General Anaesthetic Agents Flashcards
How do general anaesthetic agents work
Overton and Meyer hypothesis
Protein binding: inhib (GABA, glycine), excitatory (NMDA)
GABAa receptor: how anaes work
pentameric family of ligand gated ion channels, >30 types
alpha subunits:
alpha/gamma interface = interface benzos
Beta subunit = etomidate, barbiturates, propofol, volatiles
Anaesthetics work by opening Cl entry = hyperpolarisation
Etomidate: presented as entantiopure R(+) isomer because S(-) inactive. 30x difference in activity. Just works on GABAa. B2 and B3 more sensitive than B1
Propofol: GABAa and glycine and inhib neuronal nicotinic and 5HT3
Tell me about the Glycine receptor
major inhibitory transmitter in spinal cord
Associated with Cl similar to GABAa receptor
volatiles all markedly potentiate glycine
efficacy correlates wihth immobility rather than awareness
Tell me about the NMDA receptor
inhibition of excitatory pathways
long term signal potentiation associated with learning and memory
activated by glutamate
modulated by magnesium
inhibited in non-competitive ketamine, NO, xenon
Tell me about barbiturates
Derived from barbituric acid: condensation product of urea and malonic acid
When oxygen is exchanged for sulphur at the C2 position oxybarbiturates become thiobarbiturates
not readily soluble in water
solubility depends on transformation from keto to enol form (tautomerism): alkaline solutions
Thiobarbiturates are very lipid soluble, highly protein bound, completely metabolised in the liver
Oxybarbiturates are less lipid soluble, less protein bound and excreted unchanged in urine
Tell me about the formulation of Thiopentone formulation
Thio is a sulphur analogue of the oxybarbiturate pentobarbitone
Presentation:
It is formulated as the sodium saly and presented as a pale yellow powder. The vial contains calcium carbonate (6% by weight) and nitrogen instead of air.
Na2CO3 increases the solubility: Na2CO3 reacts with H20 to make = NaHCO3 + Na + OH-
strongly alkaline solution (ph 10.5) water soluble enol form
N2 used as air cont CO2 whould create HCO3/H+ less alkaline therefore less soluble
Tell me about Thiopental as an induction agent
Presented as a pale yellow power reconsituted with water to make a pH of 10.5
It is typically used for induction at a dose of 3-7mg/kg
Effects:
CVS: dose -dependent reduction in CO/SV/SVR
Resp: Dose dependent. largynospasm/bronchospasm
CNS: GA lasting 5-10min. Reduced cerebral 02 consumption, blood flow, blood volume, CSF Pressure. low doses antanalgesic
Renal: UO fall due to increase ADH (CNS depression and reduced CO)
Anaphylaxis: 1 in 20,000
Porphyria: exacerbate acute crisis
Kinetics:
pka 7.6 so 60% unionised at pH 7.4
only 20% unbound
12% immediately available in unbound and unionsed form
Rapid onset due to high lipid solubility
Dynamic equilibrium between protein binding and free drug: critically ill (acid + less protein), NSAID’s
Rapid emergence from single bolus due to redistribution: triexponential decline
Zero order
Intra-arterial injection: crystals due to keto formation . Inject papverine, procaine, analgesia and sympathetic block
Tell me about methohexitone
Methylated oxybarbiturate
produced as sodium salt with sodium carb dissolve in water pH 11
pKa 7.9, 75% unbound at pH 7.4
1% solution dose 1-2mg/kg
Difference from Thio: excitatory phase, hiccups/increased tone/twitches. Precipitate seizure
Tell me about propofol…
Phenolic derivate (2,6 diisopropylphenol)
highly lipid soluble
presented as 1 or 2% lipid water solution containing soya bean oil and purified egg phosphatide (lecethin)
weak organic acid with pKa 11
almost entirely unionised at pH 7.4
Induction dose 1-2mg/kg
plasma conc 4-8Ug/ml
Effects:
CVS: SVR falls due to reduced BP. reduced sympathetic and myocardial contracility
Resp: apnoea
CNS: 10% excitatory
GI: anatgonism of D2 receptor: anti emetic
Pain: on injection
Met: fat overload syndrome
Misc: hair/urine green
Kinetics:
98% protein bound to albumin
Largest VoD 4 L/kg
hepatic metabolism: 40% conjugation to glucuronide, 60% metabolised to quinol which is excreted as glucuronide and sulphate
inactive and excreted in urine
elimination half life 5-12 hours
Tell me about ketamine
Phencyclidine derivative
Racemix mixture: S 2-3x more potent than R
water soluble acidic pH 3.5-5.5
10, 50, 100mg/ml
IV dose 1-2 mg/kg
IM 5-10 mg/kg
IV sedation sedation 0.2-0.5 mg/kg
Effects:
CVS: SNS stimulation
Resp: Increased rate and laryngeal reflexes preserved. Bronchodilatation
CNS: dissociative anaesthesia. Takes 90sec. emergence phenomena. Increase oxygen consumption
GI: N&V and hypersalivation
Kinetics: plasma conc falls bi-exponentially: distribution across lipid membranes then hepatic metabolism.
Least protein bound (25%). Demethylated to the active metabolism norketamine by hepatic p450. Norketamine (30% as potent as ket) metabolised to inactive glucuronicde metabolites. Conjugated metabolites are excreted in urine
Tell me about etomidate
Imidazole derivative and an ester
presented as 0.2% solution pH 4.1. cont 35% propylene glycol for stability
0.3mg/kg
Effects:
CVS: cardio stable. minimal histamine
Met: suppresses adrenocortical function by inhibition of enzyme 11-B hydroxylase and 17-Alpha hydroxylase. Inhibition of cortisol and aldosterone synthesis.
Pain: on injection
Kinetics:
75% bound to alb
actions terminated by rapid distribution into tissues
elimination depends on hepatic metabolism
Draw IV induction agents
