Organic Pharm Chem Lecture 2 PDF

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...

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. 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. 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. 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-). 13  -------- Eq.1 Acid Strength Two logical questions to ask at this point, these are: - How one predicts in which direction an acid–base reaction lies? and - 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): 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 (table below). 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-). 14 15 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-. 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. A general rule for determining whether a chemical is strong or weak acid or base is pKa < 2: strong acid; conjugate base has no meaningful basic properties in water pKa 4 to 6: weak acid; weak conjugate base pKa 8 to 10: very weak acid; conjugate base getting stronger pKa >12: essentially no acidic properties in water; strong conjugate base 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. 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) 16 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). 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: for HA acids for BH+ acids 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%). 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. 17 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. 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. 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. 18 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. 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. 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. Drug Distribution and pKa The pKa can have a pronounced effect on the pharmacokinetics of the drug. Drugs are transported in the aqueous environment of the blood. Those drugs in an ionized form will tend to distribute throughout the body more rapidly than will un-ionized (nonpolar) molecules. then, the drug must leave the polar environment of the plasma to reach the site of action by passing through the nonpolar membranes of capillary walls, cell membranes, and the blood-brain barrier in the un-ionized (nonpolar) form. For HA acids, it is the parent acid that will readily cross these membranes. 19 The situation is just the opposite for the BH+ acids. The unionized conjugate base (B, free amine) is the species most readily crossing the nonpolar membranes. For drug molecules orally administered. The drug first encounters the acidic stomach, where the pH can range from 2 to 6 depending on the presence of food. HA acids with pKa’s of 4 to 5 will tend to be nonionic and be absorbed partially through the gastric mucosa. (The main reason most acidic drugs are absorbed from the intestinal tract rather than the stomach is that the microvilli of the intestinal mucosa provide a large surface area relative to that found in the gastric mucosa of the stomach.) In contrast, amines (pKa 9–10) will be protonated (BH+ acids) in the acidic stomach and usually will not be absorbed until reaching the mildly alkaline intestinal tract (pH 8). Once in systemic circulation, the plasma pH of 7.4 will be one of the determinants of whether the drug will tend to remain in the aqueous environment of the blood or partition across lipid membranes into hepatic tissue to be metabolized, into the kidney for excretion, into tissue depots, or to the receptor tissue. Of course, the effect of protein binding, discussed previously, can greatly alter any prediction of biodistribution based solely on pKa. 20