Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 19 Indirect-Acting Antiadrenergic Agents

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Indirect-Acting Antiadrenergic Agents  Prevent stimulation of peripheral adrenergic receptors  Two groups  Adrenergic neuron-blocking agents Decrease norepinephrine release Decrease norepinephrine release  Centrally acting alpha 2 agonists Reduce impulses along the sympathetic nerves Reduce impulses along the sympathetic nerves

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Centrally Acting Alpha 2 Agonists  Reduce the firing of sympathetic neurons  Used primarily for hypertension  Effects similar to those of the direct-acting adrenergic receptor blockers

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Centrally Acting Alpha 2 Agonists  Clonidine  Guanabenz and guanfacine  Methyldopa and methyldopate

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clonidine  Mechanism of antihypertensive action  Selective activation of alpha 2 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

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clonidine  Pharmacokinetics  Lipid-soluble  Readily absorbed following oral administration  Therapeutic uses  Two approved applications Hypertension Hypertension Severe pain Severe pain

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clonidine  Adverse effects  Drowsiness: 35% of patients  Xerostomia: 40% of patients  Rebound hypertension Withdraw slowly over 2 to 4 days Withdraw slowly over 2 to 4 days  Use in pregnancy Not recommended Not recommended  Other adverse effects Constipation, impotence, gynecomastia, and adverse CNS effects Constipation, impotence, gynecomastia, and adverse CNS effects Risk for abuse Risk for abuse

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Clonidine  Preparations, dosage, and administration  Preparations Oral and transdermal Oral and transdermal  Dosage and administration Transdermal applied every 7 days Transdermal applied every 7 days Applied to hairless upper arm or torso Applied to hairless upper arm or torso

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Guanabenz and Guanfacine  Pharmacology  Very similar to that of clonidine  Adverse effects  Xerostomia, sedation, rebound hypertension if not weaned  Dosage and administration

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Methyldopa and Methyldopate  Mechanism of action  Lowers blood pressure (BP) by acting at sites within the CNS  Causes alpha 2 activation  Not an alpha 2 agonist: taken up into brainstem and converted into alpha 2 agonist  Pharmacologic effects  Vasodilation, not cardiosuppression  Lowers BP in supine and standing subjects

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 Hepatitis, jaundice, and rarely fatal hepatic necrosis  Other adverse effects Xerostomia, sexual dysfunction, orthostatic hypotension, and CNS effects Xerostomia, sexual dysfunction, orthostatic hypotension, and CNS effects

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 Slows heart rate and reduces cardiac output  CNS effects Sedation and state of indifference Sedation and state of indifference

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Mechanism of reserpine action.