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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
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.
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.
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.
WHAT ARE THE DETERMINANTS OF
WHERE DRUGS GO?
Determinants of Drug Distribution:
• Organ blood flow
• Plasma protein binding
• Barriers to drug diffusion
• Drug transport
• Adipose tissue
• Ion trapping
• Tissue protein binding
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
WHAT IS THE EFFECT OF ION TRAPPING
ON DRUG DISTRIBUTION?
Compartment
with Low pH
Unionized
Weak Acid
Ionized
Weak Acid
Compartment
with High pH
Unionized
Weak Acid
Ionized
Weak Acid
Higher total
concentration
of weak acid
WHAT IS THE EFFECT OF ION TRAPPING
ON DRUG DISTRIBUTION?
Compartment
with Low pH
Unionized
Weak Base
Higher total
concentration
of weak base
Ionized
Weak Base
Compartment
with High pH
Unionized
Weak Base
Ionized
Weak Base
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.
WHERE DO DRUGS GO?
Now you know!!