Lecture 10 Flashcards

Drug Excretion/Elimination

1
Q

Excretion

A
  • Removes a chemical from the body and prevents drug accumulation
  • Liver and kidneys are the primary sites of excretion
  • Metabolism, aka biotransformation, is important component of excretion since metabolites are usually charged, hydrophilic, and conjugated (larger)
  • Metabolic changes alter the physicochemical properties of the drug and can make it more or less likely to be excreted
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2
Q

Renal v.s. Biliary Secretion

A
  • The one that occurs is a consequence of drug properties (ionization, adducts, etc.)
  • Renal - excretion into urine, polar, glomerular filtration, active secretion, passive reabsorption/excretion
  • Hepato/Biliary - excretion into bile (stable adducts), diffusion AND active transport
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3
Q

Renal Drug Clearence

A
  • Many can be excreted unchanged
  • Clearance is proportional to renal function
  • Metabolites MAY be excreted into urine
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4
Q

Key Renal Excretion Mechanisms (3)

A
  1. Glomerular Filtration - Bulk flow (remove)
  2. Tubular Secretion - active transport (remove)
  3. Tubular Reabsoprtion - passive reabsorption and active reabsoprtion
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5
Q

Glomerular Filtration

A
  • Non-selective, size limited
  • Most “free” drugs are small enough to be filtered, MW cut off ~1000-2000
  • Specialized pores/fenestrations and the size, shape, and charge affect the filtration
  • Pressure gradient regulates filtration, very sensitive to blood pressure
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6
Q

Tubule Secretion

A
  • Diffusion AND active transport
  • Passive diffusion utilized for small, uncharged molecules
  • Active transport for large, ionized molecules allow for greater urine concentrations
  • Depends on specific transport systems for acids or bases: transporters can be saturated, inhibited, require energy, or a specific carrier for a certain drug
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7
Q

Tubule Reabsorption

A
  • Mediated by passive diffusion
  • The concentration gradient usually favor reabsorption
  • Ionization of solutes, solute size, and solute liquid solubility may modulate passive reabsorption
  • Passive reabsorption favors small, neutral, lipophilic molecules
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8
Q

Renal Summary

A
  • Renal elimination is a balance of transport between kidney tubules and plasma
  • Multiple transport mechanisms (active and passive)
  • Drug characteristics are important for renal elimination
  • Slow decline in renal function (~1% per year) throughout adulthood occurs
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9
Q

Hepato-Biliary Excretion

A
  • Many drugs eliminated after hepatic metabolism
  • Excretion is into bile which enters the feces
  • Liver is optimized for drug metabolism and excretion
  • About 5% of administered drug dose will enter bile passively and active secretion can increase this up to 95%
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10
Q

General Pathway of Drug to Plasma to Bile

A
  • Enters hepatocytes by passive diffusion or active transport from the plasma
  • Drugs then transported to biliary epithelium by active secretory process
  • Enterohepatic cycling then occurs where a drug is secreted into the bile and is reabsorbed from the intestine into the blood.
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11
Q

Biliary Excretion

A
  • Drugs enter hepatocytes actively or passively
  • Hepatocytes secrete bile which flow to duaodenum for eleimination
  • Conjugation from Phase II aids biliary excretion by increases the molecule’s polarity and molecular size
  • Biliary excretion favors drugs with MW > 300
  • Drug conjugates are not usually reabsorbed from the bile since they are poorly recognized by reuptake systems, too ionized, and too large
  • Most drugs are excreted via the feces
  • If reabsobed, enterohepatic cycles occur
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12
Q

Other Routes of Secretion

A
  • Milk - concerning for babies whose Phase I and II activity may not be fully developed until at least 6 years of age, sometimes later
  • Lungs
  • Intestines
  • Sweat
  • Saliva
  • Other bodily fluids
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13
Q

Drug Clearance

A
  • Clearance is the decrease of drug in the bloodstream
  • For most drugs, clearance is constant over the concentration range encountered in the clinical settings (1st order elimination)
  • Total Clearance is an additive of the eliminations from all tissues
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14
Q

Excretion Definition

A

Removal of drugs from the body

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15
Q

Clearance Definition

A

The volume of plasma cleared of the drug per unit time.

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16
Q

Glomerular Filtration Definition

A

Removal of drugs by bulk flow

17
Q

Tubular Secretion Definition

A

Active transport of drug from the blood into the urine

18
Q

Tubular Reabsorption Definition

A

Passive and active reabsorption of drug from tubules back into blood

19
Q

Enterohepatic Cycling Definition

A

Biliary excretion and intestinal reabsorption of a solute, sometimes with hepatic conjugation and intestinal deconjugation