kidney excretion mechanisms functions of kidney

1. RENAL DRUG EXCRETION
AminaTariq
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2. EXCRETION OF DRUGS
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3. EXCRETION OF DRUGS
• “ Excretion is defined as the process where by drugs
or metabolites are irreversibly transferred from
internal to external environment through renal or
non renal route.”
• Excretion is the removal of waste substances from
body fluids, and predominantly occurs via urine
formed in the kidneys.
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4. TYPES OF EXCRETION
• RENAL EXCRETION
• NON RENAL EXCRETION
• Biliary excretion.
• Pulmonary excretion.
• Salivary excretion.
• Mammary excretion.
• Skin / Dermal excretion.
• Gastrointestinal excretion.
• Genital excretion
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5. • The principal organ of excretion are kidneys.
Agent that excreted in urine are :
1. water soluble
2.non volatile
3. small in molecular size(< 500 daltons.)
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6. • Most drugs are metabolised first prior to being
excreted.
• However, some drugs, such as aminoglycoside
antibiotics are polar compounds and are
excreted by the kidneys without being
metabolized first.
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7. • The excretion of drugs by the kidney utilizes three
processes, all which occur in the nephron, the microscopic
functional unit of the kidney. These processes are:
1. Glomerular filtration,
2. Tubular secretion and
3. Tubule reabsorption.
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8. Video
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9. Glomerular filtration
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10. Glomerular filtration
• The kidney filters approximately 180 L of fluid per day;
thus there is a large capacity for drug excretion via this
route.
• The major driving force for GF is the hydrostatic
pressure within glomerular capillaries
• Glomerular filtration is a unidirectional process that
occur for most small molecules(MW< 500Da)
• The glomerular barrier restricts passage of plasma
proteins, red blood cells, and other large blood
constituents. Accordingly, drugs that are bound to
these blood elements will not be effectively filtered.
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11. • Drugs bound to plasma proteins remain in the circulation;
only unbound drug is contained in the glomerular filtrate
• Large drugs like heparin or those bound to plasma-protein
cannot be filtered and are poorly excreted by glomerular
filtration.
• The normal GFR rate is 120-130 ml/min
• GFR is measured by using a drug that is eliminated
primarily by filtration only (ie, drug neither reabsorbed nor
secreted)
• Clinically inulin and creatinine are often used for this
purpose.
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12. • Factors influencing the amount of drug excreted by
filtration include the following:
• Renal blood flow influences the rate of delivery of drug to the
kidney.
• •Glomerular filtration rate can be affected by disease or age.
Glomerular filtration rate decreases by approximately 1% per
year and may be significantly compromised in elderly
patients.
• The decline in glomerular filtration rate is accelerated by
disease states such as diabetes. For drugs that are eliminated
by glomerular filtration, dosages are often adjusted based on
the patient's glomerular filtration rate.
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13. Video
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14. Active tubular secretion
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15. Active tubular secretion
• This mainly occurs in proximal tubule.
• It is an active transport process.
• Energy dependent (because the drug is
transported against a concentration gradient)
• Carrier mediated process
• The carrier system is capacity limited and may
be saturated.
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16. Tubular secretion
• Secretory mechanisms in the renal
tubules actively transport endogenous
substances and drug molecules from the
plasma in peritubular capillaries to the tubular
lumen.
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17. Two secretion mechanisms are identified.
System for secretion of organic acids/anions
E.g. Penicillin, salicylates etc uric acid secreted
System for organic base / cations
E.g. morphine, mecamylamine
hexamethonium
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18. • Tubular secretion is:
• Especially important for drugs that are highly plasma
protein bound, because these drugs are not excreted
effectively by glomerular filtration.
• Important in delivering some drugs, such as diuretics, to
their site of action in the renal tubule.
• Not affected by the degree to which a drug binds to plasma
proteins.
• Active tubular secretion rate is dependent on RPF.
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19. • Drug commonly used to measure ATS include;
• P-amino-hippuric acid (PAH)
• Iodopyracet (Diodrast)
• Sodim-o-iodo hippurate
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20. video
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21. TUBULAR REABSORPTION
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22. TUBULAR REABSORPTION
• It occurs after the glomerular filtration of drugs. It
takes place all along the renal tubules.
• Reabsorption of drugs indicated when the excretion
rate value are less than the GFR 130ml/min.e.g.
Glucose
• TR can be active or passive processes.
• Reabsorption results in increase in the half life of the
drug.
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23. TUBULAR REABSORPTION
The reabsorption of drugs
that are acids or weak
bases is influenced by
1. The pH of the fluid in
the renal tubule (ie, urine
pH) and
2. The pKa of the drug.
• The pKa of the drug is
a constant,
• but the normal urinary
pH may vary from 4.5 to
7.5 (Ave. 6.3), i.e., urine
pH 4.5 in forced
acidification and pH 7.5
in forced alkalinization.
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24. Factors affecting urinary pH
 Vegetable and fruit diets (alkaline residue diet) result in
higher urinary pH, whereas diets rich in protein result in
lower urinary pH.
 Drugs such as ascorbic acid and antacids such as sodium
carbonate may decrease (acidify) or increase (alkalinize) the
urinary pH, respectively, when administered in large
quantities.
 Intravenous fluids, such as solutions of bicarbonate or
ammonium chloride. Excretion of these solutions may
drastically change urinary pH and alter drug reabsorption
and drug excretion by the kidney.
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25. Urine pH
The greatest effect of urinary pH on reabsorption occurs for
weak acid drugs (with pKa values of 5-7) and weak base drugs
(with pKa values of 7.5-10.5.)
• For example, amphetamine (weakly basic)
In acidic urine, alkaline drugs are more readily ionised
• Salicylic acid (weakly acidic)
In alkaline urine, acidic drugs are more readily
ionised
• Ionised substances (also refered to as polar) are more
soluble in water so dissolve in the body fluids more
readily for excretion
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26. Active Tubular Reabsorption:
• Its commonly seen with endogenous substances or
nutrients that the body needs to conserve e.g.
electrolytes, glucose, vitamins, amino acids. some
ions (e.g., lithium, fluoride) and some drugs (e.g.,
furosemide).
• Uric acid is also actively re-absorbed.
• Few drugs undergo reabsorption actively.
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27. Passive Tubular Reabsorption:
• It is common for many exogenous substances
including drugs. The driving force is Conc. Gradient
which is due to re-absorption of water, sodium and
inorganic ions.
• Reabsorption is mainly depend on several factor that
are pH, pKa, lipophilicity of drug, urine flow rate.
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28. URINE FLOW RATE
• Polar drug are not affected by urine pH hence not get
reabsorbed so unaffected by urine flow rate.
• Only those drugs whose reabsorption is pH sensitive
Ex. Weak acids and bases depend on urine flow rate.
• Urine flow rate can be incresed by forced diuresis by
large fluid intake or other diuretics.
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29. Video
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30. FACTORS AFFECTING RENAL
EXCRETION
1) Urine pH and pKa affect TR
2) Urine flow rate.
3) Physicochemical properties of drug.
4) Distribution and Binding characteristic of drug.
5) Blood flow to the kidneys. Imp in GFR
6) Biological factors.
7) Drug interactions.
8) Disease states
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31. Clinical application
• Sulfisoxazole ( Gantrisin) tablets
• Sulfamethoxazole/trimethoprim (Bactrim) tablets
• Sulphonamides are N-actylated to less water soluble
metabolite.
• Both of the above sulphonamides N-actylated
metabolite more soluble in alkaline conditions.
• In acidic urine ppt of sulphonamides renal
toxicity
• To prevent crystalluria pts instructed to take these
drugs with excess of fluid intake to keep urine alkaline
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32. References
• https://www.nottingham.ac.uk/nursing/sonet/rlos/b
ioproc/kidneydrug/page_two.html
• https://www.msdmanuals.com/professional/clinical-
pharmacology/pharmacokinetics/drug-excretion
• Applied Biopharmaceutics & Pharmacokinetics, 7e
by Leon Shargel, Andrew B.C. Yu
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33. Quiz
1. How do the majority of drugs enter the kidney tubule?
A: Tubule secretion
B: Glomerular filtration
2. Penicillin is rapidly excreted
A: True
B: False
3. Reabsorption is
A: active diffusion
B: passive diffusion
4. In alkaline urine
A: acidic drugs are more readily ionised.
B: alkaline drugs are more readily ionised
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34. 5. Which renal elimination process are influenced by
protein binding?
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35. Answers
1. a
2. a
3. b
4. A
5. Glomerular filtration
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