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Pharmacodynamic Considerations for Moderate and Deep Sedation
Daniel E. BeckerDDS
Article Category: Research Article
Volume/Issue: Volume 59: Issue 1
Online Publication Date: Jan 01, 2012
DOI: 10.2344/0003-3006-59.1.28
Page Range: 28 – 42

The safe and effective use of medications for moderate and deep sedation requires a sound appreciation for pharmacokinetic principles that govern serum concentrations adequate to provide the intended effect. These principles have been presented in a previous continuing education article in this journal. 1 The goal of this article is to address pharmacodynamic principles, including mechanisms of action and the effects that follow. Depending on the provider's level of training, the desired effects range from various levels of sedation to general anesthesia

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Drug Therapy in Dental Practice: General Principles
Daniel E. BeckerDDS
Article Category: Research Article
Volume/Issue: Volume 54: Issue 1
Online Publication Date: Jan 01, 2007
DOI: 10.2344/0003-3006(2007)54[19:DTIDPG]2.0.CO;2
Page Range: 19 – 24

Pharmacodynamics concerns the actions and effects drugs produce on living tissues. Two basic correlates must be emphasized before this topic is addressed. First, drugs can be developed to modify virtually any physiologic function, but they cannot create a new function or effect. For example, salivary acini can be stimulated or inhibited from secreting saliva; they cannot be stimulated to secret insulin. Secondly, drugs must demonstrate some degree of specificity in action. Otherwise, they would produce a spectrum of undesirable effects that

Optimal Timing of Intravenous Acetaminophen Administration for Postoperative Analgesia
Maho ShinodaDDS,
Akiko NishimuraDDS, PhD,
Erika SugiyamaPhD,
Hitoshi SatoPhD, and
Takehiko IijimaDDS, PhD
Article Category: Research Article
Volume/Issue: Volume 69: Issue 2
Online Publication Date: Jul 18, 2022
DOI: 10.2344/anpr-69-02-05
Page Range: 3 – 10

plasma concentration is not considered to be an effect site. This hypothesis is supported by the measurement of APAP concentrations in cerebrospinal fluid after intravenous (IV) administration in children and adults. 10 , 11 Based on these findings, the administration of APAP 1 to 2 hours before anticipated pain and fever has been recommended in children. 12 Although the early administration of APAP is recommended for the purpose of postoperative analgesia, pharmacokinetic and pharmacodynamic studies of APAP and its exerted effect on postoperative pain are rare. The

Figure 1.; Receptors exist in both active (Ra) and inactive (Ri) states. Drugs may interact in a variety of manners, based on their ability to bind and activate these states. Antagonists bind to receptors but have no ability to activate either receptor state. Agonists bind and also activate the receptor. Agonists that activate both states equally are essentially inactive and behave similar to antagonists. Full agonists bind the active state selectively and produce a full response. Partial agonists also have some activity at the inactive state leading to a response that is less intense than that produced by a full agonist. Inverse agonists selectively activate the inactive state causing the cellular response to proceed in a manner opposite that generated by a natural agonist. Clinically, the effect may be indistinguishable from that produced by antagonists or inactive agonists.
Daniel E. Becker
Figure 1.
Figure 1.

Receptors exist in both active (Ra) and inactive (Ri) states. Drugs may interact in a variety of manners, based on their ability to bind and activate these states. Antagonists bind to receptors but have no ability to activate either receptor state. Agonists bind and also activate the receptor. Agonists that activate both states equally are essentially inactive and behave similar to antagonists. Full agonists bind the active state selectively and produce a full response. Partial agonists also have some activity at the inactive state leading to a response that is less intense than that produced by a full agonist. Inverse agonists selectively activate the inactive state causing the cellular response to proceed in a manner opposite that generated by a natural agonist. Clinically, the effect may be indistinguishable from that produced by antagonists or inactive agonists.

Figure 2.; Dose-response curves. Drug A is more potent and has greater efficacy that Drug B. However, Drug A 5 mg and Drug B 20 mg are equipotent doses for increasing heart rate 20%. Drug C is less potent than Drugs A or B, but is more effective, having no apparent ceiling to its response.
Daniel E. Becker
Figure 2.
Figure 2.

Dose-response curves. Drug A is more potent and has greater efficacy that Drug B. However, Drug A 5 mg and Drug B 20 mg are equipotent doses for increasing heart rate 20%. Drug C is less potent than Drugs A or B, but is more effective, having no apparent ceiling to its response.

Figure 1.; Drug potency versus efficacy. This dose-response curve compares 3 drugs that can be used to increase heart rate. Drug A has the greatest potency because it produces effects at the lowest dose. However, it has the least efficacy because it can increase heart rate only 80%. In contrast, Drug C has the least potency but demonstrates the greatest efficacy. Notice that Drug A 10 mg, Drug B 20 mg, and Drug C 30 mg will increase heart rate 80%. These are regarded as “equipotent” doses.
Daniel E. Becker
Figure 1.
Figure 1.

Drug potency versus efficacy. This dose-response curve compares 3 drugs that can be used to increase heart rate. Drug A has the greatest potency because it produces effects at the lowest dose. However, it has the least efficacy because it can increase heart rate only 80%. In contrast, Drug C has the least potency but demonstrates the greatest efficacy. Notice that Drug A 10 mg, Drug B 20 mg, and Drug C 30 mg will increase heart rate 80%. These are regarded as “equipotent” doses.

Figure 2.; The GABAA receptor complex. The GABAA receptor complex consists of several protein subunits, with each comprised further of subunit families. These subunits provide myriad sites or receptors at which drugs may bind. While GABA and its precise receptor is the normal “commander” of the chloride channel, benzodiazepines can potentiate its influence. Additional drugs such as propofol and barbiturates not only potentiate the influence of GABA but are able to open the channel directly.
Daniel E. Becker
Figure 2.
Figure 2.

The GABAA receptor complex. The GABAA receptor complex consists of several protein subunits, with each comprised further of subunit families. These subunits provide myriad sites or receptors at which drugs may bind. While GABA and its precise receptor is the normal “commander” of the chloride channel, benzodiazepines can potentiate its influence. Additional drugs such as propofol and barbiturates not only potentiate the influence of GABA but are able to open the channel directly.

Figure 3.; Biotransformation of various benzodiazepines. Parent drugs and their active metabolites vary in their elimination half-lives: L, >24 hours; I, 6–24 hours; and S, <6 hours (derived from Mihic and Harris7).
Daniel E. Becker
Figure 3.
Figure 3.

Biotransformation of various benzodiazepines. Parent drugs and their active metabolites vary in their elimination half-lives: L, >24 hours; I, 6–24 hours; and S, <6 hours (derived from Mihic and Harris7).

Figure 4.; Midazolam configurations. The midazolam molecule exists in an open ring, water soluble state while in formulated solutions for parenteral injection. When subjected to physiologic pH upon administration, the ring closes, rendering the molecule highly lipid soluble.
Daniel E. Becker
Figure 4.
Figure 4.

Midazolam configurations. The midazolam molecule exists in an open ring, water soluble state while in formulated solutions for parenteral injection. When subjected to physiologic pH upon administration, the ring closes, rendering the molecule highly lipid soluble.

Figure 4.; The pharmacokinetic-pharmacodynamic (PK-PD) model developed using the acetaminophen (APAP) plasma concentration and pain equivalent current (PEC) data. The PK model (A) was developed using a 2-compartment model, and PD model (B) was developed using a linear model and an effect compartment model. The symbols represent the mean and standard error (SE) that were obtained in 15 subjects. Open circles and the dashed line represent the duration of the analgesic effect of APAP estimated by PK-PD model.
Maho Shinoda,
Akiko Nishimura,
Erika Sugiyama,
Hitoshi Sato, and
Takehiko Iijima
Figure 4.
Figure 4.

The pharmacokinetic-pharmacodynamic (PK-PD) model developed using the acetaminophen (APAP) plasma concentration and pain equivalent current (PEC) data.

The PK model (A) was developed using a 2-compartment model, and PD model (B) was developed using a linear model and an effect compartment model. The symbols represent the mean and standard error (SE) that were obtained in 15 subjects. Open circles and the dashed line represent the duration of the analgesic effect of APAP estimated by PK-PD model.