Site of action

With regard to preoptic-anterior hypothalamic neurons, since no degeneration but only morphological disorganization in these have been observed after capsaicin treatment, it must tentatively be concluded that there is a disturbance in the mechanism of these neurons which endows them with the ability to respond to thermal stimuli. 

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Tissue of origin /hormone CAS Registry Number Chemical nature Site of action Effect... 

Mode of Motion. Nicotine, anabasine, and imidocloprid affect the ganglia of the insect central nervous system, faciUtating transsynaptic conduction at low concentrations and blocking conduction at higher levels. The extent of ionisation of the nicotinoids plays an important role in both their penetration through the ionic barrier of the nerve sheath to the site of action and in their interaction with the site of action, which is befleved to be the acetylcholine receptor protein. There is a marked similarity in dimensions between acetylcholine and the nicotinium ion. 

Mode of Action. DDT and its analogues specifically affect the peripheral sense organs of insects and produce violent trains of afferent impulses that result in hyperactivity, convulsions, and paralysis. Death results from metaboHc exhaustion and the production of an endogenous neurotoxin. The very high lipophilic nature of these compounds faciUtates absorption through the insect cuticle and penetration to the nerve tissue. The specific site of action is thought to be the sodium channels of the axon, through inhibition of Ca " ATPase. 

The absorption of sulfonylureas from the upper gastrointestinal tract is faidy rapid and complete. The agents are transported in the blood as protein-bound complexes. As they are released from protein-binding sites, the free (unbound) form becomes available for diffusion into tissues and to sites of action. Specific receptors are present on pancreatic islet P-ceU surfaces which bind sulfonylureas with high affinity. Binding of sulfonylureas to these receptors appears to be coupled to an ATP-sensitive channel to stimulate insulin secretion. These agents may also potentiate insulin-stimulated glucose transport in adipose tissue and skeletal muscle. 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Metabolites of vitamin D, eg, cholecalciferol (CC), are essential in maintaining the appropriate blood level of Ca ". The active metabolite, 1,25-dihydroxycholecalciferol (1,25-DHCC), is synthesized in two steps. In the fiver, CC is hydroxylated to 25-hydroxycholecalciferol (25-HCC) which, in combination with a globulin carrier, is transported to the kidney where it is converted to 1,25-DHCC. This step, which requites 1-hydroxylase formation, induced by PTH, may be the controlling step in regulating Ca " concentration. The sites of action of 1,25-DHCC are the bones and the intestine. Formation of 1,25-DHCC is limited by an inactivation process, ie, conversion of 25-HCC to 24,25-DHCC, catalyzed by 24-hydroxylase. 

Only small amounts of free T are present in plasma. Most T is bound to the specific carrier, ie, thyroxine-binding protein. T, which is very loosely bound to protein, passes rapidly from blood to cells, and accounts for 30—40% of total thyroid hormone activity (121). Most of the T may be produced by conversion of T at the site of action of the hormone by the selenoenzyme deiodinase (114). That is, T may be a prehormone requiring conversion to T to exert its metaboHc effect (123). 

Pharmacodynamics is the study of dmg action primarily in terms of dmg stmcture, site of action, and the biochemical and physiological consequences of the dmg action. The availabiUty of a dmg at its site of action is deterrnined by several processes (Fig. 1), including absorption, metaboHsm, distribution, and excretion. These processes constitute the pharmacokinetic aspects of dmg action. The onset, intensity, and duration of dmg action are deterrnined by these factors as well as by the avadabihty of the dmg at its receptor site(s) and the events initiated by receptor activation (see Drug delivery). 

Clinical Pharmacokinetics. Clinical pharmacokinetics attempts to define the relationship between dmg concentration and therapeutic response. The underlying assumption is that response is proportional to dmg concentration at the site of action. This concentration is dependent on many... 

The correlation coefficient for this equation was 0.994. Such a paraboHc dependence of activity on the partition coefficient may reflect partitioning of the dmg through several membrane barriers, which enabled the dmg to reach its site of action. 

Although most anesthetics are achiral or are adininistered as racemic mixture, the anesthetic actions are stereoselective. This property can define a specific, rather than a nonspecific, site of action. Stereoselectivity is observed for such barbiturates as thiopental, pentobarbital, and secobarbital. The (3)-enantiomer is modestly more potent (56,57). Additionally, the volatile anesthetic isoflurane also shows stereoselectivity. The (3)-enantiomer is the more active (58). Further evidence that proteins might serve as appropriate targets for general anesthetics come from observations that anesthetics inhibit the activity of the enzyme luciferase. The potencies parallel the anesthetic activities closely (59,60). 

The primary site of action is postulated to be the Hpid matrix of cell membranes. The Hpid properties which are said to be altered vary from theory to theory and include enhancing membrane fluidity volume expansion melting of gel phases increasing membrane thickness, surface tension, and lateral surface pressure and encouraging the formation of polar dislocations (10,11). Most theories postulate that changes in the Hpids influence the activities of cmcial membrane proteins such as ion channels. The Hpid theories suffer from an important drawback at clinically used concentrations, the effects of inhalational anesthetics on Hpid bilayers are very small and essentially undetectable (6,12,13). 

Fig. 1. Schematic diagram showing possible sites of action of antiasthmatic chugs.

Peripheral Antagonists. The relatively long duration of action of the thyroid hormones makes it desirable to have compounds capable of blocking them competitively at their site of action. This is desirable in the treatment of thyroid storm where the reduction of circulating hormone levels brought about by the inhibition of their synthesis is too slow. 

Another interesting approach to obtaining potent, broad-spectmm activity has been reported (127). The "dual-action" antibacterial concept involves incorporation of two moieties having complimentary antibacterial modes of action into the same molecule, and uses the mode of action of one part to release the second antibacterial at the site of action. This approach is exemplified in Ro 23—9424 (47) (127), which uses the mode of action and reactivity of the cephalosporin moiety (Fig. 2) to release the quinolone portion. 

It is known that the brain is one of the most sensitive sites of action of steroids in utero, and recently there have been suggestions that EDs may affect normal brain development and behaviour. For example, it has been alleged that in utero exposure to polychlorinated biphenyl compounds (PCBs) resulted in adverse effects on neurologic and intellectual function (memory and attention) in young children born to women who had eaten PCB contaminated fish in the USA." It has also been speculated that exposure to environmental pollutants with steroidal activity may be infinencing human sexual development and sexually controlled behavioiir." ... 

The effects of drugs in animals are usually concentration dependent and are also often animal species and site-of-action dependent " " " thus the compounds may be present naturally in diets at low levels and produce no obvious adverse effects, either on the animal, gut microflora, meat, milk or eggs. The main purpose of the use of drugs in animal feeds is to improve the animal health and welfare and often to improve growth at minimum cost to the producer.In the case of naturally produced compounds that may occur in the feedstuff s of animals, these compounds may impair animal health and performance as well as cause im-... 

The sharp bend of DNA at the TATA box induced by TBP binding is favorable for the formation of the complete DNA control module in particular, for the interaction of specific transcription factors with TFIID. Since these factors may bind to DNA several hundred base pairs away from the TATA box, and at the same time may interact with TBP through one or several TAFs, there must be several protein-DNA interactions within this module that distort the regular B-DNA structure (see Figure 9.2). The DNA bend caused by the binding of TBP to the TATA box is one important step to bring activators near to the site of action of RNA polymerase. 

Chemicals have to pass through either the skin or mucous membranes lining the respiratory airways and gastrointestinal tract to enter the circulation and reach their site of action. This process is called absorption. Different mechanisms of entry into the body also greatly affect the absorption of a compound. Passive diffusion is the most important transfer mechanism. According to Pick s law, diffusion velocity v depends on the diffusion constant (D), the surface area of the membrane (A), concentration difference across the membrane (Ac), and thickness of the membrane (L)... 

FIGURE 21.30 The sites of action of several inhibitors of electron transport and/or oxidative phosphorylation. 

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