Lecture 4

Question 1

What is First Pass Hepatic Elimination?

Answer 1

Many of the general routes of administration involve a pass through the liver, which may cause an inactivation of the drug via biotransformation known as the first-pass hepatic elimination.

Question 2

How do drugs reach their target tissue?

Answer 2

Drugs reach their target tissue usually via the blood.
Hence, independent of the mode of application, drugs have to first enter the venous branch of circulation.

Question 3

alpha phase

Answer 3

Distribution - Systemic distribution into body tissues

Question 4

beta phase

Answer 4

Elimination from body by biotransformation and excretion

Question 5

What must drugs have to overcome prior to entering the systemic circulation?

Answer 5

Prior to entering the systemic circulation, drugs have to overcome biological barriers that demarcate the body’s internal milieu from its surrounding external milieu. In addition, internal blood-tissue barriers exist in various organs.

Question 6

GI-tract barrier

Answer 6

Intestinal epithelium with brush border

Question 7

Respiratory tract barrier

Answer 7

Cillia-bearing epithelium

Question 8

Oral mucosa barrier

Answer 8

Non-keratinized squamous epithelium

Question 9

Skin barrier

Answer 9

Keratinized squamous epithelium

Question 10

Blood-brain barrier.

In order to enter cellular entities and to pass the blood-brain barrier, pharmacological substances have to be able to penetrate lipid bilayers.

Answer 10

Pore-lacking CNS endothelia

Question 11

Name and describe the cells found within the GI-tract

Answer 11

Epithelial cells - transport drug molecules from the lumen to the capillaries.
Drugs have to move from the lumen, through epithelial cells, into capillaries.

Question 12

Drugs may traverse biomembranes by..

Answer 12

• Gradient diffusion: For lipophilic (not hydrophilic) substances
• Carrier transport: Irrespective of physicochemical properties; if drug has high affinity for a specific carrier molecule
• Vesicular transport: Endocytotic uptake of extracellular fluid
• Surface receptor: Receptor-mediated endocytosis via ‘coated pits’

Question 13

Gradient diffusion through membrane for lipophilic substances.

Answer 13

• Diffusion - passive transport
• Facilitated diffusion - passive transport
• Active Transport - Primary and Secondary Active Transport

Question 14

What is diffusion? Is a transport protein needed?

Answer 14

Diffusion across a membrane is the movement of a solute down a gradient. A transport protein is not needed.

Question 15

What is facilitated diffusion? Is a transport protein needed?

Answer 15

Facilitated diffusion across a membrane is movement down a gradient with the aid of a transport protein.

Question 16

What is active Transport? Is a transport protein needed?

Answer 16

Active transport across a membrane is movement against a gradient with the aid of a transport protein.

Question 17

What is Primary Active Transport?

Answer 17

A pump actively exports H+ against a gradient

Question 18

What is Secondary Active Transport?

Answer 18

A H+ sucrose symporter can use the H+ gradient to transport sucrose against a concentration gradient into the cell.

Question 19

Membrane-associated proteins as drug targets.

Answer 19

• Integral receptor protein
• Ion Channel Protein
• Ion Pump Protein

Question 20

Integral receptor protein

Answer 20

Integral receptor proteins are a type of membrane protein that are embedded within the lipid bilayer of a cell membrane and have the ability to bind specific signaling molecules (ligands) from the extracellular environment.

Question 21

Ion channel proteins

Answer 21

When a channel is open, a solute directly diffuses through the channel to reach to the other side of the membrane.

Question 22

Ion pump protein

Answer 22

1. Na+ bind from cytosol. ATP is hydrolyzed. ADP is released and phosphate (P) is covalently attached to the pump, switching it to be the E2 conformation.
2. Na+ are released outside of the cell
3. 2 K+ bind from outside the cell
4. Phosphate Pi is released, and the pump switches to the E1 conformation, 2 K+ are released into cytosol. The process repeats.

Question 23

Transporter proteins

Answer 23

For transport to occur, a solute binds in a hydrophilic pocket exposed on one side of the membrane. The transporter then undergoes a conformational change that switches the exposure of the pocket to the other side of the membrane, where the solute is then released.

Question 24

Types of transporter proteins

Answer 24

1. Uniporter - a single solute moves in one direction
2. Symporter - Two solutes move in the same direction
3. Antiporter - two solutes move in opposite direction

Question 25

Receptor mediated endocytosis

Answer 25

1. Cargo binds to receptor and receptors aggregate. The receptors cause coat proteins to bind to the surrounding membrane. The plasma mebrane invaginates as coat proteins cause a vesicle to form.
2. The vesicle is released in the cell.
3. The protein coat is shed.
4. The vesicle fuses with an internal organelle such as a lysosome.
5. Cargo is released into the cytosol.

Question 26

What do pharmacological substances tend to bind to?

Answer 26

Pharmacological substances that have entered the blood, may form drug-protein complexes with abundant proteins such as albumin.

This is very important, since the concentration of the free drug determines the intensity of the pharmacological effect.

Question 27

Depending on the particular physicochemical properties of a drug, the distribution of a pharmacological substance will be restricted to the:

Answer 27

• Vasculature Blood
• Extracellular spaces
• Tissue receptors
• Intracellular spaces

Question 28

Biotransformation is…

Answer 28

• Biotransformation is a protective mechanism of the body to promote the efficient removal of potentially harmful substances.
• Unfortunately, this chemical modification of xenobiotic substances may also cause a loss of pharmacological potency or biological function of a drug.
• The hydrophlic status of a biotransformed substance is decisvely increased to enhance elimination via the renal route. (Phase I & Phase II)

Question 29

Phase I biotransformation reactions

Answer 29

Oxidation; Reduction; Alkylation; hydrolytic cleavage

Question 30

Phase II biotransformation reactions

Answer 30

Conjugation reactions with glucoronic acid or sulfuric acid.

Question 31

Excretory kidney function

Answer 31

The chemical derivatives of drugs or chemically unchanged drugs are eliminated in the urine. Most drugs with a molecular mass of less than 5,000 Da will be permitted to pass through the vascular walls of the glomerular capillaries.