Chlorpromazine-Tadalafil Interaction Leading to Refractory Ischemic Priapism and Penile Prosthesis Implantation

doi:10.21203/rs.3.rs-6817185/v1

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Case Report

Chlorpromazine-Tadalafil Interaction Leading to Refractory Ischemic Priapism and Penile Prosthesis Implantation

https://doi.org/10.21203/rs.3.rs-6817185/v1

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published 14 Aug, 2025

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Introduction:

Priapism is a rare urological emergency characterized by a persistent, often painful penile erection unrelated to sexual stimulation. Antipsychotic medications, including chlorpromazine, are known to cause priapism through their alpha-adrenergic blocking properties.

Case Presentation:

We present the case of a 56-year-old male who developed refractory ischemic priapism following self-medication with oral chlorpromazine for hiccups after taking tadalafil 20 mg 24 hours prior for erectile dysfunction. This combination created a clinically significant drug interaction. The patient had experienced a brief priapism episode 10 years earlier following chlorpromazine use alone, establishing chlorpromazine as the primary causative agent. Despite systematic management with corporal aspiration, intracavernosal injection of sympathomimetics, and distal T-shunt, the patient experienced recurrent priapism necessitating penile prosthesis implantation.

Discussion

After thorough exclusion of alternative etiologies, this case provides compelling evidence for chlorpromazine as a causative agent of priapism, with the synergistic interaction with phosphodiesterase type 5 inhibitors exacerbating the condition to a severe, treatment-resistant state.

Conclusion

This report emphasizes the importance of recognizing this potentially dangerous drug interaction and provides specific clinical recommendations for prevention and management.

Priapism

Chlorpromazine

Tadalafil

Drug interaction

Penile prosthesis

Ischemic priapism

Priapism is defined as a persistent penile erection lasting more than four hours, occurring without sexual stimulation and unrelieved by ejaculation [1]. It constitutes a urological emergency requiring prompt diagnosis and management to prevent long-term complications such as erectile dysfunction and penile fibrosis [1, 2]. Priapism is categorized into three types: ischemic (low-flow), non-ischemic (high-flow), and stuttering (recurrent) priapism [2].

Ischemic priapism, the most common form, results from blood stasis within the corpora cavernosa, leading to hypoxia, acidosis, and eventual tissue damage [3]. Various etiologies have been identified, including hematological disorders, malignancies, trauma, and medications [3, 4]. Among medications, antipsychotics account for approximately 50% of drug-induced priapism cases [5]. The mechanism primarily involves alpha-1 adrenergic receptor antagonism, which disrupts normal detumescence [5, 6].

Chlorpromazine, a first-generation antipsychotic of the phenothiazine class, has been associated with priapism since early reports in the 1970s [7]. Despite this established adverse effect, it remains in use for various indications, including hiccups, potentially leading to unexpected cases of priapism, particularly in self-medication scenarios [7, 8]. Although other safer alternatives for hiccup management exist (including baclofen, metoclopramide, and gabapentin), chlorpromazine remains available over the counter in some regions despite its significant side effect profile [8].

The concurrent use of medications affecting erectile function through different mechanisms may substantially increase priapism risk. Phosphodiesterase type 5 (PDE-5) inhibitors, such as tadalafil, are widely used for erectile dysfunction and function by increasing nitric oxide-mediated vasodilation in the corpus cavernosum. When combined with medications having alpha-adrenergic blocking properties like chlorpromazine, a synergistic effect may occur, potentially resulting in prolonged and refractory priapism [8, 9].

Management of ischemic priapism follows a stepwise approach, beginning with corporal aspiration and irrigation, followed by intracavernosal injection of sympathomimetic agents. When these measures fail, surgical interventions such as shunt procedures are indicated [10]. For refractory cases or those presenting after prolonged duration (> 36 hours), early penile prosthesis implantation may preserve penile length and address inevitable erectile dysfunction [10, 11].

Here, we present a case of refractory ischemic priapism induced by the interaction between chlorpromazine and tadalafil that ultimately required penile prosthesis implantation after conventional treatments failed. This case provides strong evidence for the causal relationship between this drug interaction and severe priapism, supported by the patient's prior history with chlorpromazine, clear temporal relationship, and systematic exclusion of alternative etiologies.

Clinical History and Presentation

A 56-year-old male with no significant medical history presented to our emergency department with a painful penile erection persisting for 72 hours. The patient reported taking tadalafil 20 mg (obtained without prescription) approximately 24 hours before the onset of priapism for erectile dysfunction. Tadalafil, with its known pharmacokinetic profile of 17.5-hour half-life and clinical effects lasting up to 36 hours, was still pharmacologically active when he subsequently self-medicated with oral chlorpromazine 25 mg for persistent hiccups following an upper respiratory tract infection. He had obtained the chlorpromazine without prescription from a local pharmacy.

Upon further questioning, the patient revealed experiencing a similar but briefer episode of priapism (approximately 4 hours) about 10 years earlier after taking chlorpromazine for hiccups, without concurrent use of tadalafil or other medications. At that time, the erection resolved spontaneously, and he did not seek medical attention. The patient had not recognized the connection between the medication and his previous priapism episode until the current presentation.

In the current episode, the patient recalled experiencing a brief episode of priapism (approximately 4 hours) after his first dose of chlorpromazine, which resolved spontaneously. Following a second dose of chlorpromazine 25 mg taken 12 hours after the first, he developed a persistent erection that failed to resolve, prompting him to seek medical attention after 72 hours of symptoms.

Diagnostic Evaluation

Physical examination revealed an erect, rigid, and tender penis, with the glans penis remaining flaccid. Vital signs were stable with blood pressure of 130/80 mmHg, heart rate of 78 beats per minute, respiratory rate of 16 breaths per minute, and temperature of 36.7°C. Laboratory investigations, including complete blood count, coagulation profile, renal and liver function tests, were within normal limits. Hemoglobin electrophoresis was performed to rule out sickle cell disease or trait, with negative results. Toxicology screening revealed no other substances that could contribute to priapism.

Corporal blood gas analysis revealed a pH of 6.9, a pO2 of 28 mmHg, and a pCO2 of 60 mmHg, confirming the diagnosis of ischemic priapism.

Treatment Approach

Initial management consisted of corporal aspiration using a 16-gauge butterfly needle, yielding dark, deoxygenated blood. This was followed by intracavernosal injection of 2 cc of 1:100,000 epinephrine solution. Despite these measures, detumescence was not achieved. A second attempt with a higher concentration of epinephrine (1:50,000) was also unsuccessful [10]. These first-line interventions were completed within the first two hours of presentation.

After first-line treatments failed, the patient underwent a distal T-shunt procedure within four hours of presentation, following American Urological Association guidelines for management of ischemic priapism [10]. The procedure was performed under local anesthesia, and complete detumescence was initially achieved. Postoperatively, the patient was maintained on a urethral catheter, and regular penile "milking" was performed at scheduled intervals to maintain detumescence.

Despite these interventions, priapism recurred approximately 6 hours after the shunt procedure. The recurrence was likely due to the persistence of both pharmacological agents in the circulation combined with severe corporal smooth muscle damage from the prolonged ischemia. A second attempt at shunt creation with bilateral cavernosoglanular (AlGhorab) shunts was considered but deemed unlikely to succeed given the prolonged duration of priapism and the failure of the initial shunt procedure. Considering the extended duration of the initial priapism (72 hours), we proceeded with penile prosthesis implantation to address both the refractory priapism and the anticipated erectile dysfunction [11, 12]. The decision for prosthesis implantation was made within 12 hours of the failed shunt procedure.

Follow-up and Outcomes

The patient underwent a three-piece inflatable penile prosthesis implantation under general anesthesia. The procedure successfully achieved detumescence, and the postoperative course was uneventful. The patient was discharged on the second postoperative day without complications. The implantation procedure effectively addressed both the refractory priapism and the anticipated erectile dysfunction.

At 3-month follow-up, the patient reported satisfactory functional outcomes with the penile prosthesis, with no mechanical issues or pain. The patient was able to successfully engage in sexual intercourse, and he expressed satisfaction with the cosmetic and functional results of the implant. This case was reported to our institutional pharmacovigilance committee and subsequently to the national pharmacovigilance database to alert healthcare providers about this potentially dangerous drug interaction.

Ethical Considerations and Informed Consent

This case report was prepared after obtaining detailed written informed consent from the patient. The informed consent process included explanation of how the clinical information would be used, assurance of anonymity, potential benefits of sharing the case with the medical community, and the patient's right to withdraw consent at any time. The patient was specifically informed about the publication of his medical condition, treatments received, outcomes, and the importance of reporting medication interactions for future patient safety. The study was conducted in accordance with the Declaration of Helsinki. Patient privacy and confidentiality were maintained throughout the process according to institutional protocols for case publications.

Causality Assessment and Drug Interaction Mechanism

This case provides compelling evidence for a causal relationship between the combination of chlorpromazine and tadalafil and the development of severe, refractory priapism. Several factors support this causality: (1) clear temporal relationship between drug administration and symptom onset; (2) positive rechallenge with chlorpromazine causing similar symptoms on two separate occasions 10 years apart (with the first episode involving chlorpromazine alone); (3) biological plausibility based on known pharmacological mechanisms of both drugs; (4) systematic exclusion of alternative etiologies; and (5) consistency with previous case reports of similar drug interactions [5, 8, 9].

Using the Naranjo Adverse Drug Reaction Probability Scale, our case scored 9 points (definite adverse drug reaction): previous conclusive reports (+ 1), adverse event appeared after suspected drug administration (+ 2), adverse reaction improved when the drug was discontinued (+ 1), reaction reappeared when the drug was readministered (+ 2), alternative causes ruled out (+ 2), reaction with placebo (0), drug detected in toxic concentrations (0, as serum drug levels were not measured in our patient), reaction more severe with increased dose (+ 1), similar reaction to same drug in the past (+ 1), and adverse event confirmed by objective evidence (+ 1) [13].

The pharmacological interaction between chlorpromazine and tadalafil likely created synergistic effects through complementary mechanisms. Chlorpromazine primarily acts as an alpha-1 adrenergic receptor antagonist, inhibiting normal detumescence, while tadalafil increases nitric oxide-mediated vasodilation through PDE-5 inhibition. Additionally, a pharmacokinetic interaction may have occurred, as chlorpromazine can inhibit CYP3A4, which metabolizes tadalafil [6, 9, 14]. Although we did not measure serum concentrations of either drug, the timing of medication use and symptom onset, along with the known pharmacokinetic profiles of both drugs (tadalafil half-life of 17.5 hours with effects lasting up to 36 hours; chlorpromazine half-life of 30 hours), strongly suggest overlapping drug activity that significantly impaired normal erectile physiology regulation.

The dose-response relationship was evident, as the patient's initial priapism episode resolved spontaneously after the first dose of chlorpromazine but became persistent after the second dose. This aligns with the pharmacokinetics of both medications, which have relatively long half-lives allowing for drug accumulation with repeated dosing [14, 15].

Treatment Algorithm and Decision-Making Process

The management of this patient followed a systematic, evidence-based approach in accordance with current guidelines. The American Urological Association and European Association of Urology guidelines recommend a stepwise approach to ischemic priapism [10, 16], which was meticulously followed in this case:

First-line interventions: Corporal aspiration and irrigation were performed, followed by intracavernosal injection of sympathomimetic agents (epinephrine). These interventions are recommended as initial management with a Grade A recommendation level [10].

Second-line interventions: When first-line treatments failed, a distal T-shunt procedure was performed, the recommended surgical intervention for cases refractory to pharmacological management (Grade B recommendation) [10].

Decision for penile prosthesis implantation: The decision to proceed with penile prosthesis implantation was based on several factors indicating poor prognosis for spontaneous recovery:

Prolonged duration of priapism (72 hours), far exceeding the 24–36 hour window associated with inevitable erectile dysfunction
Failure of both first-line (aspiration and sympathomimetics) and second-line (shunt) interventions
Recurrence of priapism after initially successful shunt procedure
Evidence from recent systematic reviews and meta-analyses supporting early implantation in refractory cases [11, 17]

The timing of penile prosthesis implantation in this case (after 72 + hours of priapism) is supported by multiple studies. Zacharakis et al. reported that delayed implantation was associated with significantly higher complication rates compared to early implantation [17]. Similarly, Ralph et al. demonstrated that early implantation resulted in better preservation of penile length and lower rates of revision surgery compared to delayed implantation [18].

We considered alternative approaches such as proximal shunts, observation with delayed implantation, or additional pharmacological interventions but rejected them due to the prolonged priapism duration, failure of initial treatments, and low success rates reported in similar cases [10, 16, 18].

Clinical Implications and Recommendations

Based on this case, we recommend several key actions for healthcare providers to prevent and manage similar drug interactions:

First, obtain comprehensive medication histories with specific attention to PDE-5 inhibitors when evaluating priapism. Patients using chlorpromazine, particularly for non-psychiatric indications like hiccups, should be explicitly warned about priapism risk and advised to avoid concurrent use with PDE-5 inhibitors. For hiccup management, safer alternatives such as baclofen (10 mg three times daily) or metoclopramide (10 mg three times daily) should be considered as first-line agents before resorting to chlorpromazine.

When these medications must be used together, lower starting doses of antipsychotics (e.g., chlorpromazine 10 mg instead of 25 mg) and scheduling to minimize pharmacokinetic overlap are advisable. For patients taking tadalafil, a minimum waiting period of 48–72 hours should be recommended before initiating chlorpromazine to minimize the risk of interaction. For patients presenting with priapism in the context of this drug interaction, clinicians should consider more aggressive early management, including earlier surgical intervention if standard approaches fail.

Finally, reporting such cases to pharmacovigilance systems can help establish clearer risk profiles and improve patient safety. We reported this case to our national pharmacovigilance database to contribute to the collective knowledge of this drug interaction.

Our case also highlights the risks of self-medication, particularly with drugs that have significant adverse effect profiles and potential for interactions. Physicians should educate patients about these risks when prescribing medications with known potential for serious adverse effects. Additionally, regulatory authorities should reconsider the over-the-counter availability of medications with significant side effect profiles like chlorpromazine.

This case provides strong evidence for a causal relationship between chlorpromazine as the primary agent and the development of priapism, with tadalafil co-administration leading to a more severe, refractory condition requiring penile prosthesis implantation. The patient's history of previous chlorpromazine-induced priapism without tadalafil 10 years earlier establishes chlorpromazine as the causative agent, while tadalafil likely exacerbated the condition through synergistic effects.

The case highlights the importance of recognizing potentially dangerous drug interactions affecting erectile function and demonstrates the value of a guideline-based approach to managing refractory priapism. Early consideration of penile prosthesis implantation is appropriate in cases of prolonged, treatment-resistant priapism to preserve sexual function.

Healthcare providers should remain vigilant for drug interactions in priapism cases, particularly with concurrent use of PDE-5 inhibitors and alpha-blocking agents. Patient education and careful medication reconciliation are essential in preventing this urological emergency.

Can Arici contributed to the conception and design of the case report, collected clinical data, and was a major contributor in writing the manuscript.

Mert Başaranoğlu participated in data interpretation and literature review and contributed to the drafting and revision of the manuscript.

Murat Bozlu provided critical revision for important intellectual content and supervised the clinical management of the patient.

Selahittin Çayan contributed to the surgical management of the case and reviewed the manuscript for accuracy and integrity.

Erdem Akbay coordinated the case report submission, provided final approval of the version to be published, and ensured compliance with journal requirements.

All authors read and approved the final manuscript.

Acknowledgements

The authors thank the nursing staff of the Department of Urology for their assistance in the patient's care. We also express our gratitude to the patient for providing informed consent for the publication of this case report.

Conflict of Interest

The authors declare no conflicts of interest related to this manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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No competing interests reported.

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You are reading this latest preprint version

Chlorpromazine-Tadalafil Interaction Leading to Refractory Ischemic Priapism and Penile Prosthesis Implantation

Status:

Journal Publication

Version 1

Abstract

Introduction:

Case Presentation:

Discussion

Conclusion

Introduction

Case Presentation

Clinical History and Presentation

Diagnostic Evaluation

Treatment Approach

Follow-up and Outcomes

Ethical Considerations and Informed Consent

Discussion

Causality Assessment and Drug Interaction Mechanism

Treatment Algorithm and Decision-Making Process

Clinical Implications and Recommendations

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1