What is first order kinetics, what complicates it, and how common is it?
The rate of elimination is proportional to the Cp (Concentration of the drug in the plasma). Because the Cp changes, the rate of elimination changes as well. Most clinically utilized drugs are eliminated by first order kinetics, and biologic processes for elimination (hepatic elimination and renal excretion) are first order processes.
What is zero order kinetics
In zero order kinetics, the rate of elimination is equal to a constant times the Cp^0, thus the rate of elimination is constant regardless of the Cp. Also termed saturation kinetics because normal first order processes become zero order at saturation concentrations (ie, elimintaion rate is constant, regardless of concentration).
What property of a drug is its fluctuation proportional to?
The fluctuation of a drug is proportional to its half-life. The more half-lives in the dosing interval, the greater the fluctuation.
1) What pharmacokinetic parameter measures the extend of distribution of a drug? 2) How often is the rate of distribution important? 3) What does bioavailability measure?
1) Volume of distribution. 2) Only following the first dose. 3) Bioavailability measures the extent of distribution.
What does ke represent in a graphic depiction of drug elimination?
The slope of the line. Rearrangeing ln(C2/C1)=-ket becomes ln C2 = -ke t + ln C1 (y=mx+b)
Why are half lives used to measure drug elimination?
Because most drugs are eliminated by mechanisms featuring first order kinetics, there is no constant rate (metabolic rate is proportional to Cp, which changes). However, a constant fraction of the drug is eliminated per unit time and this is independent of the total amount of the drug present. Hence, 1/2 lives are more constant measures.
Three rule of thumb estimates that involve half lives.
Time it takes for a drug to be eliminated (4-5 half lives). Time is takes to reach a steady state (4-5 half lives). Degree of fluctuations in plasma levels between doses (# of half lives in dosing intervals -> T/t1/2)
What is the Clearance (CL) and how is it calculated?
The clearance (CL) is the volume of plasma that is completely cleared of drug in a given period of time. CL = Vd x ke Measured in untis of L/hr or ml/min. It can be thought of as the proportionality constant between rate in and steady state conc (CL = (MD/tau)/(Cpss))
What factors influence the rate of hepatic clearance?
1) Blood flow to the liver - drugs with "low extraction" (inefficient metabolism) are less affected than drugs with "high extraction" (very efficient metabolism. increased blood flow will have a major effect). 2) Protein binding - only free drug is metabolized. 3) Intrinsic hepatic metabolic activity - subject to inducers and inhibitors of metabolic activity.
What factors affect renal clearance?
Renal clearance varies as kidney function varies (almost always goes down due to disease, age, or nephrotoxicity). This necessitates dose changes to prevent drug accumulation - "renal dosing".
How can we calculate the IV dose of a drug from the oral dose?
Multiply the oral dose by the bioavailability (which is almost always the oral bioavailability). Thus 100mg orally by 0.5 bioavailability equals 50mg IV.
What pharmacokinetic parameters are calculatable from a chart of ln Cp vs time?
ke - from slope of the line, Cp0 from extrapolation of B elimination phse to t = 0, t1/2 - from 0.693/ke, Vd - from Dose/Cp0. F (bioavailability) is calculated from a chart of Cp v time.
Why does it take 4-5 half lives to arrive at the steady state level or acheive elimination of a drug?
4-5 half lives will result in 94-97% of either the steady state level or elimination of a drug from the system. This is close enough to the Cpss or 0 to be considered equivalent.
Why is the time to steady state independent of the dose and how do loading doses then function to accelerate the time to SS?
The larger the dose, the higher the steady state equivalent would be, therefor steady state concentrations are unique to the dosage and still require 4-5 half lives to acheive. A loading dose acheives the Cp of a lower dose more quickly, at which point future doses are reduced to acheive the desired SS.
How is the maginitude of fluctuation of Cp calculated?
Fluctuations are equal to 1/(Cp2/Cp1), or the inverse of the fraction of drug remaining at the end of the dosing interval. Thus, given a dose after 1 half life (1/2 remaining), the Cp would fluctuate 1/.5 = 2 fold; given a dose after 2 half lives (1/4 remaining), the Cp would fluctuate 1/.25 = 4 fold; and given a dose after 3 half lives (1/8 remaining), the Cp would fluctuate 1/.125 = 8 fold.