Intravenous induction agentsThiopentone Sodium

Ketamine

Presenter: Anish MohanModerator: 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.

THIOPENTONE

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. Context sensitive half life is prolonged.

TERMINATION OF ACTION1) 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. Only unbound fraction crosses Blood-Brain-Barrier.

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 increases.

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.

Short in paediatric patient.

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.

PHARMACODYNAMICSCentral 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 pregnancy, increased in child with thermal injury.

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 systemNausea, 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-porphyriaKnown 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

KETAMINE

•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 KINETICSHIGH 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

• CORONARY ARTERY 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.•restless leg syndrome

• SIDE EFFECTS-

• EMERGENCE REACTION.

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

THANK YOU