Lecture 4 Flashcards
What is First Pass Hepatic Elimination?
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.
How do drugs reach their target tissue?
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.
alpha phase
Distribution - Systemic distribution into body tissues
beta phase
Elimination from body by biotransformation and excretion
What must drugs have to overcome prior to entering the systemic circulation?
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.
GI-tract barrier
Intestinal epithelium with brush border
Respiratory tract barrier
Cillia-bearing epithelium
Oral mucosa barrier
Non-keratinized squamous epithelium
Skin barrier
Keratinized squamous epithelium
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.
Pore-lacking CNS endothelia
Name and describe the cells found within the GI-tract
Epithelial cells - transport drug molecules from the lumen to the capillaries.
Drugs have to move from the lumen, through epithelial cells, into capillaries.
Drugs may traverse biomembranes by..
- 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’
Gradient diffusion through membrane for lipophilic substances.
- Diffusion - passive transport
- Facilitated diffusion - passive transport
- Active Transport - Primary and Secondary Active Transport
What is diffusion? Is a transport protein needed?
Diffusion across a membrane is the movement of a solute down a gradient. A transport protein is not needed.
What is facilitated diffusion? Is a transport protein needed?
Facilitated diffusion across a membrane is movement down a gradient with the aid of a transport protein.
What is active Transport? Is a transport protein needed?
Active transport across a membrane is movement against a gradient with the aid of a transport protein.
What is Primary Active Transport?
A pump actively exports H+ against a gradient
What is Secondary Active Transport?
A H+ sucrose symporter can use the H+ gradient to transport sucrose against a concentration gradient into the cell.
Membrane-associated proteins as drug targets.
- Integral receptor protein
- Ion Channel Protein
- Ion Pump Protein
Integral receptor protein
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.
Ion channel proteins
When a channel is open, a solute directly diffuses through the channel to reach to the other side of the membrane.
Ion pump protein
- 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.
- Na+ are released outside of the cell
- 2 K+ bind from outside the cell
- Phosphate Pi is released, and the pump switches to the E1 conformation, 2 K+ are released into cytosol. The process repeats.
Transporter proteins
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.
Types of transporter proteins
- Uniporter - a single solute moves in one direction
- Symporter - Two solutes move in the same direction
- Antiporter - two solutes move in opposite direction
Receptor mediated endocytosis
- 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.
- The vesicle is released in the cell.
- The protein coat is shed.
- The vesicle fuses with an internal organelle such as a lysosome.
- Cargo is released into the cytosol.
What do pharmacological substances tend to bind to?
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.
Depending on the particular physicochemical properties of a drug, the distribution of a pharmacological substance will be restricted to the:
- Vasculature Blood
- Extracellular spaces
- Tissue receptors
- Intracellular spaces
Biotransformation is…
- 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)
Phase I biotransformation reactions
Oxidation; Reduction; Alkylation; hydrolytic cleavage
Phase II biotransformation reactions
Conjugation reactions with glucoronic acid or sulfuric acid.
Excretory kidney function
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.
