PHARMACOKINETICS:
- ORDERS of EXCRETION:
- ZERO-ORDER EXCRETION: The
rate of excretion of a drug is independent of its concentration.
- General properties:
- dC/dt = -K
- A plot of the drug-concentration -vs-
time is linear.
- The half-life of the drug becomes
continually shorter as the drug is excreted.
- Examples:
- Ethanol is zero-order
in moderate quantities, because the metabolism system is
saturated. The rate of metabolism remains the same no matter
what the concentration.
- Phenytoin and
Salicylates follow zero-order kinetic at high
concentration.
- FIRST-ORDER EXCRETION: The
rate of excretion of a drug is directly proportional to its
concentration.
- General properties:
- dC/dt = -K[C]
- A plot of the log[conc] -vs- time is
linear. slope of the line = -Kel
/ 2.303
- The half-life of the drug remains
constant throughout its excretion
- Equation:
HALF-LIFE: The half-life is inversely
proportional to the Kel, constant of elimination.
The higher the elimination constant, the shorter the half-life.
COMPARTMENTS:
- One-Compartment Kinetics:
Kinetics are calculated based on the assumption that the drug is
distributed to one uniform compartment.
- One compartment kinetics implies that
the drug has a rapid equilibrium between tissues and the blood, and
that the release of the drug from any tissues is not rate-limiting
in its excretion.
- One-compartment kinetics also assumes that
the drug is distributed instantaneously throughout the body. This is
only true for IV infusion.
- Multi-Compartment Kinetics:
Most drugs follow multi-compartment kinetics to an extent.
- Biphasic Elimination Curve:
Many drugs follow a biphasic elimination curve -- first a steep
slope then a shallow slope.
- STEEP (initial) part of curve ------>
initial distribution of the drug in the body.
- SHALLOW part of curve ------> ultimate
renal excretion of drug, which is dependent on the release of
the drug from tissue compartments into the blood.
CLEARANCE: The apparent volume of blood from
which a drug is cleared per unit of time.
- CLEARANCE OF DRUG = (Vd)x(Kel)
- The higher the volume of distribution of
the drug, the more rapid is its clearance.
- The higher the elimination constant, the
more rapid is its clearance.
-
- This is based on the Dilution Principle:
- (Conc)(Volume) = (Conc)(Volume)
- Total Amount = Total Amount
- MEANING: In first-order kinetics, drug is
cleared at a constant rate. A constant fraction of the Vd is
cleared per unit time. The higher the Kel, the higher is that
fraction of volume.
- Drug Clearance of 120 ml/min ------> drug
is cleared at the same rate as GFR and is not reabsorbed. Example =
inulin
- Drug clearance of 660 ml/min ------> drug
is cleared at the same rate as RPF and is actively secreted, and not
reabsorbed. Example = PAH
- BIOAVAILABILITY: The proportion of
orally-administered drug that reaches the target tissue and has activity.
-
- AUCORAL = Area under the curve.
The total amount of drug, through time, that has any activity when
administered orally.
- AUCIV = Area under curve. The
total amount of drug, through time, that has any activity when
administered IV. This is the maximum amount of drug that will have
activity.
- 100% Bioavailability = A drug administered by
IV infusion.
- BIOEQUIVALENCE: In order for two drugs to be
bioequivalent, they must have both the same bioavailability and
the same plasma profile, i.e. the curve must have the same shape. That
means they must have the same Cmax and Tmax.
- Cmax: The maximum
plasma concentration attained by a drug-administration.
- Tmax: The time at
which maximum concentration is reached.
- REPETITIVE DOSES:
- FLUCTUATIONS: Drug levels fluctuate as you give
each dose. Several factors determine the degree to which drug levels
fluctuate.
- There are no fluctuations with continuous
IV infusion.
- Slow (more gradual) absorption also reduces
fluctuations, making it seem more like it were continuous infusion.
- The more frequent the dosing interval, the
less the fluctuations. Theoretically, if you give the drug, say,
once every 30 seconds, then it is almost like continuous IV infusion
and there are no fluctuations.
- Steady-State Concentration (CSS):
The plasma concentration of the drug once it has reached steady state.
- It takes 4 to 5 half-lives for a drug
to reach the steady state, regardless of dosage.
- After one half-life, you have attained
50% of CSS. After two half-lives, you have attained
75%, etc. Thus, after 4 or 5 half-lives, you have attained ~98%
of CSS, which is close enough for practical purposes.
- If a drug is dosed at the same interval
as its half-life, then the CSS will be twice the C0
of the drug.
- If you have a drug of dose 50 mg and a
half-life of 12 hrs, and you dose it every 12 hrs, then the
steady-state concentration you will achieve with that drug will
be 100 mg/L.
-
- D:
Dose-amount. The higher the dose amount, the higher the
Css.
: Dosage interval. The shorter the
dosage interval, the higher the Css
- F:
Availability Fraction. The higher the availability
fraction, the higher the Css.
- Kel:
Elimination Constant. The higher the
elimination constant, the lower is the Css.
Vd: Volume of
Distribution. A high volume of distribution means we're putting the
drug into a large vessel, which means we should expect a low Css.
- Cl: Clearance.
The higher the drug-clearance, the lower the Css.
-
- If you know the desired steady-state
concentration and the availability fraction, then you can
calculate the dosing rate.
- LOADING DOSE: When a drug has a long half-life,
this is a way to get to CSS much faster.
- Loading Dose = twice the regular dose,
as long as we are giving the drug at the same interval as the half-life.
-
- INTRAVENOUS INFUSION: The CSS
is equal to the input (infusion rate x volume of distribution)
divided by the output (Kel)
-
- R0 = the rate of infusion.
- Vd = the volume of distribution,
which should be equal to plasma volume, or 3.15L, or 4.5% of TBW.
- Kel = Elimination Constant
- Loading Dose in this case is just equal to
Volume of distribution time the Css:
- RENAL DISEASE: Renal disease means the drug is not
cleared as quickly ------> the drug will have a higher Css
------> we should adjust the dose downward to accommodate for the slower
clearance.
- If the fraction of renal clearance is 100%
(i.e. the drug is cleared only by the kidneys), then you decrease the
dosage by the same amount the clearance is decreased.
- For example: If you have only 60% of
renal function remaining, then you give only 60% of the original
dose.
- If the fraction of renal clearance is less then
100%, then multiply that fraction by the percent of renal function
remaining.
- For example: If you have only 60% of
renal function remaining, and 30% of the drug is cleared by the
kidney, then the dose adjustment = (60%)(30%) = 20%. The dose should
be adjusted 20%, or you should give 80% of the original dose.
-
- G = The percentage of the
original dose that we should give the patient.
If G = 60%, then we should give the patient 60% of the
original dose.
- f = The fraction of the
drug that is cleared by the kidney.
If f is 100%, then the drug is cleared only by the
kidney.
- ClCr = Creatinine clearance of
patient, and normal clearance. The ratio is the percent of normal
kidney function remaining.
- Renal disease increases the time to reach
steady-state concentration. Renal Disease ------> longer half-life
------> longer time to reach steady-state.
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