General anaesthetics 22January2013 Batch17Year2 Pharmacology

Learning objectives: 1.Definition of general anaesthesia 2.Components of general anaesthesia 3.Guedel’s clinical stages of anaesthesia 4.Balanced anaesthesia 5.Mechanism of action of anaesthetics 6.Inhalation anaesthetics : 7.MAC 8.Intravenous anaesthetics

What is general anaesthesia? General anaesthesia is a state of reversible loss of conciousness produced by general anaesthetics (intravenous / inhalation) and composed of:  Amnesia  Analgesia  Inhibition of sensory and autonomic reflexes  Skeletal muscle relaxation.

Guedel’s clinical stages of anaesthesia Observed the various depths of (anaesthesia) unconciousness nd associated bodily changes when ether alone is inhaled from the start until surgical anaesthesia is achieved. Stage 1. analgesia Stage 2. excitement Stage 3. surgical anaesthesia (plane 1—4) Stage 4. Overdose These stages of anaesthesia are rarely seen nowaday because of modern potent anaesthetic agents.

Phases of anaesthesia Induction : induce loss of conciousness using intravenous anaesthetics commonly or inhalation anaesthetics in some patients like children. Maintenance : maintain state of unconciousness using inhalation anaesthetics. Recovery : of conciousness after stopping inhalation anaesthetics. Total intravenous anaesthesia (TIVA) : both induction and maintenance of anaesthesia with intravenous anaesthetic propofol and recovery by stopping infusion.

Balanced anaesthesia Anaesthesia IV or inhalation anaesthetics Analgesia Opoid analgesics Skeletal muscle relaxation Muscle relaxant Benefit of balanced anaesthesia : rapid induction and recovery if compare with using inhalation anaesthetics alone for the whole course of anaesthesia. Disadvantage : polypharmacy

Pharmacodynamics Mechanism of action of general anaesthetics Depress spontaneous and evoked activity of neurones in many regions of the brain.  GABA A receptor-chloride channel  Antagonism of the action of the excitatory neurotransmitter glutamic acid on the N-methyl-D-aspartate(NMDA) receptor Dose response characteristics: Concept of minimum alveolar concentration (MAC) Alveolar concentration of anaesthetics that results in immobility In 50% of patients when exposed to a standard surgical stimulus.

Inhalation anaesthetics  Ether  Nitrous oxide  chloroform  Halogenated inhalation anaesthetics Halothane methoxyflurane Isoflurane Enflurane Sevoflurane desflurane

Pharmacokinetics of inhaled anaesthetics Uptake and distribution of inhaled anaesthetics depend on 1.Solubility properties of the anaesthetic 2.Anaesthetic concentration in inspired air 3.Pulmonary ventilation 4.Pulmonary blood flow 5.Arterio-venous concentration gradient

The concentration of an inhaled anaesthetic in a mixture of gas is proportional to its partial pressure. Achievement of brain concentration of inhaled anaesthetic requires transfer of anaesthetic from alveolar air  blood  brain Alveolar airbloodbrain

Inhalation anaesthetics must pass through many barriers between the anaesthesia machine and the brain.

1. Solubility of inhalation anaesthetics Blood : gas partion coefficient is used as index of solubility. The more soluble the anaesthetic is in blood, the longer it takes time to achieve anaesthetic tension in the brain. Inhalation anaesthetics Blood: gas partition coefficient Nitrous oxide0.47 Desflurane0.42 Sevoflurane0.69 Isoflurane1.40 Enflurane1.80 halothane2.30

2. Anaesthetic concentration in the inspired air Concentration of an inhaled anaesthetic in the inspired gas mixture has direct effects on  tension in alveolar gas  tension in arterial blood According to the Fick’s law Concentration in inspired gas Tension in alveolar gas Tension in arterial blood

3. Pulmonary ventilation rate and depth of ventilation  Rate of rise of anaesthetic gas tension in blood ( direct relation between ventilation and anaesthetic gas tension in blood) 4. Pulmonary blood flow Increased blood flow /increased cardiac output  washed away anaesthetics from alveoli  longer time taken to raise anaesthetic gas tension in the alveoli 5. Arterio-venous concentration gradient The wider the gap, the slower the onset of anaesthesia

Elimination Recovery from anaesthesia depends on rate of elimination of anaesthetics from the brain. Simply it is the reverse process that had happened during induction. Brain  venous blood  heart  lungs  exhaled Factors governing elimination of anaesthetics from the body 1.Blood:gas partition coefficient of anaesthetics (the less,the faster) 2.Pulmonary blood flow 3.Ventilation 4.Tissue solubility of anaesthetics Therefore, Nitrousoxide,desflurane and sevoflurane have faster recovery than isoflurane and halothane.

Effects of inhaled anaesthetics on organs and system 1. CVS  Mean BP -- Dose related drop in direct proportion to alveolar concentration  HR  Bradycardia with halothane  Increase with desflurane and isoflurane  Myocardial oxygen consumption  decreased

2. Respiration  Dose dependent decreased in tidal volume and increased respiratory rate  Decreased ventilatory response to hypoxia and hypercapnoea  Depress mucociliary function  Varying degree of bronchodilatory effect 3. Brain  Decreased cerebral metabolic rate  Increased cerebral blood flow  Seizure-like EEG activity with sevoflurane

4. Kidney  Concentration related decreased in GFR 5. Liver  Concentration-dependent decreased in hepatic blood flow  Post-halothane hepatitis 6. Uterine smooth muscle All inhalation anaesthetics are potent uterine smooth muscle relaxants except nitrous oxide

Toxicity  Hepatotoxicity – with halothane  Nephrotoxicity – metabolism of methoxyflurane,enflurane, sevoflurane have formation of fluoride ions. But methoxyflurane only has proof of renal dysfunction and is not used now.  Malignant hyperthermia (massive release of calcium from sarco plasmic reticulum of skeletal muscle cells Autosomal dominant genetic disorder of skeletal muscle Triggered by exposure to inhalation anaesthetics, succinylcholine. Important cause of anaesthetic morbidity and mortality. Specific drug -- dantrolene

Nitrous oxide Only anaesthetic gas Stored in cylinder Weak anaesthetic but good analgesic Second gas effect during induction Diffusion hypoxia during recovery Bone marrow suppression on long term use Useful in  Balanced anaesthesia  Dental anaesthesia  obstetric analgesia as entonox

Intravenous anaesthetic agents 1.Barbiturates – thiopentone sodium 2.Propofol (2,6-diisopropylphenol) 3.Etomidate 4.Ketamine 5.Benzodiazepines All of the IV anaesthetics readily cross the blood brain barrier because of high lipid solubility. Rapid induction and recovery after single bolus dose. Dose dependent cardiovascular depression. Cerebral blood flow and oxygen consumption is reduced except with ketamine.

All are metabolized in the liver and excreted through kidney. Thiopentone  Oldest iv anaesthetic  Sulpha containing barbiturate  Highly alkaline solution  irritant to tisssue  Rapid and smooth onset and recovery of anaesthesia  Antianalgesic effect  Potent cardiovascular and respiratory depressant  Metabolized in the liver to inactive metabolite  Cumulative effect on repeated dose and infusion  Used for induction of anaesthesia

Propofol  Commonly used nowaday. As IV bolus and infusion in both OT and ICU.  Milky-white solution prepared as emulsion using soya bean oil and egg phosphatide.  Pain along the vein on injection.  Rapid onset and very smooth recovery (no hang over effect like thiopentone)  Antiemetic effect  No analgesic effect  Potent CVS and respiratory depressent effect  Used for induction, maintaince and sedation in ICU

Etomidate  Another milky-white solution  Used to induce anaesthesia in patients with hypotension because of its minimal cardiovascular and respiratory depression.  No analgesic effect  Pain on injection  Myoclonic activity  Postoperative nausea and vomitting  Suppression of steroidogenesis  adrenocortical suppression

Ketamine  Produces dissociative state(catatonia, amnesia, analgesia +/-hypnosis)  Rather late onset and recovery.  Emergence hallucination  delirium(not suitable for adult patients)  Good analgesic effect  Dose related cardiovascular stimulation.  Bronchodilation  Increased upper airway secretion.  CNS – cerebral blood flow,ICP and O2 consumption are increased.  Can be given both IM and IV.

Benzodiazepine  Slower onset of action  Lesser CVS depression if compared to thiopentone and propofol  Good anxiolytic, amnesic and sedative effect  Skeletal muscle relaxation  Can be given IV, IM except diazepam.  Useful in both induction, preanaesthetic medication and sedation  under local anaesthesia.  Flumazenil is the antagonist used in benzodiazepine overdose.