Antihypertensive Agents – Drugs that Alter Sympathetic Nervous System Function Flashcards
Positive Risk Factors for “end organ damage”:
- > in African Americans
- > in men relative to premenopausal women
- smoking
- metabolic syndrome (obsesity + diabetes + dyslipidemia)
- family history of cardiovascular disease • degree of existing damage at diagnosis
Primary (Essential) Hypertension:
hypertension with no known attributable cause
Secondary Hypertension:
hypertension with identifiable cause
Labile hypertension:
BP fluctuates abruptly and repeatedly; often stress-related
Blood Pressure Regulation:
- PVR is regulated at:
- arterioles
- capacitance vessels (i.e., post-capillary venules)
- heart
- kidneys
- Coordinated by:
- baroreflexes
- renin-angiotensin-aldosterone system
Postural Baroreflex:
- carotid baroreceptors activated by stretch of the arterial wall
- baroreceptor activation inhibits central sympathetic discharge
- decreased pressure (stretch) reduces baroreceptor activity
Renal Response:
• Kidney “responsible” for long-term BP control through control of blood volume
decrease in renal perfusion –> increase salt & H2O reabsorption
decrease in renal arteriolar pressure and sympathetic stimulation (at β- receptors) stimulates renin production
• renin increases angiotensin II production
• angiotension II causes
• direct vasoconstriction
• stimulation of aldosterone production which increases Na+ absorption and blood volume
Drugs that Alter
Sympathetic Nervous System Function:
• Moderate to severe hypertension
• Sympathomimetic (adrenergic) antihypertensives classified
according to the site of action in the sympathetic reflex arc
• range of toxicity depends upon the subclass of drug
Drugs that Alter
Sympathetic Nervous System Function, cont:
All antihypertensives that alter sympathetic function can result in compensatory effects unrelated to activity of adrenergic nerves.*
*Notably – antihypertensive effects can be limited by Na+ retention and increased blood volume
sympathomimetics are most effective when used with a diuretic.
Centrally Acting Sympathoplegics:
- Reduce sympathetic outflow from brainstem vasomotor centers while retaining sensitivity to baroreceptor control
- methyldopa
- clonidine
- normal BP regulation involves modulation of baroreceptor reflexes by central adrenergic neurons
- clonidine decreases HR and CO more that methyldopa
Centrally Acting Sympathoplegics – clonidine:
- decrease BP through decrease CO (due to decrease HR & PVR, and relaxation of capacitance vessels)
- accompanied by decrease renal vascular resistance & maintenance of renal blood flow
- PK
- rapidly crosses the BBB (lipid soluble)
- effect directly related to blood concentration; short t1/2 (8-12 hrs) requires twice daily dosing
- dermal patch reduces BP for up to seven days (less sedation; local skin reactions
Centrally Acting Sympathomimetics – clonidine, cont:
• Toxicity
• dry mouth; sedation (dose-dependent)
• contraindicated for patients with depression; tricyclic antidepressants can block antihypertensive effects
• life threatening hypertensive crisis mediated by increased sympathetic NS activity if suddenly withdrawn after protracted use
• nervousness, tachycardia, headache, sweating after omitting one or two doses
• therapy should be stopped gradually while substituting other
antihypertensives
• hypertensive crisis should be treated by reinstitution of clonidine or administration of α & β-adrenergic receptor antagonists
Centrally Acting Sympathoplegics, methyldopa:
- primarily used for hypertension during pregnancy
- primarily works by reduction in PVR (variable reduction in HR & CO))
- CV reflexes remain intact; postural effects not marked (can occur with volume depletion)
- reduces renal vascular resistance (possible advantage)
- PK (oral dose)
- crosses BBB via aromatic AA transporter
- maximum effect in 4-6 hrs post-dose; persists up to 24 hrs (α- methylnorepinephrine accumulated in nerve-ending storage vesicles); t1/2 (2 hrs)
methyldopa toxicity:
- sedation; mental lethargy, impaired concentration
- infrequently – nightmares; depression; vertigo; extrapyramidal signs
- lactation (men & women)
- Coombs test (10-20% of patients) with > 12 months of therapy; rarely assoc with hemolytic anemia, hepatitis, & drug fever
Adrenergic Neuron-blocking Drugs - Guanethidine
• profound sympathetic nervous inactivation
• rarely used because of significant toxicities
• inhibits release of NE from postganglionic sympathetic nerve endings
• transported into the nerve by NET, concentrated in storage vesicles and replaces NE – resulting in gradual depletion of NE
• PK & Dosage
• t1/2 approx 5 days; gradual onset of action (1-2 weeks); duration of action
(1-2 weeks);
• Toxicity
• postural hypotension; post-exercise hypotension; delayed ejaculation; diarrhea (parasympathetic prominence)
β-adrenergic Receptor Blockers – propranolol:
• first β-blocker demonstrated effective in hypertension and
ischemic heart disease
• largely replaced by cardioselective β-blockers (e.g.,
metoprolol (Lopressor); atenolol (Tenormin))
• all useful in mild to moderate hypertension
• in severe hypertension - especially useful to prevent reflex tachycardia, when treating with direct vasodilators
• reduce mortality post-myocardial infarction
• reduce heart failure mortality

β-adrenergic Receptor Blockers – propranolol, mechanism:
- Mechanism
- nonselective β-blockade
-  BP primarily as result of  CO
- inhibits β1-receptor mediated stimulation of renin production
- reduces BP with minimal postural hypotension
- PK
- low bioavailability; t1/2 (3-5 hrs)
- Toxicity
- related to blockade of β-receptors in heart, vasculature, and bronchioles
- withdrawal syndrome – nervousness, tachycardia, angina, hypertension - likely related to up-regulation of β-adrenergic receptors (supersensitivity)
β-adrenergic Receptor Blockers – metoprolol; atenolol:
- both are cardioselective; most widely used β-blockers for hypertension
- relative receptor potency: (β1) metoprolol = propranolol; (β2) metoprolol 50-100x less potent than propranolol
- metoprolol: extensively metabolized by CYP2D6 (high first pass effect); t1/2 (4-6 hrs); extended release preparation – once daily; effective in patients with hypertension and heart failure (reduces CHF mortality)
- atenolol: not extensively metabolize (50% unchanged in urine); t1/2 (6hrs); lower effectiveness vs metoprolol may be related to inadequate blood levels with once daily dosing
β-adrenergic Receptor Blockers – nadalol, carteolol, betaxolol, bisoprolol:
- nadalol & carteolol: nonselective β-receptor blockers; not appreciably metabolized (carteolol t1/2 = 14-24 hrs), largely excreted unchanged in urine
- betaxolol & bisoprolol: β1-receptor selective; primarily metabolized in liver (CYP2D6) but long t1/2 (10-12 hrs); once daily administration
β-adrenergic Receptor Blockers –
pindolol (Visken); acebutolol (Sectral); penbutolol (Levatol):
• partial agonsists – beta blockers with intrinsic some degree of
sympathomimetic activity
• decrease BP by decreasing PVR (β2-agonist effect); depress HR & CO less than other β-blockers
• beneficial for patients with bradyarrhythmias or peripheral vascular disease
• pindolol: t1/2 (3-4 hrs) but hemodynamic effects persist for up to 24 hrs; hydroxylated & glucuronidated metabolites in urine
• acebutolol: t1/2 (3-4 hrs); extensive first pass metabolism
• penbutolol: t1/2 (5 hrs); hydroxylated & glucuronidated metabolites excreted 90% in urine
β-adrenergic Receptor Blockers – labetolol; carvedilol; nebivolol:
- β-blocking & vasodilating effects
- labetolol (racemic mix of 4 isomers): (S,R) potent α-blocker; (R,R) potent β-blocker; 3:1- β:α activity; reduce BP by decreasing PVR (α-blockade) with no significant change in HR or CO; Rx of pheochromocytoma and hypertensive emergencies (iv)
- carvedilol (racemic mix): S(-) isomer nonselective β-blocker; S(- ) & R(+) equal α-blockade potency; average t1/2 (7-10 hrs); reduces mortality in patients with CHF
- nebivolol: β1-selective; “D” is β1-blocker/”L” causes vasodilation (increases NO / induces endothelial NO synthase)
β-adrenergic Receptor Blockers – Esmolol:
- β1-selective; rapidly metabolized by RBC esterases; t1/2 (9- 10 minutes); administered by iv infusion (loading dose followed by constant infusion) with doses titrated up as needed to effect
- management of intraoperative and postoperative hypertension; hypertensive emergencies, especially with tachycardia
α1-adrenergic Receptor Blockers –
prazosin; terazosin; doxazosin:
- blocks α1-adrenergic receptors on arterioles & venules
- less reflex tachycardia than nonselective α-antagonists
- α1-receptor selectivity permits NE to exert negative feedback (α2-mediated) on its own release - reducing NE release
- dilate resistance and capacitance vessels
- salt and water retained when administered without diuretics
- more effective in conjunction with β-blockers and a diuretic
- used primarily in men with hypertension and BPH
α1-adrenergic Receptor Blockers –
prazosin;terazosin doxazosin:
- PK
* prazosin – extensively metabolized/high first pass metabolism (
