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    Reference Perhitungan Obat

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    Reference Perhitungan Obat

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    Reference Perhitungan Obat

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    of 17
    ACGESSMedicine sen nner oar ony ss neo Copyright © The McGraw-Hill Companies. Al rights reserved. Ccse wingow ‘Baeic and Clinical Pharmacology » Chapter 3, Pharmacokneics & Pharmacodynamics: Rate! Doshng & the Tine Cours of Brig Acton > PHARMACOKINETICS & PHARMACODYNAMICS: RATIONAL DOSING & THE TIME COURSE OF DRUG ACTION: INTRODUCTION ‘The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When @ medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective ‘combines the principles of pharmacokinetics with pharmacodynamics to clarity the dose-effect relationship (Figure 3-1). Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the ddose-concentration part (Holford & Sheiner, 1981). The pharmacokinetic processes of absorption, distribution, and ellmination determine how rapidly and for how long the drug will appear at the target organ. The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and ECs0, Chapter 2) Figure 3-1 Pharmacokinetics Pharmacologic effect, 1 Pharmacodynamics Clinical response x NX Toxicity Effectiveness ey alton: Mepifm aevaczmacionazom ‘ Copytight @ The MeGraw-Hil Companies, Ine All sahts reserved, ‘The relationship between dose and effect can be separated into pharmacokinetic (dose-concentration) and pharmacodynamic (concentration-etfect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and isthe focus ofthe target concentration approach t rational dosing. The three primary processes of pharmacokinetics are absorption, distribution, and elimination Figure 3+1 illustrates 2 fundamental hypothesis of pharmacology, namely, that a relationship exists between a beneficial or toxic effect ofa drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the ‘Target Concentrations and Toxic Concentrations columns in Table 3-1. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but poiats to the need to consider the time course of concentration at the actual site of pharmacolocic effect (see below). ‘Table 3-1 Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs. (See Speight & Holford, 1997, for a More Comprehensive Listing.) Drug oral Urinary Bound Clearance Volume of Half-Life Target Toxie ‘Availability Excretion in (L/h/70 Distribution (h) Concentrations Concentrations ‘Acetaminophen Acydovir ‘Amikacin ‘Amoxicillin ‘Amphotericin Ampicilin Aspirin Atenolel ‘Atropine Captopril Carbamazepine Cephalexin Cephalothin| Chloramphenicol Chlorciazepoxide Chlorocuine Chlorpropamide Cimeticine Clproftoxacin Clonidine Cyclosporine Diazepam Digitoxin Digoxin Diltiazem Disopyramige Enalapril Erythromycin Ethamautel Fluoxetine Furosemide Gentamicin Hydratazine Imipramine Indomethacin Labetalol Lidocaine thium Mepericine Methotrexate Metoproiol CF) (%) 88 2 3 62 68 56 50 65 7» 90 80 100 89 90 ca 60 95 2 100 90 0 9s 35 7 60 6 40 40 98 18 100 52 70 8 (%) ws eaeryns 1s 95 R 10 Plasma kg)? 6) o 2 1 198 4 5.46 1 08 so 1.92, 1 16.2 39 5 10.2 1 (246 30 saa 4 5.34 418 ma 282 53 10.2 7 (228 45 96 0.126 19 Ra 40 (252 2m 126 3 (246 091.62, 970.234 37 73 S04 2 5.08 ss 9 ea 384 5 36 oa 40.2 984 10 sa e724 9063 saa so 105 70 384 o Ls 38 7 “9 nu 68 (0/70 ka) 7 2 15 mg/t > 300 most. 48 24 19 23 1s 17 53 18 20 13 a 0.25 o 6a 1 aft 120 43 ” 22 50 no/mt, 98 15 molt, > 9 mg/l 18 09 1 os? 66 27 a 40 Amol, . 13,000 21a 20 ng/mL. 20 ng/mt oa 3 7 19 0.8 mai 130 4 150 2 A ngymi. as 56 200 ng/mL ——-> 400 ng/mL 7” 4B 300 ng/mL 38 161 10 ngfemt > 35 ng/ml, 500 50 Lng/mt, > ng/ml 20 37 a 6 3mo/me > 8 mg/ml. 40 3 > 0.5 ng/mt. 55 16 0 aa > 10 ma/L 2500 83 7 1s > 25 ma/l. 18 25 105 1 100 ne/rmt 1600 18 200 ng/mL > A mg/L Fo 24 1 maf > Sma/t 660 49 0.1 mgft 7 18 3mg/t. > &ma/t ss 2 OF mea > 2meg/L. 310 32 0.5 maf . 33 72 750 0M-n? > 950 umn 290 32 25 ng/mL. Metronidazole 99) 10 1 Sa 2 35 Amal Midazolem 44 56 8 76 7 19 Morphine ™ 8 3560 230 19 60 ng/mt Nifedipine so ° 945 18 0 no/mt Nortriptyine 51 2 92 30 1300 31 t0one/mt > 500 ng/mt Phenobarbital 100 a st 0.258838 98 Asmo/t > 30 mast Phenytain 90 2 89 cone a5 Cone 10 maf > 20 mat dependent* dependent? Prazosin 68 1 9 126 a 29 Procainamide 63 o 1% 36 330 3 Smo > 14 mat Propranolol 26 1 87 504 270 39 20 ng/mt Pyridostigmine 14 8s 36 ” 19 75 ne/mt Quinine 80 18 9 198 80 62 3 molt > 8mo/ Ranitidine 52 oo 1438 2a 100 ne/mt Rifampin ? 7 814468 35 Saleyicacd 100 15 a ose 3 200mg/t > 200 mat Sulfemethoxazole 100 16 2 1215 10 Teroutsing 14 56 2 14415 4 2 git Tetracydine 77 38 6 72 105 u we we Theophyline 96 18 58 35 a4 tomeft > 20 ma. Tobramycin 90 1 4628 22 Tocainige 89 38 1 108 210 “ so mo/. Tolbutamide 93 ° 9 7 59 100 mg/L Trimethoprim 100 cy 48 130 ut ‘Tubocurarine a so aa 7 2 0.6 mg/t Valproicacid 100 2 9302 ot 14 75mg > 150 m/l Vancomyen ” 35887 56 Verapamil 22 3 cs) 350 4 Warfarin 93 3 9 ons 7 Zidovudine 63 18 2% 6B 88 rn ‘convert to mL/min by multiplying the number given by 16.6 2varies with concentration. Target area under the concentration time curve after @ single dose. ‘can be estimates trom measured Cp using CL = Vran/(Kmt Cp); Vrax = 415 mg/d, Kn = 5 mg/L. See text Svarles because of concentration-dependent cearance. Knowing the relationship between dose, crug concentration, and effects allows the clinician to take Into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to @ drug. The Importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the Improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles. PHARMACOKINETICS ‘The "standard" dose of a drug Is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug (see Clinical Trials: The IND and NDA in Chapter 5 ). This dose will not be sultable for every patient. Several physiologic processes (eg, maturation of organ function in infants) ane pathologic pracesses (eg, heart fallure, renal failure) dictate dosage adjustment in individual patients. These processes modify specific pharmacokinetic parameters. The two basic parameters are clearance, the measure of the ability of the body to eliminate the drug; and volume of distribution, the ‘measure of the apparent space in the body available to contain the drug. These parameters are illustrated schematically in Figure 3-2 where the volume of the compartments into which the drugs diffuse represents the volume of distribution and the size of the outflow “érain" in Figures 3-28 and 3-2D represents the clearance. A ‘Amount inblood Blood Time Figure 3-2 Bith Eitan: Mau /uw setcanoadnesam nn mamma Copwight @ The McGraw-Hill Companies, Inc. Al rights tesereed B ‘Amount in blood ‘ Blood Sit eaeaerhiouiaecmamennacem tee Copwight @ The McGraw-Hill Companies, Inc. Al rights reserved Amount inblood —<—> 0 Time Extravascular volume BE Eaton: Cepifomeciszmediangicom nn emmaseiegyy Copwight © The MeGray-Hil Companies, Inc All sahts reserved Amount inbload Exvavascular volume 1th Edtion: Maifiww sewcemaddne.com ~ ooyiaht @ The Medrau-Hll Companies, Ine All his resend Models of drug dstbution ang elimination, The effect af adding drug to the bload by rapid intravenaus injection is represented by ‘expeling a krown amount ofthe agent Into a beaker, The time course ofthe amount of drug inthe beaker is shown inthe graphs at ‘the right. In the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to maximum followed dy a plateau Inthe second example (B), 2 route of elimination is present, and the graph shows a siow decoy ater sharp re toa maximum. Because the level of material inthe beaker falls, the “pressure” driving the elimination process aso falls, andthe ope ofthe curve decreases. Thi is an expanentil decay curve. Inthe thirs mace! (C), drug placed in the first compartment, ("blood") eauiibrtes rapidly with the second compartment ("extravascular volume”) and the amount of drug in “blood” declines ‘exponentially to anew steady state. The fourth made! (D)llustrates @ more realistic combination of elimination mechanism and ‘extravascular equiration. The resulting graph shows an early clstabution phase followed bythe slower elimination phase. Volume of Distribution Volume of cistrbution (Vg) relates the amount of drug inthe body to the concentration of drug (C) in blood or plasma: vy = Amount of drug in body jj = Mount drug in body c a The volume of cistribution may be defined with respect to blood, plasms, or water (unbound drug), depending onthe concentration used in equation (1) (C= Cy, Cp, 0F Ci). That the Ve calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of

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