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PHARMACOKINETIC

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PHARMACOKINETICS How long it takes for a drug to reach the blood circulationHow long it takes for a drug to reach the blood circulation How long it takes for a drug to reach its site of actionHow long it takes for a drug to reach its site of action How long a drug stays at its site of actionHow long a drug stays at its site of action The dose needed to produce an adequate concentration of drug at its site of actionThe dose needed to produce an adequate concentration of drug at its site of action How often a dose must be given to maintain an adequate concentration of drug at its site of actionHow often a dose must be given to maintain an adequate concentration of drug at its site of action

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Drug Absorption: the rate at which a drug enters the systemic circulation. Instantaneous for bolus intravenous administration Bioavailability: F, the fraction of the dose that reaches the systemic circulation. F=1 for IV administration. Absolute Bioavailability: Estimation of F for any other route in comparison to intravenous administration. Relative Bioavailability: Estimation of F for a dosage form to another given by an extravascular (non-intravenous) route of administration. Distribution: Movement of drug from the central compartment (tissues) to peripheral compartments (tissues) where the drug is present. Elimination: The processes that encompass the effective "removal" of drug from "the body" through excretion or metabolism. Definitions and Pharmacokinetic Terminology

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Excretion: the removal of drug from the body by a physical process such as excretion into urine, bile, or sweat Metabolism: the removal of drug from the body by metabolic transformation of the drug into other compounds. These processes include phase 1 (oxidative) or phase 2 (conjugative) metabolism Volume of Distribution: the theoretical size (volume) of the space necessary to contain the amount of drug in the body given its concentration in specific fluids. Clearance: the characterization of the volume which the body through elimination can completely remove all drug in a given period of time. Half-Life: the length of time necessary to eliminate 50% of the remaining amount of drug present in the body Definitions and Pharmacokinetic Terminology

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Steady-State: the equilibrium condition reached when the amount of drug put into the kinetic system over time exactly equals the amount of drug eliminated by the system over that same period of time. (rate in = rate out) Concentration: the measurement of the amount of drug contained in a specific volume of a biological fluid, typically plasma or urine. Cp Maximum Concentration: the highest OBSERVED concentration from those included as the measurements of the time course of drug. Cmax Time of Maximum Concentration: the time at which the highest concentration is measured from those included as the measurements of the time course of drug. Tmax Area Under the Curve: the integration of drug concentration measurements over time using calculus. AUC0-∞ AUC0-24 AUC0- t

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Clinical Pharmacokinetics Pharmacokinetic Models & Concentration-time Profiles

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A- You have a 10ml of orange squash. Put this into a 990ml of water Amount in water Volume of distribution (Vd) = 1000 Speed rise maximum plateau water one-compartment model & zero-order kinetics

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B- Each minute, empty 10ml of the orange liquid,discard this and replace it with 10ml of water. water Amount in water 10 ml/min 5 ml/min 2.5 ml /min t1/2 Co

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One compartment model, first-order kinetics This is a single compartment model, That would occur if the bloodstream was the only compartment in the body (or if the Vd = the blood volume)

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The Clearance (Cl) of a drug is the volume of plasma from which the drug is completely removed per unit time The fraction of the drug in the body eliminated per unit time is determined by the elimination constant (Ke) Elimination half life (t1/2): the time taken for plasma concentration to reduce by 50% Cl = Ke x Vd t 1/2 = 0.693/Ke *example: Vd=1000 ml Cl= 10 ml/min t 1/2 =70 min Ke=0.01 Vd=amount of drug in the body plasma drug concentration Cl= rate of elimination of drug plasma drug concentration Apparent volume of distribution: the volume of fluid in which a drug would need to be dissolved to have the same concentration in that volume as it does in plasma

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drug half-life

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two-compartment model & zero-order kinetics Why does a patient wake up after 5 minutes after an injection of thiopentone when we know that it takes several hours to eliminate this drug from the body? What happens is that, initially the drug is all in the blood and this blood goes to "vessel rich" organs; principally the brain. After a few minutes the drug starts to venture off into other tissues (fat, muscle etc) it redistributes, the concentration in the brain decreases and the patient wakes up! The drug thus redistributes into other compartments.

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C- This time put this orange squash into a beaker which has a connection with an other one rapid rise equilibrium with the second compartment steady state

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D- Again, each minute, empty 10ml of the orange liquid,discard this and replace it with 10ml of water rapid fall plateau slower gradual fall

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Semi-logarithmic graph of blood concentration versus time alpha ( ) phase: rapid redistribution phase, the alpha phase plateau: equilibrium phase (where blood concentration = tissue concentration) beta ( ) phase: the elimination phase (where blood and tissue concentrations fall in tandem) plateau

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Concentration profile depends on Route of Administration – Intravenous (bolus, infusion) – Extravascular (oral, IM, SQ) – Specialized Disposition of the drug (ADME) – distribution – metabolism – elimination

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concentration-time profile Curve generated by: 1. measuring drug concentration in plasma at time intervals after administration 2. plot drug concentration against sampling time Absorption Distribution Elimination Metabolism Excretion Usualy absorption of a drug from any site, is much more rapid than elimination from the systemic circulation

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Cpmax: maximal plasma concentration tmax: the time at which the maximal plasma concentration occured AUC: area under curve After a single dose of drug is administered, the plasma concentration increasesas the drug is absorbed, reaches a peaks absorption is completed, and then declinesas the drug is eliminated

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rate versus extent of absorption (rate varies) A>B>CA>B>C

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rate versus extent of absorption (extent varies) A>B>C (extent) A=B=C (rate) tmax

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instantenous absorption? i.v oral,i.m,sc

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other administration routes? i.m>sc>oral

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multiple dosing and drug accumulation To maintain a pharmacological effect for a prolonged period, repeated dosing is necessary. HOWEVER If the interval between repeated doses is <4 drug halflives,drug accumulation will occur. Drug has not been eliminated before next dose. 1 x t 1/2 = 50% remaining 2 x t 1/2 = 25% remaining 3 x t 1/2 = 12.5% remaining 4 x t 1/2 = 6.25% remaining

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Steady-state concentration Multiple dosing at 4 x t 1/2 or less, drug accumulates until a steady-state concentration where; rate of elimination = rate of absorption/distribution

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Steady-state concentration

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Drug plasma concentration Sub-therapeutic levels Therapeutic levels Toxic levels Why plasma concentration-dose graphics?

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