propofol vs stp
TRANSCRIPT
Basic Pharmacology of Propofol;Propofol Vs. Thiopentone
Presenter- Dr. Suresh PradhanModerator- Dr. Yogesh Dhakal
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• due to anaphylactic reactions to cremophor, this formulation was withdrawn and reformulated as emulsion of a soya oil/propofol mixture in water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
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
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%
Properties PROPOFOL THIOPENTONE
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
Properties PROPOFOL THIOPENTONE
Protein binding 98% 85%Metabolism &
excretionLIVER
Glucuronite sulphateKIDNEY
LIVEROxidation
N-dealkylationDesulfurationDestruction of
barbituric acid ring KIDNEY & BILE
Properties PROPOFOL THIOPENTONE
Metabolite Inactive pentabarbital
Extrahepatic metabolism
lung absent
Clearance ml/kg/min
20-30 3-4
Properties PROPOFOL THIOPENTONE
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 + --
Properties PROPOFOL THIOPENTONE
BP Dec.25-40% dec
HR N /dec. Dec(10-36%)
CO dec dec
CMRO2 dec dec
CBF dec dec
ICP dec dec
Properties PROPOFOL THIOPENTONE
Apnea ++dose dependent
(20-30%)
++
bronchodilation + --
anticonvulsant + +
antipruritic + --
Chronic refractory headache
+ --
properties PROPOFOL THIOPENTONE
Pain on injection ++ +
Hypotension ++ +
apnea ++ +
bronchospasm -- +
Allergic reaction + +
thrombophlebitis + ++