Pharmacotherapy for postural tachycardia syndrome.

Postural tachycardia syndrome (POTS) is a disorder characterized by the presence of orthostatic symptoms (including lightheadedness, palpitations, nausea, dyspnea, and tremulousness) as well as excessive upright tachycardia. POTS predominantly affects women of childbearing age. Treating POTS involves a multi-faceted approach using non-pharmacological and pharmacological interventions. There are no pharmacological treatments that are currently United States Food and Drug Administration (FDA) approved for POTS due to lack of randomized controlled trials. Yet, several medications can improve POTS symptoms and are supported by small prospective studies or retrospective case series. Drugs that are most commonly used for POTS target the following mechanisms 1) blood volume expansion, 2) reduction of heart rate, 3) peripheral vasoconstriction and 4) sympatholysis. Pharmacological approaches can also be used to target specific symptoms including "brain fog," fatigue, sleep, and depression. This review outlines pharmacological approaches for treating POTS and summarizes evidence supporting each treatment approach.

Cardiovascular complications in patients with autonomic failure.

Patients with autonomic failure are characterized by orthostatic hypotension, supine hypertension, high blood pressure variability, blunted heart rate variability, and often have a "non-dipping" or "reverse dipping" pattern on 24-h ambulatory blood pressure monitoring. These alterations may lead to cardiovascular and cerebrovascular changes, similar to the target organ damage found in hypertension. Often patients with autonomic failure are on treatment with anti-hypotensive drugs, which may worsen supine hypertension. The aim of this review is to summarize the evidence for cardiac, vascular, renal, and cerebrovascular damage in patients with autonomic failure.

Pharmacokinetics of the ghrelin agonist capromorelin in a single ascending dose Phase-I safety trial in spinal cord-injured and able-bodied volunteers.

STUDY DESIGN: Single centre, single ascending dose study. OBJECTIVES: To compare the pharmacokinetics and assess the safety of capromorelin, a compound that has potential to treat constipation following spinal cord injury (SCI), in groups of able-bodied and SCI volunteers. SETTING: Local population from Victoria, Australia. METHODS: Following initial screening and baseline blood collections, participants received ascending oral doses (20, 50 and then 100 mg at least 1-week apart) of capromorelin after pre-dose blood collection, followed by blood collections over the following 12 h for pharmacokinetic analysis and 1-week and 4-week follow-up blood collections for safety evaluations. Blood pressure and heart rate were monitored. RESULTS: No serious adverse events were recorded following any dose in either the able-bodied group or the SCI group. There were no abnormal blood pressure or heart rate changes. Minor adverse events resolved quickly without the need for treatment. Pharmacokinetic behaviour was broadly similar between groups, with both exhibiting dose-dependent increases in Cmax and AUC0-∞. The SCI participants showed greater variance in pharmacokinetic parameters and had a slightly delayed Tmax and half-life. CONCLUSION: Capromorelin at the doses tested was safe and well tolerated in both SCI and able-bodied participants and also showed similar pharmacokinetics with dose-dependent increases in concentration and drug exposure.

Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

OBJECTIVE: To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH). METHODS: Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities. RESULTS: From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events. CONCLUSIONS: In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

Emerging drugs for autonomic dysfunction in Parkinson's disease.

INTRODUCTION: Autonomic dysfunction, including orthostatic hypotension (OH), sialorrhea, sexual dysfunction, urinary dysfunction and constipation is a common feature of Parkinson's disease (PD). Even though its treatment has been recognized as a major unmet need in PD, there is a paucity of clinical trials to assess their treatment. AREAS COVERED: Evidence about the efficacy and safety of available treatments for autonomic dysfunction is summarized. Potential targets for upcoming therapies are then discussed in light of what is currently known about the physiopathology of each disorder in PD. Proof-of-concept trials and circumstantial evidence about treatments for autonomic dysfunction as well as upcoming clinical trials are discussed. Finally, critical aspects of clinical trials design are considered. EXPERT OPINION: Botulinum toxin (BTX) or glycopyrrolate might be used for sialorrhea whereas macrogol could be useful in constipation. There is preliminary evidence suggesting that fludrocortisone, domperidone, droxidopa or fipamezole may be effective for the treatment of OH. Tropicamide, clonidine or radiotherapy are under development for sialorrhea. Sildenafil may be effective for the treatment of erectile dysfunction; BTX or behavioral therapy for urinary incontinence and lubiprostone and probiotics for constipation. Sound clinical trials are needed in order to allow firm evidence-based recommendations about these treatments.

Intraoperative floppy iris syndrome: pathophysiology, prevention, and treatment.

PURPOSE: To extend upon previous reports, observations, and discussions of intraoperative floppy iris syndrome (IFIS) with the goal of providing new insight into the syndrome's pathophysiology, prevention, and treatment. METHODS: Following a review of IFIS and its relationship to autonomic pharmacology, evidence for anatomic changes following exposure of humans and other animals to autonomic drugs is described. The clinical implications for these findings are discussed as they relate to the treatment and prevention of this syndrome. RESULTS: IFIS has been associated with the use of adrenergic antagonists even after they have been discontinued years prior to surgery. Some investigators believe that this persistence of IFIS reflects anatomic structural change. Evidence from laboratory experiments and human clinical studies using topically applied and systemic autonomic drugs supports the possibility of anatomic changes coexisting with IFIS observed during cataract surgery. CONCLUSIONS: IFIS is a relatively rare syndrome, often associated with the use of systemic alpha-blockers and conditions that influence dilator muscle tone. Laboratory and clinical evidence supports the possibility of anatomic changes following the use of autonomic drugs. The persistence of IFIS years after cessation of treatment with alpha-blockers suggests that the potential risks of discontinuing these drugs prior to cataract surgery outweigh potential benefits.

Medication-induced hyposalivation: etiology, diagnosis, and treatment.

Polypharmacy in the nation's growing geriatric population will require increasingly complex pharmacologic management of multiple disease states. This brief review describes normal salivary function, potential causes of salivary dysfunction, oral health concerns associated with hyposalivation, diagnostic tests, and options for patient care. Medications can reduce salivary flow, creating the condition known as xerostomia. A major complication of xerostomia is the promotion of dental caries. Asking several standardized questions regarding symptoms may help confirm salivary gland hypofunction. The general approach to patients with hyposalivation and xerostomia is directed at palliative treatment for the relief of symptoms and prevention of oral complications.

Withdrawal of fall-risk-increasing drugs in older persons: effect on mobility test outcomes.

BACKGROUND: Previously, we have shown that withdrawal of fall-risk-increasing drugs (FRIDs) as a single intervention reduces falls incidence. Improvement of mobility may be an important factor in this finding and we therefore tested whether mobility tests improved after FRID withdrawal. METHODS: In a prospective cohort study of 137 geriatric outpatients (age 77.7 +/- 5.7 years), FRIDs were withdrawn in all fallers, if possible, between April 2003 and November 2004. All patients underwent mobility testing at baseline, including a 10m walking test (WT), Timed 'Up & Go' Test (TUGT), Functional Reach Test (FRT), isometric quadriceps femoris muscle strength and a body sway test. Retesting occurred at a mean follow-up of 6.7 months. The effect of FRID withdrawal (discontinuation or dose reduction) on test outcomes was calculated using both multivariate linear and binary logistic regression analyses. RESULTS: In the group of fallers with FRID withdrawal all mobility tests improved, as opposed to non-fallers and fallers without FRID withdrawal. After adjustment for confounders, the odds ratio of no improvement was 0.14 (95% CI 0.03, 0.59) for the TUGT, 0.19 (95% CI 0.04, 0.86) for the 10m WT, 0.48 (95% CI 0.14, 1.57) for the FRT, 0.46 (95% CI 0.14, 1.48) for the quadriceps strength test and 0.49 (95% CI 0.15, 1.62) for the body sway test. CONCLUSION: The results of this study suggest that FRID withdrawal may be effective as a single intervention in a geriatric setting. In addition to reducing falls (as shown in our previous study), FRID withdrawal significantly improved 10m WT and TUGT results over a mean follow-up period of 6.7 months. These tests may therefore be useful tools for monitoring the clinical effect of FRID withdrawal.

[Effects of anesthesia on postoperative micturition and urinary retention]. / Effets de l'anesthésie sur la miction et rétention aiguë d'urine postopératoire.

Postoperative micturition difficulties, considered as minor complications, have a high incidence. Acute urinary retention can follow all types of anaesthetics or operations. Surgical trauma to the pelvic nerves or to the bladder, postoperative oedema around the bladder neck, and pain-induced reflex spasm of the external and internal urethral sphincters may play a role in the development of urinary retention. Acute urinary retention is the most common complication of surgery for benign anorectal disease. The incidence of urinary retention is more likely to occur in old male patients. Preoperative urinary symptoms are not a prerequisite for developing postoperative urinary retention, although they are considered to be a risk factor. The type of anaesthetic, postoperative pain and its management may have little effect on the occurrence of postoperative urinary dysfunction. Studies on the urodynamic effects of various anaesthetic agents are rare. The parasympatholytic drugs increase bladder capacity, decrease the rate of bladder contractions and cause downward trends in urethral resistance. The barbiturates and halothane produce similar effects on urethral resistance. The anaesthetic agents decrease the intrabladder pressure and inhibit the micturition reflex. Halothane decreases bladder contractions and increases its capacity measured by the cystometrogram. Urinary retention is a side effect of opioids, particularly after intrathecal or epidural administration. Epidural morphine relaxes the detrusor muscle with a corresponding increase in the maximal bladder capacity. Spinal opioids influence the function of the lower urinary tract, by direct spinal action on the sacral nociceptive neurons and autonomic fibres, as well as by an effect on supraspinal centres. Naloxone increases detrusor pressure, decreases bladder capacity, and causes a need to void. Urinary retention is less common after a short-acting (lidocaine 5%) than after a long-acting agent (bupivacaine 0.5%). After spinal anaesthesia, detrusor strength and the ability to void restarts with the return of sacral sensation to pinprick. A single episode of bladder overdistention can result in significant morbidity. Overfilling of the bladder can stretch and damage the detrusor muscle, leading to atony of the bladder wall, so that recovery of micturition may not occur when the bladder is emptied. On the other hand, the excessive use of an indwelling catheter can lead to urinary tract infection, urethral stricture and prolonged hospital stay. Short-term prophylactic catheterisation is recommended in patients with obstructive symptoms. Patients at risk for urinary retention should be stimulated to void and provided a quiet environment in which to do so. They should be encouraged to seat, stand or ambulate as early as possible. The alpha 1 adrenergic receptor blocking agents have been used for treatment of organic or functional urinary retention. It is essential to make sure the bladder empties regularly in the postoperative period, especially in day-case surgery or in patients receiving opioid analgesia or after epidural anaesthesia.

Stroke.

Illicit drugs, appetite suppressants, decongestants, and anabolic steroids may cause stroke. Drug abuse is a common cause of stroke in young patients. Mechanisms are varied, but it is particularly important to seek out infective endocarditis and most importantly, cerebral aneurysms, vascular malformations, and cardiac disorders in cocaine abusers. Drug-induced vasoconstriction, hypertension, or vasculitis probably contributes significantly to most patients' strokes. Tobacco smoking and heavy chronic alcohol consumption are independent risk factors for stroke; moderate drinking seems to protect from stroke in white patients. Oral contraceptives may increase the risk of stroke in female patients over 35 years of age who also have other risk factors.

[Intracavernous injections of vasoactive drugs. Contribution to the study of their value in erectile impotence]. / Les injections intracaverneuses de drogues vasoactives. Contribution à l'étude de leur valeur dans l'impuissance érectile.

The obtention of an artificial erection with a single intracavernous injection (ICI) of vasoactive drugs, has upset our conceptions about erection and the approach for erectile failure. If this pharmacologic stimulation increases the reliability of some erection tests, their diagnosis value is still questioned. The complexity of both erection and vasomotricity pharmacology, make difficult the understanding of the mechanisms of these ICI. Their therapeutic value is reduced to the method by self injections, new treatment for impotence, even if it concerns only few impotent patients. Finally, the experimental feature and the unquestionable morbidity of these ICI, mainly priapism, impede their large diffusion. However, in spite of these doubts, this intracavernous pharmacology is a real progress for erection and its troubles.

Systemic effects of topical ophthalmic medications.

Ophthalmic drugs topically applied have significant systemic absorption, which may result in widespread adverse side effects. All physicians involved in the care of patients receiving these drugs should be cognizant of such actions, interactions, and toxic effects. They should also be familiar with the prevention, diagnosis, and treatment of these effects, as well as the mechanisms of systemic drug absorption.