Antihypertensive Agents – Drugs that Alter Sympathetic Nervous System Function

Question 1

Positive Risk Factors for “end organ damage”:

Answer 1

• > 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

Question 2

Primary (Essential) Hypertension:

Answer 2

hypertension with no known attributable cause

Question 3

Secondary Hypertension:

Answer 3

hypertension with identifiable cause

Question 4

Labile hypertension:

Answer 4

BP fluctuates abruptly and repeatedly; often stress-related

Question 5

Blood Pressure Regulation:

Answer 5

• PVR is regulated at:
  
  • arterioles
  • capacitance vessels (i.e., post-capillary venules)
  • heart
  • kidneys
• Coordinated by:
  
  • baroreflexes
  • renin-angiotensin-aldosterone system

Question 6

Postural Baroreflex:

Answer 6

• carotid baroreceptors activated by stretch of the arterial wall
• baroreceptor activation inhibits central sympathetic discharge
• decreased pressure (stretch) reduces baroreceptor activity

Question 7

Renal Response:

Answer 7

• 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

Question 8

Drugs that Alter

Sympathetic Nervous System Function:

Answer 8

• 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

Question 9

Drugs that Alter

Sympathetic Nervous System Function, cont:

Answer 9

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.

Question 10

Centrally Acting Sympathoplegics:

Answer 10

• 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

Question 11

Centrally Acting Sympathoplegics – clonidine:

Answer 11

• 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

Question 12

Centrally Acting Sympathomimetics – clonidine, cont:

Answer 12

• 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

Question 13

Centrally Acting Sympathoplegics, methyldopa:

Answer 13

• 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)

Question 14

methyldopa toxicity:

Answer 14

• 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

Question 15

Adrenergic Neuron-blocking Drugs - Guanethidine

Answer 15

• 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)

Question 16

β-adrenergic Receptor Blockers – propranolol:

Answer 16

• 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


Question 17

β-adrenergic Receptor Blockers – propranolol, mechanism:

Answer 17

• 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)

Question 18

β-adrenergic Receptor Blockers – metoprolol; atenolol:

Answer 18

• 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

Question 19

β-adrenergic Receptor Blockers – nadalol, carteolol, betaxolol, bisoprolol:

Answer 19

• 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

Question 20

β-adrenergic Receptor Blockers –

pindolol (Visken); acebutolol (Sectral); penbutolol (Levatol):

Answer 20

• 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

Question 21

β-adrenergic Receptor Blockers – labetolol; carvedilol; nebivolol:

Answer 21

• 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)

Question 22

β-adrenergic Receptor Blockers – Esmolol:

Answer 22

• 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

Question 23

α1-adrenergic Receptor Blockers –

prazosin; terazosin; doxazosin:

Answer 23

• 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

Question 24

α1-adrenergic Receptor Blockers –

prazosin;terazosin doxazosin:

Answer 24

• PK

* prazosin – extensively metabolized/high first pass metabolism (