16. Induction Agents Flashcards
Ideal induction agent
Physical
> Cheap and easy to make > Long shelf life at room temperature > Water soluble and so easy to store > Painless on injection > Safe if injected intra-arterially > Rapid onset time > Rapid offset time > No excitation or emergence phenomena > No accumulation following infusion > No interaction with other drugs
Biological properties:
> Analgesic
> No effects on patient’s physiology, other than rendering them unconscious
> No toxic effects
Ketamine
Uses
1 Induction agent - especially in hypotensive patient group / HD unstable
2 Procedural sedation - burns / dressing changes
3 Bronchodilator
4 Analgesic
- Induction and maintenance of anaesthesia
especially in refractory asthma
because of its profound bronchodilator effects
2
• Sedation on ICU/for short procedures,
e.g. dressing change in burns
3.
• Analgesia especially in the military field
- • In neuroaxial blockade to prolong its effect
5
• Drug of abuse
Ketamine
Effects
CVS x5
RS x4
CNS x7
GI
EFFECTS
CVS Increases • noradrenaline and adrenaline release • HR • CO • BP • Cardiac O2 consumption
RS • Inc RR • No loss laryngeal reflex • Airway maintained • Profound bronchodilation
CNS
• Dissociative anaesthesia
(i.e. strong analgesic and light ‘sleep’)
- Increase CBF/ ICP/ CMRO2
- Inc IOP
- Amnesia
• Traditionally avoided in head injury as it was thought
to Inc ICP. In fact it does this no more than opioios do.
• Emergence phenomena, delirium, hallucinations.
Reduced by co-administration of benzodiazepine
• Inc Muscle tone
GI
• Nauea and vomiting
• Salivation
Ketamine
absorption / distribtuion
ABSORPTION/ DISTRIBUTION
- Well absorbed orally and IM
- Oral bioavailability 20%
- Protein binding 20–50%
- VD 3 L/kg
- t½ 2.5 hours
Ketamine
metabolism
excretion
• Metabolised in liver by
P450
to norketamine (30% potency)
• Norketamine metabolised by conjugation
to inactive compound
• Excreted in urine
Ketamine
MOA
MOA
• Non-competitive antagonist at NMDA receptor
Weak agonist at MOP KOP and DOP receptors
• Inhibits reuptake of serotonin, dopamine and
noradrenaline
Ketamine -
What is it
Whats the preparation
Whats the dose
for induction
analgesia
Phencyclidine derivative
• Colourless solution in
glass vial:
10/50/100 mg/mL
• Available as racemic mix
or as S (+) enantiome (less delirium)
• IV/IM/PO/PR/intrathecal/
epidural administration
• Induction dose:
1–2 mg/kg IV
5–10 mg/kg IM
• Analgesic dose:
0.2–0.5 mg/kg
Ketamine
CHEMICAL PROPERTIES
• Chiral compound most
preparations are racemic,
but S-Ketamine is available
as single enantiomer
• Inhibits dopamine transporters
8x more than R-Ketamine
• S-Ketamine is twice as potent
as racemic mixture
- 3-4x affinity for NMDA receptor than R-Ketamine
- Recover mental function more quickly
Patients report more pleasant experience at doses causing same effect
• Water soluble forming
acidic solution pH 3.5–5.5
Propofol
Name
Composition
Vials
Dose
(2,6-diisopropylphenol) Phenolic derivative
• 1%/2% white lipid-water
emulsion in soya bean oil
and purified egg phosphatide
• 20/50/100 mL vials and
50 mL pre-filled syringe
DOSE • 1.5–2.5 mg/kg (adult) • 2–7 mg/kg (child) • 4–12 mcg/kg/hr maintenance
Propofol
USES
USES • Induction and maintenance of anaesthesia • Sedation • Refractory nausea and vomiting • Status epilepticus
Propofol
EFFECTS
CVS
x4
RS
4
CNS
3
GI
1
CVS • ↓ BP and SV (15%−25%) • ↓ CO (25%) • Vasodilatation secondary to NO production • Bradycardia/ asystole
RS • Depression • ↓ Laryngeal reflex • ↓ RR ↓ VT • ↓ Response to ^pCO2 and \/pO2 • Bronchodilation
CNS • Hypnotic, smooth and rapid induction ↓ CPP ↓ ICP ↓ CMRO2 • Myoclonic movements
GI
• Antiemetic
(antagonist at D2 receptor)
Propofol
SIDE-EFFECTS
• Pain on injection (improved with newer
‘Propfol-Lipura®’
which has /\ medium chain triglycerides
rendering drug more lipid-soluble)
• Epileptiform movements
(however it is not epileptogenic and is used
for treatment of status epileptious)
• Unlicensed in < 16 yr olds after complications of long-term use in ICU (fat overload syndrome, fatty deposits in liver, lung, heart and kidneys/metabolic acidosis/refractory bradycardia)
• Lipaemia with long-term use
• Green urine and hair, secondary to
quinol
metabolites
- Increased energy needed for DCCV
- Physically incompatible with atracurium
Propofol
MOA
MOA
- Uncertain
- May potentiate GABAA receptor
- May have action at cannabinoid receptor
Propofol
ABSORPTION/
DISTRIBUTION
ABSORPTION/
DISTRIBUTION
- Protein binding 98%
- VD 4 L/kg
- Rapid distribution to tissues
• Rapid elimination
(t½ 1–5 hours, context sensitive)
which may be increased following slower release from adipose tissue
Propofol
METABOLISM
AND EXCRETION
• Hepatic metabolism,
mainly conjugated to
inactive glucuronide
- Renal excretion
- Liver/renal dysfunction has little effect on metabolism
• Clearance exceeds hepatic blood flow,
suggestive of extra hepatic metabolism
• No active metabolites
Propofol
CHEMICAL PROPERTIES
CHEMICAL PROPERTIES
- Poorly water soluble
- Weak organic acid
• pKa = 11 therefore almost totally un-ionised at
pH 7.4
• pH 7.0
• Free radical
scavenger
• Physically
incompatible with
atracurium
THIOPENTONE
Type of medication
Dose
Prep
Barbiturate
• Yellow powder, 500 mg/vial
DOSE
- 3–7 mg/kg IV
- 1 g/22 kg weight PR
THIOPENTONE
USES
USES
• Induction of anaesthesia
(bolus lasts 5–10 min)
• Status epilepticus
• To achieve ‘burst
suppression’ in raised ICP
THIOPENTONE
MOA
MOA
• ^ Duration of opening of GABA Cl–
channels in CNS causes hyperpolarisation
and neuronal inhibition
THIOPENTONE
EFFECTS
CVS x4
RS X 3
CNS
4
Renal
Urine
Other
EFFECTS
CVS
- ↓ CO
- ↓SV
- ↓SVR
- May cause ^ HR
RS
- Depression
- Laryngospasm
- Bronchospasm
CNS
• Anaesthesia
- ↓CMRO2
- ↓Blood flow and volume
- ↓CSF pressure
- At low dose is antalgesic
RENAL
• ↓Urine OP
(^ADH and ↓CO)
OTHER
• Severe anaphylaxis
(1/20 000)
• Precipitates porphyria
• Intra-arterial injection ->severe pain and
spasm
and perivascular necrosis
THIOPENTONE
CHEMICAL PROPERTIES
CHEMICAL PROPERTIES
• Displays tautomerism
or
dynamic isomerism,
the
proportions of the two forms
governed by ambient pH
• Weak acid –
forms alkaline solution when
dissolved in H2O, pH 10.8.
This solution stable for many days and is
bacteriostatic because of high pH.
• Undissociated acid insoluble and
so, when packaged:
a) Sodium carbonate (6% by weight)
added to powder.
So, when dissolved, it releases –OH–,
therefore preventing accumulation of H+
and
formation of undissociated acid
b) Stored under N2 gas –
prevents acidification of
powder by CO2 in air
• pKa 7.6
therefore 60% un-ionised at pH 7.4
• Highly lipid soluble
THIOPENTONE
METABOLISM
AND EXCRETION
METABOLISM AND EXCRETION
• Hepatic oxidation by P450 ->
mainly inactive metabolites
(though pentobarbitone is active)
- Induces P450 after single dose
- Zero order kinetics with infusion
THIOPENTONE
ABSORPTION/
DISTRIBUTION
ABSORPTION/ DISTRIBUTION
• Protein binding 80%
• Of the unbound 20%,
only 12% un-ionised
and available
(as 60% ionised at pH 7.4)
• VD 2 L/kg
• Rapid emergence secondary to
rapid redistribution to tissues
• Critically ill patients
are acidotic with ↓ protein binding
therefore less thiopentone needed
• NSAIDs may ↓ protein binding and = ^^ free drug fraction
Etomidate
Type
Dose
ETOMIDATE
Imidazole hypnotic
• Clear colourless solution:
2 mg/mL in 10 mL vial
DOSE
• 0.3 mg/kg
Etomidate
MOA
MOA • ^ Duration of opening of GABA C l – channels in CNS causes hyperpolarisation and neuronal inhibition
• Only the D isomer causes hypnosis
Etomidate
USES
USES
- Induction of anaesthesia
- Treatment of Cushing’s syndrome before surgery
Etomidate
EFFECTS
CVS
4-5
RS
2
CNS X8
GI X1
EFFECTS
CVS
- Most stable induction agent
- Slight ↓ SVR
- Myocardial O2 consumption not affected
- Contractility not affected
- BP not affected
RS
- Depression
- No inhibition of hypoxic pulmonary vasoconstriction
CNS
- Hypnosis
- Tremor
• Involuntary movements • ↓ Tone • Epileptiform activity on EEG in 25% • ↓ ICP • ↓ CPP an ↓ CMRO2 • ↓ IOP
GI
• Nausea and vomiting
(especially in conjunction with opioid
Etomidate
OTHER effects
• Inhibits steroid synthesis,
by inhibition of 11b and 17a hydroxylase,
for 24 hourly after only 1 dose.
Was associated with deaths on ICU
following infusion for sedation.
Use has declined because of this and the
increasing popularity of ketamine
- Pain on injection in 25%
- Contraindicated in porphyria
- Antiplatelet activity
- Hypersensitivity and histamine release (rare)
Etomidate
CHEMICAL
PROPERTIES
CHEMICAL
PROPERTIES
• pH of solution 8.1
Pka 4.1
Etomidate
METABOLISM
AND EXCRETION
METABOLISM
AND EXCRETION
• Rapid metabolism by hepatic and plasma esterases
- May inhibit plasma cholinesterase
- Excreted in urine (90%) and bile (10%)
Etomidate
ABSORPTION/
DISTRIBUTION
ABSORPTION/ DISTRIBUTION
- Protein binding 75%
- Rapid distribution
- VD 3 L/kg
