Pharmacokinetics Study Notes PDF

**[PHARMACOKINETICS]** Pharmacokinetics is the effect of biological systems on drugs. It deals with the processes of absorption, distribution, and elimination. *[a) Effective drug concentration]* A relationship exists between the pharmacological effects of a drug and the accessible concentration...

**[PHARMACOKINETICS]** Pharmacokinetics is the effect of biological systems on drugs. It deals with the processes of absorption, distribution, and elimination. *[a) Effective drug concentration]* A relationship exists between the pharmacological effects of a drug and the accessible concentration of the drug. The effective drug concentration is the concentration of drug at the receptor site. Except for topically applied agents, the concentration at the receptor site is usually proportionate to the drug's concentration in the plasma or whole blood at equilibrium. The plasma concentration is a function of 1) the rate of input of the drug (by absorption) into the plasma, 2) the rate of distribution to the peripheral tissues (including the target organ), and 3) the rate of elimination, or loss from the body. If the rate of input is known, the remaining processes are described by 2 parameters: volume of distribution and clearance. These parameters are unique for a particular drug and may differ from patient to patient but have average values in large populations that can be used to predict drug concentrations *[b) Volume of distribution (V~d~)]* The volume of distribution is a hypothetical volume of fluid into which a drug is disseminated. The volume of distribution relates the amount of drug in the body to the plasma concentration according to the following equation: \ [\$\$Vd = \\ \\frac{\\text{Amount\\ of\\ drug\\ in\\ the\\ body}}{\\text{Plasma\\ drug\\ concentration}}\$\$]{.math.display}\ If a drug is avidly bound in peripheral tissues, the drug concentration in plasma may drop to very low values even though the total amount in the body is large. The volume of distribution of drugs that are normally bound to plasma proteins such as albumin can be altered by liver disease and kidney disease *[c) Clearance (CL)]* Clearance is the most important concept to consider when designing a rational regimen for long-term drug administration. The aim is to maintain steady-state concentrations of a drug within a therapeutic window associated with therapeutic efficacy and minimum toxicity. Assuming complete bioavailability, the steady state concentration of a drug in the body will be achieved when the rate of elimination equals the rate of administration. Dosing rate = CL x C~ss~ - Where CL is the clearance of drug from systemic circulation - C~ss~ is the steady-state concentration of drug If the desired steady-state concentration of drug in plasma is known, the rate of clearance by the patient will dictate the rate at which the drug should be administered Clearance relates the rate of elimination to the plasma concentration: \ [\$\$Cl = \\ \\frac{\\text{Rate\\ of\\ elimination\\ of\\ drug}}{\\text{Plasma\\ drug\\ concentration}}\$\$]{.math.display}\ For a drug eliminated with first-order kinetics, clearance is constant i.e. the ration of elimination to plasma concentration is the same regardless of plasma concentration. Clearance depends on the drug and the condition of the organs of elimination of the patient. *[d) Half-life (t~1/2~)]* The half-life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. Half-life is determined by volume of distribution and clearance. Half-life can be determined graphically from a plot of the blood versus time: Clearance is the measure of the body's ability to eliminate a drug. Thus, as clearance decreases, half-life would be expected to increase -- this relationship is only valid when the disease does not change the volume of distribution. Similarly, changes in protein binding of a drug may affect its clearance as well as its volume of distribution, leading to unpredictable changes in half-life. Disease, age and other variables alter the clearance of drug much more than they alter volume of distribution. *Steady-state* Dosing rate = CL x C~ss~ indicates that a steady-state concentration will eventually be achieved when a drug is administered at a constant rate. At this point drug elimination will equal the rate of drug availability Dosing rate = CL x C~ss~ still applies for intermittent dosing, but it now describes the average steady-state drug concentration during an interdose interval. *[e) Bioavailability]* The bioavailability of a drug is the fraction of the administered dose that reaches systemic circulation. The amount of drug that reaches systemic circulation depends not only on the administered dose, but also on the fraction of the dose that is absorbed and escapes first-pass metabolism. Bioavailability is 100% in the case of IV administration. After administration via other routes bioavailability is reduced by 1) incomplete absorption, 2) first-pass metabolism and 3) distribution to other tissues before the drug enters systemic circulation. If a drug is absorbed rapidly and has a small "central" volume, the concentration of drug initially will be high. It will then fall as the drug is distributed to its final larger volume. If the same drug is absorbed more slowly, it will be distributed while it is being administered, and peak concentrations will be lower and will occur later. Controlled-release preparations are designed to produce smaller fluctuations in the plasma concentration-time profile during the dosage interval compared with more immediate release formulations. Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration, with plasma drug levels achieved by IV injection, in which all of the agent enters circulation. By plotting plasma concentrations of the drug versus time, you can measure the area under the curve (AUC). AUC is used to calculate the bioavalability of a drug *Factors that influence bioavailability:* - First-pass hepatic metabolism - When a drug is absorbed across the GI tract, it enters the portal circulation before entering the systemic circulation - If a drug is rapidly metabolized by the liver, the amount of unchanged drug that gains access to the systemic circulation is decreased - Solubility of the drug - Very hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich cell membranes - Drugs that are extremely hydrophobic are also poorly absorbed because they are totally insoluble in aqueous body fluids and therefore cannot gain access to the surface of cells - For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions - Chemical instability - Some drugs are unstable in the pH of gastric contents - Other drugs are destroyed in the GIT by degradative enzymes - Nature of drug formulation - Particle size, salt form, crystal polymorphism, and the presence of exipients can influence the ease of dissolution and therefore alter the rate of absorption *Bioequivalence* Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. 2 *Therapeutic equivalence* Two similar drugs are therapeutically equivalent if they have comparable efficacy and safety *[f) Extraction]* Removal of drug by an organ can be specified as the extraction ratio i.e. fraction of the drug removed from the perfusing blood during its passage through the organ. Drugs that have a high hepatic extraction ratio have a large first-pass effect -- the bioavailability of these drugs after oral administration will be low. *[g) Dosage regimens]* A dosage regimen is a plan for drug administration over a period of time. An appropriate dosage regimen results in the achievement of therapeutic levels of the drug in 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 is used to "load" the volume of distribution with the drug. Ideally, the dosing plan is based in knowledge of both the minimum therapeutic and minimum toxic concentrations of the drug, as well as its clearance and volume of distribution. *Maintenance dose* Because the maintenance rate of drug administration is equal to the rate of elimination at the steady state, the maintenance dosage is a function of clearance: \ [\$\$Dosing\\ rate = \\frac{\\text{Clearance\\ x\\ Desired\\ plasma\\ concentration}}{\\text{Bioavailability}}\$\$]{.math.display}\ If it is important to maintain a concentration above the minimum therapeutic level at all times, either a larger dose may be given at long intervals, or smaller doses at more frequent intervals. If the difference between the toxic and the therapeutic concentrations is small, then smaller doses should be administered more frequently. *Loading dose:* If the therapeutic concentration must be achieved rapidly and the volume of distribution is large, a loading dose may be needed at onset of therapy: \ [\$\$Loading\\ dose = \\ \\frac{\\text{Vd\\ x\\ Desired\\ plasma\\ concentration}}{\\text{Bioavailability}}\$\$]{.math.display}\ *[h) Adjustment of dosage when elimination is altered by disease]* Renal disease or reduced cardiac output often reduces the clearance of drugs that depend on renal function. Alteration of clearance by liver disease is less common but may occur. Impairment of hepatic clearance occurs when liver blood flow is reduced as in heart failure. The dose in a patient with renal impairment may be corrected by multiplying the average dose for a normal person times the ratio of the patient's altered creatinine clearance to normal creatinine clearance \ [\$\$Corrected\\ dose = Average\\ dose\\ x\\ \\frac{\\text{Patien}t\^{\'}\\text{s\\ creatinine\\ clearance}}{100ml/min}\$\$]{.math.display}\ *[\ ]* *[i) Summary of equations]*