What is the difference between propofol and sulfite?
Sulfite is added to the generic formulation of propofol in the form of sodium metabisulfite (Na 2 S 2 O 5) at a concentration of 0.25 mg/ml. 74 The purpose of added sulfite, similar to the addition of EDTA, is to inhibit microbe growth after the emulsion is unsealed and extrinsically contaminated. Sulfite differs from EDTA in its actions.
Are propofols equivalent to propofol?
These two “propofols” are not equivalent – for the following reasons: Sulfite allergies are common. I myself am an asthmatic and must avoid sulfites. Chardonnay and other white wines, for example, with sulfites will place me at risk for a severe asthma attack.
What are the disadvantages of propofol emulsions?
Despite the success of propofol emulsions, drawbacks to such formulations include inherent emulsion instability, injection pain, a need for antimicrobial agents to prevent sepsis, and a concern of hyperlipidemia-related side effects.
Does thiopental acidify propofol emulsions?
Thiopental is formulated in base (pH 10.5); therefore, thiopental does not acidify propofol emulsions when mixed. Prankard and Jones 86 also previously noted that thiopental did not cause a significant droplet enlargement. Propofol emulsion mixed with other substances can also destabilize emulsions. One of note is the parenteral solution protamine.
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What ingredients are in propofol?
The octanol/water partition coefficient for propofol is 6761:1 at a pH of 6 to 8.5. In addition to the active component, propofol, the formulation also contains soybean oil (100 mg/mL), glycerol (22.5 mg/mL), egg lecithin (12 mg/mL); and disodium edetate (0.005%); with sodium hydroxide to adjust pH.
Is there sulfa in propofol?
Recently, serious side effects have been reported, including an acute anaphylactic reaction to generic propofol that contains sodium bisulfite. This sulfa allergy can cause death if propofol with the bisulfite is used.
Does propofol have a preservative in it?
Propofol without metabisulfite also decreased direct airway smooth muscle constriction. The preservative used for propofol can have a dramatic effect on its ability to attenuate bronchoconstriction.
Are there sulfites in anesthesia?
As mentioned, sulfites are added to epinephrine-containing dental anesthetics to prevent the breakdown of epinephrine. The addition of sulfites also lengthens the shelf-life of the anesthetic to more than a year. This preservative is most commonly labeled on the anesthetic carpule as potassium metabisulfite.
Who should not use propofol?
You should not use propofol if you are allergic to it, or if you have: allergies to peanuts, eggs, egg products, soybeans or soy products.
What allergy is associated with propofol?
Background: Propofol is thought to be a potential cause of allergic reactions in patients allergic to egg, soy or peanut, since current formulations contain an emulsion that includes egg lecithin and soybean oil.
What are the dangers in using propofol for anesthesia?
This medicine may cause propofol infusion syndrome, which can lead to more serious problems (eg, high potassium in the blood, high fat or cholesterol in the blood, rhabdomyolysis, enlarged liver, kidney failure, heart failure).
Should I be worried about propofol?
Propofol is a potentially deadly drug in the wrong hands, and there is no room for error. "It's only designed for people trained to do advanced cardiac life support," Dombrowski says. "It induces a deep level of sleep and sedation, and it can cause your blood pressure to go down and your breathing to stop. You can die.
How long does propofol stay in your system after surgery?
When administered intravenously, propofol is rapidly cleared from the circulation. Its clearance takes place by redistribution possibly into the lungs and more importantly in the liver. Only 0.3% of the dose is excreted, unchanged, in the urine. The elimination half-life of propofol is approximately 0.5 h to 1.5 h.
What drugs have sulfites in them?
Sulfa-containing drugs include: sulfonamide antibiotics, including sulfamethoxazole-trimethoprim (Bactrim, Septra) and erythromycin-sulfisoxazole (Eryzole, Pediazole) some diabetes medications, such as glyburide (Diabeta, Glynase PresTabs)
What medications contain sulfites?
11. What types of medications contain sulfites?adrenaline (epinephrine), isoprenaline, phenylephrine.dexamethasone and some other injectable corticosteroids.dopamine.local and dental anaesthetics containing adrenaline.aminoglycoside antibiotics.
What are people allergic to in anesthesia?
A class of medications called muscle relaxants are the most common cause of allergic reactions under anesthesia. Other medications doctors give during surgery, such as antibiotics and pain medications, are also common causes of allergic reactions.
What Anaesthetic is used for sulfa allergy?
Articaine HCl may safely be administered to patients with sulfur allergy.
What family of drugs is propofol in?
Propofol belongs to a group of drugs called general anesthetics. These work by slowing activity in the brain to prevent pain and allow sleep.
Which medication should be avoided in a patient with a sulfa allergy?
Official answer. People with a sulfa allergy typically need to avoid sulfonamide antibiotics (antibiotics containing sulfa), including: Septra and Bactrim (sulfamethoxazole-trimethoprim) Pediazole (erythromycin-sulfisoxazole)
What is propofol mixed with?
Propofol 10 mg/ml should only be mixed with the following products: glucose 50 mg/ml (5%) solution for injection, sodium chloride 9 mg/ml (0.9%) solution for injection or sodium chloride 1.8 mg/ml (0.18%) and glucose 40 mg/ml (4%) solution for injection, and preservative-free lidocaine 10 mg/ml (1%) solution for ...
Does the FDA approve sulfite?
Perhaps most important of all, my understanding of the court documents indicates that the FDA simply approved a potentially clinically different sulfite-containing formulation without requiring human testing. We physicians assume adequate testing on all newly introduced drug products, because we are under the impression that the FDA is very strict and stringent. Indeed, having testified before the FDA several times, I know they normally are indeed very stringent, as they must be to safeguard the public. The FDA is, however, constantly under public (and Congressional) pressure to reduce drug costs. Perhaps this particular “fast track” approval resulted in part from that pressure. Perhaps changing a “preservative” is usually OK, but not to sulfite, especially if the emulsion is not stable. A new sulfite-containing version of propofol is a different formulation, with a different additive, and therefore should be subjected to the same rigorous testing requirements that Zeneca was required to go through to get its EDTA propofol version of Diprivan ® through FDA approval.
Is EDTA equivalent to propofol?
Under a proposed new FDA rule, believe it or not, brand names apparently could be used on generic drugs manufactured by a competing company in the sense that the new formulation could say on it “equivalent to Diprivan ® .” That means sulfite-containing propofol could eventually be marketed as equivalent to the EDTA-propofol, which it is not.
Is propofol used in ICU?
Propofol has become widely used in ICU settings for sedation in ventilated critically ill patients. In the intensive care literature, there is extensive documentation about broncho-dilating drug formulations that produced “paradoxical bronchoconstriction.” This phenomenon has been clearly shown to be related to sulfites, and these have been removed from such preparations. In an ICU patient, increasing airway resistance might not readily be connected to a new additive in the propofol! The stability of the emulsion is also a particular issue in the ICU due to the longer-term infusions.
Does Diprivan emulsion crack?
Emulsions are definitely tricky forms in which to deliver drugs. They either “crack,” i.e., separate, or they don’t. Diprivan ® has proven stable in this regard over many years of heavy operating room/ICU use. Addition of metabisulfite requires a considerable lowering of the pH of a newly formulated version of propofol in order to employ the sulfite as an antimicrobial. The court documents indicate that Zeneca made up some propofol using a sulfite-containing product description on file with FDA. That test product using the new sulfite-containing specifications not only “cracked” under standard emulsion shaking stress testing, but also turned yellow! The “cracking” resulted in a layer of clear oil on top of the milky white suspension, a layer not readily visible to a casual glance. Further, upon mild agitation of the “cracked” emulsion, the oil rapidly disappeared, only to reappear rapidly. This means we won’t see the oil, but we could be giving it to our patients (see below regarding fat embolism). Zeneca also tested the yellow color and found it to be a linkage of two molecules of propofol (a dimer). The safety/toxicity of this dimer is unknown to me and to Zeneca. The above information comes from the sworn affidavit of Christopher Jones, PhD, a Zeneca drug development scientist who tested the sulfite-containing formula for Zeneca and reported his findings as part of the court documents filed against the FDA to try to stop release of this new formulation of propofol until/unless proper testing is done.
Is EDTA in Diprivan?
EDTA, the antimicrobial in Diprivan’s ® current formulation, was in fact tested thoroughly in patients, under FDA control, by Zeneca. Addition of EDTA is in fact a considerable improvement because of its efficacy at preventing microbial growth in Diprivan ® without changing other characteristics of the drug or the emulsion.
Did Zeneca file a lawsuit against the FDA?
Recently, anesthesiologists received a letter from Zeneca announcing that the company had taken the very unusual step of filing a lawsuit against the FDA. Zeneca also did a widespread mailing of relevant public documents; I base much of this letter on these.
Is an anesthesiologist a pharmacologist?
Anesthesiologists are excellent clinical pharmacologists, but are not knowledgeable about pharmacy, nor should they be. When a “generic” drug is substituted for a trusted brand name, we have every right to expect that the generic drug, and its formulation, will be exactly the same.
Methods
EDTA propofol emulsions were obtained from AstraZeneca Pharmaceuticals (Wilmington, DE), and metabisulfite propofol emulsions were obtained from Gensia Sicor Pharmaceuticals (Irvine, CA). Ten percent soybean oil emulsion was obtained from Fresenius Kabi Clayton, LP (Clayton, NC). The emulsions were stored within the specified guidelines until use.
Results
Thiobarbituric acid reacting substance concentrations in properly stored intact vials of sulfite propofol emulsion and EDTA propofol emulsion are shown in figure 1. Each vial of sulfite propofol emulsion showed the presence of TBARS, whereas the EDTA propofol emulsion contained no detectable TBARS.
Discussion
This study demonstrates that the oxidation of sulfite in 10% soybean oil emulsion facilitates the peroxidation of emulsion lipids.
What is the concentration of sodium metabisulfite in propofol?
Sodium metabisulfite at a concentration of 0.25 mg/ml (1.3 mm) in solution or in 10% soybean oil emulsion was used in the study. This is the concentration and form of sulfite added to propofol emulsions as an antimicrobial preservative (propofol injectable emulsion, 1%, prescribing information; Baxter Healthcare Corp., Inc.), and it is representative of the concentration added to many other drug preparations. 1 The effects of sulfite on propofol dimerization in aqueous solution and in 10% soybean oil emulsion are shown in figure 1. Aqueous sulfite alone did not cause the dimerization of propofol; however, sulfite in soybean oil emulsion did cause the formation of significant quantities of both propofol dimer and propofol dimer quinone. The addition of a small amount of ascorbic acid (0.125 mg/ml, 0.63 mm) to the sulfite-containing emulsions before reaction completely inhibited propofol dimerization.
Does propofol dimerize?
Propofol did not dimerize when added to aqueous sulfite unless soybean oil was also included. The addition of the polyunsaturated fatty acids (linoleic, linolenic, arachidonic) to sulfite-containing propofol emulsion resulted in large increases of propofol dimerization compared with stearic or oleic acid. Using biphasic mixtures of soybean oil and aqueous sulfite, propofol dimerization increased with increasing peroxide content of the oil. In propofol emulsion, lipoxidase and ferrous iron in the absence of sulfite also caused the dimerization of propofol.
Can sulfite cause propofol to dimerize?
During long-term intravenous infusions, sulfite in sulfite-containing propofol emulsions can cause the peroxidation of lipid and dimerization of propofol. This study evaluated the role of lipid in sulfite-dependent propofol dimerization by determining the effects of individual fatty acids in soybean oil emulsion and peroxidized lipids in a model system.
How to overcome the drawbacks of lipid infusion, pain, and potential for sepsis?
Attempts to overcome the drawbacks of lipid infusion, pain, and potential for sepsis have been made by modifying phospholipid-emulsified propofol emulsions. Such modifications have included increasing propofol concentrations in the emulsion, creating emulsions containing less than 10% oil, creating emulsions having oils with different fatty acid contents, and modifying emulsion droplets with protein. Investigation of emulsions with novel surfactants is another potential direction for formulation improvement, but this approach is less favored because of the added burden of having to prove the harmlessness of each new emulsifier. Hemolysis, for example, is an inherent problem with many surfactants. 43
What is the purpose of adding sulfite to propofol?
74 The purpose of added sulfite, similar to the addition of EDTA, is to inhibit microbe growth after the emulsion is unsealed and extrinsically contaminated. Sulfite differs from EDTA in its actions. It does not chelate vital trace metals but liberates small quantities of sulfur dioxide that are capable of permeating microbes and being detrimental to the cell. 75 The release of sulfur dioxide from aqueous sulfite increases as pH decreases. 76 Therefore, sulfite is more effective as the pH is decreased, and the sulfite-containing propofol emulsions have a lower pH range (4.5–6.4) than those containing no preservative or those containing EDTA (7.0–8.5). Acidity itself is in part responsible for inhibiting microbe growth. However, adjustment of pH alone cannot be used to inhibit microbe growth because acid conditions destabilize emulsions.
How long does propofol last?
Propofol emulsions have an expiration date of 2 yr after manufacture and a specified storage temperature range of 4°–22°C. 18.
What is the appearance of propofol?
The visible appearance of propofol and other emulsions as white milky solutions results from the property of small particles, but those that are large relative to the wavelength of white light, to reflect and refract light in a regular manner when dispersed. 26, Figure 3 shows the relation between particle size and the visible appearance of particle-containing solutions. The unaided eye cannot distinguish between the large range of droplet sizes in macroemulsions until the droplets enlarge to approximately 50 μm in diameter. At that size, a single droplet appears as a very small oil globule. Consequently, extensive droplet enlargement in emulsions can occur and not be detected by visual inspection. Droplets smaller than those considered to be macroemulsions (< 0.1 μm, microemulsions and micelles), are translucent or opalescent. Suspended particles less than one fourth the average wavelength of visible light (0.560 μm) allows light passing through to give this an almost clear appearance. 26 Particles less than approximately 0.01 μm, the size range of some micelles, including Cremophor EL micelles, as noted are transparent because they allow nearly all light to pass through. 26 A number of analytical techniques have been developed for measuring particle sizes. These include laser light scattering, Coulter counter, ultrasonic spectroscopy, and microscopy. 41,46,47 Laser light scattering can be used to measure particle sizes in micellular solutions as well as the larger macroemulsions.
How does propofol diffuse?
Upon administration of a propofol-containing emulsion, propofol diffuses across the droplet interface and passes into the bloodstream. Major factors that govern this process for propofol or any lipophilic drug are the drug concentration gradient, the partition coefficient, the drug diffusivity in both phases, and the interfacial area of the drug-containing oil droplets. 35 Therefore, similar to any drug releasing particle, emulsions slow the availability of free drug as compared with drugs administered in solutions in which they are molecularly dissolved. The total interfacial surface area is a highly important factor in the rate of drug release from a drug-containing droplet. This in turn is dependent on the size and number of oil droplets resulting from the injection. In a propofol emulsion with the contents noted above (10% fat emulsion), oil droplet size is a significant factor. If it were to contain uniform droplets (monodisperse) of 1.0 μm in diameter, the total oil–water surface area, or droplet–aqueous phase interface, would be 0.66 m 2 /ml. However, if the particle size were reduced to 0.1 μm, it would have a total oil–water surface area of 27.6 m 2 /ml, nearly 42 times greater. 35 The latter allows for a more rapid rate of release of propofol to the blood.
What is the purpose of a vehicle for intravenous drug administration?
The purpose of a vehicle for an intravenous drug is to evenly disperse the active ingredient in a suitable volume that allows the clinician to administer the drug in a convenient dose size while not inducing side effects that are too great. A requirement for maintaining highly lipophilic substances dispersed in an aqueous solution is for the formulation to contain additional substances, emulsifiers or surfactants, that facilitate dispersion of the drug molecule within the aqueous phase. Discovery of the anesthetic effects of propofol in the ICI labs of James Glen involved the screening and synthesis of a large array of related alkyl-substituted phenol compounds. 3 In the initial animal studies, propofol was chosen to be administered in mixtures of the common drug surfactant, Cremophor EL, and water, where the Cremophor EL concentrations ranged from 10 to 16%. 20 The first human trials of propofol were performed using a formulation of 2% propofol, 16% Cremophor EL, and 8% ethanol (written personal communication, John B. Glen, Ph.D., Glen Pharma Ltd., Knutsford, Cheshire, United Kingdom, October 27, 2004). The reason for the 2% formulation was that the potency of propofol was initially underestimated. Ethanol was included in the 2% solution to eliminate cloudiness. It was subsequently determined that 1% was a suitable concentration for anesthesia, and this lower propofol concentration in Cremophor EL (16%) did not require ethanol for clarification. Clinically, propofol injection in Cremophor EL was found to cause significant pain upon injection. The 1% formulation without ethanol was less painful upon injection. Consequently, initial development of propofol continued with the Cremophor EL–based vehicle. 21 Clinical trials were conducted in Europe (1977–1981) using 1% propofol in 16% Cremophor, and more than 1,000 patients were studied.
What causes an emulsion to degrade?
An emulsion’s ultimate stability is derived from several forces, the formation of a mechanical barrier between the oil droplets and aqueous phase, and electrostatic repulsive forces between droplets. 46 Disruption of these stabilizing forces will cause the emulsion to degrade, the end result being separation of the oil phase from the aqueous phase. The major emulsifier components in egg yolk lecithin, phosphatidylcholine and phosphatidylethanolamine, consist of lipophilic side chains (esterified fatty acids) bound to polar heads at one end ( fig. 4 ). These molecules bridge the interface between the dispersed oil droplets and water. The oil-miscible side chains interact with the soybean oil, and the polar head interacts with the aqueous phase. The phosphates and nitrogen-containing moieties are charged (negative for phosphate and positive for the choline nitrogen) and confer a polar character to the head group, allowing aqueous interactions that form a mechanical barrier.
