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Changes in seated blood pressure following drug administration. The combination of 1 mg ergotamine and 100 mg caffeine increased seated systolic blood pressure over time compared with placebo in patients with severe autonomic failure (p = 0.003). Similarly, 5–10 mg midodrine increased seated systolic blood pressure in these patients (p = 0.015), but this effect was not different from ergotamine/caffeine (p = 0.621). Data are presented as mean ± 95% confidence interval.
Source publication
Severely affected patients with autonomic failure require pressor agents to counteract the blood pressure fall and improve presyncopal symptoms upon standing. Previous studies suggest that combination ergotamine and caffeine may be effective in the treatment of autonomic failure, but the efficacy of this drug has not been evaluated in controlled tr...
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Purpose
To systematically review the evidence base for the effectiveness and safety of caffeine for the treatment of neurogenic orthostatic hypotension in adults.
Methods
Eight electronic databases were searched in January 2021. Original research studies or case reports involving adults with neurogenic orthostatic hypotension were included if caff...
Citations
... To improve its effectiveness and oral absorption rate, ergotamine is often combined with caffeine. A study reported that the combination of ergotamine and caffeine increased systolic blood pressure and improved presyncopal symptoms [7]. ...
This comprehensive literature review addresses the scarcity and limited study of hypotension treatments compared to abundant antihypertensive drugs. Hypotension, categorized as absolute, relative, or orthostatic, has diverse causes. This review explores various treatments, including drugs affecting the sympathetic nervous system, such as midodrine, dihydroergotamine, and ergotamine, which have shown efficacy in managing hypotension. Dopamine agonists/antagonists and other drugs such as ephedrine, norepinephrine, and fludrocortisone are also discussed, each with distinct mechanisms and applications. Additionally, adjunctive agents such as non-steroidal anti-inflammatory agents, caffeine, and monoamine oxidase inhibitors are reviewed for their effects on blood pressure. This review underscores the importance of understanding the efficacy and safety profiles of hypotension treatments to guide healthcare professionals in optimal drug selection and management, emphasizing the need for further research and comparative studies for evidence-based guidelines.
... Of the other studies included, one investigated ergometrine and caffeine against midodrine and the other yohimbine vs placebo (28,29). In a single-blind crossover trial, neither ergometrine and caffeine nor midodrine had a significant effect on orthostatic tolerance; however, ergotamine/caffeine improved presyncope symptoms (p=0.03) ...
... In a single-blind crossover trial, neither ergometrine and caffeine nor midodrine had a significant effect on orthostatic tolerance; however, ergotamine/caffeine improved presyncope symptoms (p=0.03) (28). A double-blind, crossover study of yohimbine, did not find any differences between baseline, yohimbine or placebo measurements (29). ...
Introduction Orthostatic hypotension (OH) is associated with cardiovascular mortality and morbidity. Non-pharmacological and pharmacological therapies are employed in the management of OH. The aim of this systematic review and meta-analysis is to provide an up-to-date review of the efficacy parameters of pharmacological therapies. Methods Medline, Embase, Cochrane Library, and Scopus were searched (inception-July 2021), and published articles with randomized control trials, meeting inclusion and exclusion criteria were quality assessed (Risk of Bias 2 tool). Assessment for trends in patient-related outcome measures and postural blood pressure improvement was undertaken. Studies reporting postural systolic blood pressure (SBP) before and after intervention in comparison to placebo were included in a meta-analysis using inverse -variance in a random-effects model. Results 19 articles were included in the systematic review. The orthostatic symptoms questionnaire (OHQ) was the most common patient-related outcome measure utilized in trials. Six studies included in the meta-analysis demonstrated that pharmacological therapies (pyridostigmine, midodrine, atomoxetine, yohimbine) improved postural SBP compared to placebo, with a mean rise of 12.50 mmHg [95% CI: 6.01, 18.98; p value<0.001, I2 =97%]. Midodrine showed the highest impact on SBP, with a mean SBP of 16.11 mmHg [95% CI: 5.59, 26.63; p=0.003, I2 =99%]. Conclusions Pharmacological treatment can significantly increase postural SBP, however with significant heterogeneity related to trial designs. Further efforts to homogenize outcome measures, incorporating symptom improvement and reduction in the postural drop and testing for a prolonged duration of therapy would strengthen the evidence, and improve the translatability of findings in clinical settings.
... Administration of most of the formulations of ET via rectal route is preferred to overcome the limitations like first-pass metabolism and low bioavailability or it is recommended to combine with CNS stimulant like caffeine. This stimulant drug works synergistically with ET to relieve the symptoms of migraine by forming soluble molecular complex and to increase the solubility of active significantly [8,9]. Various nanoparticulate formulations of ET such as nanostructured lipid carriers (NLC) and solid-lipid nanoparticles (SLN) explored to prolong the stability and therapeutic efficacy of ET via the ocular route [10,11]. ...
Purpose
The anti-migraine drugs show first-pass metabolism, short half-life, and low bioavailability resulting in repeated dose or overdose effect. Polymeric, biodegradable and highly porous nanosponges emerge as a promising carrier for migraine treatment to improve aqueous solubility, stability and bioavailability.
Method
Ergotamine nanosponges prepared by interfacial polymerization method wherein hydroxypropyl beta-cyclodextrin inclusion complex was crosslinked using toluene diisocyanate. Caffeine used as a permeation enhancer for ergotamine by forming soluble molecular complex with cyclodextrin moiety of nanosponges. Further, nanosponges were characterized for particle size, zeta potential, entrapment efficiency, percentage drug release profile, antioxidant activity, photostability and instrumental analytical studies.
Results
Caffeine significantly improved the permeation of ergotamine nanosponges. The particle size for optimized nanosponges was 693.5 ± 11.7 nm, zeta potential of − 19.4 ± 5.69 mV with high colloidal stability and maximum entrapment efficiency of 98.88 ± 2.8%. In-vitro and ex-vivo studies exhibited controlled release profiles of ergotamine 81.6% ± 3.4% and 79% ± 4.2% for 24 h, respectively. Nanosponges demonstrated higher antioxidant activity 85.68% ± 1.23% whereas photostability data showed no significant decrease in drug content indicating good stability. Fourier transform infrared spectroscopy confirmed significant interaction of ergotamine with cyclodextrin-based nanosponges.
Conclusion
Nanosponges showed improvement in bioavailability of ergotamine and long-term stability offering inexpensive, productive and safe alternative for migraine.
Graphical abstract
... Regarding OH severity, the mean standing BP was 86 mmHg and mean postural change in systolic blood pressure was 58.8 mmHg amongst participants from two studies (n = 24) [16,17]. ...
... Ergotamine is a multimodal vasoconstrictor, and caffeine has been shown to increase ergotamine's intestinal absorption [19]. This took the form of a combination tablet in two studies [14,17] and subcutaneous injection 30 min prior to caffeine administration in one study [15]. The caffeine dose administered ranged from 100 to 300 mg, and the mean was 189.1 ± 75.9 mg. ...
... Three studies were randomised [15][16][17], although in two of these the method of randomisation was not specified [15,16]. Two studies were single-blinded (participants) [17,18]. ...
Purpose
To systematically review the evidence base for the effectiveness and safety of caffeine for the treatment of neurogenic orthostatic hypotension in adults.
Methods
Eight electronic databases were searched in January 2021. Original research studies or case reports involving adults with neurogenic orthostatic hypotension were included if caffeine was an intervention and outcomes included symptoms, blood pressure or adverse effects. Relevant studies were screened and underwent qualitative analysis. Insufficient reporting precluded meta-analysis.
Results
Five studies were identified: four crossover studies and one case report summation. Study size ranged from 5 to 16 participants. Participants had neurogenic orthostatic hypotension, with a mean standing systolic blood pressure of 86 mmHg. Two studies evaluated caffeine alone. Three studies administered caffeine in combination with ergotamine. Caffeine dose ranged from 100 to 300 mg. Nature and timing of outcomes measured varied between studies, with measurements being recorded from 30 to 480 min after intervention. Caffeine/ergotamine improved symptoms in one study and reduced orthostatic blood pressure drop in two studies. Caffeine/ergotamine increased seated blood pressure in three studies, whilst the results for caffeine alone were inconsistent. No serious adverse events were reported. All studies demonstrated high risk of bias.
Conclusion
Caffeine should only be considered as a treatment for adults with neurogenic orthostatic hypotension when evidence-based treatments have been exhausted.
Systematic review registration
PROSPERO ID: CRD42020124589. Date of registration: 30/10/2020
... Other drugs include pseudoephedrine, atomoxetine (norepinephrine reuptake inhibitor), yohimbine (α2-adrenergic receptor antagonist), octreotide (somatostatin analogue), ergotamine, erythropoietin and pyridostigmine (cholinesterase inhibitor). [86][87][88][89] Atomoxetine is a norepinephrine transporter inhibitor approved for the treatment of attention deficit hyperactivity disorder (ADHD). However, in patients with autonomic impairment who have intact peripheral noradrenergic function, this medication can cause a powerful peripheral vasoconstriction, leading to blood pressure increase. ...
... The effectiveness of midodrine for increasing standing BP and improving OH symptoms is supported by findings of several subsequent randomized clinical trials [63][64][65]. Midodrine significantly increases standing systolic BP, but its use may be limited because of the magnitude of increases in sitting and supine BP (Table 1) [63,64,[73][74][75][76][77]. In a single-dose study, midodrine treatment showed dose-dependent effects on incidence of nSH after 10and 20-mg doses [65]. ...
Purpose of Review
In autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH.
Recent Findings
Pressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions.
Summary
Approaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.
... Caffeine is used for treatment of apnea of prematurity in infants between 28 and 33 weeks of gestational age; it is effective in other pathologies such as fatigue [73]; headache; migraine [72,74]; orthostatic hypotension [75]; and other neurological diseases such as depression [76], brain injury [77], anxiety [78], and Alzheimer's [79] and Parkinson's disease [80]. ...
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM.
... 8 Patients refractory to standalone therapy may benefit from combination therapy such as fludrocortisone (0.1-0.2 mg/day PO) plus midodrine (5-10 mg PO), ergotamine (1 mg PO) plus caffeine (100 mg PO), and midodrine (5-10 mg PO) or pseudoephedrine (30 mg PO) plus water (500 mL). 43,44 nOH treatments under study include atomoxetine (NCT02784535), the investigational norepinephrine and serotonin reuptake inhibitor TD-9855 (NCT02705755), and long-term efficacy of droxidopa (NCT02586623). ...
Presyncope and syncope are common medical findings, with a > 40% estimated lifetime prevalence. These conditions are often elicited by postural stress and can be recurrent and accompanied by debilitating symptoms of cerebral hypoperfusion. Therefore, it is critical for physicians to become familiar with the diagnosis and treatment of common underlying causes of presyncope and syncope. In some patients, altered postural hemodynamic responses result from a failure of compensatory autonomic nervous system reflex mechanisms. The most common presentations of presyncope and syncope secondary to this autonomic dysfunction include vasovagal syncope, neurogenic orthostatic hypotension, and postural tachycardia syndrome. The most sensitive method for diagnosis is a detailed initial evaluation with medical history, physical examination, and resting electrocardiogram to rule out cardiac syncope. Physical examination should include measurement of supine and standing blood pressure and heart rate to identify the pattern of hemodynamic regulation during orthostatic stress. Additional testing may be required in patients without a clear diagnosis after the initial evaluation. Management of patients should focus on improving symptoms and functional status and not targeting arbitrary hemodynamic values. An individualized structured and stepwise approach should be taken for treatment, starting with patient education, lifestyle modifications, and use of physical counter-pressure manoeuvres and devices to improve venous return. Pharmacologic interventions should be added only when conservative approaches are insufficient to improve symptoms. There are no gold standard approaches for pharmacologic treatment in these conditions, with medications often used off label and with limited long-term data for effectiveness.
... This combination is known to increase absorption and effectiveness of ergotamine, alpha-adrenergic agonist. It also induces venoconstriction to enhance venous return [60]. ...
Opinion statement:
Orthostatic hypotension (OH) is defined as a sustained pathological reduction in blood pressure within 3 min after orthostatic stress such as tilt-table testing or active standing. Non-neurogenic OH is caused by either decreased cardiac output or impaired vasoconstriction without a primary autonomic disorder whereas neurogenic OH results from inadequate release of norepinephrine in the vasomotor sympathetic system. Once non-neurogenic causes of OH such as medications and cardiac problems are ruled out, neurogenic OH can be considered. Neurogenic OH can accompany parkinsonian diseases in different stages and is associated with increased risk of morbidity and mortality. The pathophysiology of neurogenic OH in parkinsonian diseases includes sympathetic neurocirculatory failure and impaired cardiovagal activity. The inadequate release of peripheral norepinephrine upon orthostatic stress is a final pathologic pathway for neurogenic OH and is important for many therapeutic interventions. With mild or early autonomic failure, OH that occurs beyond 3 min of standing (defined as delayed OH) can result in orthostatic intolerance. Supine hypertension and postprandial hypotension are frequent comorbidities and may exacerbate orthostatic hypotension. The non-pharmacologic therapies should be tried initially, followed by pharmacologic treatments. Common medications used in the treatment of OH include fludrocortisone, midodrine, pyridostigmine, and droxidopa. Only midodrine and droxidopa have received FDA approval for the treatment of orthostatic hypotension.
... 31 A recent small clinical trial compared midodrine to ergotamine 1 mg with caffeine 100 mg in 12 patients and reported that the drug combination increased seated blood pressure to the same extent as midodrine and was better in improving symptoms of autonomic failure. 32 Unfortunately, there is no information about the use of caffeine alone in the treatment of autonomic failure. ...
Over the last decade, Food Regulation Authorities have concluded that coffee/caffeine consumption is not harmful if consumed at levels of 200 mg in one sitting (around 2½ cups of coffee) or 400 mg daily (around 5 cups of coffee). In addition, caffeine has many positive actions on the brain. It can increase alertness and well-being, help concentration, improve mood and limit depression. Caffeine may disturb sleep, but only in sensitive individuals. It may raise anxiety in a small subset of particularly sensitive people. Caffeine does not seem to lead to dependence, although a minority of people experience withdrawal symptoms. Caffeine can potentiate the effect of regular analgesic drugs in headache and migraine. Lifelong coffee/caffeine consumption has been associated with prevention of cognitive decline, and reduced risk of developing stroke, Parkinson's disease and Alzheimer's disease. Its consumption does not seem to influence seizure occurrence. Thus, daily coffee and caffeine intake can be part of a healthy balanced diet; its consumption does not need to be stopped in elderly people.
