Intravenous inductional agents

DR SHIV SUNDAR CHAKRABORTY

SVMCH & RC , PONDICHERRY

Goals of GA

Hypnosis (unconsciousness)

Amnesia

Analgesia

Muscle relaxation

Inhibition of nociceptive reflexes

Reduction of certain autonomic reflexes

(gag reflex, tachycardia, vasoconstriction)

Phases of General Anaesthesia

Stage I: Disorientation, altered consciousness

Stage II: Excitatory stage,

delirium, uncontrolled movement,

irregular breathing.

Goal is to move through this stage as rapidly as possible.

Stage III: Surgical anesthesia; return of regular respiration.

Plane 1: “light” anesthesia, reflexes, swallowing reflexes.

Plane 2: Loss of blink reflex, regular respiration (diaphragmatic and chest). Surgical procedures can be performed at this stage.

Plane 3: Deep anesthesia. Shallow breathing, assisted ventilation needed. Level of anesthesia for painful surgeries (e.g.; abdominal exploratory procedures).

Plane 4: Diaphragmatic respiration only, assisted ventilation is required. Cardiovascular impairment.

Stage IV: Too deep;

essentially an overdose and represents anaesthetic crisis.

This is the stage between respiratory arrest and death due to circulatory collapse.

Classification

Iv anaesthethetics

barbiturates

thiopentone methohexital

amobarbital

benzodiazepines

Diazepam,lorazepam,midazolam

etomidate ketamine propafol

GABA receptor complex

g- amino butyric acid is inhibitory neurotransmitter

Oligomeric complex of 5 glycoprotein subunits

Assemble to form cl- channel with GABA A receptor

Activation of GABA receptors increases cl conductance

hyperpolarization of post synaptic neuron

excitability of post synaptic neuron

Barbiturates

Mechanism of action

Increases duration of opening of cl- channel in GABA receptor (gabamimetic)

Depress reticular activating system in brain stem

RAS helps to maintain wakefulness

Other targets :

Adenosine receptors

Neuronal nicotinic acetyl ch receptors

nAChRs are not critical targets ( Downie et al : 2000)

At NMJ high dose decrease sensitivity of post synaptic membranes to depolarising action of acetyl ch

Structure – activity

Substitution at carbon C5 determines hypnotic potency & anticonvulsant activity.

Phenyl group in phenobarbital is anticonvulsive

Longer the branched chain more the potency

Urea + malonic acid = barbituric acid

Replacing oxygen with sulphur atom at C2 (thiopentone)

‘Thio’ group also increases the potency

Thiopentone have greater potency & shorter duration of action than pentobarbital

Replacing with methyl group ( methohexital)

Preparation

hygroscopic (attracts moisture from the atmosphere)

pale yellow powder.

Ampoules contain 500mg of sodium thiopental

6% sodium carbonate in an inert atmosphere of nitrogen

Reconstituted 20ml of water this yields a 2.5% solution (25mg/ml) with a pH of 10.8.

alkaline solution is bacteriostatic

Cont..

These highly alkaline solution are incompatible for mixture with opioids, catecholamine's, NMB drugs (acidic)

Thiopentone , methohexital are available in racemic mixture

Although , S(-) isomer is more potent than R(-)

S(-) isomer causes excessive muscular activity

Stability of commercial preparation

Refrigerated solution of thiopentone are stable up to 2 weeks

Solution of methohexital are stable up to 6 weeks

At 22 degree C thiopental is stable & sterile for 6 days (Haws et al)

Pharmacokinetics

Protein binding

Highly protein bound - 72-86 %

Hypoalbuminemia ( cirrhosis, CKD, neonates)

Displacement of binding sites

by aspirin,phenyl butazone increased unbound fraction foetal acidosis stressful

delivery

enhanced drug effect

Distribution

Factors affecting distribution:-

Lipid solubility

Protein binding

Degree of ionization

Tissue blood flow

In hypovolemia, there is decreased blood flow to skeletal muscle & fat whereas flow to brain & cardiac are maintained, leads to exaggerated brain & cardiac suppression.

Distribution to brain

Maximal brain uptake within 30 sec (rapid effect site equilibration)

10 % total dose received in 30 sec

Next 5 min half of initial peak concentration (redistribution)

Redistribution to other tissue responsible for early awakening

Prompt brain uptake is because of its high lipid solubility

Distribution to Sk Ms & fat

Sk Ms is initial site for redistribution of thiopentone

Equilibrium in Ms is seen within 15 mins

Low perfusion(shock) & elderly ,dose of thiopentone should be reduced

Maximal deposition in fat is present after 2.5 hrs

Fat is potential reservoir of drug( maintains plasma concentration)

Repeated doses can cause cumulative effect later

Dose of thiopentone should be calculated on lean body mass

Ionization Pk of thiopentone (7.6) is near blood PH

Acidosis nonionised form more lipid soluble cns effect

Alkalosis decrease barbiturate effect

Metabolic acidosis has more influence on distribution has respiratory acidosis

Metabolic acidosis H+ H+ cant cross BBB intracellular PH unchanged

unionised form

Respiratory acidosis Co2 Co2 diffusion similar change extracellular & intracellular ph

ionised form

Metabolism

Thiopentone is metabolised in liver into hydroxythiopental & carboxylic acid

They are water soluble & have little cns activity

Metabolism of methohexital is more rapid than thiopentone

Recovery with methohexital is faster (less lipid soluble)

Clearance of thiopentone in cirrhosis is equal to normal pt ( Pandele et al 1983)

Renal excretion

< 1 % thiopentone is excreted unchanged in urine

High lipid solubility favours reabsorption

High protein binding limits filtration

Osmotic diuresis & alkalinisation hastens phenobarbital excretion

Elimination half life :-

Thiopentone – 11.6 hrs , methohexital – 3.9 hrs

Shorter elimination ½ life of methohexital is due to rapid hepatic clearance

Elimination ½ life of thiopentone is prolonged in obese pt

Elimination ½ life of thiopentone is prolonged in pregnancy due to increased protein binding

Elimination ½ life of thiopentone for paediatric is shorter than adults

Effects on CNS :-

Barbiturates constricts cerebral blood vessels decrease ICP > aterial BP

cerebral perfusion pressure

Barbiturates also decrease cerebral O2 consumption

Decrease in blood flow is not detrimental

Lowers pain threshold ( antianalgesic)

Small dose can cause paradoxical excitement in elderly or in presence of pain

Clinical uses :-

Induction of anaesthesia

Thiopentone = 3-6 mg/kg (iv)

Methohexital = 1-2 mg/kg (iv)

Pentobarbital ( premedication) = 2-4 mg/kg(IM), 3 mg/kg (rectal)

Prolong infusion (barbiturate coma) saturates peripheral compartments, duration of action then directly depends on elimination ( context sensitivity)

Thiopentone has long context sensitive half life

Treatment of increased ICP

Decrease ICP even when mannitol & hyperventilation have failed to reduce effectively

Induction in pt with increased ICP

Hazard of high dose thiopentone ( 37.5mg/kg) is hypotension

Hypotension can cause decreased CPP

Inotropic support is often required

Cerebroprotection

50 – 100 mg thiopentone rapidly controls grand mal seizures

Profound EEG suppression

Low voltage fast activity to high voltage slow activity

Protect from transient ischemia ( embolism)

Avg dose of 39.5 mg/kg iv of thiopentone is used after cardiopulmonary bypass to maintain isoelectric EEG.

Doesn’t protect from global ischemia (cardiac arrest)

Methohexital is used to produce seizure activity in pt of psychomotor epilepsy, undergoing temporal lobe resection of seizure producing areas

Effects on CVS

Barbiturates depress medullary VMC sympathetic tone peripheral

vasodilation

CO & BP venous return

carotid sinus baroreceptor tachycardia (maintain CO)

Pt with hypovolemia, CHF, B blockers have

accentuated hypotension (uncompensated ), slow iv

Effects on respiration

Dose dependant depression of medulla & pontine RC

Decrease sensitivity of medullary rc to CO2

Inadequate plane may provoke laryngospasm & bronchospasm during intubation

During awakening tidal vol & RR are decreased.

Liver

Modest decrease in hepatic blood flow

Increases liver microsomal protein ( enzyme induction)

Increased metabolism of oral anticoagulants, phenytoin, TCA, vit K

Phenobarbitone used in kernicterus( increase glucoronyl tranferase)

Exaggeration of acute intermittent porphyria( D ALA synthase)

Allergic & immunological effects

Incidence of allergic rxn of thiopentone is 1/30,000 pt ( Clarke 1981)

High mortality, H/o chronic atopy

Increased incidence of nosocomial infection

Bone marrow suppression

Leukopenia

Inhibits ntF-KB, impair neutrophils ( reduces antibacterial host defence)

Intra arterial injection

Immediate vasoconstriction, pain (radiates along artery)

2.5% soln is safer

Thiopentone crystals leads to arteritis, thrombosis

Leave needle intact

Injection of normal saline

Lidocaine , papaverine,heparin

Stellate ganglion block

BENZODIAZEPINES

They have seven membered diazepine ring

5 aryl substituent & 1,4 diazepine ring

Principal pharmacologic effect

Anxiolysis

Sedation

Anticonvulsant action

Spinal chord mediated sk ms relaxation

Anterograde amnesia ( Ashton 1994)

Mechanism of action

a1 subunits of GABA A – sedative effect

a2 subunits of GABA A- anxiolytic activity

GABA A

receptor

a1 subunit

Cerebral cortex, cerebellar

cortex,thalamus

a2 subunit

Hippocampus, amygdala

Cont..

Drug induced increased affinity of receptor for GABA

Increase cl- conductance

Post synaptic neuron more resistant to excitation

BZD effect on nucleoside transport

Inhibits nucleoside transporter

Thus, decrease degradation of adenosine

Adenosine has cardio protective mechanism

Coronary vasodilator

Reduces cardiac O2 demand

MIDAZOLAM

IMIDAZOLE ring (stable in aqueous soln.)

pK is 6.15

pH dependent ring opening phenomenon

At physiological pH it is highly lipid soluble

pH >4 – lipid soluble

pH<4 – water soluble

Compatible with RL & other acidic drugs

Pharmacokinetics

Slow effect site equilibration time ( 0.9- 5.6 mins)

High lipid soluble

Rapid redistribution ( short duration of action)

Context sn ½ time of midazolam is shorter than diazepam , so it can be used for prolonged sedation as infusion in icu’s.

Elimination ½ time is 1-4 hrs

Etime is prolonged in elderly ( age related decrease in hepatic BF)

Metabolism

Rapid , liver & intestine ( p450 – CYP3A4 enzyme activity)

1 hydroxyl midazolam

Glucoronide metabolite has little seductive effect

Delayed ( cimetidine,erythromycin,ccb,antifungals )

Clearance is delayed if fentanyl is co administered

Effects on CNS

Decreases CMR O2 & CBF

Unable to produce isoelectric EEG

Dose related CBF to regions functioning with arousal, attention, memory

Cerebral vasomotor response to CO2 is preserved

Potent in status epilepticus

Ventilatory effects

Dose dependent ( 0.15 mg/kg)

Increase depression in copd

If >0.15 mg/kg + opioid – transient apnoea

Depress swallowing reflex

Depress upper airway activity

Effects on CVS

Dose (0.2 mg/kg) produces greater decrease in SBP than diazepam of 0.5 mg/kg

BP changes are due to sys vasodilation

No change in CO ( beneficial for CHF)

Does not prevent pressor response to intubation

Clinical uses:-

Preop medicine for children (0.25 mg/kg)

Intravenous sedation 1-2.5 mg iv

Induction of anaesthesia (0.1-0.2 mg/kg iv / 30-60 sec)

Facilated induction with fentanyl (50 -100 mcg iv )

Decrease dose in elderly

Post op sedation: LD – 0.5-4 mg iv MD – 1-7 mg/hr

O.5 – 1 mg/kg treat paradoxical VC motion

DIAZEPAM

Dissolved in organic solvents ( propylene glycol, Na benzoate )

pH 6.6-6.9

Dilution with water causes cloudiness ( potency unaffected)

Injection IM/IV painful

Pharmacokinetics

Peak conc in 1 hr adults / 15 – 30 mins in children

Rapid brain uptake

Rapid redistribution to fat

Obese women Vd > men

Crosses placenta

High protein bound ( HD not effective)

Metabolism

Oxidative pathway of N methylation

Desmethyl diazepam & oxazepam & little temazepam

Metabolites contribute to return of drowsiness a/f 8 hrs

Enterohepatic circulation also favour recur of sedation

Elimination ½ life 21 – 37 hrs

Liver failure increases E half life

Effects & uses:-

Minimal depression on ventilation

0.5 – 1 mg/kg minimal decrease in BP,CO

Transient decrease of baroreceptor response of HR

In addition with N20 no adverse cardiac changes

muscle relaxation ( spinal internuncial neurons)

Anticonvulsant activity

0.1 mg/kg abolishes lidocaine induced seizures

Treat delirium tremens & status epilepticus

Diazepam selectively inhibits activity in limbic system & hippocampus

If diazepam is given then long acting Fosphenytoin should also be given

Other BZD:-

Lorazepam

More potent sedative than midazolam

Max anterograde amnesia

Slow onset ( disadvantage)

Delayed weaning from ventilator

Alprazolam – Anxiolysis,preop med

Clonazepam – myoclonic & infantile spasms

Zolpidem, zaleplon – delayed sleep onset

FLUMAZENIL

1,4- imidazobenzodiazepine derivate

competitive BZD antagonist (min agonistic activity)

Initial dose 8-15 mcg/kg iv

If further required 0.1 mg iv upto 1mg every 60 sec

Maintain wakefulness = 0.1-0.4 mg/hr infusion

Propafol

2,6- di isopropyl phenol

Needs lipid vehicle for emulsification

10% soyabean oil + 2.25% glycerol+ 1.2% purified egg phosphatide

Supports bacteria growth (discard after 6 hrs)

Increase triglyceride level on infusion

Na metabisulfite preservative ( generic)

Lidocaine can be added to reduce pain

Fospropafol

Water soluble prodrug of propafol

Reduce the disadvantages of the lipid emulsion of propafol

Cont..

Endothelial cell – alkaline phosphatase

Dose dependent sedative effects

Fospropafol has higher potency

Larger Vd

Mechanism of action

Selective modulator of GABA A receptor

Decrease rate of dissociation of GABA

Doesn't alter spinal motor excitability

Pharmacokinetics

Clearance

Hepatic p450 cyt oxd (rapid & extensive)

Extra hepatic (lungs)

Metabolite – 4- hydroxypropafol

Short context sensitive life ( minimal influence by duration of infusion)

Kidney plays major role in elimination

Crosses placenta

Clinical uses:-

Induction DOC (1.5 -2.5mg/kg iv)

25 – 50 % reduce dose in elderly

Complete awakening without residual effects

Part of balanced or total anaesthetic

IVS in ICU’S ( 100 mcg/kg/min )

Maintenance ( 100-300 mcg/kg/min )

>1mg/kg reduce 35 -45% seizure duration in ECT

Non hypnotic uses:-

Decreased postop nausea & vomiting (10 – 15 mg iv)

Effective in chemotherapy induced nausea & vomiting ( effective than odansetron)

Depress subcortical areas

10 mg iv antipruritic ( neuraxial opioids & cholestasis)

>1mg/kg reduce 35 -45% seizure duration in ECT

Attenuation of bronchoconstriction (compared to thiopentone)

Metabisulfite can cause bronchoconstriction in asthma

Systemic effects:-

Decrease CMR O2 , CBF, ICP

Decrease Systemic BP (relax vascular sm – inhibit Ca+ influx)

Propafol is more effective than thiopentone in blunting pressor response to intubation & LMA

Pressor response to ephedrine is augmented

Apnoea in 25 -35% pt a/f induction

Prolong infusion green urine ( phenol )

Increase urine uric acid

Decrease IOP ( useful in laparoscopic sx)

Inhibits platelet aggregation

Bradycardia – Related Death

Profound bradycardia & asystole have been seen in healthy adult individual after induction , despite prophylactic anticholinergics (Egan & Brock ; 1991, James et al 1989,Tramer et al 1997c)

Risk is about 1.4 / 1,00,000

Refractory bradycardia in children in icu have been see (Dearlove & Dobson 1995, Bray 1995)

In this cases isoproterenol may be required

Side effects:-

Allergic reaction (phenyl nucleus & di isopropyl side chain)

Propofol infusion syndrome

Prolonged myoclonus associated with meningismus

Abuse potential (intense dreaming)

Bacterial contamination ( E.coli, P.Areruginosa)

Propofol infusion syndrome

Lactic acidosis during high dose infusion(>75mcg/kg/min)

Unexpected tachycardia > ABG > lactate level

Cytopathic hypoxia of ETC

Impaired oxd of Long chain FA

D/D:

1. Mitochondrial myopathy

2. Hyperchloremic metabolic acidosis

3. Diabetic acidosis

4. Release of tourniquet

Antioxidant properties

Potent antioxidant property that resemble Vit E

Phenolic hydroxyl group scavenges free radicle

Inhibits lipid peroxidation

Scavenges peroxynitrite ( supress phagocytosis)

Helpful in acute lung injury

Post ischemic dysfuntion, myocardial stunning

Attenuates lipid peroxidation in CABG

ETOMIDATE

Carboxylated imidazole compound

Physiologic pH lipid soluble

35% propylene glycol (pain on injection)

R isomer > S isomer

Metabolized to carboxylic acid

85% excreted in urine, 15% in bile

elimination ½ life varies from 1 – 5 hours

Effects & uses:-

Standard induction dose is 0.3mg/kg

Recovery is rapid due to redistribution to muscle and fat.

Involuntary movements which may be mistaken for generalized seizure

Small reduction in the cardiac output and blood pressure

Post operative nausea and vomiting is common

Adreno-cortical suppression

inhibits 11-B-hydroxylase

Blocks conversion of cholesterol to cortisol

Single induction dose blocks the normal stress-induced cortisol production for 4-8 hours

Up to 24 hours in elderly and debilitated patients.

Continuous infusion of etomidate for sedation in critically ill patients has been shown to increase mortality

use of etomidate has declined in recent years due to a perceived potential morbidity.

KETAMINE

Derivative of phencyclidine

Racemic mixture of the 2 stereo-isomers

R- and S+ ketamine

S ketamine has recently become available due to its more desirable pharmacological properties

Prepared in a slightly acidic solution (pH 3.5–5.5) containing 10, 50 or 100mg of Ketamine per ml.

Mechanism of action

Non-competitive antagonism at NMDA receptor in brain and spinal cord.

Other receptors :-

Opioid ( antagonist at mu, agonist at kappa)

Monoaminergic (antinociceptive function)

Muscarinic (emergence delirium, bronchodilation, sympathomimetic actions)

Na + channels & L-type Ca2+ channels (mild LA property)

pharmacokinetics

Rapid onset, short duration

High lipid soluble

Peak conc. Within 1 min (iv) & 5min (IM)

Low protein bound

High hepatic clearance ( 1 Lit/min)

Large Vd( 3 Lit/kg)

Elimination ½ life 2-3 hrs

Effects & uses:-

Analgesia (0.2-0.5 mg/kg iv)

Somatic pain > visceral

Thalamic & limbic system activity

Inhibition of spinal nociceptive pathway

Postop sedation & analgesia (1-2 mg/kg/hr)

Synergistic effect with epidural opioid & LA

Induction

1-2 mg/kg IV or 4-8 mg/kg IM (unconsciousness in 1-2min)

Duration of action of a single dose is approximately 5-10 min

Combination of propofol & ketamine is more hemodynamically stable than with fentanyl

Combination of diazepam & ketamine can be used in CAD pt

Safe for malignant hyperthermia

Avoided in pulmonary htn

Cont..

Subanesthetic doses prevent & reverse morphine induced tolerance

Improve post op depression

Single case report shown improvement in restless leg syndrome after oral ketamine(Kapur& Friedman ,2002)

Effect on CNS

Traditionally thought to increase CBF, CMR O2, ICP

Increase CBF by 60 % in normocapnia

In settings of hyperventilation & avoiding hypercapnia ketamine was found to have some beneficial effect on brain

This action is because action on NMDA receptors

Several clinical studies have been done

Abolish a activity, domination of theta activity in EEG

Clinical trials (neuro protective effect of ketamine)

Ant. Frontanelle pressure reduced in ventilated preterm neonates in NICU a/f giving 2 mg/kg of ketamine (Friesen et al 1987)

Pt undergoing cerebral aneurysm resection or craniotomy ,1mg/kg of ketamine did not increase MCA blood flow velocity & reduce ICP modestly(Mayberg 1995)

Systemic effects :-

Increase hemodynamic

Systemic BP

Pulmonary AP

CO

Cardiac work

Myocardial O2 requirement

Vasoconstriction maintains SBP at cost of tissue perfusion

Increase sympathetic outflow

Decrease need of inotropes in sepsis (decrease catecholamine uptake)

Other organs:-

Upper airway tone maintained

Bronchodilator (effective as halothane & enflurane)

Increase bronchial secretion

Inhibits platelet aggregation

Preconditioning

Activate K+ ATP channels

Mimics ischemic preconditioning

Decrease infract size

Improve stunned myocardium ( ischemic reperfused viable)

R isomer blocks this preconditioning

Opioids & volatile elicit early & late preconditioning

Emergence delirium(Psychedelic effect)

Emergence associated with

Visual & auditory hallucination

Confusional illusion

Transient cortical blindness

Morbid dreams ,vivid colours

Can occur upto 24 hrs in some pt.

Mechanism – depression of inferior colliculus , MGN & kappa receptors

Incidence & RF :-

5 – 30 %

Age > 15 yrs

Females

Dose > 2mg/kg

H/o mental illness

Midazolam & proper counselling

References:-

1. Intravenous drugs used for the induction of anaesthesia ;Dr Tom Lupton, Dr Oliver Pratt, Salford Royal Hospitals NHS Foundation Trust, Salford, UK.

2. Pharmacology & Physiology in Anaesthetic practice 4th ed, Robert K stoelting, Simon C Hiller

Thank you