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Chapter 19

Indirect-Acting Antiadrenergic Agents

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Indirect-Acting Antiadrenergic Agents

Prevent stimulation of peripheral adrenergic receptors

Two groups Adrenergic neuron-blocking agents

• Decrease norepinephrine release Centrally acting alpha2 agonists

• Reduce impulses along the sympathetic nerves

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Centrally Acting Alpha2 Agonists

Reduce the firing of sympathetic neurons Used primarily for hypertension Effects similar to those of the direct-acting

adrenergic receptor blockers

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Centrally Acting Alpha2 Agonists

Clonidine Guanabenz and guanfacine Methyldopa and methyldopate

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Clonidine

Mechanism of antihypertensive action Selective activation of alpha2 receptors in the CNS Reduces sympathetic outflow to blood vessels and

the heart Pharmacologic effects

Bradycardia and a decrease in cardiac output Minimal orthostatic hypotension

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Clonidine

Pharmacokinetics Lipid-soluble Readily absorbed following oral administration

Therapeutic uses Two approved applications

• Hypertension • Severe pain

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Clonidine

Adverse effects Drowsiness: 35% of patients Xerostomia: 40% of patients Rebound hypertension

• Withdraw slowly over 2 to 4 days Use in pregnancy

• Not recommended Other adverse effects

• Constipation, impotence, gynecomastia, and adverse CNS effects

• Risk for abuse

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Clonidine

Preparations, dosage, and administration Preparations

• Oral and transdermal Dosage and administration

• Transdermal applied every 7 days• Applied to hairless upper arm or torso

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Guanabenz and Guanfacine

Pharmacology Very similar to that of clonidine

Adverse effects Xerostomia, sedation, rebound hypertension

if not weaned Dosage and administration

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Methyldopa and Methyldopate

Mechanism of action Lowers blood pressure (BP) by acting at sites

within the CNS Causes alpha2 activation Not an alpha2 agonist: taken up into brainstem and

converted into alpha2 agonist Pharmacologic effects

Vasodilation, not cardiosuppression Lowers BP in supine and standing subjects

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Methyldopa and Methyldopate

Therapeutic use Hypertension One of the earliest drugs; no longer a first-line

drug Adverse effects

Positive Coombs’ test and hemolytic anemia Hepatotoxicity

• Hepatitis, jaundice, and rarely fatal hepatic necrosis Other adverse effects

• Xerostomia, sexual dysfunction, orthostatic hypotension, and CNS effects

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Adrenergic Neuron-Blocking Agents

Act presynaptically to reduce the release of norepinephrine from sympathetic neurons

Very little effect on release of epinephrine from adrenal medulla

Reserpine

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Reserpine

Mechanism of action Depletion of NE from postganglionic sympathetic

neurons Closely resembles alpha and beta blockade Can cause depletion of transmitters (serotonin,

catecholamines) Pharmacologic effects

Peripheral effects• Slows heart rate and reduces cardiac output

CNS effects• Sedation and state of indifference

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Reserpine

Therapeutic uses Principal indication: hypertension (but not a

preferred drug) Psychotic states (but not a preferred drug)

Adverse effects Depression Bradycardia, orthostatic hypotension, nasal

congestion GI involvement

Preparations, dosage, and administration

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Fig. 19-1. Mechanism of reserpine action.