kinetics exam 2

TISSUE PERMEABILITY - Important Physicochemical properties for drug distribution :

___x__ drugs will tend to accumulate where pH is higher while ___y___ drugs accumulate where pH is lower

Weak acidic (anionic) & neutral drugs bind to albumin. examples

Multiple (Intermittent) IV Infusion

The main plasma protein is albumin, ~?% of the total plasma

Maintenance dose formula

Cont IV Inf: One Compart Model. When infusion stops the drug concentration declines due to the first order elimination.

Basic drugs may bind to either albumin or α1-acid glycoprotein

Continuous IV Infusion: One Compartment Model.During the infusion period, as t becomes large (t = ∞)...

Intrvenous (IV) solutions may be given either as bolus dose or infused slowly at a ________

Calculation of k of elimination

Difference between single dose and multiple dose is that

The higher the protein binding of a drug, the more severe toxic reaction is expected upon displacement

ORGAN SIZE AND TISSUE PERFUSION RATE: Distribution is permeability rate limited when:

BBB: Polar natural substances, e.g., sugars, amino acids are transported to brain by active transport.

Blood-Brain Barrier:

Age: Differences among different age groups are mainly due to differences in:

Distribution is not uniform throughout the body. What major factors affect it ?

At SS, Cmax ^∞ and Cmin ^∞ fluctuate around an average drug concentration (Cave_ss)

Factors affecting protein binding:

Pharmacological effects are related closely to the free conc. of drug at its site of action,rather than the total C_P

Continuous IV infusion avoids peaks and valleys that occur with intermittent multiple dosing.

basic (cationic) drugs predominantly bind to α1-acid glycoprotein.

Thiopental is only partly ionized and passes into the brain or muscle easily.

As the pharmacological action depends on the drug conc. at the site of action...

BBB maintains homeostasis by restricting entrance of harmful chemicals & allowing the entrance of essential nutrients

Obesity: High adipose tissue can take up a more of lipophilic drug even the perfusion is low.

Time to reach steady state is only dependent on the half-life of the drug.

Maintenance IV infusion rate formula

basic (cationic) drugs examples

_______ and _____also play a role in the ionization and diffusion of drugs into cells.

if the drug is given as a salt and/or in another route of administration...

tissue permeability is the rate limiting step in the distribution of drugs that ionize at plasma pH

DRUG DISTRIBUTION : irreversible transfer of a drug between the blood and extravascular fluids and/or tissues.

Blood plasma contains 93% water. Reminder 7% dissolved compounds, primarily proteins.

Most drugs are either weak acids or weak bases and their _______ or _________ pH will depend on their pKa

Advantages of plasma protein binding:

Simple Capillary Endothelial Barrier:

Plasma concentration-time profile of a drug during multiple IV bolus injection of a fixed dose and fixed dosing interval

Continuous IV Infusion: One Compartment Model. Plasma conc. vs time curve of a drug given by constant IV infusion:

Pregnancy: During pregnancy the growth of uterus, placenta and fetus ___ the volume available for distribution of drugs.

if an IV loading dose of R/k is given followed by an IV infusion then steady Cp_ss are obtained immediately & maintained

Drugs generally get distributed by _______ diffusion process.

Covalent bond is very rare. It creates almost irreversible bonding, e.g., between cisplatin & albumin.

drug with linear pharmacokinetics, drug accumulation can be calculated according to the principle of superposition

The loading dose may be an i.v. bolus dose to achieve a Cp similar or close to the desired Cp,ss.

Loading dose (DL) is given at onset of therapy to achieve the target concentration immediately

if a second dose is given before all of the first dose is eliminated, then drug will accumulate

R_acc: measure of how much higher drug conc. at SS will be vs after a single dose

MISCELLANEOUS FACTORS AFFECTING DRUG DISTRIBUTION:

Drug binding proteins in plasma: albumin, α1-acid glycoprotein, and lipoproteins.

Continuous IV Infusion: Cp,ss and time needed to reach Cp,ss

Only _____ drug can pass through most cell membranes

Volume of distribution facts:

The average SS conc (Cave_ss ) is NOT the arithmetic mean of Cmax_ss and Cmin_ss

Highly perfused tissues such as lungs, kidneys, adrenals, liver, heart, and brain are...

For perfusion rate limited distribution, greater the blood flow, faster the distribution.

IV infusion at constant or zero order input allows precise control of plasma drug concentration to fit individual needs

The steady state concentration (Cp,ss) is achieved when: rate of drug that enters the body = rate of drug eliminated

Only unionized drugs which are generally lipophillic, rapidly cross cell membrane.

PLASMA PROTEIN BINDING OF DRUGSBinding of drugs falls into two classes:

Driving force for distribution is concentration gradient between blood & extravascular tissues.

two major independent pharmacokinetic parameters

Intravenous Infusion: This method of administration is important for drugs that...

Dose increase with no change in dosing interval to achieve lower concentration

Continuous IV Infusion: One Compartment ModelRate of drug elimination

Physiological barriers to drug distribution

BINDING OF DRUGS : A drug in body can bind to several components in the blood such as ...

Drugs having ______ easily cross capillary membrane and enter into the extracellular interstitial fluids.

Principle of Superposition: PK parameters from single dose studies can predict Cp after multiple dosage regimens

The bound form of the drug is in dynamic equilibrium with the free form in plasma & tissues (reversible binding).

At steady state, The rate of drug leaving the body is equal to rate of the drug entering the body (infusion rate).

Only the bound form of the drugs get transported into tissues or eliminated by eliminating organs.

Early doses of drug do not affect the pharmacokinetics (ADME) of subsequent doses

Only small water soluble molecules and ions of MW <50 daltons enter the cell through aqueous filled channels.

Repetitive/Multiple I.V. Bolus Injections

After a single dose drug admin : Plasma drug level rises above the MEC and and then falls above the MEC

Placenta is not an effective barrier to most of the drugs

D_L during Continuous IV Infusion : ____ needed to achieve steady state after continuous constant rate i.v. infusion

In SS : Rate of drug input = rate of drug output

Many drugs are given as a multiple dose regimen:

Dosing interval decrease with no change in dose to achieve higher concentration

The protein bound drug, being too large, cannot pass through cell membranes.

If two substances compete for the same binding sites, the one with less affinity will...

Repetitive/Multiple IV bolus: NO drug accumulation happens.

Protein binding is one of the major determinates of drug distribution

ORGAN SIZE AND TISSUE PERFUSION RATE: distribution will be perfusion rate limited when:

Continuous IV Infusion: One Compartment Model. There is no net change in the of amount of drug in the body.

at Steady State

The volume relating the amount of drug in the body to the plasma drug conc.

a condition when the rate of administration is equal to the rate of drug elimination

Drugs are distributed to:

Drugs that ionize at plasma pH can penetrate the lipoidal cell membrane

Factors affecting protein binding (contd.):

Two main parameters to adjust during multiple-dosage regimen

________________cross the Placentalbarrier by simple diffusion quite rapidly.

Cont IV Inf:time needed to reach Cp_ss:Therapeutic purp: 90% of steady state level is achieved in about 3.3 half-lives

the longer the half-life, the longer it takes to achieve steady state

Simple Cell Membrane Barrier is similar to lipoidal membranein GI absorption of drugs

As the drug administration continues, rate of drug elimination increases (as Cp and DB is increasing).