Mechanisms of renal excretion
The kidneys are the main organ of elimination. The process of blood purification consists of three physiological mechanisms:
- Glomerular filtration (filtratio glomerularis). It takes place in the renal glomeruli due to the hydrostatic pressure of the blood. The capillary endothelium and podocytes form a selective barrier that prevents molecules with a negative charge or a diameter greater than 8 nm from passing through. An important nuance: drugs bound to large plasma proteins (albumins) do not pass through the barrier, and their excretion is slowed down.
- Active tubular secretion (secretio activa). It occurs in the proximal tubules against the concentration gradient with the expenditure of ATP. Transport systems for organic acids (penicillins, furosemide) and bases (morphine) operate here. Unlike the glomerular filter, this mechanism is capable of removing substances tightly bound to plasma proteins: as the free fraction is eliminated into the tubular lumen, the equilibrium shifts, and the protein complexes dissociate. Transporters have a limited capacity, so drugs can compete for them.
- Tubular reabsorption (reabsorptio tubularis). Reverse passive reabsorption in the distal tubules. Lipophilic (nonpolar) molecules easily diffuse back into the blood, while hydrophilic (ionized) molecules cannot cross the membrane and are excreted in the urine.
Urine pH influence and "ion trapping"
The degree of ionization of weak acids and bases directly depends on the acidity of the medium. If a substance transforms into an ionized form, it becomes hydrophilic, ceases to be reabsorbed, and is excreted.
This principle is applied in clinical practice to force diuresis in cases of intoxication:
- Weak acids (barbiturates, acetylsalicylic acid) are poorly eliminated in an acidic environment. To accelerate their elimination, the urine is alkalinized (pH is increased) by intravenous administration of sodium hydrogen carbonate.
- Weak bases (alkaloids such as quinine or nicotine) are retained in the organism during an alkaline reaction. For their prompt elimination, the urine is artificially acidified with ammonium chloride.
Hepatobiliary transport and enterohepatic circulation
The liver eliminates drugs via a complex system of transporters. The hepatocyte captures molecules from the sinusoids and then, using ATP-dependent proteins (e.g., P-glycoprotein), pumps them across the canalicular membrane into the bile.
Once in the intestinal lumen with bile, a drug can enter enterohepatic circulation (circulatio enterohepatica). If the drug formed a conjugate with glucuronic acid in the liver, this bond can be hydrolyzed in the intestine. The released active lipophilic substance is reabsorbed through the intestinal wall into the portal vein system (vena portae) and returns to the liver. Such a cyclic process significantly prolongs the therapeutic effect of drugs (characteristic of morphine, ethinylestradiol, chloramphenicol).
Drugs that are practically not absorbed from the gastrointestinal tract (neomycin, vancomycin, nystatin) pass through the intestine in transit and are excreted in the feces, which is used for local treatment within the intestinal lumen.
Elimination by lungs and glands
- Lungs (excretio per pulmones): eliminate volatile liquids and gases. The elimination of ethanol vapors directly correlates with its plasma concentration, which is the principle on which breathalyzers are based.
- Salivary glands: secrete predominantly lipophilic substances via passive diffusion. The content of certain substances (paracetamol, lithium salts) in saliva can be higher than in plasma (concentration phenomenon). Due to the direct correlation with plasma concentration, saliva is often used for therapeutic drug monitoring.
- Mammary glands: the process takes place during lactation. Since breast milk has a lower pH (about 6.5) than blood plasma (7.4), weak bases (benzodiazepines, nicotine) actively accumulate in it according to the "ion trapping" principle. Lipophilic drugs also actively penetrate into milk due to the fat fraction, which creates a risk of allergic and toxic reactions in the infant (cytostatics and isoniazid are strictly contraindicated).
Briefly: answers to topical questions
What are the main pharmacokinetic parameters of excretion, including the half-life and total clearance?
The quantitative parameters of elimination are the elimination rate constant (Kelim), half-life/half-elimination time (t½), and total clearance (ClT).
- Half-life (t½) — the half-life/half-elimination period of the drug.
- Total clearance (ClT) — an indicator of the organism's ability to clear itself of the drug; it is used as the basis for individually calculating the maintenance dose.
What is the role of SLC and ABC family transporters in the excretion of drugs by the kidneys and liver?
Transporters of the SLC and ABC families provide directed transport of drugs during their elimination by the liver and kidneys.
| Organ | Role of SLC transporters | Role of ABC transporters |
|---|---|---|
| Liver | Provide the influx (uptake) of molecules from the blood into the hepatocyte across the sinusoidal membrane. | Perform ATP-dependent elimination (efflux) of substances into the bile across the canalicular membrane. |
| Kidneys | Transport hydrophilic and lipophilic ions at the basolateral and apical membranes of epithelial cells. | Pump drug conjugates out of the cell into the renal tubular lumen. |
Which kidney and liver pathologies significantly affect the dose adjustment of drugs?
Impaired renal and hepatic function can affect the need for drug dose adjustment, especially for drugs whose elimination or metabolism depends on these organs.
- Renal failure: with decreased glomerular filtration, cumulation of drugs excreted predominantly by the kidneys is possible, therefore dose adjustment is required. For diethylcarbamazine, a reduction in dosage is required when renal function is decreased to avoid cumulation and toxicity.
- Liver diseases: for drugs metabolized predominantly in the liver, a dose reduction is required when metabolic function is decreased.
- Decreased hepatic blood flow: in elderly patients or with chronic heart failure, it may require a dose reduction of lipophilic beta-blockers.
- In liver or kidney pathology, relative overdose is possible due to impaired metabolism or excretion.
To remember how to accelerate elimination in poisoning, use the rule of opposites: weak acids are actively eliminated by alkali, and weak bases by acid. The main thing is to convert the substance into an ionized form.
Class and exam questions
Why are substances bound to plasma proteins not filtered in the renal glomeruli?
The filtration barrier in the kidneys prevents large molecules with a diameter greater than 8 nm and negatively charged compounds from passing through. Since albumins are large and negatively charged, drug-protein complexes remain in the bloodstream.
How to eliminate a drug if it is almost completely bound to plasma proteins?
Such drugs are eliminated via active tubular secretion. When the free fraction is transferred into the primary urine, the equilibrium in the plasma is disrupted, and the drug begins to dissociate from the protein, becoming available for excretion.
Why is probenecid sometimes used during penicillin therapy?
Both substances are secreted in the proximal tubules via the same organic acid transporters. Probenecid competes for the transporter, thereby slowing down the excretion of penicillin and prolonging its action.
What else to study on this topic
- Clinical significance of genetic polymorphism of liver transporters (using OATP1B1 and statins as an example).
- Structural and localization features of SLC and ABC transporters in tubular epithelial cells.
- The phenomenon of drug recirculation during excretion by exocrine glands of the gastrointestinal tract.
- The effect of plasma protein binding degree on drug penetration into breast milk.
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