That Influence Drug Receptors

The term pharmacodynamics encompasses all the processes that influence the relationship between drug concentration and resulting effects. Psychotropic drugs have a wide variety of targets within neuro transmitter systems, including neurotransmitter synthesis, degradation of enzymes, storage, receptors, and specific transporter proteins. 

Psychoactive drugs can influence neurotransmission at its five different stages (Chapter 2). First, they may modify the biosynthesis of a neurotransmitter. Second, they can increase or decrease their storage within the presynaptic neuron. Third, they may stimulate or inhibit neurotransmitter release from the synaptic bouton. Fourth, they may affect the binding of the neurotransmitters to its receptor. Finally, they can retard the neurotransmitter s inactivation. Some examples of each of these stages will be given below, but it should be noted that many drugs affect several of these processes. 

Drug metabolism has been recognized as one of the key factors in the discovery of new chemical entities. A lead compound needs to not only interact with the target enzyme/receptor but also remain over a certain threshold concentration at the site of action for a defined period to produce the desired therapeutic effect. Drug metabolism together with absorption, distribution and excretion are among the factors that influence the final time-concentration relationship of drugs and therefore the potential efficacy of the compound [1],... 

Primary or secondary pharmacology can influence hematopoiesis because hematopoietic and stromal cells express many different receptors that are also therapeutic targets, such as neurotransmitters [23-25], In the mouse, an HI receptor agonist antagonized the H2-induced increase of CFU-GM by its off-target effect at the latter receptor [26], Albeit this is not an example of direct hematotoxicity, it does demonstrate that therapeutic drugs bind to targets on hematopoietic and stromal cells and influence hematopoiesis. 

Figure 1.6 Properties of a drug molecule. A drug has many properties (size, shape, topology, polarity, chirality) that influence its ability to interact with a receptor. Each of these properties is required for the unique pharmacological activity of a drug molecule.

Diastereomeric drugs— those having two or more asymmetric centers—are usually active in only one configuration. Unlike enantiomers, which have identical physicochemical properties, the absorption, distribution, receptor binding, metabolism, and every other aspect that influences the pharmacological activity of a dmg are different for each diastereomer. 

Proteins and other macromolecules are mainly cleared by high-capacity elimination processes such as renal hltration and liver metabolism. A coadministered drug can affect these processes and lead to serious drug-drug interactions. In addition, drugs that influence receptor-mediated clearance of the therapeutic protein may also result in important drug-drug interactions. 

Studies of sudden death in novice as well as experienced drug abusers found that cocaine causes vasoconstriction of the coronary arteries which seems to result from an enhancement of Ca2+ influx across myocardial membranes. However, remember that this class of drug affects other neurotransmitter systems. Cocaine inhbiits reuptake of NE and 5-HT as well as binds to the DA transporter. It increases catecholamine receptor sensitivity but does not seem to directly influence enkephalinergic receptors. In addition it also affects neurotransmission the H, Ach and phenylethylamine pathways. Activation of DA, NE or 5-HT neurons independently does not produce the euphoria associated with cocaine misuse. Euphoria seems to be related to simultaneous inteeraction between catecholamine and serotoninergic systems. 

Sequence Determination of the Brain Peptide Leucine Enkephalin A group of peptides that influence nerve transmission in certain parts of the brain has been isolated from normal brain tissue. These peptides are known as opioids, because they bind to specific receptors that also bind opiate drugs, such as morphine and naloxone. Opioids thus mimic some of the properties of opiates. Some researchers consider these peptides to be the brain s own pain killers. Using the information below, determine the amino acid sequence of the opioid leucine enkephalin. Explain how your structure is consistent with each piece of information. 

Serotonin has important influences on dopamine, but that influence is quite different in each of the four dopamine pathways. Understanding the differential serotonergic control of dopamine release in each of these four pathways is critical to understanding the differential actions of antipsychotic drugs that block only dopamine 2 receptors (i.e., the conventional antipsychotics) versus antipsychotic drugs that block both serotonin 2A and dopamine 2 receptors (i.e., the atypical antipsychotics). That is, serotonin inhibits dopamine release from dopaminergic axon terminals in the various dopamine pathways, but the degree of control differs from one dopamine pathway to another. 

Consequently, antipsychotic drugs all share a basic mechanism of action that involves dopamine receptor blockade. It is apparent, however, that they are not all equal in their ability to affect specific sub-types of dopamine receptors, and that their effectiveness and side effects are related to their affinity and preference for certain receptors. As indicated earlier, other neurotransmitters may also be involved in the pathogenesis of psychosis, and differences in specific antipsychotic medications may be related to their ability to directly or indirectly affect these other transmitters as well as block dopamine influence. Future studies will continue to clarify how current antipsychotics exert their beneficial effects and how new agents can be developed to be more selective in their effects on dopamine and other neurotransmitter pathways. 

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