pharmacology in kidney and liver disease

1. Drugs pharmacology in Liver
disease & Renal Disease
Dr Akshil Mehta

2. Drugs pharmacology in Liver disease
– Introduction
– General guidelines
– Absorption and Liver
– Metabolism in Liver
– Drug Effect on Liver
– Liver Blood Flow
– Protein Binding
– Age Effect
– Dose Adjustment
– Specific Drugs
2

3. Introduction
• Acute liver impairment interferes with drug
metabolism and elimination.
• Chronic liver impairment affects all parameters of
pharmacokinetic.
• Because most drugs are metabolized by the liver, it is
susceptible to drug toxicity.
• Impaired liver function greatly increases the risks of
adverse drug effects.
3

4. Introduction Cont’d
• Many drugs change liver function tests without
clinical signs of liver dysfunction.
• Hepatotoxicity is potentially life threatening.
• Liver is able to function with as little as 10% of
undamaged hepatic cells.
• With severe hepatic impairment, extrahepatic
metabolism becomes more important.
4

5. Introduction Cont’d
• At risk for impaired liver function include:
– Primary liver disease (eg, hepatitis, cirrhosis).
– Diseases that impair blood flow to the liver (heart
failure, shock, major surgery, or trauma).
– Hepatotoxic drugs.
– Malnourished people or those on low-protein
diets.
5

6. General guidelines
• General guidelines when using drugs include:
– Clinical signs for hepatotixicity should be sought
(nausea, vomiting, jaundice, hepatomegaly).
– Hepatotoxic drugs should be avoided if possible:
(acetaminophen, INH, statins, methotrexate,
phenytoin, aspirin and alcohol).
6

7. • Monitoring liver tests:
– Serum bilirubin levels above 4 to 5 mg/dl
– Prothrombin time greater than 1.5 times control
– Serum albumin below 2.0 g/dl
– Elevated alanine and aspartate aminotransferases
(ALT & AST).
General guidelines Cont’d
7

8. Absorption and Liver
• Some oral drugs are extensively metabolized in the
liver.
• This process is called the first-pass effect or
presystemic metabolism.
• With cirrhosis, oral drugs are distributed directly into
the systemic circulation.
• This means that oral drugs metabolized in the liver
must be given in reduced doses.
8

9. presystemic clearance
Mechanism of presystemic clearance .After drug enters
the enterocyte, it can undergo metabolism, excretion into
the intestinal lumen, or transport into the portal vein.
Similarly, the hepatocyte may accomplish metabolism and
biliary excretion prior to the entry of drug and metabolites
to the systemic circulation .
9

10. 10

11. Metabolism in Liver
• Most drugs are metabolized by enzymes in the liver
• They are called the cytochrome P450 [CYP] or the
microsomal enzymes.
• CYP system consists of 12 groups:
– Nine of them metabolize endogenous substances.
– Three of them metabolize drugs.
• The three groups that metabolize drugs are: CYP1 to
CYP3.
11

12. Metabolism in Liver Cont’d
• The CYP3 metabolizes 50% of drugs, the CYP2 45%,
and the CYP1 group 5%.
• They catalyze oxidation, reduction, hydrolysis, and
conjugation with glucuronic acid or sulfate.
• Excretion decreases when the liver cannot metabolize
lipid-soluble drugs into water-soluble ones to be
excreted by the kidneys.
• An impaired liver cannot synthesize adequate
amounts of metabolizing enzymes.
12

13. Conjugation Pic.
13

14. Elimination of drugs
14

15. 15

16. Metabolism in Liver Cont’d
• Dosage should be reduced for drugs that are
extensively metabolized in the liver including:
– Cimetidine and Ranitidine
– Diazepam and Lorazepam
– Morphine and Meperidine (Pethidine)
– Phenytoin
– Propranolol
– Verapamil.
16

17. Drug Effect on Liver
• With chronic administration, some drugs increase
metabolizing enzymes in the liver: enzyme induction.
• Enzyme induction accelerates drug metabolism and
larger doses is required.
• Rapid metabolism also increases the production of
toxic metabolites.
• Enzyme induction does not occur for 1-3 weeks
because new enzymes must be synthesized.
17

18. Drug Effect on Liver Cont’d
• Enzyme inducers consist of: phenytoin, rifampin,
phenobarbital, ethanol, and cigarette smoking.
• Tolerance and cross-tolerance are attributed to
activation of liver metabolizing enzymes.
• They also are attributed to decreased sensitivity
or numbers of receptor sites.
18

19. Drug Effect on Liver Cont’d
• Metabolism can be decreased in a process called
enzyme inhibition.
• It occurs with co-administration of drugs that
compete for the same metabolizing enzymes.
• In this case, smaller doses of the slowly metabolized
drug is needed to avoid toxicity.
• Enzyme inhibition occurs within hours or days of
starting an inhibiting agent.
• Enzyme inhibitors consist of: Cimetidine, fluoxetine,
and ketoconazole.
19

20. enzyme induction and inhibition Pic.
20

21. Drug Effect on Liver Cont’d
• Some drugs indirectly affect liver function:
– Epinephrine decreases blood flow by constricting
hepatic artery and portal vein.
– β blockers decrease blood flow by decreasing
cardiac output.
21

22. Liver Blood Flow
• Hepatic metabolism also depends on hepatic
blood flow.
• Hepatic blood flow ↓ => delivery of drug to
hepatocytes ↓ => drug metabolism ↓ => drug
toxicity ↑
22

23. Protein Binding
• Protein binding affects distribution.
• The impaired liver is unable to synthesize
plasma proteins (albumin) adequately.
• Liver impairment causes accumulation of
substances (bilirubin) that displace drugs from
protein-binding sites.
23

24. • When protein binding ↓ => free drug ↑ =>
drug distribution to sites of action &
elimination ↑
– => onset of drug action ↑
– => duration of action ↓
• When protein binding ↓ => peak blood levels
and adverse effects ↑
Protein Binding Cont’d
24

25. Protein binding Pic.
25

26. Protein binding Pic.
26

27. Age Effect
• Pharmacokinetics differs in neonates, especially
prematures, because their organs are not fully
developed.
• Until 1 year, liver function is still immature.
• Children of 1 to 12 years have increased activity
of metabolizing enzymes.
• After 12 years of age, children handle drugs
similarly to adults.
27

28. Age Effect Cont’d
• In elderly, physiologic changes alters all
pharmacokinetic processes in the liver.
• Many drugs are metabolized more slowly and
accumulate with chronic administration.
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70. 70

71. • Potentially hepatotoxic drugs include:
– Acetaminophen
– Halothane
– Isoniazid
– Sodium Valproate
– Phenytoin
– Amiodarone
– Erythromycin
– Oral Contraceptives
– Trimethoprim-Sulfamethoxazole
Specific Drugs
71

72. Acetaminophen
• A single dose of 10–15 g, produces liver injury and 25
g is fatal.
• Maximal hepatic failure occurs 4–6 days after
ingestion, and aminotransferase levels may approach
10,000 units.
• Treatment is gastric lavage, supportive measures,
and oral activated charcoal or cholestyramine.
• Neither of these agents is effective if given >30 min
after acetaminophen ingestion.
72

73. Acetaminophen Cont’d
• Administration of cysteine, or N-acetylcysteine
reduces the severity of hepatic necrosis.
• Therapy should begin within 8 h of ingestion but
may be effective after 24–36 h.
• If hepatic failure occurs despite N-acetylcysteine
therapy, liver transplantation is the only option.
73

74. Acetaminophen
metabolism
Metabolism of acetaminophen (top
center) to hepatotoxic metabolites.
(GSH, glutathione; SG, glutathione
moiety).
74

75. 75

76. Halothane
• It is an idiosyncratic hepatotoxicity.
• It causes severe hepatic necrosis in a small
number of individuals, many of whom had
previous exposure.
• Halothane is not a direct hepatotoxin but
rather a sensitizing agent.
• Adults, obese people and women have higher
risk.
76

77. Halothane Cont’d
• The case-fatality rate of halothane hepatitis is
20–40%.
• Patients with delayed spiking fever or jaundice
after halothane should not receive it again.
• Cross-reactions between halothane and
methoxyflurane is reported.
• So the latter agent should not be used after
halothane reactions.
77

78. Isoniazid
• In ~10% of adults elevated serum aminotransferase
levels develop during the first few weeks.
• In ~1% of treated patients, an illness similar to viral
hepatitis develops .
• The case-fatality rate may be 10%.
• Isoniazid hepatotoxicity is enhanced by alcohol,
rifampin, and pyrazinamide.
78

79. Sodium Valproate
• It is associated with severe hepatic toxicity and rarely,
fatalities, predominantly in children.
• Elevations of serum aminotransferase levels occurs in
45% of patients but have no clinical importance.
• Its metabolite, 4-pentenoic acid, is responsible for
hepatic injury.
• Hepatotoxicity is more common in persons with
mitochondrial enzyme deficiencies
• It may be ameliorated by IV carnitine, which valproate
therapy depletes.
79

80. Phenytoin
• Phenytoin rarely causes severe hepatitis leading to
fulminant hepatic failure.
• Hepatic injury is usually manifested within the first 2
months after phenytoin therapy.
• Aminotransferase and ALP levels is increased and
represent the potent enzyme–inducing properties of
phenytoin.
80

81. Amiodarone
• Clinically important liver disease develops in
<5% of patients.
• It has a half-life of up to 107 days so liver
injury may persist for months after stopping
the drug.
81

82. Erythromycin
• The important adverse effect is a cholestatic
reaction.
• It is more common in children than adults.
• Most of these reactions have been associated
with the estolate salt.
• The reaction usually begins during the first 2
or 3 weeks of therapy.
82

83. Oral Contraceptives
• Combination pills of estrogenic and progestational
steroids lead to intrahepatic cholestasis.
• It occurs in a small number of patients weeks to
months after taking these agents.
• The lesion is reversible on withdrawal of the agent.
• The two steroid components act synergistically on
hepatic function but the estrogen is more
responsible.
• OCPs are contraindicated in patients with a history of
recurrent jaundice of pregnancy.
83

84. Trimethoprim-Sulfamethoxazole
• In most cases, liver injury is self-limited.
• The hepatotoxicity is attributable to the
sulfamethoxazole component of the drug.
84

85. Some Features of Toxic and Drug-Induced Hepatic Injury
85

86. Drugs Pharmacology in Kidney Disease
• Drug Nephrotoxicity
• Weak Acids & Weak Bases
• Absorption
• Distribution & Protein Binding
• Metabolism & Excretion
• Age Effect
• Creatinine
• Drug selection
• Dosage
• NSAIDs & Lithium
86

87. Drug Nephrotoxicity
Drugs can lead to renal damage in a number
of different ways :
1. Alteration of renal blood flow
• NSAIDs:alteration in prostaglandin
metabolism can lead to critical reduction
in glumerular perfusion, interstitial
nephritis can also result from NSAIDs
• ACE inhibitors and ARBs: ARF or renal
impairment ????
87

88. Occurring in patients who are critically dependant
upon RAA system.
• Cyclosporine A
2. Direct tubular toxicity
• Aminoglycosides :disturbance of renal function is
seen in up to a third of patients receiving
aminoglycosides.
88

89. • Cisplatin : selectively toxic to proximal
tubules by inhibiting nuclear DNA synthesis
• Amophotercin:
3.glumerulonephritis
• Gold :
Is believed to induce an immune
complex GN
• Penicillamine :
It is dose related
89

90. 4. Other nephrotoxic effects of drugs:
• Interstitial nephritis
• Retropertoneal fibrosis
• Drug induced SLE
• Nephrogenic DI
90

91. Weak Acids & Weak Bases
• Most drugs are lipid soluble which aids their
movement across cell membranes.
• The kidneys can excrete only water-soluble
substances.
• One function of metabolism is to convert fat
soluble drugs into water-soluble metabolites.
91

92. M.H.Farjoo
Weak Acids & Weak Bases Cont,d
• Weak acids and weak bases gain or lose protons
depending on the pH.
• Their movement between aqueous & lipid
mediums varies with the pH.
• Kidney filters drugs, by changing the urine pH the
drug can be "trapped" in the urine (in overdose).
• Weak acids are excreted faster in alkaline urine
and vise versa.
92

93. Trapping of a weak base
(pyrimethamine) in the urine
when the urine is more acidic
than the blood. In the
hypothetical case illustrated,
the diffusible uncharged form
of the drug has equilibrated
across the membrane, but the
total concentration (charged
plus uncharged) in the urine is
almost eight times higher than
in the blood.
93

94. Weak Acids & Weak Bases Cont,d
• Sodium bicarbonate + phenobarbital →
increased excretion of phenobarbital.
• The sodium bicarbonate alkalinizes the urine,
raising the number of barbiturate ions in the
renal filtrate.
• The ionized particles cannot pass easily
through renal tubular membranes.
• Therefore, less drug is reabsorbed into the
blood and more is excreted by the kidneys.
94

95. Weak Acids & Weak Bases Cont,d
• A large number of drugs are weak bases. Most
of these bases are amine-containing
molecules.
• Primary, secondary, and tertiary amines
undergo protonation and vary their solubility
with pH.
• Quaternary amines are always in the poorly
lipid-soluble charged form.
95

96. 96

97. Weak Acids & Weak Bases Cont,d
• The protonated form of a weak acid is the
neutral, more lipid-soluble form.
• The unprotonated form of a weak base is the
neutral form.
• The uncharged form is more lipid-soluble.
• A weak acid is more lipid-soluble at acid pH,
and a basic drug is more lipid-soluble at
alkaline pH.
97

98. Weak Acids & Weak Bases Cont,d
Body Fluid Range of pH
Total Fluid:
Blood
Concentration
Ratios for
Sulfadiazine
(acid, pKa 6.5)
Total Fluid:
Blood
Concentration
Ratios for
Pyrimethamine
(base, pKa 7.0)
Urine 5.0-8.0 0.12-4.65 72.24-0.79
Breast milk 6.4-7.6 0.2-1.77 3.56-0.89
Jejunum, ileum
contents
7.5-8.0 1.23-3.54 0.94-0.79
Stomach contents 1.92-2.59 0.11 85,993-18,386
Prostatic secretions 6.45-7.4 0.21 3.25-1.0
Vaginal secretions 3.4-4.2 0.11 2848-452
98

99. Absorption
• Absorption of oral drugs may be decreased
indirectly in renal failure by:
– Delayed gastric emptying
– Changes in gastric pH
– GI symptoms such as vomiting and diarrhea
– Edema of the GI tract (in the presence of
generalized edema).
99

100. Absorption Cont,d
• In CRF, gastric pH is altered by:
– Oral alkalinizing agents (sodium bicarbonate,
citrate).
– Use of antacids for phosphate-binding effects.
• This causes:
– Decrease in absorption of oral drugs that require
an acidic environment for absorption.
– Increases absorption of drugs that are absorbed
from a more alkaline environment.
100

101. Distribution
• Distribution of drugs is altered by changes in ECF,
plasma protein binding, and tissue binding.
• Water-soluble drugs are distributed in ECF, including
edema fluid, which is increased in renal impairment.
• Metabolic acidosis & respiratory alkalosis that occur
in renal impairment alter tissue distribution of some
drugs.
• For example, digoxin can be displaced from tissue by
metabolic products that cannot be excreted by
impaired kidneys.
101

102. Protein Binding
• Albumin is the main drug-binding plasma
protein for acidic drugs.
• Drug binding with albumin is decreased with
renal impairment.
• This is due to decreased albumin or reduced
binding capacity.
102

103. Protein Binding Cont,d
• Reasons for decreased albumin include:
– Nephrotic states in which albumin is lost in the
urine.
– Hypermetabolic states (stress, trauma, sepsis) in
which protein breakdown exceeds protein
synthesis.
– Liver disease that decreases hepatic synthesis of
albumin.
• Reasons for reduced binding capacity include:
– Uremic toxins that compete with drugs for binding
sites.
– Structural changes in the albumin molecule.
– (e.g. Carbamylation) 103

104. Protein Binding Cont,d
• When less drug is bound to albumin:
– More unbound drug distributes into sites of
metabolism and excretion.
– The higher levels of unbound drug can result in
toxicity.
– Faster elimination can decrease drug half-life and
therapeutic effects.
104

105. Protein binding Pic.
105

106. Protein binding Pic.
106

107. Protein Binding Cont,d
• For basic drugs (clindamycin, propafenone),
alpha1-acid glycoprotein (AAG) is the main
binding protein.
• The amount of AAG increases in those with renal
transplants and those receiving hemodialysis.
• In these patients larger amounts of a basic drug is
bound and a smaller amount is free to exert an
effect.
• In c/o post op., MI, RA, Infections
107

108. Metabolism
• Metabolism can increase, decrease, or does not
change by renal impairment.
• One factor is alteration of drug metabolism in the
liver:
– In uremia, reduction and hydrolysis is slower, but oxidation
by CYP enzymes and conjugation reactions proceed at
normal rates.
• Another factor is the inability of impaired kidneys to
eliminate drugs and active metabolites:
– Metabolites may have pharmacologic activity similar to or
different from that of the parent drug.
108

109. Metabolism Cont,d
• A third factor is impaired renal metabolism of
drugs.
– The kidney contains many of the same
metabolizing enzymes found in the liver.
– For example it has renal CYP enzymes, which
metabolize some chemicals and drugs.
109

110. 110
Effect of renal disease on drug metabolismMechanisms of renal elimination of drugs

111. Excretion
• Excretion of many drugs is reduced in renal
failure.
• The kidneys normally excrete both the parent
drug and metabolites produced by the liver.
• Renal excretion includes: glomerular filtration,
tubular secretion, and tubular reabsorption all
of which is affected by renal impairment.
111

112. 112

113. 113

114. 114

115. Excretion Cont,d
• An adequate fluid intake is required to excrete
drugs by the kidneys.
• Any factor that depletes ECF increases the risk
of worsening renal impairment which include:
– Inadequate fluid intake
– Diuretic drugs
– Loss of body fluids (bleeding, vomiting, diarrhea)
115

116. Age Effect
• In the kidneys of elderly, blood flow, GFR, and
tubular secretion of drugs is decreased.
• All of these changes slow excretion and
promote accumulation of drugs in the body.
• Impaired kidney function greatly increases the
risks of adverse drug effects.
116

117. Creatinine
• Drug therapy must be individualized according to the
extent of renal impairment.
• This is determined by measuring creatinine, which is
used to calculate creatinine clearance as a measure
of the GFR.
• Creatinine is determined by muscle mass and the
GFR, so its measurement cannot be used as the sole
indicator of renal function.
• The exception is a young, relatively healthy, well-
nourished person with a sudden acute illness.
117

118. 121
Cokcroft- Gault Formula (40-80 yrs age)

119. Creatinine Cont,d
• Estimations of creatinine clearance are more
accurate for:
– Clients with stable renal function (stable serum
creatinine).
– Average muscle mass (for their age, weight, and
height).
• Estimations are less accurate for:
– Emaciated and obese clients.
– For those with changing renal function (as in acute
illness).
122

120. Creatinine Cont,d
• Serum creatinine is a relatively unreliable indicator of
renal function in elderly clients.
• Because they have diminished muscle mass, they
may have a normal creatinine even if their GFR is
markedly reduced.
• Some drugs (cimetidine and trimethoprim) increase
creatinine and create a false impression of renal
failure.
• They interfere with secretion of creatinine into
kidney tubules.
123

121. Drug selection
• Drug selection is guided by renal function and
the effects of drugs on renal function.
• Many commonly used drugs may adversely
affect renal function (NSAIDs or OTC drugs).
• Some drugs are excreted exclusively by the
kidneys (aminoglycosides, lithium).
• Some drugs are contraindicated in renal
impairment (tetracyclines except doxycycline).
124

122. Drug selection Cont,d
• Drugs can be used if safety guidelines are followed
(reducing dosage, using TDM and renal function
tests, avoiding dehydration).
• Drugs known to be nephrotoxic should be avoided
when possible.
• In some instances, however, there are no effective
substitutes and nephrotoxic drugs must be given.
• Some commonly used nephrotoxic drugs include
aminoglycoside antibiotics, amphotericin B, and
cisplatin.
125

123. Principles
• Establish type of kidney disease
• Most patients with kidney failure will already be taking
a number of drugs
• Interactions are common
• Care needed to avoid drug toxicity
• Patients with renal impairment and renal
failure
• Antihypertensives
• Phosphate binders
126

124. Dosing in renal impairment
• Loading dose does not change (usually)
• Maintenance dose or dosing interval does
T ½ often prolonged
– Reduce dose OR
– Increase dosing interval
– Some drugs have active metabolites that are themselves
excreted renally
– Warfarin, diazepam
127

125. Dosing of drugs in renal patients
Antimicrobial and antiprotozoal drugs
Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
Maximum 500 mgq 8h0.09-2.3/5-20Amoxycillin
Maximum 375 mg q12 hAmoxycillin
0.9-2.3/5-20
Clavulanic
acid1/3-4
Amoxycillin
Clavulanic acid PO
250-500 mg q6h0.8-1.5/7-20ampicillin
1g loading dose then 50% standard
dose
1/15Cefotaxime IV
128

126. Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
0.5-1 g q24h1.2/13-25Ceftazidime IV
1-2 g q24h7-9/12-24Ceftriaxone IV
750 mg q12h1.2/17Cefuroxime IV
Standard dose1.2/17Cefuroxime PO
250-500 mg q12h0.7/16Cephalexin
Treatment:50% standard dose7-14 days/5- 50 daysChloroquiine
50% standard dose q12h3-6/6-9Ciprofloxacin IV/PO
250 mg q12h2.3-6.0/-Calrithromycin
PCP treatment:Standard dose
q48h
PCP prophylaxis
25% Standard dose q48-72h
Sulphamethoxazole
10/20-50
Trimethoprime
9-13/20-49
Cotrimoxazole
IV/PO
Sulphamethoxazole/
Trimethoprime
50-75% Standard dose
Max 1.5g in 24h
1.4/5-6Erythromycin IV/PO
129

127. Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
Max PO 500 mg q6hIV 1g q 6 h0.8-1/3Flucloxacillin
Titrate to levels1.8/20-60Gentamicin IV
250 mg or 3.5 mg/kg q12 hImpenem ¼
Cilastin1/15-24
Impenem/ cilastin IV
50% standard dose q24h1.1/6-8Meropenem IV
Standard dose0.6/4.1Penoxymethyl-pencillin
4 g q12 h0.8-1.8/3.3-5.1Piperacillin IV
4.5 g q12 hPiperacillin 0.18-0.3/3.3-5.1
Dihydrochloride 1/7
Piperacillin/dihydrochloride IV
Treat,emt 5-10 mg/kg q24h9 healthy,18 malaria/ unchangedQuinine difydrochloride IV
50% standard dose9-13/20-49Trimethoprim
Titrate to levels6-8/200-250Vancomycin IV
130

128. Dosing of some drugs in renal patients
• Allopurinol-GFR 30 ml/min use
100mg,60ml/min use 200mg,90ml/min use
300mg
• Corticosteroids-no need to change the dose
• NSAIDs :-most are metabolized in the liver ,
aspirin is a good choice in renal impairment,
- In ESRD patients ,no need for dose
adjustment
131

129. • Methotrexate ,take care from hematologic
toxicity
• Sulfasalasine ,no change in dose.
• Tramadol , give dose every 12 h instead of
every 6h
• Narcotics, avoid using Darvon and
Mepiridine, for others if GFR less than
10ml/min cut 50% of the dose ,if GFR 10-
50ml/min use 75% of the dose
132

130. • Penicillamine ,avoid if GFR less than
50ml/min
• Cyclosporine, no dose adjustment in renal
insufficiency, however use of Cyclosporine
can worsen renal insufficiency
133

131. Dosage
• Dosage of many drugs needs to be decreased in renal
failure including:
– Aminoglycoside antibiotics
– Most cephalosporin antibiotics
– Fluoroquinolones
– Digoxin
• For some drugs, a smaller dose or a longer interval is
recommended in:
– Moderate renal insufficiency (creatinine clearance 10 to 50
mL/min.).
– Severe renal insufficiency (creatinine clearance < 10
mL/min.).
134

132. NSAIDs
• NSAIDs can cause renal impairment even though
they are eliminated mainly by hepatic metabolism.
• Acetaminophen is nephrotoxic in overdose because
it forms a metabolite that attacks kidney and may
cause necrosis.
• Aspirin is nephrotoxic in high doses, and protein
binding of aspirin is reduced in renal failure so that
blood levels of active drug are higher.
135

133. 136

134. NSAIDs Cont,d
• NSAIDs can decrease blood flow in the kidneys by
inhibiting synthesis of prostaglandins that dilate
renal blood vessels.
• When renal blood flow is normal, these
prostaglandins have limited activity.
• When renal blood flow is decreased, their synthesis
is increased to protect the kidneys from ischemia.
• In those who depend on PGs to maintain renal blood
flow, NSAIDs result in decreased GFR, and retention
of salt and water.
137

135. 138

136. NSAIDs Cont,d
• NSAIDs can also cause kidney damage by a
hypersensitivity reaction that leads to ARF.
• NSAIDs may adversely affect a fetus’s kidneys
when:
– Given during late pregnancy to prevent premature
labor.
– Given shortly after birth for patent ductus
arteriosus (PDA).
139

137. Aminoglycosides
• Highly effective antimicrobials
– Particularly useful in gram -ve sepsis
– bactericidal
• BUT
– Nephrotoxic
– Ototoxic
– Narrow therapeutic range
140

138. Prescribing Aminoglycosides
• Once daily regimen now recommended in patients
with normal kidneys
– High peak concentration enhances efficacy
– long post dose effect
– Single daily dose less nephrotoxic
• Dose depends on size and renal function
– Measure levels!
141

139. Intravenous contrast
• Used commonly
– CT scanning, IV urography, Angiography
– Unsafe in patients with pre-existing renal impairment
– Risk increased in diabetic nephropathy, heart failure &
dehydration
– Can precipitate end-stage renal failure
– Cumulative effect on repeated administration
• Risk reduced by using Acetylcysteine
( N Engl J Med 2000; 343:180-184 )
142

140. Spironolactone
• Class
• Potassium sparing diuretic
• Mode of action
• Antagonises the effect of aldosterone at levels MR
• Mineralocorticoid receptor (MR)–aldosterone complex
translocates to nucleus to affect gene transcription
• Indication
• Prevent hypokalaemia in patients taking diuretics or digoxin
• Improves survival in advanced heart failure (RALES 1999
Randomised Aldactone Evaluation Study)
• Antihypertensive (adjunctive third line therapy for hypertension or
first line for conns patients)
• Ascites in patients with cirrhosis
143

141. Spironolactone
• Side effects
– Antiandrogenic effects through the antagonism of
DHT (testosterone) at its binding site.
– Gynaecomastia, impotence, reduced libido
• Interactions
– Other potassium sparing drugs e.g. ACE
inhibitors/ARBs & potassium supplements
(remember ‘LoSalt’ used as NaCl substitute in
cooking)
144

142. Amphotericin
• Class
• Anti fungal agent for topical and systemic use
• Mode of action
• Lipid soluble drug. Binds steroid alcohols (ergosterol) in
the fungal cell membrane causing leakage of cellular
content and death. Effective against candida species
• Fungistatic or fungicidal depending on the
concentration
• Broad spectrum (candida, cryptosporidium)
145

143. Amphotericin
• Indications
– iv administration for systemic invasive fungal infections
– Oral for GI mycosis
• Side effects
– Local/systemic effects with infusion (fever)
– Chronic kidney dysfunction
» Decline in GFR with prolonged use
» Tubular dysfunction (membrane permeability)
» Hypokalaemia, renal tubular acidosis (bicarb wasting type
1/distal), diabetes insipidus, hypomagnesaemia
» Pre hydration/saline loading may avoid problems
Toxicity can be reduced substantially by liposomal packing of
Amphotericin
146

144. Lithium
• Lithium is not metabolized by the body.
• It is entirely excreted by the kidneys and has a
very narrow therapeutic range.
• Adequate renal function is a prerequisite for
lithium therapy.
• If it has to be given in renal impairment, the
dose must be reduced and TDM must be
done.
147

145. Lithium Cont,d
• 80% of a lithium dose is reabsorbed in the
proximal renal tubules.
• The amount of reabsorption depends on the
concentration of sodium in the proximal
tubules.
• A deficiency of sodium causes more lithium to
be reabsorbed => risk of lithium toxicity ↑.
• Excessive sodium intake lowers lithium levels
to non therapeutic ranges.
148

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