2. IV agents Flashcards
Etomidate
what is it
problem ; why
Prot bind
metab
C/I what cond
N+V?
RR?
Iimidazole
not used on ITU for sedation due to its depressant effect on the steroid axis.
Cortisol and aldosterone synthesis is depressed for up to 24 hours after a single dose.
Increased mortality is seen with its use as a sedative infusion on the ITU.
(cimitidine also imidazole deriv)
Etomidate effects on the adrenal axis is through a reversible and concentration-dependent blockade of 11β-hydroxylase and, to a lesser extent, 11β/18-hydroxylase (aldosterone synthase, CYP11B2)
even when a single dose has been given.
Redistrib
75% prot bind
metab hepatic ester + plasma cholinest
renal exc
C/I in porphyria
emitogenic
drops rr
Ketamine
what time of mix
which is more potent
by how much
Metab
By products
Most pharmacological preparations of ketamine are racemic mixtures containing equal proportions of (S)-ketamine and (R)-ketamine.
The (S) isomer alone has been shown to be twice as potent as the racemic mixture in producing anaesthesia and analgesia, and three times as potent as the single (R) isomer.
Ketamine is metabolised by hepatic microsomal cytochrome P450 enzymes.
It undergoes demethylation and hydroxylation of the cyclohexanone ring to form two major metabolites, norketamine (NK) and dehydronorketamine (DHNK), which are further biotransformed to glucuronide conjugates and then excreted in the urine.
Norketamine has 20-30% of the activity of the parent compound.
Of the two isomers of norketamine, the antinociceptive properties resided primarily in the S(+) enantiomer. Antinociception was not accompanied by significant side effects. The present findings suggest that norketamine, in particular the S(+) enantiomer, might be a useful NMDA-receptor antagonist for treatment of chronic pain involving central sensitisation.
DHNK has no significant anaesthetic or analgesic properties.
other actions which probably also contribute to its analgesic effect, including interactions with other calcium and sodium channels, cholinergic transmission, noradrenergic and serotinergic re-uptake inhibition
Less than 10% of ketamine is excreted unchanged, half in the faeces and half renally.
Fetal concentrations are approximately the same as those in the mother
Diazepam
Uses
Solubitly in H20
How is it prepared
T1/2
Metabolised to
effects on iv use
PO avail
Diazepam is a benzodiazepine which is widely used as an anticonvulsant, and produces sedatation and anxiolysis, thus it has been used for preoperative premedication.
It is insoluble in water (not soluble) and is available as an emulsion with soya bean oil (diazemuls).
It has a long half life of 20 - 70 hours and is metabolised in the liver to active metabolites (not inactive):
Desmethyldiazepam
Oxazepam
Temazepam
Nordiazepam (which has a half life of 120 hours).
Intravenous injection may cause respiratory depression and large doses can reduce the cardiac output, cause vasodilatation, drowsiness and confusion. The elderly are especially sensitive to intravenous diazepam.
It has an oral bioavailability of 85 - 100% (not 60%) and is effective when given rectally.
Intramuscular injection is painful and its absorption is unreliable.
The volume of distribution of diazepam in paediatric patients is similar to adult values but with a greatly prolonged half life.
renal disease diazepam may have a more marked effect owing to reduced protein binding and a dose reduction is appropriate.
impaired phase I metabolism in liver disease, there is increased sensitivity to diazepam and midazolam.
Ketamine
Non competitive antagonist of glutamate @the NMDA receptor
30-60s loss conc - less well define v prop
bronchodilator
SE - Dreams, PONV, rashes, hypertonus, salivation often neccesitating an anti antisialogogue
thalamocortical
CMR increase
Redistribution and the drug has a flow limited hepatic clearance.
Properties of an ideal iV agent
Physical
PK
PD
Phsyical
1 soluble in h2o 2 Stable in soln 3 No reconstituion 4 Air & light - stable 5 Long shelf life room temp 6 Not suppt bacteria 7 Compatible w/ other 8 no additive 9 cheap
PK 1 rapid onset 2 high oil/water 3 non cumulative 4 rapid & predict recovery 5 Comp metab to inactive & non toxic 6 safe renal/ hepatic impairment
PD 1 No pain inject 2 safe extravated / arter 3 no adr 4 smooth indduct - 1 arm brain 5 analgesic/emtietc/epileptic 6 Muscle releax 7 no emregence 8 no inc cbf/ icp/iop 9 red cmro2 10 min cv depression / stimm 11 min resp dperesiion 12 no his rel/ bspasm 13 no steroid syhtn 14 pregn/paed 15 not terato
TIVA
Short active / t1/2
Smooth rapid induction
high clear & elim
Prop -
Linera pharm & pk proile - ionfusion
Good recovery cvharact use w/ orthers
Peripheral loaded - greater laod to redistrib
Miantin conc in plamsa & duration
Load apredicatble - rate infusion fall match excretion
Prolong infusion context t1/12 increase
Titraed careful - rapid recovery
Useful neuroanesthesia - not impar atuoreg
Context sense t 1/2 prop
2 h
6h
9h
2h - 20min
6hh 30m
9h 50min
vary aptient to patent
Draw propofol
page 169
2,6 diisopropylphenol
What in a thio ample
Rubber topped
pale yello powder
5 ethyl 5 methyl bytyl thiobartiuric acid
6% abhydrous soium carbonate
Gaesos 0 Nitrogen = inhib oxidation
Carbonate prevent co2 - form free acid react w/ thio
Soidum ion replaces h ion associate c1 & c2 base
Readily soulbe in h2o 2.5% solution w/ ph 11 Alakline in solun ph 11 pk 7.6 - eintire ion 99.9 7.4 61% uni - more lipid souble - readily corsses bbb into lipid tissue - exert effect
less potent than methohex
S atom in thio
benefits?
Sulphar analoogue of pento barb - oxy barb
Faster onset
short durn & recovery
useful indctuoion - 1arm brain
Lip sol rap cross bbb
S in tho replace by O what molecule
C2 0 oxybarb - basic barbituate
gaba a rec - binding 0 slow onset & longer duration -
useful hyponitc & sedative - too slow induction
Where thiopentone act
In low doses is
Affect on ADH
Thio B subunit gaba a rec in cns
Increase opening cl channel = hyperpol + neuronal inhib
antalgesic
Increase ADH
- depressive effect on CVS (co down = urine ouyt down)
Reduces brain activity = decrease o2 consump + co2 prod
weak acid -
decrease pH = increased free unI drug = great response
Propofol
2,6 Diisopropyl phenol (phenol deriv)
Agonist at the GABA and glycine receptor.
Formulate white isotonic oil in water emuslion 1/2% (dt/ low solubil h2o)
10% soya bean oil 2.25% glycerol 1.2% purif egg phosphatide Naoh h2o
WEAK ACID
Ph 6-8.5
pka 11
Phys pH 7.4 0 mostly unionised - active
98% prot bound (ketamine 25%)
liver metab
IV dose 1.5-2/5mg/kg induction
4-12 mg/kg/hr maintenance
clearance 30-60ml kg min (thio 3.5)
Elim half 5-12h
vs etom 1-4h
Single bolus dose will last three to eight minutes, with the cessation of effects being due to redistribution.
elim half 5-12 (etom 1-4h)
60% Quinol
40% Glucuronide
PK prop
A - IV
D - 98% prote bound
Vd 4 l /kg
Distrub t/12 1-2 min - short duration aftger bolus
M Rapidly metab liver
inactive glucornide, sulphate & gluc conjugate of hyroxylate via ctyp450
Extra hep mech
Unaffected by renal / hep disease
Excretion Urine 0.3% unchanged clearance red renal fail clear 30-60ml.kg.min term elim 5-12h
Prop vs thiopentone
Phsyical properties
%Alkyl phenol deriv v Thobarb
Neutral aqeous emulsion v hypgroscopic yellw powder
Dose 1.5-2.5 v 4-6
Mol wt 178 v 264
pH 6-8.5 v 10.5
pKa 11 v 7.6
Prot bind 98% v 60-80%
Thio 264
Midazolam
GABAa
Uniquely structure pH dependent
BASIC
water soluble, open-ring structure when stored at pH 3.5. At pH above 4, its ring closes and midazolam becomes lipid soluble uINIONISED)
pka 6.5
89% unI at phys pH
travenous, intramuscular, nasal and oral routes. Its oral bioavailability is 40%
CYP450 isoenzyme 3A3/4.
Alfent - same - may prolong effects
Flumazenil
what is it
Acid or base
bound plasma protein &
albumin
Vd
T1/2
Risk of
Flumazenil is a benzodiazepine antagonist and is a weak lipophilic base (not acid).
It is about 50% bound to plasma proteins (not 90%) and albumin accounts for about 65% of this protein binding.
Flumazenil is extensively distributed in the extravascular space and the volume of distribution at steady state is 0.9 - 1.1 l/kg.
It has a half life of 7-15 min (initial), 20-30 min (brain), 40-80 min (terminal).
This is shorter than that of diazepam and midazolam such that there is a risk of patients becoming resedated.
Methohexitone
Methylated oyxbarbituate
Recon make 1% (10mg/ml)
pH 11
ECT and dental
may cause conusion epilietpc
prophria
high prote bind
More potent than thio
dose 1-2mg/kg (vs 3-6 for thio)
Methohexitone was used for day case procedures due to its rapid onset and offset and its use has persisted for electroconvulsive therapy (ECT) due to its epileptogenic effects on the electroencephalograph (in 20% of patients). It is no longer commercially available in the UK.
UnIonisation of
Prop
Methohex
Thio
Hence it can be seen that propofol is more unionised at plasma pH than methohexitone, which is in turn more unionised (not ionised) than thiopentone (90%, 75% and 61% respectively).
BZD mechanism action
Dependency worse with
Half lives Loraz Midaz Temeaz Diaz
Rebound anxiety occurs how long
convulsion occur
Enhancing GABA inhibition ↑ chloride ion flux .
Short acting compounds are associated with more dependency problems than long acting compounds.
Lorazepam has a half life of 12 hours
Midazolam has a half life of one to three hours
Temazepam has a half life of six to eight hours
Diazepam has a half life of 24 to 48 hours.
Rebound anxiety can occur within two days following withdrawal (not two weeks).
Convulsions may occur on withdrawing benzodiazepines but they are usually associated with rapid withdrawal.
Propofol
Name
Mechanism
Arterial injection
Urine
wby
Does it affect plt or coag?
X placenta? effect
Propofol (2,6-diisopropylphenol)
It produces unconsciousness in one arm-brain circulation time and increases the latency and decreases the amplitude of somatosensory evoked potentials (SSEPs).
Accidental intra-arterial injection is associated with severe pain, though evidence of subsequent vascular complications is limited.
Excretion of green urine,
reflecting the presence of phenols in the urine, without any alteration in renal function.
Propofol - not alter coagulation or platelet function,
intralipid has been associated with alterations in blood coagulation.
Crosses the placenta
rapidly cleared from the neonatal circulation.
Where does propofol act
Reuce opening Na channel
Potetniate glycine & GABA
Inhibit NMDA subtype
Prop vs thiopentone
PK
Onset Rapid
Recovery - Rapid
Induce - 1 arm brain
Distrub t1/2 1-2m v 5-15
Non cumlative v cumulative
Vd 4l/kg v 2.5
Clearance 30-60ml/min/kg v 3.5
Higher clearance prop - plasma fall rapid
T1/2 5-12 v 6-15
Liver - both
Oxidation v conjugation
2-6 diisopropylphenol gluc & 2-6 di isoproplyquinol gluc
vs
Thiopental carboxylic acid, hydroxythio, pentobarbital
Urine elim both <1% unchanged
Prop v Thio
PD
CNS
Reduce ICP
CPP
CMRO
Anticonvuslants
Small risk prop convuslion - epileptics
Excitatory - common prop
CVS:
Reduce SVR
CO
BP
Prop - vasodil prop stim reduction & rel NO
Vary affect HR, ocass relfax tachy , commoner brady
Thiop - compensat tachy
Resp:
Resp dperession
reduce response hypercap
Laryngeal reflex depr > prop
Thio - may laryngo / bronchocon
Renal
Unaffect prop,
thop - reduce plasma renal flow/ increase ADH, Decrease UP
Thio - no effect hepatic function
GI
Prop ?anti emti - D2 rec
Thio - splanchnic vcon
Thio - no effect uterus routine obs
Prop not license preg - high placental trasnfer, neo depression
Paeds ? - hyperlip,m meat acido
Pain eject
Thio - tissue damage extrav, art constriction, thro,mbosis
Thio - c/i in porphyria
