PHARMACOKINETIC. PHARMACOKINETICS How long it takes for a drug to reach the blood circulationHow long it takes for a drug to reach the blood circulation.

PHARMACOKINETIC

PHARMACOKINETICS

• How long it takes for a drug to reach the How long it takes for a drug to reach the blood circulationblood circulation

• How long it takes for a drug to reach its How long it takes for a drug to reach its site of actionsite 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 The dose needed to produce an adequate

concentration of drug at its site of actionconcentration of drug at its site of action• How often a dose must be given to How often a dose must be given to

maintain an adequate concentration of maintain an adequate concentration of drug at its site of actiondrug at its site of action

• 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 andPharmacokinetic Terminology

• 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 andPharmacokinetic Terminology

Definitions andPharmacokinetic Terminology

• 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

Clinical Pharmacokinetics

Pharmacokinetic Models&

Concentration-time Profiles

A- You have a 10ml of orange squash. Put this into a 990ml of water

Amount inwater

Volume of distribution (Vd) = 1000

Speed rise

maximumplateau

water

one-compartment model &

zero-order kinetics

B- Each minute, empty 10ml of the orange liquid,discard this and replace it with 10ml of water.

water

Amount inwater

10 ml/min

5 ml/min

2.5 ml /min

t1/2

Co

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)

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 Vdt1/2= 0.693/Ke

*example: Vd=1000 mlCl= 10 ml/mint1/2=70 minKe=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

drug half-life

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.

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

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

Semi-logarithmic graph of blood concentration versus time

alpha () phase: rapid redistribution phase, the alpha phaseplateau: equilibrium phase (where blood concentration = tissue concentration)beta () phase: the elimination phase (where blood and tissue concentrationsfall in tandem)

plateau

Concentration profile depends on

• Route of Administration– Intravenous (bolus, infusion)– Extravascular (oral, IM, SQ)– Specialized

• Disposition of the drug (ADME)– distribution– metabolism– elimination

concentration-time profile

• Curve generated by:1. measuring drug concentration in plasma at time

intervals after administration2. 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

Cpmax: maximal plasma concentrationtmax: the time at which the maximal plasma concentration occuredAUC: 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

rate versus extent of absorption(rate varies)

A>B>C

rate versus extent of absorption(extent varies)

A>B>C (extent)A=B=C (rate)

tmax

instantenous absorption?

i.v

oral,i.m,sc

other administration routes?

i.m>sc>oral

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 t1/2 = 50% remaining

2 x t1/2 = 25% remaining

3 x t1/2 = 12.5% remaining

4 x t1/2 = 6.25% remaining

Steady-state concentration

• Multiple dosing at 4 x t1/2 or less, drug accumulates until a steady-state concentration where;

• rate of elimination = rate of absorption/distribution

Steady-state concentration

Drug plasma Drug plasma concentrationconcentration

SubSub--therapeutic levelstherapeutic levels

Therapeutic levelsTherapeutic levels

Toxic levelsToxic levels

Why plasma concentration-dose graphics?