"Renal Excretion of Drugs (DOC)"
Renal Excretion of Drugs ADME – Absorption, Distribution, Metabolism, Excretion Protein Binding Reversible fashion & in dynamic equilibrium Unbound (free) drugs can diffuse through capillary wall Systemic effects Possible Modes of Drug Distribution Metabolised Excreted Bound drugs lose pharmacological activity momentarily & act as a drug reservoir Metabolism Usually Drugs are Hydrophobic to interact with life components (difficult to eliminate as elimination requires water solubility) Require metabolism to facilitate elimination (some drugs) Occur in Liver Kidney GIT Produce Inactive, ↑ polar (hydrophilic) compounds that can be eliminated readily by kidney Drug Excretion Major route Minor route Renal Breast milk Biliary Sweat Intestines Saliva Lungs Tears Hair Skin Renal Excretion 1. In Blood (Plasma) Elimination of Foreign chemicals (xenobiotics) 2. Extracellular Space (Plasma + Interstitial Space) (including pharmacological agents, metabolites) 3. Intracellular Space Drug altered chemically by drug metabolizing enzymes 1° in Liver 4. Bind strongly to Tissues (Plasma concentration ↓ even before elimination) Resulting (Polar) metabolite excreted in urine In form of – Parent drug, Metabolites, Conjugated compounds Kidney Function Basic Renal Processes determine the rate of drug excretion in urine Regulate blood ionic composition (Na+, K+, Ca2+, Cl-, Phosphate ions) Glomerular Filtration Regulate blood pH, osmolarity, glucose Active Tubular Secretion Regulate blood volume (Conserve/ eliminate water) Passive Tubular Reabsorption Regulation of BP (secreting enzyme renin, adjust renal resistance) Release Erythropoietin, Calcitriol Excrete wastes, foreign substances Introduction Renal Excretion Glomerular Filtration Active Tubular Secretion Passive Reabsorption Drugs that are 2 Independent Secretory Systems Urine is concentrated Filtered Not Filtered (located in Proximal Tubule) Drug is concentrated in Urine Small molecules Smaller molecules but (Organic Transport System) Concentration gradient favours Passive Diffusion (< 20 000 daltons) bound to Plasma Anion Cationic Influencing Factor Protein (eg. Albumin) (Acidic Substances) (Basic Compounds) 1. Lipophilicity (mw 68000) Aspirin Ephedrine Lipophilic Hydrophylic Drugs with clearance Highly protein bound Penicillin Epinephrine (non-ionized drugs) (ionized drugs) similar to GFR NSAIDs Cephalexin Cimetidine Readily Reabsorbed Cannot diffuse back Digoxin Penicillins Loop, Thiazide Morphine (Passive Diffusion) Therefore excreted Aminoglycosides Diuretics Diuretics Amiloride 2. Urine Flow Rate Large molecular size Acetazolamide Atropine ↓ Flow - ↑ Reabsorption for Lipophylic compound drugs Salicylates Digoxin 3. Distal Tubular pH Dextrans Methotrexate Choline Effects of Urinary pH on Drug Excretion Insulin Probenecid Dopamine Acidic Drug + Alkaline Urine = Ionized -ve charges Ethambutol Alkaline Drug + Acidic Urine = Ionized (eg. Heparin) H2-Blockers Acidic Drug + Acidic Urine = Non-Ionized (unable to cross Neostigmine Alkaline Drug + Alkaline Urine = Non-Ionized glomerular filtration Procainamide barrier freely) Quinidine Same pH Different pH Quinine Non-Ionized Ionized Trimethoprim Reabsorbed Excreted Contributing factors to filtration (Drug elimination) Drug Elimination (Kidney) (Most effective Mech.) Changing Urinary pH Glomerular Filtration Rate (GFR) 80% of Renal Plasma Flow (RPF) is exposed to Acidifiers Alkalinizers Plasma concentration of unbound (filterable) drug secretory sites Rarely used except in Sodium Bicarbonate Extent of passive reabsorption of drug 20% of RPF is filtered specialized test for Potassium Citrate (following filtration) Especially drugs that are Highly Protein Bound Renal Tubular Acidosis Sodium Citrate Can excrete bound drugs Ammonium Chloride (Independent of protein binding) Ascorbic Acid (provided binding is reversible) Additional Properties of Alkalinizers Both Carriers (Anion, Cationic) can transport ↓ Inflammation of Urinary Tract molecules against an electrochemical gradient Prevent drug crystallizing in urine (eg. Sulfonamide) Can ↓ Plasma Concentration to near Zero ↓ Uric acid stone formation Drug (eg. Penicillin) completely removed by tubular Antibacterial effect secretion during a single transit through kidney (have clearance that corresponds to RPF – 700ml/min) Precaution – Cardiac Failure, Renal Insufficiency Transport capacity can be saturated (can cause Na+ overload) Significance Salicylic acid (Aspirin) Metamphetamine (weak acid) (weak base) In poisoning Excretion 4X Faster Alkalizing the Urine In acid urine ↑ Ionized form Reabsorption not favourable Various Cation, Anion can compete with one another ↑ Excretion in its group of transport Competitiveness (example) Probenecid vs Penicillin Summary Summary (↓ required dose of Penicillin by 80%) Digoxin vs Quinidine Tubular Secretion Renal Clearance of Drugs Freely Filtered Completely removed by Active Secretion Freely Filtered Not Secreted (during a single pass through the Kidney) Nonpolar (Lipophilic) Drug Not Reabsorbed Gallamine Penicillin Mostly Reabsorbed Vitamin B12 P-Aminohippurate (PAH) Inulin Iodopyracet (Diodrast) Iothalamate Cleared at a rate equivalent to GFR Clearance during single pass through Kidney equal to Clearance equal to Urine Flow Rate Renal Plasma Flow (RPF) Estimating Renal Clearance Drug Nephrotoxicity Normal Renal Function – varies Immune Mediated Non-Immune Mediated Age Glomerulonephritis Acute Tubular Necrosis Body weight Allergic Interstitial Nephritis Hemodynamically mediated Plasma Creatinine renal failure Not reliable Obstructive Nephropathy Practical Adverse Effects of Drugs on Kidney Direct Measurement of Creatinine Clearance (CrCl) Not Practical CrCl can be estimated using Formula Cockroft & Gault Equation (useful for starting treatment in ↓ therapeutic index, renally excreted drugs) (Aminoglycosides, Digoxin) (Then use TDM) Drugs in Renal Disease Renal insufficiency can alter Pharmacokinetic parameters Absorption Oral Bioavailability Volume of Distribution Drug binding to plasma proteins Rates of Metabolism, Excretion (eg. Drug Clearance) (Alter drug concentration in plasma, at target tissue site of activity) (Alteration of Drug Efficacy, Toxicity) Extent to which renal disease affect elimination of drug depends on % of drug normally excreted unchanged Degree of Renal Impairment Principle of Prevention Active drug metabolised to Inactive compound Avoid use of potentially nephrotoxic drugs (in patients with ↑ risk) Renal function will not greatly affect elimination If usage unavoidable Drug/ Metabolite excreted unchanged via Kidneys Recognize risk factor Changes in Renal Function will influence Elimination Use specific technique to ↓ potential nephrotoxicity Uremia Excretion of Drugs Nausea, Vomiting, Diarrhoea - ↓ Absorption Unchanged Active Metabolites Neutropathy leading to delayed gastric emptying Acyclovir Adriamycin ↑ Gastric Ammonia → ↑ Gastric pH Amantadine Acebutolol Drugs require acidic pH for absorption Aminoglycosides Azathioprine (eg. Ferrous sulfate will be ↓ absorbed) Amphetamine Captopril ↓ 1st pass Hepatic Metabolism Atenolol Ceftazidime ↑ Drug Bioavailability, Concentration in Renal Failure Penicillin G Chlordiazepoxide (eg. Propranolol) Carbapenems Chloroquine Carbenicillin Ciprofloxacin Conditions - Drug Requiring Dose Adjustment – Renal Disease Chlorothiazide Cyclophosphamide > 40% of drug dose is excreted by Kidney Cimetidine Cytarabine Unchanged Clonidine Diazepam Active (toxic) metabolites Digoxin Digitoxin Drug/ Active Metabolite Furosemide Disopyramidine Narrow Therapeutic Window Gabapentin Enalapril Eliminated by Kidney (eg. Aminoglycosides, vancomycin, digoxin, lithium)-TDM Methotrexate Flecainide Kidney major site for drug Inactivation Neostigmine Meperidine Insulin Oxytetracycline Metoprolol Glucagon Propantheline Methyldopa PTH Pyridostigmine Nitrofurantoin Imipenem Vancoymycin Nitroprusside Significant ↓ in binding of drug to plasma proteins Vitamin B12 Primidone (eg. NSAIDs, Penicillin, Diuretics, Phenytoin) Lithium Procainamide ↓ Protein binding from 99 → 95% Propoxyphene (results in fourfold rise in unbound, active drug concentration) Sulfamethoxazole Valproate Drugs acting on Kidney Vidarabine Depend on Tubular Concentration for Therapeutic Effect Diuretics Antibiotics for UTI Renal Affect receptor on Nitrofurantoin, Nalidixic acid Tubular Luminal surface Curine = 100 X Cplasma Drugs are ↓ effective in ↓ GFR