Pharmacokinetics.pdf

UNIT II Basic Principles of Pharmacology ; -~?-, --- -~ ~. ·, ~ ·~ ,~t1Cf{.r,~:.,. , ,.,...

UNIT II Basic Principles of Pharmacology ; -~?-, --- -~ ~. ·, ~ ·~ ,~t1Cf{.r,~:.,. , ,., ~..,. ' I :·.., and Pharmacokinetics, Pharmacodynamics, Drug Interactions on) is the enzymatically there into cells. Metabolism (biotr ansfo rmati IPHARMACOKINETICS mediated alteration of drug struc ture. out of Excre the tion body. is the move ment of The comb inatio n of ment throu ghou t the body: drugs and their metabolites Pharmacok.inetics is the study of drug move metabolism and excre tion is called elimin ation. The four pharm acokinetic sses: absorption , distribution, There are four basic pharmacokinetic proce processes, acting in concert, determine the conce ntrati on of a drug at metabolism, and excretion (Fig. 4.1 ). Absor ption is the drug's movement the blood. Distributio n is the drug's its sites of action. fro m its site of admi nistra tion into By applying knowledge of pharm acokinetics to drug therapy, we to the inters titial space of tissues and from harm. Recall that movement from the blood can help maximize benef icial effects and minim ize ly related to the concentra- the intensity of the response to a drug is direct ize beneficial effects, a typically covered in unde r- tion of the drug at its site of action. To maxim 'Fundamental pharm acolo gic conce pts are drug must achieve concentrations that are high enoug h to elicit desired ience has demo nstra ted that a refres her ons that are graduate courses; however, exper responses; to minimize harm , we must avoid conce ntrati of pharm acoki netic s, pharm acodynarnics, and appro priate in the basic principles too high. This balan ce is achie ved by select ing the most it is a refresher, the inform a- drug interactions is usually helpful. Because route , dosage, and dosing schedule. tion in this chapter is relatively brief. Metabolism Excretion Distribution Absorption r l _J__~ Liver 1~ I ___ _. Out \ / ----,, ,,, Bile ,,- \ ,_/ I.....--, \ \ \ / Kidney I ___ _. Urine ___ _. Out ·1 1 \....__/I r-- --- - 1 Other sites l I ___ L __ _.1 membranes t hat must be ic Processes. Dotted lines represent fig. 4.1 The Four Basic Phar maco kinet. GI. Gastrointestinal. Grosse d as drugs move throughout the body 13  UNIT II Bas,.c pnn. c1p. Ies of Pharmacology. (PGP) or ,nultidrug tra PASSAGE OF DRUGS AC nrotein P-g 1>":0r GP is a transm nsporter proteit1 d ROSS MEMBRANES menuon. P embrane protem. e5e that transport All four phases of pharm s ~" acokinetics--absorpuon. d' t 'bution, metabo- of drugs out of cells. a"'id lism, and excretion-invo , ,s n h t the e~ lve drug movement. To mo th body, drugs mu st cross me ve roug ou th y em Dir. ect pene tration of the Membrane pass from the site of adm mbranes. Drugs cross m branesd assubse- e d movement throughout inistration into the blood str quently, as they leave the eam an '. Fo~ _mo st ;:; :;a te memb the body is dep vascular system to reac h the site of acuon. 1n ranes directly because (I) add1t. 1on. , drugs must cross memb. d ability top through cha nnels or pores and (2) mo mos:~dcn, excretion. Accordingly, the ranes to un dergO metabolism an large to passh them cro st drugs 11&,1 ~ factors that determine the fd ss all of the membranes. logic. memb passage O rug systems to e1P that sac across bio ranes have a pro,ou' nd m. fl uence on all aspects osf. - s of action, me b 1. ta o ism, an d excretion. pharmacokinetics. from their s1 1e. epara,."' A general rule in chemistry states that "like dissolve Biologic membranes are II Th.. h , s like i,. g most composed of layers of m dIVl ' 'da lc es · e are compose d primarily of hp1ds; t ereiore, to direct)· VJ. cells composin membranes are very cIose to one uanother- 1· 'd membranes, a drug must be 1p1 soIu ble (I'1po.. close, in fact, that drugs so phil1c). y must usually pass throug between them to cross h cells, rather than the membrane. Hence the cross a biologi~ membran ability of a drug to POLAR MOLECULES AND through single cells. e is determined primarily by its ability to pass IONS. kinds of molecules are Certam not lipid soluble and the Three Ways to Cross a penetrate membranes. Th. re',ore Cell Membrane is group consISts of pol ar molecu les and. The three most importa nt ways by which drugs cro Polar Molecules are (1) passage through ss cell membr_anes channels or pores, (2) pas Polar molecules are mo a transport system, and sage with the aid of lecules that have no net (3) direct penetration charge; howev the three, direct penetratio of the membrane. Of have an uneven distributi n of the membrane is mo on of electrical charge. Th st common. negative charges within at is, posi~ the molec~e tend to Channels and Pores from one another. Water congregate is the ~lasslC example. As Very few drugs cross memb the electrons (negative cha depicted in Fir, ranes through channels or rges) m the water molec in membranes are extrem pores. The channels in the vicinity of the oxygen ule spend mort ely small and are specific for atom than in the vicinity Consequently, only the sm certain molecules. atoms. As a result, the are of the two allest of compounds, such a around the oxygen ato sodium, can pass throug as potassium and charged, whereas the are m tends to be h these channels and the a around the hydrogen is the right one. n onl y if the channel positively charged. In acc atoms tends ord with the "like dissol molecules will dissolve ves like" rule, Transport Systems in polar solvents (such nonpolar solvents (such as as water) but Transport systems are car lipids). riers that can move drugs the cell membrane to the from one side of Ions other side. All transport sys Whether a transporter tems are selective. Ions are defined as molec will carry a particular dru ules that have a net ele drug's structure. g depends on the ctrical charge ( · positive or negative). Ex Transport systems are an cept for very small molec important means of dru to cross membranes; theref ules, ions are example, certain orally adm g transit. For ore the y must become inistered drugs could not from one side to the oth nonionized to there were transport system be absorbed unless er. Ma :,v ,) rugs are either s to move them across the or weak organic bases, wh weak organic separate the lumen of the membranes that ich (:: ·, X.",t in charged intestine from the blood. Whether a weak acid or and uncharged could not reach intracellul A number of drugs base c;,,;,:·i:· ,, RU electrica ar sites of action without by the pH of the surrou l charge is det · to move them across the a transport system nd ing r;,c'Jium. Acids cell membrane. One transp (alkaline) media, whereas ten d to ionize in orter, known as bases t -~ ~ = _/ Ionized or 0 =Lipid-solublepolardrugdrug The rape utic rang e The prac tice of regu latin g plas ma 2 drug levels to cont rol drug resp onse -0 sho uld seem a bit odd , give n that s al ( 1) drug resp onse s are rela ted to E con cent ratio ns at sites of acti on drug Mini mum effective and (2) the site of actio n of mos t :g concentratlOn is not in the bloo d. Mor e ofte n drug s a: than not, it is a prac tical imp ossi Dura tion to mea sure drug conc entr atio ns bilit y at sites of actio n. Exp erien ce has show that , for mos t drug s, there is a dire n ct correlation betw een therapeutic and toxi c responses and the amo unt of drug pres ent in plasma. The refo re, Tim e alth oug h we cann ot usua lly mea sure drug conc Dos e acti on, we can dete rmin e plas ma entr atio ns at sites of adm inist ered drug conc entr atio ns that , in turn , are Fig. 4.9 Sing le-D ose Tim e Cou rse.  CHAPTER 4 Pharmacokinetics, Pharmacodynamics, and Drug Interactions r tion. Drug levels then decline as ,metabolism and excretion Plateau Drug Levels a~soJate the drug from the body. Administering repeated doses will cause a drug to build up in the body :c, eliJll use responses cannot occur until plasma drug levels have reached there is a latent perio~ betwe~n drug administration and the f effects. The extent of this delay 1s determined by the rate of onset o until a plateau (steady level) has been achieved. What causes drug levels to reach plateau? If a second dose of a drug is administered before all o~ the p~ior dose has been eliminated, total body stores of that drug b orption. will be higher after the second dose than after the initial dose. As suc- a 5 h duration of effects is determined largely by the combination ceeding doses are administered, drug levels will climb even higher. The of::c, T ebolisrn and excretion. As long as drug levels remain greater than therapeutic respo~ses will be maintained; ~hen levels fall to th th the MEC, benefits will cease. Because metabolism and excretion drug will continue to accumulate until a state has been achieved in which the amount of drug eliminated between doses equals the amount administered. When the amount of drug eliminated between doses equals less thanprocesses most responsible for causing plasma drug levels to the dose administered, average drug levels will remain constant and platea11 are e th. d. fa)), these proc~sses are e prunary etermmants of how long drug will have been reached (Fig. 4.10). effects will persist. Time to Plateau Drug Half-Life When a drug is administered repeatedly in the same dose, plateau will Before proceeding t_o the topic of ~ultiple dosing, we need to discuss be reached in approximately four half-lives. For the hypothetical agent oncept of half-life. When a patient ceases drug use, the combination illustrated in Fig. 4.10, total body stores approached their peak near thec. will of metabolism and ex~ret:Jon ~use ~e amount of drug in the body the beginning of day 5, or approximately 4 full days after treatment to decline. The half-life of a drug 1s an mdex of just how rapidly that began. Because the half-life of this drug is I day, reaching plateau in 4 decline occurs for most drugs. The concept of half-life does not apply days is equivalent to reaching plateau in four half-lives. the elimination of all drugs. A few agents, most notably ethanol As long as dosage remains constant, the time required to reach plateau 10 (alcohol), leave the ~ody at a.'°":tant rate,_ regardless of how much is is independent of dosage size. Put another way, the time required to reach present. The implications of this kind of decline for ethanol are discussed plateau when giving repeated large doses of a particular drug is identical in Chapter 32. to the time required to reach plateau when giving repeated small doses Drug half-life is defined as the time required for the amount of drug of that drug. Referring to the drug in Fig. 4.10, just as it took four in the body to decrease by 50%. A few drugs have half-lives that are half-lives (4 days) to reach plateau when a dose of 2 g was administered extremely short--0n the order of minutes or less. In contrast, the daily, it would also take four half-lives to reach plateau if a dose of 4 g half-lives of some drugs exceed I week. were administered daily. It is true that the height of the plateau would Note that, in our definition of half-life, a percentage-not a specific be greater if a 4-g dose were given, but the time required to reach amount-o f drug is lost during one half-life. That is, the half-life plateau would not be altered by the increase in dosage. To confirm this does not specify, for example, that 2 g or 18 mg will leave the body statement, substitute a dose of 4 g in the previous exercise and see when in a given time. Rather, the half-life tells us that, no matter what the plateau is reached. amount of drug in the body may be, half (SO%) will leave during a specified period of time (the half-life). The actual amount of drug that Techniques for Reducing Fluctuations in Drug Levels is Jost during one half-life depends on just how much drug is present: As illustrated in Fig. 4.1 O, when a drug is administered repeatedly, its the more drug in the body, the larger the amount lost during one level will fluctuate between doses. The nighest levl is referred to as the half-life. , peak concentration, aittl the ~ el is_!!ferred to as the }!gJ!gh.) The concept of half-life is best understood through an example. concentration. The acceptable height of the peaks and troughs will depend Morphine provides a good illustration. The half-life of morphine is on the drug's therapeutic range: the peaks must be kept less than the approximately 3 hours. By definition, this means that body stores of toxic concentration, and the troughs must be kept greater than the morphine will decrease by SO% every 3 hours-regardless of how much MEC. If there is not much difference between the toxic concentration morphine is in the body. If there are SOmg of morphiP-,~in ti:,, body, and the MEC, then fluctuations must be kept to a minimum. 25 mg (50% of SO mg) will be lost in 3 hours; if there ,;,,: 01, The half-life of a drug determines the dosing interval (i.e., how 'C 4 0 much time separates each dose). For drugs with a short half-life,.c (I) the dosing interval must be correspondingly short. If a long dosing £ 3 interval is used, drug levels will fall to less than the MEC between.!: 2 doses, and therapeutic effects will be lost. Conversely, if a drug "' E h~ a long half-life, a long time can separate doses without loss ~ C, of benefits. 0 0 2 3 4 5 6 7 8 9 10 11 12 13 Drug Levels Produced With Repeated Doses Days Multiple dosing leads to drug accumulation. When a patient takes Fig. 4.10 Drug Accumulation With Repeated Administration. The a single dose of a drug, plasma levels simply go up and then come drug has a half-life of 1 day. The dosing schedule is 2 g given once a back down. In contrast, when a patient takes repeated doses of a day on days 1 through 9. Note that plateau is reached at about the drug, the process is more complex and results in drug accumulation. beginning of day 5 (i.e., after four half-lives). Note also that. when The factors that determine the rate and extent of accumulation are administration is discontinued, it takes approximately 4 days (tour half~ives) considered next. for most (94 %) of the drug to leave the body.  UNIT II Basic Principles of Pharmacology pro«dun!, plasma levels can be kept nearly constant. Another is administer a depot prrpamtion which releases the drug slow: ~ t; decline rapidly, thereby making management of However, when an overdose of a drug with I overdos levels of the drug will remain in the body! ong haif-lir: 1~ lli stradily. The third is to rrduce. I.,_ both the size of rad dose and ' he oth:sm: ) F examp1e, ra e management may be needed m. these insta 1or a lo ng tilt} Oe,.. -,qt rntnva (.......,ing the total daily dose constant · or hours nces. e..\IJ 1.' 24 d1r than givin~ the drug from Fig. 4.10 in 2-g doses onc~;~is altered we could give this drug in 1-g doses every 12 hours. 1 ed uld PHARMACODYNAMICS d. h uld ain unchang as wo osmg SC edule, the total daily dose wo rem ting over a range total body stores at plateau. However, instead of fluctua f Pharmacodynamics is the study of the bioch. ffi ernica1 of 2 8 between doses, levels would fluctuate over 8 range O 1 g. e ects of drugs on the body and the molecular mech a~d Ph>'si those effects are produced. To participate rational! ~ntsrns by 0 ~ Loading Doses Versus Maintenance Doses ,. d'. equaI sue, an mte.. rval "f ISCussed previously, we a m1 ·va1 d "nister a drug in repeated doses of. equ1 en t to approxunately. our fi half Ii · ves.. 1s therapeutic objective, an understanding of ph y lit acJii~. essential. armacod,..._ ''! ,.,,..,.,, chi '·teau. When plateau must be achieved more qwckly, rcqurr.,.. to a eve pw. · · 'al d · all DOSE-RESPONSE RELATIONSHIPS a1 d 1 a arge mltl ose can be administered. This arge 1mtJ 1 d ·th ose 1s c ed a loading dose. After high drug levels h~~e been establishe WI a loading The dose-response relationship (i.e., the relationshi b d ose, p Iateau can be maintained by givmg smaller doses. These smaller of an administered dose and the intensity of the re~p etween !ht doses are referred to as maintenance dos~.. · a fu ndamen!al concern m · therapeutJcs. · Dose-respo onse pr0d a:~ 1s Th cl · that use of a loading dose will shorten the tune to plateau... al f determme the m1mm amount o drug needed to elicit nse relati·o may contradict an earlier statement, which ~d that the time to maximal response a drug can elicit, and how much / r_espollse, plateau is not affected by dosage size. However, there 1s no contradiction. 0 dosage to produce the desired increase in response. IIicrease For any specified dosage, it will_alwa~ ~e about four half-lives to reach plateau. When a loading dose 1s administered ~ollowed by maintenance Basic Features of the Dose-Response Relationshi doses, the plateau is not reached for the loading dose. Rather, we have The basic characteristics of dose-response relationships are ill p simply used the loading dose to rapidly produce a drug level equivalent in Fig. 4.11. Part A shows dose-response data plotted on. to the plateau level for a smaller dose. To achieve plateau level for 1inear ~ates. Part Bshows ~e same data_plotted on _semilogarithmic COOr. the loading dose, it would be necessary to either administer repeated (i.e., the scale on which dosage 1s plotted 1s logarithmic rath. and important. doses equivalent to the loading dose for a period of four half-lives or linear). The most obVIOus characteristic reveaier administer a dose even larger than the original loading dose. these curves is that the dose-response relationship is graded. as the dosage increases, the response becomes progressively larger. ,r: Decline From Plateau drug responses are graded, therapeutic effects can be adjusted to fit When drug administration is discontinued, most (94%) of the drug in needs of each patient by raising or lowering the dosage until a res the body will be eliminated over an interval equal to approximately four of the desired intensity is achieved. half-lives. The time required for drugs to leave the body is important As indicated in Fig. 4.11, the dose-response relationship can when toxicity develops. If a drug has a short half-life, body stores will viewed as having three phases. Phase I (see Fig. 4. IIB) occurs at 100 Phase3 100 - Phase 3 ,r/ 75 Q) Q) en C "'C: g_ 0 C. 50 en Q) "' Q) c:c: cc 25 25 10 100 1000 0 10 20 30 40 50 60 70 80 90 100 Dose Dose B _A Fig. ~- Ba~ic ~~ 11 on a linear sea e.. eh T: m onents of the Dose-Response Curve. (A) A dose-response curve with dose plotte_d same dose-response relationship shown in A but with the dose plotted on a logarithmic s of the dose-response curve: Phase 1, The curve is relatively flat; dose~ are scale. Note /~e th_re~/ a;;esponse Phase 2 The curve climbs upward as bigger doses elicit correspondmg_ly t~o low to e 1c1t a s1g~~ ican 3 The cu~e level~ off' bigger doses are unable to elicit a further increase in bigger responses. r11ase , ' b h r ear scale ) response. (Phase 1 'is not indicated in A because very low doses cannot e s own on a in ·