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 50g/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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