Pharmacokinetics in Sepsis

Metadata

Author: M. Charlton
Full Title: Pharmacokinetics in Sepsis
Category: #books

Highlights

The degree of ionisation is determined by pKa and affects lipophilicity, the extent to which a drug can cross membranes and its VD. Weak bases are more ionised at pH values below their pKa; the opposite is true for weak acids. Acidaemia, frequently found in sepsis, therefore leads to an increased degree of ionisation of drugs that are weak bases (e.g. opioids, local anaesthetics) and a decreased volume of distribution. (Page 2)
Albumin and a1-acid glycoprotein (AAG) are the two main drug binding proteins in the plasma. Albumin, an anion, predominately binds proton donors (acidic drugs) in contrast to a1-acid glycoprotein, which predominantly binds basic drugs. Hypoalbuminaemia is common in sepsis, and the relationship between hypoalbuminaemia and drug pharmacokinetics is complex.7 Low serum albumin concentrations initially lead to an increase in the free fraction of highly protein-bound drugs with the potential for toxicity. However, as volume of distribution and clearance are increased, free drug concentrations may decrease to subtherapeutic levels. Highly protein-bound drugs requiring a minimal plasma concentration for clinical effect (such as antimicrobials) may require increased loading and maintenance doses to achieve the desired therapeutic effect.8 Conversely, drugs extensively bound to albumin with an immediate clinical effect may require reduced dosing. Midazolam, for instance, has a more rapid onset in the presence of hypoalbuminaemia. (Page 2)
venous Gastric emptying is delayed to some extent in almost all critically ill patients, with many having intestinal ileus, particularly after surgery. This may be compounded by opioids used for analgesia or sedation, which further reduce gastric emptying and gut peristalsis. Other factors affecting gastrointestinal (GI) absorption include hypoperfusion, congestion, mucosal oedema, motility dysfunction, continuous feeding regimens, nasogastric suctioning, and alterations of intraluminal pH (alkalinisation).4 The use of vasoactive agents for circulatory support may also decrease splanchnic blood ﬂow, gut perfusion, and therefore absorption. Together these may pose signiﬁcant problems for medicines only available in an enteral formulation (e.g. many antiretroviral, psychoactive, anticoagulants, antiparkinsonian, and antiplatelet drugs). In practice it may be possible to withhold certain medications until the enteral route is available or utilise an intravenous formulation if one exists. If unavailable, alternate routes may be considered (e.g. rotigotine patches for patients with Parkinson’s disease) as an alternative or in addition to the oral preparation if toxicity is unlikely. (Page 2)
Alpha1-acid glycoprotein is an acute-phase reactant that is increased in sepsis and other critical leading to increased binding and decreased free drug concentrations of basic protein-bound molecules. The clinical effect of drugs such as opioids may therefore be decreased. illness, (Page 2)
Most drugs are metabolised predominantly in the liver, but extrahepatic sites may be important. For example, propofol has a clearance in excess of hepatic blood ﬂow, as it is metabolised in the lungs and kidneys. (Page 2)
Hepatic drug metabolism depends on three factors: hepatic blood ﬂow, free unbound fraction of the drug, and the intrinsic enzymatic capacity of hepatocytes. Hepatic extraction ratio (ER) is the fraction of drug cleared from the blood after a single pass through the liver (intrinsic clearance ÷ hepatic blood ﬂow). Drugs can be classiﬁed as having high (>0.7), intermediate (0.30.7), or low (<0.3) ERs (Page 2)
Drugs with a high hepatic ER are rapidly cleared by the liver, and so their clearance depends on adequate hepatic blood ﬂow and less so on enzyme function. Conversely, drugs with a low hepatic ER are relatively ﬂow independent; clearance is related to hepatic enzyme activity and the proportion of free drug in plasma. (Page 2)
Redistribution of blood away from peripheral tissues with or without reduction in cardiac output can decrease the volume of distribution (VD) of some fatsoluble medications leading to higher plasma concentrations and the potential for adverse effects. This is particularly important in critical care for rapidly acting medications with concentration-dependent adverse effects such as intravenous anaesthetic, analgesic or sedative agents. (Page 2)
Endothelial damage, altered capillary permeability, and ﬂuid leak in combination with ﬂuid resuscitation may ... decreased signiﬁcantly increase the VD of hydrophilic medications (e.g. beta-lactam and aminoglycoside antibiotics), which can lead potential to underdosing. concentrations plasma and (Page 2)
renal drug clearance may be augmented by increased renal blood ﬂow associated with a hyperdynamic circulation in early sepsis, leading to increased clearance of hydrophilic molecules and under-dosage.18 Active secretion of drugs by the renal tubule is an energy-dependent process requiring adequate renal blood ﬂow, and so elimination may be reduced in AKI and sepsis. Drugs with signiﬁcant renal secretion include b-lactam antibiotics, digoxin, and furosemide. (Page 3)
signiﬁcant impact on both drug delivery to hepatocytes and cellular oxygenation required for their metabolism, as cytochrome P450 (CYP450) systems located in the pericentral area of the liver lobule are at risk of cellular hypoxia. In addition, proinﬂammatory cytokines such as tumour necrosis factor (TNF)-a and interleukin (IL)-1b and IL-6 directly affect CYP450 function, leading to reduced clearance of low ER drugs. (Page 3)
Adrenaline (epinephrine), vasopressin, and positive pressure ventilation all reduce hepatic blood ﬂow, and therefore the clearance of drugs with a high ER such as fentanyl and propofol. Therapeutic hypothermia and drug interactions (e.g. with proton pump inhibitors, macrolides, ﬂuoroquinolones, and azole antifungals), decrease enzymatic function. Prone positioning may effect hepatic blood ﬂow and function (Page 3)
Propofol, thiopental, and etomidate are highly lipid-soluble molecules with extensive protein binding (propofol 98% bound to albumin). In severe sepsis, VD is initially decreased as a consequence of centralisation of blood ﬂow. This combined with a decreased serum albumin can lead to signiﬁcantly higher free plasma concentrations in patients with sepsis, causing pronounced cardiovascular effects. Decreased cardiac output also prolongs time to induction of anaesthesia, and doses should be reduced, given slowly, and titrated to effect. (Page 3)
Renal and hepatic dysfunction have limited effects on the metabolism and clearance of propofol, and its metabolites are inactive. (Page 3)
Drugs that are primarily ﬁltered have a linear relationship between the adequacy of renal function and clearance, with a risk of drug accumulation when renal function is impaired. (Page 3)
Ketamine, unlike the other i.v. agents, can be administered via several routes. Protein binding is 25% and therefore hypoproteinaemia has little effect. Ketamine is metabolised by the cytochrome P450 system to an active metabolite, norketamine, with approximately one-third the potency of the parent compound, and so clinical effect may be prolonged in severe hepatic impairment. Norketamine is conjugated to inactive metabolites that are excreted in the urine. (Page 4)
benzylisoquinolinium compounds (e.g. atracurium) are unaffected by hepatic and renal dysfunction, and this is a potential advantage in the critically ill patient with sepsis. Atracurium is metabolised by non-speciﬁc plasma esterases and Hofmann elimination, a spontaneous non-enzymatic process that is delayed by hypothermia and acidosis. (Page 4)
Lower B:G coefﬁcients occur with haemodilution, hypoalbuminaemia, and pyrexia, leading to more rapid onset of anaesthesia. Increased cardiac output leads to slower induction of anaesthesia caused by washing out of the alveolar concentration gradient, with the converse being true when cardiac output is reduced (Page 4)
aminosteroid compounds such as rocuronium, pancuronium, and vecuronium undergo hepatic metabolism to a variable extent (more so vecuronium), to active metabolites which are subsequently excreted via the kidneys. Rocuronium undergoes minimal metabolism, predominantly excreted unchanged in the bile (~40%) with hepatic dysfunction leading to a reduced clearance and prolonged action. being (Page 4)
Benzodiazepines are lipophilic and >95% bound to albumin. Hypoalbuminaemia causes a signiﬁcant (up to three-fold) increase in VD, allowing free drug to distribute throughout adipose tissue, prolonging half-life and pharmacodynamic effect. Despite increased VD, the decrease in protein binding leads to higher initial free plasma concentrations, with a rapid pharmacological response. (Page 4)
midazolam and diazepam are ... and oxazepam, metabolised in the liver to active compounds (midazolam to 1hydroxymidazolam and 4-hydroxymidazolam; diazepam to desmethyldiazepam, 1Hydroxymidazolam has a potency similar to that of midazolam, and therefore the clinical effects of these agents can be prolonged in liver and renal failure. Lorazepam is metabolised to an inactive compound. temazepam). (Page 4)
Acquired plasma cholinesterase deﬁciency occurs in sepsis; renal, hepatic, and cardiac failure; and protein malnutrition (amongst many other causes), with the potential for prolonged neuromuscular block (Page 5)
Vascular hyporesponsiveness describes a decreased doseresponse relationship, and its aetiology is multifactorial. In patients with sepsis it includes downregulation of catecholamine receptors, increased nitric oxide and prostacyclin production, generation of oxygen free radicals and peroxynitrite, and the activation of ATP-sensitive potassium channels caused by acidaemia and increased circulating lactate; this leads to hyperpolarisation of cell membranes and vasodilatation. (Page 5)
Molecules with a high afﬁnity for sugammadex, such as ﬂucloxacillin, toremifene, and intravenous fusidic acid, may displace vecuronium from the sugammadexNMBA complex. This may lead to a delay in recovery of train-of-four, or the potential for recurarisation, although this has not been observed in clinical practice. rocuronium or (Page 5)
Hydrophilic antimicrobials (Table 3) are greatly affected by the pathophysiological changes of sepsis. They are principally conﬁned to the extracellular space with a relatively low VD and are mostly excreted by the kidneys. Endothelial dysfunction, altered protein binding, and the administration of large volumes of intravenous ﬂuids lead to an increase in the VD, leading to subtherapeutic plasma concentrations and therefore ineffective microbial clearance. This is particularly problematic with antimicrobials whose therapeutic effects are determined by the minimum time above a desired plasma concentration (‘time-dependent killing’), such as the b-lactams. (Page 5)
Opioids are weak bases, with variable degree of ionisation depending on the pKa of the drug and plasma pH. Absorption and distribution are related to the degree of ionisation, with weak bases demonstrating increased ionisation at lower pH levels, and therefore reduced absorption and distribution. (Page 5)
An increase in AAG leads to a decreased VD and decreased clearance, prolonging duration of action in sepsis. (Page 5)
Morphine and fentanyl have high hepatic ERs, and decreased clearance occurs when hepatic blood ﬂow is decreased. (Page 5)
Highly protein-bound antimicrobials may conversely have a reduced VD, but the subsequently increased free plasma concentrations lead to increased clearance, and subtherapeutic concentrations (Page 5)
Lipophilic antimicrobials (Table 4) may also require dose adjustment in cases of hepatic failure.8 For example metronidazole should be reduced to one-third of the normal dose and administered once daily. (Page 5)

Pharmacokinetics in Sepsis

Metadata

Author: M. Charlton
Full Title: Pharmacokinetics in Sepsis
Category: #books

Highlights

The degree of ionisation is determined by pKa and affects lipophilicity, the extent to which a drug can cross membranes and its VD. Weak bases are more ionised at pH values below their pKa; the opposite is true for weak acids. Acidaemia, frequently found in sepsis, therefore leads to an increased degree of ionisation of drugs that are weak bases (e.g. opioids, local anaesthetics) and a decreased volume of distribution. (Page 2)
Albumin and a1-acid glycoprotein (AAG) are the two main drug binding proteins in the plasma. Albumin, an anion, predominately binds proton donors (acidic drugs) in contrast to a1-acid glycoprotein, which predominantly binds basic drugs. Hypoalbuminaemia is common in sepsis, and the relationship between hypoalbuminaemia and drug pharmacokinetics is complex.7 Low serum albumin concentrations initially lead to an increase in the free fraction of highly protein-bound drugs with the potential for toxicity. However, as volume of distribution and clearance are increased, free drug concentrations may decrease to subtherapeutic levels. Highly protein-bound drugs requiring a minimal plasma concentration for clinical effect (such as antimicrobials) may require increased loading and maintenance doses to achieve the desired therapeutic effect.8 Conversely, drugs extensively bound to albumin with an immediate clinical effect may require reduced dosing. Midazolam, for instance, has a more rapid onset in the presence of hypoalbuminaemia. (Page 2)
venous Gastric emptying is delayed to some extent in almost all critically ill patients, with many having intestinal ileus, particularly after surgery. This may be compounded by opioids used for analgesia or sedation, which further reduce gastric emptying and gut peristalsis. Other factors affecting gastrointestinal (GI) absorption include hypoperfusion, congestion, mucosal oedema, motility dysfunction, continuous feeding regimens, nasogastric suctioning, and alterations of intraluminal pH (alkalinisation).4 The use of vasoactive agents for circulatory support may also decrease splanchnic blood ﬂow, gut perfusion, and therefore absorption. Together these may pose signiﬁcant problems for medicines only available in an enteral formulation (e.g. many antiretroviral, psychoactive, anticoagulants, antiparkinsonian, and antiplatelet drugs). In practice it may be possible to withhold certain medications until the enteral route is available or utilise an intravenous formulation if one exists. If unavailable, alternate routes may be considered (e.g. rotigotine patches for patients with Parkinson’s disease) as an alternative or in addition to the oral preparation if toxicity is unlikely. (Page 2)
Alpha1-acid glycoprotein is an acute-phase reactant that is increased in sepsis and other critical leading to increased binding and decreased free drug concentrations of basic protein-bound molecules. The clinical effect of drugs such as opioids may therefore be decreased. illness, (Page 2)
Most drugs are metabolised predominantly in the liver, but extrahepatic sites may be important. For example, propofol has a clearance in excess of hepatic blood ﬂow, as it is metabolised in the lungs and kidneys. (Page 2)
Hepatic drug metabolism depends on three factors: hepatic blood ﬂow, free unbound fraction of the drug, and the intrinsic enzymatic capacity of hepatocytes. Hepatic extraction ratio (ER) is the fraction of drug cleared from the blood after a single pass through the liver (intrinsic clearance ÷ hepatic blood ﬂow). Drugs can be classiﬁed as having high (>0.7), intermediate (0.30.7), or low (<0.3) ERs (Page 2)
Drugs with a high hepatic ER are rapidly cleared by the liver, and so their clearance depends on adequate hepatic blood ﬂow and less so on enzyme function. Conversely, drugs with a low hepatic ER are relatively ﬂow independent; clearance is related to hepatic enzyme activity and the proportion of free drug in plasma. (Page 2)
Redistribution of blood away from peripheral tissues with or without reduction in cardiac output can decrease the volume of distribution (VD) of some fatsoluble medications leading to higher plasma concentrations and the potential for adverse effects. This is particularly important in critical care for rapidly acting medications with concentration-dependent adverse effects such as intravenous anaesthetic, analgesic or sedative agents. (Page 2)
Endothelial damage, altered capillary permeability, and ﬂuid leak in combination with ﬂuid resuscitation may ... decreased signiﬁcantly increase the VD of hydrophilic medications (e.g. beta-lactam and aminoglycoside antibiotics), which can lead potential to underdosing. concentrations plasma and (Page 2)
renal drug clearance may be augmented by increased renal blood ﬂow associated with a hyperdynamic circulation in early sepsis, leading to increased clearance of hydrophilic molecules and under-dosage.18 Active secretion of drugs by the renal tubule is an energy-dependent process requiring adequate renal blood ﬂow, and so elimination may be reduced in AKI and sepsis. Drugs with signiﬁcant renal secretion include b-lactam antibiotics, digoxin, and furosemide. (Page 3)
signiﬁcant impact on both drug delivery to hepatocytes and cellular oxygenation required for their metabolism, as cytochrome P450 (CYP450) systems located in the pericentral area of the liver lobule are at risk of cellular hypoxia. In addition, proinﬂammatory cytokines such as tumour necrosis factor (TNF)-a and interleukin (IL)-1b and IL-6 directly affect CYP450 function, leading to reduced clearance of low ER drugs. (Page 3)
Adrenaline (epinephrine), vasopressin, and positive pressure ventilation all reduce hepatic blood ﬂow, and therefore the clearance of drugs with a high ER such as fentanyl and propofol. Therapeutic hypothermia and drug interactions (e.g. with proton pump inhibitors, macrolides, ﬂuoroquinolones, and azole antifungals), decrease enzymatic function. Prone positioning may effect hepatic blood ﬂow and function (Page 3)
Propofol, thiopental, and etomidate are highly lipid-soluble molecules with extensive protein binding (propofol 98% bound to albumin). In severe sepsis, VD is initially decreased as a consequence of centralisation of blood ﬂow. This combined with a decreased serum albumin can lead to signiﬁcantly higher free plasma concentrations in patients with sepsis, causing pronounced cardiovascular effects. Decreased cardiac output also prolongs time to induction of anaesthesia, and doses should be reduced, given slowly, and titrated to effect. (Page 3)
Renal and hepatic dysfunction have limited effects on the metabolism and clearance of propofol, and its metabolites are inactive. (Page 3)
Drugs that are primarily ﬁltered have a linear relationship between the adequacy of renal function and clearance, with a risk of drug accumulation when renal function is impaired. (Page 3)
Ketamine, unlike the other i.v. agents, can be administered via several routes. Protein binding is 25% and therefore hypoproteinaemia has little effect. Ketamine is metabolised by the cytochrome P450 system to an active metabolite, norketamine, with approximately one-third the potency of the parent compound, and so clinical effect may be prolonged in severe hepatic impairment. Norketamine is conjugated to inactive metabolites that are excreted in the urine. (Page 4)
benzylisoquinolinium compounds (e.g. atracurium) are unaffected by hepatic and renal dysfunction, and this is a potential advantage in the critically ill patient with sepsis. Atracurium is metabolised by non-speciﬁc plasma esterases and Hofmann elimination, a spontaneous non-enzymatic process that is delayed by hypothermia and acidosis. (Page 4)
Lower B:G coefﬁcients occur with haemodilution, hypoalbuminaemia, and pyrexia, leading to more rapid onset of anaesthesia. Increased cardiac output leads to slower induction of anaesthesia caused by washing out of the alveolar concentration gradient, with the converse being true when cardiac output is reduced (Page 4)
aminosteroid compounds such as rocuronium, pancuronium, and vecuronium undergo hepatic metabolism to a variable extent (more so vecuronium), to active metabolites which are subsequently excreted via the kidneys. Rocuronium undergoes minimal metabolism, predominantly excreted unchanged in the bile (~40%) with hepatic dysfunction leading to a reduced clearance and prolonged action. being (Page 4)
Benzodiazepines are lipophilic and >95% bound to albumin. Hypoalbuminaemia causes a signiﬁcant (up to three-fold) increase in VD, allowing free drug to distribute throughout adipose tissue, prolonging half-life and pharmacodynamic effect. Despite increased VD, the decrease in protein binding leads to higher initial free plasma concentrations, with a rapid pharmacological response. (Page 4)
midazolam and diazepam are ... and oxazepam, metabolised in the liver to active compounds (midazolam to 1hydroxymidazolam and 4-hydroxymidazolam; diazepam to desmethyldiazepam, 1Hydroxymidazolam has a potency similar to that of midazolam, and therefore the clinical effects of these agents can be prolonged in liver and renal failure. Lorazepam is metabolised to an inactive compound. temazepam). (Page 4)
Acquired plasma cholinesterase deﬁciency occurs in sepsis; renal, hepatic, and cardiac failure; and protein malnutrition (amongst many other causes), with the potential for prolonged neuromuscular block (Page 5)
Vascular hyporesponsiveness describes a decreased doseresponse relationship, and its aetiology is multifactorial. In patients with sepsis it includes downregulation of catecholamine receptors, increased nitric oxide and prostacyclin production, generation of oxygen free radicals and peroxynitrite, and the activation of ATP-sensitive potassium channels caused by acidaemia and increased circulating lactate; this leads to hyperpolarisation of cell membranes and vasodilatation. (Page 5)
Molecules with a high afﬁnity for sugammadex, such as ﬂucloxacillin, toremifene, and intravenous fusidic acid, may displace vecuronium from the sugammadexNMBA complex. This may lead to a delay in recovery of train-of-four, or the potential for recurarisation, although this has not been observed in clinical practice. rocuronium or (Page 5)
Hydrophilic antimicrobials (Table 3) are greatly affected by the pathophysiological changes of sepsis. They are principally conﬁned to the extracellular space with a relatively low VD and are mostly excreted by the kidneys. Endothelial dysfunction, altered protein binding, and the administration of large volumes of intravenous ﬂuids lead to an increase in the VD, leading to subtherapeutic plasma concentrations and therefore ineffective microbial clearance. This is particularly problematic with antimicrobials whose therapeutic effects are determined by the minimum time above a desired plasma concentration (‘time-dependent killing’), such as the b-lactams. (Page 5)
Opioids are weak bases, with variable degree of ionisation depending on the pKa of the drug and plasma pH. Absorption and distribution are related to the degree of ionisation, with weak bases demonstrating increased ionisation at lower pH levels, and therefore reduced absorption and distribution. (Page 5)
An increase in AAG leads to a decreased VD and decreased clearance, prolonging duration of action in sepsis. (Page 5)
Morphine and fentanyl have high hepatic ERs, and decreased clearance occurs when hepatic blood ﬂow is decreased. (Page 5)
Highly protein-bound antimicrobials may conversely have a reduced VD, but the subsequently increased free plasma concentrations lead to increased clearance, and subtherapeutic concentrations (Page 5)
Lipophilic antimicrobials (Table 4) may also require dose adjustment in cases of hepatic failure.8 For example metronidazole should be reduced to one-third of the normal dose and administered once daily. (Page 5)