IV ANAESTHETIC AGENTS

• THIOPENTONE SODIUM
• PROPOFOL
• KETAMINE
• MIDAZOLAM
• GENERAL PROPERTIES:
• High lipid solubility
• Poor water solubility at physiological pH
• Most are weak acids except ketamine and etomidate
• Best modulated using a 3 compartment model
• Low initial volume of distribution V1(0.1-0.2 L/kg) except ketamine(1 L/kg)
• Action terminated by distribution to VD of 1-5 L/kg over the next 5
minutes
• Most are extensively protein bound
• Part of their activity is mediated by GABA A receptors (except ketamine)
• Myocardial depressants with an additional hypotensive effects due to
vasodilatation
• Most will cause dose related respiratory depression
• Most are anticonvulsants( except etomidate and methohexitone)
• Most reduce ICP, CBF and CMRO2 but not ketamine
• Hepatic metabolism
 BARBITURIC ACID
• 2,4,6 tri-oxo-hexa hydropyrimidine
• The condensation of urea and mandelic acid-Barbituric acid and H2O
• Barbituric acid itself lacks central depressant activity
• Structure activity: substitution at C2 oxybarbiturate(O=C)
• Thiobarbiturate(S=C)
• Higher lipid solubility producing more rapid onset and shorter duration of
action than oxybarbiturate
• Lipid solubility
• In general structural changes which increase lipophilicity
 Increase hypnotic potency
 Fast on Fast off
 Rapid Onset
 Shorter duration of action
 Rapid recovery
PROPOFOL : (2,6,DI ISOPROPYL PHENOL).

INTRODUCED IN THE YEAR 1977.

PROPOFOL IS THE MOST COMMONLY USED IV ANESTHETIC TODAY. USED FOR
INDUCTION,MAINTAINANCE,AND FOR SEDATION IN AND OUTSIDE OPERATING
ROOM. ( ICU).

PHYSICOCHEMICAL PROPERTY:
GROUP- ALKYLPHENOLS .PH-7. SLIGHTLY VISCOUS MILKY WHITE EMULSION.

• HYPNOTIC AND SEDATIVE.

• OILS AT ROOM TEMPERATURE,
• INSOLUBLE IN AQUEOUS SOLUTION. HIGHLY LIPID
SOLUBLE.
THE FORMULATIONS-EMULSIONS OF 1%PROPOFOL,
10%SOYABEAN OIL,
2.25%GLYCEROL
1.2%PURIFIED EGG PHOSPHATIDE.
DISODIUM EDETATE(0.005%)ADDED AS RETARDANT OF MICROBIAL GROWTH.
• ALL FORMULATIONS ARE STABLE AT ROOM
TEMPERATURE.AND ARE NOT LIGHT SENSITIVE.5%DEXTROSE
IS USED FOR DILUTION.2% FORMULATION ARE AVAILABLE IN
EUROPE.THERE ARE TWO VARIETIES-1)DIPRIVAN HAS
DISODIUM EDETATE0.005%WITH NaOH
• 2)GENERIC-HAS SODIUM METABISULPHITE AS PRESERVATIVE.
• MECHANISM OF ACTION:
• PROPOFOL INTERACTS WITH SPECIFIC MEMBRANE
STRUCTURES THAT DECREASE RATE OF DISSOCIATION OF
GABA FROM ITS RECEPTOR, THERE BY INCREASE DURATION
OF GABA MEDIATED OPENNING OF CL CHANNEL.
 PHARMACOKINETICS

ABSORPTION:PROPOFOL IS AVAILABLE ONLY FOR IV

ADMINISTRATION.

• DISTRIBUTION: HIGHLY LIPID SOLUBLE HENCE RAPID ONSET OF

ACTION .INITIAL DISTRIBUTION HALF LIFE (2-8MIN) A
• LOWER INDUCTION DOSE RECOMMENDED IN ELDERLY PATIENTS
BCOZ OF SMALLER Vd. AND DECRAESED CLEARANCE RATE.

• ELIMINATION HALF LIFE-0.5 TO 1.5 HOURS.

• CONTEXT SENSITIVE HALF TIME OF PROPOFOL INFUSION UPTO
3hours IS 10min.UPTO 8hrs IS 40min.
• NO EVIDENCE OF IMPAIRED ELIMINATION IN
CIRRHOSES PATIENTS. ELIMINATION HALF LIFE IS
PROLONGED.
• RENAL DYSFUNCTION
DOES NOT INFLUENCE PROPOFOL CLEARANCE.
READILY CROSSES PLACENTA.
WOMEN HAVE LARGER Vd AND
HIGHER CLEARANCE.BUT ELIMINATION HALF LIFE
SAME IN MALES AND FEMALES.
• METABOLISM:RAPIDLY METABOLISED IN LIVER BY
CONJUGATION TO GLUCURONIDE,SULFATE.
• 4-OH PROPOFOL IS ACTIVE METABOLITE.
• LUNGS METABOLISE 30% OF UPTAKE AND FIRST PASS
ELIMINATION AFTER BOLUS DOSE.
 PHARMACODYNAMIC
• EFFECT ON CNS :

• THE HYPNOTIC ACTION IS MEDIATED GABA-Cl

CHANNEL CONDUCTANCE.
• NO ANALGESIC ACTION.
• ANTIEMETIC BY DECREASING SERATONIN LEVEL.
PROPOFOL DECREASES CEREBRAL METABOLIC RATE
FOR OXYGEN,DECREASES CEREBRAL BLOOD
FLOW,DECREASES ICP(30-50%) ASSOCIATED WITH
DECREASE CPP. REDUCES IOP(30-40%).
• NORMAL CEREBRAL REACTIVITY TO CO2 AND
AUTOREGULATION IS MAINTAINED DURING
PROPOFOL INFUSION.
• NEUROPROTECTIVE-BY EEG BURSTS
SUPPRESSION.(ANNEURYSMAL SURGERIES).
• ANTIOXIDENT-PHENOL RING,ACTS AS FREE RADICAL
SCAVENGER.
• ANTIOXIDANT ACTIVITY PREVENTS HYPOPERFUSION-
REPERFUSION PHENOMENON THAT CAN OCCUR DURING LAP-
SURGERY.

• NON-EPILEPTIC MYOCLONIA- EXCITATORY MOTOR ACTIVITY

ON IV INDUCTION.
• 0N RS:PROPOFOL PRODUCES DOSE DEPENDENT
DEPRESSION OF VENTILLATION WITH APNOEA WHICH IS
MARKED BY REDUCTION TV, TACHYAPNOEA, VENTILLATORY
RESPONSE TO CO2 REDUCED.
• DOUBLING OF INFUSION RATE DOES NOT INCREASE PaCO2 .
• IT’S A BRONCHO DILATOR .
• ON CVS:MOST PROMINENT EFFECT OF PROPOFOL IS A
DECREASE ARTERIAL BP BY (25-40%) WITH AN INDUCTION DOSE
OF 2-2.5mg/kg
• DIRECT MYOCARDIAL DEPRESSANT EFFECT.
• DECREASES – CARDIAC OUTPUT,STROKE VOLUME,SVR.
• HEART RATE DOES NOT CHANGE SIGNIFICANTLY. SMALLER
INCREASE IN HR INDCATE GREATER FALL IN SBP.
• ENDOCRINE: DOES NOT AFFECT ON CORTISOL
SYNTHESIS, ACTH.
• INHIBITS PHAGOCYTOSES,
PROLIFERATIVE RESPONSE OF LYMPHOCYTES.
• DOSAGE-
• INDUCTION-GA:1-2.5mg/kg REDUCED WITH INCREASING AGE.
• MAINTAINANCE-GA : 50-150mcg/kg/min COMBINED WITH
NITROUS/OPIATE.
• SEDATION : 25-75mcg/kg/min iv
• ANTIEMETIC : 10-20mg iv can repeat every 5-10min.
• USES :
• IV INDUCTION OF ANESTHESIA
• IV SEDATION
• MAINTAINANCE OF ANESTHESIA
• NON HYPNOTIC THERAUPATIC APPLICATIONS:
• ANTIEMETIC
• ANTIPRURITIC-10mgIV IN PRURITIS WITH NEURAXIAL OPIODS AND CHOLESTASES.
• ANTICONVULSANT: 1mg/kg iv
• ATTENUATION OF BRONCHOCONSTRICTION.
• SIDE EFFECTS : OF PROPOFOL DUE
TO PARENT DRUG OR ATTRIBUTED
TO OIL:WATER EMULSION.
• M/C SIDE EFFECT IS HYPOTENSION
• BRADYCARDIA
• INFECTION :PROPOFOL STRONGLY SUPPORTS GROWTH OF E-
COLI,PSEUDOMONAS.AEROGENOSA. AND IS BACTERIOSTATIC TO C.ALBICANS.

• FOR THIS REASON-AN ASEPTIC TECHNIQUE BE USED IN HANDELING

PROPOFOL

• THE CONTENTS OF VIAL SHOULD BE WITHDRAWN IN A STERILE SYRINGE

IMMIDIATELY AFTER OPENNING AND PROMPTLY ADMINISTERED.

• DISCARD REMAINING CONTENTS IF NT USED WITHIN 6hrs.

• IN ICU-DICARD AFTER 12hrs.

• PAIN ON INJECTION: FREE FRACTION OF PROPOFOL IN
AQUEOUS PHASE OF EMULSION RESULTS IN PAIN.

• DECREASED BY PRECEEDING PROPOFOL WITH

1%LIGNOCAINE./OPIATES / INJECTING INTO LARGER VEIN.
• INTRA ARTERIAL INJ: PAIN BUT NO VASCULAR COMPROMISE.
• ABUSE POTENTIAL.
• ALLERGIC REACTION.
PROPOFOL DOES NOT ALTER HEPATIC,RENAL,HEMATOLOGIC OR
FIBRINOLYTIC FUNCTION.
• PROPOFOL INFUSION SYNDROME: LACTIC ACIDOSES, ITS
RARE BUT LETHAL SYNDROME, ASSOCIATED WITH INFUSION
OF PROPOFOL AT 4mg/kg or more FOR 48hrs OR LONGER,
• IT WAS FIRST DESCRIBED IN CHILDREN .
• C/F: BRADYCARDIA L/T ASYSTOLE,
MET.ACIDOSES,RHABDOMYOLYSES, HYPERLIPIDEMIA,FATTY
LIVER, HYPERKALEMIA,SKELETAL MYOPATHY,
• THEORIES ON CAUSES:MITOCHONDRIAL
TOXICITY,DEFECT,CARBOHYDRATE DEFICIENCY,IMPAIRED
TISSUE OXYGENATION.
 MISCELLANEOUS
• MISCELLANEOUS EFFECTS:
• DOES NOT TRIGGER MALIGNANT HYPERTHERMIA.
• USED IN COPROPORPHYRIA.
• NO INFLUENCE ON CORTISOL SECRETION EVEN ON
PROLONGED PERIODS OF ADMINISTRATION.
• KETAMINE :{KETALAR,KETAJECT}
• ITS A PHENCYCLIDINE.(ARYLCYCLOHEXYL AMINE).
• 1962:FIRST SYNTHESISED BY DR.CALVIN.
• 1966:DISSOCIATIVE ANESTHESIA WAS CREATED – GUENTER
CORRSEN.
• WAS THE FIRST ANESTHETIC TO BE USED. SINCE 1970 ITS
BEEN CLINICALLY USED.
• MECH. OF ACTION :BINDS NON-COMPETITIVELY ON NMDA
RECEPTOR.
• IT DOES NOT INTERACT WITH GABA RECEPTOR.
• PHYSICO CHEMICAL PROPERTIES:
• MW-238kd, water soluble COMPOUND. ph- 3.5.
• PRESERVATIVE USED IS BENZOTHORIUM CL.
• PRODUCES PROFOUND ANALGESIA,
• PRODUCES DISSOCIATIVE ANESTHESIA CHARACTERISED BY
DISSOCIATION BTWN THALAMO CORTICAL AND LIMBIC
SYSTEM . RESEMBLES A CATALEPTIC STATE WITH VARYING
DEGREES OF HYPERTONIC,PURPOSEFULL SKELETAL
MOVEMENTS.EYES OPEN , NYSTAGMUS GAZE,PT IS
NONCOMMUNICATIVE.
• PRODUCES EMERGENCE DELIRIUM.
• PHARMACO KINETIC:
• HIGH LIPID SOLUBILITY-LARGE Vd,
• ELIMINATION ½ LIFE-2-3hrs.
• AVAILABLE IN 1%,5%,10%AQUEOUS SOLUTON.
• METABOLISM:
• MET.EXTENSIVELY IN LIVER.
• CYTO-P450:DEMETHYLATION L/T NORKETAMINE(ACTIVE
METABOLITE) 1/3-1/5th AS POTENT AS KETAMINE. ITS
RESPONSIBLE FOR PROLONGED EFFECTS OF ANALGESIA.ON
RPTD DOSE/INFUSION.
• EXCRETED THROUGH KIDNEY.
• PHARMACOLOGY:
• CNS- DOSE RELATED UNCONSCIOUSNESS AND ANALGESIA.
• IV SINGLE DOSE-2mg/kg,PRODUCES 10-15min ANESTHESIA.
• INCREASES-CMR,CBF,ICP,IOP.
• EMERGENCE REACTION-DREAMING,SENSE OF FLOATING OUT
OF THE BODY. D/T AUDITORY/VISUAL RELAY NUCLEII
DEPRESSION.
• BZD MOST AFFECTIVE IN ATTENUATING THIS REACTION.
• RS:
• BRONCHODILATOR EFFECT, ITS IV INDUCTION OF CHOICE IN
BRONCHOSPASM(COPD) .
• PROTECTIVE AIRWAY REFLEXES PRESERVED (THIS DOSENT
OBVIATE NEED FOR INTUBATION)
• INCREASES SECRETIONS(LARINGOSPASM IN LIGHT PLANES).
• CVS:
• ONLY ANESTHETIC INCREASES PVR, HR , SBP.
• DIRECT SYMPATHETIC STIMULATION.
• NEGATIVELY AFFECTS BALANCE BTWN MYOCARDIAL OXYGEN
SUPPLY N DEMAND. (C/I CAD).
• DOSE:
• INDUCTION-GA:0.5-2mg/kg iv
• 4-6mg/kg im.
• MAINTAINANCE-GA : 0.5-1mg/kg iv
• SEDATION : 0.2-0.8mg/kg iv over 2-3 min .
 USES
• ANALGESIA-GREATER FOR SOMATIC THAN VISCERAL PAIN.
• INDUCTION OF ANESTHESIA-
• MOST CANDIDATES BELONG TO ASA-GRADE 4.AND CVS DISORDERS(IHD),
REACTIVE AIRWAY DISEASE, SEPTIC SHOCK , HYPOVOLEMIA.
• IN MALIGNANT HYPERTHERMIA,
• CONGENITAL HEART DISEASE WITH RISK OF RT – LT SHUNTS.
• PAIN MANAGEMENT-CANCER PAIN,NEUROPATHIC PAIN,
ISCHEMIC/PHANTUM LIMB.
• SEDATION-PEDIATRIC GROUP THEY HAVE FEWER ADVERSE EMERGENCE
REACTION .
• REVERSAL OF OPIOD TOLERANSE.
• RESTLESS LEG SYNDROME
• SIDE EFFECTS-
• EMERGENCE REACTION.

• CONTRAIDICATED- PTS WITH HIGH ICP, ICSOL, OPEN EYE

INJURY,, VASCULAR ANNEURYSMS,PTS WITH PSYCHIATRIC
DISORDERS(SCHIZOPHRENIA).
• BENZODIAZEPINE-
• HISTORY: DIAZEPAM WAS FIRST DESCRIBED FOR IV
ANESTHETIC INDUCTION IN 1965.
• MIDAZOLAM WAS SYNTHESISED IN 1976.
• CLASSIFIED:
• SHORT ACTING-MIDAZOLAM.
• INTERMIDIATE-DIAZEPAM.
• LONG ACTING-LORAZEPAM.
• PHYSICOCHEMICAL PROPERTIES:
• MIDAZOLAM SOLUTION (1-5mg/ml) CONTAINS 0.8%
SODIUM CL, 0.01% DISODIUM EDETATE,1% BENZYL
ALCOHOL AS PRESERVATIVE.
• PH-3.5 ,
• HIGHLY LIPID SOLUBLE ACCOUNTS FOR RAPID CNS
EFFECT AND LARGE Vd.
• METABOLISM: BIOTRANSFORMATION OF BZDS OCCUR IN
LIVER. HEPATIC MICROSOMAL OXIDATION AND
GLUCURONIDE CONJUGATION.
• AGE,SMOKING, NO EFFECT ON MIDAZOLAM
BIOTRANSFORMATION.
• ALCOHOL CONSUMPTION INCREASES BIOTRANSFORMATION
OF MIDAZOLAM.
• EXCRETED LARGELY BY KIDNEYS, CAN CAUSE PROFOUND
SEDATION IN PATIENTS WITH RENAL IMPAIRMENT.
• M.O.A:
• SPECIFIC RECEPTOR SITE THAT R PART OF GABA RECEPTOR
COMPLEX.
• INCREASES EFFICIENCY OF COUPLING OF GABA RECEPTOR N
CL CHANNEL COMPLEX.
• PRODUCES CEILING EFFECT.
• PHARMACOKINETICS:
• MIDAZOLAM IS A SHORT ACTING DRUG WITH CLEARANCE
RATE 6-11ml/kg/min, AS COMPARED TO
– LORAZEPAM . 8-1.8ml/kg/min, AND
DIAZEPAM 2-5ml/kg/min.
• TERMINATION OF ACTION IS PRIMARILY BY REDISTRIBUTION.
• AGE,GENDER,RACE,ENZYME INDUCTION,HEPATIC AND RENAL
DISEASES ARE FACTORS INFLUENCING PKINETICS.
• IN OBESE PTS Vd IS INCREASED AS DRUG ACCUMALATES IN
ADiPOSE TISSUES, ELIMINATION ½ LIFE PROLONGED.
• PHARMACOLOGY:

• CNS: DOSE RELATED MANNER REDUCE CMRO2 , CBF BY 34% WITH

INDUCTION DOSE OF .15mg/kg.
• INCREASES SEIZURRE THRESSHOLD.

• RS : DOSE RELATED CENTRAL RESPIRATORY DEPRESSION.

• CO2 RESPONSE CURVE SLOPE IS FLATTER,

• 0.13-0.2mg/kg DOSE OF MIDAZOLAM PRODUCES VENTILLATORY

DEPRESSION DEPENDS ON THE RATE OF ADMINISTRATION.

• DEPRESSES UPPER AIRWAY REFLEXES.

• CVS: PREDOMINENT HEMODYNAMIC CHANGE IS REDUCTION
IN ARTERIAL BP D/T DECREASE IN SVR.
• HR,COP, VENIRICULAR FILLING PRESSURE IS MAINTAINED.
• USES:
• INDUCTION : MIDAZOLAM IS THE BZD OF CHOICE FOR
INDUCTION,
• 0.2mg/kg DOSE INDUCES ANESTHESIA IN 28sec
• ABOVE 55yrs AND ASA STATUS III .REQUIRE 20% OR MORE
REDUCTION DOSE.
• IV SEDATION: PRE-OP MEDICATION, INTRA-OP
REGIONAL/LOCAL ANESTHESIA. POST-OP.
• ORAL SEDATION
• PONV.
• DOSAGE : MIDAZOLAM
• INDUCTION- 0.1-0.2mg/kg.
• MAINTAINANCE- 0.05mg/kg.
• SEDATION -0.5-1mg.
• SIDE EFFECT : RESPIRATORY DEPRESSION.

• FLUMEZINIL : FIRST BZD RECEPTOR ANTAGONIST FOR

CLINICAL USE,
• IT’S A COMPETITIVE ANTAGONIST,
• USED TO REVERSE MIDAZOLAM {BZD}.
• DOSE: REVERSAL BZD-0.2mg repeated upto 3mg.
• MIDAZOLAM IS THE MOST WIDELY USED FOR
SEDATION IN ICU.
• 0.05-5mg/kg/min EFFECTIVE IN PROVIDING
SEDATION IN HEAMODYNAMICALLY
UNSTABLE PTS IN ICU.
 CONCLUSION
• DESPITE THE INTRODUCTION OF NEW ANESTHETIC
AGENTS ,ITS OBVIOUS THAT MANY OF THE GOALS
DESIRABLE IN AN IDEAL IV ANESTHETIC HAVE NOT
BEEN ACHIEVED WITH ANY OF THE CURRENTLY
AVAILABLE DRUGS .
• NEVERTHELESS EACH OF THESE SEDATIVE-HYPNOTIC
DRUGS CH. USEFULL WHEN COMBINED WITH
APPROPRIATE MULTIMODEL ANALGESIC
TECHNIQUE. PROVIDING AN EXCELLENT
ANESTHESIA.
THANK YOU………