Drugs pharmacology in kidney disease

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Transcript of Drugs pharmacology in kidney disease

  • 1. Drugs Pharmacology in KidneyDisease By M.H.Farjoo M.D. , Ph.D. Shahid Beheshti University of Medical Science

2. Drugs Pharmacology in Kidney DiseaseWeak Acids & Weak BasesAbsorptionDistribution & Protein BindingMetabolism & ExcretionAge EffectCreatinineDrug selectionDosageNSAIDs & LithiumM.H.Farjoo 3. Weak Acids & Weak BasesMost 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.M.H.Farjoo 4. Weak Acids & Weak Bases Cont,dWeak 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.M.H.Farjoo 5. Trapping of a weak base(pyrimethamine) in the urinewhen the urine is moreacidic than the blood. In thehypothetical case illustrated,the diffusible unchargedform of the drug hasequilibrated across themembrane, but the totalconcentration (charged plusuncharged) in the urine isalmost eight times higherthan in the blood. 6. Weak Acids & Weak Bases Cont,dSodium 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.M.H.Farjoo 7. Weak Acids & Weak Bases Cont,dA 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.M.H.Farjoo 8. Weak Acids & Weak Bases Cont,dThe 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.M.H.Farjoo 9. Weak Acids & Weak Bases Cont,dTotal Fluid:Total Fluid:Blood Blood Concentration Concentration Body FluidRange of pH Ratios forRatios forSulfadiazine Pyrimethamine (acid, pKa 6.5) (base, pKa 7.0)Urine5.0-8.00.12-4.6572.24-0.79Breast milk6.4-7.6 0.2-1.77 3.56-0.89Jejunum, ileum 7.5-8.0 1.23-3.540.94-0.79contentsStomach contents1.92-2.59 0.11 85,993-18,386Prostatic secretions 6.45-7.4 0.213.25-1.0Vaginal secretions 3.4-4.20.112848-452M.H.Farjoo 10. AbsorptionAbsorption 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).M.H.Farjoo 11. Absorption Cont,dIn 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.M.H.Farjoo 12. DistributionDistribution 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.M.H.Farjoo 13. Protein BindingAlbumin 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.M.H.Farjoo 14. Protein Binding Cont,dReasons 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.M.H.Farjoo 15. Protein Binding Cont,dWhen 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.M.H.Farjoo 16. Protein binding Pic. 17. Protein binding Pic. 18. Protein Binding Cont,dFor 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.M.H.Farjoo 19. MetabolismMetabolism 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.M.H.Farjoo 20. 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.M.H.Farjoo 21. ExcretionExcretion 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.M.H.Farjoo 22. Excretion Cont,dAn 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)M.H.Farjoo 23. Age EffectIn 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.M.H.Farjoo 24. CreatinineDrug 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.M.H.Farjoo 25. Creatinine Cont,dEstimations 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).M.H.Farjoo 26. Creatinine Cont,dSerum 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.M.H.Farjoo 27. Drug selectionDrug 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).M.H.Farjoo 28. Drug selection Cont,dDrugs 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.M.H.Farjoo 29. DosageDosage of many drugs needs to be decreased in renal failure including: Aminoglycoside antibiotics Most cephalosporin antibiotics Fluoroquinolones DigoxinFor 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.).M.H.Farjoo 30. NSAIDsNSAIDs 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.M.H.Farjoo 31. NSAIDs Cont,dNSAIDs 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.M.H.Farjoo 32. NSAIDs Cont,dNSAIDs can also cause kidney damage by a hypers