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Drugs pharmacology in Liver
disease & Renal Disease
Dr Akshil Mehta
Drugs pharmacology in Liver disease
– Introduction
– General guidelines
– Absorption and Liver
– Metabolism in Liver
– Dru...
Introduction
• Acute liver impairment interferes with drug
metabolism and elimination.
• Chronic liver impairment affects ...
Introduction Cont’d
• Many drugs change liver function tests without
clinical signs of liver dysfunction.
• Hepatotoxicity...
Introduction Cont’d
• At risk for impaired liver function include:
– Primary liver disease (eg, hepatitis, cirrhosis).
– D...
General guidelines
• General guidelines when using drugs include:
– Clinical signs for hepatotixicity should be sought
(na...
• Monitoring liver tests:
– Serum bilirubin levels above 4 to 5 mg/dl
– Prothrombin time greater than 1.5 times control
– ...
Absorption and Liver
• Some oral drugs are extensively metabolized in the
liver.
• This process is called the first-pass e...
presystemic clearance
Mechanism of presystemic clearance .After drug enters
the enterocyte, it can undergo metabolism, exc...
10
Metabolism in Liver
• Most drugs are metabolized by enzymes in the liver
• They are called the cytochrome P450 [CYP] or th...
Metabolism in Liver Cont’d
• The CYP3 metabolizes 50% of drugs, the CYP2 45%,
and the CYP1 group 5%.
• They catalyze oxida...
Conjugation Pic.
13
Elimination of drugs
14
15
Metabolism in Liver Cont’d
• Dosage should be reduced for drugs that are
extensively metabolized in the liver including:
–...
Drug Effect on Liver
• With chronic administration, some drugs increase
metabolizing enzymes in the liver: enzyme inductio...
Drug Effect on Liver Cont’d
• Enzyme inducers consist of: phenytoin, rifampin,
phenobarbital, ethanol, and cigarette smoki...
Drug Effect on Liver Cont’d
• Metabolism can be decreased in a process called
enzyme inhibition.
• It occurs with co-admin...
enzyme induction and inhibition Pic.
20
Drug Effect on Liver Cont’d
• Some drugs indirectly affect liver function:
– Epinephrine decreases blood flow by constrict...
Liver Blood Flow
• Hepatic metabolism also depends on hepatic
blood flow.
• Hepatic blood flow ↓ => delivery of drug to
he...
Protein Binding
• Protein binding affects distribution.
• The impaired liver is unable to synthesize
plasma proteins (albu...
• When protein binding ↓ => free drug ↑ =>
drug distribution to sites of action &
elimination ↑
– => onset of drug action ...
Protein binding Pic.
25
Protein binding Pic.
26
Age Effect
• Pharmacokinetics differs in neonates, especially
prematures, because their organs are not fully
developed.
• ...
Age Effect Cont’d
• In elderly, physiologic changes alters all
pharmacokinetic processes in the liver.
• Many drugs are me...
29
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• Potentially hepatotoxic drugs include:
– Acetaminophen
– Halothane
– Isoniazid
– Sodium Valproate
– Phenytoin
– Amiodaro...
Acetaminophen
• A single dose of 10–15 g, produces liver injury and 25
g is fatal.
• Maximal hepatic failure occurs 4–6 da...
Acetaminophen Cont’d
• Administration of cysteine, or N-acetylcysteine
reduces the severity of hepatic necrosis.
• Therapy...
Acetaminophen
metabolism
Metabolism of acetaminophen (top
center) to hepatotoxic metabolites.
(GSH, glutathione; SG, gluta...
75
Halothane
• It is an idiosyncratic hepatotoxicity.
• It causes severe hepatic necrosis in a small
number of individuals, m...
Halothane Cont’d
• The case-fatality rate of halothane hepatitis is
20–40%.
• Patients with delayed spiking fever or jaund...
Isoniazid
• In ~10% of adults elevated serum aminotransferase
levels develop during the first few weeks.
• In ~1% of treat...
Sodium Valproate
• It is associated with severe hepatic toxicity and rarely,
fatalities, predominantly in children.
• Elev...
Phenytoin
• Phenytoin rarely causes severe hepatitis leading to
fulminant hepatic failure.
• Hepatic injury is usually man...
Amiodarone
• Clinically important liver disease develops in
<5% of patients.
• It has a half-life of up to 107 days so liv...
Erythromycin
• The important adverse effect is a cholestatic
reaction.
• It is more common in children than adults.
• Most...
Oral Contraceptives
• Combination pills of estrogenic and progestational
steroids lead to intrahepatic cholestasis.
• It o...
Trimethoprim-Sulfamethoxazole
• In most cases, liver injury is self-limited.
• The hepatotoxicity is attributable to the
s...
Some Features of Toxic and Drug-Induced Hepatic Injury
85
Drugs Pharmacology in Kidney Disease
• Drug Nephrotoxicity
• Weak Acids & Weak Bases
• Absorption
• Distribution & Protein...
Drug Nephrotoxicity
Drugs can lead to renal damage in a number
of different ways :
1. Alteration of renal blood flow
• NSA...
Occurring in patients who are critically dependant
upon RAA system.
• Cyclosporine A
2. Direct tubular toxicity
• Aminogly...
• Cisplatin : selectively toxic to proximal
tubules by inhibiting nuclear DNA synthesis
• Amophotercin:
3.glumerulonephrit...
4. Other nephrotoxic effects of drugs:
• Interstitial nephritis
• Retropertoneal fibrosis
• Drug induced SLE
• Nephrogenic...
Weak Acids & Weak Bases
• Most drugs are lipid soluble which aids their
movement across cell membranes.
• The kidneys can ...
M.H.Farjoo
Weak Acids & Weak Bases Cont,d
• Weak acids and weak bases gain or lose protons
depending on the pH.
• Their mo...
Trapping of a weak base
(pyrimethamine) in the urine
when the urine is more acidic
than the blood. In the
hypothetical cas...
Weak Acids & Weak Bases Cont,d
• Sodium bicarbonate + phenobarbital →
increased excretion of phenobarbital.
• The sodium b...
Weak Acids & Weak Bases Cont,d
• A large number of drugs are weak bases. Most
of these bases are amine-containing
molecule...
96
Weak Acids & Weak Bases Cont,d
• The protonated form of a weak acid is the
neutral, more lipid-soluble form.
• The unproto...
Weak Acids & Weak Bases Cont,d
Body Fluid Range of pH
Total Fluid:
Blood
Concentration
Ratios for
Sulfadiazine
(acid, pKa ...
Absorption
• Absorption of oral drugs may be decreased
indirectly in renal failure by:
– Delayed gastric emptying
– Change...
Absorption Cont,d
• In CRF, gastric pH is altered by:
– Oral alkalinizing agents (sodium bicarbonate,
citrate).
– Use of a...
Distribution
• Distribution of drugs is altered by changes in ECF,
plasma protein binding, and tissue binding.
• Water-sol...
Protein Binding
• Albumin is the main drug-binding plasma
protein for acidic drugs.
• Drug binding with albumin is decreas...
Protein Binding Cont,d
• Reasons for decreased albumin include:
– Nephrotic states in which albumin is lost in the
urine.
...
Protein Binding Cont,d
• When less drug is bound to albumin:
– More unbound drug distributes into sites of
metabolism and ...
Protein binding Pic.
105
Protein binding Pic.
106
Protein Binding Cont,d
• For basic drugs (clindamycin, propafenone),
alpha1-acid glycoprotein (AAG) is the main
binding pr...
Metabolism
• Metabolism can increase, decrease, or does not
change by renal impairment.
• One factor is alteration of drug...
Metabolism Cont,d
• A third factor is impaired renal metabolism of
drugs.
– The kidney contains many of the same
metaboliz...
110
Effect of renal disease on drug metabolismMechanisms of renal elimination of drugs
Excretion
• Excretion of many drugs is reduced in renal
failure.
• The kidneys normally excrete both the parent
drug and m...
112
113
114
Excretion Cont,d
• An adequate fluid intake is required to excrete
drugs by the kidneys.
• Any factor that depletes ECF in...
Age Effect
• In the kidneys of elderly, blood flow, GFR, and
tubular secretion of drugs is decreased.
• All of these chang...
Creatinine
• Drug therapy must be individualized according to the
extent of renal impairment.
• This is determined by meas...
121
Cokcroft- Gault Formula (40-80 yrs age)
Creatinine Cont,d
• Estimations of creatinine clearance are more
accurate for:
– Clients with stable renal function (stabl...
Creatinine Cont,d
• Serum creatinine is a relatively unreliable indicator of
renal function in elderly clients.
• Because ...
Drug selection
• Drug selection is guided by renal function and
the effects of drugs on renal function.
• Many commonly us...
Drug selection Cont,d
• Drugs can be used if safety guidelines are followed
(reducing dosage, using TDM and renal function...
Principles
• Establish type of kidney disease
• Most patients with kidney failure will already be taking
a number of drugs...
Dosing in renal impairment
• Loading dose does not change (usually)
• Maintenance dose or dosing interval does
T ½ often p...
Dosing of drugs in renal patients
Antimicrobial and antiprotozoal drugs
Dosage for severe renal failureHalf-life
Normal/ES...
Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
0.5-1 g q24h1.2/13-25Ceftazidime IV
1-2 g q24h7-9/12-24Ceftr...
Dosage for severe renal failureHalf-life
Normal/ESRD
(h)
Drug
Max PO 500 mg q6hIV 1g q 6 h0.8-1/3Flucloxacillin
Titrate to...
Dosing of some drugs in renal patients
• Allopurinol-GFR 30 ml/min use
100mg,60ml/min use 200mg,90ml/min use
300mg
• Corti...
• Methotrexate ,take care from hematologic
toxicity
• Sulfasalasine ,no change in dose.
• Tramadol , give dose every 12 h ...
• Penicillamine ,avoid if GFR less than
50ml/min
• Cyclosporine, no dose adjustment in renal
insufficiency, however use of...
Dosage
• Dosage of many drugs needs to be decreased in renal
failure including:
– Aminoglycoside antibiotics
– Most cephal...
NSAIDs
• NSAIDs can cause renal impairment even though
they are eliminated mainly by hepatic metabolism.
• Acetaminophen i...
136
NSAIDs Cont,d
• NSAIDs can decrease blood flow in the kidneys by
inhibiting synthesis of prostaglandins that dilate
renal ...
138
NSAIDs Cont,d
• NSAIDs can also cause kidney damage by a
hypersensitivity reaction that leads to ARF.
• NSAIDs may adverse...
Aminoglycosides
• Highly effective antimicrobials
– Particularly useful in gram -ve sepsis
– bactericidal
• BUT
– Nephroto...
Prescribing Aminoglycosides
• Once daily regimen now recommended in patients
with normal kidneys
– High peak concentration...
Intravenous contrast
• Used commonly
– CT scanning, IV urography, Angiography
– Unsafe in patients with pre-existing renal...
Spironolactone
• Class
• Potassium sparing diuretic
• Mode of action
• Antagonises the effect of aldosterone at levels MR
...
Spironolactone
• Side effects
– Antiandrogenic effects through the antagonism of
DHT (testosterone) at its binding site.
–...
Amphotericin
• Class
• Anti fungal agent for topical and systemic use
• Mode of action
• Lipid soluble drug. Binds steroid...
Amphotericin
• Indications
– iv administration for systemic invasive fungal infections
– Oral for GI mycosis
• Side effect...
Lithium
• Lithium is not metabolized by the body.
• It is entirely excreted by the kidneys and has a
very narrow therapeut...
Lithium Cont,d
• 80% of a lithium dose is reabsorbed in the
proximal renal tubules.
• The amount of reabsorption depends o...
149
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Drug use in hepatic and renal impairment

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Drug use in hepatic and renal impairment

  1. 1. Drugs pharmacology in Liver disease & Renal Disease Dr Akshil Mehta
  2. 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. 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. 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. 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. 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. 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. 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. 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. 10
  11. 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. 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. 13. Conjugation Pic. 13
  14. 14. Elimination of drugs 14
  15. 15. 15
  16. 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. 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. 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. 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. 20. enzyme induction and inhibition Pic. 20
  21. 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. 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. 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. 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. 25. Protein binding Pic. 25
  26. 26. Protein binding Pic. 26
  27. 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. 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. 28
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  71. 71. • Potentially hepatotoxic drugs include: – Acetaminophen – Halothane – Isoniazid – Sodium Valproate – Phenytoin – Amiodarone – Erythromycin – Oral Contraceptives – Trimethoprim-Sulfamethoxazole Specific Drugs 71
  72. 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. 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. 74. Acetaminophen metabolism Metabolism of acetaminophen (top center) to hepatotoxic metabolites. (GSH, glutathione; SG, glutathione moiety). 74
  75. 75. 75
  76. 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. 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. 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. 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. 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. 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. 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. 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. 84. Trimethoprim-Sulfamethoxazole • In most cases, liver injury is self-limited. • The hepatotoxicity is attributable to the sulfamethoxazole component of the drug. 84
  85. 85. Some Features of Toxic and Drug-Induced Hepatic Injury 85
  86. 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. 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. 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. 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. 90. 4. Other nephrotoxic effects of drugs: • Interstitial nephritis • Retropertoneal fibrosis • Drug induced SLE • Nephrogenic DI 90
  91. 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. 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. 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. 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. 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. 96
  97. 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. 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. 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. 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. 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. 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. 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. 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. 105. Protein binding Pic. 105
  106. 106. Protein binding Pic. 106
  107. 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. 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. 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. 110 Effect of renal disease on drug metabolismMechanisms of renal elimination of drugs
  111. 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. 112
  113. 113. 113
  114. 114. 114
  115. 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. 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. 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. 118. 121 Cokcroft- Gault Formula (40-80 yrs age)
  119. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 133. 136
  134. 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. 135. 138
  136. 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. 137. Aminoglycosides • Highly effective antimicrobials – Particularly useful in gram -ve sepsis – bactericidal • BUT – Nephrotoxic – Ototoxic – Narrow therapeutic range 140
  138. 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. 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. 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. 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. 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. 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. 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. 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
  146. 146. 149

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