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Pceut532_Final_2004 - PHARMACEUTICS 405 Winter 2004 Name kl...

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Unformatted text preview: PHARMACEUTICS 405 Winter 2004 Name kl? Final Exam Student # March 17, 2004 Questions Points 1 12 2 16 3. 12 4 4 5. 24 6 4 7 E TOTAL 100 1. AT is a 40-year-old, 60 kg, 5'4” female who has been receiving omeprazole 30 mg/ day for the past 2 years. AT is an. extensive metabolizer of CYP2C19, (CYP2C19* 1/ * 1). As part of a research study, a 24-hour urine was collected and the following were recovered. Metabolite concentrations have been corrected for molar weight for your convenience. 24—hr urine recovery omeprazole 1 mg hydroxy—omeprazole 20 mg omeprazole sulphone 4 mg carboxy—omeprazole 2 mg hydroxy-sulphone 1 mg Given the following metabolite scheme. Omeprazole @713ch CYP3A4 hydroxyomeprazole omeprazole sulphone Carboxyomeprazole Hydroxy-sulphone A. (10 pts) Erythromycin inhibits CYP3A4 metabolism. Calculate the maximum effect of erythromycin on average steady state concentrations of omeprazole in AT. 31W ./ ,. ., 7 i’M'” Lid" __ Oil tad . : V Can mega? 1.4%,me Cl I t— 01/7 ~ Tm C53 “Zn-L" "‘- [*QOX gem/vat. 0.83? Cl B. (2 pts) If erythromycin was given to another person receiving omeprazole, who is a homozygous poor metabolizer CYP2C19*2/*2. Would the overall effect of erythromycin be greater, less or the same as you determined for AT above? gremW/x— Ca perm“ .59! ablllAEOl CM OmegDMQQI‘em Q PM ROD q largo/t rehcnm oh 44f CNPBIQV Pa/warwm .. | Exhibit,“ [FAQ polka/Ar)“ Curl/ can» (2 [WW7M Cs: 2. PS is a 30-year—old, 55 kg, 5'4" female who has been receiving sodium phenytoin 300 mg/day for the past 10 years. PS comes to your neurology clinic 6 months pregnant. She has had a seizure for the first time in over 5 years. The last time you saw her, 1 year ago, her total phenytoin was 12 ug/ml and her unbound phenytoin was 1.2. ug/ml. Her total phenytoin concentration is now 6 ug/ml. Therapeutic Range: Total phenytoin: 10 - 20 ug/ml total Unbound phenytoin: 1 — 2 ug/ml fu=0.10 S=0.92 VB=0.65 L/Kg A. (4 pts) Give two reasons why her total phenytoin concentration has decreased. J/ Glbuwiyl TCi MT B. (3 pts) What would you predict her unbound phen oin concentration is now. but {‘13 T Li her when Phonjimd CONWWM’C’T (MC/wt- b< 7919 .MSiM' C. (3 pts) PS asked your advice about breast—feeding her infant that she is going to have. What can you tell her based on what you know about phenytoin? 7PM " O [O \[QM CON predate? Mai-hep mime} wwzd ”ho/i» how: u MCQSVrabie Pkeflnji—G/u ika/ L; b (‘ (<51) ‘1” D. PS is now 75 years old, 45 kg, 5'2”" and still a female. She had moved out of the state when she was 45 yo. and this is the first time that you have seen her since then. She is still receiving phenytoin 300 mg/day. Her daughter brings her into clinic and she is extremely unsteady on her feet. Her daughter tells you that she thinks PS can no longer live on her own. You remember your kinetics class from 50 years ago and order the following labs. Total Phenytoin 18 ug/ml Albumin 2.8 gg/dl m i) (2 pts) Explain why the same dose of phenytoin has resulted in significantly higher phenytoin plasma concentrations. 7‘ , ~13 Vwmf * CW” W» 31/ OlPJC‘i (2079-043 regufirifl’ m. (”H‘e J" mbWW by W564 (NCU’A r‘cswir N o. J, “N «tame @H‘T) ii) (4 pts) Based on your kinetic evidence, what is your recommendation for PS? V i i", M (I i 5' C‘imi PM ~_- Put/@603 .1 [3 M91... :- 99 Am Teri“ _...——-——--""" O 93‘ [9%er ‘ (0.260233 HIM 3. Fill in the blanks: (2 pts each) A. CF P 3 ‘0‘“, is a metabolic enzyme in which females have significantly greater activity than males while U ET is an enzyme in which males have significantly greater activity than females. B. Decreased activity of E " gulf Cg Effie” in females compared to males maybe responsible for the increased ris of mortality in females compared to males receiving digoxin for treatment of congestive heart failure. C. The increased Ff“ 0“ ©{OVC’V‘ CE—of lithium during pregnancy could be responsible for a loss of efficacy. D. Chronic liver cirrhosis results in a decrease in the metabolism of drugs catalyzed by all‘CYP450 isozymes except for g EPZQQ . Fill in the blanks with either increased, decreased or the same:( 1 pts each): E Compared to adult levels, albumin plasma concentrations are ‘5’ in neonates, SONG» in a 1-year-old child and l; in the elderly. F. Compared to adult levels, the clearance of a drug metabolism predominately by CYP450 pathways (per kg) is J/ in neonates, T in a 1 year old child and J/ in the elderly. G. Compared to adult levels, the clearance of a drug eliminated predominately by renal clearance is J! in neonates, gem, in a 1 year old Child and L! in the elderly. ' H. The effects of acute hepatitis on CYP3A4 dependent metabolism are 6‘ 52km“? compared to the effect of chronic liver cirrhosis. 4. (4 pts) Morphine is extensively metabolized by the liver. Explain why doses of morphine need to adjusted in patients with renal disease. E Merfimne ms area: gamma molecule/2:; ,HAOAV (pi-H OxCCK/www or)»: m (tam, <2!!st 5. A] is a 68 year old male admitted for treatment of atrial fibrillation. He is 6'0” and weights 75 kg. Medical history includes mild renal dysfunction secondary to chronic hypertension. Labs: serum creatinine of 1.8 mg/dl albumin = 4.0 gm/dl. Digoxin “Facts”: VB=6 L/kg F = 0.70 S=l.0 fu = 0.7 A. (5 pts) Calculate a intravenous loading dose to target a digoxin plasma . , I m, ‘ concentrations of 1.5 ng/ml. \) (If I 3') :f'QQOwl if [2319 x (6,33) 4 S , fl 1 C ' CW“; LD :1 \I’ ‘ (C (‘90 “9 C0395) : ((0 L/IC 3 (75’ k’ - 5 m ' -- _..,_ _l’ . :5. F (I (0 LD .4 005" raj B. (10 pts) Calculate an oral maintenance dose to target a digoxin plasma concentrations of 1.3 ng/ml. a: M Lil’7 “fir/mid Cl C’ 72 . LS” Cl [DI (333$ Cl , (I; g “films (IOSQMBIQ 5797 1:3 ,1 b 335:3 MM "— w B 1: s Lomm W” C. (5 pts) Your calculated maintenance dose resulted in an average steady state digoxin plasma concentration of 2.0 ng/ml. Re-calculate the needed dose to targetl.5 ng/ml C) 33 m‘iv/O Y 7 22.0 meals! /.5’ “Sim! X z 0'9? ”‘5! Def D. (4 pts) If A] bad just entered the hospital in acute renal failure, what would the possible effect be on your calculations of the digoxin maintenance dose? ‘ 606 would MOVE. UhQU/Lgoflmelaa/ his am (fine? 52,-;vi Clo Seam Cc mm net ham halal 9t Chancq «t0 time)“ <3 new htsm Skim?) E‘sl—m vat/mt 6. (4 pts) Explain Why it is impossible to predict the effect of age, renal or liver disease on the volume of distribution of a drug? 7. The figure below represents a plot of average Steady State Concentration (Css) versus Daily Dose (D/t) of phenytoin in a patient. 'i00 .200 3:5 o 450 50‘ leioo DA‘L‘I Dose ("ma/day) A. (8 pts) From this plot, estimate the Vm & Km parameters; Provide an explanation. 4W g/Olg; , fins flyflX/(L/n 0/957 NJ? MAME @s MW5 wag/L , («s/£99m 0/E:fl/m, 14.: B. (8 pts) Calculate the Change in Woe when Css increases from 10 to 20 mg/L .__, C. Fill in the blanks below: (i) (4 pts) N0 steady state will be achieved in this patient at daily doses [email protected]____ (ii) (4 pts) In this patient, an intravenous bolus dose that achieves an initial concentration (C°) below fig mg/L will yield a plot of log concentration versus time that is linear. (iii) (4 pts) In general, a patient needs to receive at least 2. dose(s) of phenytoin in order to allow a calculation of Vrn and Krn according to the Ludden method. EQUATIONS C1 M Fm = _ = _u_ C1 D Vm' V Vm C1 = = _ Km + Css Km + Css Vm’ V ° Css Vm° Css 13/13 = --——-- = —-———- Km + Css Km + Css DR is Dosing rate DR DR = —Km —— + Vm Css K0 K0 = ~Km — + Vm Css V' m Km C V‘ mV Vm Km Km LD = V - [C desired - C observed) S ' F Css = F‘D/‘C Cl Css = D/‘C ' Km VmV-Dh (140 — Age) . (LBW) CrCl (ml/min) = for males 72 ' SCr FEMALES: multiply the above CrCl by 0.85 Serum Creatinine: normal range 0.5 - 1.5 mg/dl LBW = 50 kg + (2.3 kg for every inch over 5 feet) males LBermales = 45.5 kg + (2.3 kg for every inch over 5 feet) Digoxin: Patients without severe Congestive Heart Failure: Cl total: (0.8 mllmin/kg) (wt in kg) + (1.1 * Clcr as nil/min) Patient with severe Congestive Heart Failure C1 total = (0.33 ml/min/kg) (wt in kg) + (1.1 * Clcr as ml/min) CZH = fp * Clint ClH = Q C _§:<_D/_r1_£_fl.>_ 0-1% 33 Cl fp * Clint ss Q CU_F*(D/T) CU _fp*F*(D/T) SS 35 _ ——~_ Clint Q [PHT1tot 1 [PHTnormaliZed] = m f Where [Alb] is gm/dl P V = V V ‘— p + T ft Albumin: normal range 3.5 —5.0 gm/dl New dose = First dose - Css(desired)0-2 - Css(acshieved)‘02 KK Css=—————O m V -K m 0 IN ‘3 ...
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