Lecture 4 Flashcards
(16 cards)
Definition of Drug absorption
Drug movement from the site of administration to the bloodstream (systematic circulation)
Rate and extent of drug absorption depend on:
a. environment for drug absorption
b. chemical characteristics
c. route of administration (influences bioavailability)
Mechanisms of drug absorption from GI tract
a. Passive diffusion
b. Facilitated diffusion
c. Active transport
d. Endocytosis/Exocytosis
Factors influencing drug absorption:
a. Host factors - pH and ionisation, Blood flow to the absorption site, Total surface area available for absorption, Contact time at the absorption surface, Membrane transporters
b. Drug Factors
(not mentioned in the slide)
c. Routes of drug administration - Oral administration, Sublingual administration, Intravenous injection, Subcutaneous injection, Intramuscular injection, Inhalation route, Topical application, Rectal administration.
READ LECTURE 4 SLIDE 6-16 FOR FURTHER INFORMATION
Bioavailability
It is rate and extent to which an administered drug reaches the systemic circulation.
Amount of drug administered = amount of drug reached systemic circulation
Factors affecting Bioavailability
a. First-pass metabolism (e.g., oral administration)
b. Biotransformation (metabolism)
c. Chemical or physical characteristics of the drug
Definition of Drug Distribution
It is a process by which a drug reversibly leaves the bloodstream (after absorption) into various body compartments to achieve equilibrium.
3 Compartments of the body
a. Vascular compartment
b. Interstitial space (between blood and cells)
c. Intracellular space (inside the cells)
Factors affecting drug distribution from plasma to interstitium:
a. cardiac output
b. local blood flow
c. capillary permeability
d. local pH
e. tissue volume
f. degree of drug binding to plasma and tissue proteins
g. relative drug lipophilicity
h. disease state affecting factors a-g
Explain the phases of Drug Distribution
- Initial Phase - Initially distributed to highly vascular organs (e.g., liver, kidney and brain)
- Second phase - The muscle, skin and fat receive drug slowly
Steps in drug distribution
- Permeation of free or unbound drugs from the bloodstream (vascular compartment) into interstitial or extracellular fluids (peripheral compartment).
- Permeation of drugs from extracellular fluids into intracellular fluid (rate-limiting step)
Redistribution Definition
It refers to the change in plasma drug conc. which is significant to cause alteration/termination of drug action.
E.g., redistribution of thiopentone
- initial phase, readily penetrate BBB (high lipophilicity)->very rapid onset of action second phase, redistribute to adipose tissue termination of drug action in the brain
Factors Influencing Drug Distribution
- Blood flow
-The rate of the blood flow to the capilaries - Capillaries permeability
- Lecture 4 slide 29 - Binding to plasma proteins
- Reversible bindings to plasma proteins sequesters drugs in a nondiffusible form. -> slowing the transfer out of the vascular compartment Example Albumin - Binding to tissue proteins
- any drugs accumulate Therefore tissues are lower concentration in interstitial fluid and blood
5.Lipophilicity
-The chemical nature of drugs affect their ability to cross cell membranes
Lower and Higher Vd interpretation
Lower Vd
higher proportion of a drug stays within the vascular space due to
plasma protein binding
* Higher Vd
lower proportion of a drug stays within the vascular space due to
tissue protein binding
Four types of V d can be calculated, each with its advantages and disadvantages:
- Initial volume of distribution
* The volume calculated immediately following an IV bolus of the drug.
* Denoted as Vinitial
* Does not take into account of any phase of distribution
* Can be used to calculate the physiological volume of the central compartment - Extrapolated volume of distribution
* It is calculated after the initial phase of distribution has taken place.
* It takes the slow late stages along with the conc.-time curve (the terminal elimination
phase); extrapolate a line of best it to calculate initial conc.
* Denoted as Vextrap
* Highly inaccurate - Non-compartmental volume of distribution
* Consider only one compartment at a time
* AUC (conc.-time plot) and terminal elimination time constant calculate Vd
* Denoted as Varea
* Because terminal elimination time constant is used
Any alteration (e.g., renal failure) will affect the drug clearance - Steady-state volume of distribution
* Denoted as Vss
* It uses the amount of drug administered and Css to calculated Vss.
* Most useful clinically
Factors Influencing Vd
- Modelling factors
* Timing of drug measurement
* Pharmacokinetic model used
* Drug measurement - Drug factors
* Molecular size
* Molecular charge
* pKa
* Affinity to tissue proteins
* Affinity to plasma proteins
* Lipid solubility (most important factor) - Patient factors
* Total body volume
* Age
* Gender
* pH
* Protein levels
* Displacement
* Pregnancy
* Edema, ascites and effusion
