VF: Week 5 Pharmacokinetics excretion, clearance, and therapeutic index

What are the different routes of drug elimination?

Drugs can be eliminated in bile, feces, saliva, sweat, tears, milk, and expired air

How does lipid solubility and drug ionization affect kidney excretion?

The degree of lipid solubility and the extent of drug ionization influences how much of the drug is excreted by the kidney

What happens to drugs in the liver to facilitate kidney excretion?

Drugs undergo biotransformation in the liver, becoming water-soluble metabolites that can be excreted through the kidney

What percentage of cardiac output does the kidney receive?

The kidney receives 25% of cardiac output

What are the three mechanisms of renal drug excretion?

Glomerular filtration, active tubular secretion/reabsorption, and passive tubular reabsorption

What determines glomerular filtration of drugs?

The size of the molecule and its charge (lipophilicity) determine glomerular filtration. Protein-bound drugs are not filtered

Is glomerular filtration a unidirectional or bidirectional process?

Glomerular filtration is unidirectional, removing the drug from the blood by bulk flow

What factors does the rate of drug filtration depend on?

The rate of drug filtration depends on the extent of drug binding and the GFR (glomerular filtration rate)

Describe active tubular secretion.

Active tubular secretion is a saturable, carrier-mediated, and energy-dependent process

How are plasma protein-bound drugs secreted?

Plasma protein-bound drugs are secreted by tubular microvilli

Name three types of transporters found in the proximal tubule.

OAT (organic anion transporter), OCT (organic cation transporter), and P-gp (P-glycoprotein) are transporters in the proximal tubule

What happens to the elimination of acidic drugs in carnivores with acidic urine?

Carnivores with acidic urinary pH experience delayed elimination of drugs with low pKa/acidic drugs

What happens to the elimination of basic drugs in herbivores with alkaline urine?

Herbivores with alkaline urinary pH experience delayed elimination of drugs with high pKa/basic drugs

How does acidic or alkaline renal tubular fluid pH affect weak acid excretion?

Acidic pH decreases weak acid excretion, while alkaline pH increases it5

How does acidic or alkaline renal tubular fluid pH affect weak base excretion?

Acidic pH increases weak base excretion, while alkaline pH decreases it

What does total drug clearance depend on?

Total drug clearance depends on renal blood flow

What is the equation for total renal excretion of a drug?

Total renal excretion of drug = rate of filtration + secretion – reabsorption

What type of renal transport is utilized by unionized and lower molecular weight drugs in renal tubular fluid?

Passive tubular reabsorption

What is clearance in terms of clinical pharmacokinetics?

Systemic clearance of a drug is usually constant over the range of plasma concentrations

What order of kinetics do most drugs follow for elimination at therapeutic dosage?

First-order kinetics

What is drug half-life?

The time required to reduce the amount of a drug in the body by one-half during elimination

What happens in first-order kinetics?

A constant fraction of the drug is eliminated per unit of time

What happens in zero-order kinetics?

A constant amount of drug is eliminated per unit of time

What can cause half-lives of some drugs to be dose-dependent, resulting in zero-order kinetics?

Saturation of major metabolic pathways at therapeutic dosage

What is the relationship between half-life, volume of distribution (Vd), and systemic clearance (ClB)?

t½ = (0.693 * Vd) / ClB

What is the equation for whole-body clearance of drugs?

ClB = Cl hepatic + Cl renal + Cl other

How should you adjust the does of drugs in renal patients?

25% reduction

How should you adjust the does of drugs in liver patients?

50% reduction

Name three non-renal routes of excretion.

Bile, feces, exhaled air

How do drugs reach the intestines via the organ-specific blood flow and are expelled (by drug transporters) into the intestinal lumen?

Feces

What types of substances are eliminated through exhaled air?

Volatile anesthetic agents and essential oils

How does the pH of milk affect drug excretion?

Basic drugs are more ionized and accumulated in milk due to ion trapping

What kind of drugs permeates milk more easily?

Favors permeation of acidic compounds

What determines the shape of the plasma concentration-time curve?

Absorption, distribution, and elimination (biotransformation and excretion processes)

Name three factors that influence the plasma concentration of a drug.

Dose of the drug, formulation of the drug product, and route of administration

What are three significant terms associated with the plasma concentration-time curve?

Peak concentration (Cmax), peak time (tmax), and half-life (t½)

What is bioavailability?

The rate and extent to which a drug enters the systemic circulation unchanged

What is the bioavailability for the intravenous route?

100%

How do you calculate systemic bioavailability (F %)?

F % = (AUCpo x Dose iv) / (AUCiv x Dosepo)

How is clearance calculated?

Cl (ml/min) = (F X Dose) / AUC

What is clearance?

Pharmacokinetic measurement of the volume of plasma from which a substance is completely removed per unit time

What is the purpose of therapeutic concentration range?

A defined range of plasma concentration associated with a desirable intensity of the principal pharmacological (therapeutic) effect

What is the half-life (t½) of a drug?

The time required for the plasma concentration, as well as the amount of drug in the body, to decrease by 50 percent through the process of elimination

How is half-life calculated?

t½ = 0.693 / β, where β is the elimination rate constant of the drug

What happens to half-life in first-order kinetics?

Constant half-life

What happens to drug elimination rate in first-order kinetics?

The rate of drug elimination depends on the plasma concentration of the drug

What happens to half-life in zero-order kinetics?

Half-life depends on the plasma drug concentration

What is steady-state concentration (Css)?

When the amount of a drug being absorbed is the same amount being cleared from the body when the drug is given continuously or repeatedly

How many half-lives does it take to reach around 97% of steady-state concentration?

Approximately four to five times the half-life

How is therapeutic index calculated?

Therapeutic index = LD50/ED5

What is the main excretory organ in drug elimination?

Kidney

Which type of drugs are excreted via glomerular filtration?

Unbound, water-soluble, small molecules.

What is the significance of drug ionization in renal excretion?

Ionized drugs are less likely to be reabsorbed and more likely to be excreted.

What happens to highly protein-bound drugs in hypoalbuminemia?

Increased free drug levels, leading to a higher risk of toxicity.

How does acidic urinary pH affect weak acid drug excretion?

Weak acids are reabsorbed, reducing excretion.

How does alkaline urinary pH affect weak base drug excretion?

Weak bases are reabsorbed, reducing excretion.

What does renal clearance measure?

The volume of plasma cleared of a drug per unit time.

How is total renal drug excretion calculated?

Filtration + Secretion - Reabsorption.

What kind of drug undergoes passive tubular reabsorption?

Non-ionized, lipophilic drugs.

What kind of drug undergoes active tubular secretion?

Ionized drugs that require transporters.

How does dehydration affect drug elimination?

Reduced renal blood flow slows drug elimination.

What does systemic clearance (ClB) include?

Hepatic, renal, and other clearances.

Name a drug that follows zero-order kinetics at therapeutic doses.

Salicylate in cats.

How do liver and kidney disease affect drug clearance?

Liver disease requires a 50% dose reduction, kidney disease requires a 25% reduction.

What does a high therapeutic index indicate?

A safer drug.

What is steady-state concentration (Css)?

The drug concentration where absorption equals elimination.

What is a loading dose?

A large initial dose to reach steady-state concentration faster.

What influences the plasma concentration-time curve?

Drug dose, formulation, route of administration, elimination rate.

What is Cmax?

The peak drug concentration in plasma.

What is Tmax?

The time to reach peak plasma concentration.

What does AUC (area under the curve) represent?

The total drug exposure over time.

How does renal function affect drug elimination?

Decreased renal function reduces drug clearance.

What is the effect of glomerular filtration rate (GFR) on drug elimination?

Higher GFR increases drug elimination.

How does protein binding affect drug filtration?

Highly protein-bound drugs are not filtered.

What type of drugs accumulate in milk?

Basic drugs (ion trapping).

What is the impact of mastitis on drug excretion in milk?

Increased pH favors weak acid drugs in milk.

Why do cats have a longer half-life for some drugs?

They have deficient glucuronidation pathways.

What factor affects the enterohepatic circulation of drugs?

Biliary excretion and reabsorption.

What is the primary determinant of drug excretion via the bile?

Molecular weight and polarity.

What is ion trapping?

Drug accumulation in body compartments with different pH.

What is the relationship between drug clearance and volume of distribution (Vd)?

Clearance and Vd determine drug half-life.

What is the effect of increased renal blood flow on drug clearance?

It increases clearance.

How do lipophilic drugs get eliminated?

Through metabolism into water-soluble metabolites.

What is the significance of the plasma concentration-time curve?

It helps determine drug dosing regimens.

How does renal tubular fluid pH affect weak acid drug excretion?

Acidic pH reduces excretion, alkaline pH increases excretion.

What factor influences first-pass metabolism?

Route of administration (oral drugs undergo first-pass metabolism).

What is the impact of dose-dependent kinetics?

Drug elimination changes from first-order to zero-order at high doses.