W2-Pharmacokinetics 3 students.pdf

Clinical Application of Pharmacokinetics Dr.Leila Alblowi Table of contents 01 Understand the clinical applications of pharmacokinetics 02 Explain the significance of bioavailability (F) and volume of distribution (Vd) 03 Differentiate between first-order and zero-order kinetics 04 Expl...

Clinical Application of Pharmacokinetics Dr.Leila Alblowi Table of contents 01 Understand the clinical applications of pharmacokinetics 02 Explain the significance of bioavailability (F) and volume of distribution (Vd) 03 Differentiate between first-order and zero-order kinetics 04 Explain the drug elimination half-life 05 Calculate loading and maintenance doses CLINICAL APPLICATIONS OF PHARMACOKINETICS The interactions among drug absorption, distribution, metabolism, and excretion can : ✓ Determine the plasma concentration of a drug ✓ Dictate the drug’s ability to reach its target organ in an effective concentration. CLINICAL APPLICATIONS OF PHARMACOKINETICS A single dose is often insufficient to maintain a consistent therapeutic effect; multiple doses are needed to keep plasma concentration within therapeutic limits. Standard Doses: Clinical trials suggest standard doses for the average patient. Designing Dosing Regimen Considerations: Pharmacokinetic differences. Disease status. Pharmacogenomic profiles of individual patients. Pharmacokinetics Onset of action Peak concentration Duration of action MEC=minimum effective concentration MTC= maximum tolerated concentration  Bioavailability (F) F is the fraction of the drug that reaches the systemic circulation following administration.Depend on : 1. Route by which the drug is administered 2. Chemical form of the drug 3. Number of patient-specific factors such as gastrointestinal and hepatic transporters and enzyme F for oral admin drug is lower due to uncompleted absorption and first pass metabolism F= ?? % for IV admin drug Volume of Distribution The volume of distribution (Vd) describes the extent to which a drug partitions between the plasma and tissue compartments. Drugs with low Vd : -Retained primarily within the vascular compartment Drugs with high Vd : -Are highly distributed into adipose and other nonvascular compartments (e.g. bone, teeth, muscles)  Volume of Distribution For very highly distributed drugs, the volume of distribution is often much greater than the volume of total body water (TBW=42 liters of water, in 70-kg person) Reflecting the low concentration of drug in the vascular compartment Examples of drugs with very large volumes of distribution: ✓ Amiodarone (4,620 L) ✓ Digoxin (645 L) For a 70-kg person Elimination Drug elimination expressed as clearance (CL). Clearance is expressed in units of volume/time e.g. ml/min or l/h. The overall clearance of a drug (Cltot) is the sum of clearance rates for each mechanism involved in eliminating the drug: Cltot= CLren + CLmet + CL others It is defined as the volume of plasma which contains the total amount of drug that is removed from the body in unit time.  Clearance First-order kinetics Zero-order kinetics Most drugs exhibit first-order kinetics at standard A constant amount of drug is eliminated per unit of time. therapeutic doses. The rate of elimination is constant and does not depend The rate of elimination is directly proportional to on the drug concentration. drug concentration Phenytoin and ethanol, show saturation kinetics. Clearance mechanisms for most drugs are not Clearance mechanisms become saturated at or near saturated under normal conditions. the therapeutic concentration. Increases in plasma drug concentration lead to Once saturation happens, the clearance rate does not proportional increases in the rates of drug increase with higher plasma drug concentrations. metabolism and excretion. This can cause dangerously elevated plasma ↑Plasma drug concentration→ ↑rate of drug metabolism. concentrations, leading to toxic or lethal effects. Clearance not constant. ↑plasma drug concentration →no↑ rate of metabolism Half-life is not constant Clearance constant. Half-life is constant Comparison of first- order and zero-order elimination Comparison of first- order and zero-order elimination  Clearance The first-order elimination rate (where elimination includes both metabolism and excretion) follows Michaelis-Menten kinetics: Vmax: is the maximum rate of drug elimination Km: the drug concentration at which the rate of elimination is ½Vmax C: is the concentration of drug in the plasma E: is the elimination rate Clearance  Elimination Half-Life (t1/2) Defined as: Half-life (t1/2) is the time required for the body to eliminate 50% of the drug. Clinical significance: Knowing a drug’s elimination half-life helps clinicians estimate the dosing frequency needed to maintain the drug's plasma concentration within the therapeutic range. Unique half-life: Each drug has its own half-life (t ½), which indicates the drug's duration of action. Elimination: It typically takes 4-5 half-lives for a drug to be completely eliminated from the body.  Elimination Half-Life (t1/5) 5x t1/2= time at which the drug is “completely” (97%) eliminated from the body (single dose). 1x ½ life - 50% of the original drug removed 2x ½ life - 75% 3x ½ life - 87.5% 4x ½ life - 93.75% 5x ½ life - 96.875% E.g. drug with t1/2 =10 hr needs 50hrs (⁓2days) to be eliminated completely.  Elimination Half-Life (t1/5) Drugs with a short half-life (2–4 hours) need to be administered frequently. Drugs with a long half-life (21–24 hours) requires less frequent dosing. When designing any dosing regimen, the half-life of a drug must be carefully considered. For example: ✓ Digoxin has a long half-life (36 hours) and requires once-daily dosing. ✓ t1/5 of Amiodarone is more than 1 month  Elimination Half-Life (t1/5) All of the factors that affect the volume of distribution and clearance of a drug also affect the half-life of the drug. Decrease in drug clearance or Increase in volume of distribution: → Prolong the elimination half-life → Enhance the effect of the drug on the target organ Factors Affecting the Elimination Half-Life (t1/5)  Therapeutic Dosing and Frequency Absorption, distribution, metabolism, and excretion, play a crucial role in designing an optimal dosing regimen for a drug. Absorption : Determines the potential route(s) of administration and optimal drug dose For two drugs with the same potency, the more highly absorbed drug—a higher bioavailability—generally requires a lower dose than the more poorly absorbed drug Distribution. Highly distributed drug by a higher volume of distribution requires higher drug dosing Elimination Influences half-life and thereby determines the frequency of dosing required to maintain therapeutic plasma drug levels  Therapeutic Dosing and Frequency Therapeutic dosing aims to keep plasma drug concentrations within a safe and effective range. Peak (highest) concentration: Should be below the toxic level.. Trough (lowest) concentration: Should be above the minimally effective level Therapeutic Dosing and Frequency. Steady state  Loading Dose loading dose an initial large dose administered to achieve therapeutic plasma levels of drug rapidly before dropping down to a lower maintenance dose. Without a loading dose: It takes approximately four elimination half-lives for a drug's tissue distribution and plasma concentration to reach a steady state.  Loading Dose Example : Lidocaine has a volume of distribution of 77 L in a 70-kg person. Assuming that a steady state plasma concentration of 3.5 mg/L is needed to control ventricular arrhythmias The appropriate loading dose of lidocaine in this person can be calculated as: ????????????  Maintenance Dose It is the dose required for regular administration to maintain a target therapeutic plasma level Maintenance dose is mainly dependent on clearance Interactive session If the half-life of the medication is 6 h. How long approximately will it take for the drug to be excreted from the body? If a medication is administered in a 60 mg daily dose orally and 30 mg of the drug is absorbed from the gastrointestinal tract unchanged. What is the bioavailability of that medication? Questions