Action of drugs

A. J. Clark, The Mode of Action of Drugs on Cells, Arnold, London, 1937. 

It is amazing to note that complex processes such as drug binding to protein, activation of cells, and observation of syncytial cellular response should apparently so closely follow a model based on these simple concepts. This was not lost on A. J. Clark in his treatise on drug receptor theory The Mode of Action of Drugs on Cells [4] ... 

The ternary complex model followed by the extended ternary complex model were devised to describe the action of drugs on G-protein-coupled receptors. 

A knowledge of normal metabohsm is essential for an understanding of abnormalities underlying disease. Normal metabolism includes adaptation to periods of starvation, exercise, pregnancy, and lactation. Abnormal metabolism may result from nutritional deficiency, enzyme deficiency, abnormal secretion of hormones, or the actions of drugs and toxins. An important example of a metabolic disease is diabetes mellitus. 

Since then our knowledge of the mode of action of drugs has greatly improved and even more stringent testing of all new drugs takes place... 

The great dependence of taste on hydrophobicity was quantitatively demonstrated by Deutsch and Hansch. From the bulk of the evidence available, they reasoned that the mechanism of sweet-taste stimulation is probably not very different from the mode of action of drugs. 

The aim of this chapter is to consider the structure, distribution and functional properties of neurotransmitter receptors in the brain in general and discuss the principles of how the action of drugs at these receptors can be studied. (See relevant Chapters for detail of individual NT receptors.)... 

These approaches to receptor identification and classification were, of course, pioneered by studies with peripheral systems and isolated tissues. They are more difficult to apply to the CNS, especially in in vivo experiments, where responses depend on a complex set of interacting systems and the actual drug concentration at the receptors of interest is rarely known. However, the development of in vitro preparations (acute brain slices, organotypic brain slice cultures, tissue-cultured neurons and acutely dissociated neuronal and glial cell preparations) has allowed more quantitative pharmacological techniques to be applied to the action of drugs at neurotransmitter receptors while the development of new recording methods such as patch-clamp... 

Neurotransmitter receptors have evolved as one of the key components in the ability of the central nervous system to coordinate the behaviour of the whole animal, to process and respond to sensory input, and to adapt to change in the environment. These same receptors are therefore ideal targets for drug action because of their central role in the activity of the nervous system. A rational approach to the development of new therapeutic strategies involving the action of drugs at receptors in the nervous system is based on knowledge of receptor structure, distribution and function. 

The sites of action of drugs affecting the dopamine synapse are indicated in Fig. 7.3. Those modifying the synthesis, storage, release, uptake and metabolism of DA have been covered above in the appropriate sections on neurochemistry. The actions and uses of agonists and antagonists are outlined in Table 7.4 and covered in detail in appropriate chapters. Their structures are given in Fig. 7.6. 

Figure 8.4 The site of action of drugs that modify noradrenergic transmission...

Figure 10.2 Site of action of drugs affecting glutamate synapses...

Figure 19.8 A schematic representation of the GABAa receptor shift hypothesis. This proposes that patients with panic disorder have dysfunctional GABAa receptors such that the actions of drugs that behave as antagonists in normal subjects are expressed as inverse agonism in panic patients. It is unlikely that this theory extends to generalised anxiety disorder (GAD), for which benzodiazepine agonists are highly effective treatments, but it could explain why these drugs are relatively ineffective at treating panic disorder. (Based on Nutt et al. 1990)...

Similarly, self-administration of MDMA in monkeys trained to self-administer amphetamine (Kamien et al. 1986) or in monkeys or baboons trained to self-administer cocaine (Beardsley et al. 1986 Lamb and Griffiths 1987) probably reflects a dopaminergic component to the pharmacology of MDMA. This would be consistent with current theories of dopamine involvement in the mechanism of action of drugs with dependence liability (Wise and Bozarth 1987). 

VIII. STRUCTURE-ACTIVITY RELATIONSHIP AND MODE OF ACTION OF DRUGS... 

Compare and contrast the mechanisms of action of drugs used for ventricular rate control, conversion to sinus rhythm and maintenance of sinus rhythm in patients with AF, and explain the importance of anticoagulation for patients with AF. 

Compare and contrast the mechanisms of action of drugs used for acute termination of PSVT. 

It is expected that art will more closely approach science with the emergence of a deeper understanding of the mechanisms of action of drugs on the molecular level, and the increasing frequency with which receptors are now being isolated and studied. 

The discovery of the base-paired, double-helical structure of deoxyribonucleic acid (DNA) provides the theoretic framework for determining how the information coded into DNA sequences is replicated and how these sequences direct the synthesis of ribonucleic acid (RNA) and proteins. Already clinical medicine has taken advantage of many of these discoveries, and the future promises much more. For example, the biochemistry of the nucleic acids is central to an understanding of virus-induced diseases, the immune re-sponse, the mechanism of action of drugs and antibiotics, and the spectrum of inherited diseases. 

Fig. 21.3. Schematic diagram of the relationship between pharmacokinetics and pharmacodynamics in order to better understand the action of drugs.

Drug X is an ami mycobacterial agent that inhibits other bacteria as well as poxviruses. However, it should not be used as a single agent because resistant mutants frequently form. The responsible mutation may alter the site of action of drug X [i.e., the deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase]. What is drug X ... 

The figure below illustrates proposed sites of action of drugs. Tor each drug listedt select the site of action that the drug is most likely to inhibit (a, a receptor iT J3 receptor COMTt cat e cho l-O-methyl transferase MAOt monoamine oxidase NET norepinephrine NMNt normetanephrine). 

The figure below shows proposed sites of action of drugs. For each of the diuretic agents below, choose the anatomic site in the schematic diagram of the renal nephron where the principal action of the agent occurs. 

We will briefly elaborate on the last two of these applications in our evolving understanding of actions of drugs and rational drug dosing. 

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