Pharmacokinetics in the critically ill Flashcards
List how drug absorption might be affected by critical illness
- Delayed gastric emptying = decreased drug absorption (paracetamol)
- Higher gastric pH = Decreased drug absorption (clopidogrel)
- Increased GIT permeability = increased drug absorption (electrolyte replacement)
- Decreased mesenteric perfusion = decreased drug absorption (paracetamol)
- Increased pre-absorptive interactions = decreased drug absorption (NG feeds and phenytoin)
- Decreased active efflux = increased drug absorption (digoxin)
- Decreased skin/muscle perfusion = decreased absorption from SC or IM injections (heparin)
List how drug distribution changes during critical illness
- Decreased protein = increased free drug of highly protein bound drugs (phenytoin / NSAIDS)
- Altered protein binding due to pH changes = altered free drug (calcium)
- Increased Vd = decreased elimination of drugs, decreased plasma concentration (aminoglycosides)
- Microvascular haemodynamic dysfunction = decreased tissue perfusion (piperacilin)
- Impaired barrier functions = increased tissue penetration (benzylpenicillin into CNS)
List how drug metabolism changes in the critically ill
- Decreased hepatic blood flow = decreased clearance of high extraction drugs (propofol)
- Hypothermia = decreased hepatic clearance (midazolam)
- Hyperthermia = increased clearance due to enzyme activity (suxmethonium)
- Downregulation hepatic enzymes = decreased clearance (theophylline)
- Decreased hepatic synthetic funcion = decreased levels of soluble enzymes, decreased clearance of drugs in the plasma (sux)
List how drug elimination changes in the critically ill
- Decreased renal blood flow and funciton = decreased clearance of unchanged drugs or metabolites (everything)
- Increased GFR in hyperdynamic circulatory states = increased clearance of drugs (vancomycin)
How is digoxin bioavailability altered by increased gastric pH? Why does this occur
Increases by 10%
Digoxin undergoes per-absorptive hydrolysis at low pH (in the stomach). If PPI’s are administered the extent of this hydrolysis decreases increasing the digoxin available for absorption.
What is the difference between administering KCl IV and orally in the critically ill
There is no difference. Both equally effective at increasing K.
This is because the GIT permeability to electrolytes and small osmotic molecules is increased in critical illness while the functional absorptive capacity (requiring active transport) is reduced.
How is mesenteric perfusion affected in critical illness and what does this mean for drug absorption
- SNS –> shunts blood away from the rest and digest or non-flight and non-fight organs reducing perfusion.
- Vasopression and noradrenalin cause splanchnic vasoconstriction reducing mesenteric perfusion
- PPV + PEEP reduces venous return from the gut
All factors reduce absorption. However, Oseltamivir is the exception.
How does major abdominal surgery affect drug absorption?
Unpredictable oral pharmacokinetics
E.g. Fluconazole 30 - 100% range of bioavailability
Describe two common preabsorptive drug interactions in the ICU
- NG feeds need to be turned off 2 hours before and after oral phenytoin administration.
- Tetracylines and fluoroquinolones cannot be administered together with oral calcium (e.g. milk)
Why is the activity of apical efflux transporters like the P-glycoprotein family reduced in critical illness?
Energy is diverted in critical illness to other functions –> synthesis of apical efflux pumps like the P-glycoprotein family is neglected.
This means that, for example, Digoxin’s bioavailability will be increased after oral administration in the critically ill.
Give an example and explain how low albumin in critical illness can influence the activity of drugs
When phenytoin levels are measured, total drug levels are measures = free + bound drug
But it is only the free drug that is active.
Phenytoin is usually 90% protein bound
If albumin is low, this means that this could change to 80%.
This would mean that now there is DOUBLE the active drug in circulation.
Why is there increased total body water in the critical care setting?
How does increased total body water and increased third space fluid volume influence the volume of distribution of hydrophilic and hydrophobic drugs?
Usually related to intravenous fluid resuscitation and increased capillary permeability related to the systemic inflammatory response syndrome.
Hydrophobic drugs - unchanged Vd
Hydrophilic drugs - Increased volume of distribution
What are the implications of an increased volume of distribution?
Less drug ends up in the effective circulating volume –> reduced clearance by organs of clearance and extracorporeal clearance mechanisms.
How is the volume of distribution and clearance of hydrophobic drugs affected by increased total body water
Volume distribution unchanged
Clearance –> reduced
–> The non-lipid-bound molecules are the only ones which would usually undergo clearance; and now these molecules will be shared between the circulating volume and the expanded third fluid space.
What could be a possible benefit of increasing the volume of distribution of antibioitics
Could be of benefit because half-lives and this time above Minimum Inhibitory Concentration (MIC) will be increased, enhancing the killing power of time-dependent antibiotics.
