Induction agents Flashcards
what are the properties of an ideal induction agent?
physiochemical
* stable at room temp and in light
* doesnt need reconstituting - soluble in water
* compatible with other anaesthetic agents and giving sets
* long shelf life , doesnt fascilitate bacterial growth
pharmacodynamics
* non painful at injection, no irriation with extravasion
* quick onset - one arm circulation
* smooth predictable end point
* anaesthesia with added benefits - PONV, antiepileptic, amnesia, analgesia
* no allergies
* minimal CVS/ resp effects
* doesnt increase ICP
* sutiable in different groups - paeds, obsetrics
Pharmacokinetics
* Can be absorbed IV or IM
* very lipid soluble so large Vd - allows it to get to effect site of brain
* metabolised rapidly and doesnt accumulate so can have short CSHT for TIVA
* no active/ toxic metabolities
* safe in hepatic/ renal impairment
environemnt
* cheap to make
* non toxic waste
what are the different classes of IV induction agent?
4 main agents
propofol = phenol derivative
ketamine = phencyclidine derivative
etomidate = imidazole with ester link
thiopentone = barbiturate
others..
barbiturates = methohexital, phenobarbital
benzo = midazolam
how do the IV induction agents work?
overall reduce neuronal excitability in the brain either by increasing inhibitory NT (GABA) or decreasing excitatory (nAChR or Glutamate)
mostly via GABA allosteric modulation
propofol also inhibits NMDA, serotonin receptors and nACHR
ketamine is a non-competitive anatagonist of NMDA
what is propofol related infusion syndrome?
rare syndrome associated with prolonged infusion of propofol, mostly seen in paediatrics and in ITU.
usually after >4mg/kg/hr for >24hrs
pathophysiology:
* mitochondrial dysfunction - impaired oxidative phosphorylation - lactatic acid, ROS, oxidative stress
* cell damage - rhabdo, hyperkalaemia
* prevents B oxidation of fats
* build up of triglycerides
results in
* myocardial depression - low BP and HR and arrhythmias
* high K+, triglycerides, lactate, CK
* renal failure
* green urine
what are the risk factors for developing propofol related infusion syndrome (PRIS)?
children
sepsis
>48 hr infusion
low card, high lipid diet e.g. starvation
how is PRIS managed?
early recognition - check CK, triglycerides and pH regularly
stop propofol and switch to alternative
supportive - ionotropes , vasopresors
how is PRIS prevented?
not in children under 16yrs
limit transfusion to 4mg/kg/ hr
why does thio have a quicker onset of action to propofol?
thiopentone is a weak acid with pKA of 7.6
propofol is also a weak acid with pKA of 11
acids ionise above
at physiological pH, propofol is more unionised
HOWEVER
propofol is heavily protein bound -98%
thiopentone 80%
so more free portion of thio to cross BBB
what happens if thiopentone is given intra-arterially?
thiopentone is a barbiturate with ketone group. when put at a pH above its pKA e.g. pH of 10.5 it ionises and becomes soluble in water as its enol from C-S- Na +
the solution thio is stored in is at this pH to maintain its water solubility however this is very alkolitic and if given intra-arterially can irritate arteries causes crystalisation, spasming and thrombosis.
this can lead to extreme pain and distal ischaemia.
how is an intra-arterial injection of thiopentone managed?
quickly dilute with saline
can give lidocaine to reduce pain
can give papaverine to dilate arteries
anti-coagulation to reduce thrombosis risk
could also do a sympathetic block to improve blood flow e..g stellate ganglion block
what happens if thiopentone is given through tissued cannula?
can precipitate and cause tissue necrosis due to high pH of solution
why would a septic patient need less thio
pH of blood is lower
hence more unionised available
also lower albumin potentially increases free portion
what did NAP5 study find
looked into awareness
increased awareness in obstetric anaesthesia because
* RSI
* junior anaesthesist
* surgical stimulation short after induction
* less opioid used due to risk crossing placenta
* use of thio - mistaken for co-amox and less familiar
why may propofol have advantages in maternity over thio when reducing risk of awareness?
less likely to be mistaken for other drug e.g. co-amox
more familiar
no pre-mixing required
what is meant by dissociative anaesthesia?
a state of anaesthesia whereby an individual feels separate from their environment and in a trance like state. they are unaware of pain and sensory input.
however differs from standard anaesthesia with other agents.
this is seen with ketamine.
which group of patients are more at risk of delirium and hallucinations after ketamine use?
elderly
females
large dose
rapid bolus
what can reduce the risk of emergence phenomena with ketamine?
use of S ketamine
benzos
what do you know about the optical isomers of ketamine…
ketamine has a chiral centre and thus exists as 2 optical isomers - R and S
the S isomer is superior - with less emergence effects such as delirium and therefore reduced recovery time, also more potent (higher NMDA affinity)
overall because of improved potency, less required, so less side efects.
which agents are contraindicated in porphyria?
etomidate and thiopentone
how do the induction agents affect GABA?
positive allosteric modulation
GABA receptor consists of 2 alpha, 2 beta, 1 gamma
GABA normally binds bwtween alpha and Beta
induction agents bind beta
benzos increase frequency of opening
barbiturates increase duration of opening
overall increased chloride conductance and hyperpolarisation
describe the common themes of pharmacokinetics of induction agents…
A: lipid soluble given IV need special preparation either lipid emulsion or pH to ionise form (thio)
D: large Vd, most are highly protein bound (not ketamine
M: hepatic
E: renal
quick onset
quick offset - due to redistribution
draw a graph to show how the conc of propofol changes over time at induction and how inhaled agents increases. what is the significance of this?
propofol - wash out - negative exponential
inhaled - wash in curve
it takes longer for inhaled agents to reach a MAC of 1 than it does propofol to redistribute.
tell me about propofol
phenol derivative di iso propyl phenol
commonly used IV induction agent and for maintainance in TIVA. Also used for sedation and management of status epilepticus
Presented in lipid emulsion (egg phosphatide and soya bean) in 1% and 2% solutions.
dose of 1-3mg/kg at induction and then around 4-12mg/kg/hr to maintain at TIVA or plasma conc 5mcg/ml. (for sedation start at 10ml/hr)
Action
has a number of actions to achieve hypnosis - positive allosteric modulation of GABA, inhibition of nAChR, NMDA and serotonin receptors.
pharmacodynamics
* main effect is hypnosis/anaesthesia
* however also..
* A: reduces airway reflexes, good for laryngoscopy
* B: resp depression and apnoea, blunts responses to hypercapnoea , bronchodilation
* C: vasodilation, drops MAP, reduces myocardial contractility and HR. overall drops CO
* neuro - reduced CBF and ICP and metabolic O2 consumption.
pharmacokinetics:
weak acid with pKA 11
* A: IV use only
* D: rapidly distrubutes to brain - high lipid solubility, redistributes, large Vd 4L/kg. 98% PB
* M: hepatic metabolism - glucuronidation and quinol compounds
* E: renally excreted - high clearance 30-60ml/kg/min
* CSHT at 8 hours is 40 mins
* t1/2 is 8 hours
can propofol be used if the patient has egg allergy?
yes its a different allergen that is not present in the preparation.
tell me about ketamine
ketamine is a phencyclidine derivative
commonly used for anaesthesia induction, sedation, analgesia, refractory bronchospasm and recreational use.
comes as clearcolourless solution in different strengths for IV, IM, intrathecal, epidural use.
also available as oral tablet.
IV dose is 1-2mg/kg
IM 5-10mg/kg
for pain 10-30mg given (0.1-0.5mg/kg)
ketamine can come as a racemic mix or as an S.enantiomer.
It works via non-competitive antagonisms of NMDA to reduce neuronal excitability and pain transmission. also potentiates u receptors and has a role in dopamine and serotonin reuptake inhibition.
pharmacodynamics
* dissociative amnesia and analgesia
* slightly slower in onset than other agents = 60s (IM would be 15mins)
* other CNS effects include - increase BF, ICP and O2 consumption. increases sympathetic NS. causes nystagmus and delirium and hallucination. emergence phenomena
* CVS - tachycardia, hypertension (sympathetic response), increase CO. infact has myocardial depressive effects which are masked by sympathetic response.
* respiratory - no loss of airway reflexes, no resp depression, potent bronchodilator, can drive secretions.
* GI - N&V , increases uterine tone
pharmacokinetics:
- weak base with pKA of 7.5
- A: IV, IM , oral (BO 20%)
- D: large VD (3L/kg) , 30% PB
- M: renal - norketamine is active + glucuronides
- E: renal , clearance 17ml/kg/hr. t1/2 2-3 hours
what are the contraindications / cautions for ketamine use?
brain injury / raised ICP - although its advantage in CVS instability overides this.
eye surgery / glaucoma - due to raised pressures and nystagmus
avoid in porphyria
avoid in psychosis
avoid in severe IHD
tell me about etomidate..
imadazole derivative with ester link
used to be used for induction anaesthesia for its good CVS profile however not used as much now due to supression of 11b hydroxylase and addisonian risk.
presented as either lipid emulsion or propylene glycol (aqueous solution)
IV dose of 0.3mg/kg
works via potentiation of GABA
Pharmacodynamics
rapid onset anaesthesia 30seconds
CNS - reduces CBF, ICP, increases EEG activity in epileptic foci and hence used in ECT.
CVS - cardiostable
resp - minimal effects
however - inhibits 11b hydroxylase and 17a hydroxylase - prevents production of cortisol and aldosterone - adrenal insufficiency even after one dose
pharmacokinetics
weak base, pKA 4.2
A: IV only
D: lipid sol, Vd 3L/kg, PB 75%
M: ester hydrolyssi plasma and liver
E: renal and bile, short CSHT but cant be used as infusion due to adrenal action.
does etomidate exists as an isomers?
yes R enatiomer is 10x more potent
tell me about phenobarbital ?
barbiturate
C=0 (rather than C=S) , hence weak acid
hypnotic agent and anti-convulsant agent
presented as powder for reconstitution
how does methohexital differ from other barbiturates?
short acting
used in ECT for this reason
this is because its pKA is higher than thio so at physiological pH more is unionised. AND less protein bound than thio
tell me about thiopental
Barbiturate
used as induction anaesthetic agent, for status epilepticus and to induce coma in those with raised ICP. classically used in RSIs for its rapid onset and clear end point.
presented as a powder in a glass vial with Na2CO3 and N2 air. it is reconstituted with 20ml saline to make 2.5%solution (25mg/ml). This makes an alkaline solution of ph 10.5 for promote ionised water soluble form of thiopentone.
dose is 3-7mg/kg
allosteric GABA modulation
pharmacodynamics:
- hypnosis, anaesthesis, anticonvulsive effects
- other effects…
- CNS: reduces BF, ICP and O2 consumption
- CVS: venodilation, reduced BP, reflex tachy, myocardial depression
- Resp: reduced TV, resp rate, CO2 sensivity. histamine release and bronchospams risk.
- GI - garlic taste at induction, hepatic enzyme inducer.
- anaphylaxis risk
pharmacokinetics
weak acid, pKA 7.6 , undergoes tautomerism at physiological pH and becomes unionised.
A: only IV, rapid onset 30s
D: 2.5L/kg Vd, 80% PB
M: hepatic, some weakly active metabolites
E: renal, clearance 3-5ml/kg/min.
on repeated doses - 0 order kinetics hence cant be used as infusion
Can you compare 2 IV induction agents
draw thiopentone.. what does the S atom confer? what about methyl groups..
tautomerism - this is down to the S atom (phenobarbital can do this but not as readily). enables aqueous solution.
less electronegative than O (phenobarbital) making it more lipid soluble - quicker onset and higher potency for anaesthesia.
methyl groups are lipid soluble - promote its crossing across BBB and anaesthetic effect
specific overall structure allows it to interact with GABA A receptors
draw thiopentone as an enol water soluble.
what is this..
Ketamine
phencyclindine derivative
chiral centre is the point at which C-N bond - this carbon has 4 different groups.
why is propofol used for day case over thiopentone?
antiemetic
really good for abtunding laryngeal reflexes for airway manipulation
less risk of anaphylaxis
typically better recovery
when is thio preferred to propofol?
good for RSI as quicker onset
if there a propofol allergy
neuroanaesthesia - neuroprotective
