Pharmacokinetics Overview

Pharmacokinetics: The Dynamics of Drug Absorption, Distribution, Metabolism, and Elimination

• The human body restricts access to foreign substances. A drug must cross multiple barriers to reach its target site. Steps include absorption, distribution, surviving metabolism and elimination.
• ADME (Absorption, Distribution, Metabolism, Elimination) are the processes of pharmacokinetics. Understanding these processes increases the likelihood of successful therapy and reduces adverse drug events.
• Drug passage across membranes involves factors like molecular size, ionization state, lipid solubility, and binding to serum/tissue proteins.
• The plasma membrane is selectively permeable, composed of a lipid bilayer with embedded proteins. Proteins act as structural anchors, receptors, ion channels, or transporters.
• Passive diffusion is the primary mode of drug transport across membranes, driven by a concentration gradient.
• Carrier-mediated mechanisms (active transport and facilitated diffusion) also play a role in drug transport.
• Ion trapping is an important aspect of drug distribution: acidic drugs accumulate on basic sides; basic drugs accumulate on acidic sides.
• Ionizable drugs include carboxylic acids and amino groups (primary, secondary, tertiary).
• pH influences the absorption of ionizable drugs.
• Oral ingestion is the most common drug administration route but has limitations.
• Oral administration often requires crossing the GI tract and undergoing metabolic processes in the liver.
• Other routes of administration, like intravenous, subcutaneous, intramuscular, and topical routes, have different advantages and limitations.
• Intravenous administration bypasses the first-pass effect.
• Sublingual drugs avoid the first-pass metabolism and reach the systemic circulation quickly.
• Rate of absorption can affect the therapeutic effect of a drug, depending upon whether it's a single or repeated dose.
• Controlled-release preparations provide a sustained rate of absorption.
• The volume of distribution (V) relates the amount of drug in the body to its concentration in the blood.
• Clearance (CL) signifies the volume of body fluid cleared of drug per unit of time. CL is used for calculating dosing regimens.
• Half-life (t1/2) is the time taken for plasma concentration of a drug to reduce by 50%.
• Hepatic clearance is a significant route for drugs with high clearance and extraction ratios.
• Renal clearance depends on filtration, active secretion, and passive reabsorption. Renal excretion is a major route.
• Biliary and fecal excretion eliminate drugs that have undergone metabolism.
• Many drugs are bound to plasma proteins like albumin and a₁-acid glycoprotein, which affects tissue distribution, elimination, and clearance.
• Many drugs accumulate in tissues, acting as reservoirs for drug action.
• The blood-brain barrier (BBB) and blood-CSF barrier limit drug penetration into the central nervous system (CNS). Lipid solubility influences drug penetration into the CNS.
• Placental transfer of drugs is influenced by factors such as lipid solubility, molecular size, and degree of ionization.

Clinical Pharmacokinetics

• Clinical pharmacokinetics relates drug concentrations to pharmacological effects.
• Drugs with narrow therapeutic windows require careful monitoring and adjustment of dosage.
• Important parameters governing drug disposition include bioavailability, volume of distribution, clearance, and elimination half-life.
• Non-linear pharmacokinetics occurs when clearance, volume of distribution, or half-life change in response to dose or concentration. Saturation of binding sites, metabolism, or active transport can cause nonlinearity.

Therapeutic Drug Monitoring

• Therapeutic drug monitoring helps optimize therapy by measuring drug concentrations in biological fluids.
• Target steady-state concentrations minimize toxicity and maximize therapeutic efficacy.
• Loading doses accelerate attainment of target steady-state concentrations.
• Maintenance doses sustain the therapeutic window.
• Repeated dosing leads to steady-state concentrations.