What Controls How Much and How Fast: pH, pKa, First-Pass and Bioavailability
In Part 1 the drug learned HOW to cross a membrane. Now the harder question: why does the same drug act in 15 minutes on an empty stomach but 45 after a meal — and why is a tiny nitroglycerin tablet placed under the tongue instead of swallowed? The answers are pH, surface area, blood flow, formulation, and the liver's first tax. Master these and you can predict a drug's behaviour before you ever prescribe it.
A 58-year-old man clutches his chest in the clinic — a squeezing pain, classic angina. The nurse doesn't hand him a glass of water and a tablet to swallow. She slips a tiny tablet UNDER his tongue and tells him to let it melt. Ninety seconds later the pain eases. Why under the tongue? Why not swallow it? The answer to that single choice is the whole story of Part 2: the route and the chemistry decide whether a drug arrives in time — or arrives destroyed.
The chemistry of crossing: weak acids, weak bases and pH
Almost every drug is a weak acid or a weak base. That single fact drives its absorption. In water, such a drug exists in two forms at once: an unionized (uncharged) form that is fat-loving and crosses membranes easily, and an ionized (charged) form that is water-loving and stays stuck. Which form dominates depends on two numbers: the drug's pKa (the pH at which it is exactly 50% ionized) and the pH of the fluid it is sitting in.
The rule of thumb needs no heavy maths, just a picture: an acid dropped into acid stays calm and uncharged; a base dropped into acid grabs a proton and becomes charged. So — a weak acid (like aspirin) is mostly unionized in the acidic stomach and could be absorbed there, while a weak base is mostly ionized in the stomach and waits until the more alkaline small intestine to turn unionized and cross. "Acids like acid, bases like base" for being unionized.
The famous trap: even though aspirin (a weak acid) is unionized and "absorbable" in the stomach, MOST of it is still absorbed in the small intestine. Why? Surface area beats chemistry: the intestine's vast villi overwhelm the stomach's tiny surface, even though a smaller fraction is unionized there. Exam favourite — don't let the pH logic fool you into forgetting geometry.
Ion trapping: a one-way door
Here is a beautiful consequence. A drug crosses a membrane in its unionized form; but if the fluid on the far side has a different pH, the drug may become ionized there — and now it can't cross back. It is trapped. This "ion trapping" is not just theory; we weaponize it.
In a salicylate (aspirin) overdose we alkalinize the urine with sodium bicarbonate. In alkaline urine, the weak acid salicylate becomes ionized and is trapped in the tubule, unable to be reabsorbed — so it is flushed out faster. Ion trapping turned into a treatment. (The same principle explains why some basic drugs concentrate in acidic breast milk.)
- Only the unionized (uncharged) form crosses membranes freely.
- pKa + local pH decide the ionized : unionized ratio.
- Weak acids are unionized in acid; weak bases are unionized in base.
- Surface area still makes the small intestine the main site — even for acids.
- Ion trapping (e.g., alkalinizing urine in aspirin overdose) speeds elimination.
The physical factors: surface, blood flow, and emptying
Chemistry sets who CAN cross; physics sets how fast. Three levers matter. Surface area: the folded small intestine is unbeatable — this is why it dominates absorption. Blood flow (perfusion): fast-flowing blood on the far side sweeps absorbed drug away, keeping the concentration gradient steep and absorption quick; in shock, poor perfusion slows the absorption of intramuscular or subcutaneous drugs, so we prefer the IV route in an emergency. Gastric emptying: since the intestine does the work, anything that speeds the tablet's arrival there speeds onset.
This is why many painkillers act faster on an empty stomach: the stomach empties quickly, delivering the drug to the absorbing intestine sooner. A heavy, fatty meal slows emptying and DELAYS the onset — it usually doesn't reduce the total amount absorbed, just pushes it later. "Take on an empty stomach for faster relief" is this principle in one sentence.
Dosage forms: the same drug, dressed differently
A drug must dissolve before it can be absorbed, so the FORM it is packaged in controls how fast it becomes available. Roughly, from fastest to slowest to release: solution > suspension > capsule > tablet > coated / sustained-release. A liquid is already dissolved and acts fastest; an enteric-coated or extended-release tablet is designed on purpose to dissolve slowly — either to protect the stomach, protect the drug from acid, or spread the dose over hours.
Enteric-coated aspirin resists the stomach acid and dissolves in the intestine — gentler on the stomach lining, but slower in onset (not the form you want in a suspected heart attack, where chewable plain aspirin is used for speed).
The liver's first tax: first-pass metabolism
Now the twist that catches students. Blood leaving the gut does not flow straight to the heart and body — it is collected into the portal vein and delivered first to the liver. The liver, our chemical customs officer, may metabolize (break down) a large part of the dose before it ever reaches the general circulation. This is first-pass metabolism (the first-pass effect). For some drugs the liver takes almost everything, so very little of a swallowed dose survives.
Nitroglycerin (GTN) has such heavy first-pass metabolism that a swallowed dose is almost useless — the liver destroys it. So we give it under the tongue (sublingual): the mouth's veins drain directly into the systemic circulation, bypassing the liver, and the drug reaches the heart within seconds. That is why the nurse never handed him water. Other high first-pass drugs: propranolol, lidocaine, morphine.
The bottom line: bioavailability (F)
Add all of this up — how much dissolved, how much crossed, how much the liver took — and you get bioavailability (F): the fraction of an administered dose that reaches the systemic circulation unchanged and active. By definition an intravenous dose has F = 1 (100%), because it is placed straight into the blood. An oral dose has F somewhere between 0 and 1. Bioavailability is exactly why the oral dose of a drug is often larger than its IV dose: you must give more to account for what is lost on the way.
If a drug's oral bioavailability is 0.25 (25%), then a 100 mg tablet delivers only ~25 mg to the circulation — the other 75 mg was never absorbed or was destroyed first-pass. To match a 25 mg IV effect you'd swallow roughly 100 mg. This is the everyday arithmetic behind dose conversions.
- Surface area, blood flow and gastric emptying set the SPEED of absorption.
- Dosage form controls dissolution: solution is fastest, sustained-release is slowest.
- First-pass metabolism (liver) can destroy much of an oral dose before it acts.
- Sublingual, transdermal and IV routes bypass first-pass.
- Bioavailability (F) = fraction reaching the circulation; IV = 1, oral = 0–1.
- Saying weak acids are absorbed "only" in the stomach. Chemistry favours it there, but surface area still makes the intestine the main site.
- Confusing a delayed onset with a reduced dose. Food usually delays absorption, not necessarily its total amount.
- Forgetting that a high first-pass drug needs a much larger oral than IV dose.
- Assuming bioavailability only means "how much was absorbed". It also includes first-pass loss.
Nitroglycerin is given sublingually rather than swallowed mainly because it:
- Only the unionized form crosses; pKa and local pH decide how much is unionized.
- Surface area, blood flow, gastric emptying and dosage form set the speed.
- First-pass metabolism can gut an oral dose; sublingual/transdermal/IV bypass it.
- Bioavailability (F) sums it all: IV = 100%, oral = variable — hence larger oral doses.
- Katzung BG. Basic & Clinical Pharmacology — Pharmacokinetics: absorption, bioavailability & routes of administration.
- Brunton LL, et al. Goodman & Gilman's The Pharmacological Basis of Therapeutics — Drug absorption, bioavailability & first-pass metabolism.
- Rang HP, Dale MM, et al. Rang & Dale's Pharmacology — pH partition, ion trapping & bioavailability.
- Whalen K. Lippincott Illustrated Reviews: Pharmacology — Bioavailability & first-pass effect.
- Bertram G. Katzung & Trevor's Pharmacology Examination & Board Review — pH partition worked examples.
