Drug Excretion PDF

DRUG EXCRETION S. K. AMPONSAH  INTRODUCTION Excretion is a process whereby drugs are transferred from the internal to the external environment. Most drugs are excreted either as parent compound or as metabolite. Excretion of drug is needed for termination of pharmac...

DRUG EXCRETION S. K. AMPONSAH  INTRODUCTION Excretion is a process whereby drugs are transferred from the internal to the external environment. Most drugs are excreted either as parent compound or as metabolite. Excretion of drug is needed for termination of pharmacological action.  Types of excretion 1. Renal excretion 2. Non-renal excretion  Biliary excretion  Pulmonary excretion  Salivary excretion  Skin/dermal excretion  Mammary excretion 3/24/2022 S. K. AMPONSAH 3  1. RENAL EXCRETION The KIDNEY is the major organ for the excretion of drugs. A majority of drugs undergo renal excretion. Drugs are handled by the kidneys in the same manner as physiological substances. The drug undergoes glomerular filtration, active tubular secretion and passive reabsorption. The amount excreted is the sum of the filtered and secreted minus amount reabsorbed. 3/24/2022 S. K. AMPONSAH 4  Renal excretion Glomerular filtration Active tubular secretion Passive reabsorption Passage in urine 3/24/2022 S. K. AMPONSAH 5  (I) GLOMERULAR FILTRATION The glomerular capillary bed is such that it permits fluid filtration while restricting passage of compounds with large Mw. This selective filtration is important in that it prevents the filtration of plasma proteins (e.g., albumin). Several factors, including molecular size and charge are known to affect glomerular filtration.  Glomerular filtration All unbound drugs will be filtered as long as their molecular size is not excessively large. Compounds with an effective radius above 20 Å may have their rate of filtration restricted. Charged substances are usually filtered at slower rates than uncharged compounds, even when their molecular sizes are comparable.  Glomerular filtration Greater restriction to filtration of charged molecules is usually with anions. This is probably due to an electrostatic interaction between the anion and the fixed negative charges within the glomerular capillary wall. Other factors, e.g inflammation of the glomerular capillaries, may increase GFR and drug filtration.  Glomerular filtration Anything that alters drug-protein binding will also change drug filtration rate. Additionally, low renal plasma flow in the newborn may also decrease the glomerular filtration of drugs.  (ii) ACTIVE TUBULAR SECRETION A number of drugs can serve as substrates for the two secretory transport systems in the proximal tubule cells. These transport systems, which actively transfer drugs from blood to luminal fluid, are independent of each other. One transport system secretes organic anions, organic anion transporter (OAT), and the other secretes organic cations, organic cation transporter (OCT). Active tubular secretion  Active tubular secretion One drug substrate can compete for transport with a simultaneously administered or endogenous similarly charged compound. This competition can decrease the overall rate of excretion of each substance. A common example of this phenomena is the inhibition of penicillin excretion by competition with probenecid. After the discovery of penicillin, this drug was very expensive and in short supply, thus probenecid was used to reduce its excretion.  Compounds secreted OAT and OCT systems Organic anion transport (OAT) Organic cation transport (OCT) Acetazolamide Acetylcholine Bile salts Atropine Hydrochlorothiazides Cimetidine Furosemide Dopamine Indomethacin Epinephrine Penicillin G Morphine Prostaglandins Quinine (iii) PASSIVE TUBULAR REABSORPTION Some drugs filtered at the glomerulus can be reabsorbed in the proximal tubules. Passive reabsorption is particularly important for endogenous substances, such as ions, glucose, and amino acids. A small number of drugs may be actively reabsorbed. Passive tubular reabsorption  Passive tubular reabsorption The extent of reabsorption depends on lipid solubility of the drug. Drug metabolism facilitates excretion by forming polar metabolites that are not readily reabsorbed. Ionized drugs are also not reabsorbed across renal tubular cells. The proportion of ionized and non-ionized drugs in renal tubules is affected by urine pH. 3/24/2022 S. K. AMPONSAH 16  Passive tubular reabsorption When urine is acidic, weak acid drugs tend to be reabsorbed. Also, when urine is alkaline, weak bases are extensively reabsorbed. In case of drug overdose, increase excretion of some drugs is made possible by suitable adjustment of urine pH. Pentobarbital (a weak acid) overdose may be reduced by making the urine more alkaline with sodium bicarbonate injection. 3/24/2022 S. K. AMPONSAH 17  2. BILIARY EXCRETION A number of drugs have the potential of being excreted in bile. This favors compounds of Mw greater than 300 Dalton. Numerous conjugated metabolites including glucuronate derivatives are excreted in bile. 3/24/2022 S. K. AMPONSAH 18  Biliary excretion Conjugated drugs are often not reabsorbed from the GIT unless the conjugate is hydrolyzed by gut fllora. Chloramphenicol glucuronide, for example, is secreted into bile, where it is hydrolyzed by gastrointestinal flora and largely reabsorbed. Such continuous recirculation (enterohepatic cycling) may extend duration of action of a drug.  Enterohepatic circulation 3/24/2022 S. K. AMPONSAH 20  Clinical implications of biliary excretion Decreases in biliary excretion have been demonstrated at both ends of the age continuum. This effect occurs as a result of a decrease in one or more of the following factors: hepatic blood flow, transport into bile, or rate of bile formation. Also, the administration of one drug may influence the rate of biliary excretion of a second co- administered compound.  3. PULMONARY EXCRETION Any volatile compound, irrespective of its route of administration, has the potential for pulmonary excretion. Certainly, gases and other volatile substances that enter the body primarily through the respiratory tract are expected to be excreted by this route. No specialized transport systems are involved in the loss of substances in expired air; simple diffusion across cell membranes is predominant.  Pulmonary excretion The rate of loss of gases is not constant; it depends on the rate of respiration and pulmonary blood flow. The degree of solubility of a gas in blood also will affect the rate of gas loss. Gases such as nitrous oxide, which are not very soluble in blood, will be excreted rapidly, that is, almost at the rate at which the blood delivers the drug to the lungs.  Pulmonary excretion Agents with high blood and tissue solubility are slowly transferred from blood to the alveoli. Ethanol, which has a relatively high blood solubility, is excreted very slowly by the lungs. The breath analyzer test is based on a quantitative pulmonary excretion of ethanol. 4. EXCRETION THROUGH SWEAT AND SALIVA Excretion of drugs into sweat and saliva occurs but has only minor importance for most drugs. Excretion mainly depends on the diffusion of the un- ionized lipid-soluble form of the drug across the epithelial cells of these glands.  Excretion through sweat and saliva Compounds enter saliva and sweat at rates proportional to their molecular weight, presumably because of filtration through the aqueous channels in the secretory cell membrane. Drugs or their metabolites that are excreted into sweat may be at least partially responsible for the dermatitis and other skin reactions caused by some therapeutic agents.  Excretion through sweat and saliva Substances excreted into saliva are usually swallowed, and therefore their fate may be the same as that of orally administered drugs. The excretion of a drug into saliva accounts for the taste patients sometimes report even when a drug is administered parenterally.  5. MAMMARY EXCRETION Small amounts of drugs can be excreted in milk and this may affect the suckling neonate. A highly lipid soluble drug can accumulate in milk fat. Low-Mw, un-ionized and/or water-soluble drugs can also diffuse passively across the mammary epithelium and be transferred into milk.  Mammary excretion The greatest drug exposure occurs when feeding of neonate begins shortly after maternal drug administration. Additional factors determining exposure of the infant include milk volume consumed (about 150 mL/kg/day) and milk composition at the time of feeding. Fat content is highest in the morning and then gradually decreases until about 10 pm.  Mammary excretion Whether or not a drug accumulates during breastfeeding is also dependent on infant’s ability to eliminate drug via metabolism and excretion. In general, the ability to oxidize and conjugate drugs is low in the neonate. It follows, therefore, that drug accumulation should be less in an older infant who breast-feeds than in a neonate.