IV induction agents

Presenter: Anish Mohan
Moderator: Dr. Pavan G
S

• These are drugs that when given intravenously in
an appropriate dose, cause a rapid loss of
consciousness

CLASSIFICATION BASED ON CHEMICAL
STRUCTURE
BARBITURATES PHENCYCLIDINES
• Thiopental • Ketamine
• Thiamylal
• Methohexital BENZODIAZEPINES
• Midazolam
PHENOLS
• Propofol
IMIDAZOLES
• Etomidate

MOST COMMONLY USED ONES
• Thiopental
• Propofol
• Etomidate
• Ketamine

IDEAL IV ANAESTHETIC AGENT
• SHOULD BE WATER SOLUBLE, STABLE IN SOLUTION AND LONG SHELF LIFE.
• LACK OF PAIN ON INJECTION, VENO IRRITATION OR TISSUE DAMAGE FROM
EXTRAVASATION.
• LOW POTENTIAL TO RELEASE HISTAMINE OR PRECIPITATE HYPERSENSITIVITY
REACTIONS.
• RAPID AND SMOOTH ONSET OF ACTION.
• RAPID METABOLISM TO PHARMACOLOGICALLY INACTIVE METABOLITES.
• SHOULD PRODUCE SLEEP IN ONE ARM BRAIN CIRCULATION TIME.
• LACK OF CVS & RS DEPRESSION.
• RAPID AND SMOOTH RETURN OF CONSCIOUSNESS AND COGNITIVE SKILLS.
• ABSENCE OF POST-OPERATIVE NAUSEA AND VOMITING OR PROLONGED
SEDATION.

 Sulphur derivative of Barbituric Acid.
i.e. Thio barbiturate.
 Ultra short acting barbiturate.

POOR ANALGESIC, WEAK MUSCLE RELAXANT.
Commonest inducing agent used.

Fig : Chemical Structure of Thiopentone
Sulphur make it more lipid soluble and more potent
 Sulphur at second carbon atom position.
5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid

PROPERTIES
Highly soluble in water / NS yielding highly
alkaline solution,stable for 48 hrs.
 Powder form stable at room temperature.
 Refrigerated solution stable up to 2 week.

• PH OF 2.5% SOLUTION IS 0.5.
• COMMERCIAL PREPARATION CONTAIN IT SODIUM SALT
WITH ANHYDROUS SODIUM CARBONATE TO PREVENT
PRECIPITATION OF ACID FORM.
• AVAILABLE AS 1 GM POWDER FOR RECONSTITUTION.

• 1 GM YELLOW POWDER
• RECONSTITUTED WITH 20 ML NORMAL SALINE
TO GET 50MG/ML SOLUTION
• FROM THAT 5 ML (250MG) IS TAKEN AND
DILUTED TO 10ML
• TO BECOME 250/10 => 25MG/ML

PHARMACOKINETICS
 Onset of action of i.v. injection - 10-20 sec.
peak 30-40 sec. duration for awakening 5-15
min.
Volume of distribution is 2.5 Lit. per Kg.

 Ultimate elimination due to hepatic
metabolism.
 Effect site equilibration time is rapid.
Brain – 30 Sec. Muscle – 15 Min. Fat > 30
Min.

TERMINATION OF ACTION
1) Redistribution
a) Lipid solubility (most important factor)
 High Lipid Solubility makes it to cross blood
brain
barrier & lean body tissue rapidly.
b) Protein Binding
 Highly bound to albumin & other plasma
protein.
 72 – 86% Binding.

 Affected by physiological PH. Disease state &
parallels lipid solubility
 Hepatic disease & chronic renal disease
decrease
protein Binding, increase free form.
c) Ionization
 Only non-ionized part crosses Blood-Brain-
Barrier.
 Thiopentone has PKA 7.6 so 61% of it is
non-ionized at physiologic PH
 As PH decreases (acidosis) non-ionized form

2)Metabolism
 By liver microsomal enzymes mainly, Slightly in
CNS & kidney.
 By oxidation, dealkylation & conjugation to
hydroxy Thiopental & carboxylic acid
derivatives
more water soluble & excreted rapidly.

 Affect by hepatic enzyme activity more than blood
flow.
 Metabolism at 4-5 mg./Kg. dose exhibits first order
kinetics.
 At very high doses (300-600 mg/Kg.) exhibit zero
order kinetics.

3) Renal Excretion
 Protein Binding limits filtration.
 High lipid solubility increase
reabsorption.
Elimination Half Life 11.6 Hours
Low elimination
clearance(3.4ml/kg/min)
Prolonged in obese patient & pregnancy.

MECHANISM OF ACTION
 Sedation & Hypnosis by interaction with
inhibitory neurotransmitters GABA on GABAA
receptor.
 GABA facilitatory & GABA mimetic action.
 Increases GABA mediated transmembrane
conductance of Cl– ion  Causes
hyperpolarization & inhibition of post synaptic
neuron.

 Decrease rate of dissociation of GABA from
receptor.
In high doses itself activate GABA receptor.
 Inhibit synaptic transmission of excitatory
neurotransmitter via glutamate & neuronal
nicotinic acetylcholine receptors.

PHARMACODYNAMICS
Central nervous system
 Dose dependent effect
sedation  sleep  anaesthesia  coma.
 Acts on Reticular Activating System & Thalamus.
 Induces General Anaesthesia  loss of consciousness,
amnesia &  response to pain R.S. & C.V.S. depression.
 Depresses transmission in sympathetic nervous system,
 BP.

 Dose related  cerebral metabolic rate of
oxygen (CMRO2), reduces metabolic activity,
neuronal signalling & impulse trafficking.
 cerebral metabolic rate of oxygen (CMRO2)

 cerebral vascular resistance

 cerebral blood flow

 Intracranial pressure

Somatosensory, Brainstem auditory & visual
evoked potential are depressed.
 infract size in cerebral emboli & temporary
focal ischemia
  burst suppression, protect in profound
hypotension..

• HIGH DOSES DESULFURATION
PENTOBARBITAL
(LONG LASTING CNS DEPRESSANT)

Respiratory system .
 Neurogenic, Hypercapnic & hypoxic drive depressed.
 Depression of medullary & pontine ventilatory
centres.
 Apnoea likely in presence of narcotics.
Cough & laryngeal reflexes not depressed until high
doses given.
 Bronchospasm & laryngospasm likely in light plane,
added by sympathetic depression

Cardiovascular system
 At 5 mg/Kg doses, 10-20 mmHg decrease in BP due to
blockade.
 Compensated by carotid sinus baroreceptor mediated
increase in peripheral sympathetic nervous system
activity.
Leads to unchanged myocardial contractility & 15 – 20
beats/min increase in Heart Rate.
 Direct myocardial depression occurs at doses used
to increase intracranial pressure.

DEPRESSION OF SYMPATHETIC NERVOUS
SYSTEM & MEDULLARY VASOMOTOR CENTER

DILATATION OF PERIPHERAL CAPACITANCE
VESSEL

POOLING OF BLOOD

 VENOUS RETURN

 CARDIAC OUTPUT

 BLOOD PRESSURE

 Changes exaggerated in hypovolemic
patient, patient on B-blocker drugs &
centrally acting anti hypertensive.

SKELETAL MUSCLE
•  NEURO MUSCULAR EXCITABILITY
• SUPPRESSION OF ADRENAL CORTEX & DECREASED CORTISOL LEVEL, BUT IT IS
REVERSIBLE.

7) Liver
 Decreased hepatic blood flow
 Induction of microsomal enzyme & increase
metabolism of drugs,
For Ex. Oral-anticoagulant, Phenytoin, TCA,
Vit. K, Bile Salt, corticosteroid.
 Increased Glucouronyl transferase activity.
 Increased  aminolavilunate activity &
precipitate
porphyria’s.

• PLACENTAL TRANSFER OCCURS BUT DRUG
METABOLISED BY FOETAL LIVER & DILUTED
BY ITS BLOOD VOLUME SO LESS DEPRESSION.

CLINICAL USES
1) Induction
 3 – 5 mg/Kg. produces unconsciousness in 30
sec.
with smooth induction & rapid emergence.
 Loss of eyelid reflex & corneal reflex used for
testing induction.
 Consciousness regained 10-20 Min. but
residual
CNS depression persist for more than 12 Hours.
 Dose requirement decreased in early

 Patient with sever anaemia, burns,
malnutrition,
malignant disease, wide spread uraemia,
ulcerative colitis, intestinal obstruction
requires
lower doses.

adult child infant
Induction dose 3-5 mg/Kg. 5-6 mg/Kg 6-
8Mg/Kg.
Anaesthesia supplementation - i.v. 0.5 – 1
mg/Kg
Thiopental infusion seldom used
long context- sensitive half-time
prolong recovery period

CLINICAL USES
2) ANTICONVULSANT
• FOR RAPID CONTROL OF STATUS EPILEPTICUS
• DOSE 0.5 – 2 MG/KG. REPEATED AS NEEDED

3) Treatment of increased intracranial
pressure
Cerebral vasoconstriction

 cerebral blood Flow

 cerebral blood volume

 intracranial pressure
  cerebral metabolic O2 demand by 55%
 dose 1 – 4 mg/kg i.v.

4) Cerebral Protection
 In focal ischemia eg. Carotid
endarterectomy,
thoracic aneurysm resection, profound
controlled-hypotension, Incomplete cerebral
emboli.
 Barbiturate narcosis – i.v. bolus 8 mg/Kg.
 EEG burst suppression – mean total dose 40
mg/Kg.
 Infusion – 0.05 to 0.35 mg/Kg/min with
inotropic & ventilatory support.

SIDE EFFECTS
 Garlic onion taste.
 Allergic reaction.
 Local tissue reactions & necrosis.
 Urticarial rash, facial edema, hives,
bronchospasm
& anaphylaxis.
 Pain at injection site.

Respiratory System
 Dose related respiratory depression
 Transient apnea, patient with chronic lung
disease more susceptible.
 Laryngospasm, bronchospasm.
Central nervous system
 Emergence delirium, prolonged somnolence
&
recovery, Headache

Gastro-intestinal system
Nausea, Emesis, Salivation
Dermatologic
Phlebitis, necrosis, gangrene.
.

Contraindications
 Patient with respiratory obstruction &
inadequate airway.
 Cardiovascular instability & shock.
 Status asthmaticus.
 Porphyria’s eg. Acute intermittent,
variegate
porphyria, hereditary copro-porphyria
Known
hypersensitivity.

CAUTION
 Hypertension, hypovolemia, ischemic heart
disease,
 Acute adrenocortical insufficiency, Addison’s
disease, myxedema.
 Uraemia, septicaemia, hepatic dysfunction.
.

ACCIDENTAL INTRARTERIAL INJECTION
• INTENSE VASOCONSTRICTION
• THROMBOSIS
• TISSUE NECROSIS

TREATMENT
• INTRARTERIAL ADMININISTRATION OF
LIGNOCAINE(PROCAINE).
• HEPARINISATION
• SYMPATHECTOMY (STELLATE GANLION BLOCK,
BRACHIAL PLEXUS BLOCK).

 Thiopentone solution is highly alkaline incompatible
for mixture with drug such as opioid
catecholamines neuromuscular blocking drugs as
these are acidic in nature.
 Probenecid prolongs action, aminophylline
antagonize.
 CNS depressant eg. narcotics, sedative hypnotic,
alcohol, volatile anaesthetic agent prolongs &
potentiate its actions.
INTERACTIONS

Induces metabolism of oral anticoagulants,
digoxin, B-blocker, corticosteroids, quinidine,
theophylline.
 Action prolonged by MAO inhibitors,
chloramphenicol.

Dose should be reduced
 In geriatric- 30- 40% decrease central
compartment volume & slowed
redistribution
 Hypovolemic Patient,
High risk surgery patient with
concomitant use of narcotic & sedatives

•ITS A PHENCYCLIDINE DERIVATIVE
•WAS THE FIRST ANESTHETIC TO BE USED.
•SINCE 1970 ITS BEEN CLINICALLY USED.
•Comes in VIALS with 50mg/ml
•1mg diluted in 5ml Normal Saline to make it
10mg/ml

KETAMINE
• A PHENYLCYCLOHEXYLAMINE DERIVATIVE
• KETAMINE HYDROCHLORIDE (2-[O-CHLOROPHENYL]-2-
[METHYLAMINO] CYCLOHEXANONE HYDROCHLORIDE)
• AVAILABLE AS RACEMIC MIXTURE
• EXISTS AS 2 ISOMERS, R(-) AND S(+) FORMS
• S(+) MORE POTENT
• LIPOPHILIC
• RAPIDLY DISTRIBUTED INTO HIGHLY VASCULAR ORGANS, AND
BRAIN

 PRESERVATIVE USED IS BENZOTHORIUM CL.
 PRODUCES PROFOUND ANALGESIA,
 PRODUCES DISSOCIATIVE ANESTHESIA
CHARACTERISED BY DISSOCIATION BETWEEN
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 KINETICS
 HIGH LIPID SOLUBILITY-LARGE VD
 ELIMINATION ½ LIFE - 2-3HRS.
• DISTRIBUTION
• INITIALLY DISTRIBUTED TO HIGHLY PERFUSED TISSUES AND IS THEN REDISTRIBUTED
TO LESS WELL PERFUSED TISSUES
• REDISTRIBUTION RESULTS IN TERMINATION OF ITS ACTION
• T½Α IS ABOUT 10-15 MINUTES

METABOLISM
 EXTENSIVELY IN LIVER.
 CYTO-P450 ----> DEMETHYLATION ----> NORKETAMINE(ACTIVE
METABOLITE) 1/3-1/5TH AS POTENT AS KETAMINE.
 IT IS RESPONSIBLE FOR PROLONGED EFFECTS OF ANALGESIA.ON RPTD
DOSE/INFUSION.
 EXCRETED THROUGH KIDNEY.

PHARMACODYNAMICS
 CENTRAL NERVOUS SYSTEM
 PRODUCES DISSOCIATIVE ANAESTHESIA.
 DISSOCIATES THALAMOCORTICAL SYSTEM FROM LIMBIC SYSTEM
 PATIENTS APPEAR TO BE DISSOCIATED FROM THE ENVIRONMENT.

 DEPRESSES CNS BY BLOCKING THE NMDA RECEPTORS.
 KETAMINE CAUSES PROFOUND ANALGESIA.
 ↑CEREBRAL BLOOD FLOW, CEREBRAL METABOLIC RATE OF OXYGEN, & INTRACRANIAL
PRESSURE – NOT IDEAL FOR NEUROSURGERY & PATIENTS WITH RAISED
INTRACRANIAL PRESSURE.
 PRODUCES EMERGENT PHENOMENON, CAN BE PREVENTED BY PRIOR
ADMINISTRATION OF BENZODIAZEPINES – NOT RECOMMENDED IN PATIENTS WITH H/O
PSYCHIATRIC DISEASE.
 CAN STIMULATE SEIZURE FOCUS – NOT INDICATED IN EPILEPTIC PATIENTS.

• CARDIOVASCULAR SYSTEM
• INDIRECT EFFECT OF INCREASED CENTRALLY MEDIATED
RELEASE OF CATECHOLAMINES FROM ADRENAL MEDULLA
INCREASED
• MYOCARDIAL CONTRACTILITY,
• HEART RATE,
• SYSTEMIC VASCULAR RESISTANCE,
• BLOOD PRESSURE &
• CARDIAC OUTPUT

• NOT INDICATED IN PATIENTS WITH
• CORONARYARTERY DISEASE AND
• HYPERTENSION.
• DRUG OF CHOICE IN PATIENTS WITH
• HYPOVOLEMIA
• LOW CARDIAC OUTPUT STATES
• RIGHT → LEFTT SHUNTS.

 RESPIRATORY SYSTEM
 LITTLE EFFECT ON VENTILATORY DRIVE IN NORMAL PERSONS.
 APNOEA IN INFANTS & NEONATES WHEN GIVEN INTRAVENOUSLY.
 PRODUCES BRONCHODILATATION – USEFUL IN PATIENTS WITH
BRONCHIAL ASTHMA.
 NEAR NORMAL AIRWAY REFLEXES ARE PRESERVED.
 INDUCES COPIUS SALIVATION - AN ANTI SIALOGOGUE DRUG HAS
TO BE ADMINISTERED.

OTHER EFFECTS:
 HIGH RISK OF PONV.
 PREVENTS POST OPERATIVE SHIVERING.
 PER OPERATIVE ANALGESIC DOSE DECREASES POST OPERATIVE MORPHINE
REQUIREMENT.

MECHANISM OF ACTION
•INTERACTS WITH
• NMDA (N-METHYL-D-ASPARTATE) GLUTAMIC
ACID CA++ CHANNEL RECEPTORS IN CORTEX AND
LIMBIC SYSTEM
• CENTRAL OPIOID RECEPTORS (Μ, Κ)
• MONOAMINERGIC RECEPTORS IN SPINAL CORD
• VOLTAGE-GATED CA++ CHANNELS
• VOLTAGE-GATED NA+ CHANNELS

ANALGESIC EFFECT VIA INHIBITION OF CA++
INFLUX
• AT PRESYNAPTIC NERVE TERMINALS (Κ OPIOID RECEPTOR,
MONOAMINERGIC RECEPTORS IN SPINAL CORD,
MONOAMINERGIC RECEPTORS IN SPINAL CORD)
• AT POSTSYNAPTIC NMDA RECEPTORS

• NON-COMPETITIVE ANTAGONISM OF NMDA RECEPTOR CA++
CHANNEL PORE
• INTERACTS WITH PHENCYCLIDINE BINDING SITE STEREO
SELECTIVELY, LEADING TO SIGNIFICANT INHIBITION OF RECEPTOR
ACTIVITY, THIS ONLY OCCURS WHEN THE CHANNEL IS OPENED

KETAMINE – MECHANISM OF ACTION
• EFFECT ON VOLTAGE-SENSITIVE CA++ CHANNELS
• PRODUCES NON-COMPETITIVE INHIBITION OF K+-STIMULATED
INCREASED INTRACELLULAR CA++
• EFFECT ON OPIOID RECEPTORS
• ANTAGONIST AT Μ, AGONIST AT Κ
• S(+) KETAMINE IS 2-3 TIMES MORE POTENT THAN R(-) KETAMINE AS
AN ANALGESIC
• AFFINITY FOR RECEPTOR IS 10000 FOLD WEAKER THAN THAT OF
MORPHINE

KETAMINE – MECHANISM OF ACTION
• EFFECT ON DESCENDING INHIBITORY MONOAMINERGIC
PAIN PATHWAYS
• ANALGESIC PROPERTY MAY INVOLVE THESE PATHWAYS, ALTHOUGH DIFFICULT TO
SEPARATE KETAMINE-SENSITIVE OPIOID RECEPTOR ACTION
• LOCAL ANAESTHETIC ACTION
• BLOCKADE OF NA+ CHANNEL
• EFFECT ON MUSCARINIC RECEPTORS
• ANTAGONISTIC ACTION AS KETAMINE PRODUCES ANTICHOLINERGIC SYMPTOMS
(POST ANAESTHETIC DELIRIUM, BRONCHO DILATATION, SYMPATHOMIMETIC
ACTION)

• 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 .

CLINICAL USE OF KETAMINE
• PAIN CONTROL (LIMITED VALUE)
• KETAMINE CAN ONLY INHIBIT NMDA ACTIVITY WHEN THE RECEPTOR-
OPERATED ION CHANNEL HAD BEEN OPENED BY NOCICEPTIVE
STIMULATION, HENCE PRE-EMPTIVE ANALGESIA WITH KETAMINE IS
INEFFECTIVE
• NEUROPROTECTION
• ACTIVATION OF NMDA RECEPTOR IS IMPLICATED IN CEREBRAL
ISCHAEMIC DAMAGE, HENCE BY BLOCKING THE RECEPTOR, KETAMINE
HAS NEUROPROTECTIVE POTENTIAL
• SEPTIC SHOCK
• REDUCE THE NEED FOR INOTROPES VIA INHIBITION OF
CATECHOLAMINE UPTAKE
• REDUCE PULMONARY INJURY VIA REDUCTION IN ENDOTOXIN-
INDUCED PULMONARY HYPERTENSION AND EXTRAVASATION

CLINICAL USE OF KETAMINE
• ASTHMA THERAPY
• ANTI-INFLAMMATORY
• SPASMOLYTIC
• INCREASED CATECHOLAMINE CONCENTRATIONS,
INHIBITION OF CATECHOLAMINE UPTAKE,
• VOLTAGE-SENSITIVE CA++ CHANNEL BLOCKADE,
• INHIBITION OF POSTSYNAPTIC NICOTINIC OR
MUSCARINIC RECEPTORS

 Anaesthesia for haemorrhagic shock patients
 sympathomimetic effects
•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.

• SIDE EFFECTS-
• EMERGENCE REACTION.
• CONTRAIDICATED- PATIENTS WITH HIGH ICP, ICSOL,
OPEN EYE INJURY, VASCULAR ANNEURYSMS,PTS
WITH PSYCHIATRIC DISORDERS(SCHIZOPHRENIA).

IV induction agents

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