Pharmacokinetics in the critically ill Intensive Care Training Program Radboud University Medical Centre Nijmegen
In general... Critically ill patients are at higher risk for ADE s and more severe ADE s These ADE s lead to increased LOS and higher costs Inclusion of a pharmacist reduces the incidence of preventable ADE s
113 ICU s 27 countries 1328 patients BMJ 2009;338:b814 Risk increases with: Number of organ failures, number of medications, larger ICU units, higher P/N ratio, occupancy rate
IATROREF Study 14 medical errors 70 ICU s 1 week 1369 patients Suction circuit failure during intubation Laryngoscope dysfunction Medication administered to wrong patient Error administering anticoagulants Error administering vasoactive drugs Error administering insulin Accidental removal CVC Accidental extubation Failure to place in semirecumbent position Overinflation of ET balloon Pneumothorax related to CVC insertion Fall Delay in surgical treatment 1192 reported ME s 26.8% of patients at least 1 ME Most frequent: insulin 9.3% of patients adverse event 2 or > AE OR for death 3.09 Garrouste-Orgeas M. Am J Respir Crit Care Med 2010;181:134-142
Definition PK = movement of a drug through the body (absorption, distribution, metabolism and elimination) PD = pharmacologic response resulting from the drug once it reaches its receptor
What could go wrong?
Absorption Rate and extent a medication moves into the circulatory system Bioavailability is the fraction of the administered dose reaching the systemic circulation (often AUC) Bioavailability after enteral administration depends on amount of the drug absorbed and the first-pass effect
Single enteral administration Time to peak concentration Drug absorption dependent on Particle size Gastric ph Solubility Regional blood flow Lipophilicity Surface area Ionization Motility Dissociation rate constant Vasopressor use Altered gastric emptying Feeding tube AUC
Vasopressor use Shock and vasopressors alter splanchnic perfusion and may alter drug absorption Insufficient data available - use of i.v. route recommended
Paracetamol absorption test AUC Tarling MM. Intensive Care med 1997;23:256-260
Vasopressor use and SC absorption Dörffler-Melly J. Lancet;359:849-850
Delayed gastric emptying Incidence 40-60% based on C-13-octanoic acid breath test Slow time to peak concentration 13C octanoic acid, a medium chain fatty acid which is rapidly absorbed in the duodenum and metabolised in the liver. Following oxidation, the resulting 13CO2 is excreted into breath at a level which can easily be detected and measured by isotope ratio mass spectrometry.
Feeding tube and nutrient interactions Drugs may adhere to plastic - always flush with water Enteral feeding increases ph and may directly bind drugs - phenytoin and ciprofloxacin Withhold enteral feeding 1-2 hours before and after administration, increase dose or give intravenously
Distribution Vd describes the relation between drug dose and resultant serum concentration that volume of plasma in which the total amount of drug in the body would be required to be dissolved in order to reflect the drug concentration attained in plasma For the ICU Fluid resuscitation - plasma protein binding - tissue perfusion
Fluid resuscitation Increases plasma and interstitial water and increases Vd of hydrophylic drugs such as aminoglycosides and β-lactams Could result in therapeutic failures and development of antibiotic resistance Solution: therapeutic drug monitoring, higher loading doses
Gentamycin in septic patients 2nd day 7th day p-value Peak concentration (μg/ ml) Trough concentration (μg/ ml) 4.9 ± 1.2 6.8 ± 0.0 < 0.001 1.17 ± 0.65 1.10 ± 0.3 ns Vd (l/kg) 0.43 ± 0.12 0.29 ± 0.17 < 0.001 T1/2 (h) 4.3 ± 2.0 3.2 ± 0.71 < 0.05 Clearance (l/kg/h) 0.07 ± 0,02 0.05 ± 0.01 ns TDR (mg/kg/h) 5.14 ± 2.43 3.98 ± 1.67 < 0.001 Triginer C. Intensive Care Med 1990;16:303-306
Plasma protein binding Principal binding proteins: albumin (acidic drugs like phenytoin) and α-1 acid glycoprotein (basic drugs like lidocaine) Albumin usually decreases and α-1 acid glycoprotein usually increases during critical illness Drug effects are mediated by free or unbound fraction With hypoalbumenemia total drug concentration but unbound
Anti-epileptics and hypoalbumenemia Six- to sevenfold increase in free valproate concentration Anderson GD. Br J Clin Pharmac 1994;37:559-562
Midazolam Three-fold increase in Vd with delayed midazolam clearance Hypoalbumenemia increases free midazolam fraction which is lipophilic and distributes more freely in adipose tissue Solution: dose reduction or change to another drug less albumin bound
Morphine Critical illness increases AAG and decreases circulating free drug levels Vd decreases with> 40% and clearance decreases > 65%. This prolongs the effect of morphine
Tissue perfusion Decreased tissue perfusion may result in impaired delivery of hydrophylic drugs to non-central organs and peripheral tissues e.g. piperacillin in skelet muscle and subcutaneous tissue in patients with septic shock
Joukhadar C. Crit Care Med 2001;29:385-391
Metabolism GI tract, kidney liver, lung and brain During critical illness, hepatic enzyme activity, protein concentration and liver blood flow may change Hepatic clearance = volume of blood completely cleared of drug by liver per unit time = hepatic blood flow hepatic extraction ratio
Hepatic clearance Extraction ratio = fraction of drug removed from blood after one pass through liver: > 0.7 high, 0.3-0.7 intermediate and < 0.3 low For medications with high ER (midazolam and fentanyl) hepatic clearance depends on liver blood flow and not on liver function Vice versa for low ER (phenytoin, warfarin)
Hepatic metabolism Phase 1 - oxidation, reduction, hydrolysis make active or inactive metabolite: often CYP 450 (many with genetic polymorphisms Phase 2 - glucoronidation, sulfation, acetylation - rendering the compound water soluble
Organization of the liver - Portal acinus explains ischemic hepatitis
Oxygenation determines function Zone 3: glycogen synthesis, glycolysis, liponeogenesis, ketogenesis, glutamine formation and general detoxification
Hepatic enzyme activity Severe burns diminish CYP 450 activity Renal dysfunction decrease phase 1 & 2 activity and also the uptake of drugs and biliary excretion Cirrhosis and cholestasis decrease CYP 450 activity Inflammation decreases activity of several enzymes and increases it in others
Hepatic enzyme activity Therapeutic hypothermia decreases CYP 450 activity (midazolam, fentanyl, remifentanyl, phenobarbital, phenytoin, vecuronium) Lipid solubility, protein binding, hepatic blood flow and drug potency may also be altered
Protein binding Decreased protein binding clinically relevant for drugs with high ER such as diltiazem, fentanyl, haloperidol, lidocaine, methylprednisolone, nicardipine, propofol Less relevant for diazepam, ceftriaxone, phenytoin, warfarin and valproic acid
Hepatic blood flow NE, E and phenylephrine decrease hepatic blood flow
Elimination Renal drug clearance proportional to GFR Dose reduction often necessary but loading dose often increased due to larger Vd However - diseases with increased RBF may increase GFR and lead to lower drug levels
Especially for B-lactams, carbapenems and glycopeptides