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Janis.Y.Chen
Tue 27th August '13, 12:51am
Definition

Volume of distribution is simply the size of a compartment necessary to account for the total amount of drug in the body if it were present throughout the body at the same concentration found in the plasma.

Unbound drug in the blood provides the driving force for distribution of the agent to body tissues. If unbound drug leaves the bloodstream and distributes to tissue, it may become tissue-bound, it may remain unbound in the tissue, or if the tissue can metabolize or eliminate the drug, it may be rendered inactive and/or eliminated from the body. If the drug becomes tissue-bound, it may bind to the receptor that causes its pharmacologic or toxic effect or to a nonspecific binding site that causes no effect. Again, tissue binding is usually reversible, so that the tissue-bound drug is in equilibrium with the unbound drug in the tissue.

Factors that alter volume of distribution and loading dose

1.Decreased tissue binding of drugs in uremic patients. Decreased tissue binding will increase the C by allowing more of the drug to remain in the plasma. Therefore, if the desired plasma level remains unchanged, a smaller loading dose will be required.

2.Decreased plasma protein binding. This condition tends to increase the apparent volume of distribution because more drug that would normally be in plasma is available to equilibrate with the tissue and the tissue binding sites. Decreased plasma protein binding, however, also increases the fraction of free or active drug so that the desired C that produces a given therapeutic response decreases. So V increases and C decreases, which might results in a no net effect on the loading dose.

However, this is based on the assumption that the majority of drug in the body is actually outside the plasma compartment and that the amount of drug bound to plasma protein comprises only a small percentage of the total amount in the body. That is to say this is true so long as most of the drug is not in plasma/blood ie. large V drug.

For example, the lower plasma levels due to decreased plasma protein binding, however, produce the same free or pharmacologically active phenytoin concentration. If the target C is the same as the one in non-uremic individuals, the free drug level should be as levels twice as high in non-uremic patients because the free fraction is increased from 0.1 to 0.2 in these individuals, indicating that the target plasma concentrations in uremics should be about half of the usual target concentration. Meanwhile the V of phenytoin in uremic individuals is twofold than it in non-uremic individuals. Therefore, target C should decrease to 1/2 as that as it in normal individuals, and the V is twofold that of normal individuals, which makes a same loading dose.

CheneyHsiung
Fri 30th August '13, 10:54pm
Distribution of Geriatrics

The distribution of medications in the body depends on factors such as blood flow, plasma protein binding, and body composition, each of which may be altered with age.

The volume of distribution of water-soluble drugs is decreased.

The volume of distribution of lipohilic drugs exhibit an increasing.

The elderly may also exhibit differences in the distribution of drugs to their sites of action. For example, for an immunosuppressant that act with T-lumphocytes, the elderly had a mean 44% increase in the intracellular (T-lymphocyte)-to-whole blood concentration ratio of cyclosporine, compared with younger patients.

The activity of P-glycoprotein varies with aging. For example, verapamil labeled with carbon-11 (a positron emitter) and positron emission tomography have demonstrated decreased P-glycoprotein activity in the blood-brain barrier with aging.

The two major plasma proteins to which medications can bind are albumin and α1-acid glycoprotein, and concentrations of these proteins may change with concurrent pathologies seen with increasing age. For acidic drugs such as naproxen, phenytoin, tolbutamide, and warfarin, decreased serum albumin may lead to an increase in free fracton. An increase in α1-acid glycoprotein induced by burns, cancer, inflammatory disease, or trauma may lead to a decreased free fraction of basic drugs such as lidocaine, propranolol, quinidine, and imipramine.

TomHsiung
Thu 5th September '13, 11:35pm
Two-Compartment Models and DistributionPharmacokinetic Parameters

There are some situations in which it is more appropriate to conceptualize the body as two, and occasionally, more than two compartments when thinking about drug distribution, elimination, and pharmacologic effect.

The first compartment can be thought of as a smaller, rapidly equilibrating volume, usually made up of plasma or blood and those organs or tissues that have high blood flow and are in rapid equilibrium with the blood or plasma drug concentration. The second compartment equilibrates with the drug over a some what longer period. Any drug that distributes into the second compartment must re-equilibrate into the first compartment before it can be eliminated (the organs of liver and kidney both have high blood flow and so in rapid equilibrium with the blood or plasma drug concentration).Effects of a Two-Compartment Model on the Loading Dose and Plasma Concentration

Because some time is required for a drug to distribute into the second compartment, a rapidly administered loading dose calculated on the basis of total volume of distribution (volume of the 1st compartment plus the 2nd compartment) would result in an initial C that is higher than predicted because the volume of the 1st compartment is always smaller than the total volume. The consequences of a higher than expected C depends on whether the target organ for the clinical response behaves as though it were located in the 1st or 2nd compartment.

101
(Figure 1)

The graph shows that following rapid administration of drug into Vi, the plasma concentraion (—) follows a biphasic decay pattern. The initial decay half-life is usually due primarily to drug distribution into Vt. The second decay half-life is usually due to drug elimination from the body. The dotted line (·····) represents the drug effect when the end-organ for effect is located in Vi. Not that drug effect parallels the plasma concentration at all times. The dashed line (-----) represents the drug effect when the end-organ for effect is located in Vt. Note that initially when all of the drug is in Vi there is no drug effect. However, as distribution takes place, the drug effect increases and begins to parallel the plasma concentration only in the elimination phase after distribution is complete.Drugs with Significant and Nonsignificant Two-Compartment Modeling

As illustrated in Figure 1, the α phase for most drugs represents distribution of drug from Vi into Vt, and relatively little drug is eliminated during the distribution phase. Drug that behave in this way are generally referred to as "nonsignificant" two-compartmental drugs. "Nonsignificant" means that if the patient is not harmed by the initially elevated drug concentration in the α phase and no drug samples are taken in the α phase, then the drug can be successfully modeled as one-compartment drug (only the elimination or β phase is considered).

It is important to recognize that for some drugs, increased drug plasma concentration during the α phase can be clinically significant because the patient may experience serious toxicity if the end-organ behaves as though it lies within the initial volume of distribution. These drugs are considered to exhibit "nonsignificant" two-compartmental modeling only after the α phase or distribution has been completed. That is, plasma samples are obtained for pharmacokinetic modeling only during the β or elimination phase.

Drugs with "significant" two-compartment modeling are those that are eliminated to a significant extent during the initial α phase. For these drugs, the α phase cannot be thought of simply as distribution because significant elimination occurs as well. When a one-compartment model is used for drugs that exhibit significant drug elimination in the α phase, the actual trough concentrations will be lower than those predicted by the one-compartment model.

(More coming soon)