Drug clearance & Half Life & Dose

Drug Clearance

It refers to the ratio of rate of drug elimination to the concentration of drug in biological fluid(C).

CL = rate of elimination / C

Rate of elimination

• For most of the drugs, elimination is not saturable & rate of drug elimination is directly proportional to concentration.

Rate of elimination = CL x C

==> The difference between drug clearance and drug elimination is that :

• Clearance is Volume of blood cleared of drug per unit time and Elimination is amount of drug cleared from blood per unit time.

Total Body Clearance

• The total body systemic clearance , CLtotal is the sum of all clearances from drug metabolising and drug eliminating organs.

• Dividing the rate of elimination at each organ by concentration of drug presented to it yeilds respective clearance at that organ and sum of these is total body clearance.

CLx = rate of elimination x / C

(i.e x is kidney, liver etc)

> The kidney is often the major organ of excreation. The Liver also contributes to drug clearance through drug metabolism and excreation into the Bile.

• CL hepatic and CL renal are the most important.

Orders of Elimination

(1)

• In this constant amount of drug is eliminated from body per unit time.

•In Graph we can see constant decrease in Linear fashion.

• In this rate of elimination is independent of plasma concentration or amount in the body.

• Occurs at higher doses due to saturation of elimination mechanisms.

• No fixed half life because higher the dose more the time it would take to clear drug from plasma.

Example : Ethanol, phenytoin, Salicylates etc.

(2)

• In this constant fraction ( or percentage of total drug) is eliminated per unit time.

• In Graph we can see constant decrease exponentially with time.

• In this rate if elimination is directly proportional to plasma level (or amount).

• Most if the drugs follow first order.

• In this concentration of such drugs in blood will Dec by 50% for every half life.

For example : If half life is 2 hours then :

2 hr => 4 hr => 6 hr => 8 hr

100mg => 50mg => 25mg => 12.5mg => 6.2mg

Half Life

• It is time required to eliminate half of the drugs either from plasma or body. It is expressed as :

T1/2 = 0.693 x Vd / CL

Example :

If omeperazole (Risek) clearance is 150 ml / min

Volume of distribution is 50 L

Then :

T1/2 = 0.693 x (50 / 0.15) = 231 min half life.

Factors affecting Half-life

• Decrease renal plasma flow, example in shock, hemorrhage, and cardiac failure.

• Addition of a second drug that displaces first from albumin, increasing its Vd.

• Decrease extraction ratio example : renal disease

• Decrease metabolism example : inhibition of P450 system.

Steady State Concentration (CSS)

• A steady state plasma concentration of drug occurs when the rate of drug elimination is equal to the rate of drug administration.

It is expressed as : CSS = Ro / CL total

> Ro = rate infusion.

• Time to reach the steady state only depends on

• 95% of steady state is acheived after 4-5 T

DOSE

Types of dosages :

(a) Fixed Dose :

(b)

(c)

(d)

Example : drugs given in arrthymias.

Loading dose = desired plasma concentration x Vd

(e)

Maintenance dose = desired plasma concentration x CL total

BIOASSAY

• The estimation of concentration or potency of the substance by measurement of biologic response to that product.

Uses

• Determination of pharmacological activity of new drugs.

• To keasure the drug toxicity and unwanted effects.

• To measure concentration of known substances.

Comments

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