Pharmacokinetics2
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Transcript of Pharmacokinetics2
Excretion
KIDNEY GLOMERULAR FILTRATION: Clearance of the apparent volume
of distribution by passive filtration. • Drug with MW < 5000 ------> it is completely filtered. • Inulin is completely filtered, and its clearance can be measured to
estimate Glomerular Filtration Rate (GFR). TUBULAR SECRETION: Active secretion.
• Specific Compounds that are secreted: – para-Amino Hippurate (PAH) is completely secreted, so its clearance can
be measured to estimate Renal Blood Flow (RBF). – Penicillin-G is excreted by active secretion. Probenecid can be given to
block this secretion.
• Anionic System: The anionic secretory system generally secretes weak ACIDS:
– Penicillins, Cephalosporins – Salicylates – Thiazide Diuretics – Glucuronide conjugates
• Cationic System: The cationic secretory system generally secretes BASES, or things that are positively charged.
• Ion-Trapping: Drugs can be "trapped" in the urine, and their rate of elimination can be increased, by adjusting the pH of the urine to accommodate the drug. This is useful to make the body get rid of poisons more quickly.
– To increase excretion of acidic drugs, make the urine more basic (give HCO3-)
– To increase excretion of basic drugs, make the urine more acidic.
BILIARY EXCRETION: Some drugs are actively secreted in the biliary tract and excreted in the feces. Some of the drug may be reabsorbed via the enterohepatic circulation.
• Transporters: The liver actively transporters generally large compounds (MW > 300), or positive, negative, or neutral charge.
– Anionic Transporter: Transports some acids, such as Bile Acids, Bilirubin Glucuronides, Glucuronide conjugates, Sulfobromophthalein, Penicillins
– Neutral Transporter: Transports lipophilic agents, such as: » Steroids » Ouabain
Cationic Transporter: Transports positively charged agents, such as n-Methylnicotinamide, tubocurarine
Charcoal can be given to increase the fecal excretion of these drugs and prevent enterohepatic reabsorption.
Cholestyramine can be given to increase the rate of biliary excretion of some drugs.
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
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
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.
