Half Life of Drug, Introduction, types.pptx

Half Life

1. Biological half life and Volume of distribution – Other important parameters

2. Half life – Elimination parameter Time to decrease body drug level by one half of its initial level. Reduction in concentration due to a physiological process, i.e., biotransformation, the half life is called as elimination of biological half life. half life is time required for body to eliminate one half of drug which it contains.

3. Half life Elimination half life is a function of both, clearance and the volume of distribution of the drug .

4. Half life Biological half life is the time required for a biological system, such as that of a human, to eliminate, by natural processes, half of the amount of a substance (such as a radioactive material) that has entered it. The half life is used to determine time required for body to eliminate by metabolizing, or excretion or by both, one half of initial concentration of drug in blood.

5. Types Biological half life – already disscussed Absorption half life - time to reduce drug concentration at absorption site due to absorption by one half of its initial concentration. Distribution half life - time required to reduce concentration of drug to half of its initial concentration due to the distribution of drug.

6. Types Physical half life - time to decrease concentration of a substance to half due to physical decay. A radiopharmaceutical decays physically and time at which its concentration is reduced to half of its initial concentration is its physical half life p ertains to the radiopharmaceuticals.

7. Types Effective half life - decline in concentration of an administered radiopharmaceutical in body due to its physical disintegration as well as due to its biotransformation. – Effective half life combines both, elimination half life and the physical half life of a radiopharmaceutical.

8. Types First order half life – representing a mode of d ecay of concentration, It is time required for [C] (concentration at time t) to become equal to one half of [C] (the initial value at zero time). A drug eliminated by a first order process has a constant half life which is independent of initial concentration or dose of drug. First order half life is calculated as: ½ t = K 0.693

9. Types Zero order half life – a half life, not independent of initial concentration. Lager initial concentration, greater is half- life. Difference can be used to distinguish zero and from first order process by varying initial concentration (or order) and measuring resulting half life. t½ = 0.5 [C] k

10. Computation of half life Direct graphical method: estimation of half life by direct reading time needed for concentration to decrease by one half from any point on the log concentration time plot. From the slope of terminal log concentration time curve. The slope of curve is elimination rate constant. Using formula of first order half life, half life can be calculated.

11. Computation of half life Half life is also calculated from urine concentration data assuming that renal clearance of drug is constant, excretion rate parallels plasma concentration. However, practically, urine concentration data usually gives poor estimate due to incomplete bladder emptying and inability to collect samples frequently.

12. Relationship with other parameters t 1/ 2 Vd The clearance and volume of distribution are the two independent pharmacokinetic parameters which determine elimination half life. Cl  k  Vd  Cl  k  0.693

13. Significance of half life Reflects rate of drug elimination, similar to elimination rate constant. Drug that have a short half life (i.e., having larger elimination rate constant) are readily eliminated from the body. Half life is used in deciding appropriate dosage regimen. Drugs with shorter half life require frequent dosing during multiple administration.

14. Significance of half life It gives estimate of rate of drug removal from body It indicates efficiency of elimination process, thus change in half life reflects change in elimination organ functions such as liver biotransformation or the excretion in kidney. It is thus, a prime measure for dosage adjustment in disease status .

15. Significance of half life Drug having half-life between 3 to 4 hours are good candidates for control release formulations. Drugs reach to steady state concentration in approximately 5 half lives. A drug is completely eliminated after 10 half life and usually negligible within 7 half lives

16. Classification of Drugs on Basis of Disposition Provides a basis for classification of drugs having ultra fast, slow and very slowly disposition drugs. Ultra fast disposition (UFD) drugs has half life of less than 1 hour, Slow disposition (SD) drugs have half life of 8- 24 hours Very slow disposition (VSD) drugs have half life of more than 24 hours.

17. Factors affecting half life Affected by any factor which modifies drug metabolism and excretion. Categorized into: – Patient related , age, genetic, renal insufficiencies, hepatic insufficiencies, urine pH, gender, nutritional status, emotional status, hormonal level, body temperature, volume of distribution, etc

18. Factors affecting half life Factors related to drug - D rug- drug interaction, inhibition of drug metabolism, stimulation of drug metabolism via increased enzyme activity or via enzyme induction, therapy duration (enzyme exhausted). Combinedly related to the drug and patient.

19. Factors affecting half life Renal malfunction - renal clearance is altered if there is any disease, malfunctioning or insufficiencies of kidney. When renal clearance decreases, the half life is increase and vice versa. Hepatic disease - When liver is not functioning properly, rate of drug elimination is decreased due to a decreased metabolism leading to increase in half life of drug.

20. Factors affecting half life Urinary pH - pH changes lead altered rate of drug excretion and kidney reabsorption of the drug. Basic drugs are rapidly excreted through acidic urine and vice versa. Age - As rate of metabolism are different in various stage of human age, the half life varies in different age groups.

21. Factors affecting half life In children, liver is not well developed so metabolism rate is slow. In elder patients, system gets exhausted and thus rate is slow. GFR is also gradually decreased after age of 30 years.

22. Factors affecting half life Affinity for protein binding - Customarily, drug bound with protein is not available for drug metabolism and excretion thus leading to an increased half life. However, drugs can be categorized into restrictively cleared and non-restrictively cleared drugs. The restrictive cleared drugs are also known as binding sensitive drugs.

23. Factors affecting half life In restrictively cleared drugs, the bound drugs are not able to diffuse through cell membrane, and thus are not able to reach site of metabolism and excretion. For such drugs, increase in free drug concentration in blood makes more drug available for hepatic extraction as well as for renal excretion.

24. Factors affecting half life Non-restrictively cleared drugs are also known as binding- insensitive drugs. These drugs are extracted by liver with greater rate regardless of bound to protein or free. The elimination half life of such drug is not significantly affected by a change in degree of protein binding.

25. Factors affecting half life Drug is removed from plasma binding sites during circulation through liver by: inducing a conformation change in protein, weakening process of binding and subjecting drug to metabolism. Drugs activity secreted though the renal route are binding insensitive

26. Factors affecting half life Tissue storage - Certain drugs have an affinity for adipose tissue and thus are stored for a prolonged time period leading to an increased half life. Volume of distribution - Half life is function of both clearance and volume of distribution – A drug may have large clearance but still have a long half life due to higher value of volume of distribution

27. Factors affecting half life Co-administration of drug and drug interaction may alter the half life of one another drug by: Competing for protein binding i.e., warfarin and phenylbutazone. Competing for metabolizing enzyme if both are metabolized by the same enzyme Altering the urinary pH Enzyme inhibition - increases the half life Enzyme induction decrease the half life

28. Factors affecting half life Genetic factors - half life of drug is affected by genetic variations. – Some individuals are slow acetylators while others are fast acetylators.