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Canadian Journal of Cardiology

The Impact of Obesity on the Pharmacology of Medications Used for Cardiovascular Risk Factor Control

Published:October 27, 2014DOI:https://doi.org/10.1016/j.cjca.2014.10.025

      Abstract

      Most drugs are currently dosed empirically (fixed-dose) or based on total body weight. In obese patients, these dosing strategies might, in theory, lead to inadequate clinical effect (empiric dosing) or toxicity (weight-based dosing). Our objective was to first review body size descriptors used for drug dosing and then to examine the effect of obesity on the pharmacokinetics and pharmacodynamics of drugs used for cardiovascular risk reduction (antihypertensive agents, statins, aspirin, antidiabetic agents). We found a limited number of published studies for most drug classes. For β-blockers, volume of distribution was increased in the obese and this appears to be primarily due to greater distribution into lean tissue. In contrast, clearance was decreased, unchanged or increased, depending on the agent. This suggests that loading doses should be based on lean body weight and maintenance doses adjusted in a drug-specific fashion according to clearance alterations. For antidiabetic agents, glucose-lowering effects were slightly diminished in most studies in obese patients. Outside of these findings, in the studies reported to date, obesity did not exert a consistent, clinically important effect on drug pharmacology. Because obesity can cause drug-specific pharmacological changes for some drug classes (eg, β-blockers), there is a need to conduct further studies. To avoid detecting pharmacokinetic changes that are ultimately deemed clinically inconsequential, we suggest a “top down” approach in which clinically important outcomes are compared between obese and nonobese subjects. If important differences are found, further studies should be then performed to delineate underlying pharmacological mechanisms and inform the need for dose adjustment.

      Résumé

      La plupart des médicaments sont habituellement dosés de manière empirique (doses fixes) ou selon le poids corporel total. Chez les patients obèses, ces stratégies de dosage entraîneraient, en théorie, un effet clinique inadéquat (dosage empirique) ou une toxicité (dosage établi selon le poids). Notre objectif était d’abord de passer en revue les descripteurs de la masse corporelle utilisés pour doser les médicaments et ensuite d’examiner l’effet de l’obésité sur la pharmacocinétique et la pharmacodynamie des médicaments utilisés pour réduire le risque cardiovasculaire (antihypertenseurs, statines, aspirine, antidiabétiques). Nous avons trouvé un nombre limité d’études publiées sur la plupart des classes de médicaments. En ce qui concerne les β-bloquants, le volume de distribution était augmenté chez l’obèse, ce qui semble être principalement dû à la plus grande distribution dans les tissus maigres. En revanche, la clairance était diminuée, inchangée ou augmentée selon l’agent. Cela suggère que les doses de charge devraient être établies selon la masse du corps excluant la graisse et les doses d’entretien ajustées de manière spécifique au médicament selon les modifications de la clairance. En ce qui concerne les antidiabétiques, les effets hypoglycémiants étaient légèrement diminués dans la plupart des études chez les patients obèses. Au-delà de ces résultats, les études rapportées à ce jour ont démontré que l’obésité n’exerçait pas de manière constante un effet cliniquement important sur la pharmacologie. Puisque l’obésité peut causer des changements pharmacologiques spécifiques au médicament pour certaines classes de médicaments (p. ex., les β-bloquants), il est nécessaire de mener d’autres études. Pour éviter la détection de changements pharmacocinétiques, qui sont finalement considérés cliniquement sans conséquence, nous suggérons une approche « descendante » où les résultats importants sur le plan clinique sont comparés entre les sujets obèses et les sujets non obèses. Si des différences importantes sont observées, d’autres d’études devraient alors être réalisées pour définir les mécanismes pharmacologiques sous-jacents et appuyer la nécessité de l’ajustement des doses.
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      References

      1. World Health Organization. Media Centre. Obesity and overweight. Available at: http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed July 22, 2014.

        • Ogden C.L.
        • Carroll M.D.
        • Kit B.K.
        • Flegal K.M.
        Prevalence of childhood and adult obesity in the United States, 2011-2012.
        JAMA. 2014; 311: 806-814
        • Padwal R.S.
        Obesity, diabetes, and the metabolic syndrome: the global scourge.
        Can J Cardiol. 2014; 30: 467-472
        • Padwal R.S.
        • Sharma A.M.
        Treating severe obesity: morbid weights and morbid waits.
        CMAJ. 2009; 181: 777-778
        • Whitlock G.
        • Lewington S.
        • et al.
        • Prospective Studies Collaboration
        Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.
        Lancet. 2009; 373: 1083-1096
        • Haslam D.W.
        • James W.P.
        Obesity.
        Lancet. 2005; 366: 1197-1209
        • Ashraf M.J.
        • Baweja P.
        Obesity: the ‘huge’ problem in cardiovascular diseases.
        Mo Med. 2013; 110: 499-504
        • Benet L.Z.
        • Zia-Amirhosseini P.
        Basic principles of pharmacokinetics.
        Toxicol Pathol. 1995; 23: 115-123
        • Fan J.
        • de Lannoy I.A.
        Pharmacokinetics.
        Biochem Pharmacol. 2014; 87: 93-120
        • Cornier M.A.
        • Després J.P.
        • Davis N.
        • et al.
        Assessing adiposity: a scientific statement from the American Heart Association.
        Circulation. 2011; 124: 1996-2019
        • Ellis K.J.
        Human body composition: in vivo methods.
        Physiol Rev. 2000; 80: 649-680
        • Sutcliffe J.F.
        A review of in vivo experimental methods to determine the composition of the human body.
        Phys Med Biol. 1996; 41: 791-833
        • Roubenoff R.
        • Kehayias J.J.
        The meaning and measurement of lean body mass.
        Nutr Rev. 1991; 49: 163-175
        • Hanley M.J.
        • Abernethy D.R.
        • Greenblatt D.J.
        Effect of obesity on the pharmacokinetics of drugs in humans.
        Clin Pharmacokinet. 2010; 49: 71-87
        • Green B.
        • Duffull S.B.
        Development of a dosing strategy for enoxaparin in obese patients.
        Br J Clin Pharmacol. 2003; 56: 96-103
        • Kjellberg J.
        • Reizenstein P.
        Body composition in obesity.
        Acta Med Scand. 1970; 188: 161-169
        • Green B.
        • Duffull S.
        Caution when lean body weight is used as a size descriptor for obese subjects.
        Clin Pharmacol Ther. 2002; 72: 743-744
        • Green B.
        • Duffull S.B.
        What is the best size descriptor to use for pharmacokinetic studies in the obese?.
        Br J Clin Pharmacol. 2004; 58: 119-133
        • Duffull S.B.
        • Dooley M.J.
        • Green B.
        • Poole S.G.
        • Kirkpatrick C.M.
        A standard weight descriptor for dose adjustment in the obese patient.
        Clin Pharmacokinet. 2004; 43: 1167-1178
        • Forbes G.B.
        • Welle S.L.
        Lean body mass in obesity.
        Int J Obes. 1983; 7: 99-107
        • Womersley J.
        • Durnin J.V.
        • Boddy K.
        • Mahaffy M.
        Influence of muscular development, obesity, and age on the fat-free mass of adults.
        J Appl Physiol. 1976; 41: 223-229
        • Falagas M.E.
        • Karageorgopoulos D.E.
        Adjustment of dosing of antimicrobial agents for body weight in adults.
        Lancet. 2010; 375: 248-251
        • Cheymol G.
        • Poirier J.M.
        • Carrupt P.A.
        • et al.
        Pharmacokinetics of beta-adrenoceptor blockers in obese and normal volunteers.
        Br J Clin Pharmacol. 1997; 43: 563-570
        • Poirier J.M.
        • Le Jeunne C.
        • Cheymol G.
        • et al.
        Comparison of propranolol and sotalol pharmacokinetics in obese subjects.
        J Pharm Pharmacol. 1990; 42: 344-348
        • Ghobadi C.
        • Johnson T.N.
        • Aarabi M.
        • et al.
        Application of a systems approach to the bottom-up assessment of pharmacokinetics in obese patients: expected variations in clearance.
        Clin Pharmacokinet. 2011; 50: 809-822
        • Blouin R.A.
        • Warren G.W.
        Pharmacokinetic considerations in obesity.
        J Pharm Sci. 1999; 88: 1-7
        • Anastasio P.
        • Spitali L.
        • Frangiosa A.
        • et al.
        Glomerular filtration rate in severely overweight normotensive humans.
        Am J Kidney Dis. 2000; 35: 1144-1148
        • Nowack R.
        • Raum E.
        • Blum W.
        • Ritz E.
        Renal hemodynamics in recent-onset type II diabetes.
        Am J Kidney Dis. 1992; 20: 342-347
        • Diehl A.M.
        Nonalcoholic steatohepatitis.
        Semin Liver Dis. 1999; 19: 221-229
        • Guzzaloni G.
        • Grugni G.
        • Minocci A.
        • Moro D.
        • Morabito F.
        Liver steatosis in juvenile obesity: correlations with lipid profile, hepatic biochemical parameters and glycemic and insulinemic responses to an oral glucose tolerance test.
        Int J Obes Relat Metab Disord. 2000; 24: 772-776
        • Ratziu V.
        • Giral P.
        • Charlotte F.
        • et al.
        Liver fibrosis in overweight patients.
        Gastroenterology. 2000; 118: 1117-1123
        • Hunt C.M.
        • Watkins P.B.
        • Saenger P.
        • et al.
        Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol.
        Clin Pharmacol Ther. 1992; 51: 18-23
        • Hunt C.M.
        • Westerkam W.R.
        • Stave G.M.
        • Wilson J.A.
        Hepatic cytochrome P-4503A (CYP3A) activity in the elderly.
        Mech Ageing Dev. 1992; 64: 189-199
        • Chiney M.S.
        • Schwarzenberg S.J.
        • Johnson L.A.
        Altered xanthine oxidase and N-acetyltransferase activity in obese children.
        Br J Clin Pharmacol. 2011; 72: 109-115
        • Lucas D.
        • Farez C.
        • Bardou L.G.
        • et al.
        Cytochrome P450 2E1 activity in diabetic and obese patients as assessed by chlorzoxazone hydroxylation.
        Fundam Clin Pharmacol. 1998; 12: 553-558
        • O’Shea D.
        • Davis S.N.
        • Kim R.B.
        • Wilkinson G.R.
        Effect of fasting and obesity in humans on the 6-hydroxylation of chlorzoxazone: a putative probe of CYP2E1 activity.
        Clin Pharmacol Ther. 1994; 56: 359-367
        • Langtry H.D.
        • Balfour J.A.
        Glimepiride. A review of its use in the management of type 2 diabetes mellitus.
        Drugs. 1998; 55: 563-584
        • Shukla U.A.
        • Chi E.M.
        • Lehr K.H.
        Glimepiride pharmacokinetics in obese versus non-obese diabetic patients.
        Ann Pharmacother. 2004; 38: 30-35
        • Bowman S.L.
        • Hudson S.A.
        • Simpson G.
        • Munro J.F.
        • Clements J.A.
        A comparison of the pharmacokinetics of propranolol in obese and normal volunteers.
        Br J Clin Pharmacol. 1986; 21: 529-532
        • Cheymol G.
        • Poirier J.M.
        • Barre J.
        • Pradalier A.
        • Dry J.
        Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers.
        J Clin Pharmacol. 1987; 27: 874-879
        • Cheymol G.
        • Woestenborghs R.
        • Snoeck E.
        • et al.
        Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects.
        Eur J Clin Pharmacol. 1997; 51: 493-498
        • Wojcicki J.
        • Jaroszynska M.
        • Droździk M.
        • et al.
        Comparative pharmacokinetics and pharmacodynamics of propranolol and atenolol in normolipaemic and hyperlipidaemic obese subjects.
        Biopharm Drug Dispos. 2003; 24: 211-218
        • Galletti F.
        • Fasano M.L.
        • Ferrara L.A.
        • et al.
        Obesity and beta-blockers: influence of body fat on their kinetics and cardiovascular effects.
        J Clin Pharmacol. 1989; 29: 212-216
        • MacMahon S.W.
        • Macdonald G.J.
        • Bernstein L.
        • Andrews G.
        • Blacket R.B.
        Comparison of weight reduction with metoprolol in treatment of hypertension in young overweight patients.
        Lancet. 1985; 1: 1233-1236
        • Manrique C.
        • Whaley-Connell A.
        • Sowers J.R.
        Nebivolol in obese and non-obese hypertensive patients.
        J Clin Hypertens (Greenwich). 2009; 11: 309-315
        • Le Jeunne C.
        • Poirier J.M.
        • Cheymol G.
        • et al.
        Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers.
        Eur J Clin Pharmacol. 1991; 41: 171-174
        • Stimpel M.
        • Koch B.
        • Weber M.A.
        Comparison between moexipril and atenolol in obese postmenopausal women with hypertension.
        Maturitas. 1998; 30: 69-77
        • Cheymol G.
        Effects of obesity on pharmacokinetics implications for drug therapy.
        Clin Pharmacokinet. 2009; 39: 215-231
        • Abernethy D.R.
        • Schwartz J.B.
        Verapamil pharmacodynamics and disposition in obese hypertensive patients.
        J Cardiovasc Pharmacol. 1988; 11: 209-215
        • Wofford M.R.
        • Anderson Jr., D.C.
        • Brown C.A.
        • et al.
        Antihypertensive effect of alpha- and beta-adrenergic blockade in obese and lean hypertensive subjects.
        Am J Hypertens. 2001; 14: 694-698
        • Kato J.
        • Yokota N.
        • Tamaki N.
        • et al.
        Differential blood pressure reductions by angiotensin receptor blocker plus calcium channel blocker or diuretic in elderly hypertension with or without obesity.
        J Am Soc Hypertens. 2012; 6: 393-398
        • Weber M.A.
        • Jamersen K.
        • Bakri G.L.
        • et al.
        Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial.
        Lancet. 2013; 381: 537-545
        • Hsueh W.A.
        • Shojaee A.
        • Maa J.F.
        • Neutel J.M.
        Efficacy of amlodipine/olmesartan medoxomil +/- HCTZ in obese patients uncontrolled on antihypertensive monotherapy.
        Curr Med Res Opin. 2012; 28: 1809-1818
        • Roth E.M.
        • Oparil S.
        • Melino M.
        • et al.
        Olmesartan/amlodipine/hydrochlorothiazide in obese participants with hypertension: a TRINITY subanalysis.
        J ClinHypertens (Greenwich). 2013; 15: 584-592
        • Calhoun D.A.
        • Jones D.
        • Textor S.
        • et al.
        Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.
        Hypertension. 2008; 51: 1403-1419
        • Kotchen T.A.
        Obesity-related hypertension: epidemiology, pathophysiology, and clinical management.
        Am J Hypertens. 2010; 23: 1170-1178
        • Padwal R.S.
        • Rabkin S.
        • Khan N.
        Assessment and management of resistant hypertension.
        CMAJ. 2014; 186: E689-E697
        • Wang S.
        • Majumdar S.R.
        • Padwal R.
        BMI annual blood pressure measurements, and mortality in patients with obesity and hypertension: a retrospective cohort study.
        Blood Press Monit. 2015; 20: 32-38
        • DeGorter M.K.
        • Tirona R.G.
        • Schwarz U.I.
        • et al.
        Clinical and pharmacogenetic predictors of circulating atorvastatin and rosuvastatin concentrations in routine clinical care.
        Circ Cardiovasc Genet. 2013; 6: 400-408
        • Bordeaux B.C.
        • Qayyum R.
        • Yanek L.R.
        • et al.
        Effect of obesity on platelet reactivity and response to low-dose aspirin.
        Prev Cardiol. 2010; 13: 56-62
        • Gaglia Jr., M.A.
        • Torguson R.
        • Pakala R.
        • et al.
        Relation of body mass index to on-treatment (clopidogrel + aspirin) platelet reactivity.
        Am J Cardiol. 2011; 108: 766-771
        • Tamminen M.
        • Lassila R.
        • Westerbacka J.
        • Vehkavaara S.
        • Yki-Jarvinen H.
        Obesity is associated with impaired platelet-inhibitory effect of acetylsalicylic acid in nondiabetic subjects.
        Int J Obes Relat Metab Disord. 2003; 27: 907-911
        • Westerbacka J.
        • Yki-Järvinen H.
        • Turpeinen A.
        • et al.
        Inhibition of platelet-collagen interaction: an in vivo action of insulin abolished by insulin resistance in obesity.
        Arterioscler Thromb Vasc Biol. 2002; 22: 167-172
        • Trovati M.
        • Anfossi G.
        • Massucco P.
        • et al.
        Insulin stimulates nitric oxide synthesis in human platelets and, through nitric oxide, increases platelet concentrations of both guanosine-3', 5'-cyclic monophosphate and adenosine-3', 5'-cyclic monophosphate.
        Diabetes. 1997; 46: 742-749
        • Trovati M.
        • Mularoni E.M.
        • Burzacca S.
        • et al.
        Impaired insulin-induced platelet antiaggregating effect in obesity and in obese NIDDM patients.
        Diabetes. 1995; 44: 1318-1322
        • Jaber L.A.
        • Ducharme M.P.
        • Halapy H.
        The effects of obesity on the pharmacokinetics and pharmacodynamics of glipizide in patients with non-insulin-dependent diabetes mellitus.
        Ther Drug Monit. 1996; 18: 6-13
        • Campbell P.J.
        • Carlson M.G.
        Impact of obesity on insulin action in NIDDM.
        Diabetes. 1993; 42: 405-410
        • Jaber L.A.
        • Antal E.J.
        • Slaughter R.L.
        • Welshman I.R.
        The pharmacokinetics and pharmacodynamics of 12 weeks of glyburide therapy in obese diabetics.
        Eur J Clin Pharmacol. 1993; 45: 459-463
        • Gagnon-Auger M.
        • du Souich P.
        • Baillargeon J.P.
        • et al.
        Dose-dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study.
        Diabetes Care. 2010; 33: 2502-2507
        • Parkner T.
        • Dyrskog S.E.
        • Laursen T.
        • et al.
        Obesity does not influence the unique pharmacological properties of different biphasic insulin aspart preparations in patients with type 2 diabetes.
        Diabetes Obes Metab. 2010; 12: 414-420
        • Gupta A.
        • Braunwald E.
        • McNulty S.
        • et al.
        Obesity and the response to intensified diuretic treatment in decompensated heart failure: a DOSE trial substudy.
        J Card Fail. 2012; 18: 837-844
        • Thummel K.E.
        • Wilkinson G.R.
        In vitro and in vivo drug interactions involving human CYP3A.
        Annu Rev Pharmacol Toxicol. 1998; 38: 389-430
        • Wilkinson G.R.
        Drug metabolism and variability among patients in drug response.
        N Engl J Med. 2005; 352: 2211-2221
        • Tirona R.G.
        • Lee W.
        • Leake B.F.
        • et al.
        The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4.
        Nat Med. 2003; 9: 220-224