04: Absorption and Distribution

How do we define when a drug has reached the system and can produce systemic effects

When it reaches the aorta

Route of administration that is generally fastest

IV

Other routes that have a fairly fast time to systemic exposure

Intraosseous and inhaled

Once a drug makes it to the plasma after administration, where can it go

• Tissues (free or protein bound)

• Site of action

• Biotransformation and metabolism

• Excretion

Chemical characteristics that allow a drug to passively diffuse through the plasma membrane

Lipid soluble molecules

Chemical characteristics that require a drug to use a protein channel

Polar or water soluble molecules

Types of carrier mediated mechanisms utilized by polar drugs

• Facilitated transport

• Endocytosis

• Active transport

Type of carrier mediated transport that utilizes ATP

Active transport

Pump that is responsible for excluding molecules from the brain

P-glycoprotein pumps

Pumps involved in secreting drugs into the renal tubules

• P-glycoprotein pumps

• OATs: organic anion transporters

• OCTs: organic cation transporters

Where else do P-glycoprotein pumps act in the body

Secretion and absorption in the GIT lumen

Cellular barrier that keeps polar molecules out and ensures epithelial integrity

Tight junctions

Epithelium that typically has looser tight junctions

Certain type of capillary endothelial cells

Flux

Speed of absorption

Factors affecting flux

• Diffusion coefficient

• Lipid proportion

• Surface area of absorption

• Thickness (distance of diffusion)

Drug characteristic that modulated diffusion coefficient

Size of the molecule

Drug characteristics that promote high flux

Small lipophilic molecules

Location/tissue characteristics that increase flux

Thin tissue with large surface are (GIT, resp epithelium, etc.)

What step preceding absorption is affected by drug formulation

Dissolution time

Drug formulations that take longer to dissolve

• Tablet

• Gelatin capsule

• Powder or granule

• Suspension

How do we have compartments with high concentrations of a drug if the drug is systemic

Acid/base chemistry will alter the ionization state of the drug, trapping it in certain environments

Drug form that gets trapped in compartments

Ionized drugs (have a charge!)

Type of chemical that flips easily between ionized and unionized forms in the body

Weak acids and bases

What determines if a drug is ioniozed or unionized

Drug pKa and compartment pH

Where is a weak acid trapped

In more basic environments it exists as A^-, and it is trapped

Where is a weak base trapped

In more acidic environments it exists as BH⁺, and it is trapped

Purpose of an enteric coating

Prevents dissolution in the stomach so the drug makes it to the intestine

If aspirin, a weak acid, is taken with an enteric coating and dissolves in the basic duodenal lumen, how does it get absorbed

The dissolved aspirin will exist largely as A^- in the slightly basic duodenal lumen, The high surface area and continual blood flow means that the small proportion of aspirin existing as HA gets absorbed, and chemical equilibrium will continue to replenish that small amount of HA in the duodenal lumen. Eventually, all of the aspirin will be absorbed into the blood, where it is then again trapped as A^-.

Drug and tissue characteristics that determine distribution of a drug throughout the body

• Lipid solubility of the drug

• Perfusion of the tissue

• Tissue capacity for increased volume

• Drug binding to plasma proteins

Major plasma protein that binds up lipophilic drugs

Albumin (what else would it be)

Types of drugs that can cross the blood brain barrier

Lipophilic

Structure in the brain that keeps polar drugs out

Tight junctions

If lipophilic drugs can diffuse across the BBB, why is it so difficult to get high drug concentrations in the brain

P-glycoprotein pumps kick drugs back out

How does inflammatory disease impact drug distribution to the brain

Inflammatory conditions like meningitis may break the permeability barrier, allowing more drugs through

Areas of the brain that are outside the BBB

Circumventricular organs- they are leaky on purpose, so they need to be outside the barrier!