Introduction to Medical Pharmacology
Module 2 — Pharmacokinetics: How the Body Handles Drugs
Chapter 1 · Module 2 of 6Section 1
How a drug moves from its site of administration into the bloodstream, and why not all of it makes it there
Absorption is the process by which a drug moves from its site of administration into the systemic circulation. The fraction of an administered dose that reaches the bloodstream in active form is called bioavailability. Understanding absorption explains why the same drug can behave very differently depending on how it is given.
Most small-molecule drugs cross biological membranes by passive diffusion — moving down a concentration gradient from a region of high concentration to one of low concentration. The ability of a drug to diffuse across a lipid membrane depends largely on its lipophilicity: lipophilic (fat-soluble) drugs cross membranes readily, while highly hydrophilic (water-soluble) drugs cross poorly and may require specialized transporters. Most drugs are weak acids or weak bases, and only the un-ionized (electrically neutral) form of a drug is lipophilic enough to cross membranes by diffusion. The degree of ionization depends on the drug’s chemistry and the pH of the surrounding fluid, which is why the same drug may be well absorbed in one compartment of the body and poorly absorbed in another.
When a drug is taken orally and absorbed from the gastrointestinal tract, it does not go directly into the general circulation. Instead, it is carried through the portal vein to the liver before reaching the rest of the body. The liver contains a high concentration of drug-metabolizing enzymes, and for some drugs a substantial fraction of the absorbed dose is chemically altered by these enzymes before it ever reaches the systemic circulation. This process is called the first-pass effect, and it is why oral bioavailability is often much lower than 100 percent.
The practical consequence is significant. A drug that is almost completely inactivated by first-pass metabolism cannot be given orally at a standard dose — the amount reaching the target organs would be therapeutically insignificant. Nitroglycerin is the classic example: its first-pass metabolism is so extensive that it is given sublingually or transdermally rather than orally, bypassing the liver entirely. Other drugs simply require much higher oral doses than intravenous doses to achieve the same systemic effect, because the oral dose must compensate for what the liver removes.
Bioavailability in Clinical Terms
Bioavailability of 100 percent means all of the dose reaches systemic circulation — only intravenous administration guarantees this. Oral bioavailability is always less than 100 percent, sometimes dramatically so. When a drug is switched from intravenous to oral administration, the oral dose must be adjusted upward to account for its bioavailability. Ignoring this adjustment is a source of clinically significant dosing errors.
Section 2
How a drug spreads from the bloodstream into tissues, and what determines how widely it distributes
After a drug enters the systemic circulation, it distributes between the blood and the tissues of the body. How extensively a drug distributes — whether it stays largely in the bloodstream or penetrates deeply into organs and fat — has major consequences for its dosing, duration of action, and clinical behavior.
The volume of distribution is a pharmacokinetic concept that describes how widely a drug distributes throughout the body relative to its concentration in the plasma. A drug with a small volume of distribution remains largely within the bloodstream and does not penetrate tissues extensively. A drug with a large volume of distribution distributes broadly into tissues, so that the concentration remaining in plasma is low relative to the total amount of drug in the body.
The volume of distribution is not a real anatomical volume — it is a mathematical expression of where the drug has gone. Highly lipophilic drugs accumulate in fat tissue and can have volumes of distribution far larger than the total volume of the human body, because so little of the drug remains in plasma that the calculation yields an enormous apparent number. This has direct clinical implications: drugs with very large volumes of distribution cannot be efficiently removed from the body by dialysis, because most of the drug is in tissues rather than in the blood being filtered.
Most drugs bind reversibly to proteins in the plasma, primarily albumin. Only the unbound (free) fraction of a drug is pharmacologically active: only free drug can cross membranes, reach its target receptor, and be metabolized or eliminated. The protein-bound fraction acts as a reservoir — as free drug is removed from circulation by metabolism or elimination, drug dissociates from protein and replenishes the free pool.
Plasma protein binding becomes clinically relevant when a patient has low albumin levels, as occurs in malnutrition, liver disease, or critical illness. For a highly protein-bound drug, a drop in albumin concentration can significantly increase the free fraction, producing a stronger drug effect at the same total plasma concentration. This is one reason why standard therapeutic drug monitoring ranges, which measure total drug concentration, can be misleading in patients with hypoalbuminemia.
The brain is protected by a specialized barrier formed by the endothelial cells lining its capillaries, which are connected by unusually tight junctions that prevent most substances from passing freely from blood into brain tissue. For a drug to reach the central nervous system, it generally needs to be lipophilic, have a relatively small molecular size, and not be a substrate for the efflux transporters that actively pump substances back out of brain endothelial cells. This is why drugs intended to act in the brain are designed to be lipophilic, and why drugs intended for peripheral targets are sometimes engineered to be excluded from the central nervous system to avoid central adverse effects.
Section 3
How the body chemically transforms drugs, primarily in the liver, to prepare them for elimination
Drug metabolism is the chemical modification of a drug by the body’s enzyme systems. The liver is the primary site of drug metabolism, though the intestinal wall, lungs, and kidneys also contribute. The goal of metabolism is usually to convert a lipophilic drug molecule into a more water-soluble form that can be excreted in urine or bile.
Phase I reactions chemically modify the drug molecule by introducing or exposing a polar chemical group. The most common phase I reactions are oxidations, though reductions and hydrolysis also occur. The cytochrome P450 enzyme system, located primarily in liver cells, carries out the majority of phase I oxidative reactions. Phase I metabolism often reduces pharmacological activity, but not always: some drugs are converted by phase I reactions into active metabolites that contribute to or even carry the drug’s therapeutic effect.
Phase II reactions attach an endogenous molecule — such as glucuronic acid, sulfate, or an acetyl group — to the drug or to its phase I metabolite in a process called conjugation. The resulting conjugate is typically highly water-soluble, pharmacologically inactive, and readily excreted by the kidneys into urine or by the liver into bile. Phase II reactions complete the conversion of a lipophilic drug into a form the body can efficiently eliminate.
A prodrug is a pharmacologically inactive compound that is converted by metabolic reactions into an active drug within the body. Prodrugs are designed deliberately to take advantage of metabolism: they may improve oral absorption, mask an unpleasant taste, increase tissue selectivity, or circumvent the first-pass effect by being designed to activate only after reaching the target tissue. Enalapril, for example, is a prodrug that is converted by esterases in the liver and intestinal wall into its active form, enalaprilat, the actual angiotensin-converting enzyme inhibitor. Recognizing a drug as a prodrug matters clinically: patients with severe hepatic impairment may fail to activate prodrugs, and the drug may appear ineffective despite adequate absorption.
Metabolism Does Not Always Mean Inactivation
A common misconception is that drug metabolism always produces inactive products. In reality, some drugs are activated by metabolism (prodrugs), some produce active metabolites that contribute substantially to the drug’s effect (morphine-6-glucuronide from morphine), and some produce toxic metabolites that are responsible for organ damage at high doses (acetaminophen). Understanding the metabolic fate of a drug is essential for predicting its efficacy and toxicity, especially in patients with altered liver function.
Section 4
How the body removes drugs, and the concept of half-life that governs dosing frequency and time to steady state
Elimination is the irreversible removal of drug from the body. The two primary routes are renal excretion into urine and biliary excretion into bile. The rate of elimination determines how long a drug remains active and how frequently it needs to be dosed.
The kidney eliminates drugs and their water-soluble metabolites into urine. Drug molecules are filtered at the glomerulus, may be actively secreted into the tubular fluid, and may also be reabsorbed back into the blood from the tubule. The net result determines how much drug appears in the urine. Drugs that are primarily eliminated by the kidney accumulate in patients with reduced kidney function, because the same dose is cleared more slowly. Dose reduction or extended dosing intervals are required for renally cleared drugs in patients with kidney impairment — failure to adjust can result in drug accumulation and toxicity.
The elimination half-life is the time required for the plasma concentration of a drug to fall by 50 percent. It is the most practically useful pharmacokinetic parameter for dosing decisions. A drug with a short half-life must be dosed frequently to maintain therapeutic plasma concentrations; a drug with a long half-life can be dosed once daily or even less frequently, but also takes longer to leave the body after it is stopped.
Half-life depends on two properties of the drug: how widely it distributes through the body and how efficiently the body can clear it from plasma. A drug that distributes extensively into tissues has a longer half-life because it takes longer to remove — the tissues act as a reservoir that continuously replenishes the plasma as the plasma is cleared. A drug that is cleared very efficiently has a shorter half-life.
When a drug is given at regular intervals, plasma concentrations build up over successive doses until the amount eliminated between doses equals the amount taken in each dose. At this point the average plasma concentration no longer rises — the drug has reached steady state. For most drugs given at regular intervals, steady state is reached after approximately four to five half-lives, regardless of the dose or dosing interval. This is a clinically useful rule: a drug with a 12-hour half-life reaches steady state in roughly two to three days, while a drug with a half-life of several weeks may take months to stabilize. Loading doses are given when steady state must be achieved more rapidly than waiting four to five half-lives would permit.
Section 5
How the four pharmacokinetic processes translate into practical dosing decisions at the bedside
Pharmacokinetics is not an abstract set of equations. Every dosing decision — how much drug to give, how often, by which route, and how to adjust for a specific patient — is a pharmacokinetic decision. The four processes of absorption, distribution, metabolism, and elimination each contribute a piece of the answer.
The liver is the primary site of drug metabolism and also generates albumin. In patients with significant liver disease, two pharmacokinetic problems can arise simultaneously: impaired metabolism leads to reduced drug clearance and higher plasma concentrations at a given dose, and reduced albumin production increases the free fraction of highly protein-bound drugs. Drugs that undergo extensive first-pass metabolism may have dramatically increased bioavailability in patients with cirrhosis, because the damaged liver extracts less drug on the first pass. Standard doses of such drugs can produce toxic plasma concentrations in these patients.
The kidneys are the primary elimination route for water-soluble drugs and metabolites. In patients with reduced kidney function, renally cleared drugs accumulate with repeated dosing. The half-life of these drugs is effectively prolonged, because elimination is slower. Dosing adjustments — either reducing the dose, extending the interval, or both — are required to prevent accumulation to toxic levels. Kidney function is typically estimated using the creatinine-based estimated glomerular filtration rate, and drug prescribing references provide specific dose adjustment recommendations based on this value.
Dosing Question
Which route?
Dosing Question
How much?
Dosing Question
How often?
Dosing Question
When does it work?
This Module Versus Chapter 2
This module provides the conceptual vocabulary for pharmacokinetics: what the four processes are and why they matter. Chapter 2 covers the same territory at full depth — the specific enzyme systems responsible for metabolism, the mathematical relationships between clearance, volume of distribution and half-life, the mechanisms of pharmacokinetic drug interactions, and the quantitative tools used for therapeutic drug monitoring. The concepts introduced here are the foundation for that deeper treatment.
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| Atkinson AJ Jr, Huang SM, Lertora JJL, Markey SP, eds | Principles of Clinical Pharmacology, 3rd edition | Academic Press, 2012 |
| Wilkinson GR | Drug metabolism and variability among patients in drug response | New England Journal of Medicine, 2005; 352(21):2211–2221 |
| Brunton LL, Hilal-Dandan R, Knollmann BC, eds | Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th edition | McGraw-Hill, 2018 |
| Waller DG, Sampson AP | Medical Pharmacology and Therapeutics, 5th edition | Elsevier, 2018 |