drug use in hepatic and renal impairment

Drugs pharmacology in Liver disease & Renal Disease

Dr Akshil Mehta

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

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

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, extrahepaticmetabolism becomes more important.

4

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

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).

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• 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

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

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

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.

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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

Conjugation Pic.

13

Elimination of drugs

14

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

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.

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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.

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• 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.

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enzyme induction and inhibition Pic.

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• 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.

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Liver Blood Flow

• Hepatic metabolism also depends on hepatic blood flow.

• Hepatic blood flow ↓ => delivery of drug to hepatocytes ↓ => drug metabolism ↓ => drug toxicity ↑

22

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.

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• 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

Protein binding Pic.

25


26

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

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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• Potentially hepatotoxic drugs include:

– Acetaminophen

– Halothane

– Isoniazid

– Sodium Valproate

– Phenytoin

– Amiodarone

– Erythromycin

– Oral Contraceptives

– Trimethoprim-Sulfamethoxazole

Specific Drugs

71

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.

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Acetaminophen Cont’d

• Administration of cysteine, or N-acetylcysteinereduces 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-acetylcysteinetherapy, liver transplantation is the only option.

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Acetaminophen metabolism

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

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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.

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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.

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Isoniazid

• In ~10% of adults elevated serum aminotransferaselevels 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.

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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.

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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.

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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.

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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.

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Oral Contraceptives

• Combination pills of estrogenic and progestationalsteroids 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.

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Trimethoprim-Sulfamethoxazole

• In most cases, liver injury is self-limited.

• The hepatotoxicity is attributable to the sulfamethoxazole component of the drug.

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Some Features of Toxic and Drug-Induced Hepatic Injury

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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

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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 ????

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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.

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• 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

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4. Other nephrotoxic effects of drugs:

• Interstitial nephritis

• Retropertoneal fibrosis

• Drug induced SLE

• Nephrogenic DI

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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

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.

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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.

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• 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.

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• A large number of drugs are weak bases. Most of these bases are amine-containing molecules.

• Primary, secondary, and tertiary aminesundergo protonation and vary their solubility with pH.

• Quaternary amines are always in the poorly lipid-soluble charged form.

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• 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.

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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

contents7.5-8.0 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

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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).

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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.

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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.

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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.

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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)

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• 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.

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105


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• 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

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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.

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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.

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110Effect 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 metabolites produced by the liver.

• Renal excretion includes: glomerular filtration, tubular secretion, and tubular reabsorption all of which is affected by renal impairment.

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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)

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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.

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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.

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121

Cokcroft- Gault Formula (40-80 yrs age)

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).

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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.

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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).

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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.

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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

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

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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


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


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 h Piperacillin 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

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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

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• 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

• Penicillamine ,avoid if GFR less than 50ml/min

• Cyclosporine, no dose adjustment in renal insufficiency, however use of Cyclosporine can worsen renal insufficiency

133

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

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

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

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).

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Aminoglycosides

• Highly effective antimicrobials

– Particularly useful in gram -ve sepsis

– bactericidal

• BUT

– Nephrotoxic

– Ototoxic

– Narrow therapeutic range

140

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

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 )

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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

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)

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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

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

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

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.

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drug use in hepatic and renal impairment

Health & Medicine

liver contddosage

hepatotoxic drugs

elimination of drugs

livermost drugs

impaired liver function

liver function tests

primary liver disease

chronic liver impairment