# Presentation: 319884

## PART 1: PK IN PATIENTS REQUIRING HEMODIALYSIS

**Arthur J. Atkinson, Jr., M.D.**
**Adjunct Professor**
**Department of Molecular Pharmacology and Biochemistry**
**Feinberg School of Medicine**
**Northwestern University**

**PHARMACOKINETICS IN PATIENTS REQUIRING RENAL REPLACEMENT Rx**

## FIRST DESCRIPTION OF HEMODIALYSIS IN ANIMALS*

*** From: Abel JJ, et al. J Pharmacol Exp Ther 1914;5:275-317.**

## WILLEM J. KOLFF, M.D. (1911 - )

## ELIMINATION BY DIFFERENT ROUTES

**MEASUREMENTS**       **RENAL****   ****HEPATIC    ****DIALYSIS**
**BLOOD FLOW    ****	****           +*                 +*     ****	****      ****+**
**AFFERENT CONC.            +                   +                   ****+**
**EFFERENT CONC.            0       ****	****         0                   ****+**
**ELIMINATED DRUG        + ****	****         0                   ****+ **
**	****	****	**
***not actually measured in routine PK studies**

## IMPACT OF CLD

## GOALS OF DIALYSIS DISCUSSION

**	****EMPIRICAL**
**	****	****FICK EQUATION**
**	****	****RECOVERY CLEARANCE**
**EFFECTS OF DIALYSIS ON PHARMACOKINETICS**
**HEMODYNAMIC CHANGES DURING DIALYSIS**
**	****USE OF KINETIC METHODS FOR ANALYSIS****	****PATHOPHYSIOLOGIC CONSEQUENCES**
**	****RELEVANCE TO Rx OF DRUG TOXICITY**

**DISCUSSION OF DIALYSIS CLEARANCE**
**	****MECHANISTIC - RENKIN APPROACH**

## EUGENE RENKIN PROFESSOR EMERITUS AT UC DAVIS

## RENKIN DIALYSIS EQUATION*

- * From Renkin EM. Tr Am Soc Artific Organs 1956;2:102-5

**Q = DIALYZER BLOOD FLOW**
**P = PERMEABILITY-SURFACE AREA **
**       ****PRODUCT OF DIALYZING MEMBRANE**

**NEGLECTS: BOUNDARY EFFECTS, ULTRAFILTRATION**

## DETERMINANTS OF PERMEABILITY TERM (P or P · S)

**   ****DIALYZER MEMBRANE CHARACTERISTICS**
**	****-  MEMBRANE SURFACE AREA**
**	****-  MEMBRANE THICKNESS**
**	****-  MEMBRANE POROSITY**
**   ****DRUG BINDING TO PLASMA PROTEINS**
**   ****SOLUTE SIZE AND DIFFUSIVITY**

## DIALYZER PERMEABILITY VS. FREE WATER DIFFUSION COEFFICIENTS

*** From Gibson TP et al. Clin Pharmacol Ther 1976;20:720-6.**

_**PROCAINAMIDE/NAPA**_**:**
**RATIO OF DIALYZER **
**PERMEABILITY COEFFICIENTS*****	****1.29  ********  0.22**
**RATIO OF FREE WATER **
**DIFFUSION COEFFICIENTS****	****	****1.23**

## DIALYSIS CLEARANCE VS. DIALYZER BLOOD FLOW*

- * From Renkin EM. Tr Am Soc Artific Organs 1956;2:102-5

## GOALS OF DIALYSIS DISCUSSION

**DISCUSSION OF DIALYSIS CLEARANCE**
**	****MECHANISTIC - RENKIN APPROACH**
**	****EMPIRICAL**
**	****	****FICK EQUATION**
**	****	****RECOVERY CLEARANCE**
**EFFECTS OF DIALYSIS ON PHARMACOKINETICS**
**HEMODYNAMIC CHANGES DURING DIALYSIS**
**	****USE OF KINETIC METHODS FOR ANALYSIS****	****PATHOPHYSIOLOGIC CONSEQUENCES**

##  DATA  SOURCES FOR FICK EQUATION

**A**

**V**

**Q**

## FICK EQUATION

**Q = DIALYZER BLOOD FLOW**
**A = CONCENTRATION IN BLOOD COMING TO DIALYZER**
**V = CONCENTRATION IN BLOOD LEAVING DIALYZER**
**E = EXTRACTION RATIO**

## EXTRACTION RATIO

## CALCULATION OF RECOVERY  CLEARANCE 

**U  =  DIALYSATE CONCENTRATION**
**V  =  DIALYSATE VOLUME**
**t    =  DIALYSIS TIME**
**P  =  MEAN PLASMA CONCENTRATION**

**THE GOLD STANDARD**

## TWO DIALYSIS MYTHS

**     ****WHEN CALCULATING BLOOD CLEARANCE**
**   ****NEED TO USE PLASMA FLOW WHEN**
**     ****CALCULATING PLASMA CLEARANCE**

**TWO DIALYSIS MYTHS**

**BUT PLASMA CONCENTRATIONS PROPORTIONAL TO BLOOD CONCENTRATIONS, SO MAKES NO DIFFERENCE IN A/[A + V] RATIO**

## PLASMA VS. BLOOD CLEARANCE

## NAPA IN RBC IS DIALYZED

*** Q****EFF****  =  [ (1 - Hct) + (RBC/P) (HCT) ] Q****MEAS**

## GOALS OF DIALYSIS DISCUSSION

**DISCUSSION OF DIALYSIS CLEARANCE**
**	****MECHANISTIC - RENKIN APPROACH**
**	****EMPIRICAL**
**	****	****FICK EQUATION**
**	****	****RECOVERY CLEARANCE**
**EFFECTS OF DIALYSIS ON PHARMACOKINETICS**
**HEMODYNAMIC CHANGES DURING DIALYSIS**
**	****USE OF KINETIC METHODS FOR ANALYSIS****	****PATHOPHYSIOLOGIC CONSEQUENCES**
**	****RELEVANCE TO Rx OF DRUG TOXICITY**

##  DATA  SOURCES FOR RIGOROUS PK ANALYSIS

**A**

**V**

**Q**

**RECOVERED DRUG**

## KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*

**KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA***

- * From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.

## KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*

- * From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.

## FICK CLEARANCE EQUATION

## TWO PROBLEMS WITH FIXED-PARAMETER MODEL*

- * From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.

**1.  **_**DURING DIALYSIS**_**: [A] AND [V] DROP MORE**
**     ****THAN EXPECTED FROM DRUG RECOVERY**

**2.****  **_**AFTER DIALYSIS**_**: CONCENTRATION **
**     ****REBOUND IS LESS THAN EXPECTED**

## KINETIC MODEL USED TO ANALYZE HEMODIALYSIS DATA*

- * From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.

## REDUCTION IN CLS DURING AND AFTER HEMODIALYSIS*

- * From Stec GP, et al. Clin Pharmacol Ther 1979;26:618-28.

## RENKIN EQUATION*

*** From Renkin EM.** **Am J Physiol 1953;183:125-36**.

**Q = capillary blood flow**
**P = capillary permeability coefficient-surface**
**      ****area product (sometimes denoted P****•S).**

## GOALS OF DIALYSIS DISCUSSION

**DISCUSSION OF DIALYSIS CLEARANCE**
**	****MECHANISTIC - RENKIN APPROACH**
**	****EMPIRICAL**
**	****	****FICK EQUATION**
**	****	****RECOVERY CLEARANCE**
**EFFECTS OF DIALYSIS ON PHARMACOKINETICS**
**HEMODYNAMIC CHANGES DURING DIALYSIS**
**	****USE OF KINETIC METHODS FOR ANALYSIS****	****PATHOPHYSIOLOGIC CONSEQUENCES**
**	****RELEVANCE TO Rx OF DRUG TOXICITY**

## MULTICOMPARTMENTAL MODEL  OF INULIN AND UREA KINETICS*

*** From Atkinson AJ Jr, et al. Trends Pharmacol Sci 1991;12:96-101.**

**UREA**

##  UREA () AND INULIN () KINETICS  DURING AND AFTER HEMODIALYSIS*

*** From Bowsher DJ, et al.  J Lab Clin Med 1985;105:489-97.**

**? ****REASON FOR DIFFERENT**
**   ****CL****S**** RESPONSE**

##  RELATIONSHIP BETWEEN BLOOD FLOW (Q) AND CLI *

*** From Bowsher DJ, et al. J Lab Clin Med 1985;105:489-97. **

##  UREA AND INULIN KINETICS  DURING AND AFTER HEMODIALYSIS

*** ESTIMATED AS C.O. - Q ****S**

## RENIN-ANGIOTENSIN SYSTEM ACTIVATION  DURING AND AFTER HEMODIALYSIS*

*** From Bowsher DJ, et al.  J Lab Clin Med 1985;105:489-97.**

##  DIFFERENT MICROCIRCULATORY ACTIONS OF ANGIOTENSIN II AND AVP*

*** From Atkinson AJ Jr: The Pharmacologist 1989;31:229-34. **

##  EFFECT OF ARGININE VASOPRESSIN (AVP) ON P S*

*** From Atkinson AJ Jr: The Pharmacologist 1989;31:229-34. **

## CLINICAL CONSEQUENCES OF DIALYSIS-ASSOCIATED HEMODYNAMIC CHANGES

**IMPACT ON HEMODIALYSIS THERAPY OF DRUG TOXICITY**
**PATHOGENEIC ROLE IN DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS**

## DIALYSIS CASE HISTORY

-   **A 67 year-old woman became lethargic and confused and developed hypotension, renal insufficiency, junctional tachycardia and intraventricular conduction delay after ingesting an estimated 7gm of procainamide (PA).  Plasma PA and NAPA concentrations were 57 ****μ****g/mL and 55 ****μ****g/mL, respectively.**

## DIALYSIS CASE HISTORY (cont.)

-   **Hemodialysis was performed for 4 hr.  By the end of the second hour BP was maintained in the range of 110/80 mm Hg without vasopressor therapy.  At the end of dialysis, the patient was alert and oriented although only 340 mg of PA and 470 mg of NAPA had been removed by this procedure. **

## DIALYSIS CASE HISTORY (cont.)

-   **Fifteen hours after dialysis, PA and NAPA levels were 9.2 ****μ****g/mL and 33 ****μ****g/mL, respectively.  The patient had returned to normal sinus rhythm with QRS = 0.12 sec. **

##  KINETIC ANALYSIS OF HEMODIALYSIS FOR PROCAINAMIDE TOXICITY*

*** From: Atkinson AJ Jr, et al. Clin Pharmacol Ther 1976;20:585-92.**

## CRITERION FOR  DIALYSIS EFFICACY*

-  **CL****EC**** > 30% [CL****R**** + CL****NR ****]**

*** Levy G. Am J Med 1977;62:461-5.**

## DIALYSIS INCREASED DRUG CLEARANCE
				PA – TWO FOLD
				NAPA – 3.8 FOLD
BUT 4 hr OF DIALYSIS REMOVED < 1 gm of 7 gm DOSE
				340 mg PA
				470 mg NAPA
HOWEVER, BLOOD LEVELS FELL SUBSTANTIALLY
		PA:        25.7 μg/mL         		15.5 μg/mL
		NAPA:   47.0 μg/mL		35.5 μg/mL
     AND PATIENT’S CONDITION STABILIZED

**	****	****	****	****PA – TWO FOLD**
**	****	****	****	****NAPA – 3.8 FOLD**
**BUT 4 hr OF DIALYSIS REMOVED < 1 gm of 7 gm DOSE**
**	****	****	****	****340 mg PA**
**	****	****	****	****470 mg NAPA**
**HOWEVER, BLOOD LEVELS FELL SUBSTANTIALLY**
**	****	****PA:        25.7 μg/mL         ****	****	****15.5 μg/mL**
**	****	****NAPA:   47.0 μg/mL****	****	****35.5 μg/mL**
***     ******AND***** PATIENT’S CONDITION STABILIZED**

**WAS DIALYSIS EFFICACIOUS?**

## PA & NAPA KINETICS IN TOXIC PATIENT

|  | NORMAL |  | PATIENT |  |
| --- | --- | --- | --- | --- |
|  | PA | NAPA | PA | NAPA |
| t1/2  (hr) | 2.5 | 6.2 | 10.5 | 35.9 |
| Vdβ  (L/kg) | 1.80 | 1.76 | 0.76 | 0.63 |
| CLE  (mL/min) | 590 | 233 | 66.8 | 16.1 |
| CLD  (mL/min) |  |  | 68.3 | 45.8 |

## ESTIMATION OF Vd

-   **Question:  Why was distribution volume **
**                     ****estimate so much lower in**
**                     ****patient than in normal subjects?**

## SEQUESTRATION OF DRUG IN SOMATIC TISSUES

***CL******S****** ***

## EFFICACY OF EXTRACORPOREAL TREATMENT OF DRUG TOXICITY

**  ****TOTAL EXTENT OF DRUG REMOVAL MAY BE **
**    ****COMPROMIZED BY ****↓**** CL****S****.**** **

** ****↓**** ****CL****S ****FROM SOMATIC TISSUES CAN **
**   ****ACCELERATE ****↓** **IN DRUG CONCENTRATION **
**   ****TO WHICH VITAL ORGANS (CNS, HEART) ARE **
**   ****EXPOSED AND RESULT IN A BENEFICIAL **
**   ****CLINICAL RESPONSE > EXTENT OF DRUG **
**   ****REMOVAL.**
-  **↓**** ****CL****S**** FROM SOMATIC TISSUES ALSO**
**   ****ATTENUATES POST-DIALYSIS REBOUND****.**

## CLINICAL CONSEQUENCES OF DIALYSIS-ASSOCIATED HEMODYNAMIC CHANGES

**IMPACT ON HEMODIALYSIS THERAPY OF DRUG TOXICITY**
**PATHOGENEIC ROLE IN DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS**

## ACTIONS OF ANGIOTENSIN II & SYMPATHETIC NERVOUS SYSTEM

## ONLY SOME PATIENTS HAVE  DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS*

*** Sidhom OA, et al. Clin Pharmacol Ther 1994;56:445-51**

## CAPILLARY DERECRUITMENT (OPEN (O) & CLOSED () CAPILLARIES)

**OPEN CAPILLARIES IN MUSCLE CROSS SECTION**

**8**

**4**

## PATHOGENESIS OF DIALYSIS-ASSOCIATED SKELETAL MUSCLE CRAMPS

**HEMODIALYSIS**
**PLASMA VOLUME CONTRACTION**
**UNMODULATED SYMPATHETIC ACTIVATION**
**PERIPHERAL VASOCONSTRICTION**
**DERECRUITMENT OF MUSCLE CAPILLARIES**
**IMPAIRED MUSCLE OXYGENATION**
**SKELETAL MUSCLE CRAMPS**

**X   ******** ****NaCl, MANNITOL**

**X   ********   PRAZOSIN**

**ACE INHIBITOR  ********     ****+**

## CONCLUDING THOUGHT

**ALTHOUGH NON-COMPARTMENTAL ANALYSIS**
**OF PK DATA IS CURRENTLY IN VOGUE, IT IS **
**UNABLE TO PROVIDE INSIGHT INTO SOME IMPORTANT PHENOMENA: **
**   ****- ****IMPACT OF ****↓ SPLANCHNIC BLOOD FLOW **
**      ****(↓ CL****F****) ON BIOAVAILABILITY**
**   ****-  IMPACT OF DIALYSIS-ASSOCIATED**
**      ****HEMODYNAMIC CHANGES (****↓ CL****S****)****  **