Valsartan Dosing Regime Modulates Psychotic Events in Two Sarcoidosis Patients
Authors:
3 June 2001 (Revision 1.4: 24 Aug.2002)
Abstract
Two sarcoidosis patients have benefited from being prescribed Diovan at more frequent intervals than once a day. If administered only every 24 hours, the customary interval for treatment of hypertension, the Diovan induced hallucinations and psychedelic dreams. Psychotic events were suppressed when the dosing interval was reduced. This therapy also relieved symptoms of mild neuroses and paresthetic pain from which the patients had previously been suffering.
Introduction
Two sarcoidosis patients being treated for hypertension with the Angiotensin-II Receptor Blocker Valsartan (Diovan) have reported that the drug caused psychedelic dreams and significantly increased feelings of fatigue, anxiety, irritability and paresthetic pain.
Valsartan is not generally expected to have any psychotic effects at all, let alone reproducible and reversible effects. Known side effects do include somnolence and insomnia , but not hallucinations or psychedelic dreams.
The subject patients had been prescribed Diovan, once a day, to be taken in the morning. On the hypothesis that the adverse reactions resulted from the changes in plasma Valsartan concentration between morning and evening, it was decided to administer the Diovan more frequently. Not only did the hallucinogenic side effects disappear, but the patients reported that the Valsartan was beneficially suppressing symptoms of fatigue, anxiety, irritability and paresthetic pain which they had suffered since their sarcoid diagnoses, symptoms which had not previously responded to treatment.
Patient A, a 53 year old Caucasian male, was diagnosed with pulmonary sarcoid by thoracotomy biopsy in 1976. Although there has been no clinical evidence of any sarcoid involvement outside the lungs, the patient has for 26 years complained of debilitating migraines, in addition to numbness of the right thigh, tingling in extremities, extreme irritability and mild paranoia. The patient was prescribed Diovan, 80mg daily, in December, 1999. There was an initial alarming increase in the intensity of these symptoms, and incidents of hallucinations and ‘wild’ dreams. The Diovan prescription was adjusted to 80mg every 8 hours, and the patient has subsequently not only been normotensive, but the therapy has relieved the migraines, paresthetic pain, fatigue and mood swings.
Patient B, a 51 year old Caucasian female, was diagnosed with pulmonary sarcoidosis in 1976. Within days of commencing Diovan therapy in March 2001, 160mg daily, she reported a ‘rapid pulse’ and psychedelic dreams. After the prescription had been adjusted to 80mg every 12 hours the ‘rapid pulse’ disappeared and the patient was normotensive. Several weeks later she reported that the pain in her right leg had been reduced, and much of its strength regained. Skin lesions/nodules on her left shin had receded, and were barely visible. Additionally she reported almost total elimination of dental pain and discomfort.
Discussion:
Valsartan’s primary role is to bind with, and block, the type AT1 receptors for Angiotensin II. It also has an affinity, approximately 20,000 fold less active, for AT2 receptors. Valsartan does not bind to other hormone receptors or ion channels known to be important in cardiovascular regulation1.
Even though the pharmacokinetic half-life of Valsartan in plasma is a relatively short 6 hours, it achieves a pharmacologically satisfactory vasopressor effect when administered just once every 24 hours. However, the relief afforded to the subject Sarcoidosis patients is critically dependent on the dosing interval. Their symptoms start to re-appear some 8-12 hours after administration, and the customary 24 hour dosing interval actually makes the symptoms worse. Both patients report that psychotic events reappear within 10 to 24 hours of cessation of the Valsartan treatment.
We can compare the diurnal plasma concentration which results from the customary 160mg q.d. dosage with that resulting from 80mg every eight hours by modeling the pharmacokinetic parameters for in-vivo Valsartan absorption and clearance. It can be seen (figure 1) that the 8 hour dosing interval increases the minimum plasma concentrations more than 6 times, from 0.12 to 0.75 mg/L, while additionally maintaining a lower peak concentration (1.7 mg/L vs. 2.3 mg/L). The less onerous regime of 80mg every twelve hours used by ‘Patient B’ still yields a minimum of 0.4 mg/l, three times greater than that produced by the customary 160mg q.d. prescription.
We believe that the lack of favorable symptomatic response when the Diovan dosing interval is not commensurate with the plasma half-life is an indication that the predominant site of the drug action on the symptoms of these sarcoid patients is in the plasma compartment, including well-perfused tissue, such as the lungs and the brain.
Angiotensin II receptors have been found on BALF macrophages from patients with active sarcoidosis2. This might explain why these sarcoidosis patients are exhibiting a different reaction to Angiotensin II blockade than the typical hypertensive patient.
Gard reviewed the role of Angiotensin II in cognition and behavior3, and noted that, within the brain, Angiotensin II has been widely demonstrated to have both antidepressant and anxiolytic activity. Alternatively, the Angiotensin II receptors found in the BALF macrophages2 may in some way be associated with the sarcoid inflammatory process, or at least with the symptomology of sarcoidosis.
Consequently it is most likely that the psychotic activity is due to diurnal changes in the effectiveness of the Angiotensin blockade, rather than any inherent defect in Diovan itself.
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