Alpha lipoic acid (ALA) is recommended based on the “10,000 patient study,” which recommends 600 mg tid. This may get expensive and may cause stomach irritation. Some other doctors have found sufficient efficacy with as low as 200 mg tid, especially if autonomic dysfunction is early [7, 8, 15, 16]. “TID” is required due to the short half-life of ALA.

PE (whether Valsalva, or PC, or stand) is associated with difficult to control BP, blood glucose, or hormone level (e.g., thyroid or estrogen); difficult to describe pain syndromes; unexplained arrhythmia (palpitations) or seizure; and symptoms of depression, fatigue, exercise intolerance, persistent weight gain, sleep or GI disturbance, dizziness or lightheadedness, frequent headache or migraine, or high BP secondary to autonomic dysfunction (PE). Sympathetic excess (SE) comorbid with PE has been found to be secondary [4] to autonomic dysfunction (PE). This is perhaps the reason why the treatment of PE and SE with sympatholytics only tends to exacerbate symptoms. In these cases Valsalva or stand PE seems to always be the primary autonomic disorder.

If the patient does not demonstrate SE, cardiovascular disease, including hypertension, considers titrating low-dose anticholinergic therapy to relieve the Valsalva or stand PE and maintain normal SB (0.4< SB <3.0). While antidepressants, antipsychotics, anxiolytics, and benzodiazepines all are known to have direct or indirect anticholinergic affects, we only have significant clinical data for tricyclic antidepressants, selective norepinephrine reuptake inhibitors (SNRIs), and selective serotonin reuptake inhibitors (SSRIs). First of all, for autonomic purposes very low doses seem to be all that is required. Remember, the goal of therapy is to gently retrain the nervous system, utilizing its (extant) plasticity to advantage. Too much therapy, as would be needed to effect end-organ damage, can cause additional symptoms by “pushing the pendulum too far in the other direction.” For example, effective starting doses for the tricyclics are 10–12.5 mg QD, dinner, and 20 mg duloxetine. Given that these agents are all antidepressants and given the well-known warnings of antidepressants, it is often advisable to call these agents “anticholinergics” rather than “antidepressants” to help with compliance. This is justified since they are not being prescribed at clinical doses, and therefore the concerning side effects are greatly reduced. From an autonomic perspective, as anticholinergic agents, SSRIs seem to be the weakest of the three classes of agents. While they will mask symptoms (e.g., of depression, ADD), they do not regularly also relieve PE. The most reliable agents seem to be the tricyclics. Consider starting with very low-dose nortriptyline or amitriptyline (e.g., 12.5 mg QD, dinner), history dependent, and titrate up to 12.5 mg bid as needed. The preference is nortriptyline as it has less of a weight gain side effect. Amitriptyline is recommended when increased weight may be healthy for the patient. Note, nortriptyline seems to add about 5 lb, whereas amitriptyline seems to add 20 lb, and no amount of exercise seems to prevent either. You may comfort your patient with the fact that often the tricyclic is a short-term therapy (<18 months). The term is based on the plasticity of the patient’s ANS and the duration of the dysfunction. Furthermore, once the tricyclic is discontinued, the added weight typically comes off through normal activity. Some patients do not respond to tricyclics, or their employment may be jeopardized by a prescription of a tricyclic. To address these issues duloxetine (e.g., 20 mg QD, dinner), an SNRI, was found to be reliable and a useful substitute for nonresponders. Introduce carvedilol if larger anticholinergic dosing is required. As in all cases, if the PE is not reduced within 3 months, the patient may not be responding on a different agent may be required.

If the patient demonstrates PE with SE or with CAN or with risk of CAN (e.g., a geriatric patient or a patient diagnosed with cardiovascular disease (CVD), including hypertension), switch to or titrate carvedilol, history dependent, to relieve the Valsalva or stand PE and the SE simultaneously, and maintain normal SB (0.4< SB <3.0) or if possible low-normal SB (0.4< SB <1.0) as recommended in the geriatric cardiology literature [22]. While carvedilol, a double cocktail, is in part a beta-blocker, many (single agent) beta-blockers may exacerbate PE, causing the patient to become more unstable or difficult to control. The single agent beta-blocker may further reduce extant sympathetic feedback on (dynamic) parasympathetic activity which is already excessive, exacerbating the PE. It seems as if the alpha component of carvedilol in the face of autonomic neuropathy (even before symptoms of CAN) indirectly reduces (only) the dynamic (e.g., Valsalva or stand) PE. It does not seem to significantly affect resting (or static) parasympathetic activity. Therefore, the beta-blocker component of carvedilol treats the secondary SE associated with PE and the alpha component seems to treat the PE. This is the basis for which the switch from other beta-blockers to carvedilol is recommended. Add nortriptyline, amitriptyline, or duloxetine, history dependent, if higher doses are required.

The discovery of the efficacy of carvedilol was through its preference for patients diagnosed with diabetes and the prevalence of PE in patients diagnosed with diabetes. Prior to this, the practice was to prescribe both a sympatholytic (e.g., beta-blocker or antihypertensive) and an anticholinergic. Carvedilol, given its efficacy (in a sense), became a convenience. The single prescription was less expensive and had a higher compliance rate than the two prescriptions, especially if the two agents had different dosing times. However, the two-agent approach may still be needed if carvedilol is contraindicated for the given patient (e.g., severe asthma or COPD). Remember, PE may be demonstrated prior to symptoms. Even if the patient has none of the symptoms of PE and is geriatric or has a history of long-standing chronic disease, consider proactively prescribing very low-dose carvedilol (e.g., 3.125 mg, bid), history dependent [4]. Note, proactive dosing of (“physiologically”) younger patients does not seem to help. In fact it often causes the very symptoms attempting to be avoided.

Sympathetic withdrawal (SW) is the autonomic “definition” of orthostasis. SW is usually accompanied by abnormal BP or HR changes from resting to standing. Remember, SW may be demonstrated prior to symptoms. As such, SW is a fall risk indicator in geriatrics. SW may also contribute to elevated or high BP [3]. The relationship between SW and high BP has often been noted in patients. Patients with high BP and SW complain that they do not tolerate the anti-hypertension therapy. Shortly after dosing with the antihypertensive, they become dizzy or lightheaded. This has become a “good” autonomic sign (the “layers of the onion are being peeled away”). It means that we have unmasked the orthostatic dysfunction. In anticipation of this, many cardiologists are prescribing volume builders or vasopressors, history dependent, on an as needed basis just for this eventuality. The theory is that the hypertension is actually secondary to the SW (e.g., preclinical orthostatic dysfunction). In fact it seems to be a compensatory mechanism.

By way of explaining the compensatory mechanism, consider the following example. Assume for a given patient, 140 mmHg pressure systolic is needed for proper brain perfusion upon standing. Assume that the patient’s systolic pressure drops 7 mmHg upon standing. Therefore, to maintain proper brain perfusion, a minimum of 147 mmHg of resting systolic pressure is required by that patient. At 147 mmHg systolic pressure, resting, this patient’s physician would diagnose hypertension and prescribe an agent to reduce pressure. In this example, let us assume that the resting pressure is reduced 5–142 mmHg. Now the standing systolic pressure is below 147 mmHg again, and the patient complains of dizziness. Without knowing about SW the physician may reduce the dose to reduce the symptoms of dizziness. This is often the case and many patients live with reduced symptoms of both hypertension and orthostasis. Whereas with SW documented by P&S monitoring, a low-dose vasopressor may also be prescribed. This is possible in this case due to relatively low resting BP (<160/90 mmHg pressure [3]), assuming no supine hypertension. By prescribing both an antihypertensive and a vasopressor (or volume builder), the heart is protected by the antihypertensive and the vasculature is being treated. Assuming no vascular end-organ issues (“lazy walls,” bad valves, atherosclerosis, etc.) the vasopressor “retrains” the alpha-adrenergic system to promote vasoconstriction, which seems to reintegrate the vasculature with the heart [3], and in many patients, both symptoms are relieved and (especially “physiologic” younger) both agents may be discontinued once the autonomic dysfunction(s), dizziness, and high BP symptoms are relieved, corrected, and stabilized.

For SW, always start by recommending proper daily hydration. It seems about 40 % of the SW patients are simply dehydrated. Proper daily hydration (i.e., six to eight glasses of water throughout the day with fewer caffeinated, sugary, and alcoholic drinks) has been shown to reverse SW. The caffeinated, sugary, and alcoholic drinks are permitted, only in moderation, and an additional ounce for ounce of water is required to balance the other drinks. If after 3 months of proper hydration, symptoms persist, then consider titrating lower diuretic therapy or higher dietary salt, to build volume, history dependent. If symptoms persist, consider mechanical intervention (e.g., compression stockings). If symptoms persist, consider volume building (e.g., fludrocortisones). If symptoms persist, or resting BP is well controlled and there is no sign of supine hypertension, consider vasopressor therapy. Data exists on the efficacy and use of midodrine (ProAmatine: starting low dose, e.g., 2.5 mg QD, dinner) [3]. The last dose of midodrine should not be taken after evening meal or less than 3–4 h before bedtime or lying down for any length of time, in case of supine hypertension. Finally, in very severe cases of orthostatic hypotension with intractable hypertension or multiple system atrophy, or pure autonomic failure, pyridostigmine (Mestinon) would be recommended by physicians with special training with this class of pharmacological agents. All recommendations must be considered in terms of patient history [3, 7–14, 17, 18].

Cardiac autonomic neuropathy (CAN) is defined as RFa <0.1 bpm². This is the mathematical equivalent to the Framingham Heart Study threshold for high risk of sudden cardiac death [5, 19–21]. The time duration of this threshold follows the study’s 5-year time course for post-MI and post-CABG patients. However, for all other chronic, progressive disease patients, our doctors have found that as long as the RFa <0. 1 bpm², the patient continues to be at risk. This may be normal for patients, not only if they are post-MI and post-CABG but also if they are geriatric or have CVDs. High risk of CAN is indicated when SB is high, which indicates a concurrent, (relative) resting, sympathetic excess (SE). CAN with high SB suggests that the parasympathetics may be insufficient for slowing a ventricular tachyrhythm and preventing it from becoming fibrillation or worse. Clinical protection of the heart is recommended and may be accomplished by using sympathetic blockade (sympatholytics or adrenergic antagonists, e.g., beta-blockers, ACE Is, ARBs, or Ca⁺⁺ channel blockers), titrated against a low-normal SB (0.4< SB <1.0) [22–24]. Low-normal SB indicates more (resting) parasympathetic activity. This is recommended as cardioprotective and found to minimize mortality risk [22] Note, too much resting parasympathetic activity is associated with depression [25–32].