CHAPTER 1_| Pharmacokinetics a Pharmacokinetics explores the process of absorption, distribution, metabolism, and excretion of drugs. ADME Intravascular Administration ) extravascular Administration ) > 7 No Absorption (Gbsorption) Whole Blood or Plasma Drug For Step 1, you must be able to: % Protein Bound ) > Identify te routes of acministation. > Explain ciffusion, atsorption, distribution, metabolism, and %Free ) elimination el > Solve pharmacokinetic _(active)_) calculations for single and chronic dosing with drugs. Tr Distribution to Tissues) 100% Co —> Lungs 30% Co ——® Liver [7 be IS A ne, EP Hiner "Pharmacology" @ Therapeutic Toxic ‘A Figure 1-1.0 Geheral Principles of Pharmacokinetics © bate /taclar etonl Devaapment Corp Al gh reed Chapter 1-1Chapter 1 Pharmacokinetics BED routes of Administration (Po): * Most common route of administration © Considerations —Bioavailability Fraction (%) —p Blood Stomach —Enzymes —Motility — Diseases/Drugs —Portal circulation and first-pass metabolism by liver ex Nitroglycevin! (CAngina/ml) Dose of drug Bicavailability: fraction of drug in systemic circulation + Motility Surface area avoid oral ter taste; hildren) AFigure 1-2.0 Oral Route of Administration |" Intravenous (IV): * Introduces drug directly in circulation © No absorption « Invasive i © Intramuscular (IM): ex: Leuprolide * Alternative when IV access difficult (GnRH analog) * Depot injections for slow release over days to weeks = Subcutaneous (SQ) = Transdermal (skin patch) — Pain = Inhalation: © Fastest route of absorption —— Asthuia < Su 0 © Requires aerosolized or nebulized drug © Intrathecal: Drug introduced in subarachnoid space Chapter 1-2 Can't cross BBB Aumphotericin B tecture ES Pharmacology Clinical Application Avoiding fist pass. metabolism: + Sublingual nitroglycerin for angna + Wilidocaine for arthythoia Igantiarthythwic Grose)Chapter 1 + Pharmacokinetics Diffusion or Transport of Drug Across Membranes = Drugs may diffuse across membranes. = Drugs may be carried by proteins across membranes. 3.1 Modes of Drug Transport Across a Membrane VWTable 1-3.1 Three Basic Modes of Drug Transport Across a Membrane Mechanism | Direction ECoG fete Passive Down oradlent ®@ Girton © Facilitated | Down aradient No Yes Yes iffusion ‘Active | cee Yes. Yes Yes sersrens | ea 3.2. Diffusion Rate Amount per time (GA) _ so. Decacx ST x Se Diffusion rate depends on: . SGT e cas pores GE Mn ORI ne on f the drug diffuses down its concentration FH/PK gradient. = Two membrane parameters: PARK —Non-ionized drug is more lipid soluble and diffuses better. ‘PK _Tonized drug is more water soluble and tends not to diffuse well. » SIZE = Size of drug molecule: tecture EES Pharmacology Connection to Physiology For discussion of membrane transport see Physiology, chapter 2 WM intestine sorption Cchaptor 1-3Chapter 1 Pharmacokinetics 3.3. Role of pH and pK in lonization of Drugs = Most drugs are weak acids or weak bases ™ Most drugs exist in either non-ionized or ionized forms in an equilibrium, = This depends on: + pHof the environment "2 Stomach © pKa of the drug BlooA 7.4 ™ pH is variable Urine a PK belongs to a drug and is constant ™ pk is the pH value at which the drug is 50% ionized and 50% non-ionized Weak acia uvionizea J 100 80 Lipid soluble § & ifia soluvle § SF 5 40 2 = 20 oO pH-pk lonizea HH < pK <—— Neutral —» pH > pK Lots oP HY Fe AGas pHsek toregaac Less Ht —> Hrgoes on the Arug —> Less Hron Arug! ‘A Figure 1-3.3A Degree of lonization and Clearance vs. pH Deviation From pKa Chapter 1-4 tecture ES Pharmacology Important Concept For weak acids and weak bases: Ionized = water eoluble/better excretion |Nontonized = lpia solubie/ better ifusion Clinical ‘Application Hepatic Encephalopathy Gut bacteria mesabolize lactulose t lactic acid, acidityingthe fecal masses and causing ammonis(NFL)o become ammonium@MH) which is ionized and fall oceted, Aviwnonion betChapter 1 Pharmacokinetics ead eee ee || -.. Ora weak base? oneaa, in ratio on —_ ratio ee What is the unit difference between pH and pk? Nod 3@ps 5% is If 4, ratio is If 2, ratio is 1f3, ratio is 50%/50% 90%6/10% 99%/1% '99199%/0.1% Example: The@aDanticoagulant warfarin is 2 weak acid of PKS. 1. pH < pk, drug is mainly protonated Acidic Ph ‘3. Three units between oH and pk; <$—> 0.1% R00" ‘Conclusion: The drug is primarily non-ionized and well absorbed. AFigure 1-3.3B Approach to pH/pK Problems {© Dy /Bacar Edcational Davlopmant Corp. Al gerard tecture ES Pharmacology WA ventio? 99.492 /0.0\% protonated Chapter 1-5Chapter 1 * Pharmacokinetics 3.4. Ionization Increases Renal Clearance of Drugs = Only the free drug is filtered by the glomerulus. ®™ Both ionized and non-ionized forms of a drug are filtered. = Whereas a non-ionized drug can be secreted or reabsorbed, © Acidification of urine > \creases renal elimination © Akalrization of urine —> Increases renal elimination > R-COOH). Glomerulus Proximal tubule Secretion — fonized Drug — lon-ionized Drug AFigure 1-3.4 Renal Clearance of a Drug Chapter 1-6 tecture ES Pharmacology Clinical Application + NH,Cl Alkalinization of urine: + Nalco, (historically)Chapter 1 Pharmacokinetics the site of its administration. . ind there is no loss of drug = Extravascular administration: Less than 100% of a dose may reach the systemic circulation because of variations in bioavailability. 4.1, Plasma Level Curves from Time to peak Pl Maximal drug level obtained from one dose. ‘Time at which Cnax occurs, Lag time = Time from adminstration to appearance in blood. ‘Onset of activity = Time from administration to blood level reaching ‘minimal effective concentration (MEC), Duration of action ~ Time plasma concentration remains greater than MEC. Time to peak = Time from administration to Cras. AFigure 1-4.1 Plot of Plasma Concentration vs. Time tecture EES | Pharmacology Minvotane Concept Elimination is usualy biphasic: 11. Rapid decrease in blood concentration due to tissue distribution. 2. Slower decrease in blood Concentration due to metabolism and excretion. Cchaptor 1-7Chapter 1 + Pharmacokinetics 4.2. Bioavailability (f) Bioavailability is the fraction of a dose that reaches the systemic circulation. = Intravascular doses have 100% bioavailability (f = 1). = Bioavailability is calculated as the ratio of area under the curves of a dose given extravascularly against a dose given by IV, Intravascular dose (era iv bolus) f= Ae 00 AUC, ost s00% A 19 Drug Concentration Time AFigure 1-4.2 Comparison of Plasma Level Curves Following IV vs. Extravascular Administration IPE = 0.5 —p 50% dose given reaches blood stream > x2 dcse f= 025 > x4 f=0.1 —»xl0 to Fl tecture ES Pharmacology —> Adjust dose according Chapter 1-8 (© 00Viy char Eduetional Davalepmant Cop, AlvighterearendChapter 1 * Pharmacokinetics 4.3. Bioequivalence . of the same drug are bioequivalent © Bioequivalent formulations can be used interchangeably (e.g., generic versus trade name of the drug, capsule versus tablet). . and (see Figure 1-4.3). . and (Tage Tad (Cyraxr Tras) ® Bioequivalence is most important for drugs with narrow MEC MTC _ Tk TB AFigure 1-4.3 Formulations That Are Not Bioequivalent (© Dy /Bacar Edenton! Drvlopment Corp. Al ge reared tecture ES Pharmacology Chapter 1-9tecture ES Chapter 1 + Pharmacokinetics Pharmacology SS pistribution Eee Factors influencing distribution include: = Drug chemistry = Plasma protein binding = Tight versus fenestrated capillaries = Blood-flow rate to organs 5.1 Plasma Protein Binding ZOeet = Under normal conditions, Oarng |. Consequently, the sen = Amount ™ Plasma proteins include: - Abinity © Albumin © Globulins © Apoproteins © Glycoproteins Drug + Protein 5 — Drug-Protein Complex (Active, free) (Inactive, bound) = C@mpetitIo between drugs for plasma protein-binding sites May increase the "free fraction," possibly enhancing the effects of the drug displaced. = Example: Sulfonamides can displace bilirubin from albumin binding sites and cause in a neonate. Contraindicated 5.2 Special Barriers to Dist ution 5.2.1 Placental Barrier = Small and lipid-soluble drugs can easily cross the placental barrier = In pregnancy, there are two considerations in choosing the safest drug: * Awater-soluble alternative, if available, is the safest. Example: = is large and water soluble. is small and lipid soluble. Example: Hyperthyroidism —Methimazole is < 10% bound. 5.2.2 Blood-Brain Barrier "= Same principles as placental barrier. ® Inflammation disrupts the blood-brain barrier. Chapter 1-10 (© 00Viy/charEduetinal Davalepmant Cop, AlvightemearendChapter 1 * Pharmacokinetics math fume relating the dose given with the blood/ plasma concentration of the drugs. Dg er = Vin ™(G)s extrapolated from the elimination curve (see topic 7, mination"). = Whereas: * C, and dose are proportional to each other (x 2 Aose ———p> © C, and V, are inversely related . High Vv, incleates a drug with large tissue distribution (e.g., luoxetine V, = 2,500 L/70 ka). = Low v,nccates a drug primary ound nthe boc (e., wrosemide V, = 7.71/70 ks). irosemide . High pene oie Body tends to lower V, (e.9., furosemide = High tissue protein binding tends to increase V,. = Competition with protein binding will alter V,: © 7 Free fraction can diffuse from: —Blood to tissue and 7 V, —Tissue to blood and + Vv, —Example: Verapamil or quinidine displace: tissue-binding site, J digoxin V, aatgon Ne 5.4 Redistribution = Lipid-soluble drugs redistribute into fat tissues prior to elimination. . may than on the half-life. © With @ second dose, the blood/t /fat is less; therefore, the rate of redistribution is less and the second dose has a longer = Redistribution of anesthetics can result in prolonged residual effects (e.g., propofol, thiopental). Active | CNS Rapid il = ood pe fay—b mination AfFigure 1-54 Redistribution tecture ES Pharmacology x 2c) Micron concen Know physiological V, for Step 4: + Total body water 0.61/ke, (obesity {,tean 1) + ECF wator: 0.2 Wig + Blood: 0.08 L/kg 1a: 0.04 Lg + Fat:0.2100.35 ke, A Highva +B v4, Chapter 1-11Chapter 1 « Pharmacokinetics BO bn, Metabolism = The general principle of drug metabolism is the metabolic conversion of drug molecules to more water-soluble metabolites that are more readily excreted. © Figure 1-6.0A shows the possible outcomes of metabolism with respect to pharmacological action. Drug > Inactive metabolite(s) (most common) Drug > Active metabolite(s) (most benzodiazepines, SSRIs) Prodrug ——> Drug (soniazid, nucleoside analogs s antiviral, or anticancer drugs) AFigure 1-6.0A Biotransformation of Drugs ® Drug metabolism is often divided into phase I and phase II: * Phase I: —Involves modification of the drug molecule by oxidation, reduction, and hydrolytic reactions. —The most common enzymes involved in phase I are the cytochrome P450 (CYP) enzymes. » Phase II: —Involves conjugation of the drug molecule with enzymes known as transferases. —Examples are acetylation, glucuronidation, glutathionylation, and sulfation. Drug Phase Co eT ‘Oxigation ‘Conjugation ydrexylation ealkvlation Deamination yarolysie on coon —S Phase Aspirin Salleyiic acta ‘elucuronide of sal sm of Acetyl Salicylic Acid AFigure 1-6.0B Two Phases of Drug Metab Chapter 1-12 tecture ES | Pharmacology Minostant conn + Phase Il reaction® uouelly result in inactive, more watorgoluole metabolites, + There are ew cases of 70 mg + 60 mg + 50 mg + 40 mg ——> 30 = Graphically, the elimination is linear. lawount = The rate of elimination is independent of plasma concentration 4 (or amount in the body). It is constant at 10 mg/hr. K = Drugs with zero-order elimination have no fixed half-life: 10 © t, is variable. 80 © In the example, it takes 5 hrs to eliminate 50% of 100 mg, but | 70 4 hrs to eliminate 50% of 80 mg. + th = Drugs with zero-order elimination include: * Ethanol (except low blood levels) * Phenytoin (high therapeutic dose) * Salicylates (toxic doses) Units of Drug z 5 3 & 5 @ NoLog time Time A Figure 1-7.2 Plots of Zero-Order Kinetics Chapter 1-16 © Davy/tacha Edenton Davalpmant Corp Allighte rearvetecture ES Chapter 1 * Pharmacokinetics Pharmacology 7.3 First-Order Elimination Rate or “the normal way" Exponential etics %A constant fraction of the drug is eliminated per unit time. For example, if 100 mg of a drug is administered and its elimination half-life = 1 hour, the time course of elimination is: - 25 me Lhe thr he hr thr 200 ag —P 100 ma, 50 ma £25 mg 242.5 mg» 6.25 me —> 3125 Sw Graphically, the elimpatllh is a decaying Ssporentia. = The half-life is a constant. = The rate of elimination is directly proportional to plasma level (or the amount present): * The higher the amount, the more rapid the elimination. * In the example above, the first hour had an elimination rate of 50 mg/hr and the second hour had a rate of 25 mg/hr. = Most drugs follow first-order elimination rates. Log scale: NO ZERO 100 é Linea 1000: 4 3 3 >» 2 100 2 i \ 0 Lb time Time A Figure 1-7.3 Plots of First-Order Kinetics ik 2. © OeVn char Edvestional Dealopmant Cor Al ight raved Chapter 1-17Chapter 1 Pharmacokinetics 7.4 Graphic Analysis = Beware of linear elimination graphs. = Check the y-axis: If a log scale is used, it is a first-order kinetic plot! = The plot in Figure 1-7.4 can be used to find the t,,. Here t,, = 6 hours. © Note that the slope k, constant of proportional to t,,: D 0.7 MCo= @ © kis in "per time" unit. ination, versely lem E10 oF S40 cm] £5 2 20 t & - 10 * 2 4 6 s& 10 12 Time (he) AFigure 1-7.4 Plasma Decay Curve—first-Order Elimination 7.5 Clearance = Conceptually better than k, the slope of elimination curve in per time units! 1 \. Kidney (renal Cl) w/e) Vaxk In urine (renal Cl) le (metabolic Cl) Figure 1-7.5 Clearance tecture ES Pharmacology Chapter 1-18, (© 00Viy char Eduetinal Davalepmant Cop, AlvighterearondChapter 1 * Pharmacokinetics = Irrespective of the drug concentration, the clearance in Figure 1-7.5 is 100 mL/min. = Clearance (Cl) represents the volume of blood cleared of drug per unit of time. @Cl=Vaxk Volume Volume per ume per time Using ty, = 0.7/k Cl=V, x 0.7/t,, t, = V, x 0.7/C1 = If a drug is renally cleared, only the free fraction is filtered by the glomerulus. Example: Assume that GFR is 120 mL/min. If a drug is 50% bound to albumin, celculate its renal clearance assuming no reabsorption, no secretion (Answer: 50% x GFR = 60 mL/min). 7.6 Summary of Single-Dose Pharmacokinetics Zero-Order Kinetic: ™ Saturation/toxic doses = t,, variable '= Rate of elimination is constant First-Order Kineti © All common situations wt, constant = Rate of elimination is variable tecture ES Pharmacology Con: nection wd Physiology| Renal slearance can algo be calculated as: Joy= UZP,« Where: + U, is urine concentration of X + PIs plasma concentration of + Vis urine production rate Chapter 1-19tecture ES Chapter 1 « Pharmacokinetics Pharmacology ‘Steady state is reached when Rate in = Rate out. 8.1 Plateau Principle The time to is dependent only on the elimination Tra bme to and is independent of HOSEISI and FEEUERET of administration. Consider the example in Figure 1-8.1A: 100 units are given every t, and t,, = 1 hour. Clin (peak) Plasma Drug Concentration (meg/mL) Time (hr) AFigure 1-8.1A Plasma Levels Following IV Bolus Administration at Intervals Equal to Drug Half-Life Although it takes > 7 t¥ to reach mathematical steady state, by convention clinical steady states reached at 4-5 17, Note: A faster rate of infusion does not ‘change the time needed to achieve steady Clinical Stat}oniy tw standyeatate soneenivatio, al Css, changes. ‘Application 90% = 3.3 « hatte (mathematical steady state) Steady-state region, Time and Steady a State 50% = 1» hatte rate 6f infusion rng /min) Plasma Concentration of Drug jure 1-8.1B Rate of Infusion Chapter 1-20 (© 00Viy char Eduetinal Davalepmant Cop, Alvightemearend