Ischaemia-reperfusion injury after shock, surgery, haemorrhage, and massive transfusion is usually accompanied by a decrease in hepatic metabolism, protein expression, and CYP enzymatic activity [20]. To accentuate the level of complexity, the use of agents, such as inotropes (e.g., dobutamine) or vasodilators (e.g., nitroprusside), will increase portal and hepatic blood flow, while vasopressors (e.g., phenylephrine, norepinephrine, and epinephrine) will produce α-adrenergic-mediated vasoconstriction with the consequent reduction of blood flow [2, 13]. While liver failure has been associated with decreased CYP activity, only modest changes have been described for drugs that are metabolised by CYP2C9, and CYP3A4. Therefore, the specific effect of a particular drug will depend on the severity of liver disease and the enzymes responsible for its metabolism [16]. As an example, ketamine is metabolised by the CYPs to norketamine, an active metabolite with only one-third the potency of the parent compound; hence, the reduced metabolism in liver dysfunction will prolong its clinical effect [13]. In addition, cholestasis delays the biliary excretion of drugs and impairs CYP450 function [2]. Among the medications affected by hepatobiliary disease is rocuronium, which is mainly excreted in bile unchanged, so hepatic dysfunction leads to reduced clearance and prolonged action [10, 13]. Fentanyl and its derivatives (i.e., alfentanil, sufentanil and remifentanil) are highly liposoluble and are metabolised by the liver into inactive metabolites. As a result, these also accumulate when there is liver impairment [10].

Up to 50% of critically ill patients will suffer from acute kidney injury (AKI) [21]. Acute kidney injury not only decreases the ability to excrete water-soluble compounds through urine, but also affects metabolism independent from renal clearance. For instance, CYP3A4 activity has been inversely correlated to blood urea nitrogen (BUN) concentration [2, 21,22,23,24]. This phenomenon was illustrated by multiple studies that showed a 27% increase in CYP3A4 activity after 2 hours of dialysis, which may be related to a decrease in urea concentration [21, 23, 25]. Furthermore, numerous authors have shown that the human kidney has significant drug-metabolising capacity [26]. Cytochrome P450 enzymes 2B6, 3A4 and 3A5 have been documented to be expressed in the kidneys [24, 26, 27]. Propofol clearance provides a good example of the role of renal metabolism since its glucuronidation exceeds by 3 to 4 times what is possible through hepatic blood flow alone. Similarly, systemic clearance of morphine has been reported to exceed hepatic clearance by 38% [13, 24, 26]. Using immunohistochemistry, the expression of Phase II enzymes in the nephron has been shown in the kidney, where they are responsible for the glucuronidation of medications such as morphine and furosemide [26].

In addition to the reduced clearance and the prolonged half-life, patients with AKI have higher Vd. The combination of these factors increases the risk of drug accumulation, especially benzodiazepines and opioids in patients treated with continuous infusions. For example, midazolam in critically ill patients has a two-fold higher Vd, a three-fold prolonged half-life, and a three-fold lower Cl when compared to non-ICU patients [28, 29]. Morphine is metabolised to 3- and 6-glucuronides, the latter being the active metabolite that accumulates in renal failure [10, 13]. With this in mind, propofol and dexmedetomidine sedation protocols may be preferred for intensive care unit (ICU) patients [28, 30].

The gastrointestinal tract is affected by pathological or drug-induced haemodynamic alterations, with the consequent reduction in intestinal peristalsis, mucosal function, and drug metabolism [6]. Enteric absorption and drug availability in critically ill patients are unpredictable due to changes in gastric pH, gut oedema, loss of enteric architecture, loss of epithelial junctions, and cholestasis [13, 21]. Additionally, cellular dysfunction will lead to impaired enzymatic activity and decreased intestinal metabolism [8, 24]. The combination of these factors will result in decreased oral drug bioavailability. As a result, delayed and decreased oral paracetamol peak concentration and a reduction of more than 50% of antimicrobial absorption, namely ciprofloxacin, has been described in critically ill patients [31]. Conversely, increased daily protein intake has been linked to an increase in hepatic drug-metabolising capacity [8, 24].

The lung is not a major pathway for drug metabolism with few exceptions such as propofol and catecholamines (e.g., norepinephrine). However, respiratory failure will produce hypoxaemia that can lead to liver dysfunction and hypercapnia that may result in acidosis with the consequent decrease in renal drug clearance and changes in drug ionisation [10]. The use of mechanical ventilation to correct respiratory disturbance will have its own physiological impact. The level of positive end-expiratory pressure (PEEP) leads to directly proportional decreases in cardiac output and hepatic blood flow [1]. Similarly, prone positioning in patients with moderate/severe acute respiratory distress syndrome (ARDS) needs to be carefully performed with appropriate support to avoid the reduction of hepatic blood flow [13].

Hypoperfusion and neurohumoral activation in heart failure (HF) negatively affects the function of multiple organs, particularly by reducing blood flow to the gastrointestinal tract, the liver, and the kidneys [10, 32]. Consequently, reduced hepatic metabolic activity may potentially reduce clearance for drugs with high ER, including propofol, midazolam, and fentanyl. Because patients with HF may have reduced renal flow, clearance of drugs may decrease in proportion to the severity of haemodynamic decompensation [33]. For instance, patients with HF have 38% less clearance of propofol and almost a two-fold increase in blood concentrations [28]. Added to these disturbances, the fluid retention observed in congestive heart failure may increase the Vd of drugs [10]. Proof of this, is the four-fold increase in Vd observed in critically ill patients with a cardiac index below 1.5 L/min/m2 that resulted in dexmedetomidine accumulation and prolonged half-life [28].

During critical illness, inflammatory mediators bind to endothelium receptors causing alterations in the adhesion molecules, signalling pathways, and nitric oxide production [34, 35]. These changes disturb the blood–brain barrier and increase endothelium permeability with the consequent risk of free drug accumulation in the brain [34, 35]. For example, in meningitis, traumatic brain injury, and even non-neurological ICU patients, direct neurotoxicity has been described with the use of beta-lactams [9, 36]. Concentration-dependent neurological symptoms include delirium, decreased level of consciousness, myoclonus, seizures, confusion, aphasia, and coma [9, 36, 37]. Moreover, in patients with subarachnoid haemorrhage, there is increased penetration of morphine metabolites into the brain [35].

Prolonged administration of opioids and sedatives has been associated with tolerance, withdrawal syndrome, delirium, and worse patient outcomes [38,39,40]. Tolerance is believed to be multifactorial, it may occur due to increased expression of drug transporters with diverse affinities, desensitising of internal signalling, and up-regulation of P-glycoprotein that increases drug efflux from the central nervous system [38, 39]. Conversion of analgesia to intermittent bolus as well as sedative rotation are possible solutions to overcome this issue [38, 39]. The working hypothesis is that having drug receptors occupied for lower periods of time will decrease the incidence of tolerance and withdrawal [38, 39]. Also, receptor subtypes with different affinities can coexist, while one subtype may undergo desensitisation, other subtypes may be available for different sedatives [41]. For example, a protocol analysing the transition from fentanyl to hydromorphone was associated with a decrease in the amount of sedatives required including propofol and benzodiazepines [39]. In paediatric patients, a sedation rotation protocol showed a lower incidence of withdrawal, decreased time requiring opioid continuous infusion, and decreased ICU stay [38]. Enteral administration of methadone has also been associated with earlier discontinuation of fentanyl in mechanically ventilated patients [42].

For most drugs, the therapeutic effects are mediated by the free or unbound drug concentrations [2]. If plasma protein binding decreases, the free plasma fraction, Vd, and the half-life increase [3, 16]. In critically ill patients, changes to plasma protein levels are common. Increased vascular permeability, endothelial barrier dysfunction, and protein catabolism lead to hypoalbuminaemia; while inflammation increases alfa1-acid glycoprotein (AAG) and acute phase reactant concentrations [1, 2, 13, 21, 43]. Acidic drugs bind to the former, whereas basic drugs bind to the latter [1, 2, 13, 21, 43]. Due to low serum albumin, the free drug fraction of acidic drugs, such as ceftriaxone, daptomycin, ertapenem, and dexmedetomidine, increases with the consequent risk for toxicity [1, 13, 28, 30, 43]. For example, Boucher et al demonstrated an inverse relationship between free phenytoin and albumin concentrations [15]. Another study demonstrated an increase of valproic acid free fraction of 6 to 7 times in patients with trauma when concentrations of albumin decreased to 1.5 g/dL [15]. Moreover, in AKI the plasma protein binding to albumin is decreased due to competitive inhibition by uraemic toxins and decreased drug-albumin affinity [3]. As a result, highly protein-bound drugs that require minimal concentrations to achieve therapeutic effect may require reduced dosing, and monitoring of free concentrations of these medications is recommended [1, 43].

During shock, the release of inflammatory mediators and cytokines, metabolic acidosis, and microcirculatory impairment will result in organ hypoperfusion, cellular hypoxia, mitochondrial dysfunction, and finally multi-organ failure [2, 13, 14]. The reduction in blood perfusion to the gastrointestinal tract will result in impaired oral drug absorption, decreased hepatic blood flow may decrease drug metabolism, and the reduction of renal perfusion can affect drug elimination. In contrast to shock, the resuscitation strategies and the use of vasoactive drugs may counteract these effects by leading to a hyperdynamic state that will increase blood flow towards the major organs including the brain, heart, kidneys, and liver, with the subsequent increase of drug hepatic metabolism and renal excretion [2, 3, 13]. Additionally, hyperdynamic states increase drugs Vd, this is particularly relevant for hydrophilic antimicrobials (i.e., acyclovir, aminoglycosides, beta-lactams, fluconazole and glycopeptides) [10, 13].

Conditions such as sepsis, trauma, surgery, burns, and the use of vasopressors can lead to an increase in renal blood flow and increased renal drug clearance. Similarly, the elimination of drugs with high ER (i.e., fentanyl, morphine) is enhanced [30]. Furthermore, the inflammatory response associated with shock has been demonstrated to have a variable effect on hepatic CYP450 enzyme activity [2, 8, 44]. In trauma CYPs 2C19, 3A4, and 2E1 activity has been shown to be significantly depressed while there is an increase in CYP2C9 activity [2, 8, 44]. In sepsis, endotoxin mediated CYP inhibition has also been described [10]. Cytochrome P450 enzyme expression is also suppressed by fever and inflammatory mediators. The most important pro-inflammatory cytokines responsible for this process are interleukin 6 (IL-6) and tumour necrosis factor alfa (TNF-α) [6,7,8, 45]. The basis for this down-regulation of CYPs is not fully elucidated; however, a reduction in mRNA transcription has been suggested [17, 44]. Interleukin-6-mediated activation of the hypothalamus–pituitary–adrenal axis, also increases cortisol levels, which competitively inhibits the metabolism of CYP substrates [21]. In contrast, hypothermia has been associated with decreased blood flow towards the gastrointestinal tract, reducing drug absorption, decreasing the Vd, CYPs activity, and hepatic metabolism [2, 35].