Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, a selective α1-receptor agonist. The peak concentration of desglymidodrine is achieved about 1 hour after midodrine is administered orally. The primary indication for midodrine is the treatment of orthostatic hypotension, typically due to impaired autonomic nervous system function. Midodrine increases upright blood pressure and improves orthostatic tolerance, but it may cause hypertension when the subject is supine.
Alpha2-selective agonists decrease blood pressure through actions in the CNS that reduce sympathetic tone (“sympatholytics”) even though direct application to a blood vessel may cause vasoconstriction. Such drugs (eg, clonidine, methyl-dopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11. Sedation is a recognized side effect of these drugs, and newer α2 agonists (with activity also at imidazoline receptors) with fewer CNS side effects are available outside the USA for the treatment of hypertension (moxonidine, rilmenidine). On the other hand, the primary indication of dexmedetomidine is for sedation in an intensive care setting or before anesthesia. It also reduces the requirements for opioids in pain control. Finally, tizanidine is used as a centrally acting muscle relaxant.
Oxymetazoline is a direct-acting α agonist used as a topical decongestant because of its ability to promote constriction of the vessels in the nasal mucosa and conjunctiva. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (see Chapter 11). Oxymetazoline has significant affinity for α2A receptors.
Isoproterenol (isoprenaline) is a very potent β-receptor agonist and has little effect on α receptors. The drug has positive chronotropic and inotropic actions; because isoproterenol activates β receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9–4; Figure 9–6).
Beta subtype-selective agonists are very important because the separation of β1 and β2 effects (Table 9–2), although incomplete, is sufficient to reduce adverse effects in several clinical applications.
Beta1-selective agents (Figure 9–8) increase cardiac output with less reflex tachycardia than nonselective β agonists such as isoproterenol, because they are less effective in activating vasodilator β2 receptors. Dobutamine was initially considered a relatively β1-selective agonist, but its actions are more complex. Its chemical structure resembles dopamine, but its actions are mediated mostly by activation of α and β receptors. Clinical formulations of dobutamine are a racemic mixture of (–) and (+) isomers, each with contrasting activity at α1 and α2 receptors. The (+) isomer is a potent β1 agonist and an α1-receptor antagonist. The (–) isomer is a potent α1 agonist, which is capable of causing significant vasoconstriction when given alone. The resultant cardiovascular effects of dobutamine reflect this complex pharmacology. Dobutamine has a positive inotropic action caused by the isomer with predominantly β-receptor activity. It has relatively greater inotropic than chronotropic effect compared with isoproterenol. Activation of α1 receptors probably explains why peripheral resistance does not decrease significantly.
Beta2-selective agents (eg, Figure 9–8) have achieved an important place in the treatment of asthma and are discussed in Chapter 20).
FIGURE 9–8 Examples of β1and β2-selective agonists.