Intravenous Anesthetic Agents

Introduction

Used IV anesthetic drugs are:

1. Propofol ,Fospropofol

2.Thiopentone, Methohexital

3.Ketamine

4.Etomidate

5.Benzodiazepines (Diazepam, midazolam, lorazepam)

6.Dexmeditomidine

Chemical Structure

Propofol Thiopenton

e

Ketamine Etomidate Benzodiazepin

es

Isopropyl

phenol

Barbiturate

Replacemen

t of oxygen

at C2 with

sulphur.

Analogue of

phencyclidine

Carboxylat

ed

imidazole

Benzene ring

and 7 member

diazepine ring.

Physio chemical propertiesPRPOFO

L

THIOPENTONE KETAMINE ETOMIDATE BENZO-

DIAZEPINE

Colour Emulsion

*, milky

white

Sodium salts Clear

aqueous

solution

Clear solution Midazolam-

Clear aqueous

solution.

Conc. 1%, 2%

soln.

Medium,

long chain

triglycerides

Yellow amorphous

powder.

500mg, 1g

1%, 2%,10%

solution

2mg/ml in

35%

propylene

glycol

Lipid

Solubility

Only in

emulsion

form

Highly soluble Very Lipid

soluble

Acidic pH lipid

soluble

Lipid soluble

midazolam

Water

solubility

Insoluble Readily soluble Soluble Poorly water

soluble.

Water soluble

ph 4.5-6.4 10.5 3.5-5.5 6.9 3.5

pKa 11 7.6 7.5 4.2 6.15

Chirality Not chiral Racemic mixture Racemic Single isomer

R+

PROPOFOL

Neeeds an emulsifying agent: 1% (w/v) propofol10% soyabean oil 2.25% glycerol 1.2%purified egg phosphatide Di-sodum edetate (0.005%)

Supports bacterial growth. E.Coli and Pseudomonas.

Aseptic technique should be used during administration.

KETAMINE

Racemic mixture S+

isomer.

THIOPENTONE

Cannot be mixed with catecholamines, opioids and NMB drugs.

Powder form stable at room temp indefinately. Refrigerated- 2weeks Room temp reconstituted- 6 days

BENZODIAZEPINES:

Have a reversible ring

structure that opens at a pH

<6 and closes at pH>6.

METABOLISM

PROPOFOL THIOPENTONE KETAMINE ETOMIDATE BENZO-

DIAZEPINE

S

Liver

Ring

hydroxylation

by CytP450

4-hydroxy

propofol.

CONJUGATION

Glucuronidation

and sulfation

EXCRETED

Kidney

Inactive

metabolite

Liver

Oxidation, N-

dealkylation,

desulfration and

destruction of

barbituric acid ring.

EXCRETED

Kidneys and bile

Inactive metabolite

Liver

Demethylatio

n of ketamine

by P-450

Nor-

KetamineACTIVE

METABOLITE

Hydroxylated

and

conjugated

Water

soluble

glucuronide

metabloite.

EXCRETED

Kidney

Liver and

plasma

esterase.

Hydrolysis of

ethyl ester side

chain.

Carboxylic acid

ester.

EXCRETED

Kidney

Inactive

metabolite

Liver

1-hydroxy

midazolam.

N-dealkylation

and aliphatic

hydroxylation/

glucuronide

conjugation.

EXCRETED

Kidney

Phase I

metabolite is

active.

PharmacokineticsPROPOFOL THIO-

PENTONE

KETAMINE ETOMIDATE BENZO-

DIAZEPINES

ONSET 15-45s <30s 45-60s 15-45s 30-90s

AWAKENING 5-10mins 5-10mins 10-20mins

Full orientation

60-90mins

3-12 mins 15-30mins

RATE OF

FALL IN

PLASMA

CONC.

Redistribution

and elimination

redistribution redistribution

CONTEXT

SENSITIVE

HALF LIFE

<40mins <150mins

EXTRACTION

RATIO

low high high

After delivery of an IV bolus, the percentage of

thiopental remaining in blood rapidly decreases

as drug moves from blood to body tissues.

Initially, most thiopental is taken up by the

vessel-rich group (VRG) of tissues because of

their high blood flow. Subsequently, drug is

redistributed to muscle and to a lesser extent to

fat. Throughout this period, small but substantial

amounts of thiopental are removed and

metabolized by the liver.

Mechanism of action

PROPOFOL THIOPENTONE KETAMINE ETOMIDATE BENZO-

DIAZEPINES

Selective

modulator of

GABAa

increasing

affinity for

GABA.

Depress RAS in

brain stem.

Action via GABAa

receptor, increases

the duration of

opening of chloride

channels.

Non

competitive

binding to

phencyclidine

site on NMDA

receptors.

Weak action

at GABA.

Dissociates

THALAMUS

from LIMBIC

CORTEX.

Depresses RAS

in the brain

stem.

Binds to a

subunit of the

GABAa receptor

increasing

affinity for

GABA.

Bind to GABAa

receptor but

different site.

Increase the

frequency of

opening of the

chloride ion

channel.

SYSTEMIC EFFECTS

CENTRAL NERVOUS

SYSTEMPROPOFO

L

THIOPENTONE KETAMNE ETOMIDATE MIDAZOLAM

CMRO2

CBF

ICP

IOP − − −

DISSOCIATIVE

ANESTHESIA

✕ ✗ ✔ ✕ ✗

EMERGENCE

REACTION

✕ ✗ ✔ ✕ ✗

NYSTAGMUS ✕ ✗ ✔ ✕ ✗

SKELETAL MUSCLE

TONE

− − − −

SALIVATION

LACRIMATION

− − − −

PROPOFOL THIOPENTONE KETAMINE

NEURO-

PROTECTIV

E

• Anti oxidant

properties.

• Reduced infarct

size when

administered

immediately or 1hr

after ischemic

insult

• Decreases oxygen

demand

• Preserves CPP

(cerebral perfusion

pressure)

• Robin Hood

phenomenon

• Free radical

scavenging

• Improves

perfusion in

incomplete

cerebral

ischemia

THIOPENTONE KETAMINE ETOMIDATE

EEG

changes

• Small dose-low voltage

fast wave activity

• High dose-high voltage

slow wave activity

• Continuous infusion-

isoelectric EEG

• Abolotion of alpha

rhythm and

dominance of

theta activity.

• Onset of delta

activity co incides

with loss of

consciousness.

• Produces burst

supression at high

dose.

• Similar to

thiopentone but

frequency of

excitatory spikes

is more

CVS

PROPOFOL THIOPENTONE KETAMINE ETOMIDATE BENZO

DIAZEPINES

BP 25-40% −

unchange

d

HR Inhibits

tachycardic

response to

hypotension

.

May cause

bradycardia

−

unchange

d

CO −

unchange

d

Respiratory System

PROPOFO

L

THIOPENTONE KETAMINE ETOMIDATE BENZODIAZEPINE

S

APNEA ++ ++ + LARGE

DOSE

+ RAPID

INJECTION+

VENTILATOR

Y DRIVE

BHRONCODIL

ATATION✔ ✗ ✔✔ ✗ ✗

AIRWAY

REFLEXES intact intact intact intact

DOSESPROPOFOL THIOPENTO

NE

KETAMINE ETOMIDATE BENZO-

DIAZEPINE

S

Induction 1-2.5 mg/kg IV 3-4mg/kg 0.5-2 mg/kg

IV4-6 mg/kg IM

0.2-0.6 mg/kg

IV

0.05-

0.15 mg/kg

Maintainence 50-

150 µg/kg/min

IV combined

with N2O or an

opiate

50-100mg

every 10-20

mins

0.5-1 mg/kg IV

with N2O 50%

in O2 15-

45 µg/kg/min

IV with N2O

50-70% in O2

10 µg/kg/min

IV with N2O

and an opiate

0.05 mg/kg prn

1 µg/kg/min

Sedation 25-

75 µg/kg/min

IV

0.2-0.8 mg/kg

IV over 2-3 min

2-4 mg/kg IM

0.5-1 mg

repeated

0.07 mg/kg IM

Analgesia 0.15-

0.25 mg/kg IV.

Preventive/pre

emptive.

Anti-emetic 10-20 mg IV,

repeat every 5-

10 min or start

infusion

10 µg/kg/min

Drug interactions

PROPOFOL THIOPENTON

E

KETAMINE ETOMIDATE BENZODIAZE

PINE

• Fentanyl and

Alfentanyl

concentration

s may be

increased

with

concurrent

administratio

n.

• Contrast

media and

drugs that

occupy the

same protein

binding sites

can displace

drug.

• Ethanol,

opioids and

anti

histamines

potentiate

the CNS

depressant

effect.

• Interacts

synergisticall

y with volatile

anesthetics

• Midazolam

attenuate

ketamines

cardio-

stimulatory

effect.

• Fentanyl

increases its

plasma level

• Opioids

decrease the

myoclonusch

aracteristic.

• Eryhtromycin

inhibits

metabolism

of midazolam

• In

combination

with opioids

BP falls.

• Reduce the

MAC of

volatile

anesthetics

as much as

30%

USES

POPOFOL THIOPENTON

E

KETAMINE ETOMIDATE BENZODIAZE

PINE

INDUCTION ✔ ✔ ✔ ✔ ✔

SEDATION ✔ − ✔ ✔ ✔

MAINTAINENC

E

✔✔ ✔ ✔ ✔ ✔

ANALGESIA ✗ ✗ ✔✔ ✗ ✗

PRE-EMPTIVE

ANALGESIA

✗ ✗ ✔✔ ✗ ✗

ANTI EMETIC ✔✔ ✗ ✗ ✗ ✗

ANTI

PRURITIC

✔ ✗ ✗ ✗ ✗

ANTI

CONVULSANT

✔ ✔ ✗ − ✔

CHR.

HEADACHE

✔ ✗ ✗ ✗ ✗

AMNESTIC ✔ − ✔✔ − ✔

Side EffectsPROPOFOL THIOPENTO

NE

KETAMINE ETOMIDATE BENZODIAZ

EPINE

Pain on

injection

✔✔ ✔ ✗ ✔ ✗

Hypotension ✔✔ ✔ ✗ ✔ ✗

Bronchospas

m

✗ ✔ ✗ ✗ ✗

Allergic rxn ✔ ✔ ✗ ✗ ✗

Emergence

rxn

✗ ✗ ✔ ✗ ✗

Thrombophle

bitis

✔ ✔✔ ✗ ✗ ✗

Hangover

effect

✗ ✓ ✔ ✗ ✗

Tolerance and

dependence

✔ ✔ ✔ − −

Immunosuppr

ession

✔ − − ✔

Neutrophil

func.

✗ −

Other side effects

PROPOFOL: Risk of bacterial infection

Hypertriglyceridemia

Pulmonary Embolism

Propofol infusion syndrome: Lactic acidosis

>75mcg/kg/min for >24hrs

Unexpected tachycardia with increased anion gap

MOA- Poisoning of ETC

D/D: Hyperchloremic metabolic acidosis

Diabetic Ketoacidosis

ETOMIDATE:

Adrenocortical suppression, inhibition of 11-beta

hydroxylase.

Lasts for 4-8hrs after induction.

KETAMINE:

Emergence delirium

Symptoms: Visual auditory proprioceptive and confusional

illusions. Transient

cortical blindness.

Dreams (morbid) Hallucinations.

Mechanism: Ketamine induced depression of inferior colliculus

and medial geniculate body

Incidence: Age>15, Female, Dose>2mg/kg, H/O personality

problems

Prevention: Benzodiazepines pre-operatively 5mins before

induction.

DEXMEDITOMIDINE

Highly selective α2 adrenergic agonist.

Physicochemical properties: Active S enantiomer of meditomidine.

Water soluble.

Pharmacokinetics:

Rapid hepatic metabolism.

Conjugation.

Metabolites excreted through urine and bile.

Clearance high, elimination half life short.

Significant increase in context sensitive half time from 4mins after

10min infusion to 250 mins after 8hr infusion

Pharmacodynamics:Activation of CNS α2 receptors. Hypnosis is due to this activation in locus cerulus. Analgesia at the level of spinal cord. Sedation resembles physiologic sleep state. Decreases CBF no significant change in ICP.

CVS: HR & SVR BP Heart block asystole or sever bradycardia may occur.

RS: Mod decrease in tidal volume. Upper airway obstruction due to sedation possible.

Uses: Short term sedation of ICU patients. Adjunct to GA. Sedation during fiberoptic intubation/ regional anesthesia.

DOSE: 0.5-1mcg/kg over 10-15mins followed by infusion of 0.2-0.7mcg/kg/hr.

References

Millers 7th edition

Clinical Anesthesiology- Morgan 5th edition

Stoeltings handbook of pharmacology and

physiology in anesthetic practice. 4th edition

Clinical Anesthesia Barash 7th edition