Drug Absorption and Distribution

Question 1

Absorption

Answer 1

Absorption is the Primary *Determinant of *Bioavailability
and
*Onset of Drug Action.

Absorption = the Movement of the drug from its Site of Administration into the Bloodstream.

Depends on the drug’s dissolution, dosage form, the route of administration, stability of drug in the tissues, and the extent of metabolism prior to entry into the plasma compartment.

Question 2

Passive Diffusion and Determinants of Diffusion Rate

Answer 2

Primary mechanism for drug absorption.

Diffusion Rate = DAK (Chigh - Clow)/ Thickness

(D) Diffusion constant: inversely proportional to Molecular Weight of Drug.
= Smaller Drug, Faster Rate

(A) Area of Absorbing Membrane:
Larger Surface Area of Membrane, Faster Rate

(K) Lipid Partition Constant:
Greater Lipid Solubility of the Drug (Less Ionized), Faster Rate

Greater Concentration Gradient, Faster Rate

Thinner Membrane, Faster Rate.

Question 3

Henderson-Hasselbalch Equation

Answer 3

pH = pKa + log [unprotonated; A-; B] / [protonated; HA; BH+]

Question 4

Weak Base

Answer 4

Unprotonated = Nonionized Form
(B) (Free Base) (NH3)

Protonated = Ioniozed (salt) Form
(BH+) (NH4+)

Question 5

Weak Acid

Answer 5

Unprotonated = Ionized (salt) Form
(A-) (F-)

Protonated = Nonionized Form
(HA) (Free Acid) (HF)

Question 6

Routes of Drug Administration:

Enteral: Oral

Answer 6

Enteral = via GI tract

1) Oral: 
Stomach:  
Acidic, may degrade or precipitate drugs.
May Reduce Absorption by
--Complexes (*Adsorption, *Chelation)
--Ionization of Drugs
--Degradation by enzymes

Intestine: Major site of drug absorption with oral drugs.

• Less Acidic
• Large Surface area
• First-Pass Metabolism (Liver)
• Efflux of drugs by carrier proteins (e.g. p-glycoprotein)

Question 7

Routes of Drug Administration:

Enteral: Sublingual

Answer 7

Enteral = via GI tract

*Sublingual (under the tongue) and Buccal

Rapid and Complete Absorption (relative to swallowing)
–> Rapid effect

*Bypasses Portal Circulation First Pass metabolism.

Question 8

Routes of Drug Administration:

Enteral: Rectal

Answer 8

Enteral = via GI tract

Avoids most of First-pass metabolism.

Useful in Unconscious or Nauseated patient.

Irregular and incomplete absorption.

Question 9

Routes of Drug Administration:

Parenteral: Intravenous (IV)

Answer 9

Parenteral = Injection

Intravenous: *Fastest Onset of Action

• Flexible Rate of administration
• No recall of drug
• High potential for severe allergic reactions (anaphylaxis) and infection

Advantages of Parenteral:

• Compliance
• Faster Action
• High Bioavailability
• Avoids First-Pass Metabolism

Question 10

Routes of Drug Administration:

Parenteral: Intramuscular (IM)

Answer 10

Parenteral = Injection

Intramuscular: intragluteal (gluteus maximus), vastus lateralus, deltoid.

*Rapid Absorption and *Rapid Onset of Action.

Muscle has more blood flow than fatty tissue, so faster absorption in IM than subcutaneous.

• -*Slower Absorption from Gluteus Maximum in women because women have more fat in that region.
• -In contrast, drug uptake from all muscle sites is similar in men.

Advantages of Parenteral:

• Compliance
• Faster Action
• High Bioavailability
• Avoids First-Pass Metabolism

Question 11

Routes of Drug Administration:

Parenteral: Subcutaneous

Answer 11

Parenteral = Injection

Similar to IM, but Slower than IM.

Good route for Sustained-release drugs

Advantages of Parenteral:

• Compliance
• Faster Action
• High Bioavailability
• Avoids First-Pass Metabolism

Question 12

Routes of Drug Administration:

Parenteral: Intrathecal

Answer 12

Parenteral = Injection

Intrathecal = into Spinal column.

Good for CNS infections and Spinal blocks (childbirth), Local effects for pain and spasticity.

Good if drug can’t cross BBB.

Advantages of Parenteral:

• Compliance
• Faster Action
• High Bioavailability
• Avoids First-Pass Metabolism

Question 13

Routes of Drug Administration:

Topical

Answer 13

Topical = applied to the Skin

Primarily for Local effect.

But also some Systemic:

• -Limited to Lipid soluble, Potent compounds.
• -For Slow, Systemic Absorption; Delayed Effect, but Released from skin over Long Period of Time.

Question 14

Routes of Drug Administration:

Intranasal

Answer 14

Nasal mucosa is similar to Sublingual and Buccal mucosa.

Rapid Absorption

Avoids First-pass.

Question 15

Routes of Drug Administration:

Pulmonary

Answer 15

Alveolar epithelium is very thin (passive diffusion) and has

• Large Surface Area,
• High Blood Flow,
• Very Rapid Absorption

Question 16

Bioavailability

Answer 16

= Fraction of drug that reaches the Systemic Circulation

Question 17

Distribution

Answer 17

= the Passage of Drug from the Bloodstream to the Various Biological compartments.

(The reverse of drug absorption, so it is affected by the same factors.)

Question 18

Apparent Volume of Distribution (Vd)

Answer 18

= the **APPARENT Volume of Body Water into which the Drug Appears to Distribute.

Vd = Dose of Drug / Plasma Concentration of Drug

Interpretation of Vd:

• -If Vd Equals a Body Compartment, suggests Distribution to that Compartment.
• -If Vd is Greater than Total Body Water, suggests Localization in Tissue Site(s).

Question 19

Body Fluid Compartments

Answer 19

For a 70 Kg (154 lb) person:

Total Body Water (60% of body weight) = 42 L

Extracellular fluid (20% of bw) = 14 L

–Plasma (4% of bw) = 2.8 L (~3L)

–Interstitial fluid (16% of bw) = 11.2 L (~11L)

Intracellular fluid (40% of bw) = 28 L

Question 20

Factors that Influence Drug Distribution:

Blood Flow (Perfusion) of Tissue

Answer 20

1) Blood Flow (Perfusion) of Tissue:

–*Rapidly Perfused Tissues receive drug Quickly (Brain, Liver, Kidney)

–*Poorly Perfused Tissues receive drug Very Slowly (Fat)

Question 21

Factors that Influence Drug Distribution:

Plasma Protein Binding of Drugs

Answer 21

2) Plasma Protein Binding of Drugs:

–Reduces Rate of Distribution

–Reversible (Equilibrium)

–*Saturation of and *Competition for Protein Binding Sites at High Drug Levels (> 90% protein bound) potentially causes drug interactions (e.g. Warfarin vs. Aspirin)

–*Protein bound drug becomes Inactive Reservoir (unless the plasma is its desired site of action, e.g. warfarin)

Note:

–*The % of Total Drug Bound in the Body is NOT the SAME as the % of Drug Bound to Plasma Protein
(unless the drug distributes/remains only in the plasma).

–*The % of Total Drug Bound Decreases as Volume of Distribution (Vd) Increases
because “free” drug distributes evenly throughout Vd. (Equilibrium)

Question 22

Compartments with Unique Distribution Characteristics:

Central Nervous System (CNS)

Answer 22

High Blood Flow (Perfusion)

• Low Drug Permeability, unless drug has *High Lipid Solubility
• -due to Blood Brain Barrier (BBB).
• -capillary endothelial tight junctions, glial cells

Blood - CSF Barrier: Active transport of certain compounds

Drugs that are ionized/have low lipid solubility definitely can’t cross BBB well.

Question 23

Compartments with Unique Distribution Characteristics:

Placental Transfer

Answer 23

*Occurs Rapidly between Mother and Fetus.

Most drugs readily distribute by Passive Diffusion; dependent on Lipid Solubility and Ionization.

• Risks to Fetus:
• -Death/Abortion
• -Malformation
• -Behavioral and Developmental effects
• -Cancer later in life
• -Dependence/Withdrawal

Question 24

Drug Reservoirs

Answer 24

Stomach (or other sites or fluids) Ionizes drugs and “Traps” them:
==> pH effect of *Ion Trapping.

*Albumin binds various drugs and limits distribution.

Tissues (e.g. Liver) can avidly bind drugs.

Lipid Soluble compounds can localize in *Fat Tissue.