What is pharmacokinetics?

The study of the kinetics of drug absorption and disposition

What is the equation for the concept of distribution (V_{D}) of drugs?

Volume of beaker = Amount added/[Drug]

V_{D} = A/[D]_{P}

Where A = amount of drug in body and [D]_{P} = concentration of plasma in blood

If you want to locate a specific drug in the plamsa what value would you use?

[D]P(target)

A_{(target)} = V_{D} x [D]_{P(target) }

Where A_{target} it the amount of drug in the body required to achieve [D]_{P(target)}

What is the equation for loading dose?

LD x B = A_{target }

LD = A_{target}/B

LD = (V_{D }x [D]_{P(target)})/B

Where B is bioavailability (the fraction od administered dose absorbed from the body)

What is the equation best used for loading dose?

LD = (V_{D} x [D]_{P(target)})/B

What determines the rapid target concentration of a drug in the plasma?

Concentration of drug in plasma, bioavailability and the volume

Which will be better distributed to the body and large V_{D} or a small V_{D}?

Large

As V_{D} goes up, what happens to the [D]_{P} in tissue binding?

Goes down

How is V_{D} obtained from the body?

Give bolus of drug, measure plasma levels over time, extrapolate to find plasma level at time 0

VD = amount in body at time 0/[D]_{P}^{0} = Dose_{IV}/[D]_{P}^{0}

What is the differncce between 1 compartment and 2 compartment V_{D}?

V_{D(final)} reached in minutes with 1

VD_{(final)} reached only after delay with 2

What equation would you used if the drug exhibited 1-compartment behavior?

LD = (VD x [D]_{P(target)})/B

What equation would you use for a drug that inhibits 2-compartment behavior?

LD = (V_{?} x [D]_{P(target)})/B

? = V_{D(aplha) }or V_{D(beta)} depending on trade offs

Solve for parameters of Digoxin LD. Given:

[D]_{P(target)} = 1.5 ug/L

V_{D}= 580 L

Oral bioavailability = 0.7

Oral LD = (580 L x 1.5 ug/L) /0.7

Oral LD = 1243 ug or 1.2 mg

What is the equation for drug clearance?

Cl = Rate of Drug elimination /[D]_{P}

What are the units for Drug Clearance?

Volume/Time

Solve for drug clearnace. Given:

Rate of drug elimination = 10 mg/hr

[D]_{P} = 4 mg/L

Cl = 10 mg/hr **/** 4 mg/L

Cl = 2.5 L/hr

How are most drug eliminated by the body?

First order kinetics

Drug clearnance is a determinant of [D]_{P} at....

Steady state [D]_{P}^{SS}

When is the steady state said to exist?

Rate of Drug Administration (R_{0}) = Rate of drug elimination

Input = Output

What is the equation for steady state?

[D]_{P}^{SS} = Rate of drug eliminiation stead state/ Cl

R_{0} = Rate of Drug administration steady state

What is the maintance dose (MD)?

AMount of drug taken at regular intervals

What is the dosing interval (DI)?

Time between MDs

What is bioavailability?

Fraction of administered dose that is absorbed into systemic circulation

What is the equation for rate of drug administration?

R_{0} = (B x MD) / DI

What is the equation for drug clearance steady state?

[D]_{P}^{SS} = (B x MD) / (DI x Cl)

What is [D]_{P}^{SS} dependent on?

The ratios of MD and DI

What is [D]_{P}^{SS} a major determinant of?

Therapeutic response

Toxicity

When the goal is to provide [D]_{P(target)} how is the equation for drug clearance stead state rearranged?

MD/DI = ([D]_{P(target)} x Cl) / B

The rate of elimination most occurs in the ____ and ___.

Liver and kidney

What are the rate of renal elimination and the rate of hepatic elimination?

Cl_{R} and Cl_{H}

What is the equation for drug clearnance determination of full clearance?

(For liver and renal stuff)

Cl = Cl_{R} + Cl_{H}

What is the rate of renal elimination due to?

Glomerular filtration of drug not bound to plasma proteins

Secretion into renal tubulesof acidic and basic drugs by transport systems in proximal tubule

What is the rate of renal elimination reduced by?

Reabsoprtion of lipophilic drugs from renal tubule

Renal diseases that dec glomerular filtration and tubular secretion of drug

Competition between drugs for secretion by transport systems in the proximal tubule

What is hepatic elimination due to?

Metabolism of drugs by liver enzymes

Secretion of drugs into bile by transport systems in the hepatocytes

What is hepatic elimination reduced by?

Ionization of drugs which limits penetration of drug into hepatocytes

Competition between drigs for metabolism and/ or transport into bile

Liver disease

Genetic variation in drug metabolizing enzyme

What is heptic elimination increased by?

Induction of liver enzymes by same drug, other drug and/or environmental chemicals

Genetic variation in drug metabolizing enzymes

What equation tells the rate of drug administration?

MD/DI = ([D]_{P(target)} x Cl) / B

What is the equation for the therapeuric window?

TW = highest [D]_{P} that is safe/ lowest [D]_{P} that is therapeutically effective

What is the maximum dosing interval (DI_{max})?

The longest dosing interval that still provides non-toxic peak plasma levels of drug while providing therapeutically effective trough plasma levels of the drug

What is elimination t_{1/2}?

Time required for drug elimination process to decrease by the amount of drug in the body by 50%

What is the equation for maximum dosing interval?

DI_{max} = 1.44 x t_{1/2} x ln (TW)

Solve for the oral MD/DI for digoxin. Given:

[D]_{P}_{(target)} = 1.5 ug/L

Cl = 6.6 L/hr

Oral bioavailability = 0.7

Oral MD/DI = ([D]_{P(target)} x Cl) / B

=(1.5 ug/L x 6.6 L/hr) **/** 0.7

= 14.1 ug/L

Calculate DI_{max} for Digoxin: Given:

D_{P(effect)} > 0.8 ug/L

D_{P(toxic)} > 2.5 ug/L

t_{1/2} = 39 hrs

DI_{max} = 1.44 x t_{1/2} ln (TW)

= 1.44 x 39 hrs x ln (2.5/0.8)

= 64 hrs

Calculate the convenience use for DI of 24 hours (<64)

Oral MD/DI = 14.1 ug/L

Oral MD/24 hrs = 14.1 ug/L

Oral MD = 14.1 ug/L x 24 hrs

= 338.4 ug

=.34 mg

What is the equation for half life?

t_{1/2} = (0.693 x V_{D}) / Cl

If there is 2 compartment behavior for half life, what value should be used for distribution volume?

V_{D(beta)}

What is time to steady state (t_{ss})?

Time required to reach [D]_{P}^{SS} if the dosing regimen only involves the repeated adminstration of drug using a specific MD/DI ratio

If you have one compartment behavior, four elimination half lives:

Provide 94% of [D]_{P}^{SS} when treatment is started

Reduce [D]_{P} to 6% of [D]_{P}^{SS} when treatment stopped

If 2-compartment behavior, four elimination half-lives:

Provide > or = 94% of [D]_{P}^{SS} when treatment is started

Reduce [D]_{P} to < or = 6% of [D]_{P}^{SS} when treatment stopped

What is the equaiton for t_{SS} for 1 and 2 compartment behaviors?

t_{SS} = 4 x t_{1/2}

Calculate the t_{SS} for Digoxin. Given:

t_{1/2} = 39 hrs

t_{SS} = 4 x t_{1/2}

= 4 x 39

= 156 hrs

(loading doses often prescribed)

What are the steps to designing a dose regimen?

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- Decide whether LD is required (if so calculate)
- Determine MD/DI ratio
- Determine DI

If a patient has renal disease how would you adjust the drug?

If eliminated by the liver don't worry about it

- Re-evaluate need for drug; discontinue if possible
- Reduce dose
- Inc dose interval
- Switch to drug eliminated by liver

If a pt has liver disease how would you adjust the drug?

If eliminated by the kidneys don't worry about it

- Re-evaluate need for drug; discontinue if possible
- Reduce dose
- Inc dose interval
- Switch to drug eliminated by kidney