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Key words: Intravenous anesthesia, remifentanyl, propofol, infusion pump, .. Aguilera L. Conceptos básicos de farmacocinética farmacodinámia en TIVA. Propofol nanoemulsion is a new formulation consisting of nanoemulsified systems, characterized by the absence of lipid vehicle. Changes in drug vehicle may. Anestesia-Reanimación – A – Propofol – EM|consulte.

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The availability of medications such as remifentanyl and propofol has made anesthesiologists feel the need to understand the basics of total intravenous anesthesia TIVA. To review the basic concepts the modern anesthesiologist needs for the pharmacokinetic administration of the drugs used for intravenous anesthesia. A search of the indexed literature was done to identify educational and illustrative articles about total intravenous anesthesia concepts and pharmacokinetics. The most relevant articles were selected for this review and it was supplemented with anesthesia textbooks in the guearea of pharmacokinetics and total intravenous anesthesia.

Regardless of the instruments used or how accurate they may be, what is really important is knowing that we have the tools available and based on the estimated plasma levels, we can adjust the anesthesia to the different stages of the surgical procedure; in the case of remifentanyl, it can be adjusted to the specific conditions such as the age of the patient.

The point is that the anesthesiologist has to evolve keeping pace with the increasingly more predictable drugs now available and with the possibility of achieving a safer, more predictable and costeffective anesthesia with greater control both by the experienced professional and the trainee.

Intravenous anesthesia, remifentanyl, propofol, infusion pump, nomograms Source: Total intravenous anesthesia, TIVA is a technique for administering general anesthesia exclusively intravenously; it uses a combination of drugs with the exception of the inhaled agents, including nitrous oxide 1.

The guiding principles of total intravenous anesthesia date back towhen William Harvey described the circulation of blood: This was the beginning of an era when the physiological and the anatomical conditions of a patient could be changed with minimal trauma.

Then, for the first time inPirre Cyprien Ore administered intravenous chloral hydrate to facilitate surgical procedures. With the advent of sodium thiopental inintravenous anesthesia became popular. Halford 3 in described the use of Pentothal combined with morphine as an anesthetic technique used during World Was II, but with unfortunate outcomes because its pharmacokinetics was unknown.

The development of fast-acting, short-lasting drugs was encouraged aftergiving rise to propofol in 4 and remifentanyl in 5. The availability of these anesthetic agents began the transition from a pharmaceutical administration to a pharmacokinetic approach.

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The development of tools such as the evoked potentials in and the BIS Bispectral Index in paved the way to the idea of administering drugs based not just on their pharmacokinetic principles, but also on their pharmacodynamics 7.

Thanks to these concepts, total intravenous anesthesia is now a cost-effective and safe technique.

The development of total intravenous anesthesia is closely linked to the development of infusion systems. Infusion systems add several advantages to TIVA and make it essential for both ambulatory and highly complex procedures.

When injecting an intravenous drug aimed at a specific action, this can be done following the different phases of the drug administration: Pre-determined doses are used to reach a therapeutic threshold; this is the most usual method for administering drugs.

This situation becomes even more complex when administering multiple doses and this is why the accuracy of this phase is poor. The goal is to maintain a constant, accurate and predictable concentration within a therapeutic window that ensures the desired effect. To accomplish the goal you must take into account the amount of drug infused and any changes of the drug inside the body. The pharmacokinetic administration of a drug requires the support of infusion devices programmed according to pre-determined and studied pharmacokinetic models whose accuracy has been endorsed.

During the pharmacokinetic phase, the pharmacokinetic models are the corner stone for administering the drug There are three types of pharmacokinetic models 1: In this case the body is mathematically represented into several compartments 14not as real containers in the body but representing how the drug travels through the bloodstream from one compartment to the next.


These models can be of one or several compartments. The first is the simplest pharmacokinetic model where the body is represented as a single compartment with a predefined volume of distribution and assumes that the plasma concentration decreases exponentially following the administration of the drug as a result of a single compartment for eliminating the drug 1. The multiple compartment models figure 1 assume the existence of two or more compartments.

Most anesthetic agents follow a threecompartment model that may be represented by three containers, three volumes of distribution, three eliminations and five passage constants Aguilera 16 describes the three-compartment model as follows: The fast peripheral compartment V2 is the central compartment from which the drug perfuses rapidly. These are the relatively framacocinetica irrigated tissues such as the muscle mass. The slow peripheral compartment V3 is made of the poorly perfused tissues skin or fat ; this is the slowest diffusion central compartment.

However, to calculate these volumes, except the central volume, pharmacokinetic models must be applied using elaborated equations to predict the evolution farmacodinetica plasma concentration in time. The development of garmacocinetica concentration can be represented graphically against time resulting in three phases It is precisely at this phase that extended effects may arise and most of the actual metabolic clearance develops figure 1.

The timeline for the drug in a three-compartment model can be mathematically expressed as: This equation is very simple as a basic model for the application of non-lineal regression used to estimate the pharmacokinetic parameters, to control the continuous intravenous drug infusion using a farmacocinftica and do simulations or estimate dosing regimens The velocity constants k12, k21, k13, k31, k10, k1e and ke0 represent the equilibrium among the various compartments.

Hence, k12 represents the velocity constant between V1 and V2, k21 between V2 and V1, k13 between V1 and V3, k31 between V3 and V1, k10 the renal elimination constant figure 1. The concept is based on the idea that when a drug is administered intravenously, there is farmxcocinetica delay called hysteresis: The delay occurs because the action site of the drug is not in the plasma V1thus the drug travel from the plasma V1 to the effect-site Ve – a very small virtual volume represented as a compartment inside the central compartment Farmacocnietica.

The time the drug needs to reach an equilibrium rate between V1 and the effectsite is represented by the velocity constant k1e and the equilibrium constant between Ve and V1 is ke1. Since Ve is a very small virtual volume, k1e and Ke1 do not represent any significant values and thus are deleted.

Instead, only the outflow from Ve is taken into account. The equilibrium constant is expressed as keO or ke0, meaning that it does not flow into another compartment. The concept of hysteresis can be interpreted in terms of latency time; that is to say, the propofop of time between the administration and a pharmacological effect. They have a large ke0 and a short hysteresis and consequently, a fast onset to allow for plasma concentration adjustments within relatively narrow therapeutic ranges, providing a flexible treatment strategy.

Fentanyl and sufentanyl have an intermediate ke0 resulting in a slow onset of action 4 to 6 minutes. Morphine has a considerably smaller ke0 and a longer delay for the onset of action 19, As mentioned before, Ve is within V1. Therefore, if V1 decreases, Ve decreases as well and hence ke0 becomes smaller.

In Minto et al. Thus, for example, opioids administered at high doses for anesthetic procedures are an option to deliver adequate analgesia, decreasing the minimum alveolar concentration of inhaled agents or the plasma concentrations of intravenous hypnotic agents because of a synergistic interaction that delivers analgesic power and predictability of the clinical response since both the onset and the end of the desired clinical effect can be accurately predicted The pharmacokinetic models for the administration of intravenous drugs such as propofol 24use computer infusion software to rapidly and easily predict the desired concentrations in the blood.

One of these software programs is Diprifusorwith an average performance error of 5.

Practical Application of Nomograms of Remifentanil and Propofol

These software programs used for the intravenous administration of propofool are mainly based on two pharmacokinetic models: Marsh 26 and Schnider 27, The infusion rate to maintain a specific plasma concentration can be estimated using the following equation Since the Cp plasma concentration depends on V1 and Cl clearance or elimination of k10, then:.


The proppofol between Marsh and Schnider models basically lays on the calculation of V1. The heavier the patient, the higher the V1. For Schnider V1 is age-dependent and as mentioned before, as we age, V1 decreases.

These differences can be propoffol in the calculation of ke0 and, consequently, in the infusion rate. Studies have been done to analyze the correlation between two models prkpofol the state of sedation of the patient 30 ; however, these studies fail to consider the variables used by the different simulators Until now we have seen a lower drug consumption when the Schnider model is used The Minto model is available for remifentanyl administration 16, Though, depending on the context, remifentanyl is the ideal opioid because of its half life, we must not forget the usefulness of other opioids that can be used safely peopofol long as we know their pharmacokinetics The simultaneous administration of anesthetic agents gives rise to different interactions that can be additive, empowering or inhibitory.

Additive interactions occur when the effects of a dose of drug A are equal to the effects of a dose of drug B.

It can also be accomplished with a target effect-site concentration of propofol of 5. For instance, the effective dose 50 ED 50 for post-operative pain inhibition is 5. We could think that the dose required for the simultaneous administration of these two drugs would be 2. This is called infra-additive interaction Each point on the curve represents a possible combination between the doses of drug A and the dose of drug B to get the same effect.

This is called the surface model and shows the interaction at different levels of effect and hence of different concentrations of each drug figure 4 If we were to infer from this model the drug concentrations needed for a target effect, and identified the different concentrations that cause the same effect, what would then be the ideal concentration of each drug for delivering adequate intraoperative anesthesia and a rapid recovery of the patient? The EC 50 at the effect-site for remifentanyl and propofol after one hour of infusion were 4.

These concentrations gave the fastest awakening — 6. The EC 95 were 7.

Total Intravenous Anesthesia: from Pharmaceutics to Pharmacokinetics

The EC 50 shows a 2: This means a 3. Having the patient awake after 6 or 7 minutes may be statistically significant but clinically is not as relevant.

Learning about these models is very important because of their institutional economic impact and the availability of resources.

Adequate anesthesia can be achieved with awakening times between 6 to 8 minutes by increasing the remifentanyl dose concentration and reducing the dose of propofol, which is the most expensive drug used in intravenous anesthesia. Traditionally, before the TCI system came about, intravenous anesthetics were administered using manual regimens.

Both TCI and the manual infusion regimens deliver adequate depth of anesthesia 42 ; however, TCI is preferred because it provides for better control of the anesthesia and enhanced cardiovascular and respiratory stability A similar trial by Breslin in showed similar results in terms of depth of anesthesia and awaking times.

However, the TCI system used higher levels of propofol One of the greatest concerns for our health care institutions is the availability of stateof- the-art technology because most of our resources are devoted to treat problems arising from the never-ending situation of violence we live in.

As a result, very few institutions have a TCI for administering total intravenous anesthesia. At our hospital we managed to integrate the TCI pharmacokinetic models into nomograms that enable the administration of propofol, remifentanyl and fentanyl 48using infusion pumps to achieve a particular concentration.

Another hurdle for our public institutions is the availability of infusion pumps. In the best of cases, there is one infusion pump per room. A practical alternative commonly used is mixing remifentanyl and propofol into a single infusion The plasma concentrations of remifentanyl and propofol depend on the type of surgery table 2.