New drugs are being developed in anaesthesia, so as to reduce the number of side-effects and to improve patient outcome.
The history of anaesthesia mentions use of non-pharmacological (Cold, Concussion, Carotid compression, Nerve compression, Blood letting and Hypnosis) and pharmacological techniques (use of alcohol, opium, hyoscine, cannabis, cocaine) in ancient and mediaeval times for anaesthesia.
1850 onwards, as anaesthesia became popular, more and more surgeries were carried out under general anaesthesia. At that time, any surgery under general anaesthesia practically mandated a stay in the hospital, often to recover not from the surgery but from the effects of the anaesthesia used during the operation. Patients were woozy for hours, unable to get out of bed, nauseated and vomiting, and even if they wanted to eat, they couldn’t because their digestive systems were paralysed. People receiving anaesthesia were also at risk—a significant number died not from their disease but from the anaesthetic drugs themselves.
With better understanding of surgery, instrumentation and devices like endoscopic equipments, there was an acute need for anaesthesiologists to keep up with this pace. By the mid twentieth century, we had learnt to control mortality figures to a great extent. Obviously the need then was to take care of disturbing morbidities like severe postoperative nausea vomiting, pain, delayed recovery and prolonged hospitalisation. Most of these problems are greatly reduced today thanks to some wonderful drug molecules and better understanding of pharmacokinetics and pharmacodynamics. Day care surgeries today form a single largest group of surgeries all over the world. Most of the new anaesthesia drugs cater to the demands of these surgeries and primarily aim at an early and uneventful recovery. Some of these newer drugs which are available since last decade are reviewed below.
Premedication – Dexmedetomidine
Specific, selective alpha-2 agonist gives excellent anxiolysis and sedation pre-operatively. Its features include:
Induction and maintenance — Xenon
Xenon is Greek for stranger. It was discovered in 1898. Manufactured by fractional distillation of air and costs 2000 times more than N2O. Owing to environmental concerns, there may be no alternative but to use xenon in distant future even if it incurs an increase in cost.
Muscle relaxation – Cisatracurium
Cisatracurium besilate is a non-depolarising neuromuscular blocking agent with an intermediate duration of action, cardiostability, and faster recovery than vecuronium. Hoffman degradation as for atracurium. Compared with atracurium, less laudanosine is produced (this is then cleared renally). Well tolerated; no significant histamine release. Recovery seems NOT to be prolonged with liver or renal dysfunction.
Neuromuscular block Reversal– ORG 25969 / Sugammadex
The results of four ongoing Phase II trials indicate that a new selective relaxant binding agent, a ϒ-cyclodextrin (GC) compound, has the potential to radically change the way neuromuscular blockade is administered and reversed. Depending on the dose of the GC compound, moderate and deep neuromuscular blockade in patients receiving either rocuronium or vecuronium was reversed rapidly and safely, often in less than two minutes. This compound encapsulates muscle relaxant and promotes dissociation from Ach receptor. This is revolutionary, especially when you look at its implications in a difficult airway.
Local anaesthetics – Levobupivacaine, opivacaine
Ropivacaine: A long-acting local anaesthetic with less cardiac and central nervous system toxicity than bupivacaine, and a smaller tendency to cause motor block. It is less lipid soluble than bupivacaine and more selective for A delta and C fibres than motor nerve fibres, giving a greater degree of separation between motor and sensory blockade when used in concentrations below 0.25%. Minimum effective concentration is 0.2%. It is highly protein-bound (94%) with terminal t1/2 111 min. and maximum allowable dose is 2 mg/kg.
Levobupivacaine: The S(-)enantiomer of bupivacaine, with less cardiovascular and central nervous toxicity, a slightly longer duration of sensory block, but otherwise similar to its parent. Compared to bupivacaine it is as potent, with a trend towards longer sensory block; with epidural usage it produces less prolonged motor block; Differentiation not seen with peripheral placement; lethal dose 1.3 to 1.6 times higher; less cardiac effect including less depression of contractility and fewer arrhythmias; higher convulsive doses. It has elimination t1/2 ‘1.3 hours’, and protein binding > 97%. Recommended maximum dosage same as bupivacaine. Observe precautions as for all local anaesthetics.
Analgesics – Remifentanil
A typical μ opiate receptor agonist with ultra-rapid clearance and offset of action, that is independent of excretory organ function. It is 20 to 30 times more potent than alfentanil. Undergoes rapid hydrolysis by nonspecific esterases to almost inactive remifentanil acid. This metabolism is not altered by end-organ function or genetic variablility of specific esteraes (like plasma holinesterease); redistribution is of little consequence. Context-sensitive half time is 3-5min regardless of infusion duration. Full recovery of respiratory function occurs in ‘10 to 15 min’. Given by continuous infusion, it reduces induction dose of thiopentone by 30%; Lowers the MAC of volatile agents. Supplement with N2O, propofol or isoflurane.
New formulations of known drugs are being developed to either cut down their drawbacks or to improve their efficacy. Some of the drugs which are being worked on are Propofol, Midazolam and local anaesthetics. Drugs for hypnosis and sedation may have problems in the form of extended duration of action, unwanted cardiovascular and respiratory effects and issues with their vehicle including pain on injection, hyperlipidaemia and vulnerability to bacterial growth. Three main strategies are being employed to improve these drugs.
Reformulation: To overcome issues of formulation vehicle as in Propofol. As not a single formulation is problem free, we have multiple formulations claiming advantages. Standard- Propofol 1% and 2% in 10% soya oil as long chain triglycerides
— Addition of EDTA or sodium sulphite does not support bacterial growth but can cause allergic reaction or yellowish discolouration (more with sulphite).
— An emulsion containing long and medium chain triglycerides reduces incidence of pain on injection
— Propofol 6% in 10% soya oil reduces hyperlipidaemia
— Propofol 1% in 5% soya oil with or without EDTA – pain on injection ↑4 times
— Propofol in cyclodextrin based formulation
Pro-drug approaches: Focused mainly on propofol to achieve good water solubility. The inherent problem is of slow onset and offset of action as they need to be rapidly metabolised to liberate the active compound. e.g. Methyl phosphate pro-drug of propofol, Aquavan→ The phase III trial have been halted due to high level of adverse events.
The soft drug approach: This has been previously used in remifentanil, propanidid and mivacurium. The aim is to produce metabolically-labile agent which is hydrolysed rapidly by blood and tissue esterases so as to have rapid recovery profile. TD-4756, esters of barbiturates(Aryx) and benzodiazepine ligands(CeNeS) are some examples of such compounds.
Novel clinical uses of known drugs:
The rapid rise and fall of a few new drugs: Rapacuronium, Cleofol and Rofecoxib
Rapacuronium bromide: FDA approval for clinical use of this non-depolarising muscle relaxant came on August 8, 1999. The drug was developed as a substitute for succinylcholine in the setting of a rapid sequence induction. Clinical experience with this drug showed increased incidence of severe, life-threatening bronchospasm in children with rapid injection. Nineteen months later, on March 27, 2001, the manufacturer withdrew the drug from the market voluntarily.
Rofecoxib: This selective COX-2 inhibitor was withdrawn worldwide in October 2004 after the reports of cardiovascular risks were published.
Cleofol®: Clear propofol promoted as ‘vegetarian’ formulation of propofol fell in disrepute after reporting of very painful injection and increased incidence of severe thrombophlebitis.
The above list is obviously not comprehensive. We are still looking for an ideal local, intravenous, inhalational anaesthetic, a safe and a very effective pain killer.
This disproves the concern that use of old / less expensive drugs may compromise patient outcome and satisfaction and that newer and costlier drugs are always safer. Some suggest that national societies should create guidelines for cost-beneficial practice. Others favour physician autonomy in drug selection. There will be great reluctance to deny patients pharmacologically superior drugs based on cost alone, especially since drugs are such a small portion of the total surgical costs. The aim should be to manage and modify drug practice in anaesthesia depending on changing needs to provide value-based care.