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" !  !  " #$ %) +,- n:r$߀M'$,,Gi$2$fc%0`QAoi2$%<_޽QGUՀ.uQp2$]/fO}bh9&r2$~g2$ ݷa4_;V}`q2$[x䪁{trs2$$Oޚ]rvc 1? 3f@38#$g4CdCd0ppp@  <4BdBd. 0Luʚ;2Nʚ;<4!d!dЁ 0<4ddddЁ 0:2___PPT9/ 0? %O =53Therapeutic Drug MonitoringdRoger L. Bertholf, Ph.D. Chief of Clinical Chemistry & Toxicology Shands Jacksonville Medical Center'Why monitor plasma drug concentrations?gAvert toxicity Optimize dose/therapeutic response Detect changes in pharmacokinetics Monitor complianceD- First Principle of TDM Knowledge of serum concentrations is most helpful when the drug in question requires individualized dosing for optimal efficacy and more routine measures of therapeutic success are unavailable. Therapeutic IndexTherapeutic IndexzHigh therapeutic index NSAIDs Aspirin Tylenol Ibuprofen Sedative/hypnotics Benzodiazepines Most antibiotics Beta-blockers v  ,,! Low therapeutic index Lithium Neuroleptics Phenytoin Phenobarbital Some antibiotics Gent/Vanco/Amikacin Digoxin Immunosuppressives vP$ Introduction to PharmacokineticsWhat are pharmacokinetics? The study of the absorption, distribution, and elimination of drugs Pharmacodynamics is the study of drug effects Most drugs exert their effect at tissue receptors, but we measure drug concentration in plasma.lr`D!', F} Two Compartment Model Drug absorptioncRoute Oral Intravenous Intramuscular/subcutaneous Dermal Inhaled/intranasal Slow/sustained release 6FF @ Rate of drug absorptionFirst-pass metabolism Two Compartment Model ,Distribution (a) phase$Once drug is absorbed into the blood, it begins to distribute to tissues The amount of drug that partitions into tissues depends on . . . Lipophilicity Protein binding The partitioning of drug between blood and tissues is expressed quantitatively as the Volume of DistributionHmV} Volume of Distribution (Vd)$The Volume of Distribution (Vd) is the amount of blood, per Kg body weight, necessary to contain all of the body burden of drug at equilibrium concentration.$ Low Volume of Distribution8)Drugs with low Vd$ High Volume of Distribution9*Drugs with high Vd$Interpreting Vd$ ADrugs with low Vd are contained mostly in the plasma, because . . . They are highly water soluble (plasma water content is higher than tissues), or They are highly protein bound (which prevents them from freely diffusing into tissues Drugs with high Vd are mostly in tissues, and plasma levels may not reflect body burdenZDX3F,EExample of Vd calculation$    Example of Vd calculation$    What can affect Vd?$_Body fat index (men vs. women) Tissue perfusion (CHF or edema) Concentration of plasma proteins0"!Effect of Vd on peak plasma level$"  Two Compartment Model*Elimination (b) phase$ xCan be renal, biliary, secretory, respiratory Often depends on metabolism Is the most variable pharmacokinetic parameter> ? 1What factors affect the rate of drug elimination?DHepatic function Renal function Urine pH Genetic factors Other drugsPharmacokineticsThe Steady State TDM methodsHPLC RIA FPIA EMIT CEDIA ChromatographySeparation of components based on their. . . Solubility in mobile and stationary phases Terminology: Gas/liquid Liquid/liquid Ion exchange PartitionL-+ 0-+ 0%Chromatographic separations&Chromatographic separations'Chromatographic separations*!What is the effect on resolution?Increasing column length? Decreasing/increasing solvent polarity? Increasing flow rate? Increasing temperature? Increasing stationary phase film thickness?(HPLC Detectors+More recent TDM methods~Radioimmunoassay Fluorescence Polarization Immunoassay Enzyme-Multiplied Immunoassay Technique Cloned Enzyme Donor Immunoassay, Theophylline Bronchodilator Therapeutic range: 5 - 20 mg/mL Neonates metabolize theophylline to caffeine Vd = 0.5 L/Kg Toxic at > 20 mg/mL Nausea, vomiting, diarrhea, stomach pain, headache, insomnia, tachycardia Seizures, cardiac arrhythmia at > 35 mg/mLH~u)4 u~  > (/!Gentamycin/Tobramycin$  DWide-spectrum aminoglycoside antibiotics Vd = 0.2 L/Kg Therapeutic 4 - 10 mg/mL (peak); 0.5 - 1.5 mg/mL (trough) Toxic: 12 - 15 mg/mL Ototoxicity Nephrotoxicity C.*'Z ! 1#DigoxinImproves cardiac output in CHF patients Vd = 500 - 600 L/Kg Highly bound to tissues What does this say about small changes in plasma digoxin concentration? Therapeutic range: 1.5 - 2.0 ng/mL Toxic levels (> 2.0 ng/mL) produce arrhythmias, GI, CNS symptomsH<`d)`dt(Z,(2$ Procainamide Antiarrhythmic Active metabolite is NAPA N-acetyltransferase Fast vs. slow acetylators Vd = 2.4 L/Kg Therapeutic: 4 - 10 mg/mL Toxicity: Heart block, n/v, diaphoresis, malaise at Procainamide + NAPA > 30 mg/mLR).{). Yl"4 3% Carbamazepine  Anticonvulsant, and for Rx of TGN Active in tonic-clonic (grand mal) sz Vd = 1.5 L/Kg (lipophyllic but 25% protein-bound Therapeutic range: 4 - 12 mg/mL Toxicity in one fourth of patients Diplopia, drowsiness, nystagmus, ataxia, n/v Also, derm, hematol, hepatic "&tJ&I)J2  3#  4& PhenobarbitalAnticonvulsant (metabolite of Primidone) Long-acting barbiturate (t1/2 = 2 - 4 days) Vd = 1.0 L/Kg Therapeutic range: 15 - 40 mg/mL Toxic symptoms at > 60 mg/mL Drug interactions (induction of hepatic microsomal enzymes)d),)'_b .)(  5' Phenytoin >Most frequently prescribed anticonvulsant Vd = 1.0 L/Kg Therapeutic range: 10 - 20 mg/mL Toxicity at > 20 mg/mL Nystagmus Blurred vision Ataxia Drowsiness/ComaDp0+'0>*) &6( Valproic acid *Broad spectrum anticonvulsant, but mostly used for absence (petit mal) seizures Vd = 0.2 L/Kg Therapeutic range: 50 - 100 mg/mL (trough) Hepatotoxic@3(>P+ PB ` ___f3f` ___3f` 999MMM>?" dd@,|?" dd@   " @ `"  n?" dd@   @@``@n?" dd@  @@``PR    @ ` ` p>>     ( 5% pF  q0a  q 0a2  C BUCENG HZI8Qf3? جU,جU,8`T,8`T q0a2  C BUCENG HZIDQD? U8U8D`T8D`T 2  C BUCENG HZIEQ[? U9U9E`T9E`T dn"   G/*d6?@33@@@sf 4  Z wgֳgֳ ?  T Click to edit Master title style! !:  Tygֳgֳ ?0  RClick to edit Master text styles Second level Third level Fourth level Fifth level!     S   `~gֳgֳ ?`  Z*   `gֳgֳ ?   \*   `|gֳgֳ ?   \*H  0޽h? ??0 ___f3f Fireball   k c @  ( > pF  0    0 2  C BUCENG HZI8Qf3? جU,جU,8`T,8`T 0 2  C BUCENG HZIDQD? U8U8D`T8D`T 9Y 2  C BUCENG HZIEQ[? U9U9E`T9E`T "   G/*d6?@33@@@sf   Zgֳgֳ ?`  T Click to edit Master title style! !  Tgֳgֳ ?0 `    W#Click to edit Master subtitle style$ $   ` gֳgֳ ?`  Z*   `dśgֳgֳ ?   \*   `@ʛgֳgֳ ?   \*H  0޽h? ??0 ___f3f P=( w   ZS1 ?P    KTherapeutic Drug Monitoring   ZY1 ?    Z*    `W1 ?`P   HRoger L. Bertholf, Ph.D.    `xb1 ?`   l Page * H  0޽h ? ̙33 0$(  r  S (ӛ`  r  S ӛ    H  0޽h ? ̙33  `$(   r  S xj   r  S  k0  H  0޽h ? ffD3f  p8( ,% l  C p   l  C Dq0     fr1? T JFrom W. J. Taylor and A. L. Finn (eds.) Individualizing Drug Therapy, 1981KJH  0޽h ? ___f3f4    t( ?5Y  r  S lv     B,~v @  :   <} 0 -Plasma drug concentration^B  6Do   <  S Toxic  <   #Sub-therapeutic^B  6D0 `` ^B  6D   <` 0 G  ITherapeutic range^B  6D ^B  @ 6D `   B,0  ToxicityH  0޽h ? ffD3f^  $(  $r $ S X   r $ S  0  r $ S Зp 0  H $ 0޽h ? ffD3f  ((  (r ( S <   l ( C   H ( 0޽h ? ffD3fo     ,(  ,r , S @    , 6@  : X , 0P  , <쬞 W @ Blood , < p@ TissuedB , <DԔP PPdB  ,@ <DԔ PdB  , <DԔp@  , <ĴPTp  AbsorptiondB  , <DԔ   , < pl   Elimination , <8 BKa$ , <   \Kd$ , < Ğ J  CK-d$ , <Ȟ  \Ke$H , 0޽h ? ffD3f  @$(   @r @ S Ξ   r @ S LϞ0  H @ 0޽h ? ffD3f  WOD(   Dr D S Ԟ   6 D <x֞@`  hIV @ Inhaled > Intramuscular > Oral > Dermal$50 D <۞   7seconds D <ޞ *  5hours D <X ` )  7minutesH D 0޽h ? ffD3f   H"(   Hr H S L    H C pAXD:\Medical Clip Art\SA1CGM\DIGEST\LIVER.CGMp  H C pAXD:\Medical Clip Art\SA1CGM\DIGEST\STOMC.CGM p  H C lATD:\Medical Clip Art\SA1CGM\CIRC\AHART.CGMp dB  H <D>0@dB  H <D>  H <$8  PProdrug Active drug or Active drug Inactive metabolite or Lipid soluble drug Water soluble drugPf )^H H 0޽h ? ffD3fu   %  P(  Px P c $D    P 6@  : X P 0P  P <W ( Blood P <p( TissuedB P <DԔP PPdB P@ <DԔ PdB  P <DԔp@  P <PTp  AbsorptiondB  P <DԔ   P <X  pl   Elimination  P <   Bka$ P <   \kd$ P <   Ck-d$ P <  \ke$H P 0޽h ? ffD3f  L( 8@ Lr L S     l L C Pp  H L 0޽h ? ffD3f  h`T(   Tr T S #   r T S d$    T c $A ??` 0)x dAvH T 0޽h ? ffD3f      \6 (  \x \ c $+    \ 6(.0 H  : X \ 0 @H  \ <2 Blood \ <5 I TissuedB \ <DjJ0 dB  \@ <D)h0 h  \ <8P d  \kd$  \ <h=hP  Ck-d$  \ <A6I  @High blood concentration (mg/mL),!  \ <H\   JLow tissue concentration  \ <K VP kd << k-d \ Vd is low If kd = 0, Vd = 0.07 L/Kg (lower limit)C H  H \ 0޽h ? ffD3f  ~0'm(  r  S \   dz @ m #"2&DDDDDDDD@ @  `d1? @ L0.53 @` ?  `(l1? @ MEthanol @` >  `s1?   L0.20 @` =  `{1?  m Valproic Acid  @` <  `P1? n   L0.50 @` ;  `T1?n  l Theophylline    @` :  `1? ( n  L0.60 @` 9  `1?( n  i Primidone    @` 8  `1? (  L0.70 @` 7  `1? (  i Phenytoin    @` 6  `1?  Q 0.07-0.70   @` 5  `1?  Gentamycin/Tobramycin$   @` 4  `1? V ^0.05  0.70   @` 3  `<1?V  hAmikacin   @` 2  `1? V  Vd (L/Kg).  @` 1  `l1? V LDrug @`xB A Ho ? xB I Ho ?@ @xB J Ho ?VxB L Ho ?VxB O Ho ? xB P Ho ?VxB R Ho ?VxB T Ho ?xB V Ho ?xB X Ho ?( xB Z Ho ?( xB \ Ho ?( n xB ^ Ho ?( n xB ` Ho ?n  xB b Ho ?n  xB d Ho ?  xB f Ho ?  xB h Ho ? @xB j Ho ? @xB l Ho ? @@H  0޽h ? ___f3f   f ^ @ d(  dx d c $    d 6d0 H  : X d 0 @H  d <P Blood d < I TissuedB d <D)0 dB d@ <DjJh0 h  d < P d  \kd$  d <hP  Ck-d$  d <h6I  Low blood concentration (ng/mL)  ,  d <\   KHigh tissue concentration  d < <P kd >> k-d \ Vd is high For highly lipophilic drugs, Vd may be 100 L/KgK H  H d 0޽h ? ffD3f  P#9+(  r  S t   yv 0 9 #"."rsrrrsr0   `1? 0 K3.0 @`   `,"1? 0 i Quinidine    @`   `,*1? 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Bertholf, Ph.D.      . .C2 z(Chief of Clinical Chemistry & Toxicology         !   . .:2 A"Shands Jacksonville Medical Center   '   .--"System 0-&TNPP &՜.+,0p    On-screen Show -s >+ 1Times New RomanArialSymbol FireballMicrosoft Equation 3.0Microsoft Word DocumentTherapeutic Drug Monitoring(Why monitor plasma drug concentrations?First Principle of TDMTherapeutic IndexTherapeutic Index!Introduction to PharmacokineticsTwo Compartment ModelDrug absorptionRate of drug absorptionFirst-pass metabolismTwo Compartment ModelDistribution () phaseVolume of Distribution (Vd)Low Volume of DistributionDrugs with low VdHigh Volume of DistributionDrugs with high VdInterpreting VdExample of Vd calculationExample of Vd calculationWhat can affect Vd?"Effect of Vd on peak plasma levelTwo Compartment ModelElimination () phase2What factors affect the rate of drug elimination?PharmacokineticsThe Steady State TDM methodsChromatographyChromatographic separationsChromatographic separationsChromatographic separations"What is the effect on resolution?HPLC DetectorsMore recent TDM methods TheophyllineGentamycin/TobramycinDigoxin ProcainamideCarbamazepinePhenobarbital PhenytoinValproic acid  Fonts UsedDesign TemplateEmbedded OLE Servers Slide Titles+&_cRoger BertholfRoger Bertholf  !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%'()*+,-4Root EntrydO)PicturesxCurrent User&SummaryInformation(`\PowerPoint Document(=cDocumentSummaryInformation8