Drug Dose and Its Concentration at Receptors - Essay Example

Drug dose and its concentration at receptors A drug, once administered, has to make a long journey and interact with various body tissues to reach its target receptor site. According to Goodman, et al. (2011, ch. 2), pharmacokinetics divides this journey into the stages of absorption and distribution. The term ‘bioavailability’ refers to the fraction of the dose of the drug given that reaches its site of action. Various characteristics of the drug molecule, the method of administration of the drug used, the route of the drug before it reaches the target receptor, the interactions between the drug molecule and body tissues other than the target, and the nature of the organ where the target receptor is located, all affect the bioavailability. These factors are discussed in more detail below, based on the description of Goodman, et al. (2011, ch. 2). The characteristics of the drug molecule itself that affect the drug’s concentration at the receptor site include its molecular size, degree of ionization, lipid solubility, and its affinity for serum and tissue proteins. The plasma membrane (of skin or intestinal cells, for example) is a common barrier to drug distribution; drugs that are not lipid soluble will not be able to permeate the membrane and not reach the target site. A drug of small molecular size will travel more easily through the membranes than a larger molecule, reaching the target in higher concentrations. Ionized molecules, and those that bind to proteins, also have difficulties in passing through the membrane. If the drug has a tendency to ionize at the pH of the intestinal lumen or the blood, the ionized form will have difficulty passing through lipid plasma membranes. If the drug interacts with transporter proteins on the cell membrane, its uptake into the cell may be increased or decreased, depending on the direction in which the transporter moves the drug. For example, the P-glycoprotein in enterocytes limits the oral absorption of some cancer chemotherapeutic agents by exporting them back into the lumen of the GI tract. Similarly, it has been found that multidrug transporters such as P-glycoprotein (PGP) and members of the multidrug resistance-associated protein (MRP) family are over-expressed in capillary endothelial cells in epileptogenic brain tissue, and, by transporting anti-epileptic drugs out, these proteins may be responsible for the pharmacoresistance of the epileptic brain to anti-epileptic drugs (Löscher and Potschka, 2002). If a drug is capable of binding to plasma proteins such as albumin, then some of the drug molecules in the bloodstream bind to the proteins, while the remaining unbound drug molecules are available to reach equilibrium across all membranes and reach the target receptor. Thus, plasma protein binding limits the concentration of the drug at its site of action. When the site of action of concern is the brain, the capability of the drug to cross the blood-brain barrier determines the concentration of administered drug that can reach the target. The more lipophilic the drug in its unbound, non-ionized form, the greater will be its ability to pass through the endothelial cells forming the blood-brain barrier, and thus the higher will be its bioavailability in the brain. How the route of administration affects the fraction of the drug dose that reaches the target is also important. The most common route of administration is oral, however, this route has several implications on bioavailability, and the dose swallowed will not entirely reach the target site. Only a fraction of the ingested drug is absorbed from the intestine, depending on the factors discussed in the previous paragraph. As more absorption takes place in the intestine than the stomach, any factor that increases stomach emptying (such as such as lying down on the right side and level of physical activity) increases drug absorption as the drug reaches the intestine earlier (Queckenberg and Fuhr, 2009). Some drug molecules may be degraded by stomach acid– the level of stomach acid may affect the dose available for absorption. The absorbed drug molecules are first be taken to the liver, where liver enzymes can alter the drug molecules and lower the bioavailability: this is known as the ‘first pass effect’. The nature of the other medications being taken can also affect the activity of liver enzymes and can affect the drug dose that will be distributed. For example, an enzyme found in the liver, named cytochrome P450 (CYP) 3A4, activates the antiplatelet drug clopidogrel after it is taken orally. Only the activated form can act on platelet receptors. However, the drug atorvastatin is also a substrate for this enzyme. Thus if both medications are taken, atorvastatin competitively inhibits the activation of clopidogrel. Thus, the amount of clopidogrel activated and the concentration available to interact with platelet receptors is decreased in the presence of atorvastatin (Lau et al, 2003). In comparison to oral administration, other routes can be more or less effective. The maximum bioavailability is with the intravenous route, where all of the given drug dose will be distributed. Therefore, the dose of a drug is much lower if it is to be given intravenous rather than oral. The sublingual route allows direct drug absorption into the venous system, bypassing the first-pass effect. This route is thus used for medications that are extensively metabolized in the liver, such as nitroglycerin. The rectal route also bypasses the liver, however, absorption from the rectum is irregular and thus specific blood levels of the drug may not be achieved. When the intramuscular route is used, various external factors such as local heating, massage and exercise hasten the drug’s absorption from the injected site, so that a higher peak concentration reaches the target. The drug formulation and physical characteristics – capsule, tablet, with or without coating, particle size, differences in crystal form – can also lead to differences in bioavailability. These factors affect the disintegration of the drug in the environment and in the body, as well as the rate of dissolution, thus affecting the extent of the drug absorbed into the bloodstream. For example, in the past, dosage forms of a drug from different companies and even different preparations from the same companies sometimes differed in bioavailability. Such differences were seen mainly among oral forms of poorly soluble, slowly absorbed drugs. For example, when metronidazole was first introduced, its generic form did not have the same bioavailability as the tested drug because the manufacturer could not mimic the process of micro-sizing the drug for absorption. Cardiac output, regional blood flow, capillary permeability, and tissue volume are other factors that determine the rate of delivery and the potential amount of drug distributed into tissues and reaching the site of action. The tissues that receive a large amount of blood flow include liver, kidneys, adrenals, brain and heart and thus theoretically, a drug will reach higher concentration if the target receptor is in these tissues, rather than in a less well-perfused area such as the skin. Regional delivery and regional routes of administration can raise the drug concentration in specific target tissues. In the example of the skin, a much higher concentration of drug can be delivered if the topical, rather than oral, route is used. This was demonstrated by McClain Yentzer and Feldman (2009), whose research showed a higher concentration of corticosteroid in the superficial skin layers when topical compared to oral routes were used. In conclusion, a large number of factors affect the concentration of a drug at the site of action once it has been administered, and these are related to the nature of the drug molecule and its formulation, the state of the body’s physiology, and even the external environment. References Goodman, L. S., Brunton, L. L., Chabner, B., & Knollmann, B. C. (2011). Goodman & Gilman's The pharmacological basis of therapeutics, Twelfth Edition. New York: McGraw-Hill Medical. Löscher, W., Potschka, H. (2002). Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther, 301(1):7-14. [Online] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11907151 [Accessed 14 August 2011]. Lau, W.C., Waskell, L.A., Watkins, P.B., Neer, C.J., Horowitz, K., Hopp, A.S., Tait, A.R., Carville, D.G., Guyer, K.E., Bates, E.R. (2003). Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation, 107(1):32-7. [Online] Available from: http://www.ncbi.nlm.nih.gov/pubmed?term=PMID%3A%2012515739 [Accessed 14 August 2011]. McClain RW, Yentzer BA, Feldman SR. (2009). Comparison of skin concentrations following topical versus oral corticosteroid treatment: reconsidering the treatment of common inflammatory dermatoses. J Drugs Dermatol, 8(12):1076-9. [Online] Available from: http://www.ncbi.nlm.nih.gov/pubmed?term=PMID%3A%2020027934 [Accessed 14 August 2011]. Queckenberg, C., Fuhr, U. (2009). Influence of posture on pharmacokinetics. Eur J Clin Pharmacol, 65:109–119. [Online] Available from: http://www.ncbi.nlm.nih.gov/pubmed?term=Influence%20of%20posture%20on%20pharmacokinetics.%20Eur%20J%20Clin%20Pharmacol%2C [Accessed 14 August 2011]. Read More