<span class="center-menu">← <small>PREVIOUS: [[6.2.1. Drugs that increase blood volume]]</small> | <small>NEXT: [[6.2.3. Vasoconstrictor drugs]]</small> →</span> -------- ##### Summary >[!Summary] >- the “compensatory tachycardia” may sometimes be excessive, and contribute directly to the patient's symptoms. Therefore, many treatments do attempt to directly decrease HR in POTS[[#^1]] >- however, “normalizing” HR in POTS or excessively decreasing HR can worsen symptoms in patients with POTS. The goal is to “take the edge off” of the increased upright HR in POTS[[#^1]][[#^4]]. This usually means treating POTS patients with smaller doses than are often used for other cardiovascular diseases[[#^1]] > ----------------- > **β-Blockers** >- used to control the excessive sinus tachycardia[[#^2]] >- may exacerbate fatigue and exercise intolerance and may produce hypotension in patients with low intravascular volume[[#^3]] >- patients with a higher standing plasma norepinephrine level had a better response to β-blockers compared with patients with a lower standing plasma norepinephrine level[[#^6]] > >**Propanolol** >- propanolol is lipophilic and crosses the blood-brain barrier more than most other β-blockers, which may be important to its beneficial effects but also potential neurocognitive side effects[[#^7]] >- non-selective β adrenergic receptor antagonist, with blockade of both β1- and β2-adrenergic receptors. β2adrenergic receptor blockade leads to peripheral vasoconstriction, which might promote a “midodrine-like” effect, with a secondary reflex lowering of HR[[#^7]] >- is also used as a migraine prophylaxis medication, so there is sometimes a “dual-benefit” from using propranolol[[#^7]] >- low dose short-acting propranolol was found (10-20 mg PO) to be very effective at lowering standing HR and improving symptoms[[#^4]] ; some symptoms (mental clouding, lightheadedness and dyspnea) improved after patients received low dose propranolol, but not after they received higher dose propranolol[[#^8]] >- long-acting propranolol does not improve quality of life in POTS. Short-acting propranolol has a fairly short half-life, with each pill working for 4–5h before the effects noticeably “wear-off”, meaning that full day dosing requires taking this 4 times per day[[#^11]] > >**Bisoprolol** >- one study found that 6-week treatment with bisoprolol 5 mg daily improved symptoms[[#^12]] > >**Ivabradine** >- cardioselective agent[[#^14]] that reduces heart rate by blocking the If, or funny channel, which modulates the intrinsic pacemaker rate of the sinus node[[#^15]] >- theoretically desirable treatment for POTS because of its specific effects on lowering HR without affecting BP[[#^16]] >- a 2021 single-centre RCT found that ivabradine lowered the heart rate and improved symptoms in some patients with POTS[[#^18]] >- dispensed in 2.5 to 7.5 mg pills and given orally twice daily[[#^17]] >- side effects are relatively uncommon with ivabradine, but can include headaches, palpitations, hypertension, and visual disturbances[[#^17]] >- may be an option for POTS patients in which β-blockers are not well tolerated[[#^17]] > >**Pyridostigmine** >- peripheral acetylcholinesterase inhibitor that can increase the levels of synaptic acetylcholine at both the autonomic ganglia and the peripheral muscarinic parasympathetic receptors[[#^21]] leading to peripheral sympathetic vasoconstrictor output (and potentiating vagal effects) on standing[[#^19]] >- studies found that pyridostigmine decreased orthostatic HR and improved symptoms in POTS[[#^23]] >- increases colonic motility, which typically limits tolerability in patients who are prone to diarrhea. But in patients with early satiety, gastroparesis, or constipation, this can be a desirable side effect and improve abdominal pain and nausea[[#^23]] >- can also cause abdominal cramps, nausea, muscle twitching, headaches, and shortness of breath and should be used with caution in patients with asthma[[#^23]] >- taken orally in 30 or 60 mg doses up to three times daily. Patients usually start with 30 mg TID, and increase to 60 mg TID, if tolerated and needed[[#^23]] -------- >*“One of the cardinal hemodynamic features of POTS is tachycardia, and this often drives symptoms such as palpitation, lightheadedness, and dyspnea. Therefore, the tachycardia can seem like an ideal treatment target. However, the tachycardia is often secondary to other hemodynamics problems, including a low cardiac stroke volume, with the tachycardia needed to maintain cardiac output. However, the “compensatory tachycardia” may sometimes be excessive, and contribute directly to the patient's symptoms. Therefore, many treatments do attempt to directly decrease HR in POTS. However, “normalizing” HR in POTS or excessively decreasing HR can worsen symptoms in patients with POTS. The goal is to “take the edge off” of the increased upright HR in POTS. This usually means treating POTS patients with smaller doses than are often used for other cardiovascular diseases.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=4CJVLMHV))</small>^1 ##### 1. β-Blockers >*“β-blockers including propranolol [87,92] and cardioselective agents such as bisoprolol [90,93] to control the excessive sinus tachycardia”* <small>([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=GWCYP2W3))</small>^2 >*“Propranolol and other β-blockers may exacerbate fatigue and exercise intolerance and may produce hypotension in patients with low* <small>([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=DDY4GF3W))</small> intravascular volume.” <small>([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=UR9TCFDS))</small>^3 >*“Beta-adrenergic blockers are commonly used in cardiology clinics to control tachycardia. Many patients with POTS, however, will complain of excessive fatigue or intolerance to beta-blockers. Reducing the HR in POTS would be counter-productive if the increase in HR were purely compensatory for another physiological shortfall (e.g., low stroke volume), but could be useful if the tachycardia was “over-compensation” for the physiological stimuli. We have found low dose short-acting propranolol (10-20 mg PO) to be very effective at lowering standing HR and improving symptoms in POTS patients” *<small>([[Raj-2013]], [p. 7](zotero://open-pdf/library/items/CCJLQKRB?page=7&annotation=VEYVXMXQ))</small>^4 >*“Current therapeutic approaches using b-blockade11 can lead to partial alleviation of the tachycardia but are frequently associated with additional side effects.” *<small>([[Li-2014]], [p. 1](zotero://open-pdf/library/items/4RG2IND3?page=1&annotation=IZ4562JK))</small>^5 >*“Patients with a higher standing plasma norepinephrine level (>600 pg/mL; 29.2%) had a better response to βblockers compared with patients with a lower standing plasma norepinephrine level (<600 pg/mL; 22.9%)” *<small>([[Thieben-2007]], [p. 5](zotero://open-pdf/library/items/5WXWEQWX?page=5&annotation=KVX7FKFI))</small>^6 ###### 1.1. Propanolol >*“Propranolol is different than many other β-blockers. It is lipophilic and crosses the blood-brain barrier more than most other β-blockers, which may be important to its beneficial effects but also potential neurocognitive side effects. It is a non-selective β adrenergic receptor antagonist, with blockade of both β1- and β2-adrenergic receptors. β2adrenergic receptor blockade leads to peripheral vasoconstriction, which might promote a “midodrine-like” effect, with a secondary reflex lowering of HR. Propranolol (often at higher doses) is also used as a migraine prophylaxis medication, so there is sometimes a “dual-benefit” from using propranolol.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=AXW8QRID))</small>^7 >*“We found that: (1) low doses of propranolol significantly decreased the standing HR and orthostatic tachycardia of patients with POTS acutely compared to placebo, and that this was associated with a symptomatic improvement; (2) higher dose propranolol (more complete beta-blockade) can further restrain HR and orthostatic tachycardia but does not further improve symptoms in patients with POTS; and (3) some symptoms (mental clouding, lightheadedness and dyspnea) improved after patients received low dose propranolol, but not after they received higher dose propranolol.” *<small>([[Raj-2009a]], [p. 7](zotero://open-pdf/library/items/RTRQALDF?page=7&annotation=B2VEPTPB))</small>^8 >*“The non-selective β-AR antagonist propranolol acutely restrains orthostatic tachycardia and symptoms at doses that appear to be low enough (10-20 mg) to avoid the side effect of significant fatigue [64]. The decrease in standing HR was verified in a four-week trial of long-acting propranolol although quality of life was not improved” *<small>([[Garland-2015]], [p. 9](zotero://open-pdf/library/items/CAWTWYLR?page=9&annotation=JRQPYURD))</small>^9 >*“Most research on βblockers in POTS have investigated the effects of the non-selective β adrenergic receptor antagonist propranolol (Arnold et al., 2013;Fu et al., 2011;Raj et al., 2009 ). These studies have found that low doses of propranolol (20 mg per dose) are better tolerated in POTS than higher doses are (Raj et al., 2009). Low dose oral propranolol improves tachycardia, symptoms, and exercise capacity in POTS”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=44VWSLAM))</small>^10 >*“β-Blockers may also improve headaches but that has not been extensively studied in POTS. Long-acting propranolol does not improve quality of life in POTS (Fu et al., 2011). Short-acting propranolol has a fairly short half-life, with each pill working for 4–5h before the effects noticeably “wear-off”, meaning that full day dosing requires taking this 4 times per day. The Heart Rhythm Society Expert Consensus made propranolol 10 to 20 mg (short acting) in patients with POTS as a Class 2B recommendation”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=BZMGNNYD))</small>^11 >*“Propranolol blocks both β1- and β2-adrenergic receptors. A 2009 randomized crossover study found that low-dose oral propranolol improved tachycardia and symptoms on standing,45 and a small, randomized, double-blind study in 2013 showed improved exercise capacity46 in patients with POTS. Propranolol has a short half-life and requires dosing 4 times per day. The Canadian Cardiovascular Society gave propranolol (10–20 mg, 4  times a day) a “strong” recommendation.”* <small>([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=CSMJUIEA))</small>^12 ###### 1.2. Bisoprolol >*“One study found that 6-week treatment with bisoprolol 5 mg daily improved symptoms in a small sample of 11 POTS patients (Freitas et al., 2000).”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=MWNJTUKC))</small>^12 >*“Although most studies of β-blockers have used propranolol, bisoprolol may also be effective; better comparative data are needed.”* <small>([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=832X6JCQ))</small>^13 ##### 2. Ivabradine >*“Ivabradine is a cardioselective agent that slows HR via inhibition of the funny channel current (If) in the cardiac sinoatrial node but does not affect BP.” *<small>([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=428KRKWB))</small>^14 >*“Ivabradine reduces heart rate by blocking the If, or funny channel, which modulates the intrinsic pacemaker rate of the sinus node.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=DJVW4EGC))</small>^15 >*“Ivabradine is a theoretically desirable treatment for POTS because of its specific effects on lowering HR without affecting BP.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=2EWW2J9P))</small>^16 >*“Ivabradine is dispensed in 2.5 to 7.5 mg pills and given orally twice daily. The typical starting dose is 5 mg twice daily. Side effects are relatively uncommon with ivabradine, but can include headaches, palpitations, hypertension, and visual disturbances. Ivabradine may be an option for POTS patients in which β-blockers are not well tolerated.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=AY6A2DSG))</small>^17 >*“Ivabradine is a hyperpolarization-activated cyclic nucleotidegated channel (If) blocker that lowers sinus node rate without β-blocker effects. A 2021 single-centre RCT found that ivabradine lowered the heart rate and improved symptoms in some patients with POTS.”* <small>([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=X3TF8BPN))</small>^18 ##### 3. Pyridostigmine >*“the cholinesterase inhibitor pyridostigmine [94-96] to prolong the phasic effects of acetylcholine on the autonomic ganglia, leading to peripheral sympathetic vasoconstrictor output (and potentiating vagal effects) on standing”* <small>([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=VIFWML9V))</small>^19 >*“Pyridostigmine may potentiate muscarinic receptor activation in the gastrointestinal tract, exacerbating nausea, vomiting, abdominal cramps, and diarrhea, and in the bladder, potentiating the symptoms of detrusor hyperactivity.”* <small>([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=KPLR28GV))</small>^20 >*“Pyridostigmine is a peripheral acetylcholinesterase inhibitor that can increase the levels of synaptic acetylcholine at both the autonomic ganglia and the peripheral muscarinic parasympathetic receptors. Pyridostigmine 30-60 mg PO TID has been reported to result in chronic symptom improvement in ∼50% of POTS patients” *<small>([[Raj-2013]], [p. 7](zotero://open-pdf/library/items/CCJLQKRB?page=7&annotation=S6T8VCDW))</small>^21 >*“Increasing parasympathetic tone with pyridostigmine can also curtail HR in POTS [65] (HRS Class IIb) [8]. This agent inhibits acetylcholinesterase, thereby increasing the availability of acetylcholine at both the autonomic ganglia and the peripheral muscarinic receptors. Pyridostigmine ameliorates symptoms in patients with POTS, although nausea, vomiting and diarrhea from gut activity may lead to discontinuation in 20% of patients” *<small>([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=YMHEQP4H))</small>^22 >*“Pyridostigmine is an acetylcholinesterase inhibitor that slows the breakdown of the neurotransmitter acetylcholine in the synaptic cleft. This increases the amount of acetylcholine that can bind to nicotinic receptors in the autonomic ganglia and muscarinic receptors in the heart to decrease HR (Raj et al., 2005). Pyridostigmine can also increase colonic motility, which typically limits tolerability in patients who are prone to diarrhea. However, in patients with early satiety, gastroparesis, or constipation this can be a desirable side effect and improve abdominal pain and nausea (Stewart et al., 2018). Pyridostigmine can also cause abdominal cramps, nausea, muscle twitching, headaches, and shortness of breath and should be used with caution in patients with asthma. Pyridostigmine is taken orally in 30 or 60 mg doses up to three times daily. Patients usually start with 30 mg TID, and increase to 60 mg TID, if tolerated and needed (Kanjwal et al., 2011). Pyridostigmine has been evaluated in POTS in a single dose randomized crossover study (Raj et al., 2005), and in one long-term retrospective study (Kanjwal et al., 2011). Both these studies found that pyridostigmine decreased orthostatic HR and improved symptoms in POTS (Kanjwal et al., 2011; Raj et al., 2005). The drug was generally well tolerated in both studies.”* <small>([[Miller-2018]], [p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=Y964DVU9))</small>^23 >*“Pyridostigmine is a peripheral acetylcholinesterase inhibitor that increases synaptic acetylcholine. A 2005 study found that pyridostigmine (30–60  mg, given orally 3 times daily) can acutely decrease upright heart rate in patients with POTS;48 it acts either by directly increasing vagal tone or by increasing sympathetic vasoconstriction. Although pyridostigmine is generally well tolerated, it can increase colonic motility. It should be avoided in patients prone to diarrhea but can be helpful in patients with constipation.”* <small>([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=INLN5YGZ))</small>^24