Pharmacokinetics (Part 4) 2024-2025 University of Baghdad PDF

University of Baghdad College of Medicine 2024-2025 Title: PHARMACOKINETICS (part 4) Grade: 2nd Module: Principles of Pharmacology (PP) Speaker: Dr. Zainab Al-Jassim Date: 23 /10 / 2024  Elimination Drug eliminati...

University of Baghdad College of Medicine 2024-2025 Title: PHARMACOKINETICS (part 4) Grade: 2nd Module: Principles of Pharmacology (PP) Speaker: Dr. Zainab Al-Jassim Date: 23 /10 / 2024  Elimination Drug elimination is the removal of an administered drug from the body. It is accomplished in two ways, either by excretion of an unmetabolized drug in its intact form or by metabolic biotransformation followed by excretion. Removal of drugs from the body occurs via a number of routes. It usually relates to the kidneys through urine; but can also involve the intestines, bile, lungs, breast milk, etc. Drugs that are not absorbed after oral administration or drugs that are secreted directly into the intestines or into bile are eliminated in the feces. Excretion of drugs into sweat, saliva, tears, hair, and skin occurs only to a small extent. Patients with renal dysfunction may be unable to excrete drugs sufficiently via urine and are at risk for drug accumulation and adverse effects. Drugs must be sufficiently polar to be eliminated from the body. Renal elimination of a drug: The most important organ for drug excretion is the kidney. Renal elimination of a drug via the kidneys into urine involves the processes of: -Glomerular filtration -Active tubular secretion -Passive tubular reabsorption 1. Glomerular filtration: Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate. The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in GFR and protein binding of drugs do affect this process 2. Proximal tubular secretion: refers to the active secretion of drugs in proximal tubules. The drug is actively pumped into the urine, against its concentration gradient. Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems: one for anions (Ex., deprotonated forms of weak acids) and one for cations (Ex., protonated forms of weak bases). Competition between drugs for these carriers can occur within each transport system (Ex., Probenecid has the ability to block the transport of organic acids (e.g. penicillins) across renal proximal tubule cells which result in elevated blood levels of the penicillin and a longer duration of antimicrobial action). 3. Distal tubular reabsorption: As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may passively diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “ion trapping.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption.  Clearance: means the rate at which the organ involved removes the drug, Or is the volume of plasma cleared of the drug over a specified time period. The usual units are ml/min or L/h. The total ability of the body to clear a drug from the plasma is renal clearance plus hepatic clearance plus clearance from all other tissues. CL Total = + Cl hepatic + CL renal + CL pulmonary + CL other where CL hepatic + CL renal are typically the most important. For patients with cardiac insufficiency, kidney and liver disease, drug clearance can be severely affected. The ability of serum proteins to bind to drugs also can play a role in clearance. A decrease in serum proteins may cause an increase in free drug concentration in the plasma, thus increasing its rate of elimination from the body. Elimination rate constant (Kel): is the rate at which a drug is removed from the body. The usual unit is h−1. Kel= CL/Vd  Half- life Elimination half-life (t1/2): The time required for the concentration of the drug to reach half of its original value. T1/2=0.693/Kel about 5 half lives are required to eliminate drug dose from the body. It takes about 5 half-lives for a drug to be roughly 97% eliminated. (50%, then 75% then 87.5% then 93.75% then 96.875%). Half life is increased by an increase in the volume of distribution and increased by a decrease in the rate of clearance. (t½ = 0.693 × Vd /CL) After starting a new drug with multiple doses, about 4 to 5 half lives are required to achieve a steady state concentration of a drug in plasma. ☻What is Steady State (SS)? Rate in = Rate Out (dosing rate= eliminating rate) Reached in 4 – 5 half-lives Css: Steady-state drug concentration (e.g. the concentration measured from a blood sample once steady-state conditions have been achieved after continuous drug dosing) ❑Ex. The half-life of caffeine is approximately 5 hours and If a drug initial concentration was 100 mg/ml in plasma, then: After 1st Half-Life (5 hours): 100 mg / 2 = 50 mg After 2nd Half-Life (10 hours): 50 mg / 2 = 25 mg After 3rd Half-Life (15 hours): 25 mg / 2 = 12.5 mg After 4th Half-Life (20 hours): 12.5 mg / 2 = 6.25 mg After 5th Half-Life (25 hours): 6.25 mg / 2 = 3.125 mg after the first t1/2 it will be 50 mg/ml, after the second 25 mg/ml, the third 12.5, the fourth 6.25, the fifth 3.125. ❑Ex. If the t1/2 of paracetamol was 3 hours, then it is required (5t1/2 = 5*3) 15 hours to eliminate drug dose from the body. ❑Ex. If the t1/2 of Digoxin was 40 hours, then we need (5*40) 200 hours (=8.33 days) to achieve steady state level after multiple regular dosing.  Zero Order Kinetics First-order Kinetics Rate of elimination independent of Rate of elimination is proportional plasma concentration to plasma concentration Half Life = Not constant Half Life = Constant Constant amount is eliminated per Constant fraction is eliminated per unit of time unit of time Clearance not constant Clearance constant Very few drugs follow pure zero Most of the drugs follow first order order kinetics. Any drug at high kinetics. conc. (when metabolic or elimination pathway is saturated) may show zero order kinetics. Clinical situations resulting in changes in drug half-life:  increase in drug half-life in those with: diminished renal or hepatic blood flow (cardiogenic shock, heart failure, or hemorrhage), decreased ability to extract drug from plasma (renal disease), and in cases of decreased metabolism (drugs inhibit metabolism, cirrhosis). These patients may require a decrease in dosage or less frequent dosing intervals. In contrast, the half-life of a drug may be decreased by increased hepatic blood flow, decreased protein binding, or increased metabolism. This may necessitate higher doses or more frequent dosing intervals. Maintenance dose: is the dose of drug that is to be administered to keep the plasma concentration of a drug within a certain level at steady state. Drugs are generally administered to maintain a Css within the therapeutic window. It takes four to five half-lives for a drug to achieve Css. Loading dose: Sometimes rapid obtainment of desired plasma levels is needed (for example, in serious infections or arrhythmias). Therefore, a “loading dose” of drug is administered to achieve the desired plasma level rapidly, followed by a maintenance dose to maintain the steady state. Loading dose=(Vd )×(desired Css)/F Loading dose for IV =(Vd )×(desired Css)