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Pharmacology of Drugs and Their Kinetics and Dynamicity during Extracorporeal Life Support
*Corresponding author: Naman Shastri, Chief Consultant, Cardiac Anesthesiologist and Intensivist, EPIC Hospital, Ahmedabad, Gujarat, India. nashastri@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Shastri N, Kapoor P, Kapoor V. Pharmacology of drugs and their kinetics and dynamicity during extracorporeal life support. J Card Crit Care TSS 2023;7:32-4.
Abstract
ECMO/ECLS is now a days very common modality for saving patient life in ICU. ECMO is unphysiological circulation which hampers the multiorgan function. Direct impact by releasing of pro-inflammatory cytokinin leads to impact on the many organ homeostasis. The anaesthetist/intensivist must have enough knowledge of pKa/Pd and most importantly still we do not have ideal guidelines for drug dosing.
Keywords
Drug Pharmacology
drug kinetics
ECMO
ECLS
INTRODUCTION
Extracorporeal life support is now a days very common modality for saving patient life in intensive care unit, though patient usually is on many life-saving drugs, ionotropes, antibiotics, sedation, and anticoagulation, when they are on already mechanical ventilation. Optimal pharmacotherapy helps clinicians to manage this life support modalities in better way but at the same time pharmacokinetics and pharmacodynamics of every commonly used drugs have to be understood. Using ideal dose, avoiding certain drugs by understanding Pk/ Pd can reduce the iatrogenic complication. This is very important as extracorporeal membrane oxygenation (ECMO) is unphysiological circulation which hampers the multiorgan function. Direct impact by releasing of pro-inflammatory cytokinin leads to impact on the many organ homeostasis.
There are multiple effects on pharmacokinetics and dynamics LIE.
On drug clearance
Due to distribution of volume
Sequestration due to membrane.
DRUG CLEARENCE
Most of the data are extrapolated from the different age groups[1] and yet we do not have ideal comparable date as clearance of the drug is affected by drug distribution and metabolism by organ such as liver and kidney.[2] During initiation of the ECMO, there may be increase in cardiac output by increasing the flow and perfusion leads to increase in clearance to begin with followed by reduction.
SEQUESTRATION DUE TO MEMBRANE
When pharmacological properties are described, it is usually related to normal physiology, which is different than ECMO so, altering the dosing requirements is very important along with the interaction of the drug to membrane. The impact is due to both.
1. Drug characteristics
2. Membrane and circuit characteristics.
1. Drug characteristics: Certain characteristics of the drugs are very important like that need to be considered including molecular size, pKa, and degree of ionization, lipophilicity, and plasma protein binding.[3] Drugs with higher degree of lipophilicity and having high protein binding has have high chances of sequestration when they come in contact with the membrane and extracted by the ECMO circuit than drugs with a lower with lower lipophilicity.[4] Hence, both the characteristics play an important role in sequestration
2. Membrane and circuit characteristics: Initially, when patient is placed on ECMO, the total volume of the surface increases by many fold because of the tubing and membranes, so adsorption surface area increases. Once patient is maintained over few hours to days, this adsorption surface acts as reservoir and they start releasing the adsorbed molecules and this results in increasing drug concentration.[5] All these sequences depend up on the factors such as composition of the priming solution, the types of conduit and oxygenator materials [Table 1].[6]
| Drugs | N-Octanol/water partition coefficient | Protein binding (%) | Anticipated reported pharmacokinetic changes | Dosing recommendations and comments |
|---|---|---|---|---|
| Antibiotics aminoglycosides | <0.0 | <30 | Minimal circuit drug sequestration; enlarged Vd; decreased CL | Insufficient data to recommend optimal dosing; TDM-guided dosin |
| Beta-lactams ampicillin | 1.35 | 15–30 | Minimal to moderate circuit drug sequestration; enlarge Vd | Consider alternatives agents; less drug loss in blood primed vs. crystalloid prime circuit |
| Ceftriaxone | −1.7 | 95 | Significant circuit drug sequestration; enlarge Vd | Dosing similar to critically ill patients not on ECMO support; TDMguided dosing |
| Meropenem | −0.69 | 2 | Minimal circuit drug sequestration; enlarged Vd; circuit drug loss due tostability issues associated with the carbapenems | Dosing similar to critically ill patients not on ECMO support; TDM guided dosing; consider alternatives dosing strategies (CI or EI dosing) |
| Piperacillin/tazobactam | 0.67 | 30 | Minimal circuit drugs loss; enlarged Vd | Dosing similar to critically ill patients not on ECMO support; TDM guided dosing; consider alternatives dosing strategies (CI or EI dosing) |
| Fluoroquinolones | <2.3 | 20–40 | Minimal circuit drugs sequestration | Dosing to optimise AUC0-24/MIC |
| Vancomycin | −3.1 | 50–60 | Minimal circuit drugs | Dosing similar to critically ill |
ECMO: Extracorporeal membrane oxygenation, TDM: Therapeutic drug monitoring, AUC: Area under the curve, MIC: Minimum inhibitory concentration
Certain sedatives and analgesics and ECMO
Most used drug is fentanyl which is very having very high lipophilicity affinity so initially membrane sequestration is very high but over period, it starts releasing back to circuit so one should be very careful of the usage of fentanyl.[7] Dexmedetomidine also favor having high lipophilicity behave same as fentanyl. Hence, morphine proved to be better as compared to fentanyl. Nowadays, the practice of using sedation and analgesia has reduced significantly. Propofol is highly lipophilic and having high protein bound capacity which limits its use during ECMO. Furthermore, it may damage the membrane by its larger molecular size.[8]
Anticoagulants
Most preferred agent is heparin but since sequestration is very high nearly half of the heparin is sequestrated by tubing and priming and also depends up on the crystalloid and blood as they dilute and remove by 30–50% so heparin monitoring is very important.
Hence, to conclude whichever drug used during ECMO support, it is mandatory to have enough knowledge of pKa/ Pd and most importantly still we do not have idea guidelines to suggest ideal dosing for different population.
Declaration of patient consent
Patient’s consent not required as their identity is not disclosed or compromised.
Conflicts of interest
There are no conflicts of interest.
Financial support and sponsorship
Nil.
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