PK in critical care Flashcards
What are the key factors that can impact extravascular absorption?
- Hypotension and Vasopressors
- Altered gastric emptying
- Feeding tube/nutrient effects
What is the physiologic response of critically ill patients in a state of hypotension or shock?
shift blood flow to critical organs (brain, heart, etc.)
What will the blood flow to other organs/tissue result in, if the shift of blood flow goes to critical organs?
blood flow will decrease as a result
What can reduced blood flow to sites of absorption result in?
alter the rate and/or extent of drug absorption
What medications may be used to maintain an adequate blood pressure in patients with hemodynamic shock?
Vasopressors (dopamine, epinephrine, norepinephrine)
What delays/slows gastric emptying?
- Surgery
- traumatic brain injury
- sepsis
- burns
- opiates (may cause GI effects)
What can delay gastric emptying result in?
- Delayed time to peak concentration
2. Decreased drug stability
Some drugs may absorb to the feeding tube material. What does this cause to the total amount of drug delivered?
A decrease in the total amount of drug delivered
Drug can become clogged in enteral tubes. What should be performed to minimize accumulation of residual drug?
Adequate flushing
Enteral tube feeding can increase gastric pH. What can be altered depending on the chemical characteristics of the drug?
the absorption or stability
Enteral nutrition solutions can interact directly with drugs. What are some examples of how enteral solutions can interact directly with drugs?
Binding or chelating
Drug/nutrition interactions can reduce the oral bioavailability of certain drugs. What types of drugs can drug/nutrition interactions reduce?
- Phenytoin
- Levothyroxine
- Warfarin
How must you administer phenytoin, levothyroxine, and warfarin to avoid drug/nutrient interactions?
administer 1-2 hours before and after drug administration
What are the key factors that can impact distribution?
- IV fluid administration
- Plasma protein binding
- Tissue perfusion
T/F Lipophilic drugs tend to significantly distribute into tissues and have a smaller apparent volume of distribution?
False, larger apparent volume of distribution
T/F Hydrophilic molecules tend to remain in body water and have relatively low volumes of distribution?
True
What does plasma protein binding affect?
distribution of drugs into tissue
T/F IV fluids can result in an increase in plasma volume and total body water?
True
What are the hydrophilic drugs?
- aminoglycosides
2. beta lactams
What will hydrophilic drugs result in
Increased volume distribution
What can an increased volume of distribution do to a loading dose, half-life, and time to steady state?
increase
Why is fluid status important?
As fluid volume returns to normal levels, the apparent volume of distribution will change as well
What is the primary drug binding plasma protein?
Albumin
What are some acidic drugs
- Phenytoin
2. Diazepam
What is the importance of alpha -1 acid glycoprotein
important for basic drugs such as lidocaine and diltiazem
what can acute stress and trauma result in?
increased vascular permeability or increased protein catabolism
What may an increased vascular permeability or increased protein catabolism result in
loss of circulating plasma albumin and reduction in protein binding and increase unbound fraction of drug (increase fu)
What does an increased in unbound fraction in plasma cause?
increased volume of distribution and greater access of drug to tissue, prolonged half life, and increased time to attain steady state concentrations
What does an increase of alpha-1 glycoprotein levels result in?
increased plasma protein binding and a decrease in unbound fraction in plasma
What does a decrease in unbound fraction cause
decrease in apparent volume, a shortened half-life, and a reduced time to steady state
What does hypoperfusion lead to?
decreased delivery of drugs to target tissues and tissues into which drugs may distribute
What are the key factors of affecting metabolism
- Alterations in hepatic blood flow
- Alterations in protein binding
- Alterations in intrinsic liver clearance
- Alterations in intrinsic clearance - high extraction ration and low extraction ratio drugs
What is the primary organ of drug metabolism?
the liver
What are the high extraction ratio drugs?
drugs highly metabolized by hepatic enzymes
What are examples of high extraction ratio drugs?
- Diltiazem
- Fentanyl
- Haloperidol
- lidocaine
- propofol
What are the low extraction ratio drugs
clearance independent of hepatic blood flow
What are examples of low extraction ratio drugs?
- Diazepam
- phenytoin
- warfarin
- valproic acid
When does hepatic blood flow increase?
during earlier stages of sepsis or with administration of vasodilators (nitroglycerin)
What can a decrease blood flow occur with?
cirrhosis or with vasopressors used for hypotension and shock can reduce hepatic blood flow
What are alterations in liver blood flow expected to have minimal of?
impact on drugs with a lower extraction ratio
Alterations in protein binding of high extraction ratio drugs will affect what type of concentrations?
unbound concentrations of high extraction ratio drugs
What will an increase of unbound fraction cause in high extraction ratio drugs?
increase unbound concentrations that will interact with therapeutic targets or targets associated with adverse effects
What will alterations in protein binding have on low extraction ratio drugs and protein binding
minimal impact on unbound concentrations of a low extraction ratio drug, total concentration will be affected
Because unbound concentrations are not altered in low extraction ratio drugs, will there be a change in the amount of drug reached to its target?
No
What factors can alter the intrinsic clearance (CLi) of drugs from the liver?
- severe burns or cholestasis may decrease cytochrome p450 activity
- renal impairment can be associated with decrease hepatic clearance. As a result, clearance can be decreased even when a drug is not primarily eliminated by the kidneys
- Cirrhosis is associated with a decreased drug metabolism due to a reduced number of functional hepatocytes
- Therapeutic hypothermia may decrease CYP activity, and blood flow (enzyme inducers and inhibitors need to be considered)
what organ is responsible for non metabolic drug elimination?
the kidney
What are the three main factors involved in renal clearance of a drug?
- glomerular filtration
- secretion
- reabsorption
What are the key factors that impact renal clearance?
- AKI
- increased renal blood flow
- tubular secretion and reabsorption
Reduction in doses for patients receiving renally cleared drugs is often required in what type of patients?
patients with AKI
What can renal impairment be associated with?
decreased protein binding of highly bound drugs. Which can result in an increased Vd or alteration in hepatic clearance
What is the primary determinant of loading doses
Vd
what is tubular secretion?
the process by which drugs are actively secreted into the renal tubules for elimination in urine
Does tubular secretion enhance or reduce renal clearance?
enhance
What is tubular reabsorption
the process by which drugs re-enter the systemic circulation after being filtered at the glomerulus
Does tubular reabsorption enhance or reduce renal clearance?
reduce
Does basic drugs increase or decrease renal clearance
decrease
Does acidic drugs increase or decrease renal clearance
increase
when monitoring renal function in patients, how should Cockroft gault be monitored?
- measuring 24-hour creatine elimination in urine as a direct measure of crcl
- measurement of renal function based on plasma cystatin c
