6.2.3. Vasoconstrictor drugs

← PREVIOUS: [[6.2.2. Drugs that lower heart rate]] | NEXT: [[6.2.4. Sympatholytic drugs]] → -------- ##### Summary >[!Summary] >**Midodrine** >- prodrug that is metabolized into a peripheral α-1 receptor agonist[[#^4]] >- potent vasoconstrictor and venoconstrictor. increases blood pressure but also increases venous return, cardiac preload, and stroke volume[[#^4]] >- can increase peripheral resistance in POTS by stimulating vasoconstriction[[#^1]] and reduce venous pooling[[#^2]] >- generally well tolerated but can commonly cause mild and transient side effects such as goose bumps, piloerection, and tingling of the scalp. Less commonly midodrine can cause worsening of headaches and hypertension[[#^5]] >- can increase the risk of urinary retention in patients with functional bladder disorders by increasing contraction of the smooth muscle of the bladder neck[[#^3]] >- has a rapid onset and is short acting, working for about 4 h after each dose. optimal dosing is 5 to 15 mg, every 4 h × 3 times daily[[#^4]] (avoiding a dose near bedtime) [[#^6]]; total daily dose is less important than the dose taken at each time[[#^5]] ; can also be used as needed for acute symptom management[[#^6]] >- treatment should be initiated at a low dose (2.5–5 mg per dose) and increased in 2.5 or 5 mg increments up to 15 mg as needed for symptomatic improvement and as tolerated[[#^5]] >- may be more efficacious in neuropathic POTS patients with poor venous constriction[[#^5]] >- may be most beneficial in patients with POTS accompanied by low blood pressure[[#^6]] >- theoretically, patients with higher norepinephrine levels during tilt are less likely to respond to α-agonist therapy[[#^7]] > >**Octreotide** >- peptide that mimics somatostatin and induces splanchnic vasoconstriction[[#^9]] >- effect during standing helps to maintain venous return in POTS and inhibits the compensatory increase in HR following acute and chronic administration[[#^8]] >- however, it's only available in an injectable form, and this likely limits its use and patient acceptability[[#^8]] >- can be administered intravenously or as a subcutaneous or intramuscular injection[[#^9]] >- study found that a single dose of octreotide decreased orthostatic HR and increased standing time in POTS[[#^9]] >- treatment with long-acting intramuscular injection 10–30 mg also was found to decrease orthostatic HR, dizziness, and chronic fatigue in POTS[[#^9]] >- several potential side effects including pain at injection site, abdominal cramps, diarrhea, nausea, dizziness, bradycardia, shortness of breath, and depression[[#^10]] > >**Droxidopa** >- prodrug that can be taken up by sympathetic neurons and converted to norepinephrine, which can then bind to α-1 adrenergic receptors and increase vasoconstriction and blood pressure[[#^11]] >- However, it may increase tachycardia as well since it can be converted to epinephrine and activate β-adrenergic receptors[[#^12]] >- taken orally 100–600 mg 3 times daily[[#^13]] >- Common side effects are headache, nausea, hypertension, and tachycardia[[#^13]] >- one published clinical experience with droxidopa in POTS found that it did not significantly affect BP, HR, or quality of life but did improve orthostatic symptoms in some patients[[#^14]] >- might be useful, particularly in POTS patients with low to normal plasma norepinephrine levels or non-diabetic autonomic neuropathies[[#^15]] > >**Stimulants** >- may be useful for treating POTS for their combined effects on blood pressure and cognition[[#^16]] >- while they are central nervous system stimulants, these drugs also increase sympathetic nerve traffic and synaptic norepinephrine[[#^16]] >- they are α1 adrenergic receptor agonists and have potent effects on peripheral vasoconstriction, and β1-adrenergic receptor agonists and promote sinus tachycardia[[#^16]] > >**Modafinil** >- can improve alertness in some patients with POTS[[#^17]] >- study found that modafinil-increased orthostatic BP did not significantly worsen standing HR or acute orthostatic symptoms in POTS patients[[#^18]] >- some patients have responded to favorably to modafinil 100–200 mg twice daily[[#^19]] >- should be avoided in the evening or at bedtime to prevent insomnia[[#^19]] >- use of these drugs long term especially in younger patients is controversial because of addictive properties[[#^19]] > >**Methylphenidate** >- 10 mg 3 times daily has been shown to improve symptoms of fatigue and pre-syncope in patients with refractory POTS -------- ##### 1. Midodrine >*“Midodrine, a pro-drug of an α1-AR agonist, can increase peripheral resistance in POTS by stimulating vasoconstriction. Improvement in symptoms and orthostatic tachycardia can be associated with scalp tingling and goosebumps [58], and midodrine can cause urinary retention” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=6LDISFVY))^1 >*“1-adrenergic agonist midodrine to elicit peripheral vasoconstriction and reduce venous pooling”* ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=JZXMNZFX))^2 >*“Midodrine can increase the risk of urinary retention in patients with functional bladder disorders by increasing contraction of the smooth muscle of the bladder neck.”* ([[Benarroch-2012]], [p. 8](zotero://open-pdf/library/items/WEZLT9QC?page=8&annotation=6V3FTCBR))^3 >*“Midodrine is a prodrug that is metabolized into a peripheral α-1 receptor agonist. Midodrine is a potent vasoconstrictor and venoconstrictor. Midodrine increases blood pressure but also increases venous return, cardiac preload, and stroke volume. Midodrine has a rapid onset and is short acting, working for about 4 h after each dose. The Heart Rhythm Society Expert Consensus states that the optimal dosing for ([p. 4](zotero://open-pdf/library/items/A3CIPE3G?page=4&annotation=6KZMREV2)) midodrine is 5 to 15 mg, every 4 h × 3 times daily”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=Z8CUZR7X))^4 >*“Treatment with midodrine should be initiated at a low dose (2.5–5 mg per dose) and increased in 2.5 or 5 mg increments up to 15 mg as needed for symptomatic improvement and as tolerated. Given the short half-life of the drug, the total daily dose is less important than the dose taken at each time. Midodrine is generally well tolerated but can commonly cause mild and transient side effects such as goose bumps, piloerection, and tingling of the scalp. Less commonly midodrine can cause worsening of headaches and hypertension. Studies have shown that midodrine increases orthostatic blood pressure and decreases orthostatic HR and venous pooling in POTS (Jacob et al., 1997;Ross et al., 2014 ). One study suggests that midodrine may be more efficacious in neuropathic POTS patients with poor venous constriction (Ross et al., 2014).”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=G6JAWWXE))^5 >*“Midodrine is a peripheral α1-adrenergic receptor agonist prodrug that enhances venous return, cardiac preload and stroke volume. It may be most beneficial in patients with POTS accompanied by low blood pressure.50 It is prescribed at 2.5–10 mg every 4 hours (avoiding a dose near bedtime), but it can also be used as needed for acute symptom management.”* ([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=3AMQ4DFW))^6 >*“Theoretically, patients with higher norepinephrine levels during tilt are less likely to respond to α-agonist therapy (e.g., midodrine). One small study has shown patients with neuropathic POTS had a better HR response to midodrine when compared with patients with hyperadrenergic POTS, however symptomatic response was not evaluated.”* ([[Wells-2017]], [p. 6](zotero://open-pdf/library/items/HLELIN7I?page=6&annotation=QT7SBA4H))^7 ##### 2. Octreotide >*“The somatostatin analog octreotide is a vasoconstrictor that mainly affects the splanchnic circulation. This effect during standing helps to maintain venous return in POTS and inhibits the compensatory increase in HR following acute and chronic administration [68;69]. However, octreotide is only available in an injectable form, and this likely limits its use and patient acceptability.” *([[Garland-2015]], [p. 10](zotero://open-pdf/library/items/CAWTWYLR?page=10&annotation=CK66HMKN))^8 >*“Octreotide is a peptide that mimics somatostatin and induces splanchnic vasoconstriction. Octreotide can be administered intravenously or as a subcutaneous or intramuscular injection. A small study with 9 POTS patients found that a single dose of octreotide (0.9 μg/kg subcutaneous injection) decreased orthostatic HR and increased standing time in POTS (Hoeldtke et al., 2006). Treatment with long-acting intramuscular injection 10–30 mg also decreased orthostatic HR, dizziness, and chronic fatigue in POTS (Hoeldtke et al., 2007).”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=LSQI84DP))^9 >*“A small, retrospective analysis of 5 patients with refractory orthostatic intolerance taking octreotide (50–100 μg 3 times daily) revealed that octreotide decreased orthostatic HR and improved symptoms in POTS patients (Kanjwal et al., 2012b). Octreotide has several potential side effects including pain at injection site, abdominal cramps, diarrhea, nausea, dizziness, bradycardia, shortness of breath, and depression. Given that it is a peptide that requires parenteral injections, it can be more difficult to use than many pills.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=99QBRQ7N))^10 ##### 3. Droxidopa >*“Droxidopa is a prodrug that can be taken up by sympathetic neurons and converted to norepinephrine, which can then bind to α-1 adrenergic receptors and increase vasoconstriction and blood pressure”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=NFWHW3RJ))^11 >*“However, droxidopa may increase tachycardia as well since it can be converted to epinephrine and activate β-adrenergic receptors.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=2FPR7NM3))^12 >*“Droxidopa is taken orally 100–600 mg 3 times daily. Common side effects are headache, nausea, hypertension, and tachycardia.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=RLUX2MRY))^13 >*“The one published clinical experience with droxidopa in POTS found that it did not significantly affect BP, HR, or quality of life but did improve orthostatic symptoms in some patients (Ruzieh et al., 2017).”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=GVDLH2JP))^14 >*“This drug might be useful, particularly in POTS patients with low to normal plasma norepinephrine levels or non-diabetic autonomic neuropathies.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=G4AVPMFA))^15 ##### 4. Stimulants >*“Stimulant medications may be useful for treating POTS for their combined effects on blood pressure and cognition. While they are central nervous system stimulants, these drugs also increase sympathetic nerve traffic and synaptic norepinephrine. The result is that they are α1 adrenergic receptor agonists and have potent effects on peripheral vasoconstriction, and β1-adrenergic receptor agonists and promote sinus tachycardia.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=ARJFCIDA))^16 ###### 4.1. Modafinil >*“Many patients are also greatly troubled by mental clouding or troubles concentrating. Modafinil, a stimulant whose mechanism is not yet clear, can improve alertness in some patients with POTS.” *([[Raj-2013]], [p. 7](zotero://open-pdf/library/items/CCJLQKRB?page=7&annotation=G23RJSQB))^17 >*“Although stimulants can increase tachycardia, a recent placebo-controlled trial found that modafinil increased orthostatic BP did not significantly worsen standing HR or acute orthostatic symptoms in POTS patients (Kpaeyeh Jr et al., 2014).”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=MZMSQJC4))^18 >*“A clinical trial is in progress to assess the effects of an acute dose of modafinil on cognitive function in POTS (https://clinicaltrials.gov/ct2/ show/NCT01988883). Anecdotally, some patients have responded to favorably to modafinil 100–200 mg twice daily, although proper study data are still pending. Modafinil should be avoided in the evening or at bedtime to prevent insomnia. The use of these drugs long term especially in younger patients is controversial because of addictive properties.”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=HRSEZHTZ))^19 ###### 4.1. Methylphenidate >*“Methylphenidate (10 mg 3 times daily) has been shown to improve symptoms of fatigue and pre-syncope in (14/17) patients with refractory POTS (Kanjwal et al., 2012c).”* ([[Miller-2018]], [p. 5](zotero://open-pdf/library/items/A3CIPE3G?page=5&annotation=RN5FPI24))^20