WHERE DO DRUGS GO?

WHY BE CONCERNED ABOUT WHERE DRUGS GO?

Where drugs go determines Where Drugs Act:

• Ciprofloxacin [Cipro®] penetrates the prostate gland andtherefore is effective in bacterial prostatitis, whereas

most antibiotics do not enter the prostate andare therefore ineffective in prostatitis.

• Fexofenadine [Allegra®] is largely excluded from the brainand therefore is a “nonsedating” antihistamine, whereas

most antihistamines freely enter the brain andcause 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 andis therefore rapidly excreted by the kidneys.

• Inhalation anesthetics distribute to alveolar spaces andtherefore 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 OFWHERE DRUGS GO?

• Organ blood flow

• Barriers to drug diffusion

• Adipose tissue

• Tissue protein binding

Determinants of Drug Distribution:

• Plasma protein binding

• Drug transport

• Ion trapping

WHAT IS THE EFFECT OF ORGAN BLOODFLOW ON DRUG DISTRIBUTION?

• Organs with high blood flow will have larger amountsof 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 redistributedthroughout the body to sites

with lower blood flow.

WHAT IS THE EFFECT OF ORGAN BLOODFLOW 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 followingIV administration.

• 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?

• Capillaries in brain have tight junctions that contribute to the BBB.

• Capillaries in brain are wrapped by pericapillary glial cells thatfurther contribute to the BBB.

• The endothelial cells in brain capillaries have P-glycoprotein thatpumps drugs out of endothelial cells, and this

also contributes to the BBB.

The “blood-brain barrier (BBB)” is a special case:

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION ON

DRUG DISTRIBUTION?

• 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.

The “blood-brain barrier (BBB)” is a special case:

WHAT IS THE EFFECT OF BARRIERS TO DRUG DIFFUSION 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 ADIPOSE TISSUE 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 TISSUE PROTEINBINDING 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 PROTEINBINDING 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 increasesthe time required for the drug to

be removed from the body.

WHAT IS THE EFFECT OF PLASMA PROTEINBINDING ON DRUG DISTRIBUTION?

•Displacement of a highly plasma-protein bound drug by another drugmay 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 PLASMA PROTEINBINDING 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 DRUG TRANSPORT ON DRUG DISTRIBUTION?

BIO

LO

GIC

AL

BA

RR

IER

Compartmentwith High pH

Compartmentwith Low pH

UnionizedWeak Acid

IonizedWeak Acid

UnionizedWeak Acid

IonizedWeak Acid

Higher total concentrationof weak acid

WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION?

B

IOL

OG

ICA

L B

AR

RIE

R

Compartmentwith High pH

Compartmentwith Low pH

UnionizedWeak Base

IonizedWeak Base

UnionizedWeak Base

IonizedWeak Base

Higher total concentrationof weak base

WHAT IS THE EFFECT OF ION 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.

WHAT IS THE EFFECT OF I0N TRAPPING ON DRUG DISTRIBUTION?

WHERE DO DRUGS GO?

Now you know!!