Pharmacokinetics

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    • Pharmacokinetics
      • Pharmacokinetics describes changes in plasma drug concentration over time.
    • Distribution and elimination
      • Features of One-compartment model
        • The drug appears to distribute instantaneously after IV administration of a single dose.
        • If the mechanisms for drug elimination, such as biotransformation by hepatic enzymes and renal secretion, are not saturated following the therapeutic dose, a semilog plot of plasma concentration versus time will be linear.
        • The slope of the semilog plot is –k ,where k is the rate constant of elimination and has units of time–1, and the intercept on the y axis is C0
        • Drug elimination is first order
          • a constant fraction of drug is eliminated per unit time
          • For example, one-half of the drug is eliminated every 4 hours
          • With passage of every half –life , 50% of concentration falls down
          • First order is a rapid way of drug elimination than Zero order
          • Elimination of most drugs is a first-order process.
        • The plasma drug concentration (Ct) at any time (t) after administration is given by
          • ln Ct = ln C0kt
          • log Ct = log C0–kt/2.303
        • relationship of the plasma concentrations at any two points in time is given by
          • ln C2 = ln C1 k (t2 t1)
          • log C2 = log C1 k/2.303 (t2 t1)
        • CL = k . Vd
          • rate constant of elimination = k
          • Volume of distribution = Vd
          • whole body clearance = CL
      • Features of Two-compartment model
        • The two-compartment model is a more common model for distribution and elimination of drugs
        • Distribution phase followed by Elimination phase
          • Initial rapid changes in the plasma concentration of a drug are observed because of a distribution phase, the time required for the drug to reach an equilibrium distribution between a central compartment, such as the plasma space, and a second compartment, such as the aggregate tissues and fluids to which the drug distributes.
          • After distribution, a linear decrease in the log drug concentration is observed if the elimination phase is first order.
          • The expressions for ln Ct and CL  for a one-compartment model also apply during the elimination phase for drugs that obey a two-compartment model.
      • First-order elimination
        • It refers to the elimination of a constant fraction of drug per unit time
        • the rate of elimination is a linear function of the plasma drug concentration.
        • Occurs when elimination systems are not saturated by the drug.
      • Zero-order elimination
        • occur when therapeutic doses of drugs exceed the capacity of elimination mechanisms.
        • In this model, the plot of the log of the plasma concentration versus time will be concave upward
        • a constant amount of drug will be eliminated per unit time
        • e g 5 mg of drug will be eliminated every 4 hours
        • Unfortunately , when drugs reach toxic doses , their elimination slows down from First order into Zero order kinetics
      • Half-life (t1/2)
        • Half-life is the time it takes for the plasma drug concentration to be reduced by 50%. This concept applies only to drugs eliminated by first-order kinetics.
        • Half-life is determined from the log plasma drug concentration versus time profile for drugs fitting a one-compartment model or from the elimination phase for drugs fitting the two com- partment model
        • As long as the dose administered does not exceed the capacity of the elimination systems (i.e., the dose does not saturate those systems), the half-life will remain constant.
        • 2 Formulas you need to know for exam (High yield Facts )
          • t1/2 = 0.693/k
          • t1/2 =  0.693 X Vd /CL.
            • Half-life (t1/2)
            • elimination rate constant (k)
            • volume of distribution (Vd)
            • clearance (CL)
        • For therapeutic doses of most drugs in which first-order elimination occurs, >95% of the drug will be eliminated in a time interval equal to five half-lives
      • Multi dose kinetics
        • Repeat administration
          • If a drug that is eliminated by first-order kinetics is administered repeatedly (e.g.,one tablet every 6 hours), the average plasma concentration of the drug will increase until a mean steady-state level is reached.
          • steady-state level will not occur for drugs that exhibit zero-order elimination
          • The interval of time required to reach steady state is equal to five half-lives.
        • Steady state
          • Some fluctuation in plasma concentration will occur even at steady state.
          • Levels will be at the high point of the steady state range shortly after a dose is administered;
          • Levels will be at the low point immediately before administration of the next dose. Hence, steady state designates an average plasma concentration and the range of fluctuations above and below that level.
          • The magnitude of fluctuations can be controlled by the dosing interval
            • A shorter dosing interval decreases fluctuations,
            • A longer dosing interval increases them.
          • On cessation of multidose administration, >95% of the drug will be eliminated in a time interval equal to five half-lives if first-order kinetics applies.
        • Maintenance dose rate
          • Maintenance dose rate is the dose of a drug required per unit time to maintain a desired steady-state level in the plasma to sustain a specific therapeutic effect.
          • To determine the dose rate required to maintain an average steady-state plasma concentration of drug, multiply the desired plasma concentration by the CL:
          • Maintenance dose rate =  Desired [drug concentration]plasma  X  Clearance (CL)
          • (amount / time) = (amount / volume) X (volume / time)
          • How is this equation derived :
            • To remain at steady state, the dose rate must equal the elimination rate
            • that is, the rate at which the drug is added to the body must equal the rate at which it is eliminated.
            • elimination rate =  CL x [drug concentration]plasma.
            • Therefore, because the dose rate must equal the elimination rate to be at steady state, dose rate also equals CL x Desired [drug concentration]plasma
          • If one administers a drug at the maintenance dose rate,a steady state plasma concentration of drug will be reached in four to five half-lives.
            • Don’t confuse ,this is four to five half-lives, not four to five doses! ! ! !
        • Loading dose
          • In which situation do we administer a loading dose?
          • A large loading dose may be needed initially when the therapeutic concentration of a drug in the plasma must be achieved rapidly (e.g., a life-threatening situation in which one can- not wait for 5 half-lives for the drug to reach the desired steady-state level).
          • Loading dose = Desired [drug concentration ]plasma x Vd
          • Amount or mass = (mass / volume) x (volume)
        • Very High yield Fact  for exam
          • Volume of distribution decides Loading dose
          • Clearance decides Maintainence dose

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