Pharmacokinetics in Sepsis
Highlights
- Drug distribution depends on regional blood flow, cardiac output, body composition, age, and the physiochemical properties of the drug, such as lipid solubility, protein binding, molecular size, pKa, and degree of ionisation. (View Highlight)
- 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 higher plasma concentrations and the potential for adverse effects (View Highlight)
- Endothelial damage, altered capillary permeability, and fluid leak in combination with fluid resuscitation may significantly increase the VD of hydrophilic medications (e.g. beta-lactam and aminoglycoside antibiotics), which can lead to decreased plasma concentrations and potential underdosing (View Highlight)
- The degree of ionisation is determined by pKa and affects lipophilicity, the extent to which a drug can cross membranes and its VD (View Highlight)
- 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. (View Highlight)
- 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 (View Highlight)
- The pathophysiology of hepatic dysfunction in sepsis is complex and not fully understood. Two clinical entities may be observed. An imbalance in hepatic oxygen delivery and demand accompanied by a reduced ability of hepatocytes to extract oxygen leads to hypoxic hepatitis, characterised by increased aminotransferase concentrations (View Highlight)
- cytochrome P450 (CYP450) systems located in the pericentral area of the liver lobule are at risk of cellular hypoxia (View Highlight)
- 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 (View Highlight)
- Renal excretion comprises filtration, secretion, and reabsorption, with filtration being the primary mechanism (View Highlight)
- In contrast, 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 (View Highlight)
- 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 β-lactam antibiotics, digoxin, and furosemide (View Highlight)
- Pharmacokinetics may be altered as a consequence of reduced renal clearance and alterations in plasma protein binding, acid–base balance, and volume of distribution, together with the accumulation of organic acids such as uric and lactic acid (View Highlight)
- 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. (View Highlight)
- Thiopental has a pKa of 7.6, and is 61% unionised at physiological pH. Acidosis may therefore increase the unionised fraction and theoretically increase its clinical effects, including a greater risk of cardiovascular depression (View Highlight)
- Renal and hepatic dysfunction have limited effects on the metabolism and clearance of propofol, and its metabolites are inactive. (View Highlight)
- 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 (View Highlight)
- 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 (View Highlight)
- Hypoproteinaemia will prolong the duration of all non-depolarising NMBAs because of an increase in VD (View Highlight)
- Hypokalaemia, hypocalcaemia, hypermagnesaemia, acidosis, and hypothermia (particularly with atracurium) prolong the effect of NMBAs (View Highlight)
- Succinylcholine is rapidly hydrolysed by plasma cholinesterases after administration, to the extent that approximately only 20% of an administered dose reaches the neuromuscular junction (View Highlight)
- 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 (View Highlight)
- Neostigmine is a highly ionised molecule with low protein binding. Dose adjustment is not required. (View Highlight)
- Sugammadex and the sugammadex–NMBA complex do not bind to plasma proteins and are not metabolised. The complex is 96% excreted via the kidneys and is cleared by renal replacement therapy (View Highlight)
- 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 (View Highlight)
- Weak bases (such as opioids) are bound to AAG, an acute phase reactant whose concentration increases in cases of critical illness. An increase in AAG leads to a decreased VD and decreased clearance, prolonging duration of action in sepsis (View Highlight)
- Pharmacokinetic variability may be a less important concept when considering the vasoactive agents given their short half-lives and clinically titratable effects, but tachyphylaxis does occur (View Highlight)
- Vascular hyporesponsiveness describes a decreased dose–response 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 (View Highlight)
- 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. (View Highlight)