Central actions

P-Adrenoceptor Blockers. There is no satisfactory mechanism to explain the antihypertensive activity of P-adrenoceptor blockers (see Table 1) in humans particularly after chronic treatment (228,231—233). Reductions in heart rate correlate well with decreases in blood pressure and this may be an important mechanism. Other proposed mechanisms include reduction in PRA, reduction in cardiac output, and a central action. However, pindolol produces an antihypertensive effect without lowering PRA. In long-term treatment, the cardiac output is restored despite the decrease in arterial blood pressure and total peripheral resistance. Atenolol (Table 1), which does not penetrate into the brain is an efficacious antihypertensive agent. In short-term treatment, the blood flow to most organs (except the brain) is reduced and the total peripheral resistance may increase. 

Hyoscyamine. The natural alkaloid, 1-hyoscyamine and its d-isomeride resemble atropine (dl-hyoscyamine) qualitatively in action, but the 1-form acts more strongly on the peripheral nerves than the d- or dl-forms, though the isomerides appear to have an equal central action. 

The removal of released DA from the synaptic extracellular space to facilitate its intraneuronal metabolism is achieved by a membrane transporter that controls the synaptic concentration. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). Although it has similar amino-acid sequences to that of the NA (and GABA) transporter, there are sufficient differences for it to show some specificity. Thus DA terminals will not concentrate NA and the DA transporter is blocked by a drug such as nomifensine which has less effect on NA uptake. Despite this selectivity some compounds, e.g. amphetamine and 6-OHDA (but not MPTP), can be taken up by both neurons. The role of blocking DA uptake in the central actions of cocaine and amphetamine is considered later (Chapter 23). 

This peripheral activity may be a rational basis for the use of systemic local anaesthetics in neuropathic states since ectopic activity in damaged nerves has been shown to be highly sensitive to systemic sodium channel blockers. This too is probably part of the basis for the analgesic effects of established effective anti-convulsants that block sodium channels such as carbamazepine, although central actions are important and may even predominate. The precise actions of excitability blockers therefore remains hazy as does any clear basis for the effectiveness of antidepressants and other adrenergic agents in the treatment of neuropathic pain as both central and peripheral actions, including sympathetic effects are possible. 

Groves. P.M., and Rebec, G.V. Biochemistry and behavior Some central actions of amphetamine and antipsychotic drugs. Ann Rev Psychol 27 91-127, 1976. 

Adrien, J., Tissier, M. H., Lanfumey, L. et al. (1992). Central action of 5-HT3 receptor ligands in the regulation of sleep-wakefulness and raphe neuronal activity in the rat. Neuropharmacology 31, 519-29. 

Intrathecal (IT) Into the subarachnoid space between two of the membranes (meninges) separating the spinal cord from the vertebral column. This route is used for drugs that do not penetrate the blood-brain barrier, but which are required for their central action (e.g., antibiotics). Drugs can also be injected spinally (into the epidural space) for local anaesthesia or analgesia. 

This is a low toxic ChE reactivator (DL50 = 950 mg/kg, rats, i.m.) of central action. 

It is difficult to draw firm conclusions about the relevance of this central action of 3-blockers in animals to their clinical anti-hypertensive activity bearing in mind that brain concentrations of the different drugs varies widely... 

Pharmacology Dextromethorphan is the d-isomer of the codeine analog of levorphanol. Its cough suppressant action is due to a central action on the cough center in the medulla. Dextromethorphan 15 to 30 mg equals 8 to 15 mg codeine as an antitussive. 

Butylscopolamine and methscopolamine bromide, quaternary ammonium derivatives of scopolamine without its central actions and homatropine methylbromide, a quaternary derivative of homatropine, are less potent than atropine in antimus-carinic activity. They are used for their antispasmodic action in gastroenterology. The usual oral doses act for 6-8 hours. However, the quaternary ammonium derivatives are poorly absorbed after an oral dose and their eficacy is therefore very variable. Only parenteral administrations are recommended. 

Narcolepsy is another medically recognized indication for the use of the psychomotor stimulants. This disorder is characterized by sleep attacks, particularly during the day, sudden loss of muscle tone cataplexy), sleep paralysis, and vivid visual and auditory nightmares that may persist into the waking state. Drugs that influence the central action of adrenomimetic amines re-... 

Martensson B, Aberg-Wistedt A The use of selective serotonin reuptake inhibitors among Swedish psychiatrists. Nordic Journal of Psychiatry 50 443-450, 1996 Martin BR, Martin TJ, Fan F, et al Central actions of nicotine antagonists. Med Chem Res 2 564-577, 1993... 

Whereas antipsychotics and antidepressants are used mainly in major psychiatry , Le. in the treatment of schizophrenia and depression, anxiolytics are also used in general medicine for the treatment of neurotic, vegetative, psychosomatic and even purely physical conditions. This multiple usage is promoted by the fact that anxiolytics of the benzodiazepine type have an almost exclusively central action so that vegetative effects (dry mouth, sweating, visual disturbances, urine retention, constipation, fall in blood pressure), which can be unpleasant for patients or even hazardous, are practically absent. 

Under the effect of chlorpromazine, as 4560 RP was later to be named, patients did not lose consciousness but merely became sleepy and uninterested in everything going on around them and being done to them (Laborit et ti/.. 1952). Laborit and co-workers postulated that this strange central action suggested the use of chlorpromazine in psychiatry, e.g. in sleep therapy, where... 

Although it is not normally feasible to include comprehensive psychological or psychophysiological testing during the first tolerability trials, because medical aspects have to be paramount at this stage, it is possible to determine with considerable reliability any pronounced central actions of a substance as well as the approximate duration of such effects. Examples are effects on vigilance, attention, concentration and potential side effects such as sedation, stimulation, euphoric effects, etc. Further data also will be available as to the effects of the preparation on vital functions such as ECG, respiration and circulation, as well as on biochemical laboratory tests, liver enzyme and renal functions. 

Effect on CNS Acetylcholine when injected parenterally does not cross blood brain barrier being a quarternary ammonium compound and does not have any central action. 

---