Autonomic pharmacology

Therapeutic Uses: β-Adrenergic Receptor Antagonists

Miscellaneous Cardiovascular Uses:¹⁵²
- ß-adrenergic receptor antagonists i.e. typically propranolol (Inderal) are used in management of hypertrophic obstructive cardiomyopathy.
  - Hypertrophic Cardiomyopathy³⁴²
  - In patients with this disorder, propranolol may be effective in alleviating angina, palpitations and syncope.
    - The effectiveness of ß adrenergic antagonists in this setting is likely due to reduced outflow tract pressure gradients.
  ß-adrenergic receptor antagonists have also shown helpful in management of acute dissecting aortic aneurysm due to ß-blocker-mediated reduction in myocardial contractility and reduced rate of force development.¹⁵²
- In patients with Marfan's syndrome, chronic management with propranolol may reduce the rate of aortic dilation and associated complications including aortic dissection and regurgitation.
  - Marfan Syndrome³⁴³

Glaucoma:

Elevation of intraocular pressure, in open angle glaucoma, results in slowly occurring segmental atrophy of the optic nerve.³⁴⁴

Age-Standardized Disability-Adjusted Life Year Rates from

Glaucoma by Country per 100,000 Inhabitant³⁴⁷
Age-Standardized Disability-Adjusted Life Year Rates from

Glaucoma by Country per 100,000 Inhabitants³⁴⁷
Optic nerve damage can range from a slight reduction in upper nasal peripheral visual field to total blindness.

Simulated Glaucoma Effects on Visual Field³⁴⁵

Simulated range of vision	Simulated range of vision with advanced glaucoma

Typically open angle glaucoma occurs bilaterally, although the disorder can be asymmetric.³⁴⁴

Open angle glaucoma is painless and patients may be unaware of damage until relatively late in disease progression.³⁴⁴
- As noted, slight cupping (segmental atrophy) of the optic disc may be apparent an examination; moreover, central vision acuity is not affected even in cases of substantial overall visual field loss.
  - Absolute glaucoma is defined as total loss of both peripheral and central vision and may be associated with reduced light perception.

This section focuses on disease management using pharmacological interventions, namely ß-receptor antagonists.³⁴⁴

Other medications that may be useful include:
- α-adrenergic agonists (e.g. brimonidine)
- carbonic anhydrase inhibitors (e.g. dorzolamide, or
- prostaglandins (e.g. latanoprost).
- These agents are used topically; however, an oral carbonic anhydrase inhibitor such as acetazolamide might be used in patients who exhibit continued intraocular pressure elevation despite topical treatment.
  - Miotics such as pilocarpine and epinephrine drops are less commonly employed.

However, non-pharmacological management is often efficacious.

One example, argon laser trabeculoplasty reduces intraocular pressure in some individuals and, if determined efficacious, may be used twice on each eye.
- A newer laser treatment, selective laser trabeculoplasty may be used multiple times and each eye.
Patients presenting with persistent pressure elevation may require surgery, trabeculectomy, to create alternative drainage routes for fluid from the eye.
- For this procedure, outcomes have been improved by intraoperative application of 5-FU (5-fluorouracil) or mitomycin, agents that reduce postoperative fibrosis which may result in channel closure.
- Finally, in certain types of glaucoma (neovascular or aphakic) prosthetic drainage valves/ounce may be employed.
  - Aphakic glaucoma is glaucoma developing in an eye which has had its lens removed.
  - Neovascular glaucoma is a secondary glaucoma occurring as a result of severely reduced blood flow to the eye as may be observed in central retinal vein occlusion or with severe diabetic retinopathy.

Conventional Surgery in Glaucoma Treatment³⁴⁶

"Conventional surgery to treat glaucoma makes a new opening in the meshwork. This new opening helps fluid to leave the eye and lowers intraocular pressure. Description: Conventional surgery to treat glaucoma makes a new opening in the meshwork. This new opening helps fluid to leave the eye and lowers intraocular pressure." National Eye Institute, National Institutes of Health

Chronic open angle glaucoma may be managed by ß-adrenergic receptor antagonists. ß-receptor blockers used for this indication include:¹⁵²

ß-Adrenergic Receptor Antagonists used in Management of Open-Angle Glaucoma
betaxolol (Betaoptic)	levobetaxolol (Betaxon)	carteolol (Ocupress)
levobunolol (Betagan)	timolol (Timoptic)	metipranolol (OptiPranolol)

Examples of non-selective ß-receptor antagonists from this group are metipranolol, carteolol, timolol, and levobunolol; however, betaxolol and levobetaxolol are classified as ß₁-adrenergic receptor selective.

Topical application of these agents have very limited effect on pupillary size or accommodation and do not cause the blurred vision/night blindness observed with miotics, such as pilocarpine (Ocusert).¹⁵²
- ß-adrenergic receptor antagonists reduce aqueous humor production; this reduction is likely the basis for their therapeutic efficacy.
- In management of glaucoma, ß-adrenergic receptor blockers are administered as eyedrops within onset of action in the range of 30 min. and a duration of action of about 12-24 hours.
- These agents, despite topical application, or absorbed systemically and thus may cause cardiovascular and pulmonary adverse effects.¹⁵²
  - For example, glaucoma patients who also have bronchial asthma, severe chronic obstructive pulmonary disease (COPD) and/or bradyarrhythmias are particularly at risk for exacerbation of these conditions.
    - Some ß blockers appear protective to retinal neurons because they reduced neuronal Ca²⁺ and Na⁺ influx; these agents include metipranolol, timolol, and betaxolol, with betaxolol appearing most effective in limiting Na⁺/Ca²⁺ influx.
    - ß-adrenergic receptor antagonists also may reduce ganglion cell death and glaucoma with levobetaxolol exhibiting increase neuroprotective effect compared to timolol. The section also appears based in Na⁺ and Ca²⁺ influx blockade.¹⁵²

Other Uses:

Hyperthyroidism: ß-adrenergic receptor antagonists may be used in blunting symptoms of sympathetic hyperactivity.¹⁵²
- For example, in hyperthyroidism some presentations resemble of sympathetic excess activity.
- Supranormal thyroid hormone levels increase ß-adrenoceptor expression in some systems; not surprisingly, ß-adrenergic receptor blockers attenuate cardiovascular manifestations of hyperthyroidism and may be helpful as part of the definitive therapeutic plan.
- Propranolol limits peripheral conversion of thyroxine to triiodothyronine, beneficial effects separate from propranolol (Inderal)-mediated ß-receptor blockade. In hyperthyroid patients exhibiting cardiac enlargement, caution must accompany ß-adrenergic receptor blockade, since this treatment could induce heart failure.
Migraine: Another use of ß-receptor antagonists is in migraine prophylaxis.¹⁵²
- Although the mechanism remains to be elucidated, propranolol, metoprolol, and timolol appear effective for this indication.
  - These agents are not efficacious for treatment of acute migraine attacks.
Stage Fright: Propranolol as well as other ß-adrenergic receptor antagonists are effective in attenuating "stage fright." ¹⁵²
- Prior to performance e.g. public speaking, music recital, etc. ß-adrenergic blockade reduces manifestation of increased sympathetic nervous system activity; these manifestations may include tachycardia and muscle tremor.
- Along the same line, propranolol may be useful in essential tremor management.¹⁵²

Recurrent Variceal Bleeding Prophylaxis:

Portal hypertension is defined by a pressure gradient greater than 5 mmHg between the portal pressure and inferior vena cava pressure.³⁵¹

With gradients in excess of about 10 mmHg hepatic portal system blood flow transitions from the liver into areas exhibiting lower venous pressures.
- A consequence of this change in flow pattern is an increase in circulation and lower esophagus, abdominal wall, stomach and rectum.
  - Blood vessels in these regions may become distended then, exhibiting reduced wall thickness, and may be described as varicosities.³⁵¹
    - These structures may not retain structural integrity at these pressures. Esophageal varices describe dilated sub-mucosal lower esophageal veins; bleeding from these varices may constitute a clinical emergency.
    - Esophageal varices develop with a frequency of about 5%-8% per year in patients with cirrhosis and portal hypertension and as many as 80% of individuals with hepatic cirrhosis will develop this complication.
      - Esophageal Varices³⁵²
        
        "Gastroscopy image of esophageal varices with prominent red wale spots."
    - The likelihood of hemorrhage from esophageal varices is about 30% in patients with cirrhosis and large esophagogastric varices.
    - Bleeding from esophageal varices appears responsible for about 15%-20% of early mortality and ultimately may account for about one third of all deaths.
      - Following control of acute hemorrhage, long-term treatment is required to avoid the 60%-70% the recurrent variceal hemorrhage frequency.
Portal hypertension develops because of increased in intrahepatic resistance combined with increased portal blood flow.³⁵¹
- Band Ligation of Esophageal Varices³⁵⁴
- In cirrhosis, interaction between portal blood flow increase and increases in hepatic and portocollateral vascular resistance.
  - This interaction tends to lead to a cycle of worsening portal hypertension.
    - A consequence of this pathology is systemic vasodilation associated with neurohumoral vasodilator release.
      - These neurohumoral substances include nitric oxide, glucagon, prostaglandins, tumor necrosis factor and other cytokines.
        
        The resulting vascular effects describe a "hyperdynamic circulatory system."
        
        Another complication is angiogenesis which increases splanchnic blood flow.
  - The increase in intrahepatic resistance in the syndrome develops as a result of sinusoidal encroachment, vascular tree pruning, nodular regeneration and collagen deposition.³⁵¹
    - In addition, resistance is further enhanced by endogenous vasoconstrictor overexpression.
      - These vasoconstrictors include endothelins and leukotrienes and are accompanied by reduced production of endogenous vasodilators such as nitric oxide.
      - The increase in intrahepatic and portocollateral resistance results in ascites development or hydrothorax or both as well as varices formation and portal hypertensive gastropathy.

Patients exhibiting cirrhosis have nonspecific symptoms consistent with portal hypertension.³⁵¹

These symptoms may include muscle wasting, spider angiomata, jaundice, ascites, altered mental status and abdominal collateral vessels.

Spider Angiomata³⁵³

"Gigantic cutaneous arterial spiders - This 47-year-old patient had longstanding jaundice and ascites consequent to biopsy-proven hepatic cirrhosis."

Some abnormal laboratory findings include prolonged prothrombin time, thromocytopenia, hyperbilirubinemia, and hypoalbunemia.

Many approaches are available for both predicting and defining cirrhosis.
- Suggesting cirrhosis from radiographic studies include the presence of a small, nodular liver, ascites, intra-abdominal varices, portal and hepatic vein thrombosis and splenomegaly.
- Liver biopsy is the definitive test for diagnosing cirrhosis.
  - Other diagnostic methodologies include abdominal ultrasound, computed tomography scanning (CT scanning) and magnetic resonance imaging (MRI).
  - A Fibroscan which is an elastographic method measures, using pulse-echo ultrasound to assess liver stiffness.³⁵¹

Propranolol (Inderal) and nadolol (Corgard) have been shown helpful in primary prevention of variceal hemorrhage due to portal hypertension associated with liver cirrhosis.^152,348

ß-receptor blockers may also decrease risk of recurrent variceal bleeding.

Effective protection from variceal bleeding risk by continual pharmacological treatment requires a reduction in the portal pressure gradient to below 12 mmHg or at least by 20% of baseline values.
- The portal pressure gradient is measured as the hepatic venous pressure gradient (HVPG).

The mainstay of pharmacological therapy as noted above are the nonselective ß-adrenergic blockers notably propranolol and nadolol.

Such agents achieve the goal of appropriate portal pressure gradient reduction in about 20% to 30% of patients.

The propranolol-mediated decrease in hepatic venous pressure gradient values appears enhanced by concurrent administration of isosorbide mononitrate or by the α₁-receptor blocker prazosin.
Carvedilol exhibits both nonselective ß-adrenergic receptor blockade along with anti-α₁-adrenergic activity.³⁴⁸

Carvedilol exhibits a greater portal hypotensive effect compared to propranolol in patients with cirrhosis; however, clinical applicability of carvedilol may be limited by systemic hypotensive effects.³⁴⁸^,349

Carvedilol in Management of Portal Hypertension in Cirrhosis³⁴⁸

"Comparison of the effects of carvedilol and propranolol on HVPG. As shown, carvedilol caused a more pronounced decrease in HVPG than propranolol (A), which resulted in a significantly greater proportion of patients exhibiting a good hemodynamic response (B)."

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