Drugs Pharmacology in Kidney Disease

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.Farjoo

Drugs Pharmacology in Kidney Disease

Weak Acids & Weak Bases Absorption Distribution & Protein Binding Metabolism & Excretion Age Effect Creatinine Drug selection Dosage NSAIDs & Lithium

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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.

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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.

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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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.

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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.

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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.

Weak Acids & Weak Bases Cont,d

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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 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

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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.

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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.

Protein binding Pic.

Protein binding Pic.

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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.

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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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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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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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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.).

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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.

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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.

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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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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.

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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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