Renal Excretion

Excretion
   - Definition: Removal of drugs from the body.    - Predominantly occurs through renal excretion.
   - Facilitated by the nephrons in the kidney.
   - Eliminates drugs that are polar or polar metabolites of non-polar drugs (following drug metabolism).

Components of Renal Blood Flow:
   - Renal artery
   - Segmental arteries
   - Interlobar arteries
   - Glomerulus
   - Afferent arterioles
   - Efferent arterioles
   - Arcuate arteries
   - Peritubular capillaries
   - Interlobular arteries
   - Interlobular veins
   - Arcuate veins
   - Interlobar veins
   - Segmental veins
   - Renal vein

The rate of drug excretion by the kidney varies based on:    - Glomerular filtration
   - Tubular reabsorption
   - Active secretion

Physiology:
- Glomerulus acts as a capillary network filtering blood into the nephron.
- Blood flows from the afferent arteriole into the glomerulus. - Filters out waste products, excess ions, and water for excretion as urine.
Pharmacology:
   - Unbound drugs with molecular weight (MW) < 20,000 easily filter through the glomerulus for renal excretion.
   - Drugs bound to large proteins (e.g. albumin, MW 68,000) do not permeate.
   - Example: 98% of Warfarin is bound to albumin, allowing only 2% to be filtered into urine for excretion.

Drugs in the Nephron:
- Filtered drugs cross the glomerulus into the proximal convoluted tubule (PCT).
- Drugs can also be secreted from peritubular capillaries into the PCT.
Physiology of Secretion:
- Metabolic by-products (H+, K+, urea) are secreted from peritubular capillaries into the PCT for fluid and electrolyte balance.
Pharmacology of Tubular Secretion:
- Enhanced drug elimination is achieved via tubular secretion rather than glomerular filtration.
- Approximately 80% of drugs entering capillaries are actively secreted into the nephron, compared to ~20% entering through the glomerulus. - Involves Organic Anion Transporters (OAT), Organic Cation Transporters (OCT), and P-glycoprotein (P-gp) transporters along PCT epithelial cells.

Influx and Efflux Pumps:
   - Example of competition: Probenecid inhibits OAT, impacting drug excretion.    - OAT: Transports anionic (acidic) drugs from peritubular capillaries into PCT.
   - Example: Penicillin.    - OCT: Transports cationic (basic) drugs similarly.
   - Example: Morphine.    - Passive Diffusion: Small, lipophilic, and uncharged drugs may diffuse across membranes.    - P-gp: Pumps drugs from epithelial cells into the PCT, promoting renal drug excretion.

Physiology:
- Not all water is excreted; tubular reabsorption conserves water.
- Only ~1% of glomerular filtrate is excreted as urine.
Pharmacology:
- Small, non-ionized, lipophilic drugs can be reabsorbed back into the bloodstream from distal convoluted tubule (DCT) and peritubular capillaries.
- Reabsorbed drugs follow renal blood flow, returning to systemic circulation and prolonging effects. - Drugs that are secreted but not reabsorbed are considered renally excreted.

Definition: Ability of the kidney to irreversibly remove drugs from systemic circulation through three processes: glomerular filtration, tubular secretion, and excretion.
Calculations:
   - Total clearance:
      $CL_{Total} = CL_H + CL_R + CL_{lungs} + CL_{GIT}$    - Renal clearance:
      $CLR ext{ (mL/min)} = (1 - FR) imes [CL_F + CL_S]$
   Where:      - $1 - FR$ : Fraction of drug not reabsorbed
     - $CL_F$ : Amount of drug filtered through glomerular capillaries
     - $CL_S$ : Amount of drug secreted from peritubular capillaries into PCT

Drug Factors:
   - Ionization status of drugs
   - Plasma protein binding
   - Competition for tubular secretion
   - More details on drug-drug interactions (DDI) to be discussed.
Physiological Factors:
- Urine flow rate
Disease Factors:
- Remaining number of functional nephrons affects excretion ability.
- Relevant medical conditions include acute kidney injury and chronic kidney disease.

pH-Partition Hypothesis:
- Drugs cross membranes in an un-ionized form, influencing their passive transport.
Weak Acid and Base Dynamics:
- As drug pH and pKa are connected: - Acidic Drugs: - Non-ionized (reabsorption) when pH < pKa - Ionized (secretion) when pH > pKa - Basic Drugs: - Non-ionized (reabsorption) when pH > pKa - Ionized (secretion) when pH < pKa - Applies specifically to nephron walls.

Omeprazole:
- At urine pH 5: pH < pKa (9.6), thus likely ionized (secretion) leading to reduced reabsorption.
Ibuprofen:
- Uran pH 5: pH < pKa, therefore ionized, promoting secretion.
Atenolol:
- At pH 5: pH < pKa (9.6), also likely ionized, leading to secretion.

Only unbound drugs can be filtered through glomerular filtration. - Bound drugs are too large to pass through the glomerulus or secrete into PCT.
- Leads to decreased clearance and affects half-life of drugs eliminated primarily via kidneys.

Increased urine flow rate shortens drug contact time in tubules.
- Reduces reabsorption time and increases excretion.
Total number of functional nephrons directly impacts renal processing abilities.

CrCl serves as an estimate of the glomerular filtration rate (GFR); uses creatinine as a standard measure.
- Derived from blood specimens measuring serum creatinine (SCr) levels.
Creatinine characteristics:
- Freely filtered through the glomerulus and not significantly secreted or reabsorbed.

To ascertain renal function using creatinine clearance: - $CrCl ext{ (mL/min)} = rac{(140 - ext{age in years}) imes ext{weight (kg)}}{72 imes SCr ext{ (µmol/L)}}$
- Adjust for females: multiply by 0.85. - Note: The equation is not appropriate for elderly, children, acute kidney injuries, or obese individuals due to physiological variations.