Pharmacology Chapter: Drug Distribution & Elimination

Drug Distribution

• The process of a drug moving reversibly from the bloodstream into the extracelluar and/or intracellular fluids of tissues.
• This process is dependent on blood flow.
• Well perfused tissues (e.g., lungs, kidneys, liver, heart, brain, intestines) reach equilibrium with drugs quickly.
• Less perfused tissues (e.g., peripheral organs, skeletal muscle, skin, connective tissue, fat) have a slower equilibration time.
• Capillary structure is important for drug distribution.
• Hydrophobic drugs easily cross most membranes, while hydrophilic drugs do not.
• Protein binding (albumin and α1-acid glycoprotein) lowers the concentration of free drug.
• Bound drugs are pharmacologically inactive.

Drug Elimination

• The body eliminates drugs primarily through the kidneys (renal excretion), liver (biliary excretion), lungs (pulmonary excretion), sweat (skin), and milk (mammary).
• Renal Excretion: involves glomerular filtration, active tubular secretion, and reabsorption.
  • Glomerular filtration: Molecules less than 20 kDa are filtered. Protein-bound drugs are not filtered (albumin 68 kDa).
  • Tubular secretion: Active carrier-mediated elimination of both acidic and basic compounds. Can transport against electrochemical gradient and when drug is protein bound.
  • Reabsorption: Passive diffusion back across tubular epithelium. Lipid soluble drugs are excreted slowly.
• Biliary excretion: Lipid-soluble drug uptake, metabolism, and excretion into bile. Reabsorption in the small intestine can occur, resulting in enterohepatic circulation.
• Pulmonary excretion: Volatile molecules (e.g., anaesthetics, ethanol) are excreted via the lungs and breath.
• Skin: Drugs are secreted in sweat by passive diffusion.
• Milk: Drug concentration in milk generally reflects free concentration in blood.

Elimination Kinetics

• First-order kinetics:
  • The rate of elimination is proportional to the amount of drug present.
  • Characterized by a constant fraction of drug eliminated per unit of time.
  • Example: glomerular filtration.
• Zero-order kinetics:
  • Elimination occurs at a fixed maximum rate, independent of drug concentration.
  • Example: protein-mediated reactions (ethanol metabolism).

Half-life

• Half-life (t1/2) is the time it takes for the plasma concentration of a drug to decrease by 50%.
• It is a characteristic of the drug and the elimination process.
• It is independent of dose.
• It determines the time it takes to reach steady-state and the time required for elimination.
• A long half-life means the drug is cleared more slowly from the body.
• Steady-state is reached when the rate of drug administration equals the rate of drug elimination.
• To achieve steady-state, it takes approximately 3-5 half-lives.

Apparent Volume of Distribution (Vd)

• Represents the theoretical volume of fluid in which a drug would distribute to produce the observed plasma concentration.
• Not a real volume, it reflects the extent of drug distribution into tissues.
• A high Vd signifies that the drug is extensively distributed in the tissues, meaning only a small portion resides within the plasma.
• This can affect the half-life of the drug, leading to slower elimination.

Liver in Drug Metabolism

• Plays a significant role in drug metabolism.
• The liver contains enzymes that can transform drugs into more polar, water-soluble metabolites.
• Makes drugs easier to excrete from the body, mainly via the kidneys or bile.
• Many drugs undergo metabolism in the liver, which alters their pharmacological activity and duration of action.

Drug Distribution

• Drug distribution: The reversible movement of a drug from the bloodstream into extracellular fluid and/or cells of the tissue (intracellular fluid).
• Blood Flow: Well-perfused tissues (lungs, kidneys, liver, heart, brain, intestines) equilibrate rapidly with drugs; less perfused tissues (peripheral organs, skeletal muscle, skin, connective tissue, fat) equilibrate more slowly.
• Capillary Permeability: The 'blood-brain barrier' restricts drug entry due to tight junctions between endothelial cells, reduced pores, and a layer of astrocytes. Hydrophobic drugs easily cross membranes.
• Protein Binding: Reversible association of drugs with plasma proteins like albumin (acidic and neutral drugs) and α1-acid glycoprotein (basic drugs). Protein binding lowers the concentration of free drug, which is pharmacologically active.
• Altered Protein Binding: Reduced protein binding can occur in hypoalbuminemia (liver disease), uraemia (kidney damage), and aging. Displacement from binding sites can occur due to competition, such as when aspirin displaces warfarin.

Volume of Distribution (Vd)

• Vd Definition: A theoretical volume that reflects the drug's distribution into tissues relative to plasma. It is NOT a real volume but a ratio.
• Significance: Vd determines the relationship between plasma concentration and total drug in the body, as well as the dose required to achieve a specific plasma concentration.
• Calculation: Vd = (Total amount of drug in body) / (Plasma concentration)

Drug Elimination

• First-order Kinetics: Elimination rate is proportional to the drug concentration (a constant fraction of the drug is eliminated per unit time).
• Zero-order Kinetics: Elimination occurs at a constant rate, regardless of drug concentration.
• Plasma Half-life (t1/2): Time for plasma concentration to decrease by 50%. Independent of the dose and characteristic for a specific drug.
• Steady-state: Equilibrium reached when the rate of drug administration equals the rate of drug elimination. Aim to maintain steady-state concentration within the therapeutic range.

Drug Elimination Routes

• Kidney: Drugs eliminated via glomerular filtration, tubular secretion, or reabsorption.
• Liver: Primary site for drug metabolism.
• Lungs: Important for volatile gas elimination (e.g., anesthesia).
• Skin: Drugs secreted into sweat via passive diffusion (depending on plasma/sweat partition).
• Mammary Gland: Milk concentration reflects free drug concentration in blood.
  • Clinical relevance: Tetracyclines can cause tooth problems; chloramphenicol can cause bone marrow toxicity and 'grey baby syndrome' in babies.

Half-life (t1/2) and Steady State

• Half-life Determining Factors: Activity of metabolizing enzymes and excretion mechanisms (clearance), and drug distribution between blood and tissues (high Vd prolongs t1/2).
• Time to Steady State: Generally takes 3-5 half-lives after starting constant IV infusion or regular oral dosing.

Drug distribution - altered protein binding

• Hypoalbuminaemia (low albumin) can occur in liver disease
• Excess urea in blood from kidney damage (uraemia) can affect drug binding sites
• Lower protein-binding capacity in foetuses, neonates, and elderly patients

Competition example

• Highly protein-bound drugs (aspirin) can displace other drugs, like warfarin (anticoagulant), from protein binding sites
• Warfarin is ~98% protein bound, so only a small fraction (0.1 mg) is free to work from a 5 mg dose.
• Aspirin competes for binding sites and can displace warfarin, increasing its free concentration.

Apparent volume of distribution (Vd)

• Represents the theoretical volume a drug would occupy if it was evenly distributed in the body at the same concentration as in the plasma.
• Not a real physical volume but indicates the ratio of drug in extravascular space versus plasma space.
• Higher Vd indicates a greater tendency of the drug to move out of the plasma into other tissues.

Calculation of volume of distribution (Vd)

• Formula for Vd: Total amount of drug in the body / Plasma concentration.
• Can also be calculated by dividing the dose by the plasma concentration at time zero.

Renal Drug Excretion

• Three main processes:
  • Glomerular filtration: Filters molecules smaller than 20 kDa, protein-bound drugs are not filtered.
  • Tubular secretion: Active carrier-mediated elimination, transporting drugs against electrochemical gradients.
  • Reabsorption: Passive diffusion of lipid-soluble drugs back across the tubular epithelium, leading to slower excretion.

Biliary Excretion

• Hepatocytes take up lipid-soluble drugs, metabolize them, and excrete them into bile.
• Drugs can be reabsorbed in the small intestine, leading to inefficient excretion.
• Efficient biliary excretion requires a high molecular weight (MW > 500 Da).
• Drug conjugation with glucuronide or sulphate can increase MW for efficient excretion.

Enterohepatic Circulation

• Drug conjugates are hydrolysed by bacteria in the lower intestine, releasing active drug.
• Free drug is reabsorbed, creating a reservoir of recirculating drugs, which prolongs their action.

Pulmonary Excretion

• Volatile molecules are excreted via the lungs, e.g., anaesthetics, ethanol.

Other Excretion Routes

• Sweat: Drugs secreted into sweat by passive diffusion, depends on plasma/sweat partition.
• Milk: Drug concentration in milk reflects free concentration in blood.

Rates of Reaction (Elimination)

• First-Order Kinetics: rate of elimination proportional to the amount of drug present. Non-saturating kinetics.
• Zero-Order Kinetics: elimination occurs at a fixed maximum rate, independent of drug concentration. Saturation kinetics.

Plasma half-life (t1/2)

• Time for plasma concentration to fall by 50%.
• Determined by:
  • Activity of metabolising enzymes or excretion mechanisms
  • Distribution of drug between blood and tissues
• Clinical relevance:
  • Time it takes for a drug to reach a steady-state.
  • Time it takes for a drug to be eliminated from the body.

Steady-State

• When the rate of drug administration equals the rate of drug elimination.
• Goal of drug therapy is to maintain a steady-state concentration within the therapeutic range.

Explore the key concepts of drug distribution and elimination in this quiz. Understand how blood flow and tissue perfusion influence drug movement and the processes involved in drug excretion from the body. Test your knowledge on the factors affecting these critical pharmacological processes.