PHARMACOKINETICS JSA.pptx in clinical Pharmacology

Pharmacokinetics is a fundamental branch of pharmacology concerned with what the body does to a drug after it has been administered. It involves the study of the time course of drug absorption, distribution, metabolism, and excretion (ADME). These processes determine the concentration of a drug in various tissues and fluids of the body over time, which in turn influences the drug’s therapeutic efficacy, onset of action, duration of effect, and potential toxicity.

Understanding pharmacokinetics is critical in clinical practice, as it forms the basis for determining the appropriate drug, dose, dosage frequency, and route of administration for individual patients. Differences in pharmacokinetic profiles account for variations in drug responses among individuals and patient groups, such as the elderly, infants, pregnant women, and individuals with renal or hepatic impairment.

Pharmacokinetics works hand-in-hand with pharmacodynamics (what the drug does to the body). While pharmacodynamics deals with the biochemical and physiological effects of drugs, pharmacokinetics deals with the journey of the drug through the body, from entry to elimination. The two disciplines interact to provide the overall dose–response relationship of any medication.

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2.0 The Pharmacokinetic Processes (ADME)

2.1 Absorption

Absorption refers to the movement of a drug from the site of administration into the systemic circulation. Drugs must cross biological membranes, which are composed primarily of lipid bilayers. Therefore, the physicochemical properties of the drug, such as lipid solubility, degree of ionization, molecular size, and formulation, influence absorption.

Factors Affecting Absorption:
1. Route of administration:
• Drugs given intravenously bypass absorption.
• Oral drugs undergo first-pass metabolism in the liver.
2. Blood flow to the absorption site: Higher blood flow leads to faster absorption.
3. Surface area: The small intestine provides a large surface area, enhancing absorption.
4. Drug solubility: Lipid-soluble drugs cross membranes more easily.
5. Gastrointestinal motility: Increased motility may reduce absorption by reducing contact time.

Mechanisms of Absorption:
• Passive diffusion (most common)
• Facilitated diffusion
• Active transport
• Endocytosis and exocytosis

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2.2 Distribution

After absorption, drugs are transported by the bloodstream to tissues and organs. Distribution is influenced by blood flow, capillary permeability, and the extent of plasma protein binding. Only free (unbound) drugs are pharmacologically active.

Key Determinant: Plasma Protein Binding
• Drugs bind largely to albumin (for acidic drugs) or α-1-acid glycoprotein (for basic drugs).
• Increased protein binding decreases free drug concentration, reducing effect but prolonging duration.
• In malnutrition, burns, liver failure, and nephrotic syndrome → hypoalbuminemia → more free drug → increased risk of toxicity.

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2.3 Metabolism (Biotransformation)

1. GOMBE STATE UNIVERSITY DEPARTMENT OF PHARMACOLOGY AND THERAPEUTICS BY: UG19/MDMD/1047 TOPIC: PHARMACOKINETICS MODERATOR: MUIDEEN .O DATE: 26/09/25 1

2. Outline Introduction Key terms ADME Key parameters Clinical importance Cases Conclusion References 2

3. What is Pharmacokinetics The journey of a drug through the body Pharmacokinetics denotes the effects of biologic systems on drugs. The major processes involved in pharmacokinetics are absorption, distribution, elimination and with some even adding metabolism forming the mnemonic ADME 3

4. Key Terms Clearance: The ratio of the rate of elimination of a drug to the concentration of the drug in the plasma or blood. Units: volume/time, eg , mL/min or L/h Half-life: The time required for the amount of drug in the body or blood to fall by 50%. For drugs eliminated by first-order kinetics, this number is a constant regardless of the concentration. Units: time Bioavailabity : The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation First-pass effect: The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation Volume of distribution: The ratio of the amount of drug in the body to the drug concentration in the plasma or blood. Units: 4

5. ADME 5

6. ADME Absorption: This is simply the process by which a drug enters the systemic circulation following administration . It has a few factors which affect it which include; Route of administration; could be oral or IV Drug formulation Physiological factors 6

7. Distribution: This is the reversible transfer of a drug from the bloodstream into the tissues and organs of the body, factors affecting it include; Blood flow Plasma protein binding Lipid solubility Tissue binding 7

8. Metabolism: This is the chemical alteration of the drug by the body, primarily in the liver, it has 2 phases; Phase I: also called functionalization which refers to reactions like oxidation, reduction, hydrolysis. It is often mediated by Cytochrome P450(CYP450) enzyme Phase II: also called conjugation which refers to the drug or its metabolite is combined with another molecule e.g glucoronic acid to make it easily excretable 8

9. Excretion: the process of removing a drug and its metabolites from the body, its primary routes includes, Kidney Billiary / fecal Other routes 9

10. Key Parameters Bioavailability: is the fraction (F) of the administered dose that reaches the systemic circulation . After administration by other routes, bioavailability is generally reduced by incomplete absorption (and in the intestine, expulsion of drug by intestinal transporters), first-pass metabolism, Even for drugs with equal bioavailabilities , entry into the systemic circulation occurs over varying periods of time, depending on the drug formulation and other factors. To account for such factors, the concentration appearing in the plasma is integrated over time to obtain an inte grated total area under the plasma concentration curve ( AUC) 10

11. Clearance (CL ): relates the rate of elimination to the plasma concentration: CL= Rate of elimination of drug/Plasma drug concentration (Units = Volume per unit time. For a drug eliminated with first-order kinetics, clearance is a constant; that is, the ratio of rate of elimination to plasma con centration is the same over a broad range of plasma concentration The magnitudes of clearance for different drugs range from a small percentage of the blood flow to a maximum of the total blood flow to the organs of elimination. Clearance depends on the drug, blood flow, and the condition of the organs of elimination in the patient 11

12. The volume of distribution ( Vd ): relates the amount of drug in the body to the plasma concentration according to the following equation: Vd = Amount of drug in the body/Plasma drug concentration Unit= Volume The calculated parameter for the Vd has no direct physical equiva lent; therefore, it is usually denoted as the apparent Vd . Because the size of the compartments to which the drug may be distributed can vary with body size, Vd is sometimes expressed as Vd per kilogram of body weight ( Vd /kg) 12

13. Half-life (t1/2 ): is a derived parameter, completely determined by Vd and CL. Like clearance, half-life is a constant for drugs that follow first-order kinetics. Half-life can be determined graphically from a plot of the blood level versus time or from the following relationship: t 1/2 = 0.693xVd/CL Unit = Time Disease , age, and other variables usually alter the clearance of a drug much more than they alter its Vd . The half-life determines the rate at which blood concentration rises during a constant infusion and falls after administration is stopped 13

14. Extraction: Removal of a drug by an organ can be specified as the extraction ratio, that is, the fraction or percentage of the drug removed from the perfusing blood during its passage through the organ 14

15. Clinical importance Dosage regimen: A dosage regimen is a plan for drug administration over a period of time. An optimal dosage regimen results in the achievement of therapeutic levels of the drug in the blood without exceeding the minimum toxic concentration. To maintain the plasma concentration within a specified range over long periods of therapy, a schedule of maintenance doses is used. If it is necessary to achieve the target plasma level rapidly, a loading dose may be used to “load” the Vd with the drug . Maintenance Dosage Because the maintenance rate of drug administration is equal to the rate of elimination at steady state (this is the definition of steady state), the maintenance dosage is a function of clearance Dosing rate =CL x Desired plasma concentration/Bioavailability 15

16. Loading dose: If the therapeutic concentration must be achieved rapidly and the Vd is large, a large loading dose may be needed at the onset of therapy. This can be calculated from the following equation: Loading dose= Vd x Desired plasma concentration/Bioavailability Note that clearance does not enter into this computation. If the loading dose is large ( Vd much larger than blood volume), the dose should be given slowly to prevent toxicity due to excessively high plasma levels during the distribution phase. 16

17. Clinical importance The therapeutic window: is the safe range between the minimum therapeutic concentration and the minimum toxic concentration of a drug. These data are used to determine the acceptable range of plasma levels when designing a dosing regimen. Thus, the minimum effective concentration usually determines the desired trough levels of a drug given intermittently, whereas the mini mum toxic concentration determines the permissible peak plasma concentration. For example, the drug theophylline has a therapeutic concentration range of 8–20 mg/L but may be toxic at concentrations of more than 15–20 mg/L. The therapeutic window for a particular patient might thus be 8–16 mg/L (Figure 3–6). Unfortunately , for some drugs the therapeutic and toxic concentrations vary so greatly among patients that it is impossible to predict the therapeutic window in a given patient. Such drugs must be titrated individually in each patient. 17

18. Cases Mr Jones has zero kidney function and is undergoing hemo dialysis while awaiting a kidney transplant. He takes metfor min for type 2 diabetes mellitus and was previously stabilized (while his kidney function was adequate) at a dosage of 500 mg twice daily, given orally. The plasma concentration at this dosage with normal kidney function was found to be 1.4 mg/L. He has been on dialysis for 10 days and metformin toxicity is suspected. A blood sample now shows a metformin concentration of 4.2 mg/L. What was Mr. Jones’ clearance of metformin while his kidney function was normal? 18

19. Rate in = rate out ( elimination rate) at steady state ( ss ) CL = rate in / Cp ( ss ) = CL 1000mg/24h /1.4mg/L CL = 29.8 L/h 19

20. Ms Smith, a 65-year-old woman with pneumonia, was given tobramycin, 150 mg, intravenously. After 20 minutes, the plasma concentration was measured and was found to be 3 mg/L. Assuming no elimination of the drug in 20 minutes, what is the apparent volume of distribution of tobramycin in Ms Smith ? Vd = loading dose / Cp = =150mg/3mg/L Vd = 50 L 20

21. Conclusion Pharmacokinetics is essential for safe and effective drug therapy ADME processes determine drug concentration in the body Understanding pharmacokinetics is essential for improving patient outcomes. 21

22. References Katzung BG, Basic & Clinical pharmacology Goodman & Gilman’s. The pharmacological Basis of therapeutics Google.com U.S. Food & Drug Administration (FDA) 22