Antihypertensive actions

The antihypertensive activity of 8-aryl-6,9n-dimethyl-2,3,4,8,9,9n-hexahy-dropyrido[2,l-Z)][l,3]oxazine-7,9-dicarboxylates 79 was evaluated in conscious spontaneously hypertensive rats. They resulted in potent and long-lasting antihypertensive action (97MI14). 

Rostafnroxin, a Cardenolide Derivative with Antihypertensive Action... 

Reserpine inhibits the synaptic vesicular storage of the monoamines dopamine, serotonin and noradrenaline. As a result they leak out into the cytoplasm where they are inactivated by monoamine oxidase this causes their long-lasting depletion. The resulting low levels of dopamine underlie the antipsychotic actions of reserpine (Chapter 11), whereas the reduced noradrenaline levels underlie its antihypertensive actions. Finally, the resulting low levels of serotonin and noradrenaline mean that reserpine also induces depression. These severe side effects mean that reserpine is no longer used clinically as a treatment for schizophrenia (Chapter 11). 

Schenker E, Salzmann R (1979) Antihypertensive action of bicyclic 3-hydra-zinopyridazines. Arzneimittel-Forschung 29 1835-1843... 

Sydnonimines, and particularly 3-dialkylaminosydnonimines, were discovered as possible drug candidates due to their vasodilating and antihypertensive action [95,... 

Table 1 summarizes the antihypertensive effects of ACE inhibitory small peptides. Information of dosage is also listed. It is clear that small peptides can exert an antihypertensive action following oral administration to mild hypertensive subjects, similar to therapeutic ACE inhibitory drugs, despite their poor potency on ACE inhibitory activity. It seems likely that ca. 20-fold higher doses of small peptides than drugs are required to... 

The significance of monoamine oxidase inhibition as a contributory factor, to the antihypertensive action of some adrenergic neurone blocking dmgs (see p. 186), has received further support. The tetrahydroisoquinoline derivatives debrisoquine (VII) and guanisoquin (LXVil, R = 7-Br, = H) are... 

P-Blockers also serve to lower cardiac rate (sinus tachycardia, p. 134) and elevated blood pressure due to high cardiac output (p. 312). The mechanism underlying their antihypertensive action via reduction of peripheral resistance is unclear. 

Methyldopa is an a-methoxylated derivative of levodopa that exhibits hypotensive action by reducing overall peripheral vascular resistance and reducing heart work. Antihypertensive action of methyldopa consists of the biotransformation of methyldopa into methylnoradrenaline (methylnorepinephrine), which acts as a pseudo neurotransmitter. The current, universally accepted point of view is that the action of methyldopa is carried out through the CNS, where methylnorepinephrine, a powerful stimulant of a-adrenergic receptors of the medulla, inhibits the vasomotor center. 

Hypersensitivity to any component of the product pheochromocytoma (because the drug may stimulate secretion of catecholamines from the tumor through its antihypertensive action) acute Ml dissecting aortic aneurysm. 

Increased prostaglandin synthesis may also play a role in the antihypertensive action of captopril. 

The antihypertensive action requires several days to produce effects. Administration for less than or equal to 2 to 4 weeks is usually required for optimal therapeutic effect. The duration of the antihypertensive effect of the thiazides is sufficiently long to adequately control blood pressure with a single daily dose. 

Pharmacology The exact mechanism of ocular antihypertensive action is not established, but it appears to be a reduction of aqueous production. However, some studies show a slight increase in outflow facility with timolol and metipranolol. Pharmacokinetics ... 

Reserpine lowers elevated blood pressure as a result of neuro-transmitter depletion in peripheral postganglionic sympathetic neurons, as discussed in detail in a separate paragraph. In addition, reserpine also causes neurotransmitter depletion in central neurons involved in the regulation of sympathetic activity and blood pressure. For this reason it may be assumed that this central mechanism contributes to the antihypertensive activity of reserpine. The mechanism of the central antihypertensive action of reserpine has not been analysed in detail. 

Diazoxide is a potassium channel opener with a rapid antihypertensive action after intravenous administration. Diazoxide causes hyperglycaemia which may underlie side-effects such as nausea and vomiting, cardiac dysrhythmia and ketosis. Diazoxide was used occasionally in the management of hypertensive emergencies, but it is now largely abandoned for this indication. Diazoxide is an alternative for glucagons in patients with hypogycaemia. 

Prazosin is effective in reducing all grades of hypertension. The drug can be administered alone in mild and (in some instances) moderate hypertension. When the hypertension is moderate or severe, prazosin generally is given in combination with a thiazide diuretic and a -blocker. The antihypertensive actions of prazosin are considerably potentiated by coadministration of thiazides or other types of antihypertensive drugs. 

The reduction in plasma volume produced by p-blockers contrasts with the increased volume seen with other types of antihypertensives. Tolerance to the antihypertensive actions of p-blockers therefore is less of a problem than with the vasodilating drugs. An additional difference from the vasodilators is that plasma renin activity is reduced, rather than increased, by propranolol (Inderal). Orthostatic hypotension does not occur with p-blockers. 

I 52. Drugs that block the catecholamine uptake process (e.g., cocaine, tricyclic antidepressants, and phenothiazines) are apt to block the antihypertensive action of which of the following drugs ... 

Methyldopa (l -pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6-5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. Flowever, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa s antihypertensive effect, because the a-methylnorepinephrine released is an effective agonist at the cx adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa s antihypertensive action appears to be due to stimulation of central a adrenoceptors by a-methylnorepinephrine or a-methyldopamine. 

The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use as a nasal decongestant. 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

Ohta, T., Iwashita, A., Sasaki, S., and Kawamura, Y. (1997). Antihypertensive action of the orally administered protease hydrolysates of chum salmon head and their angiotensin I-converting enzyme inhibitory peptides. Food Sci. Technol. Int. 4, 339-343. 

Indeed, methyldopa s antihypertensive action appears to be due to stimulation of central a-adrenoceptors by -methylnorepinephrine or o-methyldopamine, based on the following evidence (1) Much lower doses of methyldopa are required to lower blood pressure in animals when the drug is administered centrally by cerebral intraventricular injection rather than intravenously. (2) a-... 

Guanadrel is a guanethidine-like drug that is also available in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar to guanethidine in mechanism of antihypertensive action. 

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