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PK & DOSE ALTERATIONS IN SELECTED DRUGS IN OBESE PATIENTS - Coggle…
PK & DOSE ALTERATIONS IN SELECTED DRUGS IN OBESE PATIENTS
Antimicrobial
Carbapenems
Meropenem
concentrations depend more on
CrCl
and obesity alone does not widely affect dosing However, standard doses may not achieve pharmacodynamic goals, particularly when targeting maximum pharmacodynamic end points in patients with higher CrCl values or with organisms having a high MIC Prolonged infusions provide a significant advantage in this setting
Penicillins and cephalosporins
have time dependent killing in which the goal is to maintain an adequate t >MIC during the dosing interval.
The data show increase in both Vd and clearance
Cefepime
pharmacokinetics have also been reported in patients with obesity One study described a pharmacodynamic model using patient specific pharmacokinetic data evaluating two dosing regimens.One of them maintained the target 60 t>MIC when the MIC was 8
Aminoglycosides
Loading dos
e should be adjusted for
IBW
.
Aminoglycosides Dosing
of aminoglycosides should be based on
ABW
Plasma level monitoring (also known as
TDM
) has been recommended to improve safety and effectiveness
A minoglycoside doses should be re evaluated daily in critically ill obese patients, and
TDM
can help optimize therapy.
Morbid obesity alters aminoglycosides pharmacokinetics, as both Vd and clearance are increased in morbidly obese patients compared to patients with normal weight
Vancomycin
loading doses
is on the basis of
TBW
( lower doses are recommended for patients with obesity)
Maintenance doses
are largely influenced by
clearance
, and a strong correlation exists between
clearance
and
weight
Initial maintenance
doses of vancomycin can be computed using a population PK estimate of vancomycin
clearance
and the target
AUC
in obese patients.
Empiric maintenanc
e depend on their
renal function
(B II).
Early and frequent monitoring of
AUC
exposure is recommended for
dose adjustment
, especially when empiric doses exceed
Measurement of
peak
and trough
concentrations
is recommended to improve the
accuracy
of vancomycin
AUC
estimation and
maintenance dose
optimization in obese patients
Crass 2018 suggested
AUC based nomogram
using a
clearance formula
with
allometric scaling
for weight can be used to estimate the
total daily maintenance dose
Antihypertensives
B-blockers
Non-significant change in Vd or Cl
Diuretis
Furosemide
The
D
iuretic
O
ptimization
S
trategies
E
valuation
(DOSE )
study evaluated the effect of furosemide on fluid loss, changes in symptoms, and
serum creatinine
in patients with
acute heart failure
In the low intensification strategy obese subjects had
greater volume loss
than nonobese subjects
In the high intensification strategy the obese subjects had a
greater fluid loss
than nonobese subjects not statistically significant
Similar improvements in
dyspnea
and freedom from
congestion
were observed in the obese and nonobese subjects
In obese subjects, the high and low intensification strategies resulted in a
similar incidenceof worsening renal function
Pharmacodynamics
Bl Pr reductions and blood pressure control rates were slightly lower in obese patients
This finding is in keeping with obesity being a known risk factor for development of
hypertension and resistant hypertension
through multiple pathways (including activation of the renin angiotensin system, sympathetic nervous system activation, and development of
sleep apnea
among others)
Ns in accomplish
Anticoagulants
Enoxaparin
Venous Thromboembolism
(VTE)
prophylaxis
In morbidly obese patients (BMI 40 kg/m 2) increasing the prophylactic dose by 30
in trauma ICU patients
VTE treatment
SC once daily (ABW) with capping the dose
(lean body weight) without capping
twice daily (TBW) without capping
All obese patients should monitor anticoagulant response due to high inter -patient variability.
For obese patients: anti Xa level monitoring is recommended
For patients > 190 kg monitor anti Xa level or reduce dose if bleeding occurs
Fondaparinux
Acute DVT/PE(Pulmonary Embolism)
-Further studies suggested that in extreme weight patients (BMI > 51 kg/m 2 ),higher levels seemed required to achieve target anti FXa levels.
-These observations suggest that increasing the dose with increasing weight might be required for fondaparinux in the management of VTE
D
eep Venous
T
hrombosis
(DVT)
prophylaxis
Prophylactic use is contraindicated in < 50 kg
DIrect Oral Anticoagulants(DOACS
Small scale studies demonstrate a lower drug exposure with increasing weight .further study and experience will determine whether the manufacturers current dosing strategy of
"one size fits all"
is correct
RELY trial ( Dabigtran)
inverse relationship between
trough & weight
The manufacturers suggest a fixed dosing schedule
Apixaban
lower mean peak, drug exposure (AUC) higher Vd .Modest effect no need for dose adjustment >120 kg
Reduce dose for <60 kg (due to increased haemorrhagic risk
Edoxaban
non renal clearance decreases
with lower body weight
Rivaroxaban
PK model of pooled data from EINSTEIN -DVT and ODIXa -DVT did not find max plasma drug level to be influenced by weight
Vd inc with weight
increased weight did not influence exposure
In a Japanese study, all bleeding events in patients< 60 kg was almost twice that of patients >60 kg, indicating the necessity of dose reduction
Edoxaban
in underweight patients (<60 kg)
In Patients >120 kg, the authors of a review suggested to either monitor effect (anti-FXa for
Apixaban
,
Edoxaban
,
Rivaroxaban
or dilute thrombin time with
Dabigatran
OR MS drug level) or switching to VKA
Warfarin
the age- and weight -based warfarin initiation nomogram could effectively predict appropriate warfarin dose due to shorter time to international normalized ratio (INR)> 2.0
Antiplatelets
Genestar
study aspirin 81 mg was not sufficient to overcome the higher baseline reactivity, due to
increased Vd
Obesity alteration of platelet function might be due to
the systemic inflammation in the obese state
Other suggests
insulin resistance
might contribute to
aspirin resistance
Aspirin&Clopidogrel
Lower response in obese
Ticagrelor&Prasugrel
Response is not altered over BW ranges
Obese individuals receiving
Prasugre
l had
lower rates of HTPR
than those taking
clopidogrel
Prasugrel
has
better effect
in obese than
clopidogrel
but still obesity is considered a reason for attenuated effect
Higher maintenance dose
in obese may eliminate the HTPR
Aspirin dose
in obese need further consideration either
TBW
or other body size descriptor
Ticagrelor
appears to have
less variable effect
in different weight group but still large scale trials are needed
the use of Prasugrel dose based on body weight specifically, MD for patients weighing less than 60 kg (due to high risk of bleeding)
Dose adjusted
for weigh
t is recommended for
clopidogrel prasugrel