Elimination of drugs
Drugs and their metabolites are eliminated primarily in urine and bile. Pulmonary elimination concerns volatile products.
The insufficiency of the elimination of a drug causes a lengthening of its half-life and a risk of accumulation with possible toxic effects. This is particularly true in cases of renal impairment.
The kidney which receives with high pressure approximately 1400 ml/mn of blood, about a quarter of the cardiac output, eliminates drugs and various other compounds from the body. From the physiological point of view, the nephron, basic unit of the kidney, acts by three different mechanisms: glomerular filtration, tubular secretion and tubular reabsorption. There are approximately 1 million nephrons per kidney.
The glomerulus can be regarded as a nonselective filter permeable to all the compounds whose molecular weight is lower than approximately 65 000. Albumin whose molecular weight is 65 000 passes only in negligible quantity, called microalbuminuria.
The filtration needs a blood pressure sufficient to allow the flow of the filtrate and to counterbalance the oncotic pressure exerted by plasma proteins, in particular albumin.
The volume filtered per minute is approximately 140 ml, about a tenth of renal blood flow rate.
The composition of the glomerular filtrate is, for the majority of components, identical to that of plasma. As the molecular weight of drugs is usually lower than 65 000, one should always find an identical concentration of the drug in the filtrate and the plasma. But this is true only for the drugs for which the percentage of plasma protein binding is negligible. The concentration of a drug in the filtrate which is normally deprived of proteins is actually identical to the concentration of its free form in plasma.
Since the molecular weight of drugs is not generally the limiting factor, their glomerular filtration depends on their binding to plasma proteins: the more bound they are, the less they are filtered.
Tubular secretion consists of compound transport from the peritubular fluid into the tubular lumen. It should be recalled that the peritubular fluid consists of blood which was already filtered at the level of the glomerulus where it was impoverished in various low-weight compounds.
The tubular secretion which is carried out at the level of the proximal tubule is an active process which requires normal cellular operation to supply the energy necessary.
A general feature of this secretion, well highlighted for organic acids such as para-aminohippuric acid, is that it is limited by a maximum transport: when the concentration increases, tubular secretion increases until a threshold then remains constant, unlike what occurs for filtration which is proportional to the plasma concentration of unbound compounds.
Molecules whose affinity for the carrier is high, like para-aminohippuric acid, are eliminated from the peritubular fluid in only one transfer. The tubular secretion of drugs is, essentially, independent of their binding to proteins, because it is reversible. This important difference from glomerular filtration can be explained as follows: at the level of the glomerulus, when the concentrations of the free molecules on both sides of the membrane are equalized, by a passive process, the filtration stops. In the tubule, as the free fraction in the peritubular fluid is secreted, there is a dissociation of the complex drug-protein and the free form is actively eliminated. Thus, tubular secretion is overall independent of the binding of the drug to proteins.
When two or several drugs eliminated by the same process are present simultaneously in the body, they enter into competition for their tubular secretion. Thus the elimination of penicillin is delayed by the administration of probenecide.
There are two secretion types:
- Secretion of organic acids
In addition to various endogenous organic acids and to para-aminohippuric acid used to explore renal blood flow rate, various drugs having an acid function are secreted in urine as anions: penicillin, beta-lactamines, salicylic acid, indomethacin, probenecid, diuretic thiazides, the majority of ACE inhibitors and various conjugated molecules. The phenomenon of competition between two molecules explains why the majority of thiazide diuretics tend to raise the level of blood uric acid by reducing its tubular secretion.
- Secretion of organic bases
In addition to the physiological organic bases like thiamine, choline and histamine, a certain number of basic drugs are secreted by the tubule for example quinine, morphine, procaine, neostigmine, amiloride and triamterene.
Tubular reabsorption consists in the transfer of molecules from the lumen of the nephron into the blood. It can be done according to two mechanisms: one active and the other passive. But certain molecules are not reabsorbed, like the para-aminohippuric acid, mannitol, insulin.
The active reabsorption concerns primarily endogenous compounds such as sodium, potassium, uric acid, glucose and amino acids, and products whose structure is very similar to that of amino acids, for example alpha-methyl-dopa. This active reabsorption which requires an intake of energy, occurs primarily in the proximal tubule. It induces secondarily a passive reabsorption of water, to maintain Iso-osmolality between tubular filtrate and peritubular fluid.
Because of this passive water reabsorption, a certain number of compounds will be in the tubular fluid at higher a concentration than in the peritubular fluid. Consequently, these compounds are passively reabsorbed if they can cross the membrane, i.e. they are neutral and liposoluble.
The neutral character, i.e. not ionized, of acids and bases depends on their pKa and the pH of the medium, hence the importance for the elimination of certain drugs of modifications of pH of the urine. To accelerate the urinary elimination of acids, it is necessary to alkalize the urine and to acidify it for bases.
Thus, the urinary elimination of phenobarbital, an acid with pKa = 7.2, is induced by the alkalization of the urine, bicarbonate administration for example. The alkalization of the tubular fluid increases the percentage of ionized molecules not reabsorbed.
On the contrary, the urinary elimination of amphetamine, a basis with pKa = 5, is increased by the acidification of the urine, ammonium chloride administration for example, which increases its percentage of ionization.
As pH of urine is between 4,5 and 8, the molecules most sensitive to pH modifications are those whose pKa is between 5 and 7,5. Modifications of urinary pH can be used for treatment of poisoning when the physicochemical characteristics of the poison are known.
The renal elimination of a drug, i.e. its renal clearance, is reduced during renal impairment and decreases with age. The knowledge of the plasma clearance of creatinine makes it possible to evaluate the degree of renal impairment and to reduce the dosage of the drugs predominantly eliminated in urine, like antibiotics such as aminoglycosides.
Digestive elimination of drugs
The digestive tract is a location of exchanges where, of course, absorption is predominant after oral administration, but secretion is far from being negligible. Actually, very often absorption is followed by secretion, itself followed by reabsorption. The entero-hepatic cycle of biliary salts and of a certain number of drugs is a particular case of this general process.
The secretion of the drugs can occur along the digestive tract: in saliva, gastric fluid, bile, intestinal secretions. This secretion is not necessarily an elimination, because the secreted drugs can be reabsorbed. The final elimination in stools results from the difference between secretion into the intestinal lumen and reabsorption. Moreover, during their transfer in the digestive tract, drugs can undergo biotransformations under the effect of digestive or microbial enzymes or because of their instability according to pH.
To study the fecal elimination of a drug, the drug must be administered by parenteral route because, after administration by oral route, it is difficult to differentiate between what was excreted and what was not absorbed.
Salivary secretion is far from being negligible because it can reach one to two liters daily. This secretion, variable during the day, particularly stimulated by meals, is almost non-existent during sleep.
The salivary elimination of various compounds, such as mercury derivatives, has been known for a long time and it is admitted generally that the salivary concentration of liposoluble drugs is the reflection of their plasma concentration in free form. But certain compounds such as iodide and spiramycin, reach salivary concentrations higher than those in plasma.
The determination of drugs in saliva, whose principal interest is to avoid the sampling of blood, could be used in therapeutic control. There is a rather good statistical correlation between blood and salivary concentrations, but with important and unpredictable individual variations. In practice, the determination of drugs in saliva is not used for therapeutic monitoring.
It should be recalled that drugs with atropinic properties inhibit salivary secretion and disturb the elimination of compounds by this route.
The study of the gastric secretion of drugs administered by parenteral route was carried out especially in animals. In fact the basic drugs such as quinine are secreted in the gastric fluid. On the other hand, the acid drugs practically do not pass, which is understood rather well if one looks at the phenomena of dissociations according to pH.
The drugs reach the liver by two different routes:
- the venous and the lymphatic system after digestive absorption and, in this case, the totality of the absorbed drug passes through the liver before being distributed in the whole body.
- the hepatic artery after parenteral administration. In this case, the drug is distributed to the whole body and only a fraction passes through the liver.
The liver binds drugs with more or less affinity and, after possible biotransformations, can excrete them in bile.
The uptake of molecules by hepatocytes occurs at a variable rate. Certain molecules are very quickly fixed by the liver: it is the case of bromosulfophthalein whose plasma decrease is a test of assessment of hepatic function. It is the same for iodized contrast agents used for radiological exploration of the biliary tract.
The liver is the principal organ of drug biotransformations with reactions of phase I, oxidations and of phase II, conjugations. These biotransformations produce more polar and of higher molecular weight mplecules, two features which facilitate their elimination in bile.
The concentration of drugs or their metabolites in the bile can be higher, equal or lower than that of the plasma. The drugs whose concentration is much higher in bile than in plasma are secreted by active processes with a maximum rate of transport (Tm) and possible competition between transported compounds. These compounds have molecular weights equal to or higher than 300 and have polar groups. Among the drugs secreted in high concentration in bile, there are antibiotics: erythromycin, spiramycine, novobiocin, ampicillin, rifampin, and other compounds such as chlorothiazide, ergot derivatives.
A certain number of practical consequences result from these facts:
- for the treatment of biliary infections, it is necessary to choose antibiotics which enter into bile in an active form and which have a suitable spectrum of activity.
- drugs can be in competition with bilirubin for active transport into bile, which explains the advent of jaundices “with free bilirubin”.
- In patients with hepatic insufficiency or obstruction of the biliary tract, the risk of accumulation of these drugs is raised.
The importance of intestinal secretion itself, apart from biliary or pancreatic secretion, was well highlighted for metals, in particular zinc.
The importance of intestinal secretion in the elimination of drugs is generally low and not well known.
The pulmonary elimination (in expired air) concerns only a low number of drugs, but for which it can represent the main route of elimination. The concerned drugs are volatile products like some general anesthetics, halothane for example, from which 60% is eliminated in the expired air. .
The elimination of ethyl alcohol by the pulmonary route is used to measure its plasma concentration. The expired air constitutes also a route of elimination of volatile solvents (ether, hexane, benzene, trichloroethylene, etc) which can be at the origin of poisoning by pulmonary absorption. Absorption or elimination depends on the relative concentrations of these products in the expired air and blood.
Other routes of elimination
The excretion of drugs in milk constitutes only a secondary route of elimination for the woman, but can constitute a danger for the neonate. When it is necessary to prescribe drugs to the mother, the problem is to know if it is necessary to stop breast feeding, either transitorily, or definitively.
In general, the percentage of the dose given passing into milk in 24 hours is lower than 1%, except for some products like iodine 131 and thiouracile where it can reach 5%. The mechanisms of transfer of drugs in milk are complex: both active and passive and influenced by the variations of the composition of milk
In spite of the low passage of drugs in milk, and partly as inactive metabolites, accidents can be observed in the new-born baby.
The excretion in the cow's milk of various drugs used in veterinary medicine or of various compounds like insecticides and weedkillers poses an important problem of hygiene and control.
Sweat can contain traces of compounds such as iodine, bromine, ethanol, salicylic acid, sulphamides and various trace elements. But the sweat elimination appears secondary compared to the renal, hepatic and pulmonary elimination.
Elimination by various secretions
One can find drugs, at least traces of them, in practically all secretions, lacrimal, nasal, bronchial or genital. These routes are secondary for the elimination of drugs but have therapeutic importance, in particular for the treatment of localized infections of microbial or parasitic origin
Artificial methods of elimination
Artificial methods of elimination are used in the case of poisoning by drugs or compounds which endanger the life of patients. One then seeks to eliminate them as fast as possible.
The digestive elimination can be increased by various processes:
- Gastric lavage used frequently because it can withdraw a considerable quantity of poison, even several hours after intake.
- Induced diarrhea, or enema, when the poison is present in large amounts in the intestine.
- Activated charcoal administration known for a long time for its capacity to adsorb a great number of molecules, in particular drugs. It is used, in oral administration or by gastric probe, to reduce the digestive absorption and the bioavailability of toxic products and drugs taken in excess by oral route. The activated charcoal must be given as soon as possible after ingestion of the supposed poison.
This digestive elimination concerns primarily the not yet absorbed drug, but part of the eliminated drug can come from secretion.
Accelerated renal elimination
To accelerate the renal elimination of toxic compounds there are two possibilities primarily: modification of pH of the urine (alkalization to induce the elimination of the acids and acidification for the bases) and osmotic diuresis by the perfusion of hyperosmolar solutions (mannitol for example). These two processes can be combined to obtain an alkalizing osmotic diuresis (sodium bicarbonate for example) or acidifying (ammonium chloride for example).
The maintenance of an high diuresis during treatments by drugs which are eliminated primarily by the kidney and can damage it, such as methotrexate and cisplatin, prevents their renal accumulation and toxicity.
Peritoneal dialysis, hemodialysis and sometimes exsanguinotransfusion are used to compensate for renal impairment.