European Heart Journal (1992) 13 {Supplement A), 18-21
Different types of centrally acting antihypertensive drugs P. A . VAN ZWIETEN
Departments of Pharmacotherapy and Cardiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
Introduction The complex pattern of circulatory regulation involves adrenergic, serotonergic and cholinergic receptors and pathways, including neuropeptides such as angiotensin II, as well as the corresponding receptors'1-21. This complex pattern of modulation and regulation offers potentially numerous targets for antihypertensive drugs, a limited number of which have been explored in detail. Two types of drugs based on such principles have been introduced into clinical medicine and used on a large scale in the management of hypertensive disease. Traditionally, the sympathetic nervous system, including its regulatory centres and pathways in the brain has offered several targets for drug treatment. In fact, virtually every functional region of the sympathetic system can be influenced by more or less specific drugs, such as the centrally acting antihypertensive agents, ganglioplegic drugs, peripheral sympathetic neuron blockers, as well as specific postsynaptic a- and /?-adrenoceptor antagonists'31. Ganglionic and postganglionic neuron blockers have virtually disappeared from the modern management of hypertension, whereas centrally acting drugs are still used in various countries, although on a smaller scale than 10 years ago. /3-adrenoceptor blockers and to a less extent a--blockers are still important agents. The centrally acting antihypertensives, acting via central cr-adrenoceptors, of which clonidine, guanfacine and ar-methyl-DOPA are the prototypes, are assumed to owe their antihypertensive potency to the stimulation of avadrenoceptors in the brainstem. This results in peripheral sympathoinhibition and a concomitant fall in blood pressure and heart rate'4"6'. More recently, some arguments have been put forward in favour of the role of specific central imidazoline receptors rather than the aforementioned ayadrenoceptors, as discussed below.
adrenoceptors, although in largely different ways. Other hybrid drugs which will not be discussed here, are the numerous newer /3-blockers, which have an additional vasodilator component. (For review see'7'). Agonists of central a2-adrenoceptors Clonidine, guanfacine and cr-methyl-DOPA are the prototypes of such compounds, and in the 1960s and 1970s a vast body of literature was devoted to their mode of action and clinical application. Globally, their mode of action at the receptor level may be summarized (and simplified) as follows: clonidine, guanfacine and o--methylnoradrenaline (the active principle of ar-methyl-DOPA, released in vivo after hydrolysis of this prodrug) are stimulants of central ar2-adrenoceptors. They are located at the level of the nucleus tractus solitarii, the vasomotor centre, the nucleus of the vagus nerve, and the various neuronal pathways interconnecting these regions. It seems likely, although methodology has so far inhibited conclusive evidence for this, that the central ayadrenoceptors involved are located at post-synaptic sites'8'. Stimulation of these receptors leads to depressed activity of the peripheral sympathetic nervous system and a concomitant fall in heart rate (Fig. 1). The peripheral sympathoinhibition may be mediated by the inhibitory bulbospinal neuron, which is assumed to be activated by ayadrenoceptor stimulation. More recently, evidence has been presented that shows that a considerable portion of the central hypotensive activity of a--methyl-DOPA is mediated by the modulation of central serotonergic pathways'81.
The clinical efficacy of clonidine, guanfacine and ar-methyl-DOPA is satisfactory and well-documented. The reason why these compounds have lost ground in the management of hypertensive disease should be Central serotonergic receptors and pathways have attributed to their side effects, which are considerable been recognized as a second important target of and in many cases subjectively unpleasant. Sedation, centrally acting antihypertensive drugs. Ketanserin dry mouth and sexual impotence are the most and urapidil are two drugs that interact with central frequently encountered adverse reactions. Since these serotonergic receptors and pathways and have been are predominantly caused by central mechanisms subject to detailed and large scale clinical investi- similar to the antihypertensive effect it is difficult to gations. They are both hybrid or multifactorial drugs, separate the therapeutic and undesired activities. A which simultaneously interact with 5-HT and a,- further problem for clonidine, and to a lesser extent for guanfacine, may be the withdrawal phenomenon, observed upon abrupt cessation of prolonged Corrapondence: Dr P. A. van Zwictcn, Departments of Phartreatment'91. For reviews on this type of centrally macotherapy and Cardiology, Academic Medical Centre, University of acting antihypertensive see'3"*1. Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 0195H568X/92/0A0018 + 04 $03.00/0
1992 The European Society of Cardiology
Centrally acting antihypertensives 19
Central nervous system
Clonidine and related drugs Inhibitory neurone
Central postsynaptic a-adrenoceptors
Central presynaptic a-adrenoceptors
Preganglionic neuron Ganglion O
Q Ganglion Peripheral sympathetic system
- Postganglionic neuron Postsynaptic a-adrenoceptors
Figure 1 Central hypotensive activity of clonidine and related drugs, triggered by the stimulation of central a-2-adrenoceptors. Two possibilities should be envisaged: (1) left: the stimulation of postsynaptic a-2-adrenoceptors enhances the activity of an inhibitory neuron and hence causes peripheral sympathoinhibition; (2) right: the stimulation of presynaptic
Different types of centrally acting antihypertensive drugs P. A . VAN ZWIETEN
Departments of Pharmacotherapy and Cardiology, Academic Medical Centre, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
Introduction The complex pattern of circulatory regulation involves adrenergic, serotonergic and cholinergic receptors and pathways, including neuropeptides such as angiotensin II, as well as the corresponding receptors'1-21. This complex pattern of modulation and regulation offers potentially numerous targets for antihypertensive drugs, a limited number of which have been explored in detail. Two types of drugs based on such principles have been introduced into clinical medicine and used on a large scale in the management of hypertensive disease. Traditionally, the sympathetic nervous system, including its regulatory centres and pathways in the brain has offered several targets for drug treatment. In fact, virtually every functional region of the sympathetic system can be influenced by more or less specific drugs, such as the centrally acting antihypertensive agents, ganglioplegic drugs, peripheral sympathetic neuron blockers, as well as specific postsynaptic a- and /?-adrenoceptor antagonists'31. Ganglionic and postganglionic neuron blockers have virtually disappeared from the modern management of hypertension, whereas centrally acting drugs are still used in various countries, although on a smaller scale than 10 years ago. /3-adrenoceptor blockers and to a less extent a--blockers are still important agents. The centrally acting antihypertensives, acting via central cr-adrenoceptors, of which clonidine, guanfacine and ar-methyl-DOPA are the prototypes, are assumed to owe their antihypertensive potency to the stimulation of avadrenoceptors in the brainstem. This results in peripheral sympathoinhibition and a concomitant fall in blood pressure and heart rate'4"6'. More recently, some arguments have been put forward in favour of the role of specific central imidazoline receptors rather than the aforementioned ayadrenoceptors, as discussed below.
adrenoceptors, although in largely different ways. Other hybrid drugs which will not be discussed here, are the numerous newer /3-blockers, which have an additional vasodilator component. (For review see'7'). Agonists of central a2-adrenoceptors Clonidine, guanfacine and cr-methyl-DOPA are the prototypes of such compounds, and in the 1960s and 1970s a vast body of literature was devoted to their mode of action and clinical application. Globally, their mode of action at the receptor level may be summarized (and simplified) as follows: clonidine, guanfacine and o--methylnoradrenaline (the active principle of ar-methyl-DOPA, released in vivo after hydrolysis of this prodrug) are stimulants of central ar2-adrenoceptors. They are located at the level of the nucleus tractus solitarii, the vasomotor centre, the nucleus of the vagus nerve, and the various neuronal pathways interconnecting these regions. It seems likely, although methodology has so far inhibited conclusive evidence for this, that the central ayadrenoceptors involved are located at post-synaptic sites'8'. Stimulation of these receptors leads to depressed activity of the peripheral sympathetic nervous system and a concomitant fall in heart rate (Fig. 1). The peripheral sympathoinhibition may be mediated by the inhibitory bulbospinal neuron, which is assumed to be activated by ayadrenoceptor stimulation. More recently, evidence has been presented that shows that a considerable portion of the central hypotensive activity of a--methyl-DOPA is mediated by the modulation of central serotonergic pathways'81.
The clinical efficacy of clonidine, guanfacine and ar-methyl-DOPA is satisfactory and well-documented. The reason why these compounds have lost ground in the management of hypertensive disease should be Central serotonergic receptors and pathways have attributed to their side effects, which are considerable been recognized as a second important target of and in many cases subjectively unpleasant. Sedation, centrally acting antihypertensive drugs. Ketanserin dry mouth and sexual impotence are the most and urapidil are two drugs that interact with central frequently encountered adverse reactions. Since these serotonergic receptors and pathways and have been are predominantly caused by central mechanisms subject to detailed and large scale clinical investi- similar to the antihypertensive effect it is difficult to gations. They are both hybrid or multifactorial drugs, separate the therapeutic and undesired activities. A which simultaneously interact with 5-HT and a,- further problem for clonidine, and to a lesser extent for guanfacine, may be the withdrawal phenomenon, observed upon abrupt cessation of prolonged Corrapondence: Dr P. A. van Zwictcn, Departments of Phartreatment'91. For reviews on this type of centrally macotherapy and Cardiology, Academic Medical Centre, University of acting antihypertensive see'3"*1. Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. 0195H568X/92/0A0018 + 04 $03.00/0
1992 The European Society of Cardiology
Centrally acting antihypertensives 19
Central nervous system
Clonidine and related drugs Inhibitory neurone
Central postsynaptic a-adrenoceptors
Central presynaptic a-adrenoceptors
Preganglionic neuron Ganglion O
Q Ganglion Peripheral sympathetic system
- Postganglionic neuron Postsynaptic a-adrenoceptors
Figure 1 Central hypotensive activity of clonidine and related drugs, triggered by the stimulation of central a-2-adrenoceptors. Two possibilities should be envisaged: (1) left: the stimulation of postsynaptic a-2-adrenoceptors enhances the activity of an inhibitory neuron and hence causes peripheral sympathoinhibition; (2) right: the stimulation of presynaptic
