Canonical Question
PK – IV Kinetics
Master answer
Continuous IV Infusion
- Volume of distribution
- Apparent volume into which a drug disperses in order to produce the observed plasma conc
- The physicochemical properties of a drug influence Vd
- lipid solubility – highly lipid soluble drugs have larger Vd
- charge characteristics – highly charged drugs have smaller volumes of distribution
- tissue binding may result in increased Vd
- pathology – renal and hepatic disease leads to increased Vd due to fluid changes
- Plasma concentration
- is the amount of drug/volume within which it is diluted
- Clearance
- is the volume of plasma from which the drug is cleared from per unit time (usually ml/min)
- it is also the dose/area under the curve
- Loading dose (mg)
- aims to achieve a required plasma concentration
- therefore = desired peak concentration (mg/L) × clearance (L/hr)
- (divided by bioavailability if not IV)
- Maintenance dose (mg/hr)
- aims to achieve a constant plasma concentration range
- is equal to the elimination of the drug
- Is desired peak concentration (mg/L) × clearance (L/hr)
Factors which affect loading dose and maintenance dose in critically ill
| Effects of critical illness | Impact on loading dose and maintenance dose |
| VOLUME OF DISTRIBUTION | |
| Increased Vd (due to fluid overload) | Increased loading dose and maintenance dose or dose rate |
| Decreased Vd (due to hypovolaemia) | Decreased loading dose and maintenance dose or dose rate |
| CLEARANCE | |
| Decreased renal clearance (due to decreased renal blood flow or renal parenchymal damage) | Decreased maintenance dose or dose rate; also possibly increased dosing interval. Loading dose could remain unchanged |
| Increased renal clearance (hyperdynamic states, eg. early sepsis) | Increased maintenance dose or dose rate; also possibly dencreased dosing interval Loading dose could remain unchanged |
| Decreased hepatic clearance (decreased hepatic blood flow or inhibited liver enzyme function) | Decreased maintenance dose or dose rate; also possibly increased dosing interval. IV loading dose could remain unchanged Oral loading dose would need to be decreased to accommodate for the decreased first pass metabolism |
| Increased hepatic clearance (increased hepatic blood flow or hepatic parenchymal clearance) | Increased maintenance dose or dose rate; also possibly decreased dosing interval. IV loading dose could remain unchanged Oral loading dose would need to be increased to accommodate for the increased first pass metabolism |
| BIOAVAILABILITY | |
| Decreased protein binding (due to lower levels of protein) | Increased free unbound fraction of the drug, which gives rise to increased clearance and increased drug effect. |
| Decreased gut absorption (due to decreased splanchnic blood flow and/or decreased peristalsis) | Variable and inconsistent absorption of an otherwise correctly calculated oral loading dose |
| Competition for protein binding (eg. where bilirubin competes for albumin binding sites) | Increased free unbound fraction of the drug |
Examples of drugs illustrating an understanding of pharmacokinetics
- Theophylline: a drug which is dosed every half-life (300mg every 8 hours), which is equivalent to a dose rate of 37.5mg/hr, which is in turn equivalent to an infusion rate of 37.5mg/hr.
- Phenobarbitone: a drug with a vast volume of distribution, where the loading dose would be massive and toxic
- Morphine: a drug which is poorly orally bioavailable; an example of how the oral loading dose is affected by bioavailability
- Phenytoin: a drug which is highly protein-bound, and which is highly affected by the low plasma albumin associated with critical illness (thus, with low total drug levels the levels of free unbound drug may still be therapeutic)
- Corrected Phenytoin = Measured Phenytoin Level / ( (adjustment x albumin) + 0.1)
- Adjustment = 0.2; In patients with Creatinine Clearance < 20, adjustment = 0.1.
- Gentamicin: a drug which is cleared rapidly by the kidneys, a clearance which is significantly affected by poor renal function. It is an example of how the loading or maintenance dose should remain unchanged; instead the dosing interval should be extended.
- Vancomycin and β-lactams: examples of drugs which are subject to increased renal clearance in the context of hyperdynamic circulatory states, for example in early sepsis.
Source: Deranged Physiology
JC 2019
Exam appearances
| Exam | Exact wording | Relationship | Success |
|---|---|---|---|
| 2009A Q10 | Describe the calculations involved in determining the loading dose and maintenance dose for an intravenous infusion (50% of marks). What factors may affect these values in the critically ill (50% of marks)? | historical_member | — |