Cerebral vasodilators

The compounds used to palliate the mnemonic and cognitive decline associated with dementia include cerebral vasodilators and the so-called nootropic agents. These materials enhance cerebral metaboHsm. Agents which enhance neurotransmitter function are in most cases cholinergic. 

Vinpocetine (2), another dmg initially categorized as a cerebral vasodilator, is a member of the vinca alkaloid family of agents (7). However, interest in this compound as a potential dmg for learning and memory deficits comes from its abiUty to act as a neuronal protectant. This compound was evaluated in 15 patients with AD over a one-year period and was ineffective in improving cognitive deficits or slowing the rate of decline (8). However, in studies of patients with chronic vascular senile cerebral dysfunction (9) and organic psycho syndrome (10), vinpocetine showed beneficial results. 

Methylpiperidine [109-05-7] is employed for making fungicides such as piperalin [3478-94-2] (119). 2,6-Dimethylpiperidine [766-17-6] is used for the antiarrhythmic pitmeno1 [61477-94-9] (120). 4-Ben2yl piperidine is used to produce ifenprodil tartrate [23210-56-2] (121), a cerebral vasodilator. 

Mefenidil (78) is a cerebral vasodilator which may be of value in treating geriatric cerebral circulatory problems. It can be synthesized by reacting benzamidine (76) with biacetyl to produce the highly reactive methylene benzimidazole adduct 77. Reaction of the latter with sodium cyanide completes the synthesis 1,26]. 

Hydergine A mixture of the three dihydro-derivatives of the alkaloids in ergotoxine. It is used as a cerebral vasodilator and reported to have nootropic effects. 

The combination of hypoxia and hypercapnia in pulmonary insufficiency results in cerebral vasodilation and increased CBF and may lead to increased intracranial pressure. Arteriovenous differences for oxygen across the brain generally decrease as a function of increased CBF, leaving CMR02 unchanged [6]. 

Vincamine (91) is the major alkaloid of V. minor, a plant used against headache and vertigo. It exerts a sedative CNS action and produces a fall in blood pressure. The principal activity is a moderate cerebral vasodilation. Clinical studies have demonstrated that i.v. administration of 91 to humans reduces the arterial blood pressure and increases cerebral blood flow and oxygen consumption. The improved cerebral hemodynamic conditions significantly and positively affect the state of patients with advanced arteriosclerosis with beneficial effects on memory, concentration, and behavior. It has thereafter been introduced under several trade names as a pharmaceutical in many European countries (232). Vobasine (32) has been widely studied it exhibits a weak CNS depressive, analgesic, and antipyretic action (21). 

Nicotinic acid, when given at the rate of several hundred milligrams a day, has pharmacological effects of which cerebral vasodilation is one. Nicotinamide does not have this effect, and hence the pharmacological effects of nicotinic acid probably do not involve simple replacement of a deficiency in an enzyme system. The fact that nicotinic acid itself in pharmacological doses appears to be of Implications for Advance in Psychiatry... 

Wei, E.P., Randad, R.S., Levasseur, J.E., Abraham, D.J., and Kontos, H.A. Effect of local change in 02 saturation of hemoglobin on cerebral vasodilation from hypoxia and hypotension. Am.J. Physiol. 1993, 265, H1439-H1443. 

Intoxication results in a characteristic intense, throbbing headache, presumably due to cerebral vasodilation, often associated with dizziness and nausea and occasionally with vomiting and abdominal pain. More severe exposure also causes hypotension, flushing, palpitation, low levels of methemoglobinemia, delirium, and depression of the central nervous system. Aggravation of these symptoms after alcohol ingestion has been observed. On repeated exposure, a tolerance to headache develops but is usually lost after a few days without exposure. At times, persistent tachycardia, diastolic hypertension, and reduced pulse pressure have been observed. On rare occasions, a worker may have an attack of angina pectoris a few days after cessation of repeated exposures, a manifestation of cardiac ischemia. Sudden death due to unheralded cardiac arrest has also been reported under these circumstances. ... 

Ginkgo leaf extract appears to act primarily as a mild cerebral vasodilator that increases cerebral blood flow and reduces blood viscosity. Ginkgolides inhibit platelet activating factor, and this may improve microcircula-tory blood flow in atherosclerotic disease with slightly increased risk of bleeding. There appears to be an antioxidant effect that may be neuroprotective. Although some studies suggested a monoamine oxidase inhibitor (MAOI) effect, this is considered to have questionable clinical relevance. 

D. Kava is often recommended for anxiety, and it appears significantly more effective than placebo for this condition. Garlic is used for cardiovascular benefits, saw palmetto for prostatic hypertrophy, and ginkgo as a cerebral vasodilator. Echinacea is considered an immunomodulating herb with potential benefit in viral illnesses. 

Figure 3.4 Graph showing mean values for cardiac index (Cl) and heart rate (HR) in young (n=20) and elderly (n=20) patients during induction of anaesthesia with isoflurane (1 MAC) in 100% oxygen. Data from McKinney MS, Fee JPH, Clarke F J. British Journal of Anaesthesia 1993 71 696-701.) anaesthesia. Marked cerebral vasodilation occurs with an increase in intracranial pressure. This can be mitigated by hyperventilation even in the presence of a space-occupying lesion.

Carbon dioxide retention caused by respiratory depression results in cerebral vasodilation. In patients with elevated intracranial pressure, this may lead to lethal alterations in brain function. 

The ergotoxine alkaloid mixture also has oxytocic and vasoconstrictor activity but is only employed medicinally as the 9,10-dihydro derivatives dihydroergotoxine (co-dergocrine), a mixture in equal proportions of dihydroergocornine, dihydroergocristine, and the dihydroergocryptines (a- and p- in the ratio 2 1). In the case of these alkaloids, reduction of the double bond appears to reverse the vasoconstrictor effect, and dihydroergotoxine has a cerebral vasodilator activity. The increased blood flow is of benefit in some cases of senility and mild dementia, and helps to improve both mental function and physical performance. 

Morphine releases histamine and may cause peripheral vasodilation and orthostatic hypotension (Figure 47.7). The cutaneous blood vessels dilate around the blush areas such as the face, neck, and upper thorax. Morphine causes cerebral vasodilation (due to increased carbon dioxide retention secondary to respiratory depression), and hence, it increases the cerebrospinal fluid pressure. Therefore, morphine should be used cautiously in patients with either meningitis or a recent head injury. When given subcutaneously, morphine is absorbed poorly whenever there is either traumatic or hemorrhagic shock. 

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