2Intravenous Anaesthetic Agents Induction with IV Anaesthetic agents is smoother and rapid than inhalational agents
3Intravenous 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
4Intravenous 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.
5Intravenous 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
6Intravenous 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
7Intravenous 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
8Intravenous 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.
9Intravenous 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.
10Intravenous 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
16ThiopentalStored in Nitrogen to prevent chemical reaction with atmospheric CO26% anhydrous sodium carbonate to increase solubility in water2.5% solution pH : 10.8Solution is hypotonicPrepared solution can be kept for 24 hrs.Oil/water partition coefficient 4.7pKa is 7.6
17Thiopental 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
18Thiopental - CNSRecovery 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 thresholdPotent anticonvulsantSympathetic effect depressed more than parasympathetic.TachycardiaMay represent altered redistributionTachycardia at induction may be due to baroreceptor inhibition caused by modest hypotension, partly because of loss of vagal tone.
20Thiopentone Respiratory System:- Ventilatory drive In spont.Vent. Vf & Vt in bronchial muscle toneLaryngospasmVentilatory drive decreases, due to reduced sensitivity of the resp. centre to CO2-increase in bronchial muscle tone, frank bronchospasm is uncommon-Laryngeal spasm precipitated by surgical stimulation or presence of secretions, blood or foreign bodies eg.oropharyngeal airway and LMA
21Thiopentone Skeletal muscle:- Uterus & Placenta:- Eye:- tone at high blood concentrationsNo direct effect on NMJUterus & Placenta:-Contractions suppressed at high dosesCrosses the placenta rapidlyFoetal blood conc. Not reach upto mother’sEye:-IOP by 40%Pupils = dilates first and then constrictsLight reflex present until surgical anaesthesia is reachedCorneal,conjunctival,eyelash and eyelid reflexes abolishedDecreased skeletal muscle tone is due to suppression of spinal cord reflexes
22Thiopentone Hepatorenal Function:- Transient impairement of liver and kidney functions.Hepatic microsomal enzymes are induced metabolism & elimination of other drugs.
23Thiopentone 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)-More free drug available in Hypoalbuminemia and malnutritionPhenylbutazone competes for same binding site on protein, so it decreases thiopentone binding.
24Thiopentone Pharmacokinetics:- (contd….) Metabolism occurs in Liver Metabolites 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.Small portion excreted unchanged in urine
25Thiopentone Dosage & adminstration:- Adminstered as 2.5% solution Initially 1-2 ml injectedHealthy adults: 4 mg/kg administered over sec.Loss of eye reflex within 30secSupplementary dose mg slowlyChildren 6 mg/kgElderly patients 2.5 – 3 mg/kgInduction smooth, preceded by the taste of garlicNo other drugs should be mixed with Thiopentone
26Thiopentone Adverse Effects:- Hypotension Respiratory depression Tissue necrosisIntra-arterial injectionLaryngospasmBronchospasmAllergic reactionsThombophlebitis-Hypotension: should not be administered in sitting position-Tissue necrosis: perivenous injection ( inject hyaluronidase)-Median Nerve damage after extravasation drug in the antecubital fossa-Intra-arterial injection:-Brachial artery, abrrent ulnar artery, intense burning pain- stop injecting the drug.-forearm and hand blanched & blisters distally-Intra-arterial thio causes profound contraction of artery accompanied by local release of norepinephrine.-Crystals of thiopentone formed in arteries leading to thrombosis caused by endarteritis.-ATP release from damaged redcells & aggregation of platelets result in emboli and may cause ischemia or gangrene of forearm, hand or fingers.-Treatment:- Leave the needle in the artery- administer vasodilator (Papavarine 20mg)- stellate ganglion or Brachial plexus block may reduce arterial spasm- IV heparin & oral anticoagulants after surgery.-Bronchospasm- precipitated in asthmatics-Allergic reactions- range from cutaneous rash to fatal anaphylaxis or anaphylactoid reactions with caridovascular collapse.-Thrombophlebitis- uncommon with 2.5% solution
27Thiopentone Indications:- Induction of Anaesthesia Maintenance of AnaestheisaTreatment of Status epilepticusReduce intracranial pressure
28Thiopentone Absolute Contraindications: Airway Obstruction Porphyria Hypersensitivity reaction to Baribiturates
29Thiopentone Precautions:- Cardiovascular disease Severe hepatic diseaseRenal diseaseMuscle diseaseReduced metabolic rateObstetricsOutpatient anaesthesiaAdrenocortical insufficiencyExtremes of ageasthma-Renal disease:- in CRF – protein binding reduced and elimination is not altered-muscle disease:- resp.depression exaggerated , eg. In pt.s with Myasthenia gravis or dystrophia myotonica-Reduced metabolic rate:-Myxoedema-Obstetrics:- excess dose may result in resp. & CVS depression of foetus.-Outpatient anaesthesia:- persistant drowsiness for hrs.
31Propofol 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
32PropofolMode of Action:- Unclear Potentiates the inhibitory transmitters glycine and GABA
33Propofol 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%
34Propofol 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.
35Propofol- pharmacodynamics CVS: % drop in Blood pressure and SVR without comp. Increase in HR-20% decrease in Cardiac output-attenuates laryngoscopic response-Vasodilatation due to NO release
36Propofol- pharmacodynamics Respiratory System:Apnea for variable durationDecreased laryngeal reflexesInfusion decreases the TV and RRDepresses ventilatory response to CO2Bronchodilatation due to direct effectPreserves the mechanism of hypoxic pulm.vaso constriction
37Propofol- pharmacodynamics Central Nervous System:-Smooth,rapid induction with rapid and clear headed recoveryIntracranial pressure,cerebral perfusion pressure, cerebral oxygen consumption reducedGIT:-Propofol has got intrinsic antiemetic properties, mediated by antagonism of dopamine D2 receptors.
38Propofol- Pharmacodynamics Renal:-Causes reduction in excretion of Na+ ionsMetabolic:-Longterm use causes hypertriglyceridemia
39Propofol 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
40Propofol-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.
41Propofol Chemical:- 2,6 – diisopropylphenol Presentation:- White oil in water emulsion containing 1 to 2% propofol in soyabean oil and purified egg phosphatideMain Action:- Hypnotic
43Ketamine Physical characteristics & presentation:- Soluble in water 1% with NaCl for istonicity5 & 10% with benzothonium chloride 0.1mg/kg as preservativepH of the solution 3.5 – 5.5pKa of Ketamine 7.5
44Ketamine Central Nervous System:- Extremely lipid soluble After IVOnset: secDuration: minAfter IMOnset: 3-4 mts.Duration: 15-25mtsPotent analgesic at subanaesthetic doses
45Ketamine Central 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
46Ketamine 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
48Ketamine Skeletal Muscle:- GI system:- Uterus & Placenta:- Eye:- Muscle tone GI system:-Salivation is increasedUterus & Placenta:-Crosses placenta readilyEye:-IOP
49Ketamine Pharmacokinetics:- 12% is bound to protein Initial 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
50Ketamine Pharmacokinetics:- contd…… 2.5% excreted unchanged in urine Elimination half-life 2.5hrs.Peak conc. Achieved after 20 mts. After IM inj.-(slowered if given with halothane,benzodiazepines or barbiturates)
51Ketamine Dosage & administration:- Induction of Anaesthesia:- 2mg/kg IV, mg/kg required every 5-10mts.8-10mg/kg IM.mg/kg or 50g/kg/min infusion for analgesia without loss of consciousness
55Total Intravenous Anaesthesia Indications:Rapid recovery and minimal hangoverMinimal cardiovascular depressionTo deliver High oxygen concentrationTo avoid nitrous oxide
56Methohexital Sodium Chemical Structure:- Sodium-α-dl-5-allyl-1-methyl-5(1-methyl-2-pentynyl) barbituratePhysical Properties & Presentation:-Two asymmetrical carbon atomsWhite powderMixed with 6% anhydrous Na2CO31% solution pH , pKa 7.9Single dose vial 100mg & multidose vials.5&2.5gm.Stable in solution for about 6 wks.(allowed only 24hrs)
57Methohexital 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
58Mthohexital Sodium CVS:- RESP:- Pharmacokinetics:- Hypotension less than thioHR increasesRESP:-Moderate hypoventilationPharmacokinetics:-More is unionized at body pH( 75%) than thioElmination half life is shorter( appx. 4hrs)
59Methohexital Sodium Dose & Administration:- Adverse effects:- 1- 1.5mg/kgAdverse effects:-CVS and Resp. depressionExcitatory phenomena during inductionEpileptiform activityPain on injectionTissue damageIntraarterial injectionAllergic reactionThrombophlebitis
60Etomidate Chemical Structure:- D-Ethyl-1-(α-methylbenzyl)-imidazole-5-carboxylatePhysical characteristics and presentation:-Soluble but unstable in waterContains 35% propylene glycol10ml ampoule contains 20mgpH is 8.1
61Etomidate Pharmacology:- Rapidly acting Duration of action 2-3 mts. Less cardiovascular depressionLarge doses may produce tachycardiaRespiratory depression is lessImpairs synthesis of cortisol from adrenal gland.Longterm infusion in ICU leads to increased infection and Mortality.
62Etomidate Pharmacodynamics:- 76% bound to protein Metabolised in liver mainly by esterase hydrolysisTerminal elimination half life 75mts.
63Etomidate Dose & administration:- Adverse effects:- 0.3mg/kg Suppression of synthesis of cortisolExcitatory phenomenonPain on injectionNausea and vomitingEmergence phenomenaVenous thrombosis