Induction agents Flashcards
What are the properties of an ideal induction agent?
- Easy storage - room temperature, long shelf life
- Easily identifiable / distinct from other agents
- Rapid onset (mainly unionized at physiological pH
- Predictable offset, rapid recovery, no accumulation on prolonged infusion
- ?Potentially reversible
- No side effects / toxicity - CVS stable, ?minimal resp depression
- No drug-drug interactions
- Safe on inadvertent intra-arterial injections
- Analgesic properties
- Safe in hepatic / renal failure
Propofol
* Chemical, uses, presentation
* Action, dose, duration, route, effects, toxicity
* Absorption, distribution, metabolism, excretion
Chemical - Phenol derivative (2,6 diisopropylphenol). Weak acid with a pKa of 11
Uses
* induction and maintenance of general anaesthesia
* Sedation in intensive care and for procedures
* Status epilepticus refractory to inital management
Presentation
* Lipid-water emulsion containing soya bean oil and egg phosphatide due to poor solubility in water, pH of 7
* Available as 1% or 2% concentrations
Action - Agonist at GABAA and glycine receptors (inhibitory)
* Binds at β-subunit of GABAA to increase the opening time of the receptor’s Cl- channel when GABA binds - resulting in membrane hyperpolarization so that there is reduced chance of an action potential being generated
Dose / duration / route
* Usual IV induction dose 1-2mg/kg
* Dose adjustments in children, elderly, CVS instability
* Emergence ~10mins after single bolus dose
* During prolonged infusion propofol accumulates in fat and context sensitive half time increases
* In morbidly obese patients - lean body weight should be used for induction, and adjusted body weight for infusion
* IV administration only, if given orally undergoes ~80-90% first pass metabolism
Effects:
* CVS - ~15-25% fall in BP, fall in systemic vascular resistance. No compensatory tachycardia (may cause bradycardia), ~20% fall in cardiac output
* Resp - Bolus dose produces apnoea and suppresses laryngeal reflexes. Infusion results in tachypnoea, reduced tidal volumes and depressed response to hypercarbia, hypoxia. May cause bronchodilation
* CNS - Smooth, rapid induction of anaesthesia. Reduced intracranial pressure, cerebral perfusion pressure and cerebral oxygen consumption. 10% display dystonic, excitatory movements. Anti-epileptic effects
* GI - Antiemetic properties, possibly due to antagonism at dopamine D2 receptors
* Other - reduced intraocular pressure
Toxicity / side effects
* Pain on injection
* Propofol infusion syndrome - Metabolic acidosis, hyperlipidaemia, rhabdomyolysis, multi-organ failure. Avoid doses >4mg/kg/hr for prolonged periods
* Quinol metabolites may cause green discolouration of urine / hair
* Unlikely to cause allergic reactions - contains lecithin, no egg protein or albumin. All protein within the soya bean oil is also removed
* No adverse effects on intra-arterial injection
Absorption - IV administration only
Distribution
* Highly protein bound - 98%
* High volume of distribution - 4L/kg
* Predominantly unionized at physiological pH
* Highly lipid soluble
Metabolism
* Hepatic - Inactive metabolites. ~40% undergoes conjugation to a glucuronide and ~60% metabolized to a quinol which is further metabolized to a glucuronide / sulphate. Significant inter-patient variability in ratio of metabolic pathways. Glucuronidation occurs through the hydroxyl group at position 1
* Renal and hepatic disease has no clinically significant effect on metabolism
* Probable extra-hepatic component of metabolism
* High hepatic extraction ratio
Excretion - Renal excretion of above inactive metabolites, and small minority of unchanged drug (0.3%). Decreased clearance in renal failure
Terminal elimination half life of 5-12 hours
Thiopentone
* Chemical, uses, presentation
* Action, dose, duration, route, effects, toxicity
* Absorption, distribution, metabolism, excretion
Chemical - The sulphur analogue of pentobarbital. Weak acid with pKa of 7.6
Uses
* Induction of anaesthesia
* Management of status epilepticus
Presentation
* Pale yellow powder containing sodium thiopental and sodium bicarbonate
* Typically 500mg sodium thiopental in a rubber-topped vial is diluted with 20mls to produce a 2.5% solution which is stable for several days
* Stored in an atmosphere of nitrogen rather than air. If air were used, carbon dioxide may react with water to produce hydrogen ions - resulting in a less alkaline solution
* When mixed with water an alkaline solution with a pH of ~11 is produced. This favours the enol form of thiopentone, which is more water soluble. When injected into the bloodstream, physiogical pH results in the keto form being produced, which is lipid soluble
Action - Agonist at GABAA receptors (inhibitory)
* Binds at β-subunit of GABAA to increase the opening time of the receptor’s Cl- channel when GABA binds - resulting in membrane hyperpolarization so that there is reduced chance of an action potential being generated
Dose / duration / route
* IV induction dose 3-7mg/kg
* Acts rapidly within one arm-brain circulation time and lasts for 5-15mins
* Can be administered rectally
* Infusion (sometimes used for cerebral protection in severe traumatic brain injuries) can result in significant accumulation due to saturation of hepatic enzymes and zero-order kinetics
Effects:
* CVS - Dose-dependent reduction in cardiac output, stroke volume, SVR and therefore BP - which may provoke a compensatory tachycardia
* Resp - Dose-dependent respiratory depression / apnoea. Does not suppress laryngeal reflexes and therefore laryngospasm may occur, may also produce bronchoconstriction
* CNS - Smooth, rapid induction of anaesthesia. Reduces intracranial pressure and cerebral oxygen consumption. Anti-epileptic effects
* Other - Depression of intestinal activity and constriction of splanchnic vasculature. Reduced renal plasma flow and increased ADH secretion may lead to reduced urine output. No effect on uterine tone. A slight, transient decrease in serum potassium may occur. Reduced intraocular pressure
Toxicity / side effects
* Severe anaphylactic reactions - seen in around 1 in 20,000 administrations
* Porphyria - may precipitate an acute crisis causing symptoms / signs such as abdominal pain, vomiting, hypertension, tachycardia, motor weakness, seizures, coma. Porphyria is a rare, hereditary disease in which there is a buildup of porphyrins. This occurs due to an abnormality of an enzyme which normally converts porphyrins to haem - an essential constituent of haemoglobin, myoglobin etc. Diagnosis by urinary porphyobilinogen (PBG), which must be protected from light. If positive, further genetic testing should follow. Treatment involves stopping trigger, avoiding fasting / catabolic state, IV haem arginate and supportive measures
* Inadvertent intra-arterial injection may cause ischaemia, pain and thrombosis. On IV injection physiological pH results in more of the drug being in its less soluble keto form. This may lead to preceipitation of thiopental crystals, which in arterial circulation may become wedged in the smaller, distal vessels. Does not occur in venous blood due to constant dilution by flow of venous blood, and the direction of flow into larger, more proximal vessels. Treatment involves stopping injection, immediate flush, analgesia, intra-arterial injection of papaverine, lidocarine / procaine, regional sympathetic block and anticoagulation
* Extravasation may lead to tissue necrosis
Absorption - IV administration only common route used
Distribution
* Highly protein bound ~65-80%
* Relatively high volume of distribution ~2.5L/kg
* Highly lipid soluble
* As thiopental is a weak acid with a pKa of 7.6, free drug is ~60% unionized at physiological pH. Therefore a lower dose may be needed for critically ill patients who are likely to be more acidotic and have reduced plasma protein binding
* Rapid emergence is due to redistribution to muscle and fat
Metabolism
* Hepatic metabolism by oxidation, mostly to inactive metabolites, but pentobarbital is an active metabolite
* When given as an infusion metabolism may become linear (zero-order) due to saturation of hepatic enzymes
* Low hepatic extraction ratio
Excretion - Renal excretion of metabolites, ~0.5% excreted unchanged
Ketamine
* Chemical, uses, presentation
* Action, dose, duration, route, effects, toxicity
* Absorption, distribution, metabolism, excretion
Chemical - Phencyclidine derivative. Weak base with a pKa of 7.5
Uses
* Induction of anaesthesia - especially in CVS instability or severe asthma
* Brief procedural sedation
* Analgesia
Presentation
* Ketamine is water soluble, and presented as a clear, colourless solution maintained at an acidic pH for stability and solubility
* Usually comes as a racemic mixture of two enantiomers in equal proportions - S+ and R-
* S+ketamine has greater affinity for the NMDA receptor and ~2-3x the potency of R-ketamine. The purely S+ketamine formulation is available, but rarely used due to cost
* Contains benzethonium chloride as a preservative
* Racemic mixture = 50:50 mixture of two enantiomers
* Enantiomers = Stereoisomers which are mirror images and cannot be superimposed on one another
Action - Non-competitive antagonist at the NMDA receptor, blocks the calcium ion channel to prevent activation of the excitatory channel, stops calcium ion influx and subsequent signalling pathways
Dose / duration / route
* IV induction: 1-2mg/kg
* IM induction: 5-10mg/kg - onset ~5mins, lasts ~30mins
* Sedation: 0.2-0.75mg/kg IV, 2-4mg/kg IM
* Can be given PO, PR, nasal or neuraxial (if preservative free)
Effects:
* CVS - Sympathetic stimulation - therefore HR, BP, CO all increase
* Resp - Resp rate increased. Laryngeal reflexes relatively preserved and patent airway usually maintained. Bronchodilation
* CNS - Dissociative anaesthesia, analgesia and amnesia. Intracranial pressure and cerebral oxygen consumption increased
* Other - Salivation. Intraocular pressure increased
Toxicity / side effects
* Emergence phenomena
* Non-prescription high dose use associated with severe interstitial cystitis
* Transient rash in ~15%
* Nausea & vomiting more common than other agents
* Most side effects are more associated with the R- enantiomer
Absorption
* IM bioavailability ~93%
* PO bioavailability ~25%
Distribution
* Relatively low protein binding ~25-50%
* Volume of distribution 3L/kg
* Highly lipid soluble
* Weak base with pKa of 7.5 - therefore ~44% unionized at physiological pH
Metabolism
* Hepatic metabolism by N-demethylation and hydroxylation via cytochrome P450
* Produces norketamine, an active metabolite which is 30% as potent as ketamine - which is further metabolized to an inactive glucuronide
Excretion - Renal excretion of metabolites
Etomidate
* Chemical, uses, presentation
* Action, dose, duration, route, effects, toxicity
* Absorption, distribution, metabolism, excretion
Chemical - Imidazole derivative. Weak base with a pKa of 4.2
Uses
* Induction of anaesthesia - especially in CVS instability
Presentation
* Clear, colourless solution containing 2mg/ml of etomidate in an aqueous solution of water and 35% propylene glycol for stability
Action - GABAA receptor agonist
Dose / duration / route
* IV induction 0.3mg/kg
Effects:
* CVS - Relative cardiovascular stability, may produce slight decrease in SVR, but BP largely unchanged
* Resp - Dose-related decrease in respiratory rate, transient apnoea
* CNS - Involuntary muscle movements in ~50%. Reduces intracranial pressure and cerebral oxygen consumption
Toxicity / side effects
* Nausea and vomiting relatively common
* Significant antiplatelet effect
* Pain on injection common
* Suppresses adrenocortical function by inhibition of the enzymes 11β-hydroxylase and 17α-hydroxylase - resulting in reduced production of cortisol and aldosterone for 24-48hrs. Now rarely used as associated with increased mortality, and effect may be seen even after single doses
Absorption - IV administration only
Distribution
* 75% protein binding
* Volume of distribution 4.5L/kg
* Weak base with a pKa of 4.2 therefore highly unionized at physiological pH
Metabolism - Rapid metabolism by plasma and hepatic esterases to produce inactive carboxylic metabolites
Excretion
* ~75-85% excreted in urine as inactive metabolites
* ~2-3% excreted in urine as unchanged drug
* The remainder is excreted in the bile
