Lecture 3: Drug Absorption And Distribution Flashcards
What is drug disposition?
Drug disposition can be consider e to be the processes a drug is subjected to by the body upon administration
What are the processes of drug disposition?
Absorption Distribution Metabolism Excretion
What is excretion also known as?
Removal from body
What is the most common route of drug administration?
Oral or rectal
Why is the oral or rectal route of drug administration most common?
Fewest complication
Most drug movement is not
Unidirectional
What are the drug administration routes?
Oral, rectal, percutaneous, intravenous, intramuscular, intrathecal, inhalational
What are the drug elimination routes?
Urine, faeces, milk, sweat, expired air
What can the lung serve as?
Route of both administration and elimination
What 2 ways can the drug molecules move around the body?
Bulk flow (I.e. bloodstream, lymphatic, cerebrospinal fluid) Diffusion (I.e. molecule by molecule over short distances)
What is the ability to cross the hydrophobic diffusion barriers strongly influenced by?
Lipid solubility
What is the concept of Bioavailability?
The fraction (F) or the administered dose that reaches the systemic circulation
What is the bioavailability of an intravenous injection?
F=1, Bioavailability=100%
What is the bioavailability for other routes?
Less than 1
What does a bioavailability of less than 1 reflect?
Gastric instability of drug First pass metabolism Reduced absorption into the circulation
What are the factors affecting drug absorption?
Gastric motility Area of absorbing surface Blood flow at absorbing surface Ingestion of food Plasma protein Binding Nature of the drug Ionised/ non ionised form
Gastric motility
Affected by disease/food How quickly the drug/ substance passes through the GI tract
Area of absorbing surface
Large surface area means more absorption across any particular membrane
Blood flow at absorbing surface
Affected by food/exercise Direct blood flow away from GI slowing digestion towards lungs/heart and exercising muscles
Ingestion of food
Possible interactions
Plasma protein binding
Equilibrium between free drug and plasma bound membrane
Nature of the drug. Ionised/ non ionised form
Most are either weak acids or weak bases Exhibit PH-dependent ionisation - dependent on PH in different areas of the body Ionised species are not lipid soluble
What sort of drugs diffuse through aqueous channels?
Water soluble drugs
What is the most important method of absorption across a membrane?
Diffusion across a membrane
Diffusion through aqueous pores/ Ion channels
Movement occurs down a concentration gradient The membrane contains small pores which allow water soluble molecules of less than 100Da through
Examples of agents that use diffusion through aqeuous pores / Ion channels
Lithium - small monovalent ion
Why is diffusion through aqeuous pores/ Ion channels not a major route for drug permeation?
Most drugs aren’t small enough
Carrier mediated transport
Active transport/ facilitates diffusion
What are the important sites for carrier mediated transport?
Important stores for such transfer, from a pharmacokinetic point of view include: renal tubule Blood brain barrier are important barriers drug must cross to be absorbed Gastrointestinal tract
What can limit the rate of permutation for carrier mediated transport?
Saturation of transporters
Pinocytosis
Concerned with the uptake of marcomolecules Engulfing membrane across very large molecules
What size of drugs can enter via pinocytosis?
Drugs of large molecular weight (1000Da or more) can permeate via this route
What is an example of of a drug that can permeate through pinocytosis?
Insulin crossing the blood brain barrier
How have researchers tried to incorporate pinocytosis into drug uptake?
Incorporating the drug into lipid liposomes
What ride drugs does diffusion through lipid Membranes allow for?
Only allow small lipid soluble non-polar drugs through
What size drugs does diffusion through lipid Membranes allow for?
Surface area and blood flow. Degree of permeation is determined through Ficks Law Knowing the percentage of drug ionised
What factors of Ficks Law are directly related to rate?
dQ/day - amount of drug diffusing with time Pk - permeability constant A - membrane area C1/C2 - concentration of drug either side of the membrane
What factors of Ficks Law are indirectly related to rate?
Membrane thickness
What is the effect of PH on drug ionisation?
Important as it allows prediction of absorption Most drugs are either weak acids or weak bases
What is PKA ?
Dissociation constant - equal to the PH at which 50% of the drug molecules are ionised
What does degree of ionisation give rise to?
Ion trapping
What does a high degree of ionisation mean?
Little crosses the membrane
Treating drug overdose
Alkaline urine means drugs won’t pass to the nephron this fam be used in the case of aspirin overdose. Urine can be alkalinized e.g. with NAOH changing ionised/unionised ratio
What is volume of distribution?
The volume of fluid required to contain the total amount of drug in the body at the same concentration as that present in the plasma
What is Cp?
Plasma concentration
How to calculate volume of distribution?
Vd = Dose/Cp
What does it mean if you have high lipid solubility?
Higher amount of your compound partitions into the cell membrane Faster rate of movement across lipid soluble fell membrane and into the inside of the cell
What makes up Fricks Law?
Steepness of the concentration gradient The surface area of the membrane across which diffusion is taking place The lipid solubility of the substance Membrane thickness
Steepness of the concentration gradient
The bigger the concentration gradient, the steeper it is, the faster the rate of diffusion
The surface area of membrane across which diffusion takes place
The larger the surface area, the greater the rate of diffusion
The lipid solubility of the substance
The greater the lipid solubility of drug, the faster the substance can diffuse down its concentration gradient through lipid bilayer Smaller transmembrane concentration for insoluble lipid hence slower diffusion
Membrane thickness
Thicker membrane means slower rate of diffusion Thinner membrane - fast rate of diffusion
What is Ion trapping?
High PH of a drug that has relatively low PKA
What are the 3 body compartments that a weak acid and a weak base would be distributed at equilibrium?
Plasma (PH 7.4) Alkaline urine (PH 8) Gastric juice ( PH 3)
What does the ratio of ionised to unionised drug govern?
PKA is the drug and PH of that compartment
What can cross the membrane?
Unionised species
What cannot cross the membrane?
Ionised species
How does drugs leave the circulation ?
Capillary filtration
What are the different body compartments that the drug can distribute to?
Transceullar water Intracellular water Interstitial water Plasma water Fat
