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WHERE DO DRUGS GO?

WHERE DO DRUGS GO?. WHY BE CONCERNED ABOUT WHERE DRUGS GO?. Where drugs go determines Where Drugs Act :. Ciprofloxacin [Cipro ® ] penetrates the prostate gland and therefore is effective in bacterial prostatitis, whereas most antibiotics do not enter the prostate and

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WHERE DO DRUGS GO?

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  1. WHERE DO DRUGS GO?

  2. WHY BE CONCERNED ABOUT WHERE DRUGS GO? Where drugs go determines Where Drugs Act: • Ciprofloxacin [Cipro®] penetrates the prostate gland and • therefore is effective in bacterial prostatitis, whereas • most antibiotics do not enter the prostate and • are therefore ineffective in prostatitis. • Fexofenadine [Allegra®] is largely excluded from the brain • and therefore is a “nonsedating” antihistamine, whereas • most antihistamines freely enter the brain and • cause marked drowsiness.

  3. WHY BE CONCERNED ABOUT WHERE DRUGS GO? Where drugs go influences Where Drugs Are Eliminated: • Penicillin is actively transported into the proximal tubules and • is therefore rapidly excreted by the kidneys. • Inhalation anesthetics distribute to alveolar spaces and • therefore are eliminated by the lungs.

  4. WHY BE CONCERNED ABOUT WHERE DRUGS GO? Where drugs go influences How Long Drugs Last In the Body : • Raloxifene [Evista®]) (for treatment of osteoporosis in • postmenopausal women) is transported by the liver into the • intestines where it is reabsorbed (enterohepatic recirculation). • This greatly increases the time raloxifene lasts in the body.

  5. WHAT ARE THE DETERMINANTS OF WHERE DRUGS GO? Determinants of Drug Distribution: • Organ blood flow • Barriers to drug diffusion • Adipose tissue • Tissue protein binding • Plasma protein binding • Drug transport • Ion trapping

  6. WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION? • Organs with high blood flow will have larger amounts • of drug delivered to them per unit time. • Organs with high blood flow will experience initial high • concentrations of drug, but these high concentrations • will diminish as the drug is redistributed • throughout the body to sites • with lower blood flow.

  7. WHAT IS THE EFFECT OF ORGAN BLOOD FLOW ON DRUG DISTRIBUTION? • Organs with high blood flow will experience larger initial effects. • Many sedative/hypnotics, such as benzodiazepines (e.g., diazepam • [Valium®]) will produce initial, but short-lived, • profound CNS effects following • IV administration.

  8. WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? • Most capillaries have pores between the endothelial • cells lining the capillaries. • These pores allow for rapid diffusion of most drugs • into the interstitial space. • In some capillary beds, however, the endothelial cells • are closely connected by “tight junctions”, and • such capillaries do not have pores • between the endothelial cells.

  9. WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? • In capillaries with tight junctions, drug molecules must diffuse across • (transcellular), rather than around (paracellular) • the endothelial cells. • Only lipophilic drugs rapidly diffuse across capillary beds • with tight junctions, whereas hydrophilic • drugs are mostly excluded.

  10. WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? The “blood-brain barrier (BBB)” is a special case: • Capillaries in brain have tight junctions that contribute to the BBB. • Capillaries in brain are wrapped by pericapillary glial cells that • further contribute to the BBB. • The endothelial cells in brain capillaries have P-glycoprotein that • pumps drugs out of endothelial cells, and this • also contributes to the BBB.

  11. WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON DRUG DISTRIBUTION? The “blood-brain barrier (BBB)” is a special case: • In general, the BBB restricts the movement of hydrophilic • drugs into brain; however, the BBB is “broken” • by ischemia and inflammation. • The BBB can be exploited to develop drugs with • reduced CNS adverse effects.

  12. WHAT IS THE EFFECT OF ADIPOSE TISSUE ON DRUG DISTRIBUTION? • Lipophilic drugs will distribute into adipose (fat) tissue. • Distribution of lipophilic drugs into fat may necessitate a larger initial • bolus of drug to achieve the desired effect. • Large depots of drug in fat may necessitate a longer period of • time for drug to be removed from the body. • The distribution of lipophilic drugs will be different • in thin versus obese patients.

  13. WHAT IS THE EFFECT OF TISSUE PROTEIN BINDING ON DRUG DISTRIBUTION? • Some drugs are highly bound to tissue proteins. • Binding of drugs by tissue may necessitate a larger initial • bolus of drug to achieve the desired effect. • Large depots of drug in tissue may necessitate a longer period • of time for drug to be removed from the body.

  14. WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION? • Some drugs are highly bound (> 90%) to plasma proteins. • Acid drugs bind to albumin and basic drugs bind to • alpha1-acid glycoprotein. • Binding of drugs by plasma proteins limits the distribution of drugs • out of the vascular compartment, necessitating more drug • initially to achieve the desired effect.

  15. WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION? • Binding of drugs may limit the delivery of drugs to drug elimination • mechanisms (for example excretion by the kidney • or metabolism by the liver), and this increases • the time required for the drug to • be removed from the body.

  16. WHAT IS THE EFFECT OF PLASMA PROTEIN BINDING ON DRUG DISTRIBUTION? • Displacement of a highly plasma-protein bound drug by another drug • may lead to drug-drug interactions because of a rapid increase • in the availability of “free” (unbound) drug. • Displacement of unconjugated bilirubin from albumin by • drugs may precipitate bilirubin • encephalopathy in newborns.

  17. WHAT IS THE EFFECT OF DRUG TRANSPORT ON DRUG DISTRIBUTION? • Transport mechanisms may increase or decrease the distribution of • drugs to certain tissues. For example, most diuretics are • transported by the proximal tubules into the nephron, • a process that delivers the diuretics • to their site of action. • Competition for transport may result in drug-drug interactions. For • example, probenecid ( a drug used for gout) blocks the transport • of diuretics into the proximal tubule and thereby markedly • blunts the effects of diuretics on salt and water excretion.

  18. WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION? Compartment with Low pH Compartment with High pH Unionized Weak Acid Unionized Weak Acid BIOLOGICAL BARRIER Higher total concentration of weak acid Ionized Weak Acid Ionized Weak Acid

  19. WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION? Compartment with Low pH Compartment with High pH Unionized Weak Base Unionized Weak Base BIOLOGICAL BARRIER Higher total concentration of weak base Ionized Weak Base Ionized Weak Base

  20. WHAT IS THE EFFECT OF I0N TRAPPING ON DRUG DISTRIBUTION? • Ion trapping can be used to distribute drugs into the urinary • compartment to increase the urinary excretion of poisons. • Example: Alkalinization of the urine with systemic administration • of sodium bicarbonate is useful for the treatment of overdoses • of aspirin and phenobarbital. • Example: Acidification of the urine with systemic administration of • ammonium chloride is useful for the treatment of • amphetamine overdoses.

  21. WHERE DO DRUGS GO? Now you know!!

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