9. VD, clearance and TCI’s Flashcards
What is intrinsic clearance of a drug?
What are the two different types of kinetics that occur at different substrate levels?
Most drugs are at a concentration below the Km of an enzyme e.g. hepatic enzymes, and so all of the delivered substrate will be metabolised at the enzyme rate. This is called first order kinetics.
If substrate concentration exceeds an enzymes maximal activity, then the metabolism rate will now become constant. Enzyme activity is now independent of substrate concentration and this is zero order kinetics.
Once the drug concentration drops and all enzymes are not maximally saturated, we return to first order kinetics.
(Look at the graphs on page 62 of pharma 9)
What common drugs can saturate their enzyme systems?
Thio and phenytoin
In the liver, how does blood flow effect drug metabolism?
What drugs are particularly effected by this?
Reflects the delivery of a substrate and so is a limiting factor in first order kinetics
Propofol and fentanyl are both dependent on hepatic flow and have high hepatic extraction ratio’s (concentration gradient between plasma and hepatocytes)
What does blaschkes triangle show?
What drugs are different examples of these factors and why?
(Diagram page 63, pharma 8)
Show drugs that are flow dependent and protein binding dependent and the ER’s
Drugs at concentrations above the KM have low ER’s as the intracellular concentration is close to plasma.
Highly protein bound with low ER’s e.g. phenytoin and warfarin, can change plasma concentration rapidly, if protein binding changes.
Highly protein bound with a high ER will not be affected by changes in protein binding
What categories of drugs can be excreted unchanged in the body and where?
Kidney filtration of highly polar unbound drugs in the bowman’s capsule
Kidney secretion of weak acids and weak bases
Volatiles via inhalational route
What are the different physiological volumes that are accounted for in Vd?
What are the sizes of the compartments?
What drugs are liable to stay in each compartment?
Intravascular: 70ml/kg so under 10L. large, polar and highly protein bound e.g. heparin. Highly protein bound drugs will distribute but just do so more slowly. E.g. propofol is 98% bound compared to fentanyl (83%), so fent is more rapid than propofol.
Extracellular: 14L. Small and polar and unable to pass through cell membranes e.g. muscle relaxants, whose Vd is usually 14L.
Intracellular: 42L. Small and able to pass through cell membranes e.g. ethanol.
Some drugs have a volume of distribution that is larger than all of the compartments together e.g. propofol 305. How do we explain this?
Very lipophillic can enter adipose
Some are moved into cells through active transport e.g. iodine
Come bind strongly to protein or nucleic acid e.g. chloroquine
How do we calculate total volume of distribution?
Calculate this by looking at total of Vd at a steady state e.g. Vss
In a 1-C model the Vd is the dose at t=0
In multi- Vss is measured from the terminal elimination phase
Vss = Cl/Tz
(tz is the time constant which is the line gradient)
Vss = (BF x dose) / (AUC x Tz)
Page 65 pharma 8.
What patient factors effect Vd?
Individual variation:
Age: different proportions of body water
Gender
Genetics: enzyme isoforms
Other drugs e.g. inducers
Hepatic failure: ascites, reduced protein synthesis and metabolic activity declines with blood flow and less intrinsic activity.
Renal: increased initial Bd and reduced clearance.
What is the target plasma concentration for propofol at induction and maintenance?
Induction = 6mcg/ml and maintenance = 3-10mg/ml
What does a TCI pump (Marsh model) do during an anaesthetic?
E.g. initial bolus, maintenance, onwards?
Initial = based on weight and target put in.
Initial bolus can take 30s, so pump gives slightly more than is calculated from Vd and target plasma concentration to compensate for the small amount of elimination and distribution that has occurred.
Maintenance: initially the pump will give the same amount that is eliminated and distributed for the first 5 mins. Then as steady state is reached, the pump will only give what is eliminated.
When we stop a propofol infusion, what happens in the different compartments?
Bolus?
What is the maximum context sensitive half life for propofol?
Cl10 is faster than either intercompartmental clearance
If only a bolus is given plasma concentration drops rapidly (about 3m), as there is very little distribution to the different compartments
After steady state e.g. infusion. Initial plasma drops quickly, but then eases off after 2nd compartment starts to redistribute and same with third.
This is context sensitive half time e.g. how much has gone to the different compartments. Longest possible infusion is steady state.
18mins.
What is the relations ship between plasma and CNS concentration at the start of propofol infusion?
CNS lags behind, hence why we often overdrive to start with (can cause more CVS instability)
What is the Schnider model?
A model that has calculated a rate constant for central compartment to effector site concentration.
Constant = Ke0.
Allows a more rapid induction with less CVS instability. Gives a smaller dose than Marsh.
What model do we use for remi?
What targets do we set?
With and without propofol?
How do we display this?
CSHT?
Minto - has a KeO component
Initial targets between 4-8ng/ml. Reduced by almost a third as synergistic effect with propofol.
Only need 30%of each drug instead of 50%. Shown on a isobologram.
Low Vd so CSHT does not vary as much as with propofol. (Max 8 mins).
