The interaction of drugs in their excretion from the body

The final stage of the pharmacokinetic interaction is excretion - the process of removing drugs or their metabolites are excreted without further chemical modification.

Excretion It carried out mainly through the kidneys, and with bile, through the intestine, lungs, saliva, then, breast milk. The latter is not significant for the mother, but it can have serious consequences for the child. Elimination of some drugs due to the milk, the pH of breast milk a few more acidic, pH than plasma, therefore substances, which are weak bases, They may be found in milk at concentrations equal to or even higher, than in blood plasma. Drugs, nonelectrolytes can easily penetrate into milk, regardless of pH.

The combination of processes of biotransformation (metabolism) and excretion of medicinal substances is known elimination. It is of practical importance and is quantitatively expressed elimination half (half-life, T_1/2), t. it is. time (in hours or minutes), during which half disappears administering to the drug (or its concentration in plasma decreases 2 times). For Example, T_1/2 tolbutamide is 5 no. However, the concomitant use of chloramphenicol T_1/2 tolbutamide increases to 14 no.

The half-life of the drug is determined by its total clearance (Cl). The total clearance is the sum of kidney (Cl_early) and extrarenal (Cl_{in / early}) clearances. Renal clearance is equal to plasma volume (in ml), completely "cleansed" from the drug for 1 m. due to its excretion in the urine. The amount of clearance define filtering, absorption and secretion kanalytsevaya. So, glucose Cl_early=0, As glucose, introduced into the blood, not only completely filtered, but completely reabsorbed. For paraaminogippurovoy acid Cl_early= 600 mL / min.^-1, as it is filtered and secreted into the lumen of the renal tubules, but practically reabsorbed.

The magnitude of renal clearance of drugs may vary as a result of their interaction kidney. The main mechanism of interaction of drugs in the kidneys believe competition between weak acids and weak bases for active tubular transport mechanisms. So, under alkaline urine increases total clearance "acid" substance (acetylsalicylic acid, fenilʙutazona, ʙarʙituratov, salitsilatov, sulfonamides). Therefore, the treatment of sulfonamides to prevent the development of their side effects is recommended alkaline water. This fact is often used in medical practice for the treatment of poisoning by barbiturates. Conversely, elimination of codeine, morfina, novocaine increases with urine acid reaction. Only under acidic conditions decomposes to ammonia, hexamethylenetetramine and formaldehyde, and who have largely antimicrobial effect. Therefore, it is advisable to combine with hexamethylenetetramine atsidifitsiruyuschimi urine means.

Competing for the active transport in the secretion in the tubules of the nephron, One drug decreases the excretion and increases in the body of another. For Example, vыvedenie digoxin amiodarone ponizhayut, verapamil; penicillins - indomethacin, phenylbutazone, acetylsalicylic acid. At the heart of the interaction of drugs lithium and thiazide diuretics increase tubular reabsorption is past, resulting in increased toxicity.

With long-term concomitant use of furosemide and indomethacin inhibition of tubular secretion occurs first and the decrease in the total clearance of the second substance, which clinically manifested decreased urine output, and the possible appearance of side effects of indomethacin. At the same time blocks the secretion of furosemide, aminoglycosides, increases their concentration in the blood, which can lead to long-term use nefronekrozu said combination. Furosemide also inhibits the clearance of ampicillin, cephalosporins.

Different transport mechanisms secretion of anions and cations. Normally displays the products of metabolism, which form conjugates with glycine, sulphates, glucuronic acid. When secretion of various compounds in the form of anion competition is observed between. This phenomenon is used for medicinal purposes. So, probenecid intensive blocks tubular secretion of penicillins, providing a high concentration in blood plasma, that is used to treat a range of infectious diseases of the genitourinary system.

Quinidine almost 2 fold increases the concentration of digoxin in the blood due to the reduction of its tubular secretion, and displacing portions of digoxin binding proteins.

Glucocorticoids can improve renal secretion salicylates, why the sudden cessation of glucocorticoid drugs can cause poisoning by salicylates.

Less than significant impact on the elimination of drugs has a change in glomerular filtration rate in the background of preparations, affecting renal blood flow. So, digoxin as to achieve compensation of circulation can increase the excretion of furosemide with a corresponding increase in its diuretic effect.

It should be borne in mind, that drug interaction on the level of secretion is of practical importance, if the basic substance alone (or an active metabolite thereof) secreted into the tubular unit than at the kidney 80%, and patient disrupt the renal filtration and reabsorption.

For drugs, not excreted through the kidneys, it is important to take into account hepatic clearance (Cl_oven). Biliary excretion is important for substances (if the molecule contains a polar and lipophilic groups; conjugation products, particularly glucuronic acid) molecular weight > 300. For substances, which undergo biotransformation in the liver or communicate it, this rate can be very high. For Example, для морфина Cl_oven = 1500 ml / min.^-1. Hepatic clearance of many drugs (Chlorpromazine and others.) decreases under the influence of inhibitors of microsomal liver enzymes, or under the influence of substances, reducing blood flow in the liver (eg, chloramphenicol, cimetidine). And vice versa, in applying liver enzyme inducers (phenobarbital, rifampicin and the like.) increased hepatic clearance.

Excretion substances then saliva plays a minor role in the overall elimination.

Thus, result of the interaction of drugs in the pharmacokinetic phase - change absorbability, bioavailability, distribution, intensity of metabolic processes and excretion - eventually causes the change of drug concentration in the blood.