tions of a given drug lead to greater absorption rates. In terms of dermal/topical application, drugs with greater periods of skin contact will be absorbed at a correspondingly higher rate. In ad- dition, children and older adults absorb topical medications more easily when compared to healthy adults. With regards to inhal- ants, greater breathing depth can maximize absorption (Watkins, 2013, p. 15). Additional physical pharmacy considerations during this stage include ionization, molecule size, partition coefficient, surface area, solubility and regional blood flow. The Partition Law governs that a drug solute will self-distribute between two sol- vents until the concentration of each solvent is equal in terms of solubility ratio (Amiji, 2014, p. 106). This extends to pH variability and drives physiologic functions, such as drug ionization in the presence of gastric fluid, and can be affected by factors such as comingling with food in the intestine. The drug may then pas- sively diffuse into intestinal capillaries and distribute in the blood. Once it reaches systemic circulation, a drug is then swiftly dis- tributed throughout the body to the organs. As the drug is transported in the blood stream, the rate of organ distribution is dependent on blood supply. Organs with greater perfusion will distribute a drug more quickly; this includes the kidneys, brain and liver (Amiji, 2014, p. 10). On the other hand, distribution is relatively slower in the skin, muscle and fat. Arterial distribution leads to the capillaries, which allow a drug to pass into the cel- lular interstitium. Free drug may bind to plasma proteins in the blood as well as tissue elements such as cellular proteins and/or structures of a cell membrane (Amiji, 2014, p. 10). The process of drug binding within organs can lead to drug buildup, which can reduce distribution rate and extend its action. This accounts for the potential for adverse effects, especially if the drug is harmful to a specific cellular tissue. Drugs primarily metabolize in the liver. Enterohepatic circulation of a drug leads to the liver via the hepatic portal system. The drug is transported to juncture with blood from the hepatic ar- tery, metabolized within the liver, and ultimately transported into hepatocytes (Amiji, 2014). The drug’s first pass metabolism oc- curs within the hepatocytes, as the drug interacts with metabolic enzymes. This process reduces the bioavailability of the drug prior to systemic circulation and must be accounted for with regards to pharmaceutical dosage. The drug and metabolites may be trans- ported either to the hepatic veins for systemic distribution, or to the gallbladder for deposition back into the intestinal lumen. The drug that returns to the intestinal lumen may either be excreted in feces or reabsorbed into enterocytes and returned to the liver for an additional round of enterohepatic circulation. This process, termed enterohepatic cycling (Amiji, 2014, p. 10), extends the pe- riod of time when the drug is present within and acting upon the body. Drugs administered across tissues in the lungs, skin, eyes and nasal mucosa bypass the first-pass effect. The epithelium of the small intestines is a significant extrahepat- ic site of metabolism, along with the placenta, skin, lungs and kidneys (Amiji, 2014, p. 12). Drug metabolism takes place in two phases. Phase I, known as functionalization , entails enzymatic ad- dition or exposure of a polar functional group to improve hydro- philicity for the purpose of excretion. In addition, Phase I may also include hydrolysis (addition of a water molecule) and reduc - tion. Many times, a drug will recirculate through the body after Phase I and may still be active in terms of pharmacological and/or toxic effects. During Phase II, known as conjugation , the remain - ing drug compound is further modified to increase the polarity and molecular weight of drugs and/or drug metabolites via ad- dition of a polar functional group, to increase hydrophilicity and prohibit passive diffusion back into systemic circulation. Common polar compounds involved in Phase II include sulfuric acid, acetic acid, amino acids and glucuronic acid (Amiji, 2014, p. 12). Protein- binding can also regulate metabolism. A pharmaceutical compound may include a protein binder in or- der to delay metabolism. Per Amiji et al. (2014), only an unbound drug can interact with a receptor and induce a given pharmaco- logical effect. Drugs also interact with proteins that are naturally
the transition from a drug’s dosage form to a molecular form that can be absorbed into the body. Factors that affect this process include the physical formulation of the drug; ionic polarity of the drug; water solubility and particle size; specificity of protein bind- ing; lipophilicity for passive diffusion; and individual active and/or passive transport across biological membranes (Amiji 2014). Pharmaceutical transport is governed by the law of thermodynam- ics, which states that a given reaction will persist in one direction or another until the free energy between the products and reac- tants is equal, i.e. the point of equilibrium. Amiji et al. (2014) apply this concept to drug transport from the gastrointestinal tract into the blood stream. Per thermodynamic principles, this reaction is facilitated because the concentration of the drug and associated free energy is greater than the concentration and energy of the drug in the blood stream. Transport of drug molecules across natural or artificial boundaries, termed solute transport , includes passive, facilitated, active and cellular transport. Passive transport is driven by differences in con- centration and chemical potential, also known as diffusion , during which molecules transport from regions of high concentration to- ward regions of low concentration, until equilibrium is achieved. Common examples of diffusion include transdermal medication and renal reabsorption. Transport of molecules by liquid or gas- eous carrier transport is known as convection . Common examples include blood transporting oxygen, pharmaceutical molecules, nutrients and other materials (Amiji, 2014, p. 118). Facilitated transport occurs when drug molecules are transported via attach- ment to a carrier, and commonly takes place across biological membranes. Active transport includes movement of molecules against a concentration gradient, from regions of low concentra- tion to those of high concentration. Chemical energy is required to facilitate active transport, the most common of which is adenosine triphosphate (ATP). Active trans - port is associated with biochemically precise regulation of nutritive molecules. Common examples include the cellular pump system of sodium and potassium across cell membranes to maintain high extracellular concentrations of sodium, and high intracellular con- centrations of potassium, for the purpose of neurologic action po- tentials (Amiji, 2014). Additional examples include hydrogen ion transport into the stomach during digestion, and P-glycoprotein action at the blood-brain barrier (additional details can be found in the “biological drug resistance” section). Cellular transport includes uptake of liquid matter and macromolecules, immune- driven phagocytosis, as well as efflux of synthesized proteins and waste products out of the cell. The latter process of efflux, known as exocytosis , is exemplified by the pancreatic secretion of insulin from beta islet cells. Transport of solvents in water is achieved by developing osmotic pressure gradients to drive a pharmaceutical across a semiperme- able membrane, most often cells and mucosal surfaces. Isotonic solvents have osmotic pressures relatively equal to biological fluids (Amiji, 2014, p. 121). Sodium chloride is a common phar- maceutical isotonic solvent, administered parenterally through an intravenous line during acute medical care. Diffusion rates can be controlled by specific design of a given membrane. This accounts for pharmaceuticals that are termed “extended” or “controlled” release. The membranes for these products are specifically de- signed, either by a manufactured polymer reservoir membrane or hydrophobic matrix. Common rate control pharmaceuticals are oral and transdermal. Absorption is the process by which a drug moves from the ad- ministration site into the bloodstream. Enteral pharmaceutical ab- sorption occurs mainly in the intestines via passive diffusion into absorptive cells known as enterocytes . Absorption rate and bio- availability can be affected by a number of physiologic, as well as pharmaceutical, factors. Medications that are more soluble in fat or lipids can be absorbed more easily from the intestines into the bloodstream. Medications with lower pH, meaning they are more acidic, are more easily absorbed in the stomach, while more basic compounds are not as readily taken in. As well, higher concentra-
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