PHARMACOKINETICS..DRUG ACCUMULATION..etc..etc..

To calculate a multiple-dose regimen for a patient or patients, pharmacokinetic

parameters are first obtained from the plasma level–time curve generated by
single-dose drug studies. With these pharmacokinetic parameters and knowledge of
the size of the dose and dosage interval (τ), the complete plasma level–time curve or
the plasma level may be predicted at any time after the beginning of the dosage
regimen.

For calculation of multiple-dose regimens, it is necessary to decide whether

successive doses of drug will have any effect on the previous dose. The principle of
superposition assumes that early doses of drug do not affect the pharmacokinetics of
subsequent doses. Therefore, the blood levels after the second, third, or nth dose
will overlay or superimpose the blood level attained after the (n-1)th dose. In

addition, the for ...

the single-dose profile, the concentration profile following a multiple

dose. The superposition principle assumes that the early doses of drug
do not affect the pharmacokinetics of subsequent doses. Therefore, the
concentration after the second and later doses will overlay or superimpose
the concentration attained after the first dose. Figure 3.9 shows an
example of superposition principle applied to two doses of a drug
following the model in Figure 3.2. The concentration produced by ...The
superposition principle assumes that the early doses of drug do not affect
the pharmacokinetics of subsequent doses. Therefore, the concentration
after the second and later doses will overlay or superimpose the
concentration attained after the ...-->>>The principle of superposition
assumes that early doses of drug do not affect the pharmacokinetics of subsequent
doses.

dose Concentration Concentration effect Pharmacokinetic

Pharmacodynamic variability variability * Figure 5-1
Pharmacokinetics and pharmacodynamics as determinants of the
dose-response relationship. The relationship between drug
concentration and the observed pharmacologic response depends on
the mechanism by which a drug exerts its effect. The response may
be the result of a direct reversible effect, which is often mediated
through binding with a specific receptor ...-->>>>Quantitatively
describe the relationship between drug, receptor, and the pharmacologic
response.

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Binding alone, however, does not elicit a pharmacological response.

Thus, we distinguish between pharmacological agonists, partial
agonists, and antagonists (blockers) depending on the intrinsic
activity of the compound (Figure 3—4). An agonist has affinity for
binding and can elicit the maximal intensity of the pharmacological
effect as the drug concentration is increased. A partial agonist
binds the receptor but elicits only a partial response (the effect
plateaus at a lower intensity) ...-->>>Explain why the intensity of
the pharmacologic response increases with drug concentrations and/or dose
up to a maximum response.

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They may also be considered ligands which display both agonistic

and antagonistic effects — when both a full agonist and partial
agonist are present, the partial agonist actually acts as a
competitive antagonist, competing with the full agonist for
receptor occupancy and producing a net decrease in the receptor
activation ...The partial agonist causes the channel to open more
frequently; in this case the partial agonist is 1 having a net
agonist action. 2 2 agonist Channel in its resting state. The
partial agonist causes the channel to open less frequently; in this
case the partial agonist is having a net antagonist action. The full
agonist opens the channel maximally and frequently. partial agonist
FIGURE 5-14 Net effect of partial agonist. Partial agonists act
either as net agonists or as net antagonists, ...->>>Explain the
difference between an agonist, a partial agonist, and an antagonist.

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Drugs with short duration of action generally have weaker bonds;

long-duration or irreversible drug–receptor interactions may have
stronger bonds such as .... Another important and desirable facet
of pharmacologic responses is selectivity of drug action,
determined by drug molecules exhibiting preferential affinity
for ...Everyone has experienced pain in response to an intense or
noxious stimulus. ... In these conditions, pathologic and sometimes
irreversible alterations in the structure and function of the
nervous system lead to se- vere and intractable pain. ... response
to a painful stimulus. The following discussion of pain and
analgesic pharmacology begins by describing the mechanisms by which
noxious stimuli lead to the perception of pain. The chapter
continues by considering the processes ...--->>>Describe the
difference between a reversible and a nonreversible pharmacologic response.

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For example, early in development, a biomarker may be used to reveal

pharmacologic activity (e.g. substrate reduction in enzyme
deficiency disorders), or may provide quantitative predictions
regarding drug performance (e.g. relative potency of the candidate
therapeutic to the target). In clinical trials, biomarkers may
assist with identifying dose-response, assessment of drug delivery
to target organs or potential safety problems. Therefore, it is
recommended that every effort to promote ...->>>Define the term
biomarker and explain how biomarkers may be used in the clinical
development of drugs.

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Show how the Emax and sigmoidal Emax model describe the relationship of the
pharmacodynamic response to drug concentration.

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Define the term pharmacokinetic–pharmacodynamic model and provide

equations that quantitatively simulates the time course of drug action.

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Explain the effect compartment in the pharmacodynamic model and name

the underlying assumptions.

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Describe the effect of changing drug dose and/or drug elimination half-life on
the duration of drug response.

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Describe how observed drug tolerance or unusual hysteresis-type drug

response may be explained using PD models based on simple drug receptor
theory.

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Define the term drug exposure and explain how it is used to improve drug
therapy and safety.