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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
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| Opioid drugs in anaesthesia |
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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 µg/kg/min
Anaesthesia: 0.25 - 0.4 µg/kg/min combined with an hypnotic
(propofol > 80mg/Kg/min or >0.3
MAC of Volatile agent)
Analgesia: 0.05 - 0.1 µg/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
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| Local anaesthetic agents |
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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
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| Non depolarising muscle relaxants |
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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 µg/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
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| 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
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| 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 µg/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
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| 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 µm) 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
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| Blood substitutes |
Top of Page |
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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).
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Rapacuronium bromide
Executive Summary
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| 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 |
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|
| Local anaesthetic agents |
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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
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| Alpha 2 and Imidazole agonists in
anaesthesia |
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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 µg/kg as a bolus dose given over 2
minutes. Continuous infusions of 0.2 to 0.7 µg/kg/hr to maintain 'appropriate
sedation' are suggested for patients in intensive care units.
Bolus dose of 2.5 µg/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 µM). 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
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| A more indepth look at ATP |
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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 µg/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 µg/kg/min with iv adenosine ; ATP
doses of 50 to 350 µg/kg/min may be used to induce hypotension without tachycardia. Doses
of 100 µg/kg/min may be effective in lowering pulmonary hypertension. ATP up to 140
µg/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 µg/kg/min!
Drug Interactions:
Unknown.
Of Note:
A curiosity: don't use this one just yet! |
Xenon Executive Summary
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| Volatile Anaesthetics |
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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. |
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