Pharmacokinetics Overview Quiz

Course Information

• Course name: PHARM 225
• Instructor: Dr. Amira Badr
• Email: [email protected]

Objectives

• Students will be able to identify pharmacokinetics.
• Students will be able to define absorption.
• Students will be able to analyze factors affecting absorption.
• Students will be able to identify drug movement mechanisms across membranes.
• Students will be able to define bioavailability.

Relationship Between Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics: the time course of drug absorption, distribution, metabolism, and excretion.
• Primary goals of pharmacokinetics; enhance efficacy and decrease toxicity.
• Pharmacodynamics: relationship between drug concentration at the site of action and resulting effect.

Pharmacokinetics Principle

• In practical therapeutics, a drug must reach its intended site of action at a sufficient concentration.
• Prodrugs are drug derivatives that require enzymatic or chemical transformation to release the active parent drug.
• Prodrugs are used to improve physicochemical or pharmacokinetic properties of pharmacological compounds.

Pharmacokinetics

• Absorption: movement of an unchanged drug from administration site to systemic circulation to reach site of action.
• Distribution: transfer of the drug from one location to another within the body.
• Metabolism: process in which drugs are altered and broken down into smaller substances (metabolites).
• Elimination (Excretion): removal of drug from body fluids (e.g., urine, bile, sweat, saliva, tears, feces, breast milk).

Pharmacokinetics (Absorption)

• Movement of Drugs: Regardless of the administration route (except IV), drugs must pass through multiple biological membranes to reach site of action.
• Bilayer of amphipathic lipids: forms a barrier in biological membranes.
• Factors Affecting Absorption:
  • Molecular size
  • Polarity
  • Partition coefficient
  • pH at administration site
  • Blood flow
  • Surface area
  • Drug stability
  • Drug formulation
  • Contact time (e.g., gastric emptying rate)

Properties of Drugs (Absorption)

• Absorption rate depends on drug lipid solubility and particle size.
• Polarity estimates the partition coefficient (ratio of drug solubility in lipids to water).
• Higher lipid solubility means faster absorption.
• Smaller molecules are absorbed more rapidly.
• The membranes of biological membranes are very permeable to O2, CO2, N2O and H2O.
• Large polar molecules (e.g., sugars, amino acids, phosphorylated intermediates) have poor permeability and require carrier proteins.

Movement of Substances Across Cell Membranes

• Gases (e.g., O2, CO2)
• Hydrophobic molecules
• Small polar molecules (e.g., H2O)
• Large polar molecules
• Charged molecules (e.g., ions)

Pharmacokinetics (Absorption)

• Many drugs (weak acids or bases) ionization varies with pH (Henderson-Hasselbalch equation).
• Only uncharged (unionized) species can diffuse across lipid membranes.

Movement of Substances Across Cell Membranes (Passive Transfer)

• Passive transfer: No energy, non-saturable
• Filtration: Hydrodynamic pressure gradients, low MW, water-soluble
• Simple diffusion: Higher concentration to lower concentration. Lipid-soluble
• Factors Determining Passive Transfer Rate
  • Membrane permeability
    • Concentration gradient
  • Molecular size
  • Lipid solubility

Specialized Transport

• Facilitated diffusion: higher concentration to lower concentration, no energy, saturable (protein carrier-mediated).
  • Example: tetracycline
• Active transport: against concentration gradient, needs energy, saturable (protein carrier-mediated).
  • Example: levodopa, 5-fluoro-uracil, 5-bromouracil
• Endocytosis: engulfing large molecules (e.g., proteins, toxins).
  • Example: botulinum and diphtheria

Passive Diffusion

• Also known as non-ionic diffusion.
• Depends on the concentration difference across the membrane
• Absorption of 90% of drugs.
• Driving force is the concentration gradient or electrochemical gradient
• Water, urea, and small lipids move by concentration gradient

Carrier-Mediated Transport Mechanism

• Involves a carrier protein that reversibly binds solute molecules.
  • Carrier-solute complex crosses the membrane.
  • Solute released, carrier returns to original position to accept new solute molecules.
• Two types: facilitated diffusion (no energy, with the concentration gradient) and active transport (energy required, against the concentration gradient).

Facilitated Diffusion

• This mechanism's driving force is the concentration gradient (downhill transport).
• In this system, no energy is involved.
• It is not inhibited by metabolic poisons that interfere with energy production.
• Example: fructose

Active Transport

• More important than facilitated diffusion.
• Driving force is against the concentration gradient (uphill transport).
• Energy (ATP) is required for the process.
• Inhibited by metabolic poisons that interfere with energy production.
• Example of substances transported: Minerals, sugars, and amino acids

Drug Absorption, Active vs. Passive

• Active transport: Energy-dependent, carrier-mediated, against concentration gradient, shows carrier saturation kinetics.
• Passive transport: Energy-independent, no carrier involved, along the concentration gradient, no saturation kinetics.

Pinocytosis (Endocytosis)

• This process is important in the absorption of oil-soluble vitamins and nutrients.
• Absorption mechanism that takes in fluids and particles.

Other Factors Affecting GIT Absorption

• Blood flow to absorptive site: greater blood flow increases absorption.
• Total surface area of absorptive site: larger surface area increases absorption.
• Contact time at absorptive site: faster gastric emptying increases absorption, while diarrhea reduces it.
• Food presence: reduces/delays drug absorption.
• Formulation factors: solid dosage forms require dissolution and solubility, aqueous solutions are absorbed quicker.

Factors Affecting GIT Absorption (Stomach)

• Small surface area for drug absorption due to lack of villi and microvilli.
• Variation in gastric emptying time affects drug absorption.
• Acid-labile drugs must not come into contact with the stomach's acidic environment.

Factors Affecting GIT Absorption (Intestine)

• Large surface area for drug absorption due to villi and microvilli.
• 7 meters long, approximately 2.5-3 cm in diameter.
• High blood flow compared to the stomach.
• pH range (5-7.5) is favorable for most drugs to remain unionized.
• Slow peristaltic movement and long transit time.
• High permeability.

Factors Affecting GIT Absorption (Large Intestine)

• Major function is to absorb water, and eliminate semi-solid feces.
• Few drugs are absorbed in this region.

Bioavailability

• Fraction of drug reaching systemic circulation unchanged after a specific route of administration.
  • (Amount of drug administered/ amount of drug reaching systemic circulation) * 100
  • IV administration gives 100% bioavailability
• First-pass effect: hepatic metabolism of drug when it's absorbed from the gut and delivered to the liver via portal circulation.
• The stronger the first pass effect, the less amount of drug that will be in systemic circulation.

Pharmacokinetics (Absorption) (Bioavailability)

• Bioavailability depends on:
  • The amount of drug absorbed from a given dosage form that reaches systemic circulation
    • First-pass effect: affected by hepatic metabolism when a drug is absorbed from the gut, and delivered to the liver via the portal circulation..
    • The greater the first pass Effect, the lower the bioavailability.

Concentration Level, Rate of Absorption

• Not only the magnitude, but also the rate of absorption, is crucial for therapeutic success.

Medicine Administration

• Different administration routes (e.g., inhaled, oral, intravenous, intramuscular, topical, rectal).

Pharmacokinetics (Distribution)

• Distribution: Movement of drugs to the sites of action through blood vessels, from the administration site after absorption.
  • Factors Affecting Distribution:
    • Blood flow
    • Capillary permeability
    • Blood brain barrier
    • Placental barrier
    • Drug structure
    • Binding to plasma proteins & tissue proteins
    • Affinity to certain organs

Capillary Permeability

• Endothelial cells in tissues other than the brain have wide slit junctions allowing easy drug movement.
• Brain capillaries have tight junctions, thus drugs must be lipophilic or carrier-mediated to enter the CNS.

Volume of Distribution

• Relates the amount of drug in the body to the drug's blood/plasma concentration.
• Helps determine the loading dose needed to reach the target plasma concentration.
  • Vd= Amount of drug in the body/ Plasma Concentration.
  • Loading dose = Vd x C (plasma concentration)

Test your knowledge on the fundamental concepts of pharmacokinetics. This quiz covers topics such as drug absorption, bioavailability, drug movement mechanisms, and the characteristics that affect a drug's efficacy. Challenge yourself to understand how drugs interact within the body!