LECTURE 2,

GENERAL ANAESTHETICS

Intravenous agents
Ketamine Propofol Thiopental Etomidate midazolam

Intravenous anaesthetics
Intravenous anaesthetics may be used either to induce anaesthesia or for maintenance of anaesthesia throughout surgery. Intravenous anaesthetics nearly all produce their effect in one arm-brain circulation time

 They are contraindicated if the anaesthetist is not confident of being able to maintain the airway (e.g. in the presence of a tumor in the pharynx or larynx) Extreme care is required in surgery of the mouth, pharynx, or larynx and in patients with acute circulatory failure (shock) or fixed cardiac output.

 To facilitate tracheal intubation, induction is usually followed by a neuromuscular blocking drug or short-acting opioid. The dose of all intravenous anesthetic drugs should be titrated to effect

 The dose and rate of administration should be reduced in the Elderly Those with hypovolaemia In cardiovascular disease Premedicated patients

PHARMACOLOGICAL EFFECTS
3 main neurophysiologic process takes place Unconsciousness Loss of response to pain stimuli Loss of reflexes(both motor and autonomic)

 At supra anaesthetic doses all can cause death by loss of cardiovascular reflexes and respiratory paralysis At cellular level these agents affect synaptic transmission and neuronal excitability Main targets of action of these agents are the cortex,thalamus,hippocampus,midbrain and spinal cord

 All agents have similar neurophysiologic profiles but differ in pharmacokinetics and toxicology Most cause cardiovascular depression by effects on myocardium and blood vessels

Total intravenous anesthesia

This is a technique in which major surgery is carried out with all drugs given intravenously. Respiration can be spontaneous, or controlled with oxygen-enriched air. Neuromuscular blocking drugs can be used to provide relaxation and prevent reflex muscle movements

 The main problem to be overcome is the assessment of depth of anesthesia. Target Control Infusion (TCI) systems can be used to titrate intravenous anaesthetic infusions to predicted plasma-drug concentrations in ventilated adult patients.

Drugs used for intravenous anesthesia

Propofol
Is a 2,6 diisopropylphenol Most popular GA It the agent of choice in ambulatory surgery Rate of onset is similar to barbiturates but recovery is rapid Postoperatively patients feel better because of reduction of nausea and vomiting

Propofol
the most widely used intravenous anesthetic It was introduced in 1983 can be used for induction or maintenance of anesthesia in adults and children, but it is not recommended in neonates. Propofol is associated with rapid recovery and less hangover effect than other intravenous anaesthetics

 Propofol has a rapid onset(30 seconds) Metabolism in the liver Excretion in the urine as glucoronide and sulfate conjugates Rapid metabolism, with a half life of 2-4mins

 Cardiovascular effects may cause bradycardia and hypotension Is good for day care surgery, has quick recovery Has less nausea and vomitting as compared to inhaled agents

 It causes pain on intravenous injection, which can be reduced by intravenous lidocaine. Significant extraneous muscle movements may occur. Rarely, convulsions, anaphylaxis, and delayed recovery from anesthesia can occur after Propofol administration the onset of convulsions can be delayed

 Propofol is associated with bradycardia Intravenous administration of an antimuscarinic drug is used to treat this. In adults, Propofol can be used for sedation during diagnostic procedures or in intensive care. It can induce Propofol infusion syndrome when administered at high doses for prolonged periods of time

 It is contraindicated in children under 17 years receiving intensive care because of the risk of potentially fatal effects including metabolic acidosis cardiac failure rhabdomyolysis, hyperlipidaemia, hepatomegaly

 Breast-feeding: present in milk but amount probably too small to be harmful

Side-effects
hypotension tachycardia, flushing; transient apnea, hyperventilation coughing,

SIDE EFFECTS..
hiccup during induction headache less commonly thrombosis phlebitis rarely arrhythmia headache vertigo, shivering euphoria;

very rarely pancreatitis, pulmonary edema sexual disinhibition, discoloration of urine

serious and sometimes fatal sideeffects

reported with prolonged infusion of doses exceeding 5 mg/kg/hour metabolic acidosis, rhabdomyolysis hyperkalaemia, cardiac failure dystonia dyskinesia

DOSE
Dose Induction of anaesthesia using 0.5% or 1% injection, by intravenous injection or infusion, ADULT under 55 years, 1.5-2.5 mg/kg at rate of 20-40 mg every 10 seconds until response;

Thiopental sodium (thiopentone sodium

is a barbiturate that is used for induction of anesthesia Has high lipid solubility and this accounts for high speed of onset Has short duration,(5mins) due to redistribution Reduces intracranial pressure Narrow margin between anaesthetic dose and cardiovascular depression

 has no analgesic properties. Induction is generally smooth and rapid, but dose-related cardiovascular and respiratory depression can occur.

 Awakening from a moderate dose of thiopental is rapid because the drug redistributes into other tissues, particularly fat. However, metabolism is slow and sedative effects can persist for 24 hours Repeated doses have a cumulative effect and recovery is much slower.

 Thiopental is not used for maintenance but only for induction accidental injection into the area around the vein or artery causes pain, local tissue necrosis

INDICATIONS
induction of general anesthesia anesthesia of short duration; reduction of raised intracranial pressure if ventilation controlled status epilepticus

Dose
Induction of general anaesthesia, by slow intravenous injection usually as a 2.5% (25 mg/mL) solution, ADULT over 18 years, fit and premedicated, initially 100 150 mg (reduced in elderly or debilitated) over 10 15 seconds (longer in elderly or debilitated), followed by further quantity if necessary according to response after 30 60 seconds; or up to 4 mg/kg (max 500 mg

 CHILD 1 month 18 years initially up to 4 mg/kg, then 1 mg/kg repeated as necessary (max total dose 7 mg/kg)

 Raised intracranial pressure, by slow intravenous injection, 1.5-3 mg/kg repeated as required.

 Status epilepticus (only if other measures fail), by slow intravenous injection as a 2.5% (25 mg/mL) solution, ADULT over 18 years, 75 125 mg as a single dose CHILD 1 month 18 years, initially up to 4 mg/kg by slow intravenous injection, then up to 8 mg/kg/hour by continuous intravenous infusion, adjusted according to response.

Etomidate
is an intravenous agent associated with rapid recovery without hangover effect. It causes less hypotension than thiopental and Propofol during induction. Etomidate produces a high incidence of extraneous muscle movement, which can be minimized by an opioid analgesic or a shortacting benzodiazepine given just before induction A wide margin of safety between anesthetic dose and dose that can cause cvs depression

 Pain on injection can be reduced by injecting into a larger vein or by giving an opioid analgesic just before induction. Etomidate suppresses adrenocortical function, particularly during continuous administration, and it should not be used for maintenance of anesthesia.

 More rapidly metabolized than thiopental Causes less hypotension than Propofol and thiopental

 Indications: induction of anaesthesia Cautions: avoid in acute porphyria

Hepatic impairment: reduce dose in liver cirrhosis Pregnancy: depresses neonatal respiration if used during delivery

 Breastfeeding: avoid for 24 hours after administration Side-effects: coughing, hiccups, shivering, allergic reaction (including Bronchospasm and anaphylaxis); respiratory depression, arrhythmia, and convulsions .

Ketamine
Is an analogue of phencyclidine Action is mainly through inhibition of NMDAtype glutamate receptors Onset is slower (1-2 mins) Is a powerful analgesic

Ketamine
It has good analgesic properties and subanaesthetic dosage and is used under specialist supervision in palliative care for pain that is unresponsive to standard treatment i.v dosing gives effect in 1-2mins Produces dissociative anaesthesia-which means marked sensory loss ,amnesia,analgesia without loss of consciousness

 Ketamine increases both blood pressure and heart rate Respiratory effects are not manifest at therapeutic doses Makes it safe However it causes raise in intracranial pressure so should be avoided in patient at risk

 Ketamine causes less hypotension than thiopental and Propofol during induction. It is used mainly for paediatric anaesthesia, particularly when repeated administration is required (such as for serial burns dressings)

 recovery is relatively slow and there is a high incidence of extraneous muscle movements The main disadvantage of Ketamine is the high incidence of hallucinations, nightmares, and other transient psychotic effects

 Are reduced by a benzodiazepine such as diazepam or midazolam. Ketamine also has abuse potential and can itself cause dependence.

midazolam
Is a benzodiazepine Is slower in onset as compared to others Causes less respiratory and CVS depression Used as a preoperative sedative Used in procedures like endoscopy where full anesthesia is not required Overdose can be reversed by flumazenil

Properties of intravenous anesthetic agents

Drug Speed of induction and recovery Fast onset, very fast recovery Main unwanted effect(s) Notes Propofol Cardiovascular and respiratory depression Rapidly metabolised Possible to use as continous infusion Causes pain at injection site Largely replaced by propofol Causes pain at injection site Risk of precipitating porphyria in susceptible patients Less cardiovascular and respiratory depression than with thiopental Causes pain at injection site Produces good analgesia and amnesia

Thiopental

Fast (accumulation occurs, giving slow recovery) Hangover Fast onset, fairly last recovery

Cardiovascular and respiratory depression

Etomidate

Excitatory effects during induction and recovery Adrenocortical suppression Psychotomimetic effects following recovery Postoperative nausea, vomiting and salivation Raised intracranial pressure

Ketamine

Slow onset, after effects common during recovery

Midazolam

Slower than other agents

Little respiratory or cardiovascular depression

Inhalational anaesthetics
Inhalational anaesthetics may be gases or volatile liquids Gaseous anaesthetics require suitable equipment for storage and administration. They may be supplied via hospital pipelines or from metal cylinders.

 Volatile liquid anaesthetics are administered using calibrated vasoprisers, using air, oxygen, or nitrous oxide oxygen mixtures as the carrier gas. To prevent hypoxia, the inspired gas mixture should contain a minimum of 25% oxygen at all times Higher concentrations of oxygen (greater than 30%) are usually required during inhalational anesthesia when nitrous oxide is being administered.

Volatile liquid anaesthetics

Volatile liquid anaesthetics can be used for induction and maintenance of anaesthesia, and following an induction with an intravenous anaesthetic.

 Volatile liquid anaesthetics can trigger malignant hyperthermia and are contraindicated in those susceptible to malignant hyperthermia. They can increase cerebrospinal pressure and should be used with caution in those with raised intracranial pressure

 They may also cause hepatotoxicity in those sensitized to halogenated anaesthetics halothane has been associated with severe hepatotoxicity

Isoflurane
is a volatile liquid anesthetic. Heart rhythm is generally stable during isoflurane anesthesia, but heart-rate can rise, particularly in younger patients May cause hypotension and is a coronary vasodilator May exacerbate cardiac ischemia in patient with coronary disease

 systemic arterial pressure can fall and cardiac output can decrease owing to a decrease in vascular resistance. Muscle relaxation occurs and the effects of muscle relaxant drugs are potentiated.

 Isoflurane can irritate mucus membranes causing cough, breath-holding, and larynospasm.

ISOFLURANE
Dose: Induction of anaesthesia, using specifically calibrated vaporizer, in oxygen or nitrous oxideoxygen, increased gradually from 0.5 3% Maintenance of anaesthesia, using specifically calibrated vaporizer, 1 2.5% in nitrous oxide oxygen; an additional 0.5 1 % may be required when given with oxygen alone; caesarean section, 0.5 0.75% in nitrous oxide-oxygen.

ISOFLURANE
Pregnancy: depresses neonatal respiration if used during delivery Breastfeeding: manufacturer advises avoid withhold for at least 12 hours after termination of anaesthesia.

ISOFLURANE
Pregnancy: depresses neonatal respiration if used during delivery. Side-effects urinary retention, leucopenia, agitation in children; dystonia, rash and seizures also reported.

Desflurane
is a rapid acting volatile liquid anesthetic Is similar to isoflurane but faster onset and recovery Has about one-fifth the potency of isoflurane. Emergence and recovery from anaesthesia are particularly rapid because of its low solubility. Useful in day care surgery

 Desflurane is not recommended for induction of anaesthesia as it is irritant to the upper respiratory tract; cough, breath-holding, apnoea, laryngospasm, and increased secretions can occur.

Sevoflurane
is a rapid acting volatile liquid anesthetic and is more potent than desflurane. Emergence and recovery are particularly rapid, but slower than desflurane. Sevoflurane is non-irritant and is therefore often used for inhalational induction of anesthesia it has little effect on heart rhythm compared with other volatile liquid anaesthetics

 Sevoflurane can interact with carbondioxde absorbents to form compound A, a potentially nephrotoxic vinyl ether.

Halothane
is a volatile liquid anesthetic that has largely been superseded by newer agents it is occasionally used for inhalation induction of anaesthesia with careful monitoring for cardio respiratory depression and arrhythmias. It is potent, induction is smooth, and the vapor is non-irritant and seldom induces coughing or breath holding.

 Halothane hepatotoxicity Severe hepatotoxicity can follow halothane anesthesia. It occurs more frequently after repeated exposure to halothane and has a high mortality.

 The risk of severe hepatotoxicity appears to be increased by repeated exposures within a short time interval, but even after a long interval (sometimes of several years), susceptible patients have been reported to develop jaundice.

 Since there is no reliable way of identifying susceptible patients, the following precautions are recommended before the use of halothane A careful anaesthetic history should be taken to determine previous exposure and previous reactions to halothane

 Repeated exposure to halothane within a period of at least 3 months should be avoided unless there are overriding clinical circumstances A history of unexplained jaundice or pyrexia in a patient following exposure to halothane is an absolute contraindication to its future use in that patient.

 Pregnancy: depresses neonatal respiration if used during delivery. Breastfeeding: present in milk withhold for 24 hours after termination of anaethesia Halothane relaxes the uterus and may give rise to postpartum bleeding limiting use in obstetrics

 Dose: Induction of anesthesia, using specifically calibrated vaporizer, in oxygen or nitrous oxideoxygen, ADULT and CHILD over 1 month, initially 0.5% then increased gradually according to response to 2-4% Maintenance of anesthesia, using specifically calibrated vaporizer, in oxygen, oxygen-air, or nitrous oxide-oxygen, ADULT and CHILD over 1 month, 0.5 2%

Nitrous Oxide
Nitrous oxide is used for maintenance of anesthesia and, in sub-anaesthetic concentrations, for analgesia. For anesthesia, nitrous oxide is commonly used in a concentration of 50 to 66% of oxygen as part of a balanced technique in association with other inhalational or intravenous agents

 Nitrous oxide is unsatisfactory as a sole anaesthetic owing to lack of potency, but is useful as part of a combination of drugs since it allows a significant reduction in dosage. Has rapid onset of action and an effective analgesic

 Nitrous oxide may have deleterious effect if used in patients with an air-containing closed space since nitrous oxide diffuses into such a space with a resulting increase in pressure. This effect may be dangerous in the presence of a pneumothorax, which may enlarge to compromise respiration, or in the presence of intracranial air after head injury.

 Hypoxia can occur immediately following the administration of nitrous oxide; additional oxygen should always be given for several minutes after stopping the flow of nitrous oxide.

 Exposure of patients to nitrous oxide for prolonged periods, either by continuous or by intermittent administration, may result in megaloblastic anemia It interferences with the action of vitamin B12 neurological toxic effects can occur without preceding overt hematological changes.

 Exposure of theatre staff to nitrous oxide should be minimized. Depression of white cell formation may also occur

 Assessment of plasma-vitamin B12 concentration should be considered in those at risk of deficiency, Nitrous oxide should not be given continuously for longer than 24 hours or more frequently than every 4 days without close supervision and hematological monitoring.

 For analgesia (without loss of consciousness), a mixture of nitrous oxide and oxygen containing 50% of each gas is used. Self-administration using a demand valve is popular in obstetric practice, for changing painful dressings, as an aid to postoperative physiotherapy, and in emergency ambulances.

 Contraindications: susceptibility to malignant hyperthermia. Pregnancy: depresses neonatal respiration if used during delivery. Dose: Maintenance of light anesthesia (using suitable anesthetic apparatus), up to 66% in oxygen. Analgesia, up to 50% in oxygen, according to the patients needs.

enflurane
Is halogenated anesthetic like halothane Has moderate speed of action Is less metabolized ,less risk of toxicity Has faster recovery than halothane Can cause seizures Is not used nowadays

ether
Obsolete Is easy to administer and control Has slow onset and recovery Causes vomiting and nausea Highly explosive and irritant

Characteristics of inhalation anesthetics

Drug Blood: Gas Oil: Gas Minimum alveolar concentration Induction/ recovery Main adverse effects and disadvantages Notes

Nitrous oxide

0.5

1.4

Fast

Few adverse effects, risk of anaemia (with prolonged or repeated use), accumulation in gaseous activities

Good analgesic effect, low potency precludes use as sole anesthetic agent normally combined with other inhalation agents

Isoflurane

1.4

91

1.2

Medium

Few adverse effects, possible risk of coronary ischemia in susceptible patients

Respiratory tract irritation, cough, bronchospasm

Widely used, has replaced halothane

Used for day-case surgery because of fast onset and recovery (comparable with nitrous oxide) Similar to desflurane Little used nowadays, significant metabolism to trifluoracetate

Desflurane

0.4

23

6.1

Fast

Sevoflurane Halothane

0.6 2.4

53 220

2.1 0.8

Fast Medium

Few reported, theoretical risk of toxicity owing to flouride Hypotension, cardiac arrhythmias, hepatotoxicity (with repeated use), malignant hyperthermia (rare)

Enflurane
Ether

1.9
12.0

98
65

0.7
1.9

Medium
Slow

Risk and convulsions (slight), malignant hyperthermia (rare)

Respiratory irritation, Nausea and vomiting, explosion risk

Has declined in use, May induce seizures

Now obsolete, except where modern facilities are lacking