Propofol vs stp

Basic Pharmacology of Propofol;Propofol Vs. Thiopentone

Presenter- Dr. Suresh PradhanModerator- Dr. Yogesh Dhakal

Propofol• substituted isopropylphenol (2,6-di-

isopropylphenol)

History

• was first prepared in early 1970s in the UK by Imperial Chemical Industries as ICI 35868

• Clinical trials followed in 1977, first by Kay and Rolly, using a form of soulbilised in cremophor EL

• confirmed the potential of propofol as an anesthetic agent

• due to anaphylactic reactions to cremophor, this formulation was withdrawn and reformulated as emulsion of a soya oil/propofol mixture in water

• the emulsified formulation was re-launched in 1986 by ICI (now AstraZeneca) under the brand name Diprivan

• is used for induction and maintenance of anesthesia and for sedation in and outside the operating room

Physicochemical Characteristics• comes as sterile, non-pyrogenic milky white

emulsion in vials or ampoules• is highly lipid soluble and is insoluble in

an aqueous solution• numerous formulations are available

commercially

• the most common formulation–1% propofol–10% soybean oil–1.2% purified egg phospholipid added as

emulsifier–2.25% of glycerol as a tonicity-adjusting

agent– sodium hydroxide to adjust the pH

• following concerns regarding microbial growth in the emulsion, ethylenediaminetetraacetic acid (EDTA) was added for its bacteriostatic activities

• in Europe, a 2% formulation and a formulation in which the emulsion contains a mixture of medium-chain and long chain triglycerides also are available

• all formulations commercially available are – stable at room temperature– not light sensitive–may be diluted with 5% dextrose in water

Commercial Preparations

• Diprivan– emulsion form– contains ethylenediaminetetraacetic acid

(EDTA-0.005%)- acts as bacteriostatic agent– contains sodium hydroxide to adjust pH to 7-8.5

• Amloflo– Low lipid emulsion preparation of propofol– Contains 5% soyabean oil and 6% egg lecithin– Doesnot require preservative or microbial

growth retardant– Equipotent to Diprivan, but associated with

higher incidence if pain on injection

• Fospropofol (Lusedra/ Aquavan)–water soluble phosphorylated prodrug of

propofol– approved in 2008 by FDA for use as anesthetic

agent– rapidly broken down by endothelial cell surface

enzyme alkaline phosphatase to form propofol– 1 mg fospropofol will liberate 0.54mg of

propofol

Features:– does not produce pain at the injection site– has higher volume of distribution– longer time to peak effect– higher potency–more prolonged pharmacodynamics effects

• Non-lipid formulation– uses cyclodextrins as solubilizing agent– cyclodextrins are ring sugar molecules that form

guest host complexes migrating between the hydrophilic center of the cyclodextrin molecule and water soluble phase

– allows propofol which is poorly soluble in water to be presented in injectable form

– after injection, propofol migrates out of cyclodextrin into the blood

Mechanism of Action

1. selective modulator of gamma amino butyric acid (GABAA) receptors

2. causes wide spread inhibition of N-methyl-D-Aspartate (NMDA) receptor through allosteric modulation rather than by open channel gating

3. increases dopamine concentration in the nucleus acumens resulting in sense of well being in the patient

4. decreases serotonin levels in the area postrema through action on GABA receptors resulting in its anti-emetic effect

5. depresses spinal cord activity manifesting as its anti-pruritic effect

Pharmacokinetics

• available only for intravenous administration•molecular weight of 178.27• isotonic• Pka- 11• protein-binding- 95-98%

Distribution

• three compartment phase linear model after intravenous injection

• following an IV bolus dose, the highly lipid soluble propofol rapidly equilibrates between the plasma and the brain, accounting for the rapid onset of anesthesia

a. Phase of Rapid Distribution– is rapidly distributed to highly perfused

organs like kidneys, heart, lungs, liver– awakening from a single bolus dose is rapid

due to a very short initial distribution half-life (1-8 mins) and rapid clearance

– plasma level of propofol decreases

b. Phase of Slow Distribution– is rapidly redistributed form the brain/

other highly perfused areas to other body tissues—first to muscle and then slowly to adipose tissues

c. Phase of Terminal Elimination–drug is slowly released from the deep

compartment with limited perfusion (adipose tissue) to plasma

Metabolism

• Rapidly metabolized in liver by conjugation to glucuronide and sulphate to produce water soluble inactive compounds, which are excreted by kidneys

• Exhibits a high systemic clearance that exceeds hepatic blood flow, implying existence of hepatic clearance

• Also oxidized by liver cytochrome to 4-hydroxypropofol which is then glucuronidated or sulphated to inactive compounds

• Pulmonary uptake of propofol is significant and influences the initial availability

• Extra-hepatic metabolism is also reported-mainly by kidneys and lungs.

• Kidneys may metabolize propofol upto 30%• Lungs play important role in extrahepatic

metabolism– 30% of uptake and first pass elimination after

bolus dose– 20-30% after continuous infusion

• Less than 1% propofol is excreted unchanged in urine and only 2% is excreted in faeces

• Onset of hypnosis- takes one arm brain circulation time; peak effect- within 90-100 seconds

• Duration of effect- 5-10 mins• Elimination half life-0.5-1.5 hours

• Context sensitive half life of infusions lasting upto 8hrs is less than 40 mins– Is minimally influenced by the duration of infusion

• Readily crosses placenta but is rapidly cleared from the neonatal circulation

Basic Pharmacology of Propofol;Propofol Vs. Thiopentone

contd….

Pharmacodynamics

• Central Nervous System Effects– dose dependent depression of cerebral cortex,

ascending reticular activating system and medullary center resulting in• sedation• hypnosis• amnesia• anesthesia• respiratory depression

– decrease in cerebral metabolic oxygen consumption, cerebral blood flow and ICP along with decrease in cerebral perfusion pressure

– anticonvulsant effect– anti-emetic effect– antipruritic properties– has no analgesic effect

• Cardiovascular effects– MAP-fall in MAP due to a drop in • systemic vascular resistance • preload• cardiac contractility

– Cardiac Output decrease more significantly in• hypovolemic patients• cardiac disease• on beta-blockers• at the extremes of age• hypertensive patients in treatment

• Respiratory System– dose dependent respiratory depression (first

depth, then rate)– inhibits hypoxic ventilatory drive and depresses

the normal response to hypercarbia– laryngeal and cough reflexes are blunted

• Hepatic and Renal Function– does not adversely affect hepatic or renal

function as reflected by measurements of liver transaminase enzymes or creatinine concentrations

• Neuromuscular Junction– provides minimal muscle relaxation though good

intubating condition may be obtained with propofol use alone

• Eyes– decreases intraocular pressure by 30-40% more

than with Thiopentone– more useful in blunting increase in IOP due to

succinylcholine or laryngoscopy

• Pregnancy & Lactation– no effect on uterine muscle tone– crosses placenta-equilibrium between foetus and

mother within 2-3 minutes– not recommended for use in lactating mother

Uses of Propofol

• induction of anesthesia– most commonly used IV induction agent– 1-2.5mg/kg, dose reduced with increasing age– blood level: 2-6mcg/ml

• maintainence of Anesthesia– bolus of 10-40mg repeated every few minutes, or– continuous infusion at 50-100mcg/kg/min IV

when combined with N2O or opiate or 100-300 mcg/kg/min when it is used alone

– is preferred anesthetic agent for TIVA in conjugation with opioids

• sedation– for short surgical procedure or icu

sedation/conscious sedation– dose- 25-75mcg/kg/min IV– preferred drug in day care surgery sedation

• antiemetic effect– 10-20mg IV bolus, can be repeated every 5-10 mins

• antipruritic effect– 10mg IV is effective in the treatment if pruritis

associated with neuraxial opioids or cholelithiasis• anti-convulsant activity– induction is occasionally accompanied by excitatory

phenomena such as muscle twitching, spontaneousmovement, opisthotonus, or hiccupping

– these reactions may occasionally mimic tonic–clonicseizures

– propofol has anticonvulsant properties and has been used successfully to terminate status epilepticus

• attenuation of bronchospasm– acts as a bronchodilator– preservative sodium metabisulfite may produce

bronchoconstriction in asthmatics• anti-oxidant- beneficial in acute lung injury

Side Effects

• bradycardia and asystole have been reported• dose dependent depression of ventilation with

apnea• allergic reactions• lactic acidosis- after prolonged infusions

>75mcg/kg/min for longer than 24 hrs• risk of infection, pain on injection,

hypertriglyceridemia with prolonged administration

Propofol Infusion Syndrome (PRIS)

• a rare but lethal complication if propofol infusion at dose 4mg/kg/hr or more for 48 hrs or longer

• initially described in children, but later on also found in critically ill patients

• presentation- acute refractory bradycardia leading to asystole in the presence of one or more of the following:– metabolic acidosis– rhabdomyolysis– hyperlipidemia– enlarged/ fatty liver

• other features may include– cardiomyopathy with acute cardiac failure– skeletal myopathy– hyperkalemia– hyperlipidemia

• major risk factors:– poor oxygen delivery– sepsis– serious cerebral injury– high propofol dose; cumulative dose of

propofol– age

– severe critical illness of CNS or respiratory origin

– infusion of catecholamines– infusion of corticosteroids– inadequate delivery of carbohydrates– subclinical mitochondrial disease

Proposed mechanisms / Pathophysiology

• proposed pathophysiology of PRIS remains controversial

• is likely multifactorial• one of the leading hypotheses involves

impaired electron transport chain function caused by propofol which eventuallycauses metabolic collapse of the body

Management

• early recognition of the manifestations is the key to managing PRIS

• if PRIS is suspected, propofol should be discontinued and an alternative sedative agent initiated

• general measures to support cardiac (vasopressors and inotropes) and renal function should be initiated promptly in patients with suspected PRIS

• hemodialysis or hemofiltration have been suggested to decrease the plasma concentrations of circulating metabolic acids and lipids

• use of extracorporeal membrane oxygenation (ECMO) for combined respiratoryand circulatory support

Propofol Vs. Thiopentone

Properties PROPOFOL THIOPENTONE

chemistry ALKYLPHENOL THIOBARBITURATE

consistency Emulsion milky white

Sodium salts(6% sodiumcarbonate) yellow amorphous powder

solubility Lipid soluble Lipid soluble

pH 7 10.5 of 2.5%


pKa 11 7.6

unionised % 99.97% 61%

onset One arm –brain time15-30 sec

10-15

peak 90-100 sec 90-100 sec

awakening 5-10 min 5-10 min

rapid fall in plasma conc.

after bolus

redistribution & elimination

redistribution


Protein binding 98% 85%Metabolism &

excretionLIVER

Glucuronite sulphateKIDNEY

LIVEROxidation

N-dealkylationDesulfurationDestruction of

barbituric acid ring KIDNEY & BILE


Metabolite Inactive pentabarbital

Extrahepatic metabolism

lung absent

Clearance ml/kg/min

20-30 3-4


Context sensitive half time(for

infusion lasting upto 8 hrs

<40 min <150min

MOA GABA GABA

Induction 1-2.5 mg/kg 3-5 adult5-6 children

6-7 infant

Properties PROPOFOL THIOPENTONENeuroprotective Reduce infarct

size when given immediately or 1 hr after ischemic insult

Decrease 02 demandPreserve CPPROBINHOOD phenomenonFree radical scavenging

Emergence reaction

+ --

Antiemetic + --


BP Dec.25-40% dec

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

CO dec dec

CMRO2 dec dec

CBF dec dec

ICP dec dec


Apnea ++dose dependent

(20-30%)

++

bronchodilation + --

anticonvulsant + +

antipruritic + --

Chronic refractory headache

+ --

properties PROPOFOL THIOPENTONE

Pain on injection ++ +

Hypotension ++ +

apnea ++ +

bronchospasm -- +

Allergic reaction + +

thrombophlebitis + ++

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Health & Medicine

Propofol vs stp