How the Body Handles Drugs
A prescription is a kinetic experiment in a living patient. The drug must enter the body, reach the target, remain long enough to act, and leave without causing unacceptable harm. Absorption, distribution, metabolism and elimination are therefore not abstract terms; they explain why vomiting defeats oral tablets, why pregnancy changes concentrations, why renal impairment causes magnesium toxicity, and why interacting drugs can turn a normal dose into a toxic one.
Start with the single distinction that organises everything else. Pharmacology has two halves, and they answer different questions:
| Half | Question it answers | One-line summary |
|---|---|---|
| Pharmacokinetics (PK) | What does the body do to the drug? | Absorption, distribution, metabolism, elimination -> the concentration-time profile |
| Pharmacodynamics (PD) | What does the drug do to the body? | Concentration at the target -> effect and toxicity |
The clinical bottom line connects them: dose drives concentration (PK), and concentration drives effect (PD). Almost every prescribing error is a failure in one of those two arrows. This chapter is mostly about the first arrow — how the body handles the drug to produce a concentration-time profile — but it closes on the second, because a concentration only matters through the effect it produces. A drug is, at its broadest, any chemical agent that alters the function of living tissue, and our job is to predict and control that alteration.
The core sequence is:
administered dose -> absorbed dose -> plasma concentration -> tissue concentration -> metabolism and clearance -> effect over time
The Primary exam does not usually ask for advanced equations, but a few relationships prevent many clinical mistakes:
| Relationship | Meaning | O&G use |
|---|---|---|
Bioavailability = fraction reaching systemic circulation | Oral dose is not the same as systemic dose | Vomiting, first-pass metabolism, severe infection route choice |
Loading dose depends mainly on Vd | Fill the apparent distribution space | Sepsis, anticonvulsants, emergency therapy |
Maintenance dose depends mainly on clearance | Replace what the body removes | Renal disease, pre-eclampsia, hepatic impairment |
Half-life depends on Vd and clearance | Long half-life can reflect large distribution or poor clearance | Accumulation and washout decisions |
Steady state takes about 4-5 half-lives | Delayed full effect after starting/changing chronic therapy | Thyroid, antidepressant, antiepileptic and antihypertensive interpretation |
The friendly way to think about it is: loading dose fills the tank; maintenance dose keeps the leak topped up. Pregnancy, sepsis, bleeding, renal failure and liver disease change the size of the tank, the leak, or both.
The One Event Behind Every Step: Crossing a Membrane
Before any of absorption, distribution, metabolism or elimination can happen, a drug molecule has to cross a barrier — the gut wall, the capillary endothelium, the cell membrane, the placenta, the renal tubule, the mammary epithelium. The whole of pharmacokinetics is, at bottom, the same physical event repeated at different barriers, so it is worth getting the mechanism straight once.
| Mechanism | How it works | What it favours |
|---|---|---|
| Passive diffusion | Movement down a concentration gradient through the lipid membrane; no energy, no carrier | Small, lipid-soluble, non-ionised molecules — most drugs, most of the time |
| Paracellular movement | Drug and water pass between cells through junctions and pores | Small water-soluble molecules; important in renal filtration |
| Facilitated diffusion | A carrier protein moves the drug down its gradient; no energy used | Substrates that fit a specific transporter |
| Active transport | A pump moves drug against its gradient using energy | Transporter substrates; can concentrate drug on one side of a barrier |
| Bulk/transcapillary flow | Drug crosses with bulk water driven by hydrostatic/osmotic pressure | Unbound drug at the capillary wall |
Two transporter families matter enough to name because they shape distribution and excretion: efflux pumps such as P-glycoprotein, which push drug back out of cells and out of the fetal compartment at the placenta, and uptake transporters, which pull drug into hepatocytes and renal tubular cells. When a drug behaves unexpectedly — lower brain or fetal levels than lipid solubility predicts, or a sudden interaction — a transporter is often the explanation.
The single most useful generalisation for O&G is this: the small, lipid-soluble, non-ionised molecule crosses everything — gut, brain, placenta and milk — by passive diffusion, while the large, water-soluble, ionised or highly protein-bound molecule is held back. Every later section (placental transfer, milk transfer, renal handling, the blood-brain barrier) is just this rule applied at a particular barrier. Keep it in mind as the spine of the chapter.
Absorption: Entry into the Circulation
Absorption is movement from the site of administration into systemic circulation. It is affected by route, formulation, pH, perfusion, gastric emptying, gut motility, vomiting, food, first-pass metabolism and adherence.
| Route | Pharmacokinetic strength | O&G weakness |
|---|---|---|
| Oral | Convenient, cheap, suitable for chronic therapy | Vomiting, ileus, delayed gastric emptying, first-pass metabolism |
| Sublingual/buccal | Mucosal absorption, partially avoids first pass | Technique matters; local side effects |
| Intravenous | Complete bioavailability, immediate effect | Requires access; rapid toxicity if wrong dose |
| Intramuscular | Useful depot or when oral/IV difficult | Shock, obesity and oedema make absorption unpredictable |
| Subcutaneous | Slow absorption, useful for insulin/heparin-like drugs | Oedema, perfusion and injection technique matter |
| Vaginal | Local reproductive tract exposure for selected agents | Bleeding, discharge and placement affect contact |
| Transdermal | Sustained delivery | Heat, skin disease, adherence and body habitus affect exposure |
| Inhaled | Local lung effect with less systemic exposure | Technique, severe attack and airway obstruction matter |
Bioavailability (F) is the fraction reaching systemic circulation unchanged. IV F is 1. Oral F may be much lower because the drug is not fully absorbed or is metabolised before reaching systemic circulation.
What Can Go Wrong Before Absorption?
| Problem | Mechanism | Clinical clue |
|---|---|---|
| Vomiting soon after dose | Drug leaves before dissolution/absorption | Hyperemesis, gastroenteritis, labour nausea |
| Ileus or delayed gastric emptying | Delayed delivery to absorptive surface | Postoperative state, opioids, labour |
| Shock | Poor gut/muscle perfusion | Septic or haemorrhagic patient needs IV route |
| First-pass metabolism | Gut/liver removes drug before systemic circulation | Oral dose much larger than IV equivalent |
| Formulation issue | Depot, enteric-coated or modified-release kinetics | Crushing tablets or wrong route changes exposure |
| Adherence barrier | Dose never reaches patient | Cost, stigma, side effects, stock-outs, partner control |
Clinical chains:
| Scenario | Kinetic explanation | Practical consequence |
|---|---|---|
| Hyperemesis with oral antibiotics | Drug may not remain in gut long enough | Use non-oral route if infection serious |
| Septic shock with IM drug | Poor muscle perfusion delays absorption | IV therapy is preferred for severe sepsis |
| Labour with delayed gastric emptying | Oral absorption and aspiration risk change | Route and anaesthetic planning matter |
| Heavy vaginal bleeding with vaginal medication | Reduced mucosal contact time | Reassess route and effectiveness |
Weak Acids, Weak Bases and Ionisation
The Henderson-Hasselbalch relationship is used in pharmacology to relate pH, pKa and the ratio of ionised to non-ionised drug. The exact form differs for weak acids and weak bases, but the clinical meaning is stable:
the non-ionised fraction crosses lipid membranes more easily; the ionised fraction is more water-soluble and may become trapped in a compartment.
| Concept | Meaning | O&G relevance |
|---|---|---|
| pKa | pH at which half the drug is ionised and half non-ionised | predicts membrane crossing and compartment trapping |
| Weak acid in alkaline fluid | more ionised | less passive membrane crossing; more renal trapping concept |
| Weak base in acidic fluid | more ionised | ion trapping can increase fetal or breastmilk exposure for some drugs |
| Non-ionised, lipid-soluble drug | crosses membranes more readily | placenta, blood-brain barrier and milk transfer |
| Highly ionised drug | crosses membranes less by passive diffusion | transfer may still occur through transporters or prolonged high exposure |