Pharmacokinetics I: Drug Administration, Absorption, and Distribution PDF

CHAPTER 2 Pharmacokinetics I: Drug Administration, Absorption, and Distribution Pharmacokinetics is the study of how the body ab- of various routes are discussed here (see Table 2-1)...

CHAPTER 2 Pharmacokinetics I: Drug Administration, Absorption, and Distribution Pharmacokinetics is the study of how the body ab- of various routes are discussed here (see Table 2-1). For sorbs, distributes, and eventually eliminates pharma- a more detailed description of the specific methodol- cological compounds. In other words, what does the ogy involved in drug administration, the references body do with the drug? This area includes the manner at the end of this chapter include several excellent re- in which the drug is administered. sources on this topic.1-3 An introduction to pharmacokinetic principles will help you understand why specific drugs are administered in certain ways. Why, for example, can some drugs be Enteral administered orally while others need to be administered by injection, inhalation, or other non-oral routes? Like- Oral wise, drugs must reach a specific organ or “target” tissue to exert therapeutic effects, and various pharmacokinetic The most common method of enteral medication ad- variables must be taken into account to maximize the ministration is through the oral route, which offers drug’s ability to reach these tissues. Finally, it is critical several distinct advantages. Oral administration is to know how the body metabolizes and eliminates a drug the easiest method for taking medications, especially so that you can be aware of problems that might arise if when self-administration is necessary or desired. The drug metabolism is altered by illness, disease, or other oral route is also relatively safe because drugs enter factors. This chapter will begin by considering various the system in a fairly controlled manner. This avoids a routes of administration. Other pharmacokinetic issues, large, sudden increase in plasma drug levels, which can such as drug absorption, distribution, and storage, will occur when the drug is administered by other methods then be addressed. Drug metabolism will be covered in such as IV injection. Most medications that are admin- the next chapter. istered orally are absorbed from the small intestine, thus utilizing the large surface area of the intestinal microvilli to enhance their entry into the body. Several disadvantages may preclude drugs from be- ROUTES OF ADMINISTRATION ing given orally. Drugs that are administered by mouth must have a relatively high degree of lipid solubility in In general, drugs can be administered via two primary order to pass through the gastrointestinal (GI) muco- routes: the alimentary canal (enteral administration) sa and into the bloodstream. Large, nonlipid-soluble or the nonalimentary routes (parenteral administra- compounds are absorbed very poorly from the ali- tion). Each route has several variations, and each offers mentary canal and will eventually be lost through the distinct advantages and disadvantages. The key features feces. Absorption of some nonlipid-soluble substances 15 16 SECTION 1 General Principles of Phar macolog y Table 2-1 ROUTES OF DRUG ADMINISTRATION Route Advantages Disadvantages Examples Enteral Oral Easy, safe, convenient Limited or erratic absorption of Analgesics; sedative-hypnotics; many some drugs; chance of first-pass others inactivation in liver Rapid onset; not subject to first-pass Drug must be easily absorbed from Nitroglycerin inactivation oral mucosa Rectal Alternative to oral route; local effect Poor or incomplete absorption; Laxatives; suppository forms of other on rectal tissues chance of rectal irritation drugs Parenteral Inhalation Rapid onset; direct application for re- Chance of tissue irritation; patient General anesthetics; antiasthmatic spiratory disorders; large surface area compliance sometimes a problem agents for systemic absorption Injection Provides more direct administration to Chance of infection if sterility is Insulin; antibiotics; anticancer drugs; target tissues; rapid onset not maintained narcotic analgesics Topical Local effects on surface of skin Only effective in treating outer Antibiotic ointments; creams used to layers of skin treat minor skin irritation and injury Transdermal Introduces drug into body without Drug must be able to pass through Nitroglycerin; motion sickness medi- breaking the skin; can provide steady, dermal layers intact cations; drugs used with phonophoresis prolonged delivery via medicated patch and iontophoresis (peptides, small proteins) can be enhanced to some A final limitation of the oral route is that the amount extent by encapsulating these agents in lipid vesicles and rate at which the drug eventually reaches the (liposomes) or biodegradable polymers. This encap- bloodstream is somewhat less predictable compared sulating technique enables the oral administration of with more direct routes, such as injection. Factors that drugs that were formerly administered only through affect intestinal absorption (e.g., intestinal infection, injection or some other parenteral route.4,5 presence of food, rate of gastric emptying, and amount Other drawbacks to the oral route include the fact of visceral blood flow) can alter the usual manner in that certain medications may irritate the stomach and which the body absorbs a drug from the GI tract.1,8,9 cause discomfort, vomiting, or even damage to the gas- tric mucosa. The acidic environment and digestive pro- Sublingual and Buccal teases in the stomach may also degrade and destroy var- ious compounds prior to absorption from the GI tract.4 Sublingual drugs are administered by placing the Drugs that are given orally are subject to a phenom- drug under the tongue. Buccal administration is enon known as the first-pass effect.1,6 After absorp- when the drug is placed between the cheek and gums. tion from the alimentary canal, the drug is transported The drugs are absorbed transmucosally (through the directly into the liver via the portal vein, where a sig- oral mucosa) into the venous system that is drain- nificant amount of the drug may be metabolized and ing the mouth region. These veins eventually carry destroyed prior to reaching its site of action. The dos- blood to the superior vena cava, which in turn carries age of the orally administered drug must be sufficient blood to the heart. Consequently, a drug adminis- enough to allow an adequate amount of the compound tered sublingually or buccally can reach the systemic to survive hepatic degradation and to eventually reach circulation without being subjected to first-pass in- the target tissue.1 Some drugs—such as nitroglycerin— activation in the liver.10,11 This provides an obvious undergo such extensive inactivation from the first-pass advantage for drugs such as nitroglycerin that would effect that it is usually preferable to administer them be destroyed in the liver when absorbed from the through non-oral routes.7 stomach or intestines.  CHAPTER 2 Pharmacokinetics I: Dr ug Administration, Absor ption, and Distribution 17 Sublingual and buccal routes can also provide faster larger nonlipid-soluble agents such as peptides, small effects than swallowing the drug and may be preferred proteins (including insulin), and DNA.16-18 for treating conditions such as acute angina and other One limitation of inhalation is that the drug could ir- types of acute or “breakthrough” pain.12,13 These routes ritate the alveoli or other areas of the respiratory tract. also offer a means of enteral administration to people Also, some patients have trouble administering drugs by who have difficulty swallowing or to patients who can- this route, and drug particles tend to be trapped by cilia not be given drugs rectally.14 However, the amount of and mucus in the respiratory tract. Both of these fac- drug that can be administered through sublingual and tors can limit the ability to predict exactly how much of buccal routes is somewhat limited, and the drug must the drug eventually reaches the lungs. Efforts continue be able to pass easily through the oral mucosa in order to advance the use of inhaled drugs by improving the to reach the venous drainage of the mouth.11 physicochemical properties of these drugs and the de- vices used to deliver them (i.e., inhalers).19-21 Chapter 26 Rectal on respiratory medications covers the technological advancements in inhaled drugs in more detail. A final method of enteral administration is via the rectum using rectal suppositories. This method is less Injection favorable because many drugs are absorbed poorly or incompletely, and irritation of the rectal mucosa may Various types of injection can be used to introduce the occur.1 Rectal administration does offer the advantage drug either systemically or locally. If sterility is not of allowing drugs to be given to a patient who is un- maintained, all types of injection can cause infection, conscious or when vomiting prevents drugs from being and certain types of injection are more difficult, if not taken orally. However, the rectal route is used most of- impossible, for the patient to self-administer. Specific ten for treating local conditions such as hemorrhoids. types of injection include IV, intra-arterial, subcutane- ous, intramuscular, and intrathecal. IV. The bolus injection of a medication into a pe- Parenteral ripheral vein allows an accurate, known quantity of the drug to be introduced into the bloodstream over a All methods of drug administration that do not use the short period of time, frequently resulting in peak lev- GI tract are termed parenteral. Parenteral adminis- els of the drug appearing almost instantaneously in the tration generally delivers the drug to the target site peripheral circulation and thus reaching the target site more directly, and the quantity of the drug that actu- rapidly. This characteristic is advantageous in emer- ally reaches the target site is often more predictable.1 gency situations when it is necessary for the medication Also, drugs given parenterally are not usually subject to exert an immediate effect. Of course, adverse reac- to first-pass inactivation in the liver. Other advantages tions may also occur because of the sudden appearance and disadvantages of various parenteral routes are dis- of large titers of the drug in the plasma. Any unexpect- cussed later in this section. ed side effects or miscalculations in the amount of the administered drug are often difficult to handle after Inhalation the full dose has been injected. In certain situations such as hospitals, an indwelling IV cannula (IV “line”) Drugs that exist in a gaseous or volatile state or that can be used to allow the prolonged, steady infusion of can be suspended as tiny droplets in an aerosol form a drug into the venous system. This method prevents may be given via inhalation. Pulmonary administration large fluctuations in the plasma concentration of the is advantageous because of the large (alveolar) surface drug and allows the dosage to be maintained at a spe- area for diffusion of the drug into the pulmonary circu- cific level for as long as desired. lation, and it is generally associated with rapid entry of Intra-arterial. Injecting a drug directly into an ar- the drug into the bloodstream.1,15 Anesthesia providers tery is a difficult and dangerous procedure. This meth- use the pulmonary route extensively when administer- od permits a large dose of the medication to reach a ing volatile general anesthetics (e.g., halothane). It is given site, such as a specific organ, and may be used to also advantageous when applying medications directly focus the administration of drugs into certain tissues. to the bronchial and alveolar tissues for the treatment Intra-arterial injections are used occasionally in che- of specific pulmonary pathologies.1 The pulmonary motherapy to administer the anticancer drug directly route has also been explored as a way to administer to the tumor site with minimal exposure of the drug to 18 SECTION 1 General Principles of Phar macolog y healthy tissues. This route may also be used to focus access to the cord.27-29 Also, intrathecal injections allow the administration of other substances such as radi- certain drugs—for example, antibiotics and anticancer opaque dyes for various diagnostic procedures. drugs—to bypass the blood-brain barrier and reach Subcutaneous (SC). Injecting medications directly the central nervous system (CNS) (see Chapter 5).1 beneath the skin is used when a local response is de- Other intrathecal injections include administration of sired, such as in certain situations requiring local anes- the drug within a tendon sheath or bursa, which may thesia. Also, an SC injection can permit a slower, more be used to treat a local condition such as inflammation prolonged release of the medication into the systemic within those structures. circulation. A primary example is insulin injection in a patient with diabetes mellitus. SC administration pro- Topical vides a relatively easy route of parenteral injection that patients can perform by themselves, providing they are Drugs given topically are applied to the surface of the properly trained. skin or mucous membranes. Topical medications pri- The SC route can also be used when a drug needs marily help treat problems that exist on the skin it- to be slowly dispersed from the injection site and self, because most medications applied directly to the absorbed into the bloodstream for several weeks or skin are absorbed fairly poorly through the epidermis months.1 A common example of this is the use of hor- and into the systemic circulation. Common examples monal contraceptive products (e.g., medroxyproges- of topical drugs include antibiotics to treat cutaneous terone; see Chapter 30).22 Other methods of controlled infections, anti-inflammatory steroids to reduce skin or prolonged-release drug preparations are addressed inflammation, and various topical products to promote in more detail later in this chapter. wound healing.30-33 To treat various ophthalmological On the other hand, SC injection can deliver only a and otic problems, medications are often applied topi- small amount of drug. Furthermore, the injected drug cally via eyedrops and eardrops, respectively.34,35 must not irritate or inflame the SC tissues. Topical application to mucous membranes is also Intramuscular (IM). The large quantity of skeletal often used to treat problems on the membrane it- muscle in the body allows this route to be easily acces- self.36,37 However, significant amounts of the drug sible for parenteral administration. IM injections are can be readily absorbed through the mucous mem- useful for treating a problem located directly in the in- brane and into the bloodstream. Topical application jected muscle. For example, botulinum toxin and other of drugs to mucous membranes can therefore provide substances can be injected directly into hyperexcitable a fairly easy and convenient way to administer drugs muscles to control certain types of muscle spasms or systemically. Certain medications, for example, can be spasticity (see Chapter 13).23,24 Alternatively, IM injection administered to the nasal mucosa via nasal spray38,39 can provide a relatively steady, prolonged release of the or to other mucous membranes to facilitate systemic drug into the systemic circulation to control conditions absorption and treat disorders throughout the body.1 such as psychosis25 or to administer certain vaccines.26 Nonetheless, the potential for adverse systemic effects IM injection provides a relatively rapid effect (i.e., must also be considered if large amounts of topically within a few minutes) while avoiding the sudden, large administered drugs are absorbed inadvertently into increase in plasma levels seen with IV injection. The ma- the body.37 jor problem with IM administration is that many drugs injected directly into a muscle cause significant amounts of local pain and prolonged soreness, which tends to Transdermal limit the use of this route for repeated injections. Intrathecal. Intrathecal injections deliver the medi- Unlike topical administration, transdermal application cation within a sheath, such as the spinal subarachnoid consists of applying drugs directly to the surface of the space (i.e., the space between the arachnoid membrane skin with the intent that they will be absorbed through and the pia mater that helps form the meninges sur- the dermal layers and into either the subcutaneous rounding the spinal cord). Injecting into the spinal tissues or the peripheral circulation. A transdermally subarachnoid space allows practitioners to apply such administered drug must possess two basic properties: drugs as narcotic analgesics, local anesthetics, and an- (1) It must be able to penetrate the skin, and (2) It tispasticity drugs directly to an area adjacent to the spi- must not be degraded to any major extent by drug- nal cord, thereby allowing these drugs to gain better metabolizing enzymes located in the dermis.40 Absorption  CHAPTER 2 Pharmacokinetics I: Dr ug Administration, Absor ption, and Distribution 19 may be enhanced by mixing the drug in an oily base or in of a drug that affects the myocardium will not have some other chemical enhancer, thus increasing solubility any pharmacological effect unless the drug is absorbed and permeability through the dermis.41,42 from the GI tract into the bloodstream. The extent Transdermal administration provides a slow, con- to which the drug reaches the systemic circulation is trolled release of the drug into the body that is effec- referred to as bioavailability, which is a parameter tive in maintaining plasma levels of the drug at a rel- expressed as the percentage of the drug administered atively constant level for prolonged periods of time.43 that reaches the bloodstream.1 For instance, if 100 mg Drugs administered transdermally are often delivered of a drug is given orally and 50 mg eventually make through medicated “patches” adhered to the skin, it into the systemic circulation, the drug is said to be much like a small adhesive bandage. This method al- 50 percent bioavailable. If 100 mg of the same com- lows the prolonged administration of drugs such as pound were injected IV, the drug would be 100 percent nitroglycerin and some motion-sickness medications bioavailable by that route. such as scopolamine. Transdermal patches can also Consequently, bioavailability depends on the route deliver other medications such as hormonal agents of administration and the drug’s ability to cross mem- (estrogen, testosterone), local anesthetics (lidocaine), brane barriers. Once in the systemic circulation, fur- opioid analgesics (fentanyl),44,45 and nicotine patches.46 ther distribution into peripheral tissues may also be Researchers continue to explore the use of the trans- important in allowing the drug to reach the target site. dermal route, and the use of transdermal patches has Many drugs must eventually leave the systemic capil- gained acceptance as a safe and effective method of ad- laries and enter other cells. Thus, drugs have to move ministering many medications. across cell membranes and tissue barriers if they are to Iontophoresis and phonophoresis also use the be distributed within the body. This section discuss- transdermal route to administer drugs. In iontopho- es the ability of these membranes to affect absorption resis, an electric current “drives” the ionized form of and distribution of drugs. the medication through the skin.47,48 Phonophoresis (also known as sonophoresis) uses ultrasound waves to enhance transmission of the medication through the Membrane Structure and Function dermis.48,49 Physical therapists often use phonophore- sis and iontophoresis to treat pain and inflammation Biological membranes throughout the body act as bar- by transmitting specific medications to subcutaneous riers that permit some substances to pass freely, while tissue such as a muscle, tendon, or bursa. The physical others pass through with difficulty or not at all. This dif- therapist follows a physician’s prescription for an anal- ferential separation serves an obvious protective effect gesic or anti-inflammatory and uses iontophoresis or and limits the distribution of the substance within the phonophoresis techniques to enhance the movement body. In effect, the body is separated into various “com- of that medication through the skin. Specific medi- partments” by these membranes. In the case of pharma- cations that can be administered via iontophoresis or cotherapeutics, a drug often needs to cross one or more phonophoresis are listed in Appendix A. The referenc- of these membrane barriers to reach the target site. es at the end of this chapter include several addition- The ability of the membrane to act as a selective al sources that provide a more detailed description of barrier is related to the membrane’s normal structure how these transdermal routes are employed.47,50,51 and physiological function. The cell membrane is composed primarily of lipids and proteins. Membrane lipids are actually phospholipids, which are composed of a polar, hydrophilic “head” (containing a phosphate BIOAVAILABILITY AND DRUG group) and a lipid, hydrophobic “tail” (Fig. 2-1). The ABSORPTION ACROSS THE CELL phospholipids appear to be arranged in a bilayer, with MEMBRANE the hydrophobic tails of the molecule oriented toward the membrane’s center and the hydrophilic heads Although several routes exist for the administration facing away from the center of the membrane. Inter- of drugs, merely introducing the drug into the body spersed throughout the lipid bilayer are membrane does not ensure that the compound will reach all tis- proteins, which can exist primarily in the outer or in- sues uniformly or that the drug will even reach the ap- ner portion of the membrane or can span the entire propriate target site. For instance, oral administration width of the cell membrane (see Fig. 2-1).