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What process is usually involved in the excretion of bound drugs?
What process is usually involved in the excretion of bound drugs?
How are protein-bound drugs eliminated from the body?
How are protein-bound drugs eliminated from the body?
Only the free drug is excreted by a linear process. Bound drugs are usually excreted by active secretion.
The determination of clearance which separates two components would result in a hybrid _____
The determination of clearance which separates two components would result in a hybrid _____
clearance
Can clearance separate components that have different ways of elimination?
Can clearance separate components that have different ways of elimination?
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Define drug clearance.
Define drug clearance.
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What does drug clearance represent?
What does drug clearance represent?
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What factors determine the amount of drug removed from the body?
What factors determine the amount of drug removed from the body?
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Glomerular filtration is a unidirectional process.
Glomerular filtration is a unidirectional process.
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Active tubular secretion of drugs requires energy and occurs from _____ to _____ concentrations.
Active tubular secretion of drugs requires energy and occurs from _____ to _____ concentrations.
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Calculate the clearance of lidocaine in L/min and L/hr if it is infused continuously at a rate of 2 mg/min and the steady-state concentration is 3 mg/L.
Calculate the clearance of lidocaine in L/min and L/hr if it is infused continuously at a rate of 2 mg/min and the steady-state concentration is 3 mg/L.
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If the theophylline clearance is 2.8 L/hr, what is the rate of intravenous administration necessary to produce a steady-state plasma theophylline concentration of 10 mg/L? Also, calculate the dose if theophylline were to be given every 12 hours.
If the theophylline clearance is 2.8 L/hr, what is the rate of intravenous administration necessary to produce a steady-state plasma theophylline concentration of 10 mg/L? Also, calculate the dose if theophylline were to be given every 12 hours.
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What is the formula for renal clearance in equation (12)?
What is the formula for renal clearance in equation (12)?
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What does the equation in (13) represent in terms of renal clearance?
What does the equation in (13) represent in terms of renal clearance?
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What is the formula for determining Maintenance Dose according to equation (16)?
What is the formula for determining Maintenance Dose according to equation (16)?
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Total clearance is the sum of metabolic clearance and renal clearance. (True/False)
Total clearance is the sum of metabolic clearance and renal clearance. (True/False)
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How is hepatic function often evaluated?
How is hepatic function often evaluated?
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How can dosing rate be adjusted for a patient with altered renal function?
How can dosing rate be adjusted for a patient with altered renal function?
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What does active secretion result in for drugs carried to the kidney?
What does active secretion result in for drugs carried to the kidney?
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Which process has very little effect on the elimination half-life of a drug mostly excreted by active secretion?
Which process has very little effect on the elimination half-life of a drug mostly excreted by active secretion?
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Protein binding has a significant effect on the elimination half-life of a drug excreted mostly by active secretion.
Protein binding has a significant effect on the elimination half-life of a drug excreted mostly by active secretion.
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Undissociated drug is more ________ soluble and has greater membrane permeability.
Undissociated drug is more ________ soluble and has greater membrane permeability.
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Match the following terms with their definitions:
Match the following terms with their definitions:
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What is the urine to plasma ratio equation for weak acids?
What is the urine to plasma ratio equation for weak acids?
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What effect does acidification of urine have on weak bases?
What effect does acidification of urine have on weak bases?
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Study Notes
Protein Bound Drugs
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Not eliminated by glomerular filtration, only the free drug is excreted through a linear process.
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Bound drugs are usually excreted by active secretion, which follows capacity-limited kinetics.
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The determination of clearance separates two components, resulting in a hybrid drug that has different elimination pathways.
The clearance of a protein-bound drug is complex and cannot be easily predicted, as it involves both filtration and secretion.
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There is no simple way to overcome the problem of determining clearance for protein-bound drugs.
Drug Clearance
- Drug clearance is the intrinsic ability of the body or its organs (usually kidneys and liver) to remove a drug from the blood or plasma.
- Clearance is not an indicator of how much drug is being removed, but rather represents the theoretical volume of blood or plasma that is completely cleared of a drug in a given time period.
Factors Affecting Clearance
- Amount of drug removed depends on plasma concentration of drug and clearance.
Steady State
- Steady state is achieved when the rate of drug administration (RA) equals the rate of drug elimination (RE).
Mathematical Representation of Clearance
- Clearance (Cl) = rate of drug elimination divided by plasma drug concentration at that time point.
- Cl = excretion rate / plasma concentration (Equation 1)
Total Body Clearance
- Total body clearance is the sum total of all clearance pathways in the body, including clearance of drug through the kidney (renal clearance) and liver (hepatic clearance).
- Expressed per kilogram body weight.
Renal Clearance
- Renal clearance is the quantitative description of the renal excretion of drugs.
- Renal excretion is a major route of elimination for many drugs, especially water-soluble drugs with low molecular weight (< 300) or those that are slowly biotransformed by the liver.
Mechanisms of Renal Clearance
- Glomerular filtration: a unidirectional process, occurs for most small molecules, including undissociated and dissociated drugs.
- Active tubular secretion: an active process that requires energy, involves a carrier-mediated system, and may be saturated.
- Tubular reabsorption: may be active or passive, influenced by pH of the renal tubule and pKa of the drug.
Glomerular Filtration
- Glomerular filtration rate is measured by using a drug that is eliminated by filtration only, such as inulin or creatinine.
- Clearance of inulin will be equal to the glomerular filtration rate, which is approximately 125-130 ml/min.
- Glomerular filtration is directly related to the free or non-protein-bound drug concentration in the plasma.
Active Tubular Secretion
- Active tubular secretion is an energy-dependent process that requires a carrier system.
- Carrier-mediated system may be saturated, and drugs with similar structures may compete for the same carrier system.
- Active tubular secretion rate is dependent on renal plasma flow.
Tubular Reabsorption
- Tubular reabsorption can be active or passive.
- pH of the renal tubule and pKa of the drug influence the reabsorption of drugs.
- Undissociated species is more lipid-soluble and has greater membrane permeability, making it easier to reabsorb.
Henderson-Hasselbalch Equation
- pH = pKa + log [ionized] / [unionized]
- Used to calculate the percentage of ionized weak acid or weak base drug in a given pH environment.
Application of Henderson-Hasselbalch Equation
- The percentage of weak acid drug ionized in any pH environment can be calculated using the equation.
- Weak acids with pKa values of less than 2 are highly ionized at all urinary pH values and are only slightly affected by pH variations.
- Weak bases with pKa values of more than 8 are highly ionized at all urinary pH values and are only slightly affected by pH variations.### pH and Urinary Excretion of Weak Acids and Bases
- The Henderson-Hasselbalch relationship can be used to derive an equation for the concentration ratio of a weak acid or basic drug between urine and plasma.
- The urine:plasma ratios for weak acids and bases can be calculated using the following equations:
- For weak acids: Urine/Plasma = (1+10^(pHurine-pKa)) / (1+10^(pHplasma-pKa))
- For weak bases: Urine/Plasma = (1+10^(pKa-pHurine)) / (1+10^(pKa-pHplasma))
- The effect of urinary pH on reabsorption is greatest for weak bases with a pKa of 7.5-10.5.
- Alkalization of the urine increases the excretion of weak acids, while acidification of the urine increases the reabsorption of weak bases.
Renal Clearance
- Renal clearance (ClR) is the rate of elimination of a drug by the kidney.
- ClR can be calculated using the following equation: ClR = (Filtration rate + Secretion rate - Reabsorption rate) / C (plasma drug concentration)
- ClR can also be calculated using the following equation: ClR = (Total amount of drug excreted over some time interval) / (Plasma conc. measured at midpoint of time interval)
Maintenance Dose
- The maintenance dose is the dose that will produce a desired average plasma concentration at steady state.
- The maintenance dose can be calculated using the following equation: Maintenance dose = (Cl)(Css ave)(τ) / (S)(F)
Factors that Alter Clearance
- Factors that can alter clearance include:
- Body weight and surface area
- Cardiac output
- Drug-drug interactions
- Extraction ratio
- Genetics
- Hepatic function
- Plasma protein binding
- Renal function
- Clearance can be adjusted for a patient's body weight and surface area using the following equations:
- Cl = (Literature Cl per m2) (Patient's BSA)
- Cl = (Literature Cl per 70kg) (Patient's BSA / 1.73 m2)
- Cl = (Literature Cl per kg) (Patient's weight in kg)
Renal and Hepatic Function
- The total clearance (ClT) is the sum of the renal clearance (Clr) and metabolic clearance (Clm).
- ClT = Clr + Clm
- In patients with renal or hepatic failure, the total clearance can be adjusted using the following equation: Cl adjusted = Clm + [(Clr) (Fraction of normal renal function remaining)]
Dosing Rate Adjustment Factor
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The dosing rate adjustment factor is used to adjust the maintenance dose for a patient with altered renal function.
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The dosing rate adjustment factor can be calculated using the following equation: Dosing rate adjustment factor = (Fraction eliminated metabolically) + [(Fraction eliminated renally) (Fraction of normal renal function remaining)]
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The dosing rate adjustment factor is used to adjust the maintenance dose for a patient with altered renal function.### Pharmacokinetics and Renal Clearance
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The learning outcome of this chapter is to understand the relation between Clearance (CL) and Volume of distribution (V).
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CL can be calculated when the rate constant (kn) is 101/day and V is 100 L.
Mechanisms of Clearance
- Renal clearance is an important mechanism, accounting for 50% of drug elimination.
- Metabolism accounts for 33% of drug elimination, with 17% of the drug being eliminated through other routes.
Dosing Rate Adjustment for Renal Impairment
- The dosing rate adjustment factor can be calculated using the formula: (Fraction Eliminated metabolically) + [(Fraction eliminated renally) × (Fraction of normal renal function remaining)].
- For a drug with 33% metabolic elimination, 50% renal elimination, and 60% remaining renal function, the dosing rate adjustment factor would be: 0.33 + (0.5 × 0.6) + 0.17 = 0.8.
Significance of Renal Function in Dosing
- Renal function affects drug clearance, and dosing adjustments are necessary in cases of renal impairment.
- Kidney function is critical in drug elimination, and dosing rates must be adjusted accordingly.
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Description
This quiz covers the elimination and excretion of protein-bound drugs, including their clearance and kinetics.
