Overview of Pharmacokinetic Parameters.pdf
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The document discusses pharmacokinetics, focusing on key parameters such as bioavailability, volume of distribution, clearance, and half-life. It defines these terms, explains their clinical significance, and outlines methods for calculating them, including the concepts of first-order and zero-order kinetics. Additionally, it provides examples and calculations related to drug dosing and elimination processes.
Overview of Pharmacokinetic Parameters.pdf
- 1. Dr. Dabal Bahadur Dhami MD Associate Professor Department of Clinical Pharmacology Karnali Academy of Health Science, Jumla, Nepal
- 2. Learning Objectives At the end of the lectures, you should be able to: - Define pharmacokinetics parameter such as - Bioavaibility - Volume of distribution (Vd.) - Plasma half-life (t1/2) - Clearance (CL) - Differentiates between first order and zero order kinetics of elimination.
- 3. Bioavailability • Definition: • Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route. • Bioavailability = AUC Oral / AUC IV × 100 • Relative bioavailability (Bioequivalence) = AUC of drug A/ AUC of Standard • Bioavailability of drug injected IV is 100%.
- 4. What is AUC ? • It is area under plasma concentration-time curve. • AUC is a measure of quantity of drugs in the body. • AUC can be calculated by the following methods: • 1. Square counting method • 2. Cutting and weighing method • 3. Planimetery • 4. Trapezoidal rule • The most commonly method used to calculate AUC is trapezoidal rule
- 5. Significance of bioavailability 1. Oral dose is more as compared to IV Dose. 2. Marked interindividual variation in first pass metabolism, hence dose adjustment required. 3. Hepatic diseases affect first pass metabolism, hence concentration achieved will be high. 4. Drug interactions can occur when 2 drugs compete for same pathway of first pass metabolism.
- 6. Volume of Distribution • a/k apparent volume of distribution(aVd) - It is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. - It is expresses in liters. - For example: amount of drug in the body is 1000mg, blood concentration is 50mg/L. What is aVd ?
- 7. Volume of distribution •Amount of a drug X administered to a patient is 4.0 g and its plasma concentration is found to be 50 mg/ml, what will be the volume of distribution of drug X? A. 100L B. 80L C. 60L D. 50L
- 8. Significance of volume of distribution 1. The higher the Vd, the lower the plasma concentration and vice versa. 2. Vd is low when a high percentage of a drug is bound to plasma proteins. 3. Tissue binding and accumulation of drugs with high Vd values raise the possibility of displacement by other agents changes in pharmacologic activity 4. Volume of distribution increases in renal failure and liver failure and decreases in dehydration. 5. Hemodialysis in drug poisoning: Drugs with low Vd can be easily removed by hemodialysis, e.g. Salicylates
- 9. Clearance (CL) Clearance (CL): defined as the volume of the plasma cleared of the drug in a unit time CL: Rate of Elimination/ Plasma concentration It is expresses as ml/minute. If given clearance is 5 ml/minute, it means that 5 ml of plasma is cleared of the drug Clinical significance: Clearance is the most important concept to be considered when a rational regimen for long-term drug administration is to be designed.
- 10. The half-life (t½) • Half-Life - is the time taken for the drug concentration to fall to half its original value. • Half-Life: derived parameter • It determines the time required to reach steady state concentration and dosage interval t ½ = 0.693 / Kel, Kel = CL / Vd t ½ = 0.693 X Vd/ CL • It provides an index of: - the time-course of drug elimination - the time-course of drug accumulation - choice of dose interval.
- 11. The half-life (t½) • The half-life of a drug is increased by - diminished renal plasma flow - hepatic blood flow - decreased extraction ratio and - decreased metabolism. • The half-life of a drug may decrease by - Increased hepatic blood flow - Decreased protein binding, and - Increased metabolism.
- 12. MCQ • A volunteer Ram will receive a new drug in a phase I clinical trial. The clearance 1.386 L/hr and the volume of distribution 80 L of the drug. The half life of the drug in him would be approximately: • (a) 83 hr • (b) 77 hr • (c) 40 hr • (d) 0.02 hr T ½ = 0.693 Vd/ CL
- 13. Significance of The half-life (t½) 1. Half-life determines frequency of administration or dosing interval of drug, e.g. If t½ is 12 hours, then drug is given twice a day 2. When rate of absorption equals rate of elimination steady state is said to be achieved. 3. Plasma protein binding increase half-life 4. Drug widely distributed and sequestrated in tissues got longer half-life, 5. Half-life is a derived parameter that changes as a function of both clearance and volume of distribution. 6. Half-life is constant in first order kinetics and increase with increase in concentration in zero order kinetics
- 14. Significance of The half-life (t½) • Approximately 5-6 half-lives are required for complete elimination of drug from the body: - 1 Half- life- 50% drug is eliminated - 2 Half - life-75% (50+25) - 3 Half life- 87.5%(50+25+12.5) - 4 half life-93.75% (50+25+12.5+6.25) - 5 half life 97% (50+25+12.5+6.25+3.125)nearly complete drug the elimination
- 15. MCQ • Elimination after 3 half lives in first order kinetics is: A. 12.5% B. 75% C. 87.5% D.94%
- 16. MCQ • Drug remaining in the body after 3 half lives is: • (a) 12.5% • (b) 75% • (c) 87.5% • (d) 94%
- 17. Drug elimination • Rate of Elimination - is the amount of drug eliminated per unit time • Rate of elimination = glomerular filtration rate (GFR) + active secretion - reabsorption (active or passive). • The plot has two slopes. - Initial rapidly declining (α) phase-due to distribution. - later less declined (β) phase-due to elimination.
- 18. MCQ • Rate of elimination of a new drug is 20 mg/hr at a steady state plasma concentration of 10 mg/L, then its renal clearance will be: • (a) 0.5 L/hr • (b) 2.0 L/hr • (c) 5.0 L/hr • (d) 20 L/hr
- 19. First order kinetic elimination • First order kinetic: the rate of elimination is directly proportional to the drug concentration, CL remains constants or constant fraction of drug present in the body is eliminated in unit time. • For example, if 80 mg of a drug is administered and its elimination half-life is 4 h, then the time course of its elimination is:
- 20. Zero order kinetics - The rate of elimination remains constants irrespective of drug concentration, CL decreases with increases in concentration or constant amount of drug is eliminated with unit time e.g ethyl alcohol, phenytoin, Aspirin etc • For example, if 80 mg is administered and 10 mg is eliminated every 4 h, then the time course of drug elimination is:
- 22. Difference in first order and zero order kinetics First order kinetic Zero order kinetics Rate of elimination is directly proportional to the plasma drug concentration Rate of elimination remains constants irrespective of plasma drug concentration CL remains constants CL decreases constant fraction of drug is eliminated at constant interval of time constant amount of drug is eliminated with unit time T1/2 always remain constant irrespective of doses T1/2 always never constant irrespective of doses Plasma fall out curve curvilinear in arithmetic and linear in logarithm Plasma fall out curve steep and linear in arithmetic and curvilinear in logarithm If dose of the drug is doubled, the duration of action is prolonged by one more half life
- 23. Loading dose & Maintenance dose • Loading dose • The "loading dose" is one or a series of quickly repeated doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly • Loading dose = Vd × Target plasma concentration • It is mainly dependent on Vd. Maintenance dose • To maintain steady state a maintenance dose is required. • Maintenance dose = CL × Target plasma concentration • It is mainly dependent on CL.
- 24. MCQ • A patient admitted to Hospital with respiratory infection for which antibiotic tobramycin is ordered. The clearance is 160 ml/ min and Vd is 40 L of tobramycin. If you wish to give an intravenous loading dose to achieve the therapeutic plasma concentration of 4 mg/L rapidly, how much should be given? a) 120mg b) 160mg c) 180mg d) 200mg Loading dose = Vd × target plasma conc. = 40 L × 4 mg/L = 160 mg
- 25. Any Question?
- 26. References