A A Pharmacology in the obese : does weight matter? Michel MRF Struys, MD, PhD Professor and Chair, Department of Anesthesia University Medical Center Groningen Groningen, The Netherlands Professor of Anesthesia, Ghent University, Gent, Belgium Pharmacokinetics. Vd and Cl? Vd = distribution volume = apparent volume in the body available for drug distribution Cl = clearance = describes the capacity of the body to eliminate the drug from the body Vd and Cl can be determined by abserving a descreasing plasmaconcentration per time unit after a specific drug administration Vd and Cl can be described using a: Model independent approach Model dependent approach 1
Describing pharmacodynamics 100 Efficacy Efficacy : - intrinsic ability of a drug to produce a given effect 0 effect Potency Dose, concentration, or other measure of exposure Individual variability - influenced by receptor coupling to G proteins, activation of second messengers, and the ability to generate ultimate physiologic responses Potency: Ref.: Miller. Anesthesia Fifth Ed. pp 45-46 - refers to the quantity of drug that must be administered to produce a specific effect Importance of morbidly obese patients? High co-morbidity and perioperative mortality High co morbidity and perioperative mortality Require anesthesia and surgery more often Alterations in distribution, binding and elimination Different pharmacodynamics Benefits or danger of kinetic/dynamic based drug administration 2
Changes in non-compartmental pharmacokinetics Problems with obesity Most drugs are given using standard-dosing guidelines without knowledge of their pharmacokinetics Pharmacokinetic data are obtained from studies with normal-weight individuals Most dosage recommendations are scaled to TBW Alterations in distribution volume, clearance and protein binding Changes in non-compartmental pharmacokinetics Changes in Vd High lipophilic substances (eg Benzo s, barbiturates): Significant increases in Vd -> Use IBW for calculations E ti if t il Exception: remifentanil -> LBM 3
Changes in Vd Changes in non-compartmental pharmacokinetics Less lipophilic substances (eg non-depolarising NMB): Little or no change in Vd -> Use LBM (or IBW + 20%) for calculations Exception: succinylcholine li -> TBW Changes in non-compartmental pharmacokinetics Changes in Clearance : Fatty infiltration of the liver or even NASH (non-alcoholic steatohepatitis) altered clearance of drugs with phase 2 conjugation pathways Increased renal glomerular filtration and tubular secretion 4
Changes in non-compartmental pharmacokinetics Changes in protein binding Albumin binding: unaltered Rise in fatty acids, triglycerids and alfa1-acid glycoprotein: free fraction of acidic drugs is unchanged free fraction of basic drugs can be increased Changes in pharmacodynamics GABA receptor and obesity Food intake and cortisol secretion are partially Food intake and cortisol secretion are partially controlled by GABA Hypercortisolism associated with allelic variation of GABA (A) alfa 6 receptor causes obesity [Rosmond et al] Various environmental factors (eg stress) might destabilize GABA hypothalamic pituary adrenal systems in those with genetic vulnerability 5
Changes in pharmacodynamics GABA receptor and obesity Elevated presynaptic GABA release in individuals with Prader-Willi or Angelman syndrome [Ebert et al] Possible hyposensitivity of a subset of GABA receptors with a compensatory increase in presynaptic GABA Reduced d exercise capacity in obese rats with high h GABA [Lee et al] GABAergic tonic inhibition is potentially responsible for obstructive hypoventilation syndrome in obese patients Changes in pharmacodynamics Opioid receptor and obesity Endogenous opioids regulate food intake, body weight and ventilatory control Weight loss and reduced food intake after chronical administration of mu-receptor antagonists [Cole et al, Marvin-Bivens et al] Increased binding of mu-receptor agonists in feeding & reward related brain regions of rats given palatable diet [Smith et al] 6
Changes in pharmacodynamics Opioid receptor and obesity Greater density of muscular beta-endorphin and delta opioid receptors in obese mice [Evans et al] Mice with late onset obesity due to a point mutation in the carboxypeptidase E have altered mu-receptor activity in select brain regions [Boudarine et al] Met-Enk is the natural ligand for these mu-receptors [Boudarine et al] Does size matter?? What weight has to be used to calculate the dosage in obese patients?» BMI (Body Mass Index)» LBM (Lean Body Mass)» IBW (Ideal Body Weight) 7
BMI Definition: weight (kg) /height² (m²) Classification: IBW = 22-28 Obesity = 29-35 Morbid obesity >40 or >35 with comorbidity Super obesity >55 LBM Definition [James et al]: men: [1.10 * weight] - [128 * (weight/ height)²] women: [1.07 * weight] - [148 * (weight/ height)²] 8
Some TCI models incorporate LBM LBM Bouillon et Al, Anesthesiology. 89(3):557-560, September 1998. LBM male as function of weight (X-axis, kg) & height (lines; cm) 100 LBM 90 80 70 60 50 40 30 20 10 150 160 170 180 190 Unity 0 0 20 40 60 80 100 120 140 160 180 Some TCI models incorporate LBM LBM LBM female as function of weight (X-axis, kg) & height (lines; cm) 150 100 160 90 170 180 80 190 70 Unity LBM 60 50 40 30 20 10 0 0 20 40 60 80 100 120 140 160 180 9
IBW Definition [Abernethy et al]: men: 49.9 + 0.89 * [height (cm) - 152.4] women: 45.4 + 0.89 * [height (cm) - 152.4] Broca Index: men: height (cm) - 100 women: height (cm) - 105 Volatile anesthetic drugs Halothane Deposition in adipose tissue Reductive hepatic metabolism (halothane hepatitis) Enflurane Blood/gas partition coefficient reduces with weight, possibly lowering the MAC Faster increase in inorganic fluoride (fluoride nephrotoxicity) Sevoflurane Higher < > indifferent fluoride concentration compared to non-obese 10
Volatile anesthetic drugs Inhaled anesthetic of choice?? Desflurane < > Sevoflurane Volatile anesthetic drugs -BIS guided sevo or des with the use of inhalation bolus technique -Remifentanil guided by hemodynamic responses. 11
Intra-operative results Hypertension (% of time) : sevoflurane = desflurane Hypotension (% of time) Overall : sevoflurane >desflurane Bolusperiod : sevoflurane = desflurane Hypnotic stability (BIS) Overall : sevoflurane > desflurane Bolusperiod : desflurane more overshoot than sevoflurane Immediate recovery : desflurane faster than sevoflurane (2 min!) Recovery : - sedation score : sevo=des - Aldrete score = sevo = des - Oxygen saturation : sevo = des - VAS pain scores : sevo = des - PONV : at 30 and 60 min : sevo = des at 120 min : sevo < des Volatile anesthetic drugs Nitrous oxide [Luce et al] Rapid elimination Analgesic properties High oxygen demand -> limited use 12
Volatile anesthetic drugs Advantages compared with IV anesthetics MAC (analgesic effect) and MAC-awake (absence of memory) correlate with the end-tidal concentrations of the anesthetics End-tidal concentration ~ age and temperature, but weight correction is not necessary Permanent monitoring of end-tidal concentration possible Stable ratio between arterial partial pressure and end-tidal partial pressure Optimization in inhaled drug administration by using inhalation bolus technique and closed-circuit anesthesia systems Midazolam Linear increased Vd and elimination half-life, but unchanged total clearance values [Greenblatt et al] Continuous infusion ~ IBW [Reves et al] 13
Thiopental Increased Vd and elimination half-life, but unchanged total clearance values [Buckley et al] Adequate dosage: 7.5 mg/kg IBW [Buckley et al] Analgesics & opioids Alfentanil Decreased clearance and prolonged t ½ ß, but unchanged max. plasma concentration and Vd -> LBM [Bentley et al] No effect on clearance, but increased central compartment volume -> TBW [Maître et al] 14
Analgesics & opioids Fentanyl No difference in beta-elimination half-life (t ½ ß) [Bentley et al] Shibutani et al : The Shibutani correction for the Cp : Corrected Cp = Cp Shafer * (1 + (196.4 * e -0.025kg 53.66)/100) Fentanyl, alfentanil and remifentanil Dosage ~ corrected BW -> Decreased arterial pressures after induction, but in all groups within acceptable limits [Salihoglu et al] Analgesics & opioids Sufentanil Prolonged t ½ ß and increased Vd Loading dose ~ TBW [Schwartz et al] Maintenance dose must be prudently reduced Pharmacokineticset of Gepts et al > accurately prediction of Pharmacokinetic set of Gepts et al -> accurately prediction of sufentanil plasma concentrations in morbidly obese patients, but BMI > 40 -> overestimation of sufentanil plasma concentration [Slepchenko et al] TCI using Gepts model -> no weight correction necessary 15
Analgesics & opioids remifentanil Maintenance dose ~ age and LBM [Minto et al] Maintenance dose ~ LBM [Egan et al] TCI applying Minto model -> TBW, age, height and gender Analgesics & opioids Paracetamol (acetaminophen) Vd is increased in overweight and in men, but distribution in weight exceeding IBW is less then in IBW [Abernethy et al] Higher clearance [Abernethy et al] Oral dosage ~ IBW [Lee et al] 16
Propofol Induction dose ~ IBW [Gepts et al, Kirby et al, Redfern et al] Plasma propofol concentration at the end of surgery after a fixed rate infusion ~ TBW [Hirota et al] No accumulation in morbidly obese patients if dosage for maintenance of anesthesia ~ corrected BW [Servin et al] corrected body weight = IBW + (0.4 * excess weight) Propofol : we have TCI? Can we use it? Pharmacokinetical models predict a set concentration in one of the pharmacokinetical compartments These models have been implemented into TCI devices -> rapid achievement and maintenance of the desired predicted concentration in a specific compartment 17
Propofol Different 3-compartmental models (with their specific covariates) exist : Marsh: weight-adjusted -> Diprifusor Gepts: corrected BW Schüttler: weight, height and age Schnider: weight, height and LBM -> new commercial device :Alaris, Fresenius Hands on TIVA TCI: Practical Cases The difference between fixed keo vs. individualized Keo based on TTPE 18
Three compartment model with effect site: Drug Administration I V 2 k 12 V 1 k 13 V 3 k 21 Central Compartment k 31 Rapidly Equilibrating Compartment Slowly Equilibrating Compartment k 10 k 1e Effect Site V e k e0 19
TCI The models Propofol Model Marsh et al., BJA 67:41-48, 1991. Vc = 0.228 * weight (litres * kg). k10 = 0.119/min. k12 = 0.112/min. k13 = 0.0419/min. k21 = 0.055/min. k31 = 0.0033/min. k41 = 0.26/min. Model Marsh et al., BJA 67:41-48, 1991. Vc = 0.228*weight(litres * kg). k10 = 0.119/min. k12 = 0.112/min. k13 = 0.0419/min. k21 = 0.055/min. k31 = 0.0033/min. k41 for tpeak = 1.6min (Schnider et al., Anesthesiology 90:1502-16,1999) TCI The models Propofol Model Schnider et al. Anesthesiology 1998,88:1170-1182. Vc = 4.27. V2 = 18.9-0.391*(age-53). V3 = 238. cl1 = 1.89 + 0.0456*(weight- 77) - 0.0681*(lbm-59) + 0.0264*(height-177). cl2 = 1.29-0.024*(age-53). cl3 = 0.836. k41 = 0.456 min -1 (Schnider et al. Anesthesiology 90:1502-16,1999). M d ls h id t l A th i l 1998 88 1170 1182 Model Schnider et al. Anesthesiology 1998,88:1170-1182. Vc = 4.27. V2 = 18.9-0.391*(age-53). V3 = 238. cl1 = 1.89 + 0.0456*(weight- 77) - 0.0681*(lbm-59) + 0.0264*(height-177). cl2 = 1.29-0.024*(age-53). cl3 = 0.836. k41 for tpeak = 1.6 min (Schnider et al. Anesthesiology 90:1502-16,1999). 20
TCI The models Remifentanil Model: Minto, Anesthesiology 86:10-33, 1997. A = (age-40). L = (lbm-55) Vc = 5.1-0.0201*A + 0.072*L Cl1 = 2.6-0.0162*A + 0.0191*L V2 = 9.82-0.0811*A + 0.108*L Cl2 = 2.05-0.0301*A V3 = 5.42 Cl3 = 0.076-0.00113*A k41 = 0.595-0.007*A Reference : Minto et al. Anesthesiology 2003; 99: 324-33 21
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Schnider kinetics with Ce calculated using ke0 = 0.456 min -1 Schnider kinetics with Ce calculated using tpeak = 1.6 min -1 23
Schnider model with fixed ke0 Schnider fixed ke0 6 Concentration 5 4 3 2 Cp 75kg µg/ml Ce 75kg µg/ml Cp 105kg µg/ml Ce105kg µg/ml Cp 135kg µg/ml Ce 135kg µg/ml 1 0 0 20 40 60 80 100 120 140 Time(s) Schnider model with fixed TPeak 24
Difference when Ce T =5 µg/ml Difference when CeT=5 µg/ml 25
Difference Difference 26
Does size matter? 27