### Clearance (CL)

a measure of the body's ability to eliminate the drug = Rate of elimination (amount/time) / plasma drug concentration (amount/volume) -> units = volume per unit time -> how much volume of blood you have to clear per unit time to get rid of the drug

### First order elimination

rate of elimination = CL x C -> most drugs follow this with low plasma drug concentration (at high concentrations there is a VMAX because the transporters are saturable)

### Extraction ratio (ER)

the ratio of the hepatic clearance of a drug (CL-liver) to the hepatic blood flow (Q) = CL-liver/Q -> Q = 1.5 L/min in a person weighing 70kg -> ratio of drug that when it enters the liver is cleared by the liver in one pass -> high > .7, low <.3

### High extraction ratio

clearance is blood flow dependent, have large first pass effect -> bioavailability is low after oral administration -> morphine, Lidocaine, verapamil, propanolol and nitroglycerin

### Low extraction ratio

clearance capacity limited (liver controls the clearance) -> phenytoin and warfarin -> clearance is relatively independent of hepatic blood flow (not efficiently cleared by liver), primarily determined by the metabolizing capacity of the liver and by the free drug fraction\

### Drugs with intermediate extraction ratios

hepatic clearance is dependent on hepatic blood flow, metabolizing capacity of liver and free drug fraction -> aspirin, quinadine, codeine, nortriptyline

### Bioavailability (F)

the fraction of drug absorbed as such into the systemic circulation = f x (1-ER) where f is the fraction of drug absorbed and (1-ER) is the fraction of drug that escapes extraction by the liver

### Volume of distribution (VD)

the volume that would be required to contain all of the drug in the body at the same concentration as in the blood or plasma = amount of drug in the body / plasma drug concentration -> if the plasma drug concentration is maintained at a low level this will be very large (e.g. Quinacrine -> bound to peripheral tissues), if it is contained within the blood at a high concentration this will be very small

### Half life

the amount of time it takes to change the amount of drug in the body by 50% during elimination (or during a constant infusion) = .693 x VD/CL -> determines the rate at which blood concentration rises during a constant infusion and falls after administration is stopped (in clinical situations steady state is said to be attained after 4 of these) -> DOES NOT depend on the dose

### Calculate the volume of distribution (VD) given a loading dose and the plasma drug concentration at time zero

= Dose/C0 -> extrapolate the curve back to the y axis to get C0 (plasma drug concentration at time 0)

### KE

= CL/VD = rate constant for elimination of the drug -> bigger clearance the faster elimination happens, the larger the VD the slower elimination happens = .693/(t1/2)

### Describe the concept of steady-state with regard to plasma drug concentrations (saturation kinetics)

rate of elimination = (Vmax x C) / (Km + C), at high drug concentrations, the rate of elimination approaches Vmax (zero order kinetics -> constant amount of drug is eliminated per unit time)

### List examples of drugs that follow zero-order kinetics

aspirin at high doses, ethanol and phenytoin regardless of the concentration, the elimination is always the same -> clearance will increase as concentration drops (desaturation of the enzymes)

### Maintenance dose

= dosing rate x dosing interval -> used to maintain a steady state of drug in the body -> dosing rate = rate of elimination = CL x TC / F -> TC = target concentration

### Calculate the drug plasma levels reached after a given number of half lives during drug administration

1 t1/2 = 50%, 2 t1/2 = 75%, 3 t1/2 = 87.5%, 4 t1/2 = 93.75% (after 4 it is assumed that we have reached steady state)

### Calculate the drug plasma levels reached after a given number of half lives after drug administration is discontinued

1 t1/2 = 50%, 2 t1/2 = 25%, 3 t1/2 = 12.5%, 4 t1/2 = 6.25% (after 4 it is assumed that we have reached steady state)

### Given the half-life of a drug, calculate the accumulation factor (AF)

= 1 / (fraction lost in one dosing interval) = 1 / (1 - fraction remaining) -> predicts the ratio of the peak concentration at steady state to the peak concentration after the first dose -> for a drug given once every half life this will = 1/.5 = 2, 2 half lives will = 1/.25 = 4