Pharmacokinetics

What is pharmacokinetics?

how the body effects a drug

What is pharmacodynamics?

how the drug effects the body

What do drug pharmacodynamics depend on?

the achieved concentration of the active compound and the target site… which depends on ADME

True or False: appropriate and accurate drug dosing in the ICU is crucial for therapeutic success

true

What are the three key factors of PKPD in critically ill patients?

1. multiple medications are often required to treat the underlying disorder and coexisting comorbidities → increases the risk of drug-drug interactions and adverse drug events

2. critical illness results in pathophysiologic changes that may modify the medications’ exposure

3. the use of organ support can contribute to inter and intra-patient variability in the drug’s pharmacokinetics (renal replacement therapy-RRT)

What is the bioavailability of intravenous medications?

100%

What is the concern with intravenous administration?

does not guarantee penetration of the drug into sites outside the circulatory system

What is the bioavailability of enteral administration?

variable

What is the concern with enteral administration?

concern for alterations in drug absorption

What is the benefit of SQ/IM/SL administration?

avoids first pass metabolism by the liver → can increase the bioavailability of a drug

True or False: clinicians should be aware of similar concerns for altered absorption in critically ill patients with sepsis or shock states because of changes in perfusion for SQ/IM/SL administration

true

What is the usage of inhalation as a route of administration?

usually chosen to reduce systemic exposure and/or achieve a high concentration in the pulmonary tissue

How does decreased gastrointestinal perfusion effect absorption?

decreases

What can cause decreased gastrointestinal perfusion in the ICU?

hypotension and shock, vasopressor use, trauma to the GI tract, or thromboembolic effects

How does increased GI transit time and delayed gastric emptying effect absorption?

decrease

What can cause increase GI transit time and delayed gastric emptying?

burns, medications (ex. opioids), electrolyte abnormalities, hyperglycemia, ileus, surgery, shock, traumatic brain injury

How does decreased GI transit time effect aborption?

can increase or decrease

What can cause decreased GI transit time?

medications (ex. prokinetic agents, metoclopramide), diarrhea, high stoma output

How does decreased GI transit time differ in absorption for different drugs?

can increase rate of absorption if delivering to site more quickly or decrease the extent by moving them past their site of absorption too fast

How do drug-enteral feed interactions effect absorption?

can cause decrease

What is the solution for drug-enteral feed interactions?

IV medications preferred to avoid interaction; hold enteral nutrition 1-2 hours before and after drug administration if enteral

What are examples of medications that interact with enteral feeds?

fluoroquinolones, levothyroxine, phenytoin, warfarin

How does an increase in gastric pH effect absorption?

decrease for some medications

What medications rely on a lower pH?

ketoconazole, itraconazole, atazanavir, indinavir, dasitinib, mycophenolate mofetil, cefpodoxime, and dipyridamole

What medications rely on a higher pH?

nifedipine, digoxin, alendronate

What medications increase the gastric pH?

PPIs and H2RAs

How can you assess absorption of a medication?

monitor therapeutic effect or drug levels if available

What is distribution?

a PK variable describing the relationship between the dose of a drug and the resulting serum concentration; an important factor to consider is the ability of the individual drug to penetrate/distribute into tissues

What is distribution influenced by?

a drug’s affinity for water (hydrophilic) or fat (lipophilic)

What is fluid resuscitation?

an essential intervention used in many critically ill patients

How does fluid resuscitation effect distribution?

increased fluid volume → increase in total body water → increase Vd for hydrophilic drugs → decreased serum concentration of hydrophilic drugs

What is capillary leak syndrome?

occurs in vasodilatory shock states where plasma in the blood leaks from the capillaries into surrounding tissues in the body

How do you overcome the effects of fluid status on distribution?

therapeutic drug monitoring, applying loading doses when appropriate, optimize drug dosing regimens

What are the predominant plasma proteins that drugs bind to?

albumin and alpha-1 acid glycoprotein (AAG)

What drugs tend to bind to albumin?

acidic drugs

What drugs tend to bind to AAG?

basic drugs

How does critical illness effect plasma protein binding?

AAG has been shown to increase; increased vascular permeability and protein catabolism can result in decreased albumin concentrations due to acute stress

What drug concentrations mediate the therapuetic drug effects?

free/unbound drug

How can you manage critically ill patients with hypoalbuminemia?

consider dose reductions in drugs that are heavily bound to albumin or change to alternative drugs with low to no protein binding to albumin

What is an example of a highly protein bound drug?

phenytoin

What is an example of a drug that has high AAG binding?

morphine

How does increased AAG concentration in critically ill patients effect distribution?

can decreased Vd and clearance

How does tissue perfusion effect distribution?

hypoperfusion in critically ill patients result in decreased delivery of hydrophilic medications by the blood to the capillary beds; this further can limit drug efficacy at the site of action

What is the predominant site for drug metabolism?

liver

What is hepatic clearnace?

volume of blood that is completely cleared of drug by the liver per unit in time

True or False: the ability of the liver to remove drugs from systemic circulation is proportional to blood flow through the liver and the hepatic extraction ratio of the drug

true

What is a high extraction ratio?

>0.7

What is hepatic extraction ratio?

the fraction of drug removed from the blood after one pass through the liver

What is an intermediate extraction ratio?

0.3-0.7

What is a low extraction ratio?

< 0.3

What do drugs with high extraction ratios depend on?

primarily on liver blood flow, less sensitive to changes in liver function

What do drugs with low extraction ratios depend on?

influences by changes in liver function, less sensitive to changes in hepatic blood flow

What are examples of medications with high extraction ratios?

morphine, fentanyl, propofol, dexmedetomidine, ketamine, lidocaine

What are the examples of medications with intermediate extraction ratios?

aspirin, vecuronium

What are examples of medications with low extraction ratios?

carbamazepine, phenytoin, valproic acid, phenobarbital, diazepam, lorazepam, rocuronium, theophylline

What is phase 1 metabolism?

hydrolysis, dealkylation, or reduction of molecules

What is phase 2 metbaolism?

glucuronidation, sulfation, acetylation

What phase of metabolism are CYP enzymes resposible for?

phase 1

What phase of metabolism adds large polar molecules to render the compound water soluble to promote urinary drug elimination?

phase 2

What can effect metabolism in the critically ill population?

severe burn injury, renal dysfunction, cirrhosis

What phase of metabolism does serve burns effect?

phase 1 (CYP enzymes diminished)

What phase of metabolism does renal dysfunction effect?

both phase 1 and phase 2

How does cirrhosis effect metbaolism?

decrease in hepatic enzyme activity due to reduction in functional hepatocytes

How do active drugs get effected by changes in metabolism?

higher drug concentrations and risk of toxicity

How do prodrugs get effected by changes in metabolism?

low efficacy of the drug

How does therapeutic hypothermia effect metabolism?

has show to decrease the metabolic clearance of many drugs

True or False: during the rewarming phase of therapeutic hypothermia, alterations in metabolism will begin to normalize

true

What things effect hepatic blood flow?

severe sepsis and septic shock, cirrhosis, vasopressor use, and vasodilator use

How does severe sepsis and septic shock effect hepatic blood flow?

cardiac output increases in the early stage and decreases in the late stage → alters blood flow to the liver; microcirculatory dysfunction that occurs during systemic inflammatory response syndrome → decreased organ perfusion

How does cirrhosis effect hepatic blood flow?

intra and extra hepatic portal-systemic shunting occurs → decreased hepatic blood flow

How do vasopressors effect hepatic blood flow?

alpha adrenergic mediated vasoconstriction of the hepatic artery and portal vein → decreased hepatic blood flow

How does vasodilator use effect hepatic blood?

reduce hepatic vascular resistance → increases hepatic blood flow

How does decreased hepatic blood flow effect drug metabolism?

possibly toxic effects at normal doses

How do you manage decreased hepatic blood flow?

dose adjustments (often lower doses), therapeutic drug monitoring

How does increased hepatic blood flow effect drug metabolism?

lower concentration of drug in the body → less efficacy

How do you manage increased hepatic blood flow?

therapeutic drug monitoring, may need higher doses

How are most drugs and metabolites excreted/eliminated?

the kidney

True or False: critically ill patients commonly develop an acute kidney injury (AKI) but can also have augmented renal clearnace

true

What can effect excretion in critically ill patients?

augmented renal clearance, AKI/ reduced renal clearance, and renal replacement therapy

What is augmented renal clearnace?

a condition where the kidneys remove medications from the body faster than usual; >130 mL/min

What can augmented renal clearance lead to?

subtherapeutic drug concentrations and treatment failure if not properly managed

What conditions can lead to increased renal blood flow, which leads to increased drug clearance?

early sepsis, burns, surgery, trauma

What antibiotics are eliminated by the kidneys?

beta lactams, carbapenems, glycopeptides

How can you manage medications that are affected by augmented renal clearance?

consider increasing the dose or frequency of dosing

What is the most accurate way to determine GFR in critically ill patients?

24 hour urine collection

How do you manage medications that are affected by AKI and reduced renal clearance?

decreases in frequency or dose of medications and therapeutic drug monitoring if available OR utilize drugs with limited renal clearance

What is peritoneal dialysis?

a mode of dialysis where a catheter is placed into the abdomen where dialysate is periodically flushed through the abdominal cavity to draw out waste products

What is hemodyalisys?

a mode of dialysis that filters blood and is done intermittently for a shorter period of time; typically used in hemodynamically stable patients that can tolerate large shifts in fluid

What is continuous renal replacement therapy?

slow dialysis over a 24hr period; used in patients that are hemodynamically unstable who can’t tolerate large fluid shifts over a short period of time

What characteristics of a drug makes it less likely to be removed via RRT?

large molecular weight, increased protein binding, and large Vd