Ionization, Protein Binding & Renal Drug Elimination
Why charge, albumin, and the tubule decide how long a drug stays
Ionization and Membrane Crossing
Lipid solubility rules. Most drugs cross membranes by passive diffusion, which only the uncharged (nonionized) form can do; the ionized form is water-soluble and stays on its side of the membrane. Because most drugs are weak acids or weak bases, the ionized fraction depends on the local pH relative to the drug's pKa.
Henderson–Hasselbalch. For a weak acid, pH = pKa + log([A−]/[HA]); for a weak base, pH = pKa + log([B]/[BH+]). At pH = pKa a drug is 50% ionized, and each pH unit away changes the ratio 10-fold, so two units on the ionizing side leaves only about 1% nonionized.
| Feature | Weak acids | Weak bases |
|---|---|---|
| Nonionized when | pH < pKa | pH > pKa |
| Trapped in | Alkaline fluid | Acidic fluid |
| Examples | Salicylates, phenobarbital, methotrexate, warfarin, NSAIDs | Amphetamine, PCP, TCAs, opioids, local anesthetics |
| Excretion enhanced by | Alkaline urine (sodium bicarbonate) | Acidic urine (ammonium chloride; rarely used) |
| Main plasma carrier | Albumin | α1-Acid glycoprotein |
Clinical consequences. Local anesthetics such as lidocaine (an amide) are weak bases (pKa about 8). In infected, acidic tissue more drug is ionized and cannot enter the nerve, so the block fails; for the same reason they become trapped in an acidotic fetus.
Ion Trapping to Enhance Elimination
Principle. A drug accumulates on the side of a membrane where it is ionized. Filtered drug that stays ionized in tubular fluid cannot diffuse back into blood and is excreted.
Urinary alkalinization. Intravenous sodium bicarbonate raises urine pH (target about 7.5–8), ionizing weak acids. It is standard for significant salicylate poisoning, where alkaline plasma also draws salicylate out of the brain, and is used for phenobarbital overdose and high-dose methotrexate, where it also keeps methotrexate soluble and prevents crystal nephropathy.
Urinary acidification. Ammonium chloride increases excretion of weak bases such as amphetamine and PCP in theory, but it is essentially abandoned: little benefit, worse systemic acidosis, and more myoglobin-induced kidney injury in rhabdomyolysis.
Bicarbonate in tricyclic antidepressant overdose is not ion trapping. TCAs are weak bases, so alkaline urine would not speed their excretion; the sodium load and alkalemia reduce TCA blockade of cardiac fast Na+ channels and narrow the QRS (a QRS >100 ms is the usual trigger). TCAs are also highly protein-bound with a large volume of distribution, so hemodialysis does not remove them, whereas lithium, a small cation that pH cannot trap, is removed by hemodialysis in severe toxicity.
Plasma Protein Binding
Binding proteins. Albumin binds acidic drugs: warfarin, phenytoin, valproate, NSAIDs, sulfonamides. α1-Acid glycoprotein binds basic drugs such as lidocaine, propranolol, and TCAs; as an acute-phase reactant it rises with inflammation, trauma, and myocardial infarction.
Only free drug counts. Unbound drug reaches receptors, crosses membranes, is filtered, and is metabolized; bound drug is an inactive reservoir. Binding matters most for highly bound drugs with a narrow therapeutic index.
Phenytoin. Hypoalbuminemia (cirrhosis, nephrotic syndrome, malnutrition) and uremia (retained solutes displace it from albumin) raise the free fraction, so nystagmus and ataxia can appear while the total level looks therapeutic; a free phenytoin level is more reliable.
Bilirubin displacement. Sulfonamides and ceftriaxone displace unconjugated bilirubin from albumin. In a neonate the freed bilirubin crosses the immature blood–brain barrier and injures the basal ganglia (kernicterus), so these drugs are avoided in jaundiced newborns.
In adults, displacement alone raises free drug only transiently because the extra free drug is also cleared faster. The warfarin–TMP-SMX interaction that raises the INR is mainly CYP2C9 inhibition.
Renal Handling and Dose Adjustment
- Glomerular filtrationOnly unbound drug is filtered; the rate depends on GFR and the free fraction.
- Proximal tubular secretionActive transport that works even on protein-bound drug: organic anion transporters (OATs) secrete acids, organic cation transporters (OCTs) secrete bases.
- Passive reabsorptionNonionized, lipid-soluble drug diffuses back from the lumen; urine pH controls how much.
| Transporter | Substrates | Key inhibitors and effects |
|---|---|---|
| OATs (organic anion) | Penicillins, cephalosporins, methotrexate, loop and thiazide diuretics | Probenecid: ↑penicillin levels, ↓methotrexate clearance |
| OCTs (organic cation) | Metformin, creatinine | Cimetidine, trimethoprim: ↑serum creatinine without ↓GFR |
Creatinine artifact. Blocking creatinine secretion raises serum creatinine modestly while true GFR and BUN are unchanged, a pattern distinct from interstitial nephritis or prerenal azotemia. Loop diuretics must be secreted by OATs to reach their luminal site of action, so in chronic kidney disease, where retained organic acids compete for secretion, higher doses are needed.
Dosing by clearance. Renally cleared drugs need smaller doses or longer intervals as creatinine clearance falls, usually estimated by Cockcroft–Gault: CrCl = (140 − age) × weight in kg / (72 × serum creatinine), × 0.85 for women. Key examples are aminoglycosides and vancomycin (level-guided dosing), lithium (reabsorbed with sodium, so dehydration and thiazides raise levels), enoxaparin (reduced dose when CrCl <30 mL/min), DOACs (dabigatran is the most renally dependent), and metformin (avoid when eGFR <30).
A "normal" serum creatinine can hide a markedly reduced creatinine clearance in elderly, low-muscle-mass patients.