Clinical Pharmacokinetics Fundamental hypothesis: a relationship exists between the pharmacological or toxic response to a drug and the accessible concentration of the drug (e.g., in blood). Volume of distribution (V d ) Clearance (CL) Bioavailability (F) Half life

Volume of Distribution Volume of distribution (V d ) relates the amount of drug in the body to the plasma concentration of drug (C). **The apparent volume of distribution is a calculated space and does not always conform to any actual anatomic space.** note: Vd is the fluid volume the drug would have to be distributed in if Cp were representative of the drug concentration throughout the body.

DrugVd(L/70 kg body) Chlroquine13000 Warfarine9.8

Clearance (CL) Clearance is the most important property to consider when a rational regimen for long-term drug administration is designed. The clinician usually wants to maintain steady-state drug concentrations known to be within the therapeutic range.

Clearance of most drugs is constant over a range of concentrations. This means that elimination is not saturated and its rate is directly proportional to the drug concentration: this is a description of 1st-order elimination.

Capacity limited elimination (zero order)  Phenytoin, Ethanol and Aspirin

Flow dependent elimination Alprenolol Lidocaine Amitriptyline Meperidine Morphine Imipramine Propranolol Isonizide Verapamil Labetalol

CL in a given organ may be defined in terms of blood flow and [drug]. Q = blood flow to organ (volume/min) C A = arterial drug conc. (mass/volume) C V = venous drug conc. rate of elimination = (Q x C A ) - (Q x C V ) = Q (C A -C V )

Extraction Ratio Division of the previous equation by the concentration of drug that enters the given organ of elimination yields an expression for clearance of the drug by the organ: CL organ = Q(C A -C V /C A ) = Q x E E is referred to as the extraction ratio Rate of elimination = (Q x C A ) - (Q x C V ) = Q (C A -C V )

Half Life Half life is the time required to change the plasma concentration to one-half or twice of its original value

Half Life Half-life is the time taken for the concentration of drug in blood to fall by a half

Time to Steady State Time to steady state depends on half life Half life DOES NOT depend on:  Dose  Dosage Interval Tss = 4 x t ½

Time to drug accumulation and elimination

Effect of half life on plasma concentration at the beginning of dosing

Effect of half life on plasma concentration at the end of dosing

How do you change the plasma concentration? To change the plasma concentration:  Change the dose  Change the dosage interval

Bioavailability The fraction of unchanged drug reaching the systemic circulation following administration by any route.

The target concentration approaches to designing a rational dosage regimen

Maintenace Dose Dosing rate ss = Rate of elimination ss Dosing rate ss = CL X TC If the bioavailability is less than 100 percent then And if we want to give the drug intermittently: Maintenace Dose = Dosing rate x Dosing interval

Loading Dose Loading dose = V d X TC While the estimation of the amount of a loading dose may be quite correct, the rate of administration can be crucial in preventing excessive drug concentration, and slow administration of an intravenous drug (over minutes rather than seconds) is almost prudent practice

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