1 intavenous anaesthetic agents dr.c.n.chandra sekhar

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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 solubleRapid recovery –Rapid redistributionAnalgesic at subanaesthetic ConcentrationMinimal CV and Resp. depressionNo emetic effectsNo emergence phenomenaNo Interaction with NMBD

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Intravenous Anaesthetic Agents

Properties of the Ideal IV Anaesthetic Agent:No pain on injectionNo venous sequelaeSafe if injected inadvertantly into an arteryNo toxic effects on other organsNo release of HistamineNo hypersensitivity reactionsWater soluble formulationLong shelf-lifeNo stimulation of Porphyrias.

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Intravenous Anaesthetic Agents

Pharmacokinetics of IV Anaesthetic Agents:After IV rapid in plasma conc. slower

declineAnaesthesia 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 binding2.Blood flow to the brain3.Extracellular pH & pKa of the drug4.The relative solubilities of the drug in lipid

and water5.Speed of Injection

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Intravenous Anaesthetic Agents

1.Protein Binding: Only unbound drug is free to cross the BBBLow plasma proteinDisplacement 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 BBBThe 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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Lean

Viscera

Fat

Pool

% of Dose

0.06 0.125 025 0.5 1 2 4 8 16 32 128 mts

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Classification of Intravenous Anaesthetics

Rapidly acting agents:Barbiturates

MethohexitalThiobarbiturates- thiopental, thiamylal

Imidazole compounds: eg.etomidateSterically hindered alkyl phenols: eg. PropofolSteroids: eg. Eltanalone, Althesin, MinaxoloneEugenol: eg. Propanidid

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Classification of Intravenous Anaesthetics

Slower- acting agents:KetamineBenzodiazepines:- Diazepam, flunitrazepam,

midazolamLarge-dose opioids:- Fentanyl, Alfentanil,

Sufentanil, remifentanilNeurolept combinations:- Opioid +

Neuroleptic

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N

C=O

N

R

C ‖O

O ‖C

C

R

R

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Thiopental Sodium

Chemical Structure:-Sodium 5-ethyl – 5(1-methylbutyl) – 2

thiobarbiturate

Physical properties & Presentation:-Sulphur analogue of pentobarbitalTaste = bitterColour = yellowishState = powderSmell = 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 : 10.8Solution is hypotonicPrepared solution can be kept for 24 hrs.Oil/water partition coefficient 4.7pKa is 7.6

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Thiopental

Central Nervous System:-Onset <30sec after IV injection delayed if CO is lowProgressive depression of CNS and spinal cord

reflexesHypnotic action – potentAnalgesic effect – poorCMRCBF 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 effectReduces pain threshold

Potent anticonvulsantSympathetic effect depressed more than

parasympathetic.Tachycardia

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Thiopentone

Cardiovascular System:-Myocardial contractility depressedPeripheral vasodilationHypotensionHR

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Thiopentone

Respiratory System:-Ventilatory drive In spont.Vent. Vf & Vt in bronchial muscle toneLaryngospasm

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ThiopentoneSkeletal muscle:-

tone at high blood concentrationsNo direct effect on NMJ

Uterus & Placenta:-Contractions suppressed at high dosesCrosses the placenta rapidlyFoetal blood conc. Not reach upto mother’s

Eye:-IOP by 40%Pupils = dilates first and then constrictsLight reflex present until surgical anaesthesia is reachedCorneal,conjunctival,eyelash and eyelid reflexes abolished

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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 alkalemiaConc. Of free drug in hyperventilationDiffuses readily into CNS because of high lipid

solubility.Predominantly unionized (61%) at body pHConsciousness 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 LiverMetabolites excreted in UrineTerminal elimination half-life 11.5 hrs.Metabolism is a Zero order process30% of original drug remain after 24 hrs.Hangover effect commonElimination impaired in elderlyIn 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% solutionInitially 1-2 ml injectedHealthy adults: 4 mg/kg administered over 15-20 sec. Loss of eye reflex within 30secSupplementary dose 50-100mg slowlyChildren 6 mg/kgElderly patients 2.5 – 3 mg/kgInduction smooth, preceded by the taste of garlicNo other drugs should be mixed with Thiopentone

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Thiopentone

Adverse Effects:-HypotensionRespiratory depressionTissue necrosisIntra-arterial injectionLaryngospasmBronchospasmAllergic reactionsThombophlebitis

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Thiopentone

Indications:-Induction of AnaesthesiaMaintenance of AnaestheisaTreatment of Status epilepticusReduce intracranial pressure

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Thiopentone

Absolute Contraindications:Airway ObstructionPorphyriaHypersensitivity reaction to Baribiturates

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Thiopentone

Precautions:-Cardiovascular diseaseSevere hepatic diseaseRenal diseaseMuscle diseaseReduced metabolic rateObstetricsOutpatient anaesthesiaAdrenocortical insufficiencyExtremes of ageasthma

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Thiopentone

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Propofol

Indications:For induction and Maintenance of General

anaesthesiaSedation in Intensive Care Unit and during

Regional anaesthesia techniquesFor treatment of refractory nausea and

vomiting in patients receiving chemotherapyTreatment of status epilepticus

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Propofol

Mode of Action:- Unclear. Potentiates the inhibitory transmitters

glycine and GABA

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Propofol

Routes of Adminstration and Dose: Intravenous bolus dose 1.5 – 2.5 mg/kg for

inductionMaintenance 4-12mg/kg/hourFor 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 dosePlasma 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 durationDecreased laryngeal reflexesInfusion decreases the TV and RRDepresses ventilatory response to CO2

Bronchodilatation due to direct effectPreserves the mechanism of hypoxic

pulm.vaso constriction

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Propofol- pharmacodynamics

Central Nervous System:-Smooth,rapid induction with rapid and clear headed

recoveryIntracranial 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% subjectsEpileptiform movementsFacial parasthesiasBradycardiaNeurological sequelae in children after longterm

use of propofol for sedationQuinol metabolites give green colour to urine

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Propofol-Pharmacokinetics

Distribution:-97% protein bound in plasmaVD is 700 – 1500 LDistribution half-life is 1.3 – 4.1minutes.

Metabolism:-Rapidly metabolised in the liverPrimarily 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

1965Phencyclidine derivativeDissociative anaesthesiaChemical structure:-

2(o-chlorophenyl)-2(methylamino)-cyclohexanone hydrochloride

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Ketamine

Physical characteristics & presentation:-Soluble in water1% with NaCl for istonicity5 & 10% with benzothonium chloride

0.1mg/kg as preservativepH of the solution 3.5 – 5.5pKa of Ketamine 7.5

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Ketamine

Central Nervous System:-Extremely lipid soluble

After IVOnset: 30-60 secDuration: 10-15 min

After IMOnset: 3-4 mts.Duration: 15-25mts

Potent analgesic at subanaesthetic doses

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KetamineCentral Nervous System:- (contd…)

Amnesia persists 1 hr. after recovery of consciousnessInduction smoothEmergence delirium,restlessness,disorientation &

agitationEEG changes – loss of alpha activity & predominant

theta activityCMRCBF CBV ICP

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Ketamine

Cardiovascular System:-Arterial pressure by 25%HR by 20%CO may increaseMyocardial O2 consumption Myocardial sensitivity to EpinephrineVasodilatation in tissues innervated by -adrenergic

receptors & vasoconstriction in those with - receptors

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Ketamine

Respiratory System:-Transient apnoeaPharyngeal & laryngeal reflexes, patent

airway maintainedBronchial 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 proteinInitial peak conc.after IV injection decreases

after drug distributesMetabolism is by liver demethylation &

hydroxylation of cyclohexanone ring (nor-ketamine is the active metabolite)

80% of injected drug excreted as glucuronides

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Ketamine

Pharmacokinetics:- contd……2.5% excreted unchanged in urineElimination 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 &

hallucinationsHypertension & tachycardiaProlonged recoveryIncreased salivationIncreased ICPAllergic reactions

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Ketamine

Indications:-High risk patients:- (shocked patients)Paediatric anaesthesiaDifficult locationsAnalgesia & sedationDeveloping countries

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Ketamine

Absolute contraindications:-Airway obstructionRaised ICP

Precautions:-Cardiovascular diseasesRepeated administrationVisceral stimulationOutpatient anaesthesia (not suitable for adults)

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Total Intravenous Anaesthesia

Indications:Rapid recovery and minimal hangoverMinimal cardiovascular depressionTo 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-2-

pentynyl) barbiturate

Physical Properties & Presentation:-Two asymmetrical carbon atomsWhite powderMixed with 6% anhydrous Na2CO3

1% solution pH 11.1 , pKa 7.9Single dose vial 100mg & multidose vials.5&2.5gm.Stable in solution for about 6 wks.(allowed only

24hrs)

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Methohexital Sodium

Pharmacodynamics:-Central Nervous System:-

Induction 15-30sec.Recovery more rapid than thio (2-3mts.)Drowsiness persists for several hoursEpileptiform activity in EEG seen in epileptic

patients.In sufficient doses acts as anticonvulsant

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Mthohexital Sodium

CVS:-Hypotension less than thioHR increases

RESP:-Moderate hypoventilation

Pharmacokinetics:-More is unionized at body pH( 75%) than thioElmination half life is shorter( appx. 4hrs)

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Methohexital Sodium

Dose & Administration:-1- 1.5mg/kg

Adverse effects:-CVS and Resp. depressionExcitatory phenomena during inductionEpileptiform activityPain on injectionTissue damageIntraarterial injectionAllergic reactionThrombophlebitis

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Etomidate

Chemical Structure:-D-Ethyl-1-(α-methylbenzyl)-imidazole-5-

carboxylate

Physical characteristics and presentation:-Soluble but unstable in waterContains 35% propylene glycol10ml ampoule contains 20mgpH is 8.1

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Etomidate

Pharmacology:-Rapidly actingDuration of action 2-3 mts.Less cardiovascular depressionLarge doses may produce tachycardiaRespiratory 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 proteinMetabolised in liver mainly by esterase

hydrolysisTerminal elimination half life 75mts.

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Etomidate

Dose & administration:-0.3mg/kg

Adverse effects:-Suppression of synthesis of cortisolExcitatory phenomenonPain on injectionNausea and vomitingEmergence phenomenaVenous thrombosis

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Incidence of Adverse reactions:

Thiopentone : 1:14000-1:20000Methohexital : 1:1600- 1:7000Althesin : 1:400- 1:11000Propanidid : 1:500- 1:1700Etomidate :1: 450000Propofol :1:50000- 100000