6.2. Pharmacological interventions

← PREVIOUS: [[6.1. Lifestyle modifications and non-pharmacological approaches]] | NEXT: [[6.2.1. Drugs that increase blood volume]] → -------- ##### Summary >[!Summary] >- The Food and Drug Administration has not approved any medications for the treatment of POTS. Therefore, all agents used for this disorder are “off label”[[#^1]] > >**Recommendations** >1. Class I: none[[#^8]] >2. Class IIA: exercise training and acute saline infusion[[#^8]] >3. Class IIB: increased fluid and salt intake, midodrine, β-blockers, fludrocortisone, pyridostigmine, clonidine and alpha-methyldopa[[#^8]] >----------- >- adverse effects of these drugs can limit their use in patients with POTS because of the presence of comorbid symptoms (β-blockers, fludrocortisone, midodrine, SSRI all provided partial relief of symptoms in 40%-60%)[[#^2]] >- study found no differences in the symptomatic response of different patient subgroups to drugs commonly used to treat POTS[[#^5]] >- the overall effects of pharmacological therapy are modest and the most affected patients remain handicapped[[#^6]][[#^8]] >- the physician and patient are often left alone with a decision which drug to test, in many situations applying an ex iuvantibus method, resulting in that polypharmacy is frequent[[#^8]] >- Empirical trials of medications are generally adopted based on the clinician’s impression of the POTS[[#^23]] >- Typically, clinicians test various drugs directed at controlling heart rate, increasing peripheral vasoconstriction and increasing intravascular volume[[#^8]][[#^24]] >- Patient presentations can vary tremendously, and the pharmacological approach to symptomatic improvement has to be individualized[[#^10]] >- Further augmentation of medication will often be necessary. These medications can often be used in combination with each other due to distinct pharmacological mechanisms of action[[#^12]] >- Often treating other POTS symptoms such as tachycardia and lightheadedness also improves brain fog[[#^13]] >- pharmacological agents reported to improve brain fog were intravenous (IV) saline (77 %), stimulant medications (67 %), salt tablets (54 %), intramuscular (IM) vitamin B-12 injections (48 %), and midodrine (45 %)[[#^01]] >- interventions most commonly reported to make brain fog worse were serotonin–norepinephrine reuptake inhibitors or SNRIs (30 %), tricyclic antidepressants (25 %), β1 antagonists (22 %), non-selective β antagonists (20 %), and fludrocortisone (17 %)[[#^01]] > >--------------------- > >**Drugs that increase blood volume** > | DRUG | RATIONALE | CONSIDERATIONS | DOSING | USED BY | |:---------------------------- |:----------------------- |:-------------------------- |:--------------------------------------------- |:------------ | | Salt supplementation |*N/S*|*N/S*|1g orally 3 to 5 times daily with food[[#^9]]|63%[[#^025]]| | Oral Rehydration Salts (ORS) |*N/S*|*N/S*|1-2L daily or less as needed[[#^9]]|*N/S*| | Fludrocortisone | Volume expansion[[#^3]] |Serum potassium should be monitored[[#^22]]|0.1 to 0.2mg daily[[#^9]][[#^22]]| 39.5%[[#^4]] ; 28%[[#^025]] | | Desmopressin (DDAVP) |*N/S*|Serum sodium should be monitored if used chronically[[#^22]]|0.1 to 0.2mg as needed[[#^9]][[#^22]]|*N/S*| | Erythropoietin |*N/S*|Hematocrit should be monitored[[#^9]]|10,000 IU weekly[[#^9]]|*N/S*| |Acute IV saline|*N/S*|*N/S*|2L intravenous over 2-3h[[#^9]]|*N/S*| |Chronic IV saline|*N/S*|Avoid long-term use and placement of central catheters[[#^9]] |2L given intravenously once weekly[[#^9]]|*N/S*| > >--------------------- > >**Drugs that lower heart rate** > |DRUG| RATIONALE | CONSIDERATIONS | DOSING | USED BY | |:---------------------------------------------------------------- |:---------------------------------------------------------------------------------------------------------- |:------------------------------------------------------------------------------------------- |:------ |:------------ | |Propanolol| Reduce sympathetic influence on the sinus node[[#^3]] |May be potentially useful to treat comorbidities (anxiety, migraine)[[#^3]] ; possible that patients with antibodies to adrenergic receptors will have blunted response[[#^20]] ; can worsen asthma[[#^22]]|10-20mg orally up to 4 times daily[[#^9]][[#^22]]| 76.7%[[#^4]] | | Ivabradine |*N/S*|*N/S*|2.5-7.5mg orally twice daily[[#^9]][[#^22]]|*N/S*| | Pyridostigmine | Potentiates ganglionic sympathoexcitation during orthostatic stress[[#^3]] ; may contribute to reducing HR | May help visceral hypomotility but may exacerbate symptoms of visceral hypermotility[[#^3]] ; possible that patients with muscarinic receptor antibodies will have a more favorable response[[#^20]] |30-60mg orally up to 3 times daily[[#^9]][[#^22]]| 5.3%[[#^4]] | > >- β-blockers should be started at low doses because patients may have β-blocker-adrenoceptor supersensitivity[[#^3]] >- β-blockers may exacerbate fatigue or produce hypotension if used without concomitant nonpharmacological approaches[[#^3]] > >--------------------- > >**Vasoconstrictor drugs** > | DRUG | RATIONALE | CONSIDERATIONS | DOSING | USED BY | |:---------------- |:------------------------------------------------ |:-------------------------------------------------- |:-------------------------------------------------------------------------- |:------------ | | Midodrine | Vasoconstriction (reduces venous pooling)[[#^3]] | May worsen GI symptoms or urinary retention[[#^3]] ; possible that patients with antibodies to adrenergic receptors will have blunted response[[#^20]] |2.5-15mg orally 3 times daily[[#^9]][[#^22]]| 31.6%[[#^4]] ; 18%[[#^025]]| | Octreotide |*N/S*|*N/S* | Long-acting intramuscular injection 10-30mg[[#^9]] |*N/S*| | Droxidopa |*N/S*|*N/S*| 100-600mg 3 times daily[[#^9]] |*N/S*| | Modafinil | |*N/S*|50-200mg orally 1-2 times daily[[#^9]]|*N/S*| | Methylphenidate |*N/S*|*N/S*| 10mg orally 2-3 times a day. Last dose should be avoided before bed[[#^9]] |*N/S*| > >- IV saline is reported by patients to be a very successful treatment for brain fog [[#^14]] > >-------------------------- > >**Sympatholytic drugs** > |DRUG|RATIONALE|CONSIDERATIONS|DOSING|USED BY| |:--|:--|:--|:--|:--| |Clonidine|*N/S*|withdrawal can lead to rebound tachycardia and hypertension[[#^22]]|0.1-0.2mg orally 2-3 times daily or long acting patch[[#^9]][[#^22]] ; start with low dose[[#^22]]|11.8%[[#^4]]| |Methyldopa|*N/S*|*N/S*|125-250mg orally twice daily[[#^9]][[#^22]] ; start with low dose[[#^22]] |*N/S*| > >-------------------------- > >**Other** > >- vitamin B12 injections have been reported by some patients as a successful treatment for brain fog[[#^15]] >- one study found that an acute oral dose of melatonin decreases HR while standing in POTS compared to placebo[[#^16]] >- if POTS indeed has an autoimmune basis, this could significantly alter treatment strategies. Intravenous immunoglobulin (IVIG), plasmapheresis/plasma exchange and other immunotherapy drugs may become potential treatments to clear these antibodies[[#^18]] > >--------------------- > >**Suggested Approaches** > >1. **Approach proposed in Miller-2018**[[#^11]] > >- Initial approach: Salt supplements, fludrocortisone ; Low dose β-blockers, pyridostigmine ; Midodrine >- Secondary approach: Acute IV saline, desmopressin, oral rehydration salts ; Ivabradine ; Stimulants, octreotide ; Methyldopa, clonidine >- Only use in refractory cases: Chronic IV saline, erythropoietin ; Droxidopa > >2. **Targeting specific symptoms**[[#^19]] > >- Tachychardia, Palpitation: β-Blockers (Low Dose) >- Blood Pooling, HR not too high: Midodrine >- Orthostatic Hypertension: β-Blockers (Low Dose) ; Methyldopa, Clonidine >- Hypovolemia: Fludrocortisone, DDAVP >- Hypotension, Frequent Syncope: Midodrine ; Fludrocortisone, DDAVP >- Constipation: Pyridostigmine >- Brain Fog, Cognitive Issues: Modafinil, Stimulants > 3. **Based on Subtypes** > >**Hyperadrenergic POTS** > >- volume expansion and reduction of sympathetic action (central/peripheral)[[#^01]] >- some patients seem to be helped by propranolol at a dose of 10 mg/ day (central effect seems to work better than the β-selective lipophilic agent such as atenolol)[[#^25]] >- particularly difficult subset of patients with unstable hypertensive responses (BP responses up to 250/150 mmHg on standing) respond to oral phenobarbital beginning with 60 mg at night and 15 mg in the morning[[#^25]] >- an alternative treatment is clonidine (administered in dose of 0.1mg bid and increased to maximal tolerated dose)[[#^25]] >- therapy in these cases targets a decrease in sympathetic tone both centrally and peripherally. Central sympatholytics such as methyldopa ( sometimes better tolerated due to its longer half-life) or clonidine may be used[[#^26]] >- peripheral β-adrenergic blockade may be better tolerated by these patients than by those with primary hypovolemia[[#^26]] >- β-blockers and centrally acting sympatholytics work better in patients presumed to have hyperadrenergic variant of POTS[[#^30]] > >**Hypovolemic POTS** >- volume expansion[[#^01]] >- will do well with expanding plasma volume with generous salt intake and fludrocortisone[[#^31]][[#^33]] >- fludrocortisone, with doses up to 0.4 mg in young subjects, can be used initially, with the dose adjusted downwards to a maintenance dose of 0.1 to 0.2 mg/day[[#^32]] > >**Neuropathic POTS** >- low-dose midodrine with some volume expansion[[#^01]] >- best treated with fludrocortisone and an α-agonist (midodrine appears to work best)[[#^34]][[#^35]] -------- >![[Zotero/Zotero Images/Ross-2013-11-x74-y397.png#invert_B| 900]] >([[Ross-2013]], [p. 11](zotero://open-pdf/library/items/5NBCV5L2?page=11&annotation=WEVW9FHD)) > >*“The POTS treatments most commonly tried by study subjects were fludrocortisone (59 %), midodrine (56 %), salt tablets (51 %), selective serotonin reuptake inhibitors (SSRIs) (50 %), and β1 antagonists (49 %). As shown in Fig. 3b, the pharmacological agents reported to improve brain fog were intravenous (IV) saline (77 %), stimulant medications (67 %), salt tablets (54 %), intramuscular (IM) vitamin B-12 injections (48 %), and midodrine (45 %). The interventions most commonly reported to make brain fog worse were serotonin–norepinephrine reuptake inhibitors or SNRIs (30 %), tricyclic antidepressants (25 %), β1 antagonists (22 %), non-selective β antagonists (20 %), and fludrocortisone (17 %)”* ([[Ross-2013]], [p. 4](zotero://open-pdf/library/items/5NBCV5L2?page=4&annotation=5IZJNPQM))^01 >![[Zotero/Zotero Images/Wells-2017-7-x65-y65.png]] >([[Wells-2017]], [p. 7](zotero://open-pdf/library/items/HLELIN7I?page=7&annotation=7FYKYQZA)) >![[Raj-2013-13-x64-y119.png#invert_B| 800]] >([[Raj-2013]], [p. 13](zotero://open-pdf/library/items/CCJLQKRB?page=13&annotation=TFTBGM57)) >![[Fedorowski-2019-10-x52-y81.png#invert_B| 750]] >([p. 10](zotero://open-pdf/library/items/BZ35QDLR?page=10&annotation=4SH2BWZG)) >![[Fedorowski-2019-11-x67-y137.png#invert_B| 750]] >([[Fedorowski-2019]], [p. 11](zotero://open-pdf/library/items/BZ35QDLR?page=11&annotation=5UVY2SLB)) >![[Zotero/Zotero Images/Raj-2022-5-x302-y502.png#invert_B| 450]] >([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=86ZHEYEP)) >*“The Food and Drug Administration has not approved any medications for the treatment of POTS. Therefore, all agents used for this disorder are “off label”” *([[Raj-2013]], [p. 6](zotero://open-pdf/library/items/CCJLQKRB?page=6&annotation=KR9QQPWJ))^1 >*“adverse effects of these drugs can limit their use in patients with POTS because of the presence of comorbid symptoms”* ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=M6HFK3DE))^2 >![[Benarroch-2012-9-x40-y492.png#invert_B| 870]] >([[Benarroch-2012]], [p. 9](zotero://open-pdf/library/items/WEZLT9QC?page=9&annotation=7E5S23NE))^3 >![[Thieben-2007-5-x50-y550.png#invert_B| 450]] >([[Thieben-2007]], [p. 5](zotero://open-pdf/library/items/5WXWEQWX?page=5&annotation=DPLJXZY6))^4 >*“Our study found no differences in the symptomatic response of different patient subgroups to drugs commonly used to treat POTS. By patient reporting, β-blockers, fludrocortisone, midodrine, and selective serotonin reuptake inhibitors all provided partial relief of symptoms in 40% to 60% of patients.” *([[Thieben-2007]], [p. 6](zotero://open-pdf/library/items/5WXWEQWX?page=6&annotation=3EYWNLSL))^5 >*“We concluded from the results that midodrine and intravenous saline, when given in the short term, are effective in decreasing symptoms on tilt in patients with POTS.” *([[Thieben-2007]], [p. 6](zotero://open-pdf/library/items/5WXWEQWX?page=6&annotation=Y5BXL84V))^6 >*“In more symptomatic patients, different drugs directed at controlling heart rate, increasing peripheral vasoconstriction and intravascular volume can be tested. However, the overall effects of pharmacological therapy are modest and the most affected patients remain handicapped.” *([[Fedorowski-2019]], [p. 1](zotero://open-pdf/library/items/BZ35QDLR?page=1&annotation=IWKXKCAT))^7 >*“It should be kept in mind, however, that large randomized trials are not available [71], there are no Class I recommendations to date [3] and the only Class IIA recommendations are exercise training against chronic symptoms and acute saline infusion in decompensated POTS [3] both with positive effects on plasma volume [72]. Among Class IIB recommendations are increased fluid and salt intake, midodrine, beta-blockers, fludrocortisone, pyridostigmine, clonidine and alpha-methyldopa [3]. Consequently, the physician and patient are often left alone with a decision which drug to test, in many situations applying an ex iuvantibus method, resulting in that polypharmacy is frequent. Typically, clinicians test various drugs directed at controlling heart rate, increasing peripheral vasoconstriction and increasing intravascular volume (Table 5). However, the overall effects of pharmacological therapy are modest and the most symptomatic patients remain severely affected by the disease even if combination of different drugs is applied” *([[Fedorowski-2019]], [p. 9](zotero://open-pdf/library/items/BZ35QDLR?page=9&annotation=29QTXG7J))^8 >![[Zotero/Zotero Images/Miller-2018-2-x33-y44.png]] >([[Miller-2018]], [p. 2](zotero://open-pdf/library/items/A3CIPE3G?page=2&annotation=6JN66MRY)) ^9 >*“There is not a “correct” approach to initiating non-pharmacological therapy in patients with POTS. Patient presentations can vary tremendously, and the pharmacological approach to symptomatic improvement has to be individualized.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=NWXH2RC5))^10 >*“Further augmentation of medication will often be necessary. These medications can often be used in combination with each other due to distinct pharmacological mechanisms of action.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=RKFTETKS))^12 >*“Often treating other POTS symptoms such as tachycardia and lightheadedness also improves brain fog.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=ZZVTTQFY))^13 >*“Intravenous saline is reported by patients to be a very successful treatment for brain fog (Ross et al., 2013).”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=7D2TC9CJ))^14 >*“Other patient-reported successful treatments for brain fog include stimulant medications (amphetamine-based and modafinil), salt tablets, and vitamin B12 injections (Ross et al., 2013), although none have been studied specifically to see if they do improve cognitive function.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=SV7WJ9X4))^15 >*“One study found that an acute oral dose of melatonin decreases HR while standing in POTS compared to placebo (Green et al., 2014) Melatonin also decreases the sympathetic response to orthostatic stress in healthy humans (Ray, 2003). Whether melatonin improves sleep or daytime symptoms in POTS remains unknown. However, melatonin supplementation may be particularly useful in POTS patients taking B-blockers since patients taking B-blockers can lower melatonin (Fares, 2011)”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=LMAZPBX2))^16 >![[Zotero/Zotero Images/Miller-2018-6-x27-y34.png]] >([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=D33MX6B6)) > >1. *“In the initial visit, we will institute a myriad of non-pharmacological approaches. Unless the patient's presentation is quite severe, we may ( [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=2FRFTTBA)) hold off on pharmacological approaches at this time to see the effects of the non-pharmacological approaches.* >2. *If the HR on standing is very high (> 130 bpm) and/or palpitation are a prominent symptom, we will prescribe propranolol 20 mg PO QID (or QID PRN) to take the edge off of the HR increases.* >3. *If there is a strong suspicion of a neuropathic pattern, then we will prescribe midodrine 5 mg PO Q4H ×3, with nominal dosing times of 8 am, noon, and 4 pm. This suspicion for inadequate vasoconstriction or venoconstriction can manifest in different ways. For example, during the head-up tilt test with continuous blood pressure monitoring, one can often get estimates of vascular resistance. If vascular resistance is quite low and seems to be driving the tachycardia, we will be more likely to use midodrine. If a patient reports that they are often relatively asymptomatic when walking, but get quite symptomatic when standing still, this suggests that enhancing venous return with midodrine-induced venoconstriction might be useful. Finally, if the HR is not high on standing (100–110 bpm), and prominent symptoms include lightheadedness but not palpitation, then we will preferentially use midodrine over propranolol.* >4. *If the patient does not report significant diarrhea, or if the patient has a tendency to constipation, then we will prescribe pyridostigmine at a starting dose of 30 mg PO TID.”* ([[Miller-2018]], [p. 6](zotero://open-pdf/library/items/A3CIPE3G?page=6&annotation=JE9NP56Q))^11 >*“If POTS indeed has an autoimmune basis, this could significantly alter treatment strategies. Intravenous immunoglobulin (IVIG), plasmapheresis/plasma exchange and other immunotherapy drugs may become potential treatments to clear these antibodies.”* ([[Miller-2018]], [p. 7](zotero://open-pdf/library/items/A3CIPE3G?page=7&annotation=QANDDTIE))^18 >![[Zotero/Zotero Images/Miller-2018-7-x19-y275.png#invert_B| 600]] >([[Miller-2018]], [p. 7](zotero://open-pdf/library/items/A3CIPE3G?page=7&annotation=IZ5IEFTW))^19 >*“it is possible that patients with antibodies to adrenergic receptors will have blunted responses to midodrine and β-blockers and patients with muscarinic receptor antibodies will have a more favorable response to pyridostigmine.”* ([[Miller-2018]], [p. 8](zotero://open-pdf/library/items/A3CIPE3G?page=8&annotation=3JQRTHBZ))^20 >*“Pharmacologic treatments should be considered if patients have severe symptoms at initial presentation or are still symptomatic after nonpharmacologic strategies have been tried.”* ([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=BWEPQ5V4))^21 >![[Zotero/Zotero Images/Raj-2022-6-x41-y369.png#invert_B| 800]] >([[Raj-2022]], [p. 6](zotero://open-pdf/library/items/YN8BG2FZ?page=6&annotation=NF3MM52X))^22 >*“Empirical trials of medications are generally adopted based on the clinician’s impression of the POTS phenotype”* ([[Wells-2017]], [p. 8](zotero://open-pdf/library/items/HLELIN7I?page=8&annotation=H6RVBIRA))^23 >*“In practice, single or combination therapies directed at increasing intravascular volume, increasing peripheral vasoconstriction and controlling HR are often employed.”* ([[Wells-2017]], [p. 8](zotero://open-pdf/library/items/HLELIN7I?page=8&annotation=4IC6YTCH))^24 >*“The majority (25/40 ; 63%) of patients responded to salt supplementation and remained on salt supplements. The next most useful drug was β-adrenergic antagonists, and 16 (40 %) of 40 patients continued to take these drugs. Much more limited information was available on other medications. Eleven (28%) of 40 patients responded to fludrocortisone, and 7 (18 %) of 40 to midodrine. Five patients continued to take midodrine ; 4, fludrocortisone; 2, clonazepam ; and 1, a calcium channel blocking agent.” *([[Sandroni-1999]], [p. 3](zotero://open-pdf/library/items/X25GXI7E?page=3&annotation=A4VIIJTZ))^025 #### Based on Subtypes >![[Low-2009-15-x41-y105.png#invert_B| 900]] >([[Low-2009]], [p. 15](zotero://open-pdf/library/items/I4WAD8AG?page=15&annotation=7NCUBK5P))^01 ##### [[5.1. Hyperadrenergic POTS | Hyperadrenergic POTS]] >*“Some patients seem to be helped by propranolol (e.g., Inderal), a non-β-selective lipophilic agent at a dose of 10 mg/ day. Presumably, a significant part of its benefit is because of a central effect since it seems to work better than the β-selective lipophilic agent such as atenolol. A particularly difficult subset of patients has unstable hypertensive responses to tilt. Some of these patients have BP responses up to 250/150 mmHg on standing. Some of these patients with autonomic instability respond to oral phenobarbital beginning with 60 mg at night and 15 mg q AM. An alternative treatment is clonidine or another α2 agonist. Clonidine is administered in a dose of 0.1 mg bid and increasing to the maximally tolerated doses. Reports of response to microvascular decompression of the brain-stem have been reported, but its role is as yet undefined.” *([[Low-2009]], [p. 7](zotero://open-pdf/library/items/I4WAD8AG?page=7&annotation=ENKTN29J))^25 >*“Therapy in these cases targets a decrease in sympathetic tone both centrally and peripherally. Central sympatholytics such as methyldopa or clonidine may be used. Peripheral beta-adrenergic blockade may be better tolerated by these patients than by those with primary hypovolemia.” *([[Raj-2013]], [p. 3](zotero://open-pdf/library/items/CCJLQKRB?page=3&annotation=AZLGC2TZ))^26 >*“Central sympatholytic agents can be useful in patients with the central hyperadrenergic form of POTS, but may not be as well tolerated in neuropathic POTS. Clonidine is an alpha-2 agonist that acts centrally to decrease sympathetic nervous system outflow.” *([[Raj-2013]], [p. 7](zotero://open-pdf/library/items/CCJLQKRB?page=7&annotation=2GCLF8U8))^27 >*“Methyldopa 125-250 mg PO BID is a false neurotransmitter that is sometimes better tolerated due to its longer half-life.” *([[Raj-2013]], [p. 7](zotero://open-pdf/library/items/CCJLQKRB?page=7&annotation=7R9K3PBY))^28 >![[Zotero/Zotero Images/Kanjwal-2011-3-x308-y519.png]] >([[Kanjwal-2011]], [p. 3](zotero://open-pdf/library/items/R4GMHSS7?page=3&annotation=32PLFX8S))^29 >*“our observations that beta-blockers and centrally acting sympatholytics work better in patients presumed to have hyperadrenergic variant of POTS were consistent with those in other series”* ([[Kanjwal-2011]], [p. 4](zotero://open-pdf/library/items/R4GMHSS7?page=4&annotation=LLYQ9U7P))^30 ##### [[5.2. Hypovolemic POTS | Hypovolemic POTS]] >*“The hypovolemic patient will do well with expanding plasma volume with generous salt intake and fludrocortisone.” *([[Low-2009]], [p. 6](zotero://open-pdf/library/items/I4WAD8AG?page=6&annotation=WGT6FRYQ))^31 >*“Fludrocortisone, with doses up to 0.4 mg in young subjects, can be used initially, with the dose adjusted downwards to a maintenance dose of 0.1 to 0.2 mg/day.” *([[Low-2009]], [p. 7](zotero://open-pdf/library/items/I4WAD8AG?page=7&annotation=VCR5KJZ7))^32 >*“In patients in whom the presence of hypovolemia is either known or strongly suspected, fludrocortisone (aldosterone analogue) is often used. Through enhanced sodium retention, it should expand the plasma volume.” *([[Raj-2013]], [p. 6](zotero://open-pdf/library/items/CCJLQKRB?page=6&annotation=LYLWJIXY))^33 ##### [[5.3. Neuropathic POTS (associated with small fiber neuropathy) | Neuropathic POTS]] >*“best treated with fludrocortisone and an α-agonist. Midodrine appears to work best in terms of absorption, predictable duration of action, and lack of CNS side effects. The dose of midodrine is usually 5 mg 3 times a day. Some patients do better when midodrine is combined with pyridostigmine at the dose of 60 mg 3 times a day. Alternative agents such as ephedrine, phenylpropanolamine, and methylphenidate are largely of historical interest.” *([[Low-2009]], [p. 7](zotero://open-pdf/library/items/I4WAD8AG?page=7&annotation=58QSS752))^34 >*“Midodrine is a peripheral alpha-1 agonist that serves as a vasoconstrictor. It might be most useful in patients with “neuropathic POTS”, which can be associated with a failure of vascular resistance.” *([[Raj-2013]], [p. 6](zotero://open-pdf/library/items/CCJLQKRB?page=6&annotation=QCTKSYI9))^35