Pharmacology Drug Absorption and Bioavailability

Overview of ADME

• ADME stands for absorption, distribution, metabolism, and excretion
• Pharmacology is the study of substances that interact with living systems
• Drugs affect biologic function
• Pharmacokinetics (PK) describes how the body absorbs, distributes, metabolizes, and eliminates drugs
• Pharmacodynamics (PD) is the action and effects of bioactive substances on living organisms

Objectives

• Relate dose-response curve to therapeutic index
• Compare and contrast effects of drug administration routes on onset, intensity and duration
• Describe first-pass effect and its impact on bioavailability
• Describe factors influencing drug absorption
• Describe factors influencing drug distribution
• Describe the pharmacokinetic consequences of drug metabolism
• Identify major enzymatic reactions in phases I and II drug metabolism
• Explain the roles of filtration, secretion, and reabsorption in renal drug excretion
• Predict drug excretion routes based on drug properties
• Describe relationships between drug elimination and steady-state drug concentrations

Key Terms

• Pharmacology: Study of substances with living systems through chemical processes, especially binding to regulatory molecules
• Drug: Substance that changes biological function
• Pharmacokinetics (PK): Process of drug absorption, distribution, metabolism, and elimination within the body
• Pharmacodynamics (PD): Action and effects of bioactive substances on living organisms
• Absorption: Process of a substance entering blood circulation
• Distribution: Dispersion of a substance throughout the body's fluids and tissues
• Metabolism: Transformation of a substance into other substances
• Excretion: Removal of substances from the body

Absorption, Distribution, Metabolism & Excretion

• Absorption: Process of drugs entering the bloodstream from the site of administration
• Distribution: Dispersion of drugs throughout various tissues and fluids
• Metabolism: Transformation of drugs into other substances
• Excretion: Removal of drugs or metabolites from the body

The Core of ADME

• Active drug must reach the target receptor at sufficient levels and for an adequate duration to modify biological response
• Biological response to drugs varies between individuals
• Understanding pharmacokinetics and pharmacodynamics is vital for adjusting dosages and selecting appropriate drugs
• Drug toxicity is also related to ADME

Dose-Response Curve

• Shows relationship between drug dose and response
• A minimum dose is needed for a significant response
• Response increases with dose until a maximum effect is reached
• Variability and slope illustrate the range and speed of response changes with increasing doses

Therapeutic Index

• Range of doses creating an effective medication without unacceptable adverse events
• Determined from quantal dose-response curves
• Therapeutic window is the clinically useful range between the minimum effective and minimum toxic doses

First-Pass Metabolism

• Drugs absorbed via the GI tract are metabolized to a varying degree in the liver before reaching systemic circulation
• First-pass effect significantly reduces bioavailability for certain drugs

Distribution

• The movement of drugs from the bloodstream to different body compartments. Factors affecting distribution include tissue permeability, blood flow, and binding to plasma proteins.

Protein Binding

• Albumin, β-globulin, and α-acid glycoprotein bind drugs and play a crucial role in drug distribution and activity within the body
• Drugs bound to proteins are inactive

Apparent Volume of Distribution (Vd)

• A measure of the volume of body fluid in which a drug is distributed
• Vd can be greater than the actual physical body volume

Metabolism

• The body's transformation of the drug through chemical reactions
• Metabolism can lead to the formation of inactive or active metabolites, which may have varying degrees of activity compared to the parent drug
• Metabolism can alter the pharmacokinetic properties of a drug

Phase I Metabolism

• Adds chemical groups to drug molecules to make them more water-soluble for excretion
• Includes oxidation, reduction, hydrolysis, etc
• Enzymes catalyze these reactions

Phase II Metabolism

• Involves conjugation reactions with endogenous molecules
• These molecules enhance water solubility and facilitate excretion

Renal vs Biliary Excretion

• Renal excretion is the removal of drugs via urine routes
• Biliary excretion refers to removing drugs via bile into the feces
• Glomerular filtration, active secretion, and passive reabsorption are critical to renal excretion
• Diffusion and active secretion are important in hepatic excretion

Renal Drug Excretion

• Kidney excretes many drugs either unchanged or as metabolites.
• Three key transport mechanisms (glomerular filtration, tubular secretion, and tubular reabsorption) regulate renal excretion

Kidney, Nephron and Glomerular Filtration

• The kidney is the primary organ for renal excretion
• The nephron is the functional unit of the kidney
• Glomerular filtration is the non-selective process of removing small molecules, including drugs, from the bloodstream into the nephron

Tubular Secretion

• Active transport process for large and ionized molecules for high urine concentrations.
• Specific transport systems such as carriers play a significant role in the process

Tubular Reabsorption

• Passive diffusion is the process of small, neutral, and lipophilic molecules moving from the urine back into the blood

Biliary Drug Excretion

• Drugs enter hepatocytes where they are secreted into bile
• Factors like conjugation, molecular size influence biliary excretion
• 5% of drugs are excreted in bile; however, active secretion can raise this to nearly 95%.

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