Renal Excretion of Drugs

ADME Absorption, Distribution, Metabolism, Excretion

Possible Modes of Drug Distribution

1. In Blood (Plasma)
2. Extracellular Space (Plasma + Interstitial Space)
3. Intracellular Space
4. Bind strongly to Tissues (Plasma concentration even before
elimination)
Kidney Function
Regulate blood ionic composition (Na+, K+, Ca2+, Cl-,
Phosphate ions)
Regulate blood pH, osmolarity, glucose
Regulate blood volume (Conserve/ eliminate water)
Regulation of BP (secreting enzyme renin, adjust renal
resistance)
Release Erythropoietin, Calcitriol
Excrete wastes, foreign substances
Introduction

Protein Binding

Drug Excretion
Major route
Renal
Biliary
Intestines
Lungs

Minor route
Breast milk
Sweat
Saliva
Tears
Hair
Skin

Renal Excretion
Elimination of Foreign chemicals (xenobiotics)
(including pharmacological agents, metabolites)
Drug altered chemically by drug metabolizing enzymes 1 in
Liver
Resulting (Polar) metabolite excreted in urine
In form of Parent drug, Metabolites, Conjugated compounds
Basic Renal Processes determine the rate of drug
excretion in urine
Glomerular Filtration
Active Tubular Secretion
Passive Tubular Reabsorption
Reversible fashion & in dynamic equilibrium
Unbound (free) drugs can diffuse through capillary wall
Systemic effects
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
Renal Excretion
Glomerular Filtration
Active Tubular Secretion
Drugs that are
2 Independent Secretory Systems
(located in Proximal Tubule)
Filtered
Not Filtered
Small molecules
Smaller molecules
(Organic Transport System)
(< 20 000 daltons)
but bound to
Anion
Plasma Protein
(Acidic Substances)
(eg. Albumin) (mw
Aspirin
Penicillin
68000)
Cephalexin
Drugs with
Highly protein
Loop, Thiazide
clearance similar bound
Diuretics
to GFR
NSAIDs
Acetazolamide
Digoxin
Penicillins
Salicylates
Aminoglycosides
Diuretics
Methotrexate
Large molecular
Probenecid
size drugs
Dextrans
Insulin
-ve charges
(eg. Heparin)
(unable to cross
glomerular
filtration barrier
freely)

Passive Reabsorption
Urine is concentrated
Drug is concentrated in Urine
Concentration gradient favours Passive
Diffusion
Influencing Factor
1. Lipophilicity
Lipophilic
Hydrophylic
(non-ionized
(ionized drugs)
drugs)
Readily
Cannot diffuse
Reabsorbed
back
Therefore excreted
(Passive Diffusion)
2. Urine Flow Rate
Flow - Reabsorption for Lipophylic
compound
3. Distal Tubular pH
Effects of Urinary pH on Drug
Excretion
Acidic Drug + Alkaline Urine = Ionized
Alkaline Drug + Acidic Urine = Ionized
Acidic Drug + Acidic Urine = Non-Ionized
Alkaline Drug + Alkaline Urine = NonIonized
Same pH
Non-Ionized
Reabsorbed

Different pH
Ionized
Excreted

Contributing factors to filtration (Drug

elimination)
Glomerular Filtration Rate (GFR)
Plasma concentration of unbound
(filterable) drug
Extent of passive reabsorption of drug
(following filtration)

Summary

Drug Elimination (Kidney) (Most

effective Mech.)
80% of Renal Plasma Flow (RPF) is exposed
to secretory sites
20% of RPF is filtered
Especially drugs that are Highly Protein
Bound
Can excrete bound drugs
(Independent of protein binding)
(provided binding is reversible)
Both Carriers (Anion, Cationic) can
transport molecules against an
electrochemical gradient
Can Plasma Concentration to near Zero
Drug (eg. Penicillin) completely removed by
tubular secretion during a single transit
through kidney
(have clearance that corresponds to RPF
700ml/min)
Transport capacity can be saturated

Various Cation, Anion can compete with

one another in its group of transport
Competitiveness (example)
Probenecid vs Penicillin
( required dose of Penicillin by 80%)
Digoxin vs Quinidine

Changing Urinary pH
Acidifiers
Alkalinizers
Rarely used except Sodium
in specialized test
Bicarbonate
Potassium Citrate
for Renal Tubular
Sodium Citrate
Acidosis
Ammonium
Chloride
Ascorbic Acid
Additional Properties of Alkalinizers
Inflammation of Urinary Tract
Prevent drug crystallizing in urine (eg.
Sulfonamide)
Uric acid stone formation
Antibacterial effect
Precaution Cardiac Failure, Renal
Insufficiency
(can cause Na+ overload)
Significance
Salicylic acid
(Aspirin)
(weak acid)
In poisoning
Alkalizing the
Urine
Ionized form
Reabsorption not
favourable
Excretion

Metamphetamin
e
(weak base)
Excretion 4X Faster
In acid urine

Summary

Tubular Secretion
Renal Clearance of Drugs
Freely Filtered
Not Secreted
Not Reabsorbed
Gallamine
Vitamin B12
Inulin
Iothalamate
Cleared at a rate equivalent to GFR

Completely removed by Active

Secretion
(during a single pass through the
Kidney)
Penicillin
P-Aminohippurate (PAH)
Iodopyracet (Diodrast)

Freely Filtered
Nonpolar (Lipophilic) Drug

Clearance during single pass through

Kidney equal to Renal Plasma Flow (RPF)

Clearance equal to Urine Flow Rate

Estimating Renal Clearance

Normal Renal Function varies
Age
Body weight
Plasma Creatinine
Not reliable
Practical
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)

Mostly Reabsorbed

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
Active drug metabolised to Inactive compound

Renal function will not greatly affect elimination

Drug/ Metabolite excreted unchanged via Kidneys
Changes in Renal Function will influence Elimination
Uremia
Nausea, Vomiting, Diarrhoea - Absorption
Neutropathy leading to delayed gastric emptying
Gastric Ammonia Gastric pH
Drugs require acidic pH for absorption
(eg. Ferrous sulfate will be absorbed)
1st pass Hepatic Metabolism
Drug Bioavailability, Concentration in Renal Failure
(eg. Propranolol)
Conditions - Drug Requiring Dose Adjustment Renal
Disease
> 40% of drug dose is excreted by Kidney
Unchanged
Active (toxic) metabolites
Drug/ Active Metabolite
Narrow Therapeutic Window
Eliminated by Kidney (eg. Aminoglycosides, vancomycin,
digoxin, lithium)-TDM
Kidney major site for drug Inactivation
Insulin
Glucagon
PTH
Imipenem
Significant in binding of drug to plasma proteins
(eg. NSAIDs, Penicillin, Diuretics, Phenytoin)
Protein binding from 99 95%
(results in fourfold rise in unbound, active drug concentration)
Drugs acting on Kidney
Depend on Tubular Concentration for Therapeutic Effect
Diuretics
Antibiotics for UTI
Affect receptor on
Nitrofurantoin, Nalidixic acid
Tubular Luminal surface
Curine = 100 X Cplasma
Drugs are effective in GFR

Drug Nephrotoxicity
Immune Mediated
Glomerulonephritis
Allergic Interstitial Nephritis

Non-Immune Mediated
Acute Tubular Necrosis
Hemodynamically mediated
renal failure
Obstructive Nephropathy
Adverse Effects of Drugs on Kidney

Principle of Prevention
Avoid use of potentially nephrotoxic drugs (in patients with
risk)
If usage unavoidable
Recognize risk factor
Use specific technique to potential nephrotoxicity
Excretion of Drugs
Unchanged
Acyclovir
Amantadine
Aminoglycosides
Amphetamine
Atenolol
Penicillin G
Carbapenems
Carbenicillin
Chlorothiazide
Cimetidine
Clonidine
Digoxin
Furosemide
Gabapentin
Methotrexate
Neostigmine
Oxytetracycline
Propantheline
Pyridostigmine
Vancoymycin
Vitamin B12
Lithium

Renal

Active Metabolites
Adriamycin
Acebutolol
Azathioprine
Captopril
Ceftazidime
Chlordiazepoxide
Chloroquine
Ciprofloxacin
Cyclophosphamide
Cytarabine
Diazepam
Digitoxin
Disopyramidine
Enalapril
Flecainide
Meperidine
Metoprolol
Methyldopa
Nitrofurantoin
Nitroprusside
Primidone
Procainamide
Propoxyphene
Sulfamethoxazole
Valproate
Vidarabine