New Drugs in Anaesthesia

Introduction

What new form will a "routine" anaesthetic take in the next few years?   In this lecture we look at a few fairly recent arrivals, defining their appropriate role in modern anaesthesia, and looking at novel clinical applications.  This is also a "wish" list of forthcoming attractions, that we believe will revolutionise anaesthesia, making the experience safer and more pleasant for the patient, as well as making the anaesthesia provider look incredibly proficient.  Not all the drugs listed here will make their way into clinical practice, some just won't make the grade and others are just too far fetched to have a genuine cost-benefit advantage.

We have presented an "executive summary" on this page which is meant to tempt you into learning more.  As will all knowledge in anaesthesia, we must always study the basics first, so the drugs are hyperlinked back to pages that contain a more detailed explanation of the drug as well as other similar drugs in the same class.

Premedication

Induction

Muscle Relaxation

Anaesthetic maintenance

Analgesia

Regional anaesthesia

Fluid management and resuscitation

 

Remifentanil
Executive Summary

Opioid drugs in anaesthesia Top of Page
Clinical Potential:
A typical mu opiate receptor agonist with ultra-rapid clearance and offset of action, that is independent of excretory organ function
Pharmacodynamics:
Pharmacodynamic variability occurs, as for all opioids (So titrate to effect). 20 to 30 times more potent than alfentanil.
Pharmacokinetics:
Rapid hydrolysis by nonspecific esterases to almost inactive remifentanil acid by nonspecific esterases; This metabolism is not altered by end organ function or genetic variablility of specific esteraes (like plasma cholinesterease); redistribution is of little consequence. Age and volume of distribution have minor effects on clearance; huge doses are rapidly cleared. t 1/2 K e0 is 1.0-1.5 min. Context-sensitive half time is 3-5min regardless of infusion duration! Full recovery of respiratory function occurs in '10 to 15 min'.
Dosage:
Given by continuous infusion (steady state in 10 min!) to avoid muscle rigidity with bolus dose
Co-Induction: 0.5-1 g/kg/min
Anaesthesia: 0.25 - 0.4 g/kg/min combined with an hypnotic
(propofol > 80mg/Kg/min or >0.3 MAC of Volatile agent)
Analgesia: 0.05 - 0.1 g/kg/min combined with a benzodiazepine (midazolam 2-6mg)
Adverse Effects:
1.  If you don't anticipate and prevent postoperative pain, this will be severe and difficult to control.
2.  Bradycardia may occur.
3.  Dose-dependent respiratory depression occurs.
4.  Muscle rigidity occurs.
5.  NOT for epidural use as the lypholised poweder contains 15mg of glycine
Drug Interactions:
1. Remifentanil reduces induction dose of thiopentone by 30%;
2. Lowers the MAC of volatiles. Supplement with N 2 O, propofol, or isoflurane - remifentanil given alone does NOT suppress awareness.
Of Note:
Is there merit in using this agent if we then have to give other analgesics (eg. morphine) for post-operative pain?

 

Ropivacaine
Executive Summary

Local anaesthetic agents Top of Page
Clinical Potential:
A long-acting local anaesthetic with less cardiac and central nervous system toxicity than bupivacaine, and a smaller tendency to cause motor block.
Pharmacodynamics:
Less lipid soluble than bupivacaine; 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%.  Less arrhythmogenic than bupivacaine.
Pharmacokinetics:
Highly protein-bound (94%); Inactivated by Cytochrome P450 (hydroxylation); Terminal t 1/2 111 min; V Dss 59+-7 L (adults).
Dosage:
Minimum effective concentration 0.2%; Recommended maximum dosage
20-40mg for bolus dose in an epidural; 28mg/hr (14mls/hr of 0.2% solution) for labour epidural infusion; and 20-30mg every 30 or more minutes for epidural bolus doses. 
Adverse Effects:
As for other local anaesthetics such as bupivacaine: hypotension, nausea; and infrequently vomiting, bradycardia, urinary retention.
Arrhythmias and seizures will occur with overdose.
Drug Interactions:
Unclear. Do NOT use with other local anaesthetics.
Of Note:
1. Combination with adrenaline not available.
2. Caution with liver disease.
3. Not in children under 12 yr.
4. No experience with infusions over 24 hr!
5. NOT (yet) approved for spinal anaesthesia.

 

Cisatracurium
Executive Summary

Non depolarising muscle relaxants Top of Page
Clinical Potential:
Cisatracurium besilate is a non-depolarising neuromuscular blocking agent with an intermediate duration of action, cardiostability, and faster recovery than vecuronium.
Pharmacodynamics:
ED 95 ~ 0.05mg/kg; 2* ED 95 produces 99+% twitch suppression in 4.6 to 5.8 min (delayed with renal failure and age, sooner with liver dysfunction). Clinical duration with 2*ED 95 is 33-45 min; anticholinesterases aid recovery once started. Haemodynamically stable.
Pharmacokinetics:
V ss 0.11 to 0.16 L/kg; ('uni-compartment') Hoffman degradation as for atracurium. Clearance is 0.27 to 0.34 L/h/kg. t 1/2 beta 22 to 35 min. Compared with atracurium, less laudanosine is produced (this is then cleared renally).
Dosage:
Good intubating conditions in >= 89% of patients after 120 s with 3*ED 95 ; similar to atracurium.
Intra-op infuse 1.2 to 1.5 g/kg/min to maintain 95% block (adults); in ICU higher doses have been required.
Adverse Effects:
Appear infrequent (hypotension, bradycardia or bronchospasm decidedly uncommon).
Drug Interactions:
Unknown.
Of Note:
Well tolerated; NO significant histamine appears to be released. Recovery seems NOT to be prolonged with liver or renal dysfunction. Does NOT compete with suxamethonium for rapid sequence intubation.

 

Celecoxib
Executive Summary

Top of Page
Clinical Potential:
A selective COX-2 inhibitor of great merit for management of pain due to chronic inflammation in rheumatoid or osteo-arthritis, but its use in acute pain is unclear at best!
Pharmacodynamics:
375 times more selective for COX-2 than COX-1; therefore causes less gastric damage and possibly less renal dysfunction.
Pharmacokinetics:
Highly protein bound (97%); V ss ~ 400 L (adults). Extensive liver metabolism by CYP 2C9. t 1/2 11 hours.
Dosage:
Fifty to 200 mg BD (similar efficacy to naproxen 500mg BD). After dental extraction 100 - 400 mg similar to aspirin 650mg, 200mg less effective than ibuprofen 400mg.
Adverse Effects:
More renal side-effects than placebo. GIT intolerance is similar to placebo.
Allergy may occur if there is a history of sulfonamide allergy.
Drug Interactions:
Potential for interaction with CYP2C9 inhibitors (?), and WARFARIN (? inhibition of 2C9).
Of Note:
Who knows whether this is of use in the post-operative period? We suspect its use will be limited!

 

Dopexamine
Executive Summary

Top of Page
Clinical Potential:
Touted as an agent for splanchnic resuscitation, the role of this controversial drug remains unclear! It may have a role in acute management of heart failure.
Pharmacodynamics:
Agonist at DA1 and beta-2 adrenergic receptors. No direct effect on beta-1 or alpha receptors, but may inhibit neuronal noradrenaline re-uptake! Causes vasodilatation, natriuresis (at least in some studies), however splanchnic ischaemia has been reported when combined with dobutamine. In contrast, protective effects on the liver have been reported in a porcine model of sepsis. The beta-2 effect probably accounts for positive cardiac inotropic activity. Complex anti-inflammatory effects may occur.
Pharmacokinetics:
?
Dosage:
Conventionally 1 to 6 g/kg/min IV infusion.
Adverse Effects:
Unclear. Cardiac effects (tachycardia, hypertension) are usually mild.
Drug Interactions:
Unknown.
Of Note:
Whom should we believe?

 

Fluorocarbon emulsions
Executive Summary

Blood substitutes Top of Page
Clinical Potential:
Perfluorocarbon emulsions are agents with the potential for ensuring tissue oxygenation during marked haemodilution.
Pharmacodynamics:
~ 500 Dalton hyperfluorinated hydrocarbons, they are immiscible in water and thus administered as fine (0.2 m) particles emulsified using surfactant. Oxygen carriage is linear with PO 2 . Second-generation emulsions (Oxygent TM - perflubron based, and Oxyfluor TM - perfluorodichlorooctane based) have enhanced oxygen- carrying capacity, higher stability, and egg-yolk based emulsifiers. Third-generation preparations are in preclinical development.
Pharmacokinetics:
Excretion is as vapour by the lung after reticuloendothelial passage!
Dosage:
1.35 g/kg appears to support O 2 delivery.
Adverse Effects:
A flu-like syndrome may occur 4-6 hr post-infusion (due to liberation of cytokines during phagocytosis of emulsion particles). Fever and moderate thrombocytopaenia may occur.
Complement activation occurred with first-generation products due to the surfactant (Pluronic F-68).
Drug Interactions:
Unclear.
Of Note:
Other potential uses are in partial liquid ventilation, organ preservation; PTCA flush (now withdrawn).

 

Haemoglobin (Hb) solutions
Executive Summary

Blood substitutes Top of Page

Clinical Potential:
A source of great hope for those concerned by the limitation of current transfusion options, widespread use of these solutions is precluded by unresolved questions concerning metabolism, potential toxicity, and brief (< 24 hr) duration of action.
Pharmacodynamics:
Because free Hb solutions are toxic (activate complement, coagulation, kinins; are nephrotoxic; cause vasoconstriction, and more) and poor carriers of oxygen (P50 of ~ 12-14mmHg), a variety of complex formulations have been tried. these include:

  • mutant recombinant human Hb ('higher P50, few side-effects');
  • internally stabilised tetramers;
  • polymerised Hb;
  • cross-linked dimers (less nephrotoxic) eg diaspirin linked (HemAssist);
  • conjugation with other molecules;
  • pyridoxylation;
  • membrane-encapsulation (potential problems due to binding of endotoxin).

Pharmacokinetics:
This is poorly characterised, but depends on the formulation.
Dosage:
Unclear.
Adverse Effects:
Depend on formulation; most consistent is vasoconstriction.
Drug Interactions:
?
Of Note:
Metabolism is very poorly characterised. Haemolysis may be simulated or masked. Haematocrit becomes of questionable value. P50 differs. Interference with eg. bilirubin assay. Methaemoglobin formation from these formulations could be disastrous, with marked oxidative stress. (Many unresolved problems).

 

Rapacuronium bromide
Executive Summary

Non depolarising muscle relaxants Top of Page
Clinical Potential:
A cardiostable steroid 'succinylcholine replacement' with quick recovery, further shortened by neostigmine!
Pharmacodynamics:
With 1.5 mg/kg onset in just over a minute and clinical duration 10-16 min;
With 2.5 mg/kg ~90% of patients have excellent intubation conditions at 1 minute, the clinical duration of 20 minutes can be shortned to 10 minutes by the addition of neostigmine 0.04-0.07 mg/kg given 2 minutes after the dose. Minimal changes with age;  
Pharmacokinetics:
V ss ~ 0.31 - 0.46 L/kg; K e0 for plasma:neuromuscular junction equilibration 0.38 to 0.42 min; Rapid clearance (0.42 - 0.67 L/h/kg), forms ORG-9488 by hydrolysis, a potent muscle relaxant, which accumulates with multiple doses or infusions
Dosage:
1.5mg/kg for elective endotracheal intubation; 2.5mg/kg for rapid sequence intubation
Adverse Effects:
Mild reactions related to minimal histamine. Significantly better side effect profile than suxemethonium chloride.
Drug Interactions: Unknown.
Of Note:
In the largest study to date, acceptable intubating conditions significantly less common than with suxamethonium (89% v 97%) at 1 minute with the 1.5mg/kg dose

 

Levobupivacaine Executive Summary

Local anaesthetic agents Top of Page
Clinical Potential:
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.
Pharmacodynamics:
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. Has not been compared at equipotent anaesthetic doses with ropivicaine.
Pharmacokinetics:
Elimination t 1/2 '1.3 hours', V D 67L in adult volunteers; protein binding > 97%; Metabolism by CYP 1A2 and 3A4. Crosses placenta; No racemisation in vivo.
Dosage:
Minimum effective concentration 0.085%; Recommended maximum dosage
150mg for single dose epidural; 12.5mg/hr (10mls/hr of 0.125% solution) for labour epidural infusion; 18.75mg/hr (15mls/hr of 0.125% solution) for epidural infusion; and 25mg every 15 or more minutes for epidural bolus doses. 
15mg for intrathecal placement. 2.5mg/kg for nerve blocks in paediatric patients.
Adverse Effects:
Potential for hypotension .. cardiac arrest: observe precautions as for all local anaesthetics. Cardiotoxicity and CNS toxicity as noted.
Drug Interactions:
Unknown.
Of Note:
(1) Don't use 0.75% in obsetrics; (2) Not for paracervical or Bier's block; (3) Avoid if hypersensitivity to amides (rare).

 

Dexmedetomidine
Executive Summary

Alpha 2 and Imidazole agonists in anaesthesia Top of Page
Clinical Potential:
Potent alpha-2 agonist which can be used as an anxiolytic, to improve intra operative haemdynamic stability, to decrease intra-operative hypnotic requirments and as an analgesic.
Pharmacodynamics:
Specific, selective alpha-2 agonist giving excellent anxiolysis and sedation pre-operatively.  Haemodynamic stability, low heart rate and anaesthesia intra-operatively.  The benefits also extend into the post-operative period with prophylaxis against ischaemic events, analgesia and reduced shivering.
Pharmacokinetics:
Dexmedetomidine has non linear pharmacokinetics! High concentrations cause vasoconstriction which decreases the initial volume of distribution and the intercompartmental clearance.  Low concentrations allow the central vasodilatation to occur.
T 1/2 alpha = 9min, beta=2hr. Clearance 0.5 L/h.kg; V ss 1.33 L/kg. 94% protein bound; Subject to an increasing "context sensitive half time" during infusions.
Dosage:
Only available in parentral formulation. 1 g/kg as a bolus dose given over 2 minutes.  Continuous infusions of 0.2 to 0.7 g/kg/hr to maintain 'appropriate sedation' are suggested for patients in intensive care units.
Bolus dose of 2.5 g/kg for intra-operative usage.  With the availability of atipamezole expected,  we will have the ability to preform a "reversible intravenous anaesthetic technique"
Adverse Effects:
Hypotension is common (30%); bradycardia in 10%; otherwise similar to placebo.
Drug Interactions:
Inhibits CYP2D6 (IC 50 1.8 M). Potential for interactions.
Of Note:
Peri-operative usage of more selective alpha 2 and imidazoline receptor agonists is a distinct possiblity for the not to distant future.  We will soon be meeting patients on imidazoline agonists for the control of hypertension.

 

Adenosine triphosphate!!
Executive Summary

A more indepth look at ATP Top of Page
Clinical Potential:
ATP, the energy currency inside all cells, has profound extracellular effects, both by itself and through its metabolite adenosine. A wealth of new uses may be just around the corner!
Pharmacodynamics:
Extracellular ATP affects neurotransmission, muscle (including heart) contraction, platelets, vessels and the liver, mainly through binding purinergic P2 receptors. (Adenosine binds a variety of P1 receptors). Pharmacodynamics of ATP in plasma have been poorly studied.
Pharmacokinetics:
IV ATP moves rapidly into erythrocytes at infusion rates of up to 50 g/kg/min; ectonucleotidases on vascular endothelia also rapidly degrade ATP. Plasma half-life is 0.6 to 1.5 seconds.
Dosage:
Although ATP has analgesic, cardiac, vascular and anti-tumour effects, dosages are still unclear. Surgical pain reduction occurs at 50-70 g/kg/min with iv adenosine ; ATP doses of 50 to 350 g/kg/min may be used to induce hypotension without tachycardia. Doses of 100 g/kg/min may be effective in lowering pulmonary hypertension. ATP up to 140 g/kg/min has however been used as a stress test for myocardial ischaemia (combined with echocardiography or thallium scanning).
Adverse Effects:
Adenosine boluses may induce discomfort, tachypnoea, flushing, chest pain, nausea, bradycardia and even atrial fibrillation! ATP effects may be similar but are very transient, although anginal-type pain is common above 75 g/kg/min!
Drug Interactions:
Unknown.
Of Note:
A curiosity: don't use this one just yet!

 

Xenon Executive Summary

Volatile Anaesthetics Top of Page
Clinical Potential:
Alone and strange, xenon is by many yardsticks the ideal anaesthetic agent.
Routine usage is becomming a posiblity with the new Physioflex machine, the new large xenon plant in South Africa, linked to SASOL and the abolition of xenon in sattelite engines.
Pharmacodynamics:
Although inert, the bulky electron shell of xenon allows it to interact with lipids and a variety of proteins including plasma membrane calcium pumps, nociceptive neurones and even cytochrome P450 (but NOT myocardial voltage-gated channels)! Cardiovascular effects are minimal.
Pharmacokinetics:
There is no metabolism. The blood/gas partition coefficient (0.115) is low. Induction and emergence are rapid. MAC is ~ 0.71. The average adult takes up 6 L of Xe during the first hour of anaesthesia, with rapidly decreasing requirements from then.
Administration:
Using Xe 70% mixed with 30% O 2 , hypnosis and analgesia are adequate.
(Few) Adverse Effects:
Malignant hypermetabolic syndrome is NOT triggered. In contrast to nitrous oxide, diffusion hypoxia and bowel distension is minimal.
Drug Interactions:
None described.
Of Note:
The density of Xe makes most conventional flowmeters inaccurate and unreliable.