Pharmacokinetics

Lecture5 DRUG CLEARANCE BY THE KIDNEY
Drugs must be sufficiently polar to be eliminated from the body. Removal
of drugs from the body occurs via a number of routes, the most important
being elimination through the kidney into the urine. Patients with renal
dysfunction may be unable to excrete drugs and are at risk for drug accumulation
and adverse effects.
Renal elimination of a drug
Elimination of drugs via the kidneys into urine involves the processes
of glomerular filtration, active tubular secretion, and passive tubular
reabsorption.
1. Glomerular filtration: Drugs enter the kidney through renal arteries,
which divide to form a glomerular capillary plexus. Free drug
(not bound to albumin) flows through the capillary slits into the
Bowman space as part of the glomerular filtrate . The
glomerular filtration rate (GFR) is normally about 125 mL/min but
may diminish significantly in renal disease. Lipid solubility and pH
do not influence the passage of drugs into the glomerular filtrate.
However, variations in GFR and protein binding of drugs do affect
this process.
2. Proximal tubular secretion: Drugs that were not transferred into
the glomerular filtrate leave the glomeruli through efferent arterioles,
which divide to form a capillary plexus surrounding the nephric lumen
in the proximal tubule. Secretion primarily occurs in the proximal
tubules by two energy-requiring active transport systems: one for
anions (for example, deprotonated forms of weak acids) and one for
cations (for example, protonated forms of weak bases). Each of these
transport systems shows low specificity and can transport many
compounds. Thus, competition between drugs for these carriers can
occur within each transport system. [Note: Premature infants and
neonates have an incompletely developed tubular secretory mechanism
and, thus, may retain certain drugs in the glomerular filtrate.]
3. Distal tubular reabsorption: As a drug moves toward the distal
convoluted tubule, its concentration increases and exceeds
that of the perivascular space. The drug, if uncharged, may diffuse
out of the nephric lumen, back into the systemic circulation.
Manipulating the urine pH to increase the fraction of ionized drug
in the lumen may be done to minimize the amount of back diffusion
and increase the clearance of an undesirable drug. As a general
rule, weak acids can be eliminated by alkalinization of the urine,
whereas elimination of weak bases may be increased by acidification
of the urine. This process is called “ion trapping.” For example,
a patient presenting with phenobarbital (weak acid) overdose can
be given bicarbonate, which alkalinizes the urine and keeps the
drug ionized, thereby decreasing its reabsorption.
4. Role of drug metabolism: Most drugs are lipid soluble and, without
chemical modification, would diffuse out of the tubular lumen when
the drug concentration in the filtrate becomes greater than that in the
perivascular space. To minimize this reabsorption, drugs are modified
primarily in the liver into more polar substances via phase I and
phase II reactions . The polar or ionized conjugates
are unable to back diffuse out of the kidney lumen
CLEARANCE BY OTHER ROUTES
Drug clearance may also occur via the intestines, bile, lungs, and breast
milk, among others. Drugs that are not absorbed after oral administration
or drugs that are secreted directly into the intestines or into bile are eliminated
in the feces. The lungs are primarily involved in the elimination of
anesthetic gases (for example, isoflurane). Elimination of drugs in breast
milk may expose the breast-feeding infant to medications and/or metabolites
being taken by the mother and is a potential source of undesirable
side effects to the infant. Excretion of most drugs into sweat, saliva, tears,
hair, and skin occurs only to a small extent. Total body clearance and
drug half-life are important measures of drug clearance that are used to
optimize drug therapy and minimize toxicity.
DESIGN AND OPTIMIZATION
OF DOSAGE REGIMEN
To initiate drug therapy, the clinician must select the appropriate route
of administration, dosage, and dosing interval. Selection of a regimen
depends on various patient and drug factors, including how rapidly therapeutic
levels of a drug must be achieved. The regimen is then further
refined, or optimized, to maximize benefit and minimize adverse effects.
. Continuous infusion regimens
Therapy may consist of a single dose of a drug, for example, a sleepinducing
agent, such as zolpidem. More commonly, drugs are continually
administered, either as an IV infusion or in oral fixed-dose/
fixed-time interval regimens (for example, “one tablet every 4 hours”).
Continuous or repeated administration results in accumulation of the
drug until a steady state occurs. Steady-state concentration is reached
when the rate of drug elimination is equal to the rate of drug administration,
such that the plasma and tissue levels remain relatively constant.
. Plasma concentration of a drug following IV infusion: With
continuous IV infusion, the rate of drug entry into the body is constant.
Most drugs exhibit first-order elimination, that is, a constant
fraction of the drug is cleared per unit of time. Therefore, the rate of
drug elimination increases proportionately as the plasma concentration
increases. Following initiation of a continuous IV infusion,
the plasma concentration of a drug rises until a steady state (rate of
drug elimination equals rate of drug administration) is reached, at
which point the plasma concentration of the drug remains constant.
Influence of the rate of infusion on steady-state concentration:
The steady-state plasma concentration (Css) is directly
proportional to the infusion rate. For example, if the infusion
rate is doubled, the Css is doubled Furthermore,
the Css is inversely proportional to the clearance of the drug.
Thus, any factor that decreases clearance, such as liver or kidney
disease, increases the Css of an infused drug (assuming
Vd remains constant). Factors that increase clearance, such as
increased metabolism, decrease the Css.
Time required to reach the steady-state drug concentration:
The concentration of a drug rises from zero at the start of
the infusion to its ultimate steady-state level, Css .
The rate constant for attainment of steady state is the rate constant
for total body elimination of the drug. Thus, 50% of Css of a
drug is observed after the time elapsed, since the infusion, t, is
equal to t1/2, where t1/2 (or half-life) is the time required for the drug
concentration to change by 50%. After another half-life, the drug
concentration approaches 75% of Css . The drug concentration
is 87.5% of Css at 3 half-lives and 90% at 3.3 half-lives.
Thus, a drug reaches steady state in about four to five half-lives.
The sole determinant of the rate that a drug achieves steady
state is the half-life (t1/2) of the drug, and this rate is influenced
only by factors that affect the half-life. The rate of approach to
steady state is not affected by the rate of drug infusion. When the
infusion is stopped, the plasma concentration of a drug declines
(washes out) to zero with the same time course observed in
approaching the steady state.
Fixed-dose/fixed-time regimens
Administration of a drug by fixed doses rather than by continuous
infusion is often more convenient. However, fixed doses of IV or oral
medications given at fixed intervals result in time-dependent fluctuations
in the circulating level of drug, which contrasts with the smooth
ascent of drug concentration observed with continuous infusion.
Multiple IV injections: When a drug is given repeatedly at regular
intervals, the plasma concentration increases until a steady state
is reached . Because most drugs are given at inter-vals shorter than five half-lives and are eliminated exponentially with
time, some drug from the first dose remains in the body when the
second dose is administered, some from the second dose remains
when the third dose is given, and so forth. Therefore, the drug accumulates
until, within the dosing interval, the rate of drug elimination
equals the rate of drug administration and a steady state is achieved
Effect of dosing frequency: With repeated administration at
regular intervals, the plasma concentration of a drug oscillates
about a mean. Using smaller doses at shorter intervals reduces
the amplitude of fluctuations in drug concentration. However,
the Css is affected by neither the dosing frequency (assuming
the same total daily dose is administered) nor the rate at which
the steady state is approached.
. Example of achievement of steady state using different
dosage regimens: Curve B of Figure 1.23 shows the amount
of drug in the body when 1 unit of a drug is administered IV and
repeated at a dosing interval that corresponds to the half-life
of the drug. At the end of the first dosing interval, 0.50 units
of drug remain from the first dose when the second dose is
administered. At the end of the second dosing interval, 0.75
units are present when the third dose is given. The minimal
amount of drug remaining during the dosing interval progressively
approaches a value of 1.00 unit, whereas the maximal
value immediately following drug administration progressively
approaches 2.00 units. Therefore, at the steady state, 1.00
unit of drug is lost during the dosing interval, which is exactly
matched by the rate of administration. That is, the “rate in”
equals the “rate out.” As in the case for IV infusion, 90% of the
steady-state value is achieved in 3.3 half-lives
Multiple oral administrations: Most drugs that are administered
on an outpatient basis are oral medications taken at a specific
dose one, two, or three times daily. In contrast to IV injection, orally
administered drugs may be absorbed slowly, and the plasma concentration
of the drug is influenced by both the rate of absorption
and the rate of elimination (Figure 1.24).
C. Optimization of dose
The goal of drug therapy is to achieve and maintain concentrations
within a therapeutic response window while minimizing toxicity and/
or side effects. With careful titration, most drugs can achieve this goal.
If the therapeutic window of the drug is small (for
example, digoxin, warfarin, and cyclosporine), extra caution should
be taken in selecting a dosage regimen, and monitoring of drug levels
may help ensure attainment of the therapeutic range. Drug regimens
are administered as a maintenance dose and may require a loading
dose if rapid effects are warranted. For drugs with a defined therapeutic
range, drug concentrations are subsequently measured, and the
dosage and frequency are then adjusted to obtain the desired levels.
. Maintenance dose: Drugs are generally administered to maintain
a Css within the therapeutic window. It takes four to five
half-lives for a drug to achieve Css. To achieve a given concentra-
tion, the rate of administration and the rate of elimination of the
drug are important. The dosing rate can be determined by knowing
the target concentration in plasma (Cp), clearance (CL) of the
drug from the systemic circulation, and the fraction (F) absorbed
(bioavailability):
Loading dose: Sometimes rapid obtainment of desired plasma
levels is needed (for example, in serious infections or arrhythmias).
Therefore, a “loading dose” of drug is administered to achieve the
desired plasma level rapidly, followed by a maintenance dose to
maintain the steady state Loading doses can be given as a single dose or a series of doses.
Disadvantages of loading doses include increased risk of drug toxicity
and a longer time for the plasma concentration to fall if excess
levels occur. A loading dose is most useful for drugs that have a
relatively long half-life. Without an initial loading dose, these drugs
would take a long time to reach a therapeutic value that corresponds
to the steady-state level.