‫مصر‬ ‫في‬ ‫بكم‬ ‫وسهال‬ ‫اهال‬
BIENVENUE EN EGYPTE
WELCOME IN EGYPT
3/24/2023 1

Tarek Mohamed El Tantawy
MD, MSc Nephrology – Ain Shams University
Egyptian Nephrology Fellowship Trainer – MNGH
Secretary-General of the Dakhlia Nephrology Group
HQM – Cambridge
3/24/2023 2

On average, patients with chronic kidney diseases are taking
many different medications to manage not only their
underlying disease (such as diabetes, hypertension) but also
the symptoms related to their renal impairment (i.e, problems
with bone mineral disorder, anemia).
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Introduction

The frequency of adverse drug reactions
increases with:
 The degree of renal dysfunction
 The age of the patient
 The number of comorbid conditions
 The number of medications used
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 Properties of the drug
 Technical aspects of the dialysis procedure
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What Determines Drug Dialyzability?

Dialysis and drug clearance
 Patients on dialysis are subjected to extracorporeal
clearance of small molecules, including many drugs.
 The extent to which dialysis removes a particular drug
from plasma is dependent on its water solubility,
molecular weight, protein binding and volume of
distribution.
 Many reference sources guidance contain lists of drugs
cleared by dialysis.
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Properties of the drug
 Molecular size
 Protein binding
 Volume of distribution
 Water solubility
 Plasma clearance
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Molecular Weight
 The movement of drugs or other solutes is largely
determined by the size of these molecules in
relation to the pore size of the membrane.
 As a general rule, smaller molecular weight
substances will pass through the membrane more
easily than larger molecular weight substances.
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Protein Binding
 Drugs with a high degree of protein binding will
have a low plasma concentration of unbound drug
available for dialysis.
Protein binding may decrease in uremic serum.
Should this change in binding be substantial,
increased dialyzability of free drug may occur.
 The peritoneal membrane does permit the passage
of some proteins, there may be some limited drug-
protein removal with peritoneal dialysis.
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Volume of Distribution
A drug with a large volume of distribution is
distributed widely throughout tissues and is
present in relatively small amounts in the blood.
 Factors that contribute to a large volume of
distribution include a high degree of lipid
solubility and low plasma protein binding.
 Drugs with a large volume of distribution are
likely to be dialyzed minimally.
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Water Solubility
 The dialysate used for either hemodialysis or
peritoneal dialysis is an aqueous solution.
 Drugs with high water solubility will be dialyzed
to a greater extent than those with high lipid
solubility.
 Highly lipid-soluble drugs tend to be distributed
throughout tissues, and therefore only a small
fraction of the drug is present in plasma and
accessible for dialysis.
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Plasma Clearance
 The inherent metabolic clearance, the sum of
renal and nonrenal clearance is often termed the
“plasma clearance” of a drug.
 In dialysis patients, renal clearance is largely
replaced by dialysis clearance.
 If non renal clearance is large compared to renal
clearance, the contribution of dialysis to total drug
removal is low.
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Clearance
Consider the magnitude of renal component of the total
clearance of the drug and any active metabolites.
For drugs subject to significant renal clearance, the marked
decrease of GFR seen in dialysis patients results in an
increase in half life and drug accumulation. These changes
also apply to renally cleared drug metabolites which may be
active or toxic.
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The Dialysis Membrane
 The characteristics of the dialysis membrane determine
to a large extent the dialysis of drugs.
 Pore size, surface area, and geometry are the primary
determinants of the performance of a given membrane.
 Patients receiving high membrane permeability dialysis
will require more drug compared with those receiving
standard hemodialysis.
 Individualized therapeutic drug monitoring may be
necessary.
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Dialysis Membranes
Membrane type can also be an important factor. This does
not only relate to the clearance characteristics of the dialyzer,
but to charge upon the membrane resulting in differential
removal of drugs dependent on their charge or degree of
binding to heavily positively charged proteins.
 For instance very large differences in the removal of
recombinant hirudin by differing membranes was noted, the
main differences being charge related, clearly with
significant consequences for safe anticoagulation with this
agent.
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Blood and Dialysate Flow Rates
Increased blood flow rates during hemodialysis
will deliver greater amounts of drug to the dialysis
membrane.
As the drug concentration increases in the
dialysate, the flow rate of the dialysis solution also
becomes important .
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Sieving Coefficient
 The ratio of drug concentration in the ultrafiltrate to
the prefilter plasma water concentration of the drug.
 If the sieving coefficient is close to 1.0, the drug
has relatively free passage across the filter.
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Sieving Coefficient
 Amikacin 0.88 in vivo PSa
 Amphotericin 0.40 in vivo PSa
 Ampicillin 0.69 in vivo PSa
 Cefotaxime 0.51 in vivo PSa
 Cefoxitin 0.30 in vivo PSa
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Calculating Drug Doses In CKD
The increased half life also prolongs the time to achieve a
steady state which means a longer period is required before
judging the maximal effect of the drug.
Given the longer time to the steady state, a loading dose can
be considered if giving a renally adjusted dose could lead to a
delay in reaching a therapeutic serum concentration (e.g in
treating severe infection).
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Calculating Loading Dose
 A loading dose equivalent to the dose given to a
patient with normal renal function should always
be given to patients with CKD if the drug's half-life
is particularly long and if the physical examination
suggests normal extracellular fluid volume.
 If the loading dose of a drug is not known, it can
be calculated from the following expression:
Loading dose = Vd × IBW × Cp
In this equation, Vd is the drug's volume of distribution in L/kg, IBW is
the patient's ideal body weight (kg), and Cp is the desired steady-state
plasma drug concentration.
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Dose reduction
Several methods can be used to determine subsequent
drug doses. The fraction of the normal dose
recommended for a patient with CKD can be calculated
as follows:
Df = t1/2 normal / t1/2 renal failure
In this equation, Df is the fraction of the normal dose to be given, t½
normal is the elimination half-life of the drug in a patient with normal
renal function, and t½ renal failure is the elimination half-life of the drug
in a patient with renal failure.
Dose in CKD = Normal dose × Df
 This method is effective for drugs with a narrow
therapeutic range and short plasma half-life.
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Prolonging interval
This method is particularly useful for drugs with a
broad therapeutic range and long plasma half-life.
 The dose interval in CKD can be estimated from
the following expression, in which Df is the dose
fraction:
Dose interval in CKD = Normal dose × interval / Df
If the range between therapeutic and toxic levels is
too narrow, potentially toxic or subtherapeutic
plasma concentrations result.
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Therapeutic Index
 A drug with a wide
therapeutic Index may be
safely given without a
dose reduction
 A drug with narrow
therapeutic index will
require substantial dose
reduction.
Goals of Therapy
 Maintain efficacy
 Avoid accumulation and
toxicity
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A combined approach
Using the dose-reduction and interval-prolongation
methods is often practical.
 After the average daily dose is calculated, it can be
divided into convenient dosing intervals.
 The dosing interval may be prolonged if the peak level is
most important.
 When the minimum trough level must be maintained, it
is preferable to modify the individual dose or use a
combination of dose and interval methods to determine
the correct dosing strategy.
 Drugs removed by dialysis given once daily should be
given after the dialysis treatment
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Special types of Dialysis
26
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high-flux dialysis
 During, high-flux dialysis the volume of distribution and
percent of protein binding of the drug are more important
determinants of drug clearance.
 Drugs that are not highly protein bound and have relatively
small volumes of distribution, drug removal occurs by diffusion
and parallels urea clearance, despite a very large molecular
mass.
 The removal of drugs during high-flux dialysis depends more
on treatment time, blood and dialysate flow rates, distribution
volume, and binding of the drug to serum proteins.
 Much more drug is removed during high-flux dialysis than
previously estimated for conventional HD.
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Daily and Nocturnal HD
Certainly daily dialysis in the acute setting can
result in significant under dosing with a variety of
important drugs.
 Slow nocturnal dialysis requires a significant
increase in drug dosage to achieve adequate
therapeutic levels as compared to conventional
three times a week hemodialysis.
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CRRT
Molecular weight, membrane characteristics, blood
flow rate, and the addition of dialysate determine the
rate and extent of drug removal during continuous
renal replacement therapies (CRRT).
 Molecular weight affects drug removal by diffusion
during dialysis more than during convection during
CRRT because of the large pore size of membranes
used for CRRT.
Because most drugs are < 1500 D, drug removal by
CRRT does not depend greatly on molecular weight.
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CRRT
The volume of distribution of a drug is the most important
factor determining removal by CRRT. Drugs with a large
volume of distribution are highly tissue bound and not
accessible to extracorporeal circuit in quantities sufficient to
result in substantial removal by CRRT.
Even if the extraction across the artificial membrane is
100%, only a small amount of a drug with a large volume of
distribution is removed.
A volume of distribution > 0.7 L/kg substantially decreases
CRRT drug removal.
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CRRT
The volume of fluid exchanged may also be important,
particularly given the wider spread application of “high
dose” CRRT in the intensive care setting.
Actual drug handling may be significantly different to be
predicted in high-efficiency CRRT, especially for drugs
with narrow therapeutic indices.
This may result in under dosing with such agents as
vancomycin during such therapies.
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CRRT
 Drug protein binding also determines how much is removed
during CRRT. Only unbound drug is available for elimination
by CRRT. Protein binding of > 80% provides a substantial
barrier to drug removal by convection or diffusion.
 The addition of diffusion by continuous dialysis increases
drug clearance, depending on blood and dialysate flow rates.
As during high flux dialysis, drug removal parallels the
removal of urea and creatinine.
 The simplest method for estimating drug removal during
CRRT is to estimate urea or creatinine clearance during the
procedure.
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Drug Removal By Dialysis
The hemodialysis clearance of a drug can be
estimated from the following relationship:
ClHD = Clurea × (60/ MWdrug)
In this equation, ClHD is the drug's clearance by hemodialysis, Clurea
is the clearance of urea by the dialyzer, and MWdrug is the molecular
weight of the drug. The urea clearance for most standard dialyzers
varies between 150 and 200 mL/minute.
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ANTIBIOTIC
ANTI -
DIABETIC
STATIN
OTHER
DRUGS
ANTI-
HYPERTENSIVE
WHICH
&
HOW
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Dose modification for patients with
chronic kidney diseases
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Antibiotic Use in HD
 Which antibiotic is most commonly prescribed for
hemodialysis patients?
 Vancomycin
 Followed by?
 Third or fourth generation cephalosporins
 Cefazolin (first generation)
Snyder, et al. ICHE 2013; 34(4):349-357
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Antibiotics use in HD
 Many antibiotics require dose adjustment in patients
receiving dialysis.
Approximately 1/3 of antibiotic use in outpatient HD units is
inappropriate !
Snyder, et al. ICHE 2013; 34(4):349-357
 Therapeutic Guidelines Texts: Antibiotic provides a
comprehensive and user-friendly reference.
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Antibiotic. Version 15. In: eTG complete [Internet]. Melbourne: Therapeutic Guidelines Limited; 2014.

Antibiotics use in Hemodialysis
 Quinolones, sulfamethoxazole with trimethoprim,
glycopeptides and aminoglycosides all require significant
dose reductions.
(Trimethoprim should be avoided in patients due to the risk
of hyperkalaemia and bone marrow suppression).
 Nitrofurantoin is primarily renally excreted, and relies on
urinary concentration to achieve its effect.
It is rarely associated with neurotoxicity and life-threatening
pulmonary toxicity. It should be avoided in patients on
dialysis.
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Antibiotics use in Hemodialysis
 Cephalosporins and penicillins have wider therapeutic
indices and vary in the need for dose adjustment.
(Once-daily doses should be prescribed after haemodialysis).
 The antiviral drug aciclovir and its prodrugs, famciclovir and
valaciclovir, are extensively renally excreted. These drugs
accumulate rapidly in patients on dialysis and may cause
severe neurological toxicity.
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Aminoglycosides
Ototoxicity & Nephrotoxicity Risks
• Elderly
• Renal dysfunction
• Extended therapy
• Genetic risk for ototoxicity
• Elevated peak concentrations
(Ototoxicity)
• Elevated trough concentrations
(Nephrotoxicity)
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Prescribing aminoglycosides in CKD
patients
Ccr >80 60-80 40-60 30-40 20-30 10-20 <10
GM 5.1 4 3.5 2.5 4 3 2
Ami 15 12 7.5 4 7.5 4 3
q24h mg/kg Q48h mg/kg
The Sanford Guide to antimicrobial therapy 34th edition 2004
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Antihypertensive Agents: Dosing Requirements in
Patients with Chronic Kidney Disease
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0

Statins: Dosing Requirements in
Patients with Chronic Kidney Disease
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Hypoglycemic Agents: Dosing Requirements
in Patients with Chronic Kidney Disease
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Analgesics
 Most analgesics are eliminated by hepatic biotransformation.
However, important changes in their metabolism and protein
binding occur. The accumulation of active metabolites results
in prolonged oversedation. The formation of toxic metabolites
can cause CNS toxicity and seizures.
 Prolonged narcosis is associated with codeine and
dihydrocodeine, whereas the use of fentanyl may lead to
prolonged sedation.
 Furthermore given the recognized importance of retained
residual renal function in the outcomes for dialysis patients
aspirin (at analgesic doses) and nonsteroidal agents should be
avoided in HD patients.
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Common Agents: Dosing Requirements in
Patients with Chronic Kidney Disease
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Conclusion
 Impaired kidney function alters drugs pharmacokinetics.
 Administration of a loading dose depends on the target plasma
level & Volume of distribution.
 Adaptation of the maintenance dose to the patients on HD should
be carried out.
Dose modification is crucial to produce the desired effect while
avoiding drug toxicity
 Measurement of serum concentration should be done especially
with drugs with a narrow therapeutic windows.
 For drugs with appreciable dialytic clearance, a supplementary
dose is given post intermittent HD.
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Conclusion
 Clearance by HD depends on factors affecting drug
dialysability related to drug, dialysis & membrane properties.
 Extracorporeal drug clearance can be calculated based on
dialysate flow rate & protein binding.
Recognising that patients on dialysis are more prone to drug
toxicity is the first step in avoiding harm.
 There are many easily accessible reference sources to guide
dose adjustments in renal failure.
 Clinical judgement is always required to balance the required
treatment intensity against the risk of toxicity or inefficacy of
drugs in an individual patient.
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Conclusion
 Multiple practitioners often share the care of patients
on dialysis (e.g. GPs, specialist physicians and vascular
surgeons).
Information about the adjusted dosing regimen should
be included in correspondence and, where appropriate,
explain why the dose has been adjusted, to avoid
confusion.
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