22.2 — How a Drug Travels Through You

Take a paracetamol tablet and it relieves your headache in about half an hour. Inject the same amount into a vein and it works in minutes. Rub it on your skin and nothing happens at all.

Same molecule, same dose, completely different results — because what a drug does depends entirely on how much of it reaches the target, and when.

That is pharmacokinetics: what the body does to the drug, as distinct from pharmacodynamics, which is what the drug does to the body.

Four stages, traditionally abbreviated ADME: absorption, distribution, metabolism, excretion.

Absorption — getting in

A swallowed drug has to dissolve, survive the stomach, cross the gut wall, and get into the bloodstream.

Crossing the gut wall means crossing cell membranes, which are made of fat (Chapter 1.4).

So fat-soluble molecules cross easily and water-soluble ones do not. This single fact drives most of what follows in this chapter.

Most absorption happens in the small intestine, because of its enormous surface area (Chapter 9.3) — even for drugs that are absorbed better in acid, simply because there is so much more surface there.

What changes absorption:

Food. Slows stomach emptying, so most drugs are absorbed more slowly with food. Some are absorbed better with it — fat-soluble drugs need fat present. Some are absorbed worse — levothyroxine and several antibiotics (Chapter 21.4).

Other drugs. Antacids, calcium and iron bind certain drugs in the gut and prevent absorption entirely, which is why the instruction to separate them by a few hours is not a nicety.

Gut motility and disease. Vomiting, diarrhoea, or bowel surgery all change it.

First-pass metabolism

And this is the concept that explains many otherwise puzzling facts about doses.

Blood leaving the gut does not go straight into general circulation. It goes first to the liver, through the portal vein (Chapter 9.4).

So the liver gets to work on the drug before the rest of the body sees any of it.

For some drugs this destroys most of the dose.

Glyceryl trinitrate is almost completely eliminated on first pass, which is why it is given under the tongue — the veins there drain directly into general circulation, bypassing the liver.

Morphine has roughly 30 percent oral bioavailability, which is why the oral dose is around three times the injected one. That ratio is a common source of serious dosing errors when switching routes.

Bioavailability — the fraction of the dose that reaches general circulation. Intravenous is 100 percent by definition. Everything else is less.

Distribution — spreading out

Once in the blood, the drug spreads into tissues.

Fat-soluble drugs spread widely, including into fat and into the brain. Water-soluble drugs stay mostly in the blood and the fluid between cells.

Which produces some practical consequences:

Fat-soluble drugs accumulate in fat tissue and are released slowly afterwards. Which is why diazepam has such a long tail of effect, and why some drugs behave differently in people with very different body composition.

The blood–brain barrier (Chapter 11.10) — a tight seal that excludes most water-soluble molecules.

Which explains a great deal: why loratadine causes less drowsiness than chlorphenamine, why levodopa is used rather than dopamine (Chapter 20.3), and why treating brain infections requires antibiotics that can actually get in.

The placenta is a much weaker barrier, so most drugs reach the fetus (Chapter 4.6), which is why prescribing in pregnancy is done carefully.

Protein binding. Many drugs travel bound to albumin in the blood.

And only the unbound fraction is active, because only free drug can leave the bloodstream and reach a target. Which is why low albumin — in liver disease, kidney disease or severe illness — can raise the active fraction of a highly bound drug such as phenytoin even when the total measured level looks normal.

Metabolism — breaking it down

Mostly in the liver, mostly to make the drug more water-soluble so the kidneys can excrete it.

Because the kidney filters blood and excretes water-soluble things. A fat-soluble drug filtered into the urine would simply be reabsorbed back across the tubule wall. So the liver's job is to convert fat-soluble to water-soluble.

Two phases:

Phase I — adding or exposing a reactive group, usually by oxidation. The cytochrome P450 enzyme family does most of this.

Phase II — attaching a large water-soluble molecule, which makes the product easy to excrete.

Cytochrome P450, and why it matters

A family of enzymes, of which CYP3A4 handles perhaps half of all drugs.

Two things can happen to these enzymes, and both cause clinically important interactions:

Inhibition — another drug blocks the enzyme. The first drug is broken down more slowly, so its level rises. This happens within hours to days.

Common inhibitors: clarithromycin and erythromycin, ketoconazole and other antifungals, ritonavir, fluoxetine and paroxetine, amiodarone, and grapefruit juice.

And grapefruit is a genuine example rather than a curiosity. It inhibits CYP3A4 in the gut wall, and it can raise the levels of some statins, calcium channel blockers and immunosuppressants substantially — enough to cause real harm with some combinations. One glass can have an effect lasting more than a day.

Induction — another drug increases the amount of enzyme. The first drug is cleared faster, so its level falls and it stops working. This takes days to weeks, because new enzyme has to be made.

Common inducers: rifampicin, carbamazepine, phenytoin, phenobarbital, and St John's wort.

And St John's wort is worth flagging precisely because it is sold as a harmless herbal remedy. It has caused contraceptive failure, transplant rejection by lowering immunosuppressant levels, and reduced effectiveness of HIV treatment. "Natural" says nothing at all about whether something interacts.

Induction has a second trap: when the inducer is stopped, the enzyme levels fall back over weeks, and the other drug's level rises again. So the interaction happens twice — once on starting and once on stopping.

Prodrugs

Some drugs are inactive until metabolised.

Codeine becomes morphine. Enalapril becomes enalaprilat. Clopidogrel requires activation.

Which reverses the usual logic: an enzyme inhibitor makes a prodrug less effective rather than more. Someone taking omeprazole with clopidogrel may get less antiplatelet effect, which is why pantoprazole is often preferred in that combination.

Excretion — getting out

Mostly the kidneys, by three processes (Chapter 10.2): filtration at the glomerulus, active secretion into the tubule, and reabsorption back out of it.

Which is why kidney function determines the dose of many drugs, and why a falling eGFR means reviewing everything a person takes.

Drugs cleared largely unchanged by the kidney — and therefore needing dose reduction in kidney disease — include digoxin, lithium, metformin, gabapentin, and most penicillins.

Some drugs are excreted in bile into the gut. A few are then reabsorbed and recirculated — enterohepatic circulation — which extends their duration.

And small amounts leave in sweat, saliva, breath and breast milk. Breast milk matters practically, and for most common medicines the amount transferred is small; specific advice depends on the drug.

Half-life, and why it decides the dosing schedule

Half-life is the time for the concentration to fall by half.

And the useful rule that follows: after around 4 to 5 half-lives, a drug is essentially gone — and it takes the same 4 to 5 half-lives to reach a steady level when you start taking it regularly.

Both directions, the same number. Which answers two practical questions at once.

A drug with a 24-hour half-life takes about 5 days to reach full effect. Which is why judging whether a blood pressure drug is working after two days is meaningless.

And it explains loading doses. If you cannot wait five half-lives, you give a larger first dose to fill the space immediately, then smaller maintenance doses to hold it there. This is why antibiotics for serious infection, and drugs like amiodarone and digoxin, are loaded.

Short half-life means frequent dosing or a modified-release formulation.

And a specific consequence: missing a dose of a short half-life drug matters far more than missing a dose of a long one. Missing one levothyroxine tablet, with a half-life of about a week, changes almost nothing. Missing doses of a short-acting antiepileptic can precipitate a seizure.

What changes all of this

Age. Newborns have immature liver enzymes and reduced kidney function. Older people have reduced kidney function — frequently without a raised creatinine, because muscle mass is lower — plus more body fat, less water, and greater sensitivity to sedatives.

Liver disease — reduced metabolism, reduced albumin, and reduced first-pass effect.

Kidney disease — reduced excretion.

Heart failure — reduced blood flow to gut, liver and kidneys, changing all four stages.

Genetics — as with CYP2D6 and codeine (Chapter 22.1).

Pregnancy — increased blood volume, increased kidney clearance, and changed enzyme activity, so some drugs need higher doses.

And obesity, which changes distribution differently for fat-soluble and water-soluble drugs, so a single "adjust for weight" rule does not work.

What this means when you take a tablet

"On an empty stomach" and "with food" are absorption instructions, and they change how much drug you get.

"Do not take with milk or antacids" means chemical binding in the gut, and ignoring it can mean getting almost none of the dose.

"Do not crush" usually means a modified-release formulation — crushing it delivers a whole day's dose at once, which has killed people.

"Avoid grapefruit" is a metabolism instruction with real consequences.

And "take at the same time each day" exists because steady levels are what produce steady effects.

None of these instructions are arbitrary. Every one of them is a fact from this chapter written as a sentence on a label.

What the next page fixes

Chapter 22.3 covers dose and response — why more is not always better, why the dose–response curve has the shape it has, and where the idea of a "safe dose" actually comes from.