Transcript Document
Intavenous Anaesthetic Agents
Dr.C.N.Chandra Sekhar
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Intravenous Anaesthetic Agents
Induction with IV Anaesthetic agents is
smoother and rapid than inhalational
agents
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Intravenous Anaesthetic Agents
Properties of the Ideal IV Anaesthetic Agent:
Rapid onset – mainly unionized at blood pH
- highly lipid soluble
Rapid recovery –Rapid redistribution
Analgesic at subanaesthetic Concentration
Minimal CV and Resp. depression
No emetic effects
No emergence phenomena
No Interaction with NMBD
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Intravenous Anaesthetic Agents
Properties of the Ideal IV Anaesthetic Agent:
No pain on injection
No venous sequelae
Safe if injected inadvertantly into an artery
No toxic effects on other organs
No release of Histamine
No hypersensitivity reactions
Water soluble formulation
Long shelf-life
No stimulation of Porphyrias.
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Intravenous Anaesthetic Agents
Pharmacokinetics of IV Anaesthetic
Agents:
After IV rapid in plasma conc. slower
decline
Anaesthesia is produced by diffusion of drug
from arterial blood across BBB into the
brain
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Intravenous Anaesthetic Agents
Rate of transfer into the brain and
anaesthetic effect is regulated by:
1.Protein binding
2.Blood flow to the brain
3.Extracellular pH & pKa of the drug
4.The relative solubilities of the drug in lipid
and water
5.Speed of Injection
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Intravenous Anaesthetic Agents
1.Protein Binding: Only unbound drug is
free to cross the BBB
Low plasma protein
Displacement from proteins by other drugs
increase free drug conc.
Hyperventilation decreases protein binding
and increases anaesthetic effect
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Intravenous Anaesthetic Agents
2.Blood Flow to the Brain:
Reduced blood flow
reduced delivery
of the drug.
If CBF is decreased due to low Cardiac
output---initial blood conc. Higher than N,
i.e Anaesthetic effect may be delayed but
enhanced.
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Intravenous Anaesthetic Agents
3.Extracellular pH & pKa of the drug:
Only non-ionized fraction of the drug
penetrates the lipid BBB
The potency of the drug depends on the
degree of ionization at the pH of
extracellular fluid & pKa of the drug.
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Intravenous Anaesthetic Agents
4.The relative solubilities of the drug in
lipid and Water:
High lipid solubility enhances transfer into
brain.
5.Speed of Injection:
Rapid IV adminstration high initial conc.
increases speed of induction and extent of
CV and Resp.side effects
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Pool
Lean
% of
Dose
Viscera
Fat
0.06 0.125 025
0.5 1 2 4
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16 32
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128 mts
Classification of Intravenous
Anaesthetics
Rapidly acting agents:
Barbiturates
Methohexital
Thiobarbiturates- thiopental, thiamylal
Imidazole compounds: eg.etomidate
Sterically hindered alkyl phenols: eg. Propofol
Steroids: eg. Eltanalone, Althesin, Minaxolone
Eugenol: eg. Propanidid
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Classification of Intravenous
Anaesthetics
Slower- acting agents:
Ketamine
Benzodiazepines:- Diazepam, flunitrazepam,
midazolam
Large-dose opioids:- Fentanyl, Alfentanil,
Sufentanil, remifentanil
Neurolept combinations:- Opioid +
Neuroleptic
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O
‖
C
N
R
C=O
C
R
C
‖
O
N
R
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Thiopental Sodium
Chemical Structure:Sodium 5-ethyl – 5(1-methylbutyl) – 2
thiobarbiturate
Physical properties & Presentation:Sulphur analogue of pentobarbital
Taste = bitter
Colour = yellowish
State
= powder
Smell = garlic
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Thiopental
Stored in Nitrogen to prevent chemical reaction
with atmospheric CO2
6% anhydrous sodium carbonate to increase
solubility in water
2.5% solution pH : 10.8
Solution is hypotonic
Prepared solution can be kept for 24 hrs.
Oil/water partition coefficient 4.7
pKa is 7.6
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Thiopental
Central Nervous System:Onset <30sec after IV injection
delayed if CO is low
Progressive depression of CNS and spinal cord
reflexes
Hypnotic action – potent
Analgesic effect – poor
CMR
CBF
CBV
ICP
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Thiopental - CNS
Recovery of consciousness occurs at high blood
concentrations if a large dose is given or if the
drug is injected rapidly (acute tolerance)
Consciousness regained in 5-10mts.
At subanaesthetic conc.
Antanalgesic effect
Reduces pain threshold
Potent anticonvulsant
Sympathetic effect depressed more than
parasympathetic.
Tachycardia
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Thiopentone
Cardiovascular System:Myocardial contractility depressed
Peripheral vasodilation
Hypotension
HR
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Thiopentone
Respiratory System:Ventilatory drive
In spont.Vent. Vf & Vt
in bronchial muscle tone
Laryngospasm
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Thiopentone
Skeletal muscle: tone at high blood concentrations
No direct effect on NMJ
Uterus & Placenta:Contractions suppressed at high doses
Crosses the placenta rapidly
Foetal blood conc. Not reach upto mother’s
Eye:IOP by 40%
Pupils = dilates first and then constricts
Light reflex present until surgical anaesthesia is
reached
Corneal,conjunctival,eyelash and eyelid reflexes21
Thiopentone
Hepatorenal Function:Transient impairement of liver and kidney
functions.
Hepatic microsomal enzymes are induced
metabolism & elimination of other drugs.
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Thiopentone
Pharmacokinetics:75-85% drug is protein bound (mostly albumin)
Protein binding affected by pH I.e by alkalemia
Conc. Of free drug in hyperventilation
Diffuses readily into CNS because of high lipid
solubility.
Predominantly unionized (61%) at body pH
Consciousness returns when the brain concentration
returns to a threshold value( vary from patient to
patient)
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Thiopentone
Pharmacokinetics:- (contd….)
Metabolism occurs in Liver
Metabolites excreted in Urine
Terminal elimination half-life 11.5 hrs.
Metabolism is a Zero order process
30% of original drug remain after 24 hrs.
Hangover effect common
Elimination impaired in elderly
In obese dose should be based on lean body mass as
distribution to fat is slow.
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Thiopentone
Dosage & adminstration:Adminstered as 2.5% solution
Initially 1-2 ml injected
Healthy adults: 4 mg/kg administered over 15-20
sec.
Loss of eye reflex within 30sec
Supplementary dose 50-100mg slowly
Children 6 mg/kg
Elderly patients 2.5 – 3 mg/kg
Induction smooth, preceded by the taste of garlic
No other drugs should be mixed with Thiopentone
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Thiopentone
Adverse Effects:Hypotension
Respiratory depression
Tissue necrosis
Intra-arterial injection
Laryngospasm
Bronchospasm
Allergic reactions
Thombophlebitis
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Thiopentone
Indications:Induction of Anaesthesia
Maintenance of Anaestheisa
Treatment of Status epilepticus
Reduce intracranial pressure
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Thiopentone
Absolute Contraindications:
Airway Obstruction
Porphyria
Hypersensitivity reaction to Baribiturates
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Thiopentone
Precautions:Cardiovascular disease
Severe hepatic disease
Renal disease
Muscle disease
Reduced metabolic rate
Obstetrics
Outpatient anaesthesia
Adrenocortical insufficiency
Extremes of age
asthma
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Thiopentone
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Propofol
Indications:
For induction and Maintenance of General
anaesthesia
Sedation in Intensive Care Unit and during
Regional anaesthesia techniques
For treatment of refractory nausea and
vomiting in patients receiving chemotherapy
Treatment of status epilepticus
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Propofol
Mode of Action:-
transmitters
and GABA
Unclear.
Potentiates the
inhibitory
glycine
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Propofol
Routes of Adminstration and Dose:
Intravenous bolus dose 1.5 – 2.5 mg/kg for
induction
Maintenance 4-12mg/kg/hour
For children induction dose should be
increased by 50% and Manintenance
infusion by 25-50%
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Propofol
Consciousness lost in 30 sec.
Recovery about 10mts after a single dose
Plasma concentration of 2-6mcg/ml
associated with hypnosis.
Plasma conc. of 0.5 – 1.5 mcg/ml
associated with sedation.
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Propofol- pharmacodynamics
CVS: -
-15-25% drop in Blood pressure
and SVR without comp.
Increase
in HR
-20% decrease in Cardiac output
-attenuates laryngoscopic response
-Vasodilatation due to NO release
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Propofol- pharmacodynamics
Respiratory System:
Apnea for variable duration
Decreased laryngeal reflexes
Infusion decreases the TV and RR
Depresses ventilatory response to CO2
Bronchodilatation due to direct effect
Preserves the mechanism of hypoxic
pulm.vaso constriction
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Propofol- pharmacodynamics
Central Nervous System:Smooth,rapid induction with rapid and clear headed
recovery
Intracranial pressure,cerebral perfusion pressure,
cerebral oxygen consumption reduced
GIT:Propofol has got intrinsic antiemetic properties,
mediated by antagonism of dopamine D2 receptors.
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Propofol- Pharmacodynamics
Renal:Causes reduction in excretion of Na+ ions
Metabolic:Longterm use causes hypertriglyceridemia
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Propofol
Toxicity and side effects:Pain on injection seen in 28% subjects
Epileptiform movements
Facial parasthesias
Bradycardia
Neurological sequelae in children after longterm use
of propofol for sedation
Quinol metabolites give green colour to urine
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Propofol-Pharmacokinetics
Distribution:97% protein bound in plasma
VD is 700 – 1500 L
Distribution half-life is 1.3 – 4.1minutes.
Metabolism:Rapidly metabolised in the liver
Primarily to inactive glucuronide and sulphate
conjugates and the corresponding quinol.
Renal and hepatic disease have no significant effect
on the metabolism.
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Propofol
Chemical:-
2,6 – diisopropylphenol
Presentation:- White oil in water emulsion
containing 1 to 2% propofol
in soyabean oil and purified
egg phosphatide
Main Action:-
Hypnotic
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Ketamine Hydrochloride
1965
Phencyclidine derivative
Dissociative anaesthesia
Chemical structure:2(o-chlorophenyl)-2(methylamino)cyclohexanone hydrochloride
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Ketamine
Physical characteristics & presentation:Soluble in water
1% with NaCl for istonicity
5 & 10% with benzothonium chloride
0.1mg/kg as preservative
pH of the solution 3.5 – 5.5
pKa of Ketamine 7.5
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Ketamine
Central Nervous System:Extremely lipid soluble
After IV
Onset: 30-60 sec
Duration: 10-15 min
After IM
Onset: 3-4 mts.
Duration: 15-25mts
Potent analgesic at subanaesthetic doses
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Ketamine
Central Nervous System:- (contd…)
Amnesia persists 1 hr. after recovery of consciousness
Induction smooth
Emergence delirium,restlessness,disorientation &
agitation
EEG changes – loss of alpha activity & predominant
theta activity
CMR
CBF
CBV
ICP
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Ketamine
Cardiovascular System:Arterial pressure by 25%
HR by 20%
CO may increase
Myocardial O2 consumption
Myocardial sensitivity to Epinephrine
Vasodilatation in tissues innervated by -adrenergic
receptors & vasoconstriction in those with receptors
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Ketamine
Respiratory System:Transient apnoea
Pharyngeal & laryngeal reflexes, patent
airway maintained
Bronchial muscle is dilated
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Ketamine
Skeletal Muscle:Muscle tone
GI system:Salivation is increased
Uterus & Placenta:Crosses placenta readily
Eye:IOP
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Ketamine
Pharmacokinetics:12% is bound to protein
Initial peak conc.after IV injection decreases
after drug distributes
Metabolism is by liver demethylation &
hydroxylation of cyclohexanone ring (norketamine is the active metabolite)
80% of injected drug excreted as
glucuronides
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Ketamine
Pharmacokinetics:- contd……
2.5% excreted unchanged in urine
Elimination half-life 2.5hrs.
Peak conc. Achieved after 20 mts. After IM
inj.
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Ketamine
Dosage & administration:Induction of Anaesthesia:2mg/kg IV, 1-1.5mg/kg required every 5-10mts.
8-10mg/kg IM.
0.25-0.5mg/kg or 50g/kg/min infusion for
analgesia without loss of consciousness
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Ketamine
Adverse effects:
Emergence delirium,nightmares &
hallucinations
Hypertension & tachycardia
Prolonged recovery
Increased salivation
Increased ICP
Allergic reactions
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Ketamine
Indications:High risk patients:- (shocked patients)
Paediatric anaesthesia
Difficult locations
Analgesia & sedation
Developing countries
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Ketamine
Absolute contraindications:Airway obstruction
Raised ICP
Precautions:Cardiovascular diseases
Repeated administration
Visceral stimulation
Outpatient anaesthesia (not suitable for adults)
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Total Intravenous Anaesthesia
Indications:
Rapid recovery and minimal hangover
Minimal cardiovascular depression
To deliver High oxygen concentration
To avoid nitrous oxide
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Methohexital Sodium
Chemical Structure:Sodium-α-dl-5-allyl-1-methyl-5(1-methyl-2pentynyl) barbiturate
Physical Properties & Presentation:Two asymmetrical carbon atoms
White powder
Mixed with 6% anhydrous Na2CO3
1% solution pH 11.1 , pKa 7.9
Single dose vial 100mg & multidose vials.5&2.5gm.
Stable in solution for about 6 wks.(allowed only 56
24hrs)
Methohexital Sodium
Pharmacodynamics:Central Nervous System:Induction 15-30sec.
Recovery more rapid than thio (2-3mts.)
Drowsiness persists for several hours
Epileptiform activity in EEG seen in epileptic
patients.
In sufficient doses acts as anticonvulsant
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Mthohexital Sodium
CVS:Hypotension less than thio
HR increases
RESP:Moderate hypoventilation
Pharmacokinetics:More is unionized at body pH( 75%) than thio
Elmination half life is shorter( appx. 4hrs)
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Methohexital Sodium
Dose & Administration:1- 1.5mg/kg
Adverse effects:CVS and Resp. depression
Excitatory phenomena during induction
Epileptiform activity
Pain on injection
Tissue damage
Intraarterial injection
Allergic reaction
Thrombophlebitis
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Etomidate
Chemical Structure:D-Ethyl-1-(α-methylbenzyl)-imidazole-5-carboxylate
Physical characteristics and presentation:Soluble but unstable in water
Contains 35% propylene glycol
10ml ampoule contains 20mg
pH is 8.1
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Etomidate
Pharmacology:Rapidly acting
Duration of action 2-3 mts.
Less cardiovascular depression
Large doses may produce tachycardia
Respiratory depression is less
Impairs synthesis of cortisol from adrenal gland.
Longterm infusion in ICU leads to increased
infection and Mortality.
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Etomidate
Pharmacodynamics:76% bound to protein
Metabolised in liver mainly by esterase
hydrolysis
Terminal elimination half life 75mts.
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Etomidate
Dose & administration:0.3mg/kg
Adverse effects:Suppression of synthesis of cortisol
Excitatory phenomenon
Pain on injection
Nausea and vomiting
Emergence phenomena
Venous thrombosis
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Incidence of Adverse reactions:
Thiopentone
Methohexital
Althesin
Propanidid
Etomidate
Propofol
: 1:14000-1:20000
: 1:1600- 1:7000
: 1:400- 1:11000
: 1:500- 1:1700
:1: 450000
:1:50000- 100000
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