Lecture 10: Pharmacokinetics IV Flashcards
Target plasma levels for a drug in the average patient are determined…
- from results of clinical trials (different doses) of drug under development
- clinical experience using clinically approved drugs.
Drug clearance
- Fundamental pharmacokinetics parameter that relates the rate of elimination of a drug to its plasma concentration (C):
-> Clearance (CL [L/h]) can be conceptualized in two ways:
—->1. Defined as the rate f elimination of the drug from the body relative to the concentration of the drug in plasma (Css= steady-state concentration).
2. Volume of plasma containing the total amount of drug that is removed from the body in unit time. - At steady-state infusion of a drug
1. CL[L/h] =X (infusion [mg/h])/Css (drug conc. [mg/L])
—-> 2. Rate of drug elimination [mg/h]= C[mg/L] x CL[L/h]
first-order kinetics
The amount of drug that is metabolized or excreted in a given unit of time (rate of drug elimination) is directly proportional to the concentration of drug.
-Majority of drugs -> first order kinetics when standard therapeutic doses.
- Clearance mechanisms for most drugs are not saturated under ordinary circumstances.
^ in plasma [drug] >< ^ in rate of drug metabolism and excretion.
Clearance = (Metabolism + Excretion) / [Drug]plasma
- rate follows menten kinetics
E= Vmax x C / Km + C
E=> elimination rate
C=> [Drug]plasma
Semilogarithmic
- After IV administration plasma drug concentration declines rapidly as drug distributes -> after the rapid decline a slower decline follows as the drug is metabolized and excreted.
zero-order kinetics
- Small # of drugs and recreational substances demonstrate saturation kinetics.
–> clearance mechanisms become saturated at or near the therapeutic concentration of drug. - Once saturation done, clearance rate fails to increase with increasing [drug]plasma.
- The drug elimination rate remains constant despite increasing plasma drug levels.
saturation kinetics
- Saturating kinetics of alcohol elimination in humans. The blood alcohol concentration falls linearly (4mmol/1 per hour)
–> stays the same
–> rate doesn’t change
drug half-life
The amount of time over which the drug concentration in the plasma decreases to one-half of its original value.
- Allows clinician to estimate the frequency of dosing required to maintain the plasma concentration of the drug in the therapeutic range.
–> t1/2 the lower it is, it is eliminated faster.
Describe single-compartment model used to describe pharmacokinetics
- Volume that is equivalent to the volume of distribution.
In this model the elimination half-life depends on:
–> volume of distribution (deciding initial dose of the drug)
–> clearance of the drug (maintenance doses)
A. constant IV infusion: C increases from 0 to a steady-state (Css), when stopped C declines to 0.
B. IV bolus dose: C rises abruptly then declines towards 0. (exponential decline)
C. Extrapolation: back to the ordinate at zero time gives an estimate of C0 the concentration at 0 and hence the Vd the volume of distribution.
- Oversimplification
Describe two-compartment model used to describe pharmacokinetics
introduces a separate ‘peripheral’ compartment to represent the tissue, in communication with the ‘central’ plasma compartment.
- tissues are lumped together as a peripheral compartment
- drug can enter/leave peripheral compartment only via the central compartment, includes plasma or plasma plus some extravascular space.
First phase - fast phase (alpha-phase), the redistribution of the drug.
Second phase - slow phase (beta-phase) represents elimination from plasma.
-distribution has happened.
Identify factors affecting drug elimination half-life
- cytochrome P450 enzymes
–> can be induced, increasing the rate of drug inactivation. - inhibited -> decreasing rate of drug inactivation.
- Decreased cardiac output reduces the amount of blood.
- Renal failure decreases drug excretion.
Describe repeated dosage in terms of half-life and saturation kinetics; loading dose; and maintenance dose
- Concentration will rise to a mean steady-state concentration with an approximately exponential time course, but will oscillate (through Q/Vd)
Half-life
- a steady state is effectively achieved after three to five half-lives.
-Speedier steady state -> starting with larger loading dose.
Loading dose
- Significant for drugs with high volumes of distribution.
- Administered in order to compensate for drug distribution into the tissues.
Dose(loading) = Vd x Css
Maintenance dose
- Once the steady-state plasma drug concentration is achieved.
–> subsequent doses need to replace only the amount of drug that is lost through metabolism and excretion.
- Dependent on drug clearance
‘rate in’ = ‘rate out’ at ss
Dose(maintenance) = Clearance x Css
- rate ^ than calculated maintenance dose = accumulate to toxic levels
Clearance & the steady-state concentration
Clearance is defined as the rate of elimination of the drug from the body relative to the concentration of the drug in plasma (Css = steady-state concentration.
drug concentration at zero time & the volume of distribution
both values found via extrapolation
-related via the equation -> C0= Q/Vd
Maintenance dose & clearance
The maintenance dose dependent on the drug clearance (rate of elimination)
Dose(maintenance) = Clearance x Css
Loading dose & the volume of distribution
- the size of the loading dose is determined by the volume of distribution.
Half-life: practical applications
- After bolus injection or after infusion is discontinued falls towards 0:
–> after 1 half-life, concentration will have fallen to half the initial concentration.
–> after 2, fallen to one-quarter.
–> after 3, to one-eighth… - The longer the half life the longer the drug will persist in the body.
- During chronic drug administration the longer the half-life the longer it will take for the drug to accumulate to its steady-state level.
–> 1 t1/2 to reach 50% of ss value
–> 2 to reach 75%
–> 3 to reach 87.5%… - Half life of 24h will take 3-5 days
- if too slow then a loading dose would be used.
