Pharm 3: ADME/Pharmacokinetics Part 1: Absorption

Process of pharmacokinetics (how body affects drug)

What is ADME?

Absorption, distribution, metabolism (biotransformation), elimination (clearance)

What does ADME stand for?

1. All drugs are poisons

2. No drug is a silver bullet

3. All doses are guesses (i.e., an estimate); treat each patient as an individual

4. Complacency kills

Four rules to live by for safe drug usage

Pharmacokinetics

Quantitative study of the time course of drug absorption, distribution, metabolism, and elimination (ADME)

Dose to achieve the desired therapeutic blood concentrations

Frequency with which the drug must be administered to maintain therapeutic blood concentrations

Time required to achieve steady-state concentrations of the drug

Time required to eliminate the drug from the body

What can you determine using knowledge of the quantitative relationships in ADME?

Obtain a drug concentration in the therapeutic range for your patient

Goal of pharmacokinetics

Absorption

Movement of a drug from its site of administration into the bloodstream

Distribution

Movement of a drug from bloodstream into the other body fluids and tissues

Metabolism

Chemical transformation of a drug within the tissues, generally to enhance elimination of that drug and its metabolites (liver)

Elimination

Excretion of a drug out of body by various pathways (Kidney is the major excretory organ)

Lipid-soluble, water-soluble, amphipathic, weak

Drugs must be sufficiently ___ to move across lipid membranes.

Drugs also must be sufficiently ___ in the plasma.

Therefore, most drugs are ___ (have both hydrophilic and hydrophobic parts).

This is why most drugs are ___ acids and bases.

Filtration, passive diffusion, facilitated diffusion, active transport, endocytosis (pinocytosis, phagocytosis)

Five ways to cross a biological membrane

Filtration

1. Small, water-soluble molecules pass through pores and channels

2. Down a pressure gradient (e.g., generated by heart)

100

Most membranes don’t let molecules get filtered with MW > ___ Daltons

Small, uncharged, hydrophilic

What are the characteristics of molecules that enter through membrane pores and are filtered?

Ethanol, urea

Two examples of molecules that are filtered

Ionized

Most ___ compounds cannot enter by filtration.

Passive diffusion

1. The major entry route for drugs in the body

2. No specificity or transport proteins involved = direct passage through lipid bilayer

3. Requires a concentration gradient [C_outside ] > [C_inside]

4. Mainly lipid-soluble drugs (but not too lipid soluble!)

5. No energy requirements

6. No competition for absorption

7. Not saturable

Lipid-soluble, non-ionized

What are the characteristics of molecules that are transported through passive diffusion?

Non-ionized

Only the ___ form of a drug can diffuse across the cell membrane.

pH partition theory

The two physical properties (both are drug-specific) that determine passage are:

1. Ionization state at the pH under study (PKa of the drug)

2. The lipid-water partition coefficient of the compound

Ficke’s Law

Describes diffusion through a medium such as a membrane

KA (C₂ - C₁) / d

What is Ficke’s Law?

Strong acids and bases

Tend to ionize completely in solution

Weak acids and bases

Only partially ionize when they are in solution (which makes them the perfect drugs)

Ionized, non-ionized

Most pharmaceutical drugs are weak acids or weak bases and exist in solution in an equilibrium between the ___ (polar, water-soluble) and ___ (nonpolar, lipid-soluble) states, that equilibrium being specific for each drug

Non-ionized

According to the pH partition hypothesis, only drugs in the ___ form can cross lipid membranes

pH of the medium, dissociation constant of the drug

What does the ratio of ionized to non-ionized drug molecules depend on?

pKa

The pH at which 50% of the drug is in the non-ionized form and 50% is in the ionized form

Henderson-Hasselbalch equation

What is the ratio of ionized to non-ionized drug molecules described by?

Opposite

Rule of thumb:

A compound is ionized in the ___ pH.

Unionized, ionized

In the stomach, weak acids are ___, while weak bases are ___.

[Hint: Acidic environment]

Ionized, unionized

In the intestines, weak acids are ___, while weak bases are ___.

[Hint: Basic environment]

Alkalize, acidify

To get rid of acidic drug in urine —> ___

To get rid of basic drug in urine —> ___

Alkalizer

Is sodium bicarbonate an acidifier or an alkalizer?

Acidifier

Is ammonium chloride an acidifier or an alkalizer?

5.5 to 7.0

What is the pH range of carnivores?

7.0 to 8.0

What is the pH range of herbivores?

Lower

The pH of carnivores is typically [lower or higher] than herbivores.

Carrier-mediated transport

1. Two kinds: Facilitated diffusion and active transport

   1. Transport proteins are involved

   2. Saturable

   3. Selective

   4. Competitive inhibition among structurally-related compounds

Facilitated diffusion

Type of carrier-mediated transport

1. No energy required

2. Requires concentration gradient (e.g., [C_outside ] > [C_inside])

Active transport

Type of carrier-mediated transport

1. Metabolic energy required

2. Operates against concentration gradient (e.g., [C_outside ] < [C_inside])

3. Primary: Na-KATPase, MDR (p-glycoprotein), HATPase

4. Secondary: Na-glucose co-transportation

Specific, saturated, inhibition, energy

1. Facilitated diffusion requires a ___ membrane protein carrier system.

2. Since it involves a carrier protein, it can be ___

3. Carriers are subject to reversible (usually competitive) and irreversible ___

4. This system is passive and doesn’t require ___

Specific, energy, concentration

Active transport requires a ___ membrane protein carrier system.

Active transport requires metabolic ___ and can work against a ___.

Inhibited, saturated

Active transport can be [stimulated/inhibited] by metabolic poisons (e.g., inhibitors of energy generation).

Active transport can be ___ at high substrate concentrations.

Endocytosis

1. Not well understood

2. Compound (particle or microbe) slowly engulfed by cell surface and taken up

3. LDLs (and cholesterol) absorbed this way in liver

4. This is also specific = has membrane receptor

5. Need energy

6. When another mechanism can’t be found or is unlikely, it is often assumed that this process is occurring

1. Lipid solubility

2. Particle size (micronized or microcrystalline forms

3. Ionized/Unionized (pH at the absorption site)

4. Route of administration

5. Stability of drug at site

6. Blood flow to site of administration

7. Concentration gradient (Frick’s)

8. Surface area at site and thickness of barrier (Frick’s)

9. Species differences (e.g., sulfonamide Tmax 12-18 hours in cattle vs. 2-4 hours in dogs)

General factors that influence drug absorption

Enteral, parenteral, topical, inhalation

Routes of drug administration

Oral (primary)

Rectal (in vomiting and sub-/unconscious animals)

Buccal and sublingual

Enteral routes of drug administration

Stomach, small intestine

Two organs of oral drug absorption

Stomach

Which organ of oral drug absorption?:

(Poor absorption)

1. Small surface area

2. Thick mucus-covered membrane

3. Low pH

Small intestine

Which organ of oral drug absorption?:

(Excellent absorption)

1. Large surface area

2. Thin epithelial membrane

3. Neutral pH

Intestine

Major uptake organ with tremendous epithelial surface area

Stability of the compound (pH in stomach and bacterial enzymes)

Blood flow to the intestine

Rate of gastric emptying and gastric and intestinal motility

First pass effect

What factors are the rate and extent of oral absorption dependent on?

First pass effect

The loss of drug as it passes for the first time through the absorption process, the GI tract, and then through the portal vein to the liver for metabolism

1. Drug loss due to:

   1. Lack of absorption from GI tract– excreted in feces

   2. Metabolism of parent drug to metabolites by the liver

Bioavailability (F; %)

The fraction of the dosed parent drug that reaches the systemic circulation unchanged

100%

What is the bioavailability of IV drugs?

Less than 100%

What is the bioavailability of oral drugs?

Intravenous, intramuscular, subcutaneous, intradermal

Common parenteral administration routes

Intravenous (IV or i.v.)

Which parenteral route?:

(Circumvents absorption)

1. Bolus (quickly) vs. infusion (slow)

2. Most dangerous route

Intramuscular (IM or i.m.)

Which parenteral route?:

1. Large volumes, irritation

2. Drug injected into muscle mass

Subcutaneous (SC, SQ, or s.c.)

Which parenteral route?:

Drug injected deep under the skin into the subcutis

Intradermal (ID)

Which parenteral route?:

Drug injected within (not beneath) the skin with very small needles (e.g., TB test)

Surface area of tissue capillaries, blood flow, drug’s solubility in intestinal fluids

What is the absorption rate from IM and SC sites determined by?

Parenteral

Situated or occurring outside the intestines

Lipid solubility of the drug

What is the degree of absorption in topical drugs dependent on?

Oral

What is the only route of administration that is greatly impacted by the first pass effect?