Chapter 19

1. Chapter 19 Indirect-Acting Antiadrenergic Agents

2. 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

3. 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

4. Centrally Acting Alpha2 Agonists • Clonidine • Guanabenz and guanfacine • Methyldopa and methyldopate

5. 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

6. Clonidine • Pharmacokinetics • Lipid-soluble • Readily absorbed following oral administration • Therapeutic uses • Two approved applications • Hypertension • Severe pain

7. 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

8. Clonidine • Preparations, dosage, and administration • Preparations • Oral and transdermal • Dosage and administration • Transdermal applied every 7 days • Applied to hairless upper arm or torso

9. Guanabenz and Guanfacine • Pharmacology • Very similar to that of clonidine • Adverse effects • Xerostomia, sedation, rebound hypertension if not weaned • Dosage and administration

10. 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

11. 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

12. 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

13. 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

14. 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

15. Fig. 19-1. Mechanism of reserpine action.