PLASMA HALF LIFE ( t 1/2 )

 Minimum Effective Concentration (MEC): The plasma drug concentration below which a patient’s response is too small for clinical benefit.  Peak Plasma & Trough Concentration : The maximum & minimum drug conc. achieved during repeated dosing cycles.  Target Concentration : The plasma concentration required to produce desired therapeutic effect.

Definition: The time required for the concentration of the drug in the plasma to decrease to one half of its initial value after the peak has been reached.  It is designated as t ½.  A useful parameter derived from Vd & CL.  Important for rational drug therapy because it helps in designing & planning the dosage regimens

 Assimilation kinetics  Elimination kinetics  Plasma half life is a measure of the elimination kinetics  Peak level- beyond which further assimilation cannot take place and elimination processes take over

 It can be calculated by following relationship: t ½ = 0.7 x Vd CL

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 Decline in Plasma Concentration starting at any steady-state plasma concentration (100 %) of a drug, it will fall as follows:  After 1 t ½ to 50 %  After 2 t ½ to 25 %  After 3 t ½ to 12.5 %  After 4 t ½ to 6.25 %  After 5 t ½ to %

t ½Plasma conc. (mg)

1. Volume of distribution 2. Plasma protein binding 3. Clearance 4. Kinetics Pattern 5. Presence of second drug 6. Diseases 7. Active metabolites 8. Enterohepatic circulation 9. Hepatic blood flow

 Large Vd = long t 1/2

 Albumin  Globulin  Free drug  Bound drug  Class I drugs  Class II drugs

 Increased clearance = decreased t 1/2

 First order kinetics/Exponential kinetics/linear  Uniform or fixed fraction of drug is eliminated in a unit time  t1/2 independent of the drug concentration  constant t ½  Zero order kinetics/Saturation kinetics/non-linear  Michaelis Menten kinetics  Fixed amount of drug is eliminated in a unit of time  Increase dose = t ½ prolonged

First order  Plasma conc. is 100 mg and fraction eliminated is 10 %/hr  So after 1 hr 10 % is eliminated = 10 mg, leaving 90 mg  After 2 nd hr again 10 % is eliminated = 9 mg, leaving 81 mg  After 3 rd hr 10 % of 81 mg is eliminated =8.1 mg, leaving 72.9 mg  After 4 th hr 10 % of 72.9 mg= 7.29 mg, leaving 65.6 mg Changing the dose t 1/2 is not changed

Time (hrs)Plasma conc (mg)

Zero order  100mg dose and amount eliminated is 10mg/hr  So after 1hr 90mg remains  After 2hrs 8omg remains  After 3hrs = 70mg  4hrs =60mg  5hrs = 50mg Increasing dose will increase t 1/2 as enzymes become saturated and elimination capacity decreases

Time (hrs)Plasma conc (mg)

Drugs following zero order kinetics  Aspirin  Phenytoin  Alcohol

 Enzyme inducers ↑ metabolism ( ↓ t ½ )  Enzyme inhibitors ↓ metabolism ( ↑ t ½ )

 Diseases of organ of metabolism/excretion  Hepatic & renal disease  Change in Vd  Change in plasma protein binding

 Biological half life (duration of action) longer than plasma half life ?  Aspirin  Omeprazole

 Aspirin – salicylate  Morphine – morphine 6 glucoronide

 Drugs excreted in bile are reabsorbed from intestine and plasma half life is prolonged  Rifampin  Morphine

 Decreased hepatic blood flow e.g. in cardiogenic shock, cardiac failure, hemorrhage  Prolonged t ½ of drugs with flow dependent CL/extensive hepatic first pass metabolism

 Rate of elimination  Duration of action  Dosing interval  Designing a dosing regimen  Time for steady state concentration  Time for complete elimination

 t ½ indicates rate of elimination  97 % drug eliminated in 5 t ½  Increase t 1/2 – elimination is slow  Decrease t 1/2 – elimination is fast

 t ½ indicates the duration of action of a drug  longer t ½ -long duration of action  shorter t ½ -short duration of action

 t ½ indicates the dosing interval  longer t ½ -long dose interval  shorter t ½ -short dose interval

 t ½ is important for designing a dosage regimen.  It is a plan for drug administration over a period of time.  The interval between doses should not be less than 4 t ½.  Drugs with short half life --- More frequent dosing.  Drugs with long half life --- Less frequent dosing.  Loading dose for drugs with large Vd.

 Time for Steady State (SS)  Rate of elimination equals the Rate of drug administration  Time to reach SS is 4-5 t ½  Time to reach SS is not affected by dose of drug  Time for complete elimination  Important incase of certain adverse effects

 When constant dose of a drug is repeated before 5 t1/2. it would achieve higher peak concentration, because some remnant of the previous dose will be present in the body  This continues with every dose until progressively increasing rate of elimination balances the amount administered over the dose interval  Plasma concentration plateaus and fluctuates about an average steady state level

Plasma Half Life of Some drugs:  Esmolol 09 Min  Aspirin 15 Min  Morphine 1.9 Hours  Propranolol 3.9 Hours  Digoxin 50 Hours  Digitoxin 161 Hours

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