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Renal Excretion of Drugs

ADME – Absorption, Distribution, Metabolism, Excretion Protein Bindi ng

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
(diffi cult to eliminate as elimination requires water solubility)
Require metabolism to facilitate elimination (some drugs)
Occur in
Liver
Kidney
GIT
Produce Inactive, ↑ polar (hydrophilic) compou nds 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 Processe s determine the rate of drug excretion in urine
Regulate blood ionic comp osition (Na+, K+, Ca2+, Cl-, Phos phate 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
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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 Compoun ds) 1. Lipophilicity
(mw 68000) Aspirin Ephedrine Lipophilic Hydrophylic
Drugs with clearance Highly protein bound Penicillin Epinephrine (non-ioni zed drugs) (ionized drugs)
similar to GFR NSAIDs Cephalexin Cimetidine Readily Reabsorbed Cannot diffuse ba ck
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 compoun d
drugs Salicylates Digoxin 3. Distal Tubular pH
Dextrans Methotrexate Choline Effects of Urinary pH on Drug Excretion
Insulin Acidic Drug + Alkaline Urine = Ionized
Probenecid Dopamine
-ve charges Alkaline Drug + Acidic Urine = Ionized
Ethambutol
(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-Ionize d 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 unb ound (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
(Independe nt 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 ↑ ExcreƟon
in its group of transport
Competitiveness (example )
Probenecid vs Penicillin
Summary Summary
(↓ required dose of Peni cillin 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-Aminohipp urate (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)
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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 unchange d via Kidneys Recognize risk factor
Changes in Renal Function will influence Elimination Use specific tech nique to ↓ potential nephrotoxicity

Uremia Excretion of Drugs

Nausea, Vomiting, Diarrhoea - ↓ Absorption Unchange d 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, ConcentraHon in Renal Failure Penicillin G Chlordiazepoxide
(eg. Propranolol) Carbapenems Chloroquine
Carbenicillin Ciprofloxaci n
Conditions - Drug Requiring Dose Adjustment – Renal Disease Chlorothiazide Cyclophospha mide
> 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 unbou nd, active drug concentration)
Sulfamethoxazole
Valproate
Drugs acting on Kidney
Vidarabine
Depend on Tubular Conce ntration 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