2013/05/28 1
Induction Agents
2013/05/28 2
Basic concepts
� One arm-brain circulation time
� Compartments
� Protein binding
� Redistribution vs. Metabolism
� Receptor binding
2013/05/28 3
One arm-brain circulation time
� From introduction into circulation
� ↓
� Pharmacological effect on target organ
2013/05/28 4
One arm-brain circulation time
� Prolonged by
– Decreased cardiac output
– Old age
– Hypothermia
� Clinical implication:
– Inject slowly – wait for effect
Compartments
2013/05/28 5
2013/05/28 6
Compartments
� Blood supply → distribution
� IV induction agent
– Vessel rich group – (brain, heart, kidney, liver)
– Muscle
– Fat
– Bone
2013/05/28 7
Protein binding
� All induction agents - high protein binding
– (>75% except ketamine -12%)
� Active drug = free fraction
– Low protein/albumin = increased free fraction
� Overdose!!!!
� Clinical implication:
– Half the calculated dose, inject slowly
Redistribution
2013/05/28 8
2013/05/28 9
Redistribution vs. Metabolism
� Redistribution
– From one compartment to another
– Decreased [] in vessel rich group
– Arousal → hang over effect
� Metabolism
– Inactivation, breakdown in organ systems
– Elimination via renal, GIT
2013/05/28 10
Receptor binding
� GABAA agonists
– Cl- channel openers
– Inhibitory effect on exitation
� NMDA antagonists (Ketamine)
– Ca2+ channel blocker
2013/05/28 11
Ideal induction agent
� Safe
� Easy to use
� Cheap
� No / minimal cardiovascular effects
� Rapid distribution and metabolism
� No active metabolites
� Analgesia
2013/05/28 12
Ideal induction agent (cont’d)
� No allergic reactions
� No pain upon administration
� No involuntary movements
� No nausea and vomiting
2013/05/28 13
Classification
� Barbiturates - Sodium thiopentone
- Methohexital
� Non-barbiturates - Etomidate
- Propofol
- Ketamine
- Benzodiazepines
2013/05/28 14
STP “Pentothal”
2013/05/28 15
STP “Pentothal”� Synthesized by Lundy in 1932 / 1934
� Pearl Harbour as sole agent � killed many
� Ultra-short acting thiobarbiturate
� Sulphur analogue of pentobarbitone
� Yellow powder, garlic smell, bitter taste
� Preparation: 2,5% = 25mg/ml (500mg/20ml)
� 85% plasma protein binding (albumin)
� 10-15% per hour metabolised by liver
2013/05/28 16
STP “Pentothal”
� Free (unionised) fraction crosses BBB
� Barbiturates are inherently acidic
� Dissolved STP pH = 10,5
– due to added 6% Sodium Carbonate
� Acidosis � excess H+
2013/05/28 17
STP “Pentothal”
� Acidosis � excess H+
Acidic drugs will ionize less
↑↑↑↑ Unionized fraction
↑↑↑↑ Fraction to cross BBB
2013/05/28 18
STP “Pentothal”� Induction agents = lipid soluble
↑ lipid solubility � ↑ plasma protein binding
eg. STP / Methohexitone = 85% Propofol 95%
↓↓↓↓ plasma proteins
↑↑↑↑ free fraction
↑↑↑↑ fraction available to cross BBB
2013/05/28 19
STP “Pentothal” (cont’d)CNS
� Induction in one arm-brain circulation time
� Anticonvulsant
� Anti-analgesic in small dose
� Decreases intracranial pressure
- ↓ CBF
- ↓ CSF production
- ↓ CMRO2
2013/05/28 20
STP “Pentothal” (cont’d)CNS
� Degree of cerebral protection in area of
focal ischaemia if administered before the
ischaemic insult
� Does not protect against global ischaemia
� ↓ intraocular pressure
2013/05/28 21
STP “Pentothal” (cont’d)
RESPIRATORY
� Sensitizes the upper airway
– (compared with Propofol)
� Apnoea 2-3 min
2013/05/28 22
STP “Pentothal” (cont’d)
CVS
� ↓BP � vasodilation + myocardial depression
� Be careful in FIXED CARDIAC OUTPUT!
� Intra-arterial injection
� Extravenous injection
never use stronger than 2,5% STP
2013/05/28 23
STP “Pentothal” (cont’d)INTRA-ARTERIAL INJECTION:
– BURNS / DELAYED OR ABSENT INDUCTION
– Stop injecting!
– Don’t remove the canula!
– Flush with IV fluids Dilute STP
– Lignocaine ↓ Burning
– Heparin Prevent thrombosis
– Brachial plexus block Vasodilation
– Papaverine Vasodilation
2013/05/28 24
STP “Pentothal” (cont’d)EXTRAVENOUS INJECTION:
– BURNS!!
– Stop injecting!
– Not as harmful as intra-arterial injection
– May cause local ulceration if > 2,5%
2013/05/28 25
STP “Pentothal” (cont’d)
� Absolute contraindications
– Porhyria variegata
– Airway obstruction
– Fixed cardiac output
– Severe shock
� Relative contraindications
– Atopic asthma
– Severe liver disease, anaemia
– Myxoedema
2013/05/28 26
PROPOFOL“MILK OF AMNESIA”“MILK OF AMNESIA”“MILK OF AMNESIA”“MILK OF AMNESIA”
2013/05/28 27
PROPOFOL
� 2,6 di-isopropylphenol
� Highly lipid soluble
� Emulsion: - soybean oil
- egg phosphatide
- glycerol
� Excellent medium for Candida
� Feeling of well-being (addiction)
� Erotic feelings!
2013/05/28 28
PROPOFOL (cont’d)
� CVS
– ↓ BP by 30-40%
– No tachycardia!
� RESPIRATORY
– Apnoea if injected fast
– ↓ Sensitivity of upper airway
2013/05/28 29
PROPOFOL (cont’d)
� BURNING
– large vein
– fast running drip
– Lignocaine
� 10mg in 20ml Propofol
� 1mg IV before Propofol
– Opioid
– “Lipuro” – medium chain fatty acids
2013/05/28 30
PROPOFOL (cont’d)
Too good to be true?� No hangover / accumulation
� Anti-emetic
� Anxiolytic
� Amnesia
� Anti-pruritus
� VIAGRA-IN-A-VIAL…!
2013/05/28 31
PROPOFOL (cont’d)
� Ideal agent for TIVA
� Ideal agent for Conscious Sedation
� Ideal agent for placement of LMA
� Excitatory phenomena - myoclonus
- opisthotonus
2013/05/28 32
PROPOFOL (cont’d)
� PROPOFOL INFUSION SYNDROME (PRIS)
CLINICAL FEATURES OF PRIS
1. Sudden onset of marked bradycardia / complete heart block
that is resistant to treatment
2. Lipaemic plasma
3. Hepatomegaly
4. Metabolic acidosis (base deficit > 10 mmol/l)
5. Rhabdomyolysis & Myoglobinuria
6. Multi-organ failure
2013/05/28 33
PROPOFOL INFUSION
SYNDROME (PRIS)
�PATHOGENESIS:– Blockade of L-CAT - ↓ FFA transfer
– ↓ mitochondrial O2 utilization
– ↓ fatty acid β oxidation
– ↓ APT production
– ↑ FFA in blood
2013/05/28 34
PROPOFOL (cont’d)
�TREATMENT:
� Prevention � keep Propofol infusion rate < 4mg/kg/h
and for not more than 24 hour
� Dialysis / plasmapheresis
� Pacemaker
�
PROPOFOL Side effects
� Burns on injection
� Drops BP by 30-40%
� Myoclonus
� Apnoea for 30 sec
� PRIS
2013/05/28 35
2013/05/28 36
ETOMIDATE
2013/05/28 37
ETOMIDATE
� Carboxylated imidazole
� Protein binding = 75%
� EEG ≈ grand mal epilepsy
� ↑Cough and hiccoughing
� Burns
� Thrombophlebitis
� ↑ PONV
� Myoclonus
2013/05/28 38
ETOMIDATE
BRAND / BURNS
BEWE / MYOCLONUS
BRAAK / NAUSEA
BYNIER / ADRENALS
BAIE DUUR / VERY EXPENSIVE
UNWANTED EFFECTS OF ETOMIDATE
2013/05/28 39
ETOMIDATE (cont’d)
� Adrenal cortex inhibition
2013/05/28 40
ETOMIDATE (cont’d)
� Adrenal cortex inhibition
- 11β-hydroxilase inhibition (and 17α-)
- Lasts for 8 h after single bolus
- Vitamin C restores cortisol to normal levels
� NB: Problem with TIVA and single shot induction!
� Hypnotic [ ] = 200nM/ml
� Adrenal suppression [ ] = 10nM/ml
2013/05/28 41
ETOMIDATE (cont’d)
� Remarkable :
- CARDIOVASCULAR STABILITY!
(Alteration in BP, pulse rate negligible)
� Indicated for:
– IHD, hypertensive disease
– Valvular disease
– Cardiac surgery
2013/05/28 42
KETAMINE
� Phencyclidine derivative
� Related to LSD
(lysergic acid diethylamide)
2013/05/28 43
KETAMINE (cont’d)
� What makes KETAMINE different?
– Analgesic
– Cataleptic state
– Dissociation
– Nystagmus
– Protects airway reflexes to certain extend?
– Increased lacrimation, salivation, skeletal muscle tone
2013/05/28 44
KETAMINE (cont’d)
� What makes KETAMINE different?
– Acts on NMDA receptors (antagonist)� protective
– ↑CMRO2, ICP, IOP
– Petit mal activity on EEG
– Hallucinations, delirium, dreams
– Bronchodilator
– Apnoea in very large doses
– Ideal sole anaesthetic agent
2013/05/28 45
KETAMINE (cont’d)
� What makes KETAMINE different?
– ↑ Catecholamine release & ↓ re-uptake:
� ↑ BP
� ↑ Pulse rate
BUT � Direct myocardial suppression
2013/05/28 46
KETAMINE (cont’d)
� What makes KETAMINE different?
↑↑↑↑ ↑↑↑↑ ↑↑↑↑ Catecholamines
Direct ↓↓↓↓ Myocardium
↑↑↑↑ ↑↑↑↑ BP
↑↑↑↑ ↑↑↑↑ Pulse rate
↑↑↑↑ ↑↑↑↑ CO
2013/05/28 47
KETAMINE (cont’d)
� What makes KETAMINE different?
Myocardial suppression ↓ No release of Catecholamines
↓ BP
↓ Pulse rate
↓ CO
2013/05/28 48
KETAMINE (cont’d)
� What makes KETAMINE different?
Very large therapeutic index!� IV = 1-2mg/kg
� IM = 3-5 mg/kg
� PO/rectal = 5-10mg/kg
2013/05/28 49
KETAMINE (cont’d)
Contraindications for Ketamine:
- Hypertension
- Ischaemic heart disease
- ↑ ICP
- Open eye injury
- Psychiatric problems
- Epileptics
- Aneurisms
- Decompensated shock (NA depleted)
2013/05/28 50
Dexmedetomidine
� Highly selective α2 agonist
� Long T½ = ↑ to reach Css
� Used as infusion
– Bolus 1μg/kg for 10 min
– Constant infusion 0,2-0,7μg/kg
� Registered only for:
– Post cardiac surgery sedation for 24h
2013/05/28 51
Dexmedetomidine
� Advantages
– Sedation
– Analgesia
– No respiratory depression
– Anti-shivering agent
� Disadvantages
– Biphasic blood pressure response
– Followed by severe hypotension
2013/05/28 52
BY THE WAY….
ONE ABSOLUTE CONTRAINDICATION
FOR THE ADMINISTRATION OF ALL
THE INDUCTION AGENTS AND ALL
THE MUSCLE RELAXANTS IS…
2013/05/28 53
BY THE WAY….
…A COMPROMISED AIRWAY!
(……and that includes Ketamine)
2013/05/28 54
BY THE WAY….
ETOMIDATE
+
PROPOFOL