(7B) Drug-drug interactions: Pharmacokinetics (Absorption & Distribution)

Volume of Distribution

extent of tissue distribution

• Low Vd →

• High Vd →

• Low Vd → drug stays mostly in plasma.

• High Vd → drug distributes extensively into tissues.

Distribution is affected by:

• lipophilicity

• protein binding

• tissue binding

• blood flow

• transporters.

Aging →

↓ lean body mass + ↑ body fat

Aging

Lipophilic drug →

↑ Vd → prolonged effects / possible accumulation

Aging

lipophilic drug example

• Amiodarone

  • high Vd

Obesity →

↑ adipose tissue

Obesity

For lipophilic drugs:

↑ adipose tissue → ↑ Vd → drug stored in fat → prolonged half-life

Obesity

In obesity, why might a higher loading dose sometimes be needed?

To reach the desired plasma concentration quickly because the lipophilic drug may have a larger Vd.

Obesity

For hydrophilic drugs: Vd and total body weight connection?

Vd does NOT increase proportionally with total body weight.

Obesity

General anesthetic in obesity:

Know the mechanism:

• Lipophilic anesthetic → brain + fat

  • Fat acts as a drug reservoir.

• Later: fat → blood → brain again

  • → longer effect / possible rebound anesthesia.

Blood-Brain Barrier

Drugs cross the BBB more easily when they are:

• small

• lipophilic

• uncharged/non-ionized

Blood-Brain Barrier

P-glycoprotein

P-gp = efflux pump.

It pumps drug out of the CNS.

Blood-Brain Barrier

P-gp inhibition →

drug pumped out less → CNS drug levels ↑ → possible CNS toxicity/sedation ↑

Placenta

• Most drugs can cross the placenta to some extent.

• Lipophilic drugs cross more readily.

• Professor also emphasized small drugs.

Placenta

Concern:

• fetal toxicity

• teratogenicity.

Third Spacing

abnormal/pathologic accumulation of fluid.

Third Spacing

Examples

• ascites - extra water-containing space

• pleural effusion

• edema.

Third Spacing

hydrophilic drug →

more space to distribute → Vd ↑