PK2 - Distribution Flashcards
What is distribution and when does it occur?
It is the movement of drug from SYSTEMIC CIRCULATION –> OTHER TISSUES
It begins shortly after the first drug molecules enter the bloodstream
What are the three parts of the distribution pathway?
Blood plasma –> extracellular tissue fluids –> cells
Does a majority of each dose reach target receptor sites?
No, only a small fraction does
Most of each drug dose goes where it ISNT needed. Like a lipid soluble drup accumulating in fat
What 4 factors affect drug distribution (just name them)
- Physicochemical properties of the drug
- Anatomy and physiology of the animal
- Plasma protein binding
- Tissue drug binding
What are the three physicochemical properties of the drug
-solubility
-degree of ionization
-size, molecular weight (if too large it will stay in bloodstream and only pass through glomeruli)
What happens with drugs and tissue perfusion? Short and long term
-In short term; organs with higher blood flow receive more drug (brain, kidney, heart, liver)
-Longer term, the majority of the dose redistributes to larger but less well perfused tissues (muscle, fat, viscera) as equilibration between tissues occur
What can change clinical results relating to tissue perfusion? Example
Disease/trauma can reduce flow to an organ which changes them
Ex avascular fragments of bone w compound fracture
How long does it take for drug to distribute to entire blood volume once it enters?
1-2 minutes
What type of substances enter CNS very slowly due to BBB?
Water soluble substances will enter CNS very slowly.
Systemic administration of these are useless if intended site is CNS
What type of drugs cross the BBB well?
Drugs with high lipid solubility and low protein binding
What molecules cannot cross BBB at all
BBB is totally impermeable to plasma proteins
What do glial cells do for the BBB?
They make the capillaries much less permeable to water soluble substances
What drugs are highly bound to plasma proteins?
-NSAIDs ; aspirin
-Anticoagulants; warfarin
What are the features of plasma protein binding?
-Binding is reversible, a molecule can bind and unbind repeatedly
-Bound and unbound drugs are in equilibriud
What is the main plasma protein binder that affects drug distribution?
Mainly albulin, its a major carrier of weak acids
What is the effect of a protein bound drug on half life and ability to enter tissues?
Protein bound fractin of drug cant enter tissues to produce desired effect and cant be excreted. So they circulate through the blood until they dissociate from the carrier protein, which INCREASES THE HALF LIFE of the drug but DECREASES INTENSITY of effect
What happens when certain drugs distribute preferentially to tissues other than blood?
-They can bind to tissue proteins, nucleic acids, phospolipids
-Fat soluble drugs can accumulate in adipose and other fatty tissues (more easily cross BBB)
-Some drugs can bind to bone (and irreversibly become part of the growing bone/teeth)
When giving lidocaine (weak base) that needs to be ABSORBED into neurons to reach target receptors. Will the lidocaine be more or less effective in the infected tissue if its more acidic than normal tissue?
Less effective…. since more of the ionized form of the drug, so you would need a higher dose
What are the two major compartments from a pharmacokinetic POV?
-Vascular compartment
-Everything else
What does Vd tell you?
Volume into which a dose of drug appears to have been diluted in the body
What does a high Vd tell you?
-increased amt of drug in tissues
-decreased rate of excretion
What does a Vd equal to blood volume mean?
It means none of the drug has diffused out of the blood compartment
What will the Vd be if half the drug given diffuses out of the bloodstream?
Only half of the dose will be left in the blood so the Vd = it will be double the blood volume
What will the Vd be if 2/3 the drug given diffuses out of the bloodstream?
Only 1/3 of the dose left in the blood so the Vd would be triple the blood volume
What does a Vd of 10x the normal blood volume tell us?
That only 1/10 of the dose still remains in the patients blood
What are the acceptable units for Vd?
L/kg of BW
mL/kg BW
What dosing adjustments do you have to make when a drug has a small Vd?
It may require larger doses to be effective since only a small proportion of molecules leave the bloodstream to reach the target tissue
What changes to exretion can you expect when a drug has a large Vd?
Drugs with large Vd take longer to excrete since they must be in the vasculature to be delivered to an organ of elimination
What is the Vd of water soluble drugs?
-These drugs tend to stay in the ECF (plasma space and interstitial fluid)
-Usually IONIZED
-They have small-intermediate Vd values
-DOES NOT include intracellular fluids
What is the Vd of lipid soluble drugs?
-They have high Vd values
-Drugs bind extensively to tissue sites outside of the plasma space
-Usuall UNIONIZED
What is Vd useful for calculating?
A loading dose of a drug needed to achieve a specific plasma drug concentration
If a patient is overdosing on a weak acid, what form is excreted more?
Favours A- form so more can be excreted
If a patient is overdosing on a weak base, what form is excreted more?
Favours BH+ form so more can be excreted
