Organic 1 - Drug Distribution.pdf

Organic Pharmaceutical Chemistry Drug distribution Organic| Drug Distribution Contents : Distribution after Oral Administration 4 Parenteral Administration 15 Protein Binding 26 Tissue Depots 33 Organic| Drug Distribution A drug is a chemical molecule. Following introduction into the body, a drug mu...

Organic Pharmaceutical Chemistry Drug distribution Organic| Drug Distribution Contents : Distribution after Oral Administration 4 Parenteral Administration 15 Protein Binding 26 Tissue Depots 33 Organic| Drug Distribution A drug is a chemical molecule. Following introduction into the body, a drug must pass through many barriers, survive alternate sites of attachment and storage, and avoid significant metabolic destruction before it reaches the site of action, usually a receptor on or in a cell. Organic| Drug Distribution Distribution after Oral Administration : When the drug is administered orally, the drug must go into solution to pass through the gastrointestinal mucosa. Even drugs administered as true solutions may not remain in solution as they enter the acidic stomach and then pass into the alkaline intestinal tract. The ability of the drug to dissolve is governed by several factors, including: 1. Its chemical structure. 2. Variation in particle size and particle surface area. 3. Nature of the crystal form. 4. Type of tablet coating. 5. Type of tablet matrix. Organic| Drug Distribution By varying the dosage form and physical characteristics of the drug, it is possible to have a drug dissolve quickly or slowly. Chemical modification is also used to a limited extent to facilitate a drug reaching its desired target. Organic| Drug Distribution Any compound passing through the gastrointestinal tract will encounter a large number and variety of digestive and bacterial enzymes, which, in theory, can degrade the drug molecule, therefore, a new drug molecule under investigation will likely be dropped from further consideration if it cannot survive in the intestinal tract or its oral bioavailability is low, leading to necessitating an alternate route, including parenteral, buccal, or transdermal, when there is no effective alternative for this new drug, or this new drug is more effective than existing products and can be administered by one of these alternate routes. Organic| Drug Distribution An example is olsalazine, used in the treatment of ulcerative colitis. This drug is a dimer of the pharmacologically active mesalamine (5-aminosalicylic acid). Organic| Drug Distribution The latter is not effective orally because it is metabolized to inactive forms before reaching the colon. The dimeric form passes through a significant portion of the intestinal tract before being cleaved by the intestinal bacteria to two equivalents of mesalamine. Organic| Drug Distribution In contrast, these same digestive enzymes can be used to be advantageous. Example, chloramphenicol is water soluble enough (2.5 mg/mL) to come in contact with the taste receptors on the tongue, producing an unpalatable bitterness. Organic| Drug Distribution To mask this intense bitter taste, the palmitic acid moiety is added as an ester of the primary hydroxyl of chloramphenicol (i.e. chloramphenicol palmitate). This reduces the parent drug’s water solubility (1.05 mg/mL), enough so that it can be formulated as a suspension that passes over the bitter taste receptors on the tongue. Once in the intestinal tract, the ester linkage is hydrolyzed by the digestive esterases to the active antibiotic chloramphenicol and the very common dietary fatty acid palmitic acid. Organic| Drug Distribution Olsalazine and chloramphenicol palmitate are examples of prodrugs. Most prodrugs are compounds that are inactive in their native form but are easily metabolized to the active agent. Olsalazine and chloramphenicol palmitate are examples of prodrugs that are cleaved to smaller compounds, one of which is the active drug. Occasionally, the prodrug approach is used to enhance the absorption of a drug that is poorly absorbed from the gastrointestinal tract. Organic| Drug Distribution Enalapril is the ethyl ester of enalaprilic acid, an active inhibitor of angiotensin-converting enzyme (ACE). The ester prodrug is much more readily absorbed orally than the pharmacologically active carboxylic acid. Organic| Drug Distribution Unless the drug is intended to act locally in the gastrointestinal tract, it will have to pass through the gastrointestinal mucosal barrier into venous circulation to reach the site of the receptor. Organic| Drug Distribution This journey involves distribution or partitioning between: 1. The aqueous environment of the gastrointestinal tract. 2. The lipid bilayer cell membrane of the mucosal cells. 3. Possibly the aqueous interior of the mucosal cells. 4. The lipid bilayer membranes on the venous side of the gastrointestinal tract. 5. The aqueous environment of venous circulation. Organic| Drug Distribution Parenteral Administration : Many times, there will be therapeutic advantages in bypassing the intestinal barrier by using parenteral (injectable) dosage forms. These include: 1. Patients who, because of illness, cannot tolerate or are incapable of accepting drugs orally. 2. Some drugs are so rapidly and completely metabolized to inactive products in the liver (first-pass effect) that oral administration is precluded. Organic| Drug Distribution This does not mean the drug administered by injection is not opposed by some of the obstacles which can occur regardless to route of administration. These are: 1. Intravenous administration places the drug directly into the circulatory system where it will be rapidly distributed throughout the body, which can put the drug (in addition to the receptors) in to many unwanted places including tissue depots and the liver (where most biotransformations occur). Organic| Drug Distribution 2. Subcutaneous and intramuscular injections show slow distribution of the drug because it must diffuse from the site of injection into systemic circulation. These parenteral routes produce a depot in the tissues from which the drug must reach the blood or lymph. Once in systemic circulation, the drug will undergo the same distributive phenomena as orally and intravenously administered agents before reaching the target receptor. Organic| Drug Distribution 3. The blood-brain barrier, BBB, permeation: like other route of administration, parenterally administered drugs may not cross the BBB which is composed of membranes of tightly joined epithelial cells lining the cerebral capillaries which protects the brain from exposure to a large number of metabolites and chemicals. Organic| Drug Distribution This makes it is possible to bypass the BBB by injecting the drug directly into specific organs or areas of the body. Intraspinal (ex. local anesthetics) and intracerebral routes will place the drug directly into the spinal fluid or brain, respectively. Organic| Drug Distribution The prodrug approach can also be used to alter the solubility characteristics, which, in turn, can increase the flexibility in formulating dosage forms. For example, the solubility of methylprednisolone can be altered from one to another form as follow: 1. Methylprednisolone: it is slightly water-insoluble and is normally found in tablets. Organic| Drug Distribution 2. Methylprednisolone acetate: it is essentially water-insoluble. This acetate ester is found in topical ointments and sterile aqueous suspensions for intramuscular injection. It is hydrolyzed to the active methylprednisolone by the patient’s own systemic hydrolytic enzymes (esterases). 3. Methylprednisolone sodium succinate: it is water-soluble sodium salt of succinate ester. It is used in oral, intravenous, and intramuscular dosage forms. The succinate esters are hydrolyzed to the active methylprednisolone by the patient’s own systemic hydrolytic enzymes (esterases). Organic| Drug Distribution Organic| Drug Distribution Another example of how prodrug design can significantly alter biodistribution and biological half-life illustrated by the two drugs based on the retinoic acid structure used systemically to treat psoriasis, a nonmalignant hyperplasia. Organic| Drug Distribution Etretinate has a 120-day terminal half-life after 6 months of therapy. In contrast, the active metabolite, acitretin, has a 33-96 hour terminal half-life. Both drugs are potentially teratogenic. Organic| Drug Distribution Acitretin, with its shorter half-life, is recommended for a woman who would like to become pregnant, because it can clear from her body within a reasonable time frame. Organic| Drug Distribution Protein Binding : Once the drug enters the systemic circulation, it can undergo several events. It may stay in solution, but many drugs will be bound to the serum proteins, usually albumin. Organic| Drug Distribution The drug can remain in systemic circulation bound to albumin for a considerable period and not be available to the sites of biotransformation, the pharmacological receptors, and excretion. Organic| Drug Distribution Protein binding can have a profound effect on the: 1. Drug’s effective solubility. A drug with such poor water solubility that therapeutic concentrations of the unbound (active) drug normally cannot be maintained still can be a very effective agent. The albumin–drug complex acts as a reservoir by providing large enough concentrations of free drug to cause a pharmacological response at the receptor. Organic| Drug Distribution 2. Drug’s biodistribution. Protein binding may also limit access to certain body compartments. The placenta is able to block passage of proteins from maternal to fetal circulation. Thus, drugs that normally would be expected to cross the placental barrier and possibly harm the fetus are retained in the maternal circulation, bound to the mother’s serum proteins. Organic| Drug Distribution 3. Drug’s half-life in the body and drug’s duration of action. Drug’s half-life in the body and drug’s duration of action. The albumin–drug complex acts as a reservoir by providing large enough concentrations of free drug to cause a pharmacological response at the receptor. The drug–protein complex is too large to pass through the renal glomerular membranes, preventing rapid excretion of the drug. Protein binding limits the amount of drug available for biotransformation and for interaction with specific receptor sites. Organic| Drug Distribution 3. Drug’s half-life in the body and drug’s duration of action. For example, the large, polar trypanocide suramin remains in the body in the protein-bound form for as long as 3 months (t1/2 = 50 days). The maintenance dose for this drug is based on weekly administration. At first, this might seem to be an advantage to the patient, but when the patient have serious adverse reactions, a significant length of time will be required before the concentration of drug falls below toxic levels. Organic| Drug Distribution 4. Interaction with other drugs. The drug–protein binding phenomenon can lead to some clinically significant drug– drug interactions that result when one drug displaces another from the binding site on albumin. For example, a large number of drugs can displace the anticoagulant warfarin from its albumin-binding sites. This increases the effective concentration of warfarin at the receptor, leading to an increased prothrombin time (increased time for clot formation) and potential hemorrhage. Organic| Drug Distribution Tissue Depots : The drug can also be stored in tissue depots. Neutral fat constitutes some 20% to 50% of body weight and constitutes a depot of considerable importance. The more lipophilic the drug, the more likely it will concentrate in these pharmacologically inert depots. The ultra–short-acting, lipophilic barbiturate thiopental’s concentration rapidly decreases below its effective concentration following administration. Organic| Drug Distribution It disappears into tissue protein, redistributes into body fat, and then slowly diffuses back out of the tissue depots but in concentrations too low for a pharmacological response. Thus, only the initially administered thiopental is present in high enough concentrations to combine with its receptors. The remaining thiopental diffuses out of the tissue depots into systemic circulation, in concentrations too small to be effective, which then is metabolized in the liver, and is excreted. Organic| Drug Distribution In general, structural changes in the barbiturate series that favor partitioning into the lipid tissue stores decrease duration of action but increase central nervous system (CNS) depression. Conversely, the barbiturates with the slowest onset of action and longest duration of action contain the more polar side chains. This latter group of barbiturates both enters and leaves the CNS more slowly than the more lipophilic thiopental. Organic| Drug Distribution