**2. Parameters of pharamacodynamics**

Parameters of PD illustrate the mode of action/interaction of the drug in the active site of the target. It is important that the drug should meet the PD parameters of concentration to inhibit the function of the target [1]. The drug responses can be manifested by the PD parameters.

#### **2.1 Mechanism of action**

Mechanism of action (MoA) is simply a biochemical interaction resulted in physiological response. This mechanism is enacted by the process called signal transduction which provides the description of the drug's (chemical) action (i.e. transmission of signal (chemical/drug) from the surface of the cell to the cytoplasm and/or nucleus of the cell) in the body/cell/receptor. At the beginning of this process, the cell recognizes the signal that bound to the receptor which is embedded either in the plasma membrane or present in the intracellular region. Transduction of signal takes place in the mid-way of the signal transduction process. Here the multi-step pathway utilized to carry out the rapid transmission of signal to the series of molecules. Protein kinases and protein phosphatases are the enzymes, trigger the phosphorylation cascade, and dephosphorylation processes in respect to activate and deactivate the protein. As a result of this, the secondary messengers transmit the signals brought from the cell surface receptor to the intracellular receptor to exhibit the cellular response by making changes in gene regulation processes.

Traditional methods (Direct approach) like affinity chromatography, and modern "omics" related high throughput methods (Indirect approach) are aid to identify the drug's mode of action by comparing the diseased cell (i. e., cell treated with the drug) with the normal cell [2]. The determination of MoA of a drug advantages in the categorization of the patients who are all exposing the similar kind of response to the treatment and estimation of accurate dosage of the drug can be done by monitoring the patients' target pathway [3].

### *2.1.1 Grouping of drugs based on mode of action*

The signal transduction process allows us to group the drugs based on their binding mode and effects (either positive or negative). In general, drugs (ligands)

#### *Trending Advancements in Technologies Pertinent to Therapeutical Pharmacodynamics DOI: http://dx.doi.org/10.5772/intechopen.107341*

can be grouped into two (i) Agonist, and (ii) Antagonist. *Agonist* is a kind of drug that imitates the ligand embedded within the receptor structure that exhibits positive effect and produces biological response by activating the receptor in the signal transduction process. In simple words, it tends to replicate the expected (positive) reaction. More or less agonists possess the ability to meet up the maximum response by partially engrossing the receptors.

There are four different kinds of agonists lie under a single umbrella. The first type is the *full agonist* that means, it causes maximum amount of biological effect at maximum concentration. The second type is the *partial agonist,* that causes less maximum effect and therefore it receives partial response from the activation of receptor. The third type is an *inverse agonist* that binds with the receptor which is already in active state to minimize its activity. The fourth type of agonist is the *biased agonist* which makes the receptor capable of giving signals with various efficacies in their multiple downstream pathways.

*Antagonist* is another kind of drug that has no intrinsic activity in the receptor to produce any response. It prevents the agonist to bind at the receptor binding site by its increased concentration and reduces the fractional occupancy of the drug [4]. It forms a number of irreversible covalent bonds that will elongate the pharmacological activity [5].

There are two types of pharmacologic antagonist viz. *Competitive antagonists*, as its name says battle with the agonist to bind in the same active site of the receptor. *Non-competitive antagonists* lower the capacity of an agonist in its response towards the irreversible binding of the antagonist to the receptor. It produces a large antagonistic effect as an outcome [6].

#### **2.2 Dosage and its response**

PD encourages the utilization of several mathematical models namely, fixed effect model, logarithmic model, Emax model, and sigmoid Emax model [6] to explain the PD parameters such as efficacy (Emax), potency (EC50), equilibrium rate constant (K), and sigmoidicity constant (n). These PD parameters can feature the drug-target interaction and their effect in the magnitude and duration of drug response. Rashed [7] estimated the magnitude and duration of response by comparing the maximum observed effect (MOE) to a sequence of doses and he also estimated the time taken for the half-life effect at various concentrations.

*Efficacy* (Emax) is the maximum response caused by the drug that evaluates the relationship between concentration and effect. *Potency* (EC50) is the concentration of the drug at a stationary state which shows the half of the maximum effect. When the potency increases, the response from the respective concentration will decrease. This depends on some properties such as the receptor density, efficiency of stimulus–response mechanisms which is in use, drug affinity, and drug efficacy denoted in terms of EC50/ED50/Kd [6]. The hill coefficient (g) is an empiric parameter derived from the sigmoidicity of the effect-concentration correlation which defines the relationship between drug concentration and its effect. The hill coefficient value of >2 indicates a steep relationship, >3 indicates that it can be either all or none effect. The sigmoidicity constant (n) is a linear relationship of concentration-effect profile. The relationship between n and effect is inversely proportional (i.e.,) the increase in will decrease the concentration.

*Affinity* of a drug is also one of a parameter to be concern, defined by the time course and strength of binding of the drug with its target at certain degree of

concentration and it falls under the factors which are essential to determine the potency of a drug [5].

Some other parameters to be considered in PD are drug dissociation (Kd), receptor occupancy, up and down regulation of receptor. The *drug dissociation* (Kd) value shows how strongly the drug binds to its receptor for example, if the Kd value obtain from analysis is low, it is the indication of strong binding and higher affinity of a drug. The fundamental of *receptor occupancy* lies in the law of mass action, which says that an excellent PD response can only be attained if the number of receptors covered by the drug is more. The *up and down regulations of receptor* have been happened due to the long-time subjection of a receptor to an antagonist and/or an agonist [8].

#### **2.3 Therapeutic index**

The therapeutic index (TI) is one of the parameters help to determine and optimize safety and efficacy of the drug. It can be referred as the ratio of the drug's dosage at which the drug attains the no toxicity state [9]. It differentiates the drug effect caused at a particular concentration of blood from the amount of the effect that causes toxicity [10]. TI is the composition of drug effect (ED50), toxic effect (TD50), and lethal effect (LD50). ED50 can be define as a scale of the concentration at which the half percent (50%) of patients exhibiting a particular pharmacologic effect. TD50 the amount of dosage needed to exhibit a particular toxic effect. LD50 is the prediction of the amount of dosage used to kill 50% of patients.
