Pharmacokinetics II Flashcards
Do all drugs distrubute throughout the body after administration?
Once absorbed from adiministration site a drug could potentially distribute into:
- plasma
- interstital fluid
- transcellular fluid
- Intracellular fluid
They may also remain at the site of administration
What is Volume of Distrubution (Vd)?
A measure of the volume of fluid required to contain the total amount of the drug at its plasma concentration
As the body has lots of compartments the drug concentration will be different throughout these compartments
Circulation, ECF and ICF
Describe compartmental distrubutuion
a. The drug could reamin in the circulation (heavy molecular weight)
b. Could distribute into extracellular fluid, reducing the plasma concentration
c. Could distrubute into total body water, further reducing plasma concentration
Why is Vd Important?
- Enables prediction of whether the drug selected for administration is likely to reach the target site at an effective concentration
- Vd can be used to determine the loading dose necessary to achieve the target plasma concentration
What factors effect drug distrubution in the body?
Depends upon the drugs ability to:
- leave plasma and enter interstitial fluid
- cross cell membrane barriers
These processes are affected by:
- drug size
- drug plasma protein binding
- integrity of endothelial cell barrier
- the drug ionisation level
How does drug plasam protein binding affect its distrubution?
The drugs ability to bind to plasma proteins such as albumin and globulin will affect its ability to circulate within the blood. The plasma protein and free drug are in equilibrium and only the free drug is able to pass the endotheilial cell barrier.
The extent to which a drug binds to these proteins is variable - there are species specific differences in the extent to which plasma protein binding occurs (small but significant difference).
How does drug plasam protein binding affect its distrubution?
The drugs ability to bind to plasma proteins such as albumin and globulin will affect its ability to circulate within the blood. The plasma protein and free drug are in equilibrium and only the free drug is able to pass the endotheilial cell barrier.
The extent to which a drug binds to these proteins is variable - there are species specific differences in the extent to which plasma protein binding occurs (small but significant difference).
Why do drugs accumulate in the tissues?
- High lipid solubility - leads to accumulation in the fat tissue (has a low vascular supply meaning drug leaves slowly)
- Ion trapping - due to differences in pH across cell barriers
- Binding to a site (unrelated to the target molecule) within a tissue or cell
What are the pathways of elimination of a drug?
Water Soluble Drugs:
- Not readily absorbed like lipophilic drugs
- Blood filtered by the kidney and drug is excreted via urine
Lipophilic Drugs:
- More likely to enter the liver
- Drug conjugated by bile or excreted in the faeces
- Conjugation can cause lipophilic drug to become water soluble drug or drug metabolite is also an active drug e.g. codeine metabolised into morphine (much more potent drug)
What is the main site of drug metabolism?
The liver however, drugs can also be metabolised in other tissues e.g. plasma, GIT wall, lung and kidney
What enzyme family in the liver is important for drug metabolism?
Cytochrome P-450 (CYP) enzyme family
What is the main site of drug elimination?
Occurs primarily in the urine and bile but can also occur in the faeces
What is enterohepatic (re)cycling?
A process whereby the liver cells transfer drugs or drug conjugates to the bile
- drug then delivered to intestines
- conjugates hydrolysed by enzymes
- the free drug is the reabsrobed
- this increases the amount of drug in the GIT and available for absorption
What are the different types of renal excretion of drugs?
- No filtration (proteins > 70,000 kD)
- Partial excretion (drugs bound to plasma proteins; free drug is filtered)
- Filtered then completley reabsorbed (e.g. glucose)
- Filtered then partially reabsorbed from the tubules, partially excreted (most drugs)
- Filtered then no reabsorption from the tubules (ionised, water soluble drugs; many drug metabolites)
- Filtered the actively secreted (may be energy dependent) into the tubuls (some drugs and some drug metabolites)
What is the elimination half-life of a drug (t1/2)?
Time taken for 50% fall in drug concentration in the plasma
