University of Al-Ameed

College of Dentistry

Department of pharmacology

Haider Edrees Elmoosawy

M.B.Ch.B
MSc. Clinical Pharmacology
❖ One of the most important drug-related problems in patients
with chronic kidney disease (CKD) is medication dosing errors

❖ Kidneys are essential for elimination of drugs or their

metabolites .

❖ some reports suggest that between 5-20% of cases of

acute renal failure can be directly attributed to drugs and
chemicals
❖CKD changes both ph.Kinetics and
Ph.dynamics of the drugs.
The clearance of drugs eliminated primarily
by renal filtration is decreased by renal
disease.
❖ Many medications and their metabolites are
eliminated primarily through the kidneys.
❖Thus, adequate renal function is important
to avoid toxicity
 Drug-induced kidney disease constitutes an
important cause of acute renal failure and chronic
kidney disease .
 Common risk factors are :
• old age ( due to impaired glomerular
filtration)
• volume -depleted state (hypovolemia)
• pre-existing renal dysfunction
• coexisting use of other nephrotoxins.
The incidence of drug-induced nephrotoxicity
has been increasing with:
ever-increasing number of drugs and
easy availability of over-the-counter (OTC)
medications
How to calculate the eGFR

 Creatine clearance (ml/min.):

 Males: ([140-age] × weight in
kg)/(serum creatinine × 72) (Females
: X0.85)
Types of Renal Failure
 The causes of acute renal failure can be broadly
grouped into three major categories .
 decreased renal blood flow (pre-renal causes; 40-
70% of cases)
 direct renal parenchymal damage (intrinsic renal
causes; 10-50% of cases),
 obstructed urine flow (post-renal or obstructive
causes; 10% of cases).
 If a drug (or its active metabolites) is eliminated
predominantly by the kidneys, it will tend to
accumulate and so the maintenance dose must be
reduced
 Patients with CKD often have alterations in their
pharmacokinetic
 drug absorption,
 distribution,
 protein binding,
 biotransformation and
 renal excretion
 Effects on Absorption
A-Increase gastric pH: secondary to ammonia formation in the gut.
acid-reducing drugs are common in this population. Drugs affected
are furosemide (Lasix) , ferrous sulfate (best absorbed in acidic
media)
 B-gastroparesis ; result in delayed gastric emptying, and this may
prolong the time to reach maximum drug concentrations.
 intestinal mucosa congestion can cause delay absorption
 -diarrhea and vomiting are common in CKD and are a cause of
impaired absorption of many drugs.
Effects on Distribution
 Acidicdrugs bound to albumin,
 Hypoalbuminemia (decreased serum proteins) and
competition for binding sites by other drugs,
metabolites, and accumulating endogenous
substances may displace drugs from plasma protein
binding sites leading to increased levels of free
concentrations of drugs and this will lead to drug-
related toxicities
Effects on metabolism
 Renal dysfunction significantly alters hepatic
biotransformation’s; these can increase,
decrease or remain unchanged.
 In general, phase I hydrolysis and reduction
reactions are slowed in CKD.
 Phase II metabolic reactions are also affected by
renal dysfunction
Effects on Elimination
Renal excretion of medications is dependent
on glomerular filtration rate, renal tubular
secretion and reabsorption.
In CKD, medication elimination by glomerular
filtration is decreased, resulting in a
prolonged free drug elimination half-life.
Dosage Adjustment According to
Renal Function
 There are certain points to be focused on when prescribing:
 1- Initial assessment and drug history: previous drug
exposure, toxicity, allergies, the patient`s current
medication. Check for liver function and serum albumin.
 2- Evaluate the degree of renal impairment according to
GFR and creatine clearance. The GFR is the most reliable
index for estimation. Creatine clearance can also be used.
 3- Selection of drugs with minimal or no renal toxicity.
 5- Continuous monitoring of the patient`s status for renal
function and other parameters.
Examples of
drugs that
require dose
adjustment or
avoidance in
renal failure
 A)
ACE inhibitors : captopril, enalapril, lisinopril,
perindopril, ramipril
 These drugs can cause acute renal failure which
occurs in patients with bilateral renal artery
stenosis, heart failure or volume depletion due to
diarrhea or excessive diuretic effects.
 This is because Ang II-mediated vasoconstriction
of the efferent arteriole helps maintain GFR
when renal perfusion is low.
  Hence ACEI cause a sudden decline in GFR due to loss
ACEI
of efferent arteriolar tone.
 In bilateral obstruction of renal arteries (> 70%);
efferent arteriolar tone is necessary for maintaining
GFR.
 Therefore, ACEI in such cases can cause renal failure.
This may be associated with oliguria and fluid
retention
Analgesics
 B) Analgesics: including NSAIDs, morphine and
tramadol
 NSAIDs : about 1-5% in patients taking NSAIDs, Renal
PGs function primarily as vasodilators in the
kidneys.
 When there is prolonged renal vasoconstriction that
develops during settings of advanced age, heart
failure, and kidney failure, PGs synthesis is
upregulated (increased)

 Under these conditions when kidney function is
compromised, the production of PGs serves an
important role to preserve renal blood flow and
protect GFR by decreasing pre-glomerular
(afferent) arterial resistance
 In these conditions, even intermittent use of
NSAIDs can decrease blood flow through the
glomerulus and increase the risk of acute kidney
injury.
Other analgesics that should be used
with cation in CKD are morphine and
tramadol
These are called opiates ( morphine-
like drugs) that act centrally and used
in cases of sever pain.
Antibiotics
 Aminoglycosides (AGs) : these drugs better to be avoided

in patients with CKD .the dose should be strictly adjusted .

 Their t1/2 is two hours in normal individuals but may extend

to 30-60 hours in patients with CKD.

 The drug is actively concentrated in the renal cortex and

proximal tubular cells achieve maximum concentration

 Accumulation of AGs may lead to :
 ARF, proximal tubular dysfunction, proteinuria,
glycosuria, (electrolyte disturbances hypokalemia,
hypocalcemia, hypomagnesemia
 This damage is reversible and recover in 4-6 weeks
after cessation of therapy, except when there is
pre-existing renal disease.

 Some patients may progress to chronic interstitial

nephritis.
Aminoglycosides
 Penicillins :
 such as amoxicillin and co-amoxiclav
(augmentin)
 The dose should be adjusted according to
creatine clearance .
 For example, when the GFR is 10-30 ml/min
the frequency is reduced from three times to
twice daily.
 When the GFR is below 10mi/min the dose
should be further reduced to once daily dose.
 Penicillin G should also be adjusted in renal
failure
 Cephalosporins :
 these drugs cause interstitial
nephritis if used for two weeks or
more. Dose calculation is therefore
very important.
 The nephrotoxicity is usually dose-
related and occur only with high
doses. Renal tubule is the usual site
for toxicity.
 Ceftriaxone is excreted through bile

Safe
and feces and therefore safe to be
used in renal insufficiency.
 Vancomycin: vancomycin is very well known to be nephrotoxic
specially if used with other nephrotoxic drugs.

 Quinolones: most can be used with mild renal insufficiency, but

when GFR is below 20 ml/min, caution should be considered.

 Ciprofloxacin and levofloxacin are 80% excreted in urine , the

dose should be halved in such case. Moxifloxacin undergoes
hepatic elimination; dose adjustment is not necessary.

 80%
80%
safe
 Rifampicin ( Rifadin) : Incidence
of rifampicin nephrotoxicity
varies from 1.8% to 16% of all
ARF.. It causes acute interstitial
nephritis.
 It usually occurs after months
of therapy, such as treatment of
tuberculosis (TB), but may
occur as early as two weeks.
Beta-blockers
acebutolol, atenolol, nadolol,
sotalol have renal-dependant
elimination
While: Bisoprolol (concore),
carvedilol, metoprolol, propranolol
(Inderal) can be used safely in
renal failure.
 Beta-
blockers
not safe in
CKD
Beta-blockers safe in CKD
  Immnuosuppressants : azathioprine
Other  Cytotoxic, anti-cancer drugs
drugs that  Amphotericin-B
should be  Antidiabeticdrugs : acarbose, insulin,
used metformin, sulfonylureas
cautiously  Antivirals: acyclovir
in CKD