Pharmacokinetics in sepsis

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Tags: pharmacology, Sepsis,

Abstract

Notes

Annotations

(8/17/2022, 12:03:01 AM)

Absorption

“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

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.” Go to annotation (Charlton and Thompson, 2019, p. 8)

Distribution

“Redistribution of blood away from peripheral tissues with or without reduction in cardiac output can decrease the volume of distribution (VD) of some fat-soluble medications leading to ↑ 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.” Go to annotation (Charlton and Thompson, 2019, p. 8)

“Endothelial damage, altered capillary permeability, and fluid leak in combination with fluid resuscitation may significantly ↑ VD of hydrophilic medications (e.g. beta-lactam and aminoglycoside antibiotics), which can lead to ↓ plasma concentrations and potential underdosing.” (Charlton and Thompson, 2019, p. 8)

“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 ↑ ionised at pH < pKa; the opposite is true for weak acids. Acidaemia, frequently found in sepsis, therefore leads to an ↑ ionisation of drugs that are weak bases (e.g. opioids, local anaesthetics) and a ↓ volume of distribution.” Go to annotation (Charlton and Thompson, 2019, p. 8)

“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. ↓ serum albumin concentrations initially lead to an ↑ 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.” Go to annotation (Charlton and Thompson, 2019, p. 8)

“Alpha1-acid glycoprotein is an acute phase reactant that is increased in sepsis and other critical illness, leading to ↑ binding and ↓ free drug concentrations of basic protein-bound molecules. The clinical effect of drugs such as opioids may therefore be decreased.” Go to annotation (Charlton and Thompson, 2019, p. 8)

Metabolism

“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.” Go to annotation (Charlton and Thompson, 2019, p. 8)

“Hepatic drug metabolism depends on three factors:

  1. hepatic blood flow,
  2. free unbound fraction of the drug, and
  3. 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 (0.3-0.7), or low (<0.3) ERs” Go to annotation (Charlton and Thompson, 2019, p. 8)

“Drugs with a ↑ 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 ↓ hepatic ER are relatively flow independent; clearance is related to hepatic enzyme activity and the proportion of free drug in plasma.” Go to annotation (Charlton and Thompson, 2019, p. 8)

“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 ↓ clearance of low ER drugs.” Go to annotation (Charlton and Thompson, 2019, p. 9)

“Adrenaline (epinephrine), vasopressin, and positive pressure ventilation all ↓ hepatic blood flow, and therefore the clearance of drugs with a ↑ ER such as fentanyl and propofol. Therapeutic hypothermia and drug interactions (e.g. with proton pump inhibitors, macrolides, fluoroquinolones, and azole antifungals), ↓ enzymatic function. Prone positioning may effect hepatic blood flow and function” Go to annotation (Charlton and Thompson, 2019, p. 9)

“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.” Go to annotation (Charlton and Thompson, 2019, p. 9)

“renal drug clearance may be augmented by ↑ renal blood flow associated with a hyperdynamic circulation in early sepsis, leading to increased clearance of hydrophilic molecules and under-dosage. 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” Go to annotation (Charlton and Thompson, 2019, p. 9)

“Propofol, thiopental, and etomidate are highly lipid-soluble molecules with extensive protein binding (propofol 98% bound to albumin). In severe sepsis, VD is initially ↓ as a consequence of centralisation of blood flow. This combined with a ↓ serum albumin can lead to significantly ↑ free plasma concentrations in patients with sepsis, causing pronounced cardiovascular effects. ↓ cardiac output also prolongs time to induction of anaesthesia, and doses should be reduced, given slowly, and titrated to effect.” Go to annotation (Charlton and Thompson, 2019, p. 9)

“Renal and hepatic dysfunction have limited effects on the metabolism and clearance of propofol, and its metabolites are inactive.” Go to annotation (Charlton and Thompson, 2019, p. 9)

“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.” Go to annotation (Charlton and Thompson, 2019, p. 10)

“Lower B:G coefficients occur with haemodilution, hypoalbuminaemia, and pyrexia, leading to more rapid onset of anaesthesia. ↑ 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” Go to annotation (Charlton and Thompson, 2019, p. 10)

“Benzodiazepine 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.” Go to annotation (Charlton and Thompson, 2019, p. 10)

“midazolam and diazepam are metabolised in the liver to active compounds (midazolam to 1hydroxymidazolam and 4-hydroxymidazolam; diazepam to desmethyldiazepam, oxazepam, and temazepam). 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.” (Charlton and Thompson, 2019, p. 10)

“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.” Go to annotation (Charlton and Thompson, 2019, p. 10)

“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, being predominantly excreted unchanged in the bile (~40%) with hepatic dysfunction leading to a reduced clearance and prolonged action.” Go to annotation (Charlton and Thompson, 2019, p. 10)

“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” Go to annotation (Charlton and Thompson, 2019, p. 11)

“Molecules with a high affinity for sugammadex, such as flucloxacillin, toremifene, and intravenous fusidic acid, may displace rocuronium or vecuronium from the sugammadex-NMBA 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.” Go to annotation (Charlton and Thompson, 2019, p. 11)

“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.” Go to annotation (Charlton and Thompson, 2019, p. 11)

“↑ AAG leads to a ↓ VD and ↓ clearance, prolonging duration of action in sepsis.” Go to annotation (Charlton and Thompson, 2019, p. 11)

“Morphine and fentanyl have ↑ hepatic ERs, and ↓ clearance occurs when ↓ hepatic blood flow” Go to annotation (Charlton and Thompson, 2019, p. 11)

“Vascular hyporesponsiveness describes a decreased dose-response relationship, and its aetiology is multifactorial. In patients with sepsis it includes downregulation of catecholamine receptors, ↑ 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.” Go to annotation (Charlton and Thompson, 2019, p. 11)

“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-lactam” Go to annotation (Charlton and Thompson, 2019, p. 11)

“Highly protein-bound antimicrobials may conversely have a ↓ VD, but the subsequently ↑ free plasma concentrations lead to ↑ clearance, and subtherapeutic concentrations” Go to annotation (Charlton and Thompson, 2019, p. 11)

“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.” Go to annotation (Charlton and Thompson, 2019, p. 11)

References to check out