Renal Excretion of Drugs (DOC)

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					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