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Elucidation of the Pathophysiology of Intradialytic Muscle Cramps: Pharmacokinetics Applied to Translational Research

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Elucidation of the Pathophysiology of Intradialytic Muscle Cramps: Pharmacokinetics Applied to Translational Research 2019;27(4):119-122 TCP Transl Clin Pharmacol https://doi.org/10.12793/tcp.2019.27.4.119 Elucidation of the pathophysiology of intradialytic muscle cramps: pharmacokinetics applied to translational research Arthur J. Atkinson, Jr.* TUTORIAL Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA *Correspondence: Arthur J. Atkinson, Jr.; E-mail: [email protected] In the conventional concept of translational research, investigations flow from the laboratory Received 17 Oct 2019 bench to the bedside. However, clinical research can also serve as the starting point for subsequent Accepted 7 Dec 2019 laboratory investigations that then lead back to the bedside. This article chronicles the evolution of a Keywords series of studies in which a detailed analysis of pharmacokinetics in hemodialysis patients revealed Capillary physiology, new physiological insight that, through a systems approach incorporating kinetic, physicochemical, Hemodialysis, Intradialytic cramps, physiologic, and clinical trial results, led to an elucidation of the pathophysiology of intradialytic Pharmacokinetics, skeletal muscle cramps. Based on this understanding, a therapeutic path forward is proposed. Renin-angiotensin system, Sympathetic nervous system pISSN: 2289-0882 eISSN: 2383-5427 Introduction Because the central compartment of the model represented in- After preliminary observations indicated that procainamide’s travascular space, it was concluded that the intercompartmental acetylated metabolite, N acetylprocainamide (NAPA), had clearances of the model represented the process of transcapil- antiarrhythmic activity in procainamide-treated patients,[1] lary exchange. and pharmacokinetic studies in healthy subjects indicated that NAPA’s longer elimination half-life would permit a more conve- Identification of model compartments and nient dosing interval than recommended for procainamide,[2] components of intercompartmental clearance patient trials were begun to further develop this metabolite as A similar three-compartment model was used to study the ki- an antiarrhythmic drug in its own right.[3] As part of the sub- netics of simultaneously injected inulin and urea in dogs[5] and sequent development program, NAPA pharmacokinetics were in healthy human subjects.[6] The following permeability-flow investigated in functionally anephric patients in a study that was equation, which has a long history[7] but was first developed by conducted in continuity before, during, and after hemodialysis. Renkin[8] to describe solute transfer across isolated perfused [4] Using a three-compartment mammillary model in which hind leg capillaries of cats in terms of their blood flow (Q) and the volume of the central compartment corresponded to plasma permeability coefficient-surface area products (P·S), was then volume, it was observed that the intercompartmental clearance used to interpret the intercompartmental clearance (CLI) re- to the slowly equilibrating peripheral compartment was reduced sults: during hemodialysis by an average of 77% and only partially –P·S/Q CL = Q (1 - e ) returned to normal in the first few hours after hemodialysis. I Since the transcapillary exchange of inulin is not restricted Copyright © 2019 Arthur J. Atkinson, Jr. It is identical to the Creative Commons Attribution Non-Commercial License by molecular size,[9] it was assumed that the ratio of P·S values (http://creativecommons.org/licenses/by-nc/3.0/). for inulin and urea would be the same as the ratio of their free- This paper meets the requirement of KS X ISO 9706, ISO 9706-1994 and water diffusion coefficients. In this way, simultaneous Renkin ANSI/NISO Z.39.48-1992 (Permanence of Paper). clearance equations for urea and inulin, and this ratio were used Reviewer to calculate values for blood flows and aggregate capillary P·S This article was invited and reviewed by the editors of TCP. values for the two peripheral compartments of the model. It was 119 Vol. 27, No.4, Dec 30, 2019 Pathophysiology of intradialytic cramps TCPTransl Clin Pharmacol found that the sum of the compartmental blood flows averaged 97% of measured cardiac output (range 83–113%) in dogs,[5] and in humans 5.39 ± 0.49 L/min, similar to the independently measured cardiac output value of 5.47 ± 0.40 L/min.[6] Further confirmation of the validity of this approach was provided by a pharmacokinetic study in dogs in which inulin, urea, and theophylline were injected simultaneously.[10] Theophyl- line kinetics were modeled with a similar three-compartment Figure 1. Schematic drawing of a skeletal muscle capillary showing arteriolar R and venular R resistances. Whereas arginine vasopres- model, and its intercompartmental clearances were similar to A V sin (AVP) acts solely on RA, resulting in closure of some capillaries, an- the blood flows estimated for the corresponding inulin and urea giotensin II (AII) acts on both RA and RV in such a way that the ratio of R /R is sufficient to maintain capillary patency and functional surface compartments. The anatomic identity of the peripheral model V A area. compartments was then explored by studying the pharmaco- kinetics of these three compounds in dogs after splenectomy and enterectomy.[11] Because this surgical procedure removed approximately half of the volume of the rapidly equilibrating sist in compartment identification.[11] In this study, there was but less than 20% of their slowly equilibrating inulin and urea a marked reduction in slow compartment P·S values that was peripheral compartments, it was concluded that the fast equili- correlated with a surgery-induced elevation in plasma levels brating compartment was composed primarily of splanchnic of arginine vasopressin (AVP) such that AVP levels of 45 pg/ tissues, and the slowly equilibrating compartment was made up ml resulted in an almost 50% decrease in P·S values.[13] The primarily of skeletal muscle and other somatic tissues. Based on observed reduction in P·S values results from the fact that AVP previous morphologic studies, it was inferred that the difference acts solely to increase precapillary arteriolar resistance and so in transcapillary exchange rates of the peripheral compartments lowers intracapillary pressure to the extent that functional capil- reflected the fact these three compounds reached the interstitial lary density decreases and aggregate capillary surface area is re- fluid of splanchnic organs primarily by diffusing through the duced (Fig. 1).[14] On the other hand, angiotensin II (AII) acts in relatively large fenestrations of splanchnic capillaries, whereas a balanced fashion to constrict both precapillary and postcapil- they reached somatic tissues through the much narrower endo- lary resistance vessels in such a way that sufficient intracapillary thelial cell junctions of continuous capillaries. hydrostatic pressure is retained to maintain patency.[15] Studies in a canine hemodialysis model Subsequent clinical studies This modeling approach subsequently was used to analyze Although kinetic studies in both hemodialyzed patients and inulin and urea distribution kinetics before, during, and after dogs indicated that this procedure was accompanied by sub- hemodialysis of dogs with intact kidneys.[12] During the two- stantial hemodynamic changes that were likely related to the hour hemodialysis session, mean arterial pressure fell by less occurrence of skeletal muscle cramps, they failed to provide than 5%, but total peripheral resistance increased by 47%, and evidence as to why only some hemodialyzed patients experi- cardiac output fell by 35%. These hemodynamic changes were enced these cramps. The study of hemodynamic and hormonal accompanied by marked reductions in the slow CLI of inulin responses to hemodialysis is complicated by the concurrence of and urea to 19% and 63% of their respective predialysis values. both osmotic and volume stimuli during the procedure and by Using the simultaneous Renkin equation approach, it was esti- the possible dialytic removal of vasoactive substances. Because mated that this corresponded to a 90% reduction in blood flow of the role played by plasma volume contraction in initiating to this compartment during hemodialysis. These changes were intradialytic cramps, head-up tilt was selected as a relatively only somewhat attenuated during the two hours after hemodi- well-controlled volume stress that could be used for compar- alysis. In contrast to these marked changes, the P·S values for ing the responses of 8 patients who frequently experienced this compartment were not significantly reduced, signifying that intradialytic cramps with those of 8 patients who cramped there was no significant derecruitment of capillaries supplying infrequently.[16] Baseline blood pressure, plasma renin activity skeletal muscles and other somatic compartment components. and plasma norepinephrine and arginine vasopressin concen- There also was no significant change in the blood flows or P·S trations were similar in both groups. After equilibration in the values calculated for the more rapidly equilibrating splanchnic recumbent position, the patients were brought to a 60° tilt for compartment. up to 1 hr. Systolic blood pressure rapidly fell by an average of The additional observation was made that these changes were 17% in patients who cramped infrequently but only by an aver- accompanied by activation of the renin-angiotensin system. age of 10% in frequently cramping patients. The ratio of tilt/ The stability of somatic compartment
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