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Pharmacology in the obese :

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does weight matter ?

Michel MRF Struys, MD, PhD

Professor and Chair, Department of AnesthesiaProfessor and Chair, Department of Anesthesia University Medical Center GroningenGroningen, The Netherlands

Professor of Anesthesia, Ghent University, Gent, Belgium

Pharmacokinetics …. Vd and Cl ?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 theCl 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

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Describing pharmacodynamicsDescribing pharmacodynamics10

0 Efficacy Efficacy :

- intrinsic ability of a drug to produce

0ef

fect

Potency

Individual variability

Dose, concentration, or

a given effect

- influenced by receptor coupling to G proteins, activation of second messengers, and the ability to generate ultimate physiologic responses

Potency:other measure of exposure Potency:

- refers to the quantity of drug that must be administered to produce a specific effect

Ref.: Miller. Anesthesia… Fifth Ed. pp 45-46

Importance of morbidly obese patients?

• High co-morbidity and perioperative mortalityHigh 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

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Changes in non-compartmental pharmacokinetics

• Problems with obesityProblems with obesity

– Most drugs are given using standard-dosing guidelines without knowledge of their pharmacokinetics

– Pharmacokinetic data are obtained from studies with normal-weight individualsg

– Most dosage recommendations are scaled to TBW

– Alterations in distribution volume, clearance and protein binding


• Changes in Vd• 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

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• Changes in Vd• Changes in Vd– Less lipophilic substances (eg non-depolarising NMB):

• Little or no change in Vd -> Use LBM (or IBW + 20%) for calculations

E ti i l h li• Exception: succinylcholine -> TBW


• Changes in Clearance :• 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

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• Changes in protein binding• 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 partiallyFood 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

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Changes in pharmacodynamics

• GABA receptor and obesityGABA 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

R d d i i i b i h hi h GABA– Reduced exercise capacity in obese rats with high GABA [Lee et al]

• GABAergic tonic inhibition is potentially responsible for “obstructive hypoventilation syndrome” in obese patients


• Opioid receptor and obesityOpioid 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]

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• Opioid receptor and obesityOpioid 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]

Application of pharmacokinetics in the obese patient

“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)

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• BMI• BMI

– Definition: weight (kg) /height² (m²)

– Classification:• IBW = 22-28• Obesity = 29-35• Morbid obesity >40

or >35 with comorbidity• Super obesity >55


• LBM• LBM

– Definition [James et al]:• men: [1.10 * weight] - [128 * (weight/ height)²]• women: [1.07 * weight] - [148 * (weight/ height)²]

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LBMSome TCI models incorporate LBM

LBM male as function of weight (X-axis, kg) & height (lines; cm)

100

Bouillon et Al, Anesthesiology. 89(3):557-560, September 1998.

40

50

60

70

80

90 150

160

170

180

190

Unity

LBM

0

10

20

30

0 20 40 60 80 100 120 140 160 180

LBM female as function of weight (X-axis, kg) & height (lines; cm)

100150

160

Some TCI models incorporate LBM

LBM

40

50

60

70

80

90 170

180

190

Unity

LBM

0

10

20

30

0 20 40 60 80 100 120 140 160 180

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• IBW• 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 drugsVolatile anesthetic drugs– Halothane

• Deposition in adipose tissue• Reductive hepatic metabolism (halothane hepatitis)

– Enflurane• Blood/gas partition coefficient reduces with weight,

ibl l i th MACpossibly lowering the MAC• Faster increase in inorganic fluoride (fluoride nephrotoxicity)

– Sevoflurane• Higher < > indifferent fluoride concentration

compared to non-obese

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• Volatile anesthetic drugs• 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.

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Intra-operative results

• Hypertension (% of time) : sevoflurane = desflurane

• Hypotension (% of time) O ll fl > d fl– 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• Volatile anesthetic drugs– Nitrous oxide

[Luce et al]• Rapid elimination• Analgesic properties• High oxygen demand -> limited use

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• Volatile anesthetic drugs• 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 possibleg p• 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• Midazolam– Linear increased Vd and elimination half-life,

but unchanged total clearance values [Greenblatt et al]

– Continuous infusion ~ IBW [Reves et al][Reves et al]

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• Thiopental• Thiopental– Increased Vd and elimination half-life,

but unchanged total clearance values [Buckley et al]

– Adequate dosage: 7.5 mg/kg IBW [B kl l][Buckley et al]


• Analgesics & opioids• 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]

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• Analgesics & opioids• 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• Analgesics & opioids– Sufentanil

• Prolonged t ½ ß and increased Vd• Loading dose ~ TBW

[Schwartz et al]• Maintenance dose must be prudently reduced• Pharmacokinetic set 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

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• Analgesics & opioids• Analgesics & opioids– remifentanil

• Maintenance dose ~ age and LBM [Minto et al]

• Maintenance dose ~ LBM[Egan et al][Egan et al]

• TCI applying Minto model -> TBW, age, height and gender


• Analgesics & opioids• Analgesics & opioids– Paracetamol (acetaminophen)

• Vd is increased in overweight and in men, butdistribution in weight exceeding IBW is less then in IBW[Abernethy et al]

• Higher clearance [Abernethy et al][Abernethy et al]

• Oral dosage ~ IBW[Lee et al]

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• PropofolPropofol– 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 ?• 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

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• Propofol• 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 betweenfixed keo vs. individualized

Keo based on TTPEKeo based on TTPE

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Three compartment model with effect site:

Drug Administration

I

V 2 k 12 V 1 k 13 V 3Rapidly Equilibrating

Compartmentk 21

CentralCompartment

k 31Slowly Equilibrating

Compartment

k 10

Effect SiteV e

k 1e

k e0

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Propofol

TCI… The models

• 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.V 0 228* i h (li * k ) k10 0 119/ i k12 0 112/ i k13– 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)

Propofol

TCI… The models

• 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 l S 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).

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Remifentanil

TCI… The models

• 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

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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

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Schnider fixed ke0

Schnider model with fixed ke0

3

4

5

6

Con

cent

ratio

n

Cp 75kg µg/mlCe 75kg µg/mlCp 105kg µg/mlCe105kg µg/mlCp 135kg µg/mlCe 135kg µg/ml

0

1

2

0 20 40 60 80 100 120 140

Time(s)

C

Schnider model with fixed TPeak

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Difference when CeT=5 µg/ml

Difference when CeT=5 µg/ml

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Difference

Difference

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Does size matter?

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