USMLE1 General Pharmacology-3

General Pharmacology

Elimination of drugs:

Concerns the processes involved in the elimination of drugs from the body (and/or plasma) and their kinetic characteristics. The major modes of drug elimination are:

·         Bio-transformation to inactive metabolites

·         Excretion via the kidney.

·         Excretion via other modes including the bile duct (HBS), lungs and sweat.

2 types of elimination

• Zero Order elimination Rate
• First-Order elimination Rate

Zero Order elimination Rate

·         Rate of elimination is independent of plasma concentration (or the amount in the body).

·         A constant amount of drug is eliminated per unit time

·         for example, if 80 mg is administered and 10 mg is eliminated every 4 hrs, the time course of drug elimination is: 80 mgà 70 mgà60 mgà50mgà40mg(each 10 mg in 4 hrs.)

• Drugs with zero order elimination have no fixed half-life. Graphically ,  zero order elimination follows a straight-line  decay versus time.

Drugs with zero order elimination include

·         Ethanol (except for low doses),

·         Phenytoin (high therapeutic dose),

·         Salicylates (toxic doses).

ELIMINATION KINETIC

·         Zero order is due to saturation of elimination mechanisms; e.g, drug-metabolizing reactions have reached Vmax.

Most drugs follow first order kinetic

First-Order Elimination Rate

·         Rate of elimination is directly proportional to plasma level. The higher the amount, the more rapid the elimination.

·         A constant fraction of the drug is eliminated per unit time. Graphically , first order elimination follows an exponential decay versus time.

• For example, if 80 mg of a drug is administered and its elimination half-life = 4 hrs, the time course of its elimination is:80 mg à40 mgà20mgà10 mgà5 mg(each step 4 hrs)

Clearance is defined as the volume of blood cleared of the drug in unit time.

OR

Volume of plasma from which all drugs are removed in a given time.

·         Drug clearance is concerned with the rate at which  drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output.

·         It represents the relation-ship between the rate of drug elimination and its plasma level.

For drugs with first-order elimination, clearance is constant because the rate of elimination is directly proportional to the plasma level.

·         Total body clearance may involve several processes, depending on different routes of drug elimination.

·         CL= CLr + CLnr

Where CLr = renal clearance and  CLnr = non renal clearance.

·         With no active secretion or reabsorption, the renal clearance is same as glomerular filtration rate(CLr =GFR)

• Half life of drug : Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level) is called the elimination half-life (t ½).

T ½ = 0.7 x Vd/CL

Steady state(Css):

·         Css is the desired plasma concentration of drug required for optimal activity.

·         Steady rate is reached either when rate in (Rate of infusion) = rate out (Rate of elimination) or when values associated with a dosing interval are same as those in succeeding interval.

• Css is achieved in which plasma conc of drug remains constant.

The time to reach steady state is dependant on the elimination half-life of a drug

·         Although it takes > 7 t ½ to reach mathematical steady state , by convention clinical steady state is accepted to be reached at 4 t ½.

• Css = Ro/CLt

Ro- infusion rate, CLt - total body clearance e.g Css of plasma conc is directly proportional to infusion rate. If infusion is doubled the plasma conc ultimately achieved at the Css is doubled.

·         Css inversely proportional to clearance of the drug. In CRF decreases CL, so increase Css of an infused drug.

·         If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled.

·         Irrespective of the rate of infusion, it takes the same amount of time to reach steady state.

·         A similar relationship can exist for the other forms of drug administration (e.g, per oral)- doubling oral doses can double the average plasma levels of  a drug.

Maintenance Dose:

In most clinical situations, drugs are administered in such way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated .

·         At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out").

 IN Css, 

Dosing rate (rate of infusion) = Rate of elimination

                             = CL x target plasma conc

If intermittent doses are given, the maintenance dose is calculated from:

Maintenance dose (MD) = Dosing rate(rate of infusion) x Dosing interval                   

Loading Dose: A single dose of drug injected to achieve the desired plasma level rapidly

·         Loading dose (LD): LD =Vd  x  Css , where  Css = plasma at steady state , the desired plasma concentration of drug required for optimal activity.

·         Adjustment may be needed in calculations with bioavailability < f =1 ; for example, if f = 0.5 , the LD must be doubled.