetics exceeding 1.2 MAC are rarely used, and 2–3 MAC is often lethal.

PHARMACOKINETICS OF INHALATIONAL ANAESTHETICS

Inhalational anesthetics are gases or vapors that diffuse rapidly across pulmonary alveoli and tissue barriers. The depth of anesthesia depends on the potency of the agent (MAC is an index of potency) and its partial pressure (PP) in the brain, while induction and recovery depend on the rate of change of PP in the brain. Transfer of the anesthetic between lung and brain depends on a series of tension gradients which may be summarized as—

Alveoli Blood Brain Factors affecting the PP of anesthetic attained in the brain are—

• PP of anesthetic in the inspired gas This is proportional to its concentration in the inspired gas mixture. Higher the inspired tension more anesthetic will be transferred to the blood. Thus, induction can be hastened by administering the GA at high concentration in the beginning.

• Pulmonary ventilation It governs delivery of the GA to the alveoli. Hyperventilation will bring in more anesthetic per minute and respiratory depression will have the opposite effect. Influence of minute volume on rate of induction is greatest in the case of agents which have high blood solubility because their PP in blood takes a long time to approach the PP in alveoli. However, it does not affect the terminal depth of anesthesia attained with any concentration of a GA.

• Alveolar exchange The GAs diffuses freely across alveoli, but if alveolar ventilation and perfusion are mismatched (as occurs in emphysema and other lung diseases) the attainment of equilibrium between alveoli and blood is delayed: well perfused alveoli may not be well ventilated blood draining these alveoli carries less anesthetic and dilutes the blood coming from well ventilated alveoli. Induction and recovery both are slowed.

• Solubility of anesthetic in blood This is the most important property determining induction and recovery. Large amount of an anesthetic that is highly soluble in blood (ether) must dissolve before its PP is raised. The rise as well as fall of PP in blood and consequently induction as well as recovery are slow. Drugs with low blood solubility, e.g. N2O, sevoflurane, desflurane induce quickly.

• Blood: gas partition coefficient (λ) given by the ratio of the concentration of the anesthetic in blood to that in the gas phase at equilibrium is the index of solubility of the GA in blood.

• Solubility of anesthetic in tissues Relative solubility of the anesthetic in blood and tissue determines its concentration in that tissue at equilibrium. Most of GAs are equally soluble in

• lean tissues as in blood, but more soluble in fatty tissue. Anesthetics with higher lipid solubility (halothane) continue to enter adipose tissue for hours and also leave it slowly. The concentration of these agents is much higher in white matter than in grey matter.

• Cerebral blood flow Brain is a highly perfused organ as such GAs are quickly delivered to it. This can be hastened by CO2 inhalation which causes cerebral vasodilatation—induction and recovery are accelerated. Carbon dioxide stimulates respiration, and this also speeds up the transport.

• Elimination When anesthetic administration is discontinued, gradients are reversed, and the channel of absorption (pulmonary epithelium) becomes the channel of elimination. All inhaled anesthetics are mainly eliminated through lungs. The same factors which govern induction also govern recovery. Anesthetics, in general, continue to enter and persist for long periods in adipose tissue because of their high lipid solubility and low blood flow to fatty tissues. Muscles occupy an intermediate position between brain and adipose tissue. Most GAs are eliminated unchanged. Metabolism is significant only for halothane which is >20% metabolized in liver. Others are practically not metabolized. Recovery may be delayed after prolonged anesthesia, especially in case of more lipid-soluble anesthetics (halothane, isoflurane), because large quantities of the anesthetic have entered the muscle and fat, from which it is released slowly into blood.

• Second gas effect and diffusion hypoxia In the initial part of induction, diffusion gradient from alveoli to blood is high and larger quantity of anesthetic is entering blood. If the inhaled concentration of anesthetic is high, substantial loss of alveolar gas volume will occur and the gas mixture will be sucked in, independent of ventilatory exchange—gas flow will be higher than tidal volume. This is significant only with N2O, since it is given at 70–80% concentration.

• though it has low solubility in blood, about 1 liter/min of N2O enters blood in the first few minutes—gas flow is 1 liter/min higher than minute volume. If another potent anesthetic, e.g. halothane (1–2%) is being given at the same time, it also will be delivered to blood at a rate 1 liter/min higher than minute volume and induction will be faster—second gas effect.

• The reverse occurs when N2O is discontinued after prolonged anesthesia—N2O having low blood solubility rapidly diffuses into alveoli and dilutes the alveolar air—PP of oxygen in alveoli is reduced. The resulting hypoxia, called diffusion hypoxia, is not of much consequence if cardiopulmonary reserve is normal, but may be dangerous if it is low. This can be prevented by continuing 100% O2 inhalation for a few minutes after discontinuing N2O, instead of straight away switching over to air. Diffusion hypoxia is not significant with other anesthetics because they are administered at low concentrations (0.2–4%) and cannot dilute alveolar air by more than 1–2%.

TECHNIQUES OF INHALATION OF ANAESTHETICS

Different techniques are used according to facility available, agent used, condition of the patient, type and duration of operation.

• Open drop method Liquid anesthetic is poured over a mask with gauze and its vapor is inhaled with air. A lot of anesthetic vapor escapes in the surroundings and the concentration of anesthetic breathed by the patient cannot be determined. It is wasteful—can be used only for cheap anesthetics. Some rebreathing does occur in this method. However, it is simple and requires no special apparatus. Ether is the only agent used by this method, especially in children.

• Through anesthetic machines Use is made of gas cylinders, specialized graduated vaporizers, flow meters, unidirectional valves, corrugated rubber tubing and reservoir bag.

The gases are delivered to the patient through a tightly fitting face mask or endotracheal tube. Administration of the anesthetic can be more precisely controlled and in many situations its concentration determined. Respiration can be controlled and assisted by the anesthetist.

• Open system the exhaled gases are allowed to escape through a valve and fresh anesthetic mixture is drawn in each time. No rebreathing is allowed—flow rates are high—more drug is consumed. However, inhaled O2 and anesthetic concentration can be accurately delivered

• Closed system The patient rebreathes the exhaled gas mixture after it has circulated through soda lime which absorbs CO2. Only as much O2 and anesthetic as have been taken up by the patient are added to the circuit. The flow rates are low; especially useful for expensive and explosive agents (little anesthetic escapes in the surrounding air) e.g., halothane, enflurane, isoflurane. However, control of inhaled anesthetic concentration is difficult.

• Semi closed system Partial rebreathing is allowed through a partially closed valve. Conditions are intermediate with moderate flow rates.

Properties of an ideal anesthetic

• For the patient It should be pleasant, nonirritating, should not cause nausea or vomiting. Induction and recovery should be fast with no aftereffects.

• For the surgeon It should provide adequate analgesia, immobility and muscle relaxation. It should be noninflammable and nonexplosive so that cautery may be used.

• For the anesthetist Its administration should be easy, controllable and versatile.

• Margin of safety should be wide—no fall in BP. Heart, liver and other organs should not be affected. It should be potent so that low concentrations are needed, and oxygenation of the patient does not suffer. Rapid adjustments in depth of anesthesia should be possible. It should be cheap, stable and easily stored. It should not react with rubber tubing or soda lime.

The important physical and anesthetic properties of inhalational an aesthetics are presented in

INHALATIONAL ANAESTHETICS

• Nitrous oxide (N2O) It is a colorless, odorless, heavier than air, noninflammable gas supplied under pressure in steel cylinders. It is nonirritating, but low potency anesthetic; unconsciousness cannot be produced in all individuals without concomitant hypoxia: MAC is 105% implying that even pure N2O cannot produce adequate anesthesia at 1 atmosphere pressure. Patients maintained on 70% N2O + 30% O2 along with muscle relaxants often recall the events during anesthesia, but some lose awareness completely.

• Nitrous oxide is a good analgesic; even 20% produces analgesia equivalent to that produced by conventional doses of morphine. It is a poor muscle relaxant; neuromuscular blockers are often required. Onset of N2O action is quick and smooth (but thiopentone is often used for induction), recovery is rapid: both because of its low blood solubility. Second gas effect and diffusion hypoxia occur with N2O only. Postanaesthetic nausea is not marked.

• Nitrous oxide is generally used as a carrier and adjuvant to other anesthetics. A mixture of 70% N2O + 25–30% O2 + 0.2–2% another potent anesthetic is employed for most surgical procedures. In this way concentration of the other anesthetic can be reduced to 1/3 for the same level of anesthesia. Because N2O has little effect on respiration, heart and BP: breathing and circulation are better maintained with the mixture than with the potent anesthetic given alone in full doses. However, N2O can expand pneumothorax and other abnormal air pockets in the body.

• As the sole agent, N2O (50%) has been used with O2 for dental and obstetric analgesia. It is nontoxic to liver, kidney and brain. Metabolism of N2O does not occur; it is quickly removed from body by lungs. It is cheap and very commonly used.

• Ether (Diethyl ether) It is a highly volatile liquid, produces irritating vapors which are inflammable and explosive 

• Ether is a potent anesthetic, produces good analgesia and marked muscle relaxation by reducing Ach output from motor nerve endings —dose of competitive neuromuscular blockers should be reduced to about 1/3.

• It is highly soluble in blood—induction is prolonged and unpleasant with struggling, breath-holding, salivation and marked respiratory secretions (atropine must be given as premedication to prevent the patient from drowning in his own secretions). Recovery is slow; postanesthetic nausea, vomiting and retching are marked.

• BP and respiration are generally well maintained because of reflex stimulation and high sympathetic tone. It does not sensitize the heart to Ard and is not hepatotoxic.

•  Ether is not used now in developed countries because of its unpleasant and inflammable properties. However, it is still used in developing countries, particularly in peripheral areas because it is—cheap, can be given by open drop method (though congestion of eye, soreness of trachea and ether burns on face can occur) without the need for any equipment, and is relatively safe even in inexperienced hands.

• Halothane (FLUOTHANE) It is a volatile liquid with sweet odor, nonirritant and noninflammable. Solubility in blood is intermediate— induction is reasonably quick and pleasant.

• It is a potent inaesthetic—precise control of administered concentration is essential. For induction 2-4% and for maintenance 0.5–1% is delivered by the use of a special vaporizer. It is not a good analgesic or muscle relaxant; however, it potentiates competitive neuromuscular blockers.

• Halothane causes direct depression of myocardial contractility by reducing intracellular Ca2+ concentration. Moreover, sympathetic activity fails to increase (as occurs with ether). Cardiac output is reduced with deepening anesthesia. BP starts falling early and parallels the depth. Many vascular beds dilate but total peripheral resistance is not significantly reduced. Heart rate is reduced by vagal stimulation, direct depression of SA nodal automaticity and lack of baroreceptor activation even when BP falls. It tends to sensitize the heart to the arrhythmogenic action of Adr. The electrophysiological effects are conducive to re-entry—tachyarrhythmias occur occasionally.

• Halothane causes relatively greater depressions of respiration; breathing is shallow and rapid—PP of CO2 in blood rises if respiration is not assisted. Ventilatory support with added oxygen is frequently required. It tends to accentuate perfusion-ventilation mismatch in the lungs by causing vasodilatation in hypoxic alveoli.

• heed early and coughing is suppressed while bronchi dilate—preferred for asthmatics. It inhibits intestinal and uterine contractions. This property is utilized for assisting external or internal version during late pregnancy. However, its use during labor can prolong delivery and increase postpartum blood loss.    

• Urine formation is decreased during halothane anesthesia—primarily due to low g.f.r. as a result of fall in BP.

• Hepatitis occurs in susceptible individuals (approximately 1 in 10,000) especially after repeated use. A metabolite of halothane is probably involved—causes chemical or immunological injury.

• A genetically determined reaction malignant hyperthermia occurs rarely. Many susceptible subjects have an abnormal RyR (Ryanodine receptor) calcium channel at the sarcoplasmic reticulum of the skeletal muscles, which is triggered by halothane to release massive amounts of Ca2+ intracellularly causing persistent muscle contraction and increased heat production. Succinylcholine accentuates the condition (see Ch. 25). Rapid external cooling, bicarbonate infusion, 100% O2 inhalation and i.v. dantrolene are used to treat malignant hyperthermia.

• About 20% of halothane that enters blood is metabolized in the liver, the rest is exhaled out. Elimination may continue for 24–48 hours after prolonged administration. Recovery from halothane anesthesia is smooth and reasonably quick; shivering may occur, but nausea and vomiting are rare. Psychomotor performance and mental ability remain depressed for several hours after regaining consciousness.         

• It is currently one of the most popular anesthetics because of nonirritant, noninflammable, pleasant and rapid action, particularly suitable for induction and maintenance in children and as maintenance anesthetic in adults. However, in affluent countries it has been largely replaced by the newer agents which are costly. Its deficiencies in terms of poor analgesia and muscle relaxation are compensated by concomitant use of N2O or opioids and neuromuscular blockers.

• Enflurane This faster acting substitute of halothane has similar actions but is less soluble in blood and fat; accumulates in the body to a lesser extent. Because of its propensity to provoke seizures at deeper levels of anesthesia, it has been superseded by isoflurane which has other desirable properties as well

• Isoflurane (SOFANE) It is a later introduced (1981) isomer of enflurane; has similar properties, but about 1½ times more potent, more volatile and less soluble in blood. It produces relatively rapid induction and recovery, and is administered through a special vaporizer; 1.5–3% induces anesthesia in 7–10 min, and 1–2% is used for maintenance

• Magnitude of fall in BP is similar to halothane but is primarily due to vasodilatation while cardiac output is well maintained. Heart rate is increased. These cardiovascular effects probably result from stimulation of β adrenergic receptors, but it does not sensitize the heart to adrenergic arrhythmias. Coronary circulation is maintained: safer in patients with myocardial ischemia. Respiratory depression is prominent, and assistance is usually needed to avoid hypercarbia. Secretions are slightly increased. Uterine and skeletal muscle relaxation is similar to halothane. Metabolism of isoflurane is negligible. Renal and hepatic toxicity has not been encountered. Postanaesthetic nausea and vomiting is low. Pupils do not dilate, and light reflex is not lost even at deeper levels. Though slightly irritant, isoflurane has many advantages, i.e., better adjustment of depth of anesthesia and low toxicity. It is a good maintenance anesthetic, but not preferred for induction. It does not provoke seizures and is preferred for neurosurgery. Isoflurane has become the routine anesthetic, but use may be restricted due to cost

• Desflurane It is a newer all fluorinated congener of isoflurane which has gained popularity as an anesthetic for outpatient surgery in western countries. Though it is highly volatile, a thermostatically heated special vape

• riser is used to deliver a precise concentration of pure desflurane vapor in the carrier gas (N2O + O2) mixture. Its distinctive properties are lower oil: gas partition coefficient and very low solubility in blood as well as in tissues, because of which induction and recovery are very fast. Depth of anesthesia changes rapidly with change in inhaled concentration. Postanesthetic cognitive and motor impairment is short-lived— patient can be discharged a few hours after surgery.

• Desflurane is less potent than isoflurane; higher concentration has to be used for induction—irritates air passage—may induce coughing, breath-holding and laryngospasm because of somewhat pungent odor making it unsuitable for induction. Rapid induction sometimes causes brief sympathetic stimulation and tachycardia. Degree of respiratory depression, muscle relaxation, vasodilatation and fall in BP, as well as maintained cardiac contractility and coronary circulation are like isoflurane. Lack of seizure provoking potential or arrhythmogenicity and absence of liver as well as kidney toxicity are also similar to isoflurane. It is exhaled unchanged, but more rapidly. As such, desflurane can serve as a good alternative to isoflurane for routine surgery as well, especially prolonged operations.

• Sevoflurane This new polyfluorinated anesthetic has properties intermediate between isoflurane and desflurane. Solubility in blood and tissues as well as potency are less than isoflurane but more than desflurane.

• Induction and emergence from anesthesia are fast and rapid changes in depth can be achieved. Absence of pungency makes it pleasant and administrable through face mask. Unlike desflurane, it poses no problem in induction; acceptability is good even by pediatric patients. Recovery is smooth; orientation, cognitive and motor functions are regained almost as quickly as with desflurane. Sevoflurane is suitable both for outpatient as well as inpatient surgery, but its high cost and need for high-flow open system makes it very expensive to use. In India, only high-end hospitals are using it.

• Sevoflurane does not cause sympathetic stimulation and airway irritation even during rapid induction. Fall in BP is due to vasodilatation as well as modest cardiac depression. Respiratory depression, absence of seizure and arrhythmia precipitating propensity are similar to isoflurane. About 3% of absorbed sevoflurane is metabolized, but the amount of fluoride liberated is safe for kidney and liver. However, it is degraded by soda lime—not recommended for use in closed circuit.

INTRAVENOUS ANAESTHETICS

INDUCING AGENTS

These are drugs which on i.e. injection produce loss of consciousness in one arm-brain circulation time (~11 sec); are generally used for induction because of rapidity of onset of action. Anesthesia is then usually maintained by an inhalational agent. They also serve to reduce the amount of maintenance anesthetic. Supplemented with analgesics and muscle relaxants, they can also be used as the sole anesthetic.

• Thiopentone sod. It is an ultrashort acting thiobarbiturate, highly soluble in water yielding a very alkaline solution, which must be prepared freshly before injection. Extravasation of the solution or inadvertent intraarterial injection produces intense pain—necrosis and gangrene may occur.

• Injected i.v. (3–5 mg/kg) as a 2.5% solution, it produces unconsciousness in 15–20 sec. Its undissociated form has high lipid solubility— enters brain almost instantaneously. Initial distribution depends on organ blood flow— brain gets large amounts. However, as other less vascular tissues (muscle, fat) gradually take up the drug, blood concentration falls and it back diffuses from the brain: consciousness is regained in 6–10 min (t½ of distribution phase is 3 min).

• On repeated injection, the extracerebral sites are gradually filled up—lower doses produce anesthesia which lasts longer. Its ultimate disposal occurs mainly by hepatic metabolism (elimination t½ is 7–12 hr), but this is irrelevant for termination of action of a single dose. Residual CNS depression may persist for > 12 hr. The patient should not be allowed to leave the hospital without an attendant before this time.

• Thiopentone is a poor analgesic. Painful procedures should not be carried out under its influence unless an opioid or N2O has been given; otherwise, the patient may struggle, shout and show reflex changes in BP and respiration

• It is a weak muscle relaxant; does not irritate air passages. Respiratory depression with inducing doses of thiopentone is generally transient, but with large doses it can be severe. BP falls immediately after injection mainly due to vasodilatation but recovers rapidly. Cardiovascular collapse may occur if hypovolemia, shock or sepsis are present. It does not sensitize the heart to Ard, arrhythmias are rare

• Thiopentone is a commonly used inducing agent. It can be employed as the sole anesthetic for short operations that are not painful.

• Adverse effects Laryngospasm occurs generally when respiratory secretions or other irritants are present, or when intubation is attempted while anesthesia is light. It can be prevented by atropine premedication and administration of succinylcholine immediately after thiopentone. Succinylcholine and thiophen-tone react chemically—should not be mixed in the same syringe.

• Shivering and delirium may occur during recovery. Pain in the postoperative period is likely to induce restlessness; adequate analgesia should be provided. Postanesthetic nausea and vomiting are uncommon

• It can precipitate acute intermittent porphyria in susceptible individuals—contraindicated.

• Other uses Occasionally used for rapid control of convulsions. Gradual i.v. infusion of subanesthetic doses can be used to facilitate verbal communication with psychiatric patients and for ‘narcoanalysis’ of criminals; acts by knocking off guarding. PENTOTHAL, INTRAVAL SODIUM 0.5, 1 g powder for making fresh injectable solution

• Methohexitone sod. It is similar to thiopentone, 3 times more potent, has a quicker and briefer (5–8 min) action. Excitement during induction and recovery is more common. It is more rapidly metabolized (t½ 4 hr) than thiopentone: patient may be roadworthy more quickly.

• Propofol Currently, propofol has superseded thiopentone as an i.v. anesthetic, both for induction as well as maintenance. It is an oily liquid employed as a 1% emulsion. Unconsciousness after propofol injection occurs in 15–45 sec and lasts 5–10 min. Propofol distributes rapidly (distribution t½ 2–4 min). Elimination t½ (100 min) is much shorter than that of thiopentone due to rapid metabolism.

• Intermittent injection or continuous infusion of propofol is frequently used for total i.v. anesthesia when supplemented by fentanyl. It lacks airway irritancy and is particularly suited for outpatient surgery, because residual impairment is less marked and shorter-lasting. Incidence of postoperative nausea and vomiting is low; patient acceptability is very good. Excitatory effects and involuntary movements are noted in few patients. Induction apnea lasting ~1 min is common. Fall in BP due primarily to vasodilatation with less marked cardiac depression occurs consistently, and is occasionally severe, but short lasting. Bradycardia is also frequent. Maintenance anesthesia with propofol produces dose-dependent respiratory depression which is more marked than with thiopentone. Pain during injection is also frequent; can be minimized by combining with lidocaine. Dose: 2 mg/kg bolus i.v. for induction; 9 mg/kg/hr for maintenance.

• PROPOVAN 10 mg/ml and 20 mg/ml in 10, 20 ml vials

• In subanesthetic doses (2.4 mg/kg/hr) it is the drug of choice for sedating intubated patients in intensive care units. However, it is not approved for such use in children; prolonged sedation with higher doses has caused severe metabolic effects and heart failure even in adults.

• Etomidate It is another induction anesthetic, which has a briefer duration of action (4–8 min) than thiopentone; produces little cardiovascular and respiratory depression, but motor restlessness and rigidity is more prominent as are pain on injection or nausea and vomiting on recovery. It is a poor analgesic and has not found much Favour.

SLOWER ACTING DRUGS

• Benzodiazepines (BZDs) In addition to preanesthetic medication, BZDs are now frequently used for inducing, maintaining and supplementing anesthesia as well as for ‘conscious sedation’. Relatively large doses (diazepam 0.2–0.3 mg/kg or equivalent) injected i.v. produce sedation, amnesia and then unconsciousness in 5–10 min. If no other anesthetic or opioid is given, the patient becomes responsive in 1 hr or so due to redistribution of the drug (distribution t½ of diazepam is 15 min), but amnesia persists for 2–3 hr and sedation for 6 hr or more. Recovery is further delayed if larger doses are given. BZDs are poor analgesics: an opioid or N2O is usually added if the procedure is painful.

• By themselves, BZDs donor markedly depress respiration, cardiac contractility or BP, but when opioids are also given these functions are considerably compromised. BZDs decrease muscle tone by central action but require neuromuscular blocking drugs for muscle relaxation of surgical grade. They do not provoke postoperative nausea or vomiting. Involuntary movements are not stimulated.

• BZDs are now the preferred drugs for endoscopies, cardiac catheterization, angiographies, conscious sedation during local/regional anesthesia, fracture setting, ECT, etc. They are a frequent component of balanced anesthesia employing several drugs. The anesthetic action of BZDs can be rapidly reversed by flumazenil 0.5–2 mg i.v.

• Diazepam 0.2–0.5 mg/kg by slow undiluted injection in a running i.v. drip: this technique reduces the burning sensation in the vein and incidence of thrombophlebitis. VALIUM, CALMPOSE 10 mg/2 ml inj.

• Lorazepam Three times more potent, slower acting and less irritating than diazepam. It distributes more gradually—awakening may be delayed. Amnesia is more profound. Dose 2–4 mg (0.04 mg/kg) i.v. CALMESE 4 mg/2 ml inj.

• Midazolam This BZD is water soluble, nonirritating to veins, faster and shorter acting and 3 times more potent than diazepam. It is being preferred over diazepam for anesthetic use: 1–2.5 mg i.v. followed by 1/4th supplemental doses. Also used for sedation of intubated and mechanically ventilated patients and in other critical care anesthesia as 0.02–0.1 mg/kg/hr continuous i.v. infusion. FULSED, MEZOLAM, SHORTAL 1 mg/ml, 5 mg/ml inj.

• Midazolam This BZD is water soluble, nonirritating to veins, faster and shorter acting and 3 times more potent than diazepam. It is being preferred over diazepam for anesthetic use: 1–2.5 mg i.v. followed by 1/4th supplemental doses. Also used for sedation of intubated and mechanically ventilated patients and in other critical care anesthesia as 0.02–0.1 mg/kg/hr continuous i.v. infusion. FULSED, MEZOLAM, SHORTAL 1 mg/ml, 5 mg/ml inj.

• Respiration is not depressed, airway reflexes are maintained, muscle tone increases; limb movements occur and eyes may remain open.

• Heart rate, cardiac output and BP are elevated due to sympathetic stimulation. A dose of 1–3 (average 1.5) mg/kg i.v. or 5 mg/kg i.m. produces the above effects within a minute, and recovery starts after 10–15 min, but patient remains amnesic for 1–2 hr. Emergence delirium, hallucinations and involuntary movements occur in upto 50% patients during recovery; but the injection is not painful. Children tolerate the drug better. Ketamine is metabolized in the liver and has an elimination t½ of 3–4 hr.

• Ketamine has been used for operations on the head and neck, in patients who have bled, in asthmatics (relieves bronchospasm), in those who do not want to lose consciousness and for short operations. It is good for repeated use; particularly suitable for burn dressing. Combined with diazepam, it has found use in angiographies, cardiac catheterization and trauma surgery. It may be dangerous for hypertensives, in ischaemic heart disease and in those with raised intracranial pressure (it increases cerebral blood flow), but is good for hypovolemic patients. KETMIN, KETAMAX, ANEKET 50 mg/ml in 2 ml amp, 10 ml vial.

• 3. Fentanyl This short acting (30–50 min) potent opioid analgesic related to pethidine is generally given i.v. at the beginning of painful surgical procedures. Reflex effects of painful stimuli are abolished. It is frequently used to supplement anesthetics in balanced anesthesia. This permits use of lower anesthetic concentrations with better hemodynamic stability. Combined with BZDs, it can obviate the need for inhaled anesthetics for diagnostic, endoscopic, angiographic and other minor procedures in poor risk patients, as well as for burn dressing. Anesthetic awareness with dreadful recall is a risk.

• After i.v. fentanyl (2–4 μg/kg) the patient remains drowsy but conscious and his cooperation can be commanded. Respiratory depression is marked, but predictable; the patient may be encouraged to breathe and assistance

• may be provided. Tone of chest muscles may increase with rapid fentanyl injection: a muscle relaxant is then required to facilitate mechanical ventilation. Heart rate decreases, because fentanyl stimulates vagus. Fall in BP is slight and heart is not sensitized to Adr. Supplemental doses of fentanyl are needed every 30 min or so, but recovery is prolonged after repeated doses.

• Nausea, vomiting and itching often occurs during recovery. The opioid antagonist naloxone can be used to counteract persisting respiratory depression and mental clouding. Fentanyl is also employed as adjunct to spinal and nerve block anesthesia, and to relieve postoperative pain. TROFENTYL, FENT 50 μg/ml in 2 ml amp, 10 ml vial

• In the past fentanyl was combined with the short acting neuroleptic triperidol to produce neurolept analgesia. Since the combination produces marked fall in BP, respiratory depression and occasionally cardiac arrhythmia, it is outmoded.

• Alfentanil, Sentamil and remifentanil are still shorter acting analogues which can be used in place of fentanyl.

• 4. Dexmedetomidine Activation of central α2 adrenergic receptors has been known to cause sedation and analgesia. Clonidine (a selective α2 agonist antihypertensive) given before surgery reduces anesthetic requirement. Dexmedetomidine is a centrally active selective α2A agonist that has been recently introduced for sedating critically ill/ventilated patients in intensive care units. Analgesia and sedation are produced with little respiratory depression, amnesia or an aesthesia. It is administered by i.v. infusion. Side effects are similar to those with clonidine, viz. hypotension, bradycardia and dry mouth.

CONSCIOUS SEDATION

Conscious sedation’ is a monitored state of altered consciousness that can be employed (supplemented with local/regional anesthesia), to carryout diagnostic/short therapeutic/dental procedures in apprehensive subjects or medically compromised patients, in place of general anesthesia. It allows the operative procedure to be performed with minimal physiologic and psychologic stress. In conscious sedation, drugs are used to produce a state of CNS depression (but not unconsciousness), sufficient to withstand the trespass of the procedure, while maintaining communication with the patient, who at the same time responds to commands and is able to maintain a patent airway. The difference between conscious sedation and anesthesia is one of degree. The protective airway and other reflexes are not lost, making it safer. Drugs used for conscious sedation are:

• Diazepam It is injected i.v. in small (1–2 mg) repeated doses or by slow infusion until the desired level of sedation is produced indicated by relaxation, indifference, slurring of speech, ptosis, etc. Further injection is stopped, after which this state lasts for about 1 hour and psychomotor impairment persists for 6–24 hours; an escort is needed to take back the patient home. Flumazenil can be used to reverse the sedation, but repeated doses are needed.

• Midazolam (i.v.) is a shorter acting alternative to diazepam. Oral diazepam administered 1 hr before is also used with the limitation that level of sedation cannot be titrated. The patient remains sedated (not roadworthy) for several hours.

• Propofol Because of brief action, it has to be administered by continuous i.v. infusion regulated by infusion pump throughout the procedure. However, level of sedation can be altered during the procedure and recovery is relatively quick, permitting early discharge of the patient.

• Nitrous oxide The patient is made to breathe 100% oxygen through a nose piece or hood and N2O is added in 10% increments (to a maximum of 50%) till the desired level of sedation assessed by constant verbal contact is obtained. This is maintained till the procedure is performed. Thereafter, N2O is switched off, but 100% O2 is continued for next 5 min. The patient is generally roadworthy in 30–60 min

• Fentanyl Injected i.v. (1–2 μg/kg every 15–30 min), it can be used alone or in combination with midazolam/ propofol

COMPLICATIONS OF GENERAL ANAESTHESIA

A. During anesthesia

• Respiratory depression and hypercarbia. 

• Salivation, respiratory secretions—less now as nonirritant anesthetics are mostly used. 

• Cardiac arrhythmias, asystole. 

• Fall in BP 

• Aspiration of gastric contents: acid pneumonitis. 

• Laryngospasm and asphyxia. 

• Awareness: dreadful perception and recall of events during surgery—by use of light anesthesia + analgesics and muscle relaxants. 

• Delirium, convulsions and other excitatory effects are generally seen with i.e. anesthetics—especially if phenothiazines o hyoscine have been given in premedication. These are suppressed by opioids. 

• Fire and explosion—rare now due to use of non-inflammable agents.

B. After anesthesia

• Nausea and vomiting. 

• Persisting sedation: impaired psychomotor function. 

• Pneumonia, atelectasis.

•  Organ toxicities: liver, kidney damage. 

• Nerve palsies—due to faulty positioning. 

• Emergence delirium. 

• Cognitive defects: prolonged excess cognitive decline has been observed in some patients, especially the elderly, who have undergone general anesthesia, particularly of long duration.

DRUG INTERACTIONS

• Patients on antihypertensives given general anesthetics—BP may fall markedly. 

• Neuroleptics, opioids, clonidine and monoamine oxidase inhibitors potentiate anesthetics. 

• Halothane sensitizes heart to Ard.

•  If a patient on corticosteroids is to be anaesthetized, give 100 mg hydrocortisone intraoperatively because an aesthesia is a stress—can precipitate adrenal insufficiency and cardiovascular collapse. 

• Insulin need of a diabetic is increased during GA: switch over to plain insulin even if the patient is on oral hypoglycemics.

PREANAESTHETIC MEDICATION

Preanesthetic medication refers to the use of drugs before anesthesia to make it more pleasant and safe. The aims are:

• Relief of anxiety and apprehension preoperatively and to facilitate smooth induction. 

• Amnesia for pre- and postoperative events. 

• Supplement analgesic action of anesthetics and potentiate them so that less anesthetic is needed.

• Decrease secretions and vagal stimulation caused by anesthetics. 

• Antiemetic effect extending to the postoperative period. 

• Decrease acidity and volume of gastric juice so that it is less damaging if aspirated.

Different drugs achieve different purposes. One or more drugs may be used in a patient depending on the needs.

• Sedative-antianxiety drugs Benzodiazepine's like diazepam (5–10 mg oral) or lorazepam (2 mg or 0.05 mg/kg a.m. 1 hour before) have become popular drugs for preanesthetic medication because they produce tranquility and smoothen induction; there is loss of recall of perioperative events (especially with lorazepam) with little respiratory depression or accentuation of postoperative vomiting. They counteract CNS toxicity of local anesthetics and are being used along with pethidine/fentanyl for a variety of minor surgical and endoscopic procedures.

• Midazolam is a good amnesic with potent and shorter lasting action; it is also better suited for i.v. injection, due to water solubility

• Promethazine (50 mg a.m.) is an antihistaminic with sedative, antiemetic and anticholinergic properties. It causes little respiratory depression.

• Opioids Morphine (10 mg) or pethidine (50–100 mg), a.m. allay anxiety and apprehension of the operation, produce pre- and postoperative analgesia, smoothen induction, reduce the dose of anesthetic required and supplement poor analgesic (thiopentone, halothane) or weak anesthetics (N2O). Postoperative restlessness is also reduced.

• Disadvantages They depress respiration, interfere with pupillary signs of anesthesia, may cause fall in BP during anesthesia, can precipitate asthma and tend to delay recovery. Other disadvantages are lack of amnesia, flushing, delayed gastric emptying and biliary spasm. Some patients experience dysphoria. Morphine particularly contributes to postoperative constipation, vomiting and urinary retention. Tachycardia sometimes occurs when pethidine has been used

• Use of opioids is now mostly restricted to those having preoperative pain. When indicated, fentanyl is mostly injected i.e. just before induction.

• Anticholinergics Atropine or hyoscine (0.6 mg a.m./i.e.) have been used, primarily to reduce salivary and bronchial secretions. Need for their use is now less compelling because of the increasing employment of non-irritant anesthetics. However, they must be given beforehand when ether is used. The main aim of their use now is to prevent vagal bradycardia and hypotension (which occur reflex due to certain surgical procedures), and prophylaxis of laryngospasm which is precipitated by respiratory secretions. Hyoscine, in addition, produces amnesia and antiemetic effect, but tends to delay recovery. Some patients get disoriented; emergence delirium is more common. They dilate pupils, abolish the pupillary signs and increase chances of gastric reflux by decreasing tone of lower esophageal sphincter (LES). They should not be used in febrile patients. Dryness of mouth in the pre- and postoperative period may be distressing.

• Glycopyrrolate (0.1–0.3 mg i.m.) is a longer acting quaternary atropine substitute. It is a potent antisecretory and intracardiac drug; acts rapidly and is less likely to produce central effects (see Ch. 8).

• Neuroleptics Chlorpromazine (25 mg), triflupromazine (10 mg) or haloperidol (2–4 mg) i.m. are infrequently used in premedication. They allay anxiety, smoothen induction and have antiemetic action. However, they potentiate respiratory depression and hypotension caused by the an aesthetics and delay recovery.

• Involuntary movements and muscle dystonia's can occur, especially in children.

• H2 blockers Patients undergoing prolonged operations, caesarian section and obese patients are at increased risk of gastric regurgitation and aspiration pneumonia. Ranitidine (150 mg) or famotidine (20 mg) given night before and in the morning benefit by raising pH of gastric juice; may also reduce its volume and thus chances of regurgitation. Prevention of stress ulcers is another advantage. They are now routinely used before prolonged surgery

• The proton pump inhibitor omeprazole/ pantoprazole is an alternative.

• Antiemetics Metoclopramide 10–20 mg a.m. preoperatively is effective in reducing postoperative vomiting. By enhancing gastric emptying and tone of LES, it reduces the chances of reflux and its aspiration. Extrapyramidal effects and motor restlessness can occur. Combined use of metoclopramide and H2 blockers is more effective.

• Domperidone is nearly as effective and does not produce extrapyramidal side effects

• After its success in cancer chemotherapy induced vomiting, the selective 5-HT3 blocker Ondansetron (4–8 mg i.e.) has been found highly effective in reducing the incidence of post anesthetic nausea and vomiting as well (see Ch. 47).