Dr. Deepali Jamgade

Dr.Pradeepa Chevala

Guided by: DR . S MANIMALA RAO

1872

•PIERRE-CYPRIEN ORE’ (French Surgeon) used chloral hydrate

1864

•ADOLF VON BAYER – On Saint Barbara’s Day discovered barbituricacid. Coined the term Barbitute as acombination of Barbara and urea. (no sedative properties)

•1n 1903 – Emil fischer discovered hexobarbital. Helmut Weesestudied it

1934

•John Lundy of clinic of mayo studied sod .thiopental – balanced anesthesia

• In 1941 – pearl harbour – many deaths with use of STP due to cardiovascular depressant effects.

1956 - Replacements like

• HYDROXYDIONE (steroid; thrombophlebitis)

• ALTHESIN (mixture of alphaxolone and alphadolone; has rapid onset and recovery; rejected because of hypersensitivty reactions)

• PROPANIDID (solubilized in Cremephor EL; rejected because of hypersensitivity reactions)

In 1973 – Etomidate – minimal hemodynamic depression . Used use in pts with severe CVS disease

1962 – 1978

• Ketamine – unique as it does not cause CVS depression but post op hallnications are present

• Benzodiazepines were studied for anxiolysis without same degree of sedation as thiopentone ;1963 – diazepam 1978 - midazolam

1977

• Propofol was discovered

• Alkylphenol compound with antiemetic properties and depressionof laryngeal reflexes so easy placement of supraglottic airways

What are i.v. induction agent ?

Agent cause a rapid reversible loss of consciousness.

TIME :- “one arm-brain (A→B)circulation time” this time

also depend on cardiac output and ejection fraction .

Normal A → B circulation time is 15-20 sec.

They are used:

To induce anaesthesia prior to other drugs being given to

maintain anaesthesia.

To maintain anaesthesia for longer procedures by

intravenous infusion. To provide sedation. Use for day care

/ short / opd procedure

Drug conc. In CNS decreased and patient becomes awake (due to redistribution of drug)

Repeat intermittent bolus Continuous sedation required

Unbound high lipid soluble and unionized drug crosses BBB quickly

Drug conc. Increases in VRG organs

Slowly sec. uptake by diffussionto other tissue

Drug injected in vein reaches the blood

Some % bind to protein Rest % of drug free/unbound

Several factors :-

Route of administration

Age ( ↓ with age )

Lean body mass ( fat free ) (muscular > fatty

)

↓ in low cardiac output state( body

compensate to accordingly to maintain

cerebral perfusion )

↓ in Hypoprotenemia ( nutritional,

nephropathy , PIH )

Rapid onset and offset

Analgesia at subanesthetic dose

Minimal cardio respiratory depression

No emetic effect

No excitatory and emergence phenomenon

No interaction with N-M blocking agent

No pain on injection

No venous sequel ( venous thrombosis)

No toxic effect on other organs

No release of histamine ( bronchospasm )

Water soluble formulation and long self life

No hypersensitivity

No stimulation of porphyria

No adrenocortical suppression

GABAA RECEPTOR

HIGHEST NUMBER IN OLFACTORY BULB, CEREBRAL CORTEX, CEREBELLUM,

HIPPOCAMPUS, SUBSTANTIA NIGRA, INF. COLLICULUS

LOWER DENSITY IN STRIATUM , LOWER BRAIN STEM AND SPINS

ALPHA 1 – CAUSES

Sedation ,

anterograde amnesia

, and anticonvulsant

properties.

ALPHA 2 – causes

anxiolysis ms.

Relaxant

Major inhibitory Neuro-transmitter in the CNS

= GABA

Active GABA A receptor => Cl - influx =>

Hyperpolarisation

Propofol & barbiturates slow GABA A receptor

dissociation

Benzodiazepines increase GABA A to receptor

coupling

Ketamine acts at NMDA receptor

These effects lead to sedative & hypnotic

effects

Increasing dose => sedation => hypnosis

All iv anesthetics affect other organ systems

Potential for respiratory depression

Potential for CVS depression

Potential for altered CBF/ICP

Hypovolemia => severe hemodynamic effects

seen due to decreased blood pool

Use lower doses!

Rapid onset and rapid offset , no excitatory effect .

Yellow amorphous powder , in atmosphere of nitrogen

Ultra short acting barbiturate.

@C5

-aryl or alkyl group (hypnotic)

-phenyl gr. (anti convulsant)

@ C2

-O2 (oxybarb.)

-Sulfur (thiobarbiturate)

@C1-

Replacement of oxygen at C2 with sulphur.

Diluted to 2.5 % solution ,can be stored for 48 hr ↓refrigerator , Concentration >5 % cause pain

Highly Alkaline pH 10.5, contain 6 % NaHCO3

↓ in alkalinity cause ppt of solution , so avoid to dilute in acidic solution , RL .

Co-adm of vec, atra , midaz , alfentanilform ppt in I.V. line and occlude the vein

Sedation & Hypnosis by interaction with

inhibitory neurotransmitters GABA on GABAA

receptor.

GABA facilitatory & GABA mimetic action.

GABAA receptor has 5 glycoprotein sub unit.

Increases GABA mediated transmembrane conductance

of Cl– ion, Causes hyperpolarization & inhibition of

post synaptic neuron.

At low concentrations, barbiturates enhance the effects of GABA,

decreasing the rate of dissociation of GABA from its receptor–

sedative-hypnotic effects of the barbiturates.

At higher concentrations, the barbiturates directly activate the

chloride channels without the binding of GABA, acting as the

agonist itself.

The GABA-mimetic effect at slightly higher concentrations may

be responsible for what is termed barbiturate anesthesia.

Onset of action of i.v. injection - 10-20 sec.

peak 30-40 sec. duration for awakening 5-15 min.

Prompt awakening after single i.v. inj. is due to rapid redistribution to lean body tissue (muscle)

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.

Excretion-< 1% excreted unchanged in the urine

Volume of distribution – 2.5L/Kg

Rapid distribution half life – 8.5 Min

Slow distribution half life – 62.7 Min

Elimination Half Life 11.6 Hours

Clearance(3.4ml/kg/min)

Prolonged in obese patient,elderly,pregnancy.

Short in paediatric patient.

1) Redistribution

- Lipid solubility (most important factor)

High Lipid Solubility makes it to cross blood brain

barrier & lean body tissue rapidly.

- Protein Binding

Highly bound to albumin & other plasma protein 72 – 86% Binding.

Only unbound fraction crosses Blood-Brain-Barrier.

-Ionization

Only non-ionized part crosses BBB.

Thiopentone has pKA 7.6 so 61% of it is non-ionized at physiologic PH

-Conc. Gradient between CSF and Plasma

2)Metabolism

By liver microsomal enzymes mainly, Slightly in CNS & kidney. 10

– 24 % Metabolised each hour.

OXIDATION of Aryl, Alkyl or Phenyl moeity @ C5

N-DEALKYLATION

DESULFURATION

DESTRUCTION of Barbituric ring

Conjugation with glucoronide to hydroxythiopentol & carboxylic

acid derivatives to form water soluble metabolites.

Excreted in urine

Act on GABA a receptor lead to Cl influx –hyperpolarisation of cell membrane -↑threshold of excitability of post synaptic neuron .

This is highly lipid soluble drug cross BBB –fast onset of axon

AT plasma pH around 50 % unionized drug ; in acidosis condition unionized % ↑; dose requirement ↓

Dose dependent↓ CBF, ↓ ICP, ↓ CMRO 2

CPP= (MAP-ICP ) but { ↓ICP > ↓MAP } ; CPP preserve

Sedation and loss of consciousness

retrograde amnesia and depression of vasomotor centre.

Induction and maintenance of anesthesia

Rate of adm α onset

Termination of effect take 5-10 min to awake ( after bolus )

Awakening depend on :-

Volume of distribution

Plasma concentration

Redistribution and Clearance

Alteration in metabolism

CNS sensitivity ↑ with age

Pupil and eye :- initially pupil contract but then dilate .

Pupillary response is lost with surgical anaesthesia .

loss of eyelash reflex is commonly used as endpoint for adequate induction dose .

Following traumatic brain injury, infusion of thiopental to produce a “barbiturate coma” lowers intracranial pressure and may improve neurological outcome.

Anticonvulsant property

Thiopental have no analgesic action and may be antianalgesic in low dose .

Burst suppression of EEG can be induced with high doses when used in treatment of status epilepticus or intractable rise in ICP following head injury .

Dose related resp depression ,peak resp depression after (1-1.5 min) after adm of bolus dose .

More susceptible patient ch lung disease , Airway obst

Apnea :- transient apnea for 25 sec only in 20 % cases.

Double apnea :- 1 st during adm of drug > transient >after 4-5 breath 2 nd apnea last for longer period .

during this period ventilation must be assessed –controlled ventilation .

↓minute ventilation , ↓ sensitivity to raised CO2

Airway reflexes preserved not suitable for LMA insertion ,may cause coughing and laryngospasm

C/I in St. asthmaticus

When choosing an induction agent, the

primary goals are as follows:

(1) to preserve maternal blood pressure,

cardiac output, and uterine blood flow;

(2) to minimize fetal and neonatal

depression;

(3) to ensure maternal hypnosis and

amnesia.

Umbilical blood and maternal blood concentration equal by the time of delivery

At this dose fetal brain suppression does not occur

Fetal CNS depression occur at >= 8mg/kg

Haemodynamic effect unlikely at this dose in normal pregnant women

Within 30 sec drug can be found in umbilical cord

Umbilical venous blood concentration peaks in 1 min

Thiopental <4 mg/kg; prompt,reliable induction

Reach in maternal blood, induce patient

Readily cross the placenta

First effect dose dependent peripheral vasodilatation

- ve inotropic effect - ↓ Ca to myocardial fiber

↓BP

↓ CO (↓venous return , vasodilatation, -veinotropic effect , ↓CNS symp outflow )

Tachycardia ( 10-36 %) Via baroreceptormediated symp reflex in response to ↓ CO & BP

CAD patient on induction ↑HR - ↑myocardial demand of O2

ECG changes :-prolonged QT , flattened T wave ,vent arrhythmia

eg - acidotic patient ,long term dialysis , Cirrhosis

Indications Induction of anaesthesia

Control convulsions

Decreased ICP

Neuroprotection

Contraindications ABSOLUTE COPD Severe asthama porphyria Previous hypersensitivity Allergy to sulphur

PRECAUTIONS : Stenotic valvular disease Severe hepatic disease Renal impairment

Anticonvulsant

for rapid control of status epilepticus

dose 0.5 – 2 mg/kg. repeated as needed

Treatment of increased intracranial pressure

CMRO2 by 55%, CBF

dose 1 – 4 mg/kg i.v.

CPP is maintained

ADVANTAGE :-

Rapid induction

Don’t sensitize myocardium to adrenaline

No nausea and vomiting

Other uses Anticonvulsant In psychiatric patient Narcoanalysis

DISADVANTAGE :-Pharyngeal and laryngeal reflex persist →apnea –controlled ventilation

Resp depression Hypotension

Poor analgesic and muscle relaxant

Gangrene and necrosis

Shivering and delirium

Stop injection immediately ,

leave the canula insitu , and dilute with

immediate inj of saline

Give intra-arterial inj of LA + vasodilator

Lidocaine 50 mg ( 5 ml of 1 %) + phenoxybenzamine( α blocker)0.5 mg bolus

or 50-200 µg/min infusion.

Consider systemic papaverine 40-80 mg

Consider sympathetic block ( brachial plexus

block or stellate ganglion block )

Start i.v heparin infusion

Give intra arterial hydrocort Postpone

surgery Consult vascular surgeon

•diazepam was synthesised by Sternbach in 1959

DIAZEPAM

•by Bell in 1961

OXAZEPAM,

•by Fryer and Walser in 1976

MIDAZOLAM

•existence of BZR was first discussed in Milan in 1971

•isolation and receptor-ligand interaction were demonstrated in 1977

•this has resulted in the generation of a number of new ligands and a specific antagonist

BENZODIAZEPINE RECEPTOR (BZR)

DIAZEPAM MIDAZOLAM

COMPOSITION milliliter of diazepam

solution (5 mg)

contains propylene

glycol 0.4 mL,

alcohol 0.1 mL,

benzyl alcohol

0.015 mL, and

sodium

benzoate/benzoic

acid in water for

injection

(pH 6.2 to 6.9)

solution (1 or

5 mg/mL) contains

0.8% sodium chloride

and 0.01% disodium

edetate,

with 1% benzyl

alcohol as a

preservative.

The pH is adjusted to

3 with hydrochloric

acid and sodium

hydroxide

DIAZEPAM MIDAZOLAM

MOLECULAR

WEIGHT

284.7 362

PKa 3.3 6.2

WATER SOLUBLE NO YES

LIPID SOLUBLE YES

HIGHLY LIPOPHILIC

YES

HIGHLY LIPOPHILIC

(DUE TO IMIDAZOLE

RING)

DIAZEPAM MIDAZOLAM

EQUIVALENT DOSE

(mg)

0.3 – 0.5 0.15 - 0.3

VOLUME OF

DISTRIBUTION

(L/KG)

1 - 1.5 0.3 – 0.5

PROTEIN BINDING 96 -98 % 96 -98 %

CLEARANCE

(ml/kg/min)

0.2 - 0.5 6 - 8

DIAZEPAM MIDAZOLAM

MECHANISM Oxidation of methylene

group of diazepine ring;

Finally glucuronidation of

metabolite

Oxidation at imidazole

ring;

And further glucuronidation

METABOLITES 1.Desmethyldiazepam

2.Oxazepam

3.temazepam

1. 1-hyddroxymidazolam

2. 4-hydroxymidazolam

ELIMINATION Kidney

(e.t1/2 21-37 hours)

Increased in cimetidine

use, old age , cirrhosis of

liver

Kidney

(e.t1/2 1-4 hours)

Increased in cimetidine

,erythromycin ,CC Blockers

, old age , cirrhosis of liver

(mainly by hepatic microsomal oxidation and glucoronide conjugation)

CNS EFFECTS RESPIRATORY EFFECTS

Dose dependent↓ CBF, ↓CMRO 2 (ratio maintained by midazolam)

Increase in seizure initiation threshold

20% - Anxiolysis 30-50% - sedation 60% - unconsciousness

SLEEP CYCLE-

alpha activity is decreased

increase in low voltage, fast activity, especially beta

the amplitude of somato-sensory EP's is reduced

"pre-anaesthetic" doses-↓alveolar ventilation

the peak onset of ventilatory depression following midazolam (0.15 -0.3 mg/kg) is at ~ 3 min and lasts for ~ 15 mins

in patients with obstructive pulmonary disease - respiratory depression, CO2 retention and narcosis

decreases the MAC of inhalational anaesthetics

in "pre-anaesthetic" doses they decrease the BP and increase HR

decrease peripheral resistance - flunitrazepam - midazolam

decrease LV work and cardiac output - diazepam – lorazepam

baroreceptor reflexes generally remain intact, though, there is

some depression

the hypotensive effect is minimal and usually less than that seen

with thiopentone

the effect is possibly slightly greater with midazolam and is dose

related

in patients with elevated cardiac filling pressures, both

midazolam and diazepam produce a "nitroglycerine like" effect,

reducing preload and increasing cardiac output

diazepam increases coronary blood flow in man, possibly by

increasing interstitial concentrations of adenosine

INTRAVENOUS SEDATION

ORAL SEDATION

INDUCTION OF ANAESTHESIA

DIAZEPAM MIDAZOLAM

INDUCTION 0.3 – 0.5 mg/kg

(Given in 5 to 15

sec; induction in

39 sec)

0.05 – 0.15 mg/kg

(Given in 5 to 15

sec; induction in

28 sec)

MAINTAINENCE 0.1 mg/kg 0.05 mg/kg

SEDATION 2 mg 0.5 - 1 mg

ADVANTAGES DISADVANTAGES

Better amnesia ( 1-2

hours)

Smoother

haemodynamic course

(in healthy patients)

Less opioid

requirement

Less dosage required

if used with opioids

Accumulate in blood

Prolonged arousal time compared to other I.vinduction agents

In hemodynamicallycompromised patients cvsdepression.

Dosage affected by age, sex , gender , obesity , enzyme induction , hepatic and renal diseases

Longer context sensitive half life.

Ketamine is a phencyclidine derivative

Rapid onset 30-60 sec ;

high lipid soluble ( 5× thiopental )

Hypnosis ,amnesia Dissociative anaesthesia , intense analgesic ( SOMATIC > VISCERAL ), ,rapid clearance

Cardio stimulation property

Minimal effect on resp system

Sympathomimetic effect

IOA choice for ASA – IV and hemodynamic compromised state the possibility of emergence delirium limits the clinical usefulness of ketamine.

Ketamine has advantages over Propofol and etomidate in being water soluble

NMDA Receptors antagonist :-

Opioid Receptors:-

Muscarinic Receptors:-

The fact that ketamine produces anticholinergicsymptoms (emergence delirium, Bronchodilation, sympathomimetics action) suggests that an antagonist effect of ketamine at muscarinicreceptors is more likely than an agonist effect.

Sodium Channels:- Consistent with its mild local anesthetic-like properties, ketamine interacts with voltage-gated sodium channels sharing a binding site with local anesthetics

Induction of general anesthesia 0.5-2 mg/kg IV;

4-6 mg/kg IM

Maintenance of general

anesthesia

0.5-1 mg/kg IV with N2O 50% in

O2

15-45 µg/kg/min IV with N2O 50-

70% in O2

30-90 µg/kg/min IV without N2O

Sedation and analgesia 0.2-0.8 mg/kg IV over 2-

3 min 2-4 mg/kg IM

Preemptive/preventive analgesia 0.15-0.25 mg/kg IV

Intra thecal ketamine 0.5-0.75 mg/kg

Emergence phenomenon (psychadelic effect) visual , auditory, propioceptive and confusional illusion ,delirium and cortical blindness

Bodily detachment / dissociative anesthesia

Preventive measures

LOC in 30-60 sec i.v and 2-4 min after i.m (end point Nystagmus in horizontal gaze)

Consciousness regain in (10-20)min

Full orientation in (60-90)min

Ketamine water soluble; consider dose dependending factor

1-2mg/kg i.v and 4-6 mg/kg i.m Apnea rare but can be there

↑CMRO2, ↑ ICP(d/t ↑symp tone ),↑IOT,↑ CBF (↑CBF> ↑CMRO2)

Dissociative anaesthesia ( cataleptic state )

Corneal , cough , swallow reflex +nt

Amnesia not prominent as compare with BZD ↑muscle tone , purposeless movement , Ө wave on EEG , petit mal type seizure activity in hippocampus

Primary site of axon in CNS thalamoneocorticalprojection system .

Depress cortical and thalamus function Stimulate limbic and hippocampal function

Associated with vivid dreaming , sense of floating of body, illusion , ext sensory experience , excitement , confusion , euphoria , fear .

Occur with ketamine due to depression of auditory and visual relay nuclei .

The loss of skin and musculoskeletal sensations results in a decreased ability to perceive gravity, thereby producing a sensation of bodily detachment or floating in space.

These feature last for 1 hr.

Factor affecting emergence reaction

Age ( adult > child )

Gender( female > male )

Dose (↑)

Concurrent drug ( BZD priming 5 min before ketamine )

Preop counseling

Sympathomimetic action ↑BP, ↑HR , ↑ CO

↑ SBP is 20 to 40 mm Hg, with a slightly increase in DBP, increases progressively during the first 3 to 5 minutes after an intravenous injection of ketamine and then decreases to predrug levels over the next 10 to 20 minutes.

↑ myocardial O2 demand – provided by adequate CO &↓ coronary vascular resistance .

These effect are more apparent in 1 st bolus dose than 2 nd dose .

Ketamine ↑ pul artery pressure – caution use in left side stenoticvalvular lesion .

Tachycardia and hypertension by ketamine can be prevented by premedication with BZD or continuous inhalational agent

Cautiously use in IHD

Useful in pt of cong heart Ds even in whom propensity for R-L shunt exist

Min effect on central resp drive

Transient (1-3 ) min ↓ in minute ventilation

Large dose produce apnea

Bronchial muscle relaxant { when given in patient of bronchospasm – pul compliance increased }

Bronchodilation make this a potentially useful drug for the rapid intravenous induction of anesthesia in patients with asthma.

Ketamine as effective as halothane

Resp problem in children are due to ↑ secretion ( salivation )-cause upper airway obstruction – laryngospasm

Increase pulmonayl artery pressure

Preserve cough and upper airway reflex so not useful with LMA

When choosing an induction agent, the

primary goals are as follows:

(1) to preserve maternal blood pressure,

cardiac output, and uterine blood flow;

(2) to minimize fetal and neonatal

depression; and

(3) to ensure maternal hypnosis and amnesia.

Fetal outcome same in both induction with ketamine or thio

Provide both analgesia and hypnosis,maternal awareness less as compared to thiopentone alone

Ketamine rapidly cross the placenta and at max conc in fetal blood in 1.5 to 2 mins

Large dose (>1 mg/kg) increased uterine tone

Ketamine excellent choice for i.v induction in LSCS at 1mg/kg

Rapid onset, sympathomimetic Best in hypovolemia and asthama patient

ADVANTAGE

increase HR,BP,CO

In asthmatic

For short procedure

Combination with BZD can use in cardiac catheterization and angiography .

In OPD surgical procedure

Good analgesic property

DISADVANTAGE

limb movement and Nystagmus

Emergence phenomenon in 50 %

Hypertensive

Increased ICP , IOT

Uterine stimulation

Schizophrenia , psychosis

Poor muscle relaxation

INDICATION

CVS except IHD and Resp. disorder

Hemodynamic compromised ( pericarditis , cardiac tamponade , CM , shock )

Traumatic and septic shock

As component in TIVA with midaz and propofol provide better hemodynamic stability

In cancer patient , neuropathy

Phantom or ischaemic limb pain

Fibromyalgia , visceral pain

Migraine

CONTRAINDICATION

↑ ICP , SOL brain

Large size Infarct

Ophthalmic injury

IHD

Vascular aneurysm

Schizophrenia

Most frequently use I.V. anaesthetic drug today

Milky white ;

pH 7.0 - 8.5 ;

isotonic to plasma

Fospropofol prodrug

Stable at room temp ;

Not light sensitive

Dilution :- water insoluble ;

Compatible in DNS Dilution cause cracking of emulsion , spontaneous degradation

Concern regarding microbial growth in emulsion – disodium edetate (0.005%) added to retard the bact. Growth

Sedation in and outside of OT

Concern regarding induction and emergence myoclonic ,jerk

Painful injection in small vessel take care of it

2,6 –di-isopropylphenol

Rapid onset 15-45 sec and offset , rapid offset even after prolonged infusion ( small context sensitive half time )

Metabolize in liver with Glucuronide and sulfateconjugation .

Extra hepatic metabolism + lung ; inactive metabolite Mainly excreted by kidney

Propofol causes the most marked fall in blood pressure of all the induction drugs. This is mainly due to systemic vasodilatation. There may be an accompanying slight increase in heart rate. The fall in blood pressure is dose dependent and is most marked in the elderly and in shocked patients. This can be minimized by slow injection – avoiding inadvertent overdose.

By the removal of Cremophor consists of 1%

(wt/ vol ) Propofol 10% soybean oil 2.25%

glycerol 1.2% purified egg phosphatide To

prevent microbial growth in the emulsion,

disodium edetate (0.005%) was added as a

retardant of bacterial growth.

If a dilute solution of propofol is required, it

is compatible with 5% dextrose in water.

Fospropofol (Aquavan)soon going to be

approved by FDA, a phosphorylated prodrug

of Propofol,

Clinical use Dose

Induction of general

anaesthesia

•1-2.5mg/kg,dose reduced with increasing

age,induction dose in 2 yr(2.9mg/kg),in 6-

12 yr(2.2 mg/kg)

Maintainance of

general anaesthesia

100-200mcg/kg/min without N2O & opiates

50-150mcg/kg/min with n2O & opiate

Sedation(with little

analgesic & amnesic)

25-75 mcg/kg/min I.V.,concious sedation

Antiemetic 10-20mg I.V.can repeat every 5-10 min

orstart 10mcg/kg/min infusion

Dose and therapeutic conc dependent action

Hypnotic action by enhancing GABA induced chloride current

Onset with 2.5 mg/kg 15-30 sec with peak effect in 90-100 sec.

Duration of hypnosis 5-10 min depending on redistribution and Vd

Subhypnotic dose – sedation and amnesia infusion @2mg/kg/hr

Propofol have shown direct depressant effect on neuron of spinal cord

sense of well being ( ↑dopamine conc in nucleus accumbence- phenomenon seen in drug abuser and pleasure seeking behavior.

Antiemetic action may be explained by ↓in serotonin level .

↓ ICP , acutely ↓ IOP -(propofol >Thio )effective in preventing raised IOP with scolin and intubation response

Neuroprotective role ↓ controversies ;due to antioxidant axn by inhibiting lipid peroxidation

Just or 1 hr after to ischemic insult produce reduction in size of infarct at sedation dose @ 25-75 µg/kg/min as compared to awake control with intralipid.

Burst suppression @blood level > 8µg/ml –better neurological outcome and less brain injury

EEG effect – ( α → ϒ → Ө ) wave Seizure like activity reported mainly on induction and emergence . Dose dependent anticonvulsant activity +nt

On induction dose and rate of adm dependent↓ BP (25-40 %) in comparable dose (propofol >Thiopental)

↓ SBP and DBP , ↓ MAP

↓ CO, ↓ SV , ↓ SVR ( 15-25 %)

HR ↓(-10 +_10 % ) to baseline; Propofol either may reset or may inhibit the baroreflex, reducing the tachycardia response to hypotension

MAP ↓ ( -10-40 %)

Propofol at high concentrations (10 µg/mL) abolishes the inotropic effect of α but not β adrenoreceptorstimulation, and enhances the lusitropic (relaxation) effect of β stimulation

CNS induced ↓ sympathetic drive on heart - cardio depression

In patient with valvular lesion ↓( PA and PCWP ) – due to ↓ pre and afterload .

cardio depression ( bolus > infusion )

Continuous Infusion cause significant ↓ in myocardial blood flow and oxygen demand

For better hemodynamic stability use one or more additive induction agent ( fentanyl , Midazolam )with propofol .

Bradycardia-related Death:-Profound bradycardiaand asystole after the administration of Propofoldespite prophylactic Anticholinergics. thus suggesting that Propofol induce a suppression of sympathetic nervous system activity. The treatment of Propofol-induced bradycardia may require the administration of a β-agonist, such as isoproterenol.

Profound resp depressant

Apnea occur depend on dose , speed of injection, concomitant premedication

Occur in 25- 30 % cases ,may last for >30 sec ,may ↑by adding opiate in premedication

Apnea risk max in this agent than other

Apnea precedes with marked ↓ TV and tachypnoea.

A maintenance infusion (100 µg/kg/min) results in a 40% ↓TV and a 20% ↑ RR ,

Propofol (50 to 120 µg/kg/min) also depresses the Ventilatory response to hypoxia, presumably by a direct action on carotid body chemoreceptor

Reduces airway and pharyngeal reflexes- use with LMA

Bronchoconstriction ( thiopental > propofol),Bronchodilation prevent intraop wheeze.

Proconvulsant Activity:-The majority of reported Propofol-induced seizures during the induction of anesthesia or emergence from anesthesia reflect spontaneous excitatory movements of sub cortical origin.

Abuse Potential :-Intense dreaming activity, amorous behaviour, and hallucinations have been reported during recovery from the effects of Propofol.

Bacterial Growth:-growth of Escherichia coli and Pseudomonas aeruginosa.

Pain on Injection:-As little as 0.2 mg/kg of lidocaine(mixed with the propofol) is effective in reducing but not eliminating this discomfort.

Mini – Bier Block –APPLY tourniquet give 1mg /kg of lidocaine 15-20 sec before propofol adm then remove tourniquet

Complication in prolonged infusion patient

Propofol infusion syndrome(PIS) in (pediatric> adult) patients receiving prolonged high-dose infusions of Propofol (>75 µg/kg per minute) for longer than 24 hours.

Associated with :-

metabolic acidosis,

lipidaemia,

cardiac arrhythmias

Unexpected tachycardia

Increase mortality

Significant bradycardia with scoline

Induction with propofol@1-2mg/kg

Marked decrease in B.P Decrease uteroplacental circulation

Advantages

Rapid induction

Anti emetic effect

TIVA

Agent of choice for

day care surgery

Disadvantages

Induction apnoea

Hypotension

Dose dependant bradycardia

Dose dependant respdepression

Pain during injection

It is also euphorigenicbut does not have residual psychotic effects like Ketamine

Etomidate is a carboxylated imidazole & prepared as a fat emulsion,

its effects on GABA A receptors

Etomidate A→B circulation time 1 min,

The clearance of etomidate is about five times that for thiopental;

Likewise, the context-sensitive half-time of etomidate is less likely to be increased by continuous infusion, as compared with thiopental.

Etomidate (0.2 to 0.4 mg/kg IV) IOC especially in the presence of an unstable cardiovascular system.

Involuntary myoclonic movements are common during the induction due to alterations in the balance of inhibitory and excitatory influences on the thalamocortical tract.

Awakening after a single intravenous dose of etomidate is more rapid than after barbiturates.

The principal limiting factor in the clinical use of etomidate for the induction of anesthesia is the ability of this drug to transiently depress adrenocortical function

Clinical use Dose

Induction of general anaesthesia 0.2-0.6mg/kg I.V

Maintainance of general

anaesthesia

10mcg/kg/min I.V. with N2o & an

opiate

Sedation & Analgesia Limited to periods of brief

sedation because of inhibition of

steriod synthesis

↓ CBF , ↓ CMR02 , ↓ ICP

Myoclonus (spontaneous movements) occurs

in 50% to 80% of patients receiving etomidate

in the absence of premedication. etomidate-

induced Myoclonus appears to be

disinhibition of subcortical structures that

normally suppress extra pyramidal motor

activity.

Cardiovascular stability (minimal changes in

heart rate, stroke volume, cardiac output) is

characteristic of induction of anesthesia

using 0.3 mg/kg IV of etomidate So it may

differ from most other intravenous

anesthetics in that depressive effects on

myocardial contractility are minimal at the

concentrations needed for the production of

anesthesia.

The depressant effects of etomidate on

ventilation seem to be less than those of

barbiturates, although apnea may

occasionally accompany a rapid intravenous

injection of the drug.

Limitation of etomidate Etomidate causes

adrenocortical suppression by producing a

dose-dependent inhibition of the conversion

of cholesterol to cortisol

properties PROPOFOL THIOPENTONE KETAMINE

chemistry ALKYLPHENOL THIOBARBITURATE ARYLCYCLOHEXYL

AMINE

consistency Emulsion milky

white

Sodium salts(6%

sodium

carbonate)yellow

amorphous powder

Clear aquaous

solution

solubility Lipid soluble Lipid soluble Lipid soluble

ph 7 10.5 of 2.5% 3.5-5.5

pka 11 7.6 7.5

Unionised % 99.97% 61% 55.7%

onset One arm –brain

time15-30 sec

10-15 30-60

peak 90-100 sec 90-100 sec 90-100sec

awakening 5-10 min 5-10 min 10-20 min

Rapid fall in

plasma conc.

After bolus

Redistribution &

elimination

redistribution redistribution

properties PROPOFOL THIOPENTONE KETAMINE

Protein binding 98% 85% 60%

Metabolism &

excretion

LIVER

Glucuronite

sulphate

KIDNEY

LIVER

Oxidation

N-dealkylation

Desulfuration

Destruction of

barbituric acid

ring

KIDNEY & BILE

LIVER

Norketamine

Hydroxynorketam

ine

KIDNEY

metabolite Inactive pentabarbital Norketamine 20-

30%

Extrahepatic

metabolism

lung absent absent

Clearance

ml/kg/min

20-30 3-4 12-14

properties PROPOFOL THIOPENTONE KETAMINE

Content

sensitive half

time(for

infusion lasting

upto 8 hrs

<40 min <150min <40 min

MOA GABA GABA NMDA(thalamoc

ortical &

limbic)

Induction 1-2.5 mg/kg 3-5 adult

5-6 children

6-7 infant

0.5-2 mg/kg

maintenance 50-

150ug/kg/min

15-

45ug/kg/min

sedation 25-

75ug/kg/min

0.2-0.8mg/kg

analgesia 25-

75ug/kg/min

Conscious

sedation

0.2-0.8mg/kg

properties PROPOFOL THIOPENTONE KETAMINE

Neuroprotective Reduce infarct

size when adm

immediately or

1 hr after

ischemic insult

Decrese 02

demand

Preserve CPP

ROBINHOOD

phenomenon

Free radical

scavenging

Improve

perfusion in

incomplete

cerebral

ischemia

Dissociative

anasthesia

- -- +

Emergence

reaction

+ -- +

Upper airway

reflexes

-- -- +

Salivation &

lacrimation

-- -- ++

antiemetic + -- -

Sk musle tone -- -- increase

relaxant -- -- +

propeties PROPOFOL THIOPENTONE KETAMINE

BP Dec.25-40% dec increase

HR N /dec. Dec(10-36%) inc

CO Dec. dec inc

CMRO2 Dec. dec inc

CBF Dec. dec inc

ICP Dec. dec inc

ICP Dec. dec inc

APNEA ++dose

dependent (20-

30%)

++ Higher dose

Min ventilation dec dec inc

bronchodilation + -- +

anticonvulsant + + --

antipruritic + -- --

Chronic

refractory

headache

+ -- --

properties PROPOFOL THIOPENTONE KETAMINE

Pain on

injection

++ + --

Hypotension ++ + --

apnea ++ + +/-

bronchospasm -- + --

Allergic

reaction

+ + --

thrombophlebit

is

+ ++ --

A patient with intestinal obstruction requires

an emergency laparotomy. Which induction

drug would you use?

Any patient with intestinal obstruction must

be assumed to have a potentially full

stomach.

Traditionally a rapid sequence induction

would be performed with preoxygenation ,

cricoid pressure, thiopental and

suxamethonium.

Thiopental is chosen due to its rapid, well

defined onset at a predetermined dose. This

is also the method of choice of induction for

caesarean section.

A patient requires a burns dressing change.

Which induction drug would you use?

Ketamine is an ideal drug to be used for minor procedures.

For burns dressing changes, a sub-anaesthetic dose can be used. It will provide sedation and analgesia, preserving the protective airway reflexes.

Ketamine is often combined with benzodiazepine premedication to reduce the dose requirement and emergence reactions, and sometimes an anti-sialagogue (e.g. glycopyrrolate, glycopyrronium bromide) to reduce airway secretions

A patient with a history of heart failure

requires a general anaesthetic. Which

induction drug would you choose?

drug of choice would be etomidate due to its limited effect on the cardiovascular system. However some anaesthetists avoid etomidate all together due to its effect on steroid synthesis.

Ketamine could also be considered due to its relative cardiovascular stability.

Propofol and thiopental are also options, but potentially cause more cardiac depression. The important issue is that which ever induction drug is used, the lowest possible dose is given, it is given slowly and it is titrated to effect.

Intra-arterial blood pressure monitoring should be considered if available.

A patient with porphyria comes for an

inguinal hernia repair and is requesting a

general anaesthetic. Which induction drug

would you use?

A patient with porphyria comes for an inguinal hernia repair and is requesting a general anaesthetic. Which induction drug would you use?

The porphyrias are a group of disease characterised by overproduction and excretion of porphyrins(intermediate compounds produced during haemoprotein synthesis).

Acute attacks may be precipitated by drugs, stress, infection, alcohol, pregnancy and starvation.

Propofol would be the ideal induction drug to use in this case – being safe to use in patients with porphyria.

Thiopental and etomidate should be avoided as they can precipitate a porphyric crisis

An adult patient requires sedation on the

intensive care unit. Which of the induction

drugs would be appropriate to run as an

infusion?

A propofol infusion would be appropriate.

Midazolam could also be given in addition, or

as an alternative to propofol.

Thiopental should be avoided due to

accumulation, and etomidate should be

avoided due its effect on adrenal steroid

hormone synthesis.

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