Organic 2 - Drug Metabolism PDF

Organic Pharmaceutical Chemistry Drug Metabolism Organic| Drug Metabolism Contents : Excretion 10 The Receptors 12 Acid–Base Properties of Drugs 19 Acid Strength 21 Percent Ionization 29 Organic| Drug Metabolism All substances in the circulatory system, including drugs, metabolites, and nutrients, w...

Organic Pharmaceutical Chemistry Drug Metabolism Organic| Drug Metabolism Contents : Excretion 10 The Receptors 12 Acid–Base Properties of Drugs 19 Acid Strength 21 Percent Ionization 29 Organic| Drug Metabolism All substances in the circulatory system, including drugs, metabolites, and nutrients, will pass through the liver. Most molecules absorbed from the gastrointestinal tract enter the portal vein and are initially transported to the liver. A significant proportion of a drug will partition or be transported into the hepatocyte, where it may be metabolized by hepatic enzymes to inactive chemicals during the initial trip through the liver, by what is known as the first pass effect. Organic| Drug Metabolism Lidocaine is a classic example of the significance of the first-pass effect. Over 60% of this local anesthetic antiarrhythmic agent is metabolized during its initial passage through the liver, resulting in it being impractical to administer orally. When used for cardiac arrhythmias, it is administered intravenously. Organic| Drug Metabolism This rapid metabolism of lidocaine is useful when stabilizing a patient with cardiac arrhythmias. Lidocaine should be administered intravenously in too much quantities where toxic responses will tend to decrease because of rapid biotransformation to inactive metabolites. Organic| Drug Metabolism An understanding of the metabolic labile site on lidocaine led to the development of the primary amine analog tocainide. In contrast to lidocaine’s half-life of less than 2 hours, tocainide’s half-life is approximately 15 hours, with 40% of the drug excreted unchanged. Organic| Drug Metabolism A study of the metabolic fate of a drug is required for all new drug products. Where we have different situation: 1. Active parent drug converted to in active metabolites. Example lidocaine. 2. An inactive parent drug that is converted to an active metabolite ex. the nonsteroidal anti-inflammatory agent sulindac being reduced to the active sulfide metabolite, the immunosuppressant azathioprine being cleaved to the purine antimetabolite 6-mercaptopurine, and purine and pyrimidine antimetabolites and antiviral agent acyclovir being converted to their nucleotide form acyclovir triphosphate. Organic| Drug Metabolism 3. Often both the parent drug and its metabolite are active. Example about 75% to 80% of phenacetin (now withdrawn from the U.S. market) is converted to acetaminophen. In the tricyclic antidepressant series, imipramine and amitriptyline are N-demethylated to desipramine and nortriptyline, respectively. Organic| Drug Metabolism Although a drug’s metabolism can be a source of hindrance for the medicinal chemist, pharmacist, and physician and lead to inconvenience and compliance problems with the patient, it is fortunate that the body has the ability to metabolize foreign molecules (xenobiotics). Otherwise, many of these substances could remain in the body for years especially certain lipophilic chemical pollutants, including the once very popular insecticide dichlorodiphenyltrichloroethane (DDT). After entering the body, these chemicals reside in body tissues, slowly diffusing out of the depots and potentially harming the individual on a chronic basis for several years. Organic| Drug Metabolism Excretion : The main route of excretion of a drug and its metabolites is 1. Through the kidney. 2. For some drugs, enterohepatic circulation, in which the drug reenters the intestinal tract from the liver through the bile duct and be excreted in the feces. 3. Milk of nursing mothers and so they must be worried, because drugs and their metabolites can be excreted in human milk and be ingested by the nursing infant. Organic| Drug Metabolism Several variables make dosing regimens must be more frequent: If the situation does not favor formation of the drug–receptor complex, higher and usually more frequent doses must be administered. If partitioning into tissue stores or metabolic degradation and/or excretion is favored, it will take more of the drug and usually more frequent administration to maintain therapeutic concentrations at the receptor. Organic| Drug Metabolism The Receptors : Pharmacological response consists of a drug binding to a specific receptor. Many drug receptors are the same as those used by endogenously produced ligands. Example cholinergic agents and synthetic corticosteroids interact with the same receptors as acetylcholine and cortisone bind to them. Organic| Drug Metabolism Binding of drugs to receptors may produce desired or undesired effects. This is depending on 1. The biological distribution of these receptors. Example, the nonsteroidal anti-inflammatory drugs combine with the desired cyclooxygenase receptors at the site of the inflammation and the undesired cyclooxygenase receptors in the gastrointestinal mucosa, causing severe discomfort and sometimes ulceration. Organic| Drug Metabolism 2. Biological distribution of drugs, i.e. the organs and tissues that can be reached by the drug and contain these receptors. Unlike the first generation antihistamines, the second-generation antihistamines, like fexofenadine, are claimed to cause less sedation because it does not readily penetrate the blood-brain barrier. 3. Various receptors with similar structural requirements are found in several organs and tissues. Organic| Drug Metabolism Drug-receptor interaction is an equilibrium process. A good ability to fit the receptor favors binding and the desired pharmacological response. In contrast, a poor fit favors the reverse reaction and the amount of drug bound to the receptor is too small which leads to a much smaller pharmacological effect. Organic| Drug Metabolism Many variables contribute to a drug’s binding to the receptor. These include: 1. The structural classes, since most drugs that belong to the same pharmacological class have certain structural features in common. 2. The 3D shape of the molecule. Very slight changes in structure could cause significant changes in biological activity. These structural variations could increase or decrease activity or change an agonist into an antagonist. 3. The types of chemical bonding involved in the binding of the drug to the receptor. Organic| Drug Metabolism The initial receptor model was based on a rigid lock-and-key concept, with the drug (key) fitting into a receptor (lock). It has been used to explain why certain structural features produce a predictable pharmacological action. Recent model must realize that both the drug and the receptor can have considerable flexibility. The receptor can undergo an adjustment in 3D structure when the drug makes contact, i.e. the drug docks with the receptor. Organic| Drug Metabolism The fit of drugs onto or into macromolecules is not always an all-or-none process as pictured by the earlier lock-and-key concept of a receptor. Rather, it appears to be a continuous process, as indicated by regular increase and decrease in biological activity of a homologous series of drugs. Drug-receptor association may produce productive changes in the configuration of the macromolecule, leading to agonist responses, an antagonistic or blocking response. Similarly, strong drug-receptor associations may lead to unproductive changes in the configuration of the macromolecule, leading to an antagonistic or blocking response. Organic| Drug Metabolism Acid–Base Properties of Drugs : Most drugs used today can be classified as acids or bases. A drug’s acid–base properties can greatly influence its biodistribution and partitioning characteristics. In their definition, an acid is defined as a proton donor and a base is defined as a proton acceptor. Un-ionized acids, like carboxylic acids, donate their protons forming ionized conjugate bases, carboxylate. In contrast, ionized acids, like ammonium compounds, donate proton and yield un-ionized conjugate bases (amine derivatives). Similarly for un-ionized and ionized bases accept protons and yield their ionized and un-ionized conjugated acids respectively. Organic| Drug Metabolism Acid/Conjugated Base and Base/Conjugated Acid Pairs : In biological systems, drug molecules face water everywhere and an acid-base reaction can occur. Water is an amphoteric molecule, can be either a weak base accepting a proton from acidic drugs to form the strongly acidic hydrated proton or hydronium ion (H3O+), or a weak acid donating a proton to a basic drug to form the strongly basic hydroxide anion (OH-). Organic| Drug Metabolism Acid Strength : Two logical questions to ask at this point, these are: 1. How one predicts in which direction an acid–base reaction lies? 2. To what extent the reaction goes to completion? The common physicochemical measurement that contains this information is known as the pKa. The pKa is the negative logarithm of the modified equilibrium constant, Ka which can be calculated as follow (depending on Eq.1): Organic| Drug Metabolism the Ka or pKa are modified equilibrium constants that indicate the extent to which the acid (proton donor) reacts with water to form conjugate acid and conjugate base. The equilibrium for a strong acid (low pKa) in water lies to the right, favoring the formation of products (conjugate acid and conjugate base). The equilibrium for a weak acid (high pKa) in water lies to the left, meaning that the conjugate acid is a better proton donor than the parent acid is or that the conjugate base is a good proton acceptor. It is important to recognize that a pKa for a base (B) is in reality the pKa of the conjugate acid (acid donor or protonated form, BH+) of the base, and the pKa for an acid (AH) is the pKa of its conjugate base (proton acceptor or deprotonated form, A-). Organic| Drug Metabolism Organic| Drug Metabolism Organic| Drug Metabolism Hydrochloric acid, a Ka of 1.26 x 106 means that the product of the molar concentrations of the conjugate acid, [H3O+], and the conjugate base, [Cl-], is huge relative to the denominator term, [HCl]. In other words, there essentially is no unreacted HCl left in an aqueous solution of hydrochloric acid. At the other extreme is ephedrine HCl with a pKa of 9.6 or a Ka of 2.51 x 1010-. Organic| Drug Metabolism Here, the denominator representing the concentration of ephedrine HCl greatly predominates over that of the products, which, in this example, is ephedrine (conjugate base) and H3O+ (conjugate acid). In other words, the protonated form of ephedrine is a very poor proton donor. Free ephedrine (the conjugate base in this reaction) is an excellent proton acceptor. Organic| Drug Metabolism A general rule for determining whether a chemical is strong or weak acid or base is: 1. pKa < 2: strong acid; conjugate base has no meaningful basic properties in water 2. pKa 4 to 6: weak acid; weak conjugate base 3. pKa 8 to 10: very weak acid; conjugate base getting stronger 4. pKa >12: essentially no acidic properties in water; strong conjugate base Organic| Drug Metabolism Percent Ionization : Using the drug’s pKa, we can adjust the pH to ensure maximum water solubility (ionic form of the drug) or maximum solubility in nonpolar media (un-ionic form). This is why understanding the drug’s acid–base chemistry becomes important. Organic| Drug Metabolism Acids can be divided into two types, HA and BH+, on the basis of the ionic form of the acid (or conjugate base). HA acids go from un-ionized acids to ionized conjugate bases. In contrast, BH+ acids go from ionized (polar) acids to un-ionized (nonpolar) conjugate bases. In general, pharmaceutically important HA acids include the inorganic acids (e.g., HCl, H2SO4), enols (e.g., barbiturates, hydantoins), carboxylic acids, and amides and imides (e.g., sulfonamides and saccharin, respectively). Organic| Drug Metabolism The chemistry is simpler for the pharmaceutically important BH+ acids: They are all protonated amines. The percent ionization of a drug is calculated by using equations below: Organic| Drug Metabolism when pH = pKa, the compound is 50% ionized (or 50% un-ionized). In other words, when the pKa is equal to the pH, the molar concentration of the acid equals the molar concentration of its conjugate base. In the Henderson-Hasselbalch equation, pKa = pH when log [conjugate base]/[acid] = 1. An increase of 1 pH unit from the pKa (increase in alkalinity) causes an HA acid (ex. indomethacin) to become 90.9% in the ionized conjugate base form, but in a BH+ acid (ex. ephedrine HCl) decreasing its percent ionization to only 9.1%. An increase of 2 pH units essentially shifts an HA acid to complete ionization (99%) and a BH+ acid to the nonionic conjugate base form (0.99%). Organic| Drug Metabolism Just the opposite is seen when the medium is made more acidic relative to the drug’s pKa value. Increasing the hydrogen ion concentration (decreasing the pH) will shift the equilibrium to the left, thereby increasing the concentration of the acid and decreasing the concentration of conjugate base. Table below summarizes the relation of percent ionization and the pKa. Organic| Drug Metabolism Organic| Drug Metabolism A polyfunctional drug can have several pKa’s (e.g., amoxicillin). At physiological pH, the carboxylic acid (HA acid; pKa1 2.4) will be in the ionized carboxylate form, the primary amine (BH+ acid; pKa2 7.4) will be 50% protonated and 50% in the free amine form, and the phenol (HA acid; pKa3 9.6) will be in the un-ionized protonated form. Organic| Drug Metabolism Knowledge of percent ionization makes it easier to explain and predict why the use of some preparations can cause problems and discomfort as a result of pH extremes. Phenytoin (HA acid; pKa 8.3) injection must be adjusted to pH 12 with sodium hydroxide to ensure complete ionization and maximize water solubility. Organic| Drug Metabolism In theory, a pH of 10.3 will result in 99.0% of the drug being an anionic water-soluble conjugate base. To lower the concentration of phenytoin in the insoluble acid form even further and maintain excess alkalinity, the pH is raised to 12 to obtain 99.98% of the drug in the ionized form. This highly alkaline solution is irritating to the patient and generally cannot be administered as an admixture with other intravenous fluids that are buffered more closely at physiological pH 7.4. This decrease in pH would result in the parent unionized phenytoin precipitating out of solution. Organic| Drug Metabolism Tropicamide is an anticholinergic drug administered as eye drops for its mydriatic response during eye examinations. With a pKa of 5.2, the drug has to be buffered near pH 4 to obtain more than 90% ionization. The acidic eye drops can sting. Some ophthalmologists use local anesthetic eye drops to minimize the patient’s discomfort. Organic| Drug Metabolism The only atom with a meaningful pKa is the pyridine nitrogen. The amide nitrogen has no acid–base properties in aqueous media. Adjustments in pH to maintain water solubility can sometimes lead to chemical stability problems. An example is indomethacin (HA acid; pKa 4.5), which is unstable in alkaline media. Therefore, the preferred oral liquid dosage form is a suspension buffered at pH 4 to 5. Organic| Drug Metabolism Because this is near the drug’s pKa, only 50% will be in the water-soluble form. There is a medical indication requiring intravenous administration of indomethacin to premature infants. The intravenous dosage form is the sodium salt, which is reconstituted just prior to use.