Nasal Spray May Provide New Answer for Erectile Dysfunction

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Enhanced Bioavailability of Tadalafil after Intranasal Administration in Beagle Dogs

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Abstract

Tadalafil is an oral selective phosphodiesterase type-5 inhibitor with demonstrated efficacy and safety that is used to treat erectile dysfunction. The purpose of this study is to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in beagle dogs. Fourteen 13-month-old male beagle dogs were randomly divided into two groups, and were given 5 mg tadalafil orally or intranasally in a parallel design. Blood samples were collected before and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 36 h after administration. The plasma concentration of tadalafil was determined via liquid chromatography-tandem mass spectrometry (LC-MS/MS). The systemic exposure and absorption rate of tadalafil were significantly greater in the intranasal administration group than in the oral administration group. A one-compartment model with first-order absorption and elimination was sufficient to explain the pharmacokinetic characteristics observed after both oral and intranasal administration. This study indicates that the development of tadalafil nasal delivery systems is feasible and may lead to better results than the conventional oral route.

1. Introduction

Tadalafil is a selective inhibitor of phosphodiesterase type-5 (PDE5), an enzyme that inactivates cyclic guanosine monophosphate (cGMP), and has demonstrated efficacy and safety as an oral therapy for erectile dysfunction (ED) [1,2]. Furthermore, tadalafil has a greater selectivity for PDE5 than sildenafil, the first approved PDE5 inhibitor, and one of the most widely used PDE5 inhibitors worldwide [3]. Tadalafil also has a prolonged half-life, with a low volume of distribution, slow hepatic clearance, and approximately 80% bioavailability in human. The pharmacokinetic properties of tadalafil facilitate a prolonged duration of action through once-daily dosing, so that sexual spontaneity may be more easily restored [4].

The original formulation of tadalafil was released in 2003 as a film-coated tablet for oral administration [5]. However, this formulation has been inconvenient for patients, as it must be swallowed with water. More importantly, as ED is frequently associated with depression, increased anxiety, poor self-esteem, and compromised interpersonal relationships [6], ED patients require a treatment that has a rapid onset and a long half-life, allowing for easy administration.

In order to meet patients’ needs, various formulations have been investigated, including orodispersible formulations, orally disintegrating film formulations, and transdermal patches [5,7,8,9,10,11]. In addition, the pharmacokinetics of sildenafil and udenafil have been investigated, following intranasal administration in animals [12,13]. Relative to oral administration, intranasal administration has several advantages, including a fast onset of effectiveness due to rapid absorption, avoidance of intestinal and hepatic first-pass effects, greater bioavailability allowing for lower doses, a reduction in gastrointestinal disturbances, a reduced risk of overdose, non-invasive administration, ease of convenience and self-medication, and improved patient compliance [14,15,16]. However, pharmacokinetic and formulation studies of tadalafil following intranasal administration have not yet been performed.

Thus, the purpose of this study was to compare the pharmacokinetic properties of tadalafil after conventional oral tablet administration and novel intranasal administration in beagle dogs. The pharmacokinetic parameters of tadalafil were obtained via noncompartmental analysis and modeling. This study furthers the possibility of intranasal tadalafil administration as a novel drug delivery system.

2. Materials and Methods

2.1. Chemicals and Reagents

Tadalafil and sildenafil citrate (internal standard—IS) were purchased from Sigma Chemical Co. (St. Louis, MO, USA) for use in liquid chromatography-tandem mass spectrometry (LC-MS/MS). High-performance (HP)LC-grade acetonitrile and methanol were purchased from Burdick and Jackson (Muskegon, MI, USA). All of the other chemicals and solvents were of the highest analytical grade available. Cialis ® tablets containing 5-mg tadalafil were purchased from Lilly Korea Co., Ltd. (Seoul, Korea).

2.2. Animal Study

Fourteen 13-month-old male beagle dogs weighing 9.19–12.27 kg were provided by Woojungbio., Co., Ltd. (Suwon, Korea) and were kept individually in controlled environments at a temperature of 23 ± 2 °C and a 12/12 h light/dark cycle for a two-week acclimatization period. A quantitative pellet diet was given at a fixed time each day, and water was offered ad libitum. All of the physical examinations and blood tests were acceptable for use in the experiments.

The animal experiments were conducted in accordance with the Guidelines for the Care and Use of Laboratory Animals, and were approved by the Institutional Review Board of the nonclinical contract research organization, KPC laboratory (approval date: 29 September 2017). The fourteen dogs were randomly divided into two groups. The dogs in group A (n = 7) were administered tadalafil 5 mg (Cialis ® 5 mg) orally in the morning after an overnight fast. The dogs in group B (n = 7) were administered tadalafil 5 mg intranasally using a manual pump spray unit that delivered 120 μL of the formulation per spray. The ingredients of the nasal spray formulation were as follows: 30% polyethylene glycol (PEG) 400, 50% transcutol HP, and 5% Tween 80 in normal saline. A total volume of 240 μL formulation was sprayed into both of the dogs’ nostrils at a dose of 5 mg for each dog. The dogs’ heads were elevated for approximately 30 s during the administration, and for approximately 30 s after the administration. No food or water was allowed until 4 h and 2 h after administration, respectively. The blood samples (approximately 1.5 mL) were deposited into heparinized tubes before (0 h) and 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, and 36 h following the drug administration. All of the blood samples were centrifuged for 2 min at 10,000 rpm (13,416 × g), and the plasma was stored at −70 °C until the HPLC-MS/MS analysis.

2.3. Determination of Tadalafil Concentration in Plasma Using LC-MS/MS

The plasma concentrations of tadalafil were quantified via LC-MS/MS using an Agilent 1260 series (Agilent Technologies, Santa Clara, CA, USA) and API 2000 MS/MS system (Applied Biosystems, Foster City, CA, USA), equipped with an electrospray ionization interface to generate positive ions [M − H] + . An HPLC chromatographic separation was performed on a Zorbax SB C₁₈ column (50 × 4.6 mm, 5 μm) with Phenomenex SecurityGuard Cartridges (C₁₈, 4.0 × 3.0 mm, Macclesfield Cheshire, U.K.). The mobile phase composition was a mixture of acetonitrile—10 mM ammonium formate buffer (70:30, v/v, pH 3.0 with formic acid) at a flow rate of 300 μL/min. The column and autosampler were set at 30 and 10 °C, respectively. The analytes were detected using the multiple-reaction-monitoring (MRM) mode at transitions of m/z 390.1→268.2 for tadalafil and m/z 475.3→100.0 for the IS. The collision energy, and declustering and collision exit potentials were set to 17, 76, and 12 V for tadalafil, and 31, 91, and 10 V for the IS. The ion spray voltage and entrance potential were set to 5500 and 10 V, respectively. The dwell time was 150 ms for the analytes. The data were processed using the Analyst 1.4.1 software.

The tadalafil and the IS were extracted from the plasma matrix via protein precipitation. In an Eppendorf tube ® , 600 μL of acetonitrile containing the IS (500 ng/mL) was added to a 100 μL-plasma sample. After vortex mixing and centrifugation at 12,000 rpm for 5 min, an aliquot of supernatant (300 μL) was transferred to an autosampler vial, and 5 μL of the sample was injected into the LC-MS/MS system. The method validation was carried out according to the United States Food and Drug Administration Bioanalytical Method Validation Guidance [17], and the linearity for tadalafil was achieved between 1–1000 ng/mL. The intra- and inter-day precisions (n = 5) of the assay were 4.2–11.8%, and the intra- and inter-day accuracies (n = 5) were 89.7–110.2%. The short-term (room temperature for 6 h), post-extraction (4 °C for 24 h), freeze–thaw (−70 °C after three cycles), and long-term stabilities (−70 °C for 1 month) were adequate. The pharmacokinetic samples were conducted using the same procedure.

2.4. Noncompartmental Pharmacokinetic Analysis

The noncompartmental pharmacokinetic analyses were evaluated using WinNonlin Standard Edition software, version 5.2 (Pharsight Corp., Mountain View, CA, USA) [18]. The area under the plasma concentration versus time curve from 0 to 36 h (AUC_36h) was assessed using the linear trapezoidal methodology, and was extrapolated to infinity (AUC_inf). The maximum plasma concentration (C_max) and time to reach C_max (T_max) for tadalafil were directly obtained from the individual observed data. The terminal phase elimination rate (λ_z) was estimated using a log-linear regression of the observed plasma concentration point in the terminal phase, and the elimination half-life (t_1/2) was calculated as 0.693/λ_z. The apparent total clearance (Cl_t/F) and volume of distribution (V_z/F) were calculated using the formulas dose/AUC_inf and dose/(K_el·AUC_inf), respectively.

2.5. Pharmacokinetic Modeling Analysis

A one-compartment pharmacokinetic model with first-order absorption and elimination rate constants was applied to describe the pharmacokinetic profiles of tadalafil after oral and intranasal administration in dogs. Two differential equations were consisted to explain the changes in the amount of tadalafil between the depot and central compartments after oral and intranasal administration, namely:

where A(1) and A(2) indicate the amounts of tadalafil in the depot and central compartments, respectively; K_a is the first-order absorption rate constant for tadalafil from the depot to the central compartment; and K_el is the first-order elimination rate constant for tadalafil. The differential equations were fitted to the dataset using the maximum likelihood expectation maximization (MLEM) algorithm in ADAPT 5 (Biomedical Simulation Resource, Los Angeles, CA, USA) [19]. The data below the quantification limit (BQL;

The plasma concentrations of tadalafil (C_p) after oral and intranasal administration were calculated using the following equation:

where V_c/F is the volume of distribution in the central compartment. The equations were applied to the data using ADAPT 5, under the assumption that the standard deviation of the measurement error was a linear function of the measured quantity (Var[ε_i(t_i)] = (σ₀ + σ_IC(t_i)) 2 ). The model evolution was conducted using the goodness of fit, Akaike’s information criterion (AIC), Schwartz’s Bayesian information criterion (SC), the sum of squares of the residuals, visual examination of the distribution of residuals, log-likelihoods, coefficients of variation of parameter estimates, and parameter correlation matrices [20].

2.6. Statistical Analysis

The data are represented as the mean ± standard deviation. The differences in the noncompartmental model pharmacokinetic parameters of tadalafil between the oral and intranasal administrations were tested using the student t-test. The statistical significance was assigned to p-values less than 0.05. All of the statistical analyses were conducted using SPSS software (version 20.0; SPSS, Chicago, IL, USA).

3. Results

3.1. Noncompartmental Pharmacokinetic Analysis

The plasma concentration versus time profiles of tadalafil after the oral and intranasal administration of a 5 mg dose are shown in Figure 1 , and the corresponding noncompartmental pharmacokinetic parameters are listed in Table 1 . Following the oral administration, the maximum concentration of tadalafil was 59.49 ± 9.22 ng/mL at 1.71 ± 0.39 h, and the AUC_36h and AUC_inf were 472.66 ± 102.70 ng·h/mL and 479.33 ± 102.88 ng·h/mL, respectively. Following intranasal administration, the maximum concentration of tadalafil was 76.45 ± 12.07 ng/mL at 1.50 ± 0.41 h, and the AUC_36h and AUC_inf were 771.10 ± 216.72 ng·h/mL and 790.23 ± 224.91 ng·h/mL, respectively. Compared with the oral administration group, the intranasal administration group exhibited significantly greater values for C_max(1.29-fold, p < 0.05), AUC_36h (1.63-fold, p < 0.01), and AUC_inf (1.65-fold, p < 0.01). However, there was no significant difference in the T_max values between the oral and intranasal administrations.

Mean plasma concentration–time curves (A) and the corresponding graph converted to a semi-log scale (B) for the oral and intranasal administration of 5 mg tadalafil in dogs. Each point represents the mean ± standard deviation (SD). Solid lines indicate the final model fits.

Table 1

Noncompartmental pharmacokinetic parameters for the oral and intranasal administration of 5 mg tadalafil to dogs. Data are presented as the mean ± standard deviation (SD).

Parameter (Units)	Oral (n = 7)	Intranasal (n = 7)	p Value
Tmax (h)	1.71 ± 0.39	1.50 ± 0.41	0.337
Cmax (ng/mL)	59.49 ± 9.22	76.45 ± 12.07	p < 0.05
AUC36h (ng·h/mL)	472.66 ± 102.70	771.10 ± 216.72	p < 0.01
AUCinf (ng·h/mL)	479.33 ± 102.88	790.23 ± 224.91	p < 0.01
λz (h −1 )	0.17 ± 0.04	0.13 ± 0.04	0.06
t1/2 (h)	4.17 ± 1.01	5.79 ± 1.47	p < 0.05
Clt/F (L/h)	10.87 ± 2.43	6.98 ± 2.77	p < 0.05
Vz/F (L)	64.13 ± 14.80	53.63 ± 5.07	0.101

T_max—the time to reach C_max; C_max—peak plasma concentration; AUC_36h—area under the plasma concentration-versus-time curve from time zero to 36 h; AUC_inf—AUC_36h extrapolated to infinity; λ_z— terminal elimination rate constant; t_1/2—elimination half-life; Cl_t/F—apparent total body clearance; V_z/F—volume of distribution.

3.2. Pharmacokinetic Model Analysis

A one-compartment pharmacokinetic model with first-order absorption and elimination rate constants successfully described the pharmacokinetic properties after oral and intranasal administration of 5 mg tadalafil to dogs. In Figure 1 , the solid lines and circles show the one-compartment pharmacokinetic model fits and observations, respectively, of the average plasma concentration–time profiles for tadalafil. The diagnostic plots of the residuals versus time and residuals versus observation data are shown in Figure 2 . In addition, the final estimates for the model parameters are listed in Table 2 .

Diagnostic plots obtained from the final pharmacokinetic model of tadalafil after oral (closed circles) and intranasal administration (open circles) in dogs. (A) Residuals versus time after dose; (B) residuals versus observed concentrations.

Table 2

Pharmacokinetic parameters for tadalafil estimated using a one-compartment model with first-order absorption and elimination constants for both the oral and intranasal administration of 5 mg tadalafil to dogs. Data are presented as mean ± standard deviation (SD).

K_a—absorption rate constant; K_el—elimination rate constant; V_c/F—volume of distribution of tadalafil in the central compartment.

Among the model parameters, the value of K_a for the intranasal administration of tadalafil was significantly greater than that for the oral administration (p < 0.001). Moreover, the value for V_c/F for the intranasal administration of tadalafil was significantly lower than that for the oral administration (p < 0.05). However, there was no significant difference in the values of K_el after oral and intranasal administration.

4. Discussion

In this study, the pharmacokinetic properties of 5 mg oral and intranasal tadalafil were compared after administration in dogs. The pharmacokinetic parameters of tadalafil were obtained via noncompartmental analysis and pharmacokinetic modeling analysis. The pharmacokinetic exposures following the intranasal administration of tadalafil were statistically greater than those following oral administration. In particular, the absorption rate was statistically faster and the bioavailability was statistically greater for the intranasal administration relative to the oral administration, based on the modeling analysis.

The pharmacokinetics of the PDE5 inhibitors using various administration routes have previously been assessed in animals and humans [5,7,8,9,10,12,13,21]. Particularly, the intranasal delivery of PDE5 inhibitors has been highlighted because of its advantages [22]. Indeed, the pharmacokinetics of sildenafil and udenafil have been examined in previous studies. Until now, however, there have been not yet been any studies of tadalafil in animals or humans.

Previous studies of sildenafil and udenafil showed shorter T_max values and a higher exposure for the intranasal versus oral administration [12,13,21]. Similarly, in this study, the pharmacokinetic tadalafil exposure after intranasal administration was significant higher than after oral administration. However, T_max did not differ significantly between intranasal and oral administration. This may be due to the fact that the T_max for tadalafil after oral administration was already short, so the faster absorption found in intranasal drug delivery might not affect T_max.

The results of the modeling approaches were consistent with a noncompartmental analysis ( Figure 3 ). The absorption rate constant (K_a) was greater following the intranasal administration versus oral administration in dogs. Further, the value of V_c/F in the intranasal administered group was smaller than that for the oral administered group. The difference in V_c/F might be caused by the increased bioavailability (F) in the intranasal group, and might not be affected on distribution. The elimination rate constant (K_el) was smaller in the intranasal group, but this finding did not reach statistical significance (p = 0.053). These results suggest that the intranasal administration of tadalafil led to a faster and greater absorption than the oral administration.

Box plot of model parameters for tadalafil after oral and intranasal administration in dogs (n = 7/group). The median is displayed as (−) and the mean as (···). Boxes are drawn from 25th to 75th percentiles, and whiskers extend from 5th to 95th percentiles. Circles lie outside the range of the 5th to 95th percentiles.

A dog model is useful for the assessment of pharmacokinetic parameters for human scale dosing [23]; however, there are no previous studies that examine the pharmacokinetics of tadalafil in dogs, except for the pharmacology review of Cialis ® for U.S. FDA approval, and we determined to undertake the analysis. There are some differences in the pharmacokinetic parameters of tadalafil between dogs (t_1/2 = 4.17 h; F = 10–18% for oral administration) and humans (t_1/2 = 17.5 h; F = 80% for oral administration), particularly the considerably longer half-life and higher oral bioavailability in humans [24,25]. Further, tadalafil is mainly metabolized by CYP3A4 in humans, but dogs have different CYP isoforms and activities than humans [26]. In addition, it is well known that the metabolic rate of small animals is much faster than that of humans [27]. Therefore, this discrepancy may be attributable to the interspecies pharmacokinetic differences between humans and dogs.

The intranasal administration of PDE5 inhibitors for the treatment of ED has several potential advantages over the conventional oral routes. Among the intranasal administration methods, nasal sprays are better absorbed and have a higher bioavailability than nasal drops [28,29]. However, the disadvantages of intranasal administration must be considered, including nasal debris, inflammation, and nasal cavity anatomy alteration. In particular, nasal congestion is one of the mechanism-related adverse effects of PDE5 inhibitors [30], so a safety study will be required.

5. Conclusions

The pharmacokinetics of tadalafil were compared following the oral and intranasal administration of 5 mg tadalafil to dogs. The systemic exposures and absorption rates of tadalafil were significantly greater in the intranasal group, relative to those in the oral group. This study indicates the feasibility and benefits of developing a tadalafil nasal delivery system over the conventional oral route.

Author Contributions

M.-S.K. and I.-h.B. conceived and designed the experiments; J.-S.K. performed the experiments; M.-S.K., I.-h.B., and J.-S.K. analyzed the data and wrote the paper.

Funding

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT, and Future Planning (NRF- 2017R1C1B1006483). This research was supported by the Basic Science Research Program through the National Research Foundation of Korea(NRF), funded by the Ministry of Education (NRF-2018R1D1A1B07048150).

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; and in the decision to publish the results.

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Nasal Spray May Provide New Answer for Erectile Dysfunction

Feb. 9, 2001 — The latest treatment for erectile dysfunction comes in a thumb-sized atomizer that delivers enough of the drug to coat the nasal passages: spray, wait 15 minutes, and “you are good for about an hour,” says Carl Spana, PhD, president and CEO of Palatin Technologies Inc., the Princeton, N.J.-based drug manufacturer.

The new drug, with the name PT-141, is about four years away from approval by the FDA, Spana tells WebMD. Because the drug works on the central nervous system to stimulate nerves to release molecules that cause tiny blood vessels in the penis to open, or dilate, “we expect PT-141 to work on all types of erectile dysfunction, regardless of the cause,” says Spana.

Erectile dysfunction can be caused by a number of medical conditions, such as diabetes, high blood pressure, and high cholesterol, or by damage resulting from prostate cancer surgery. Besides these “organic” causes, the failure to achieve and/or maintain an erection can also be caused by psychogenic factors, says Spana. “We think this drug should work in all patients . it will release signaling molecules that stimulate vasodilators to vasodilate by acting like a turbo-charged signal,” he says.

If this new drug makes it through all the safety and effectiveness trials required for FDA approval, it could not only be a valuable treatment but also could put Spana’s tiny company on the map. Right now, the company has only one approved drug — a type of high-tech dye that allows radiologists to pinpoint the site of an infection.

When Viagra hit the market in 1998, it revolutionized the treatment of erectile dysfunction and added millions of dollars to the profit column of Pfizer, its maker. But it doesn’t work for everyone, and that remaining need combined with the expectation of a financial bonanza continues to drive researchers to come up with new drugs.

Hunter Wessells, MD, an associate professor of urology at the University of Washington, says PT-141 has the potential to be “the ideal [erectile dysfunction] drug. The goal for therapy has always been to get a fast-acting, easy-to-administer drug with minimal side effects and good efficacy. A nasal spray also covers the on-demand aspect that has been applied to the concept of the ideal drug for treatment of [erectile dysfunction].”

Administering a drug through the nose is not a novel idea, says Wessells, who points out that this route is already used for Imitrex, a drug used to treat migraine headaches. He explains that drugs are quickly absorbed through the linings of the nasal passages and thus may enter the bloodstream even faster than drugs administered as pills.

While PT-141 is a central nervous system stimulator, Viagra works by helping to relax smooth muscle cells, which increases the blood flow to the penis and thus makes it easier to achieve and maintain an erection. Men are advised to take Viagra an hour before attempting sexual relations, and the drug’s effect lasts for about 4 hours.

A few years ago, while teaching at the University of Arizona, Wessells conducted clinical studies of a “molecule that is similar to PT-141.That drug was administered with a subcutaneous injection,” he says. “We studied 20 subjects with 39 administrations and found no serious side effects and no cardiovascular side effects.” Some men who have heart disease can’t take Viagra because it adversely enhances the affect of common heart drugs called nitrates.

Last year there was a great deal of excitement generated by another Viagra alternative called Uprima. That drug was recommended for FDA approval last April, but just as the FDA was poised to issue a final decision, the manufacturer, TAP Pharmaceuticals, withdrew the new drug application. Several vocal opponents of the drug said it caused fainting spells, which in one case caused a car accident when a man passed out at the wheel. The drug also causes nausea, and men were advised to avoid eating when taking the drug, which is given as a lozenge.

Martha McKennitt, a spokeswoman for TAP Pharmaceuticals, which is a joint venture of Abbott Laboratories of Abbott Park, Ill., and Takeda Chemical Industries of Japan, tells WebMD that the company “plans to meet this quarter with the FDA to determine when to resume the approval process” for Uprima.

“There is some overlap of the side effects profile between drugs like PT-141 and [Uprima], at least as far as nausea,” says Wessells. But he says that the effects do not appear as pronounced.

Although Wessells tells WebMD that he is not directly involved in the studies of PT-141, Spana says that Wessells serves on Palatin’s clinical advisory board.

PT-141 is now being tested in safety trials in healthy men. Spana expects to complete those studies by May and then begin dose trials in 60 men with erectile dysfunction. Those studies will be used to determine the most effective dose of the drug, he says. When the dose studies are complete, hopefully later this year, the company plans to “enter pivotal studies by the second quarter of 2002,” says Spana. Pivotal studies, also called phase 3 trials, are the final studies required by the FDA before a drug can be considered for approval. “If all goes well,” he says, “we will have the FDA approval by late 2003 or early 2004.”

My Boner-Pill Habit Became a Dependence on Nasal Spray

In the summer of 2015, my wife decided that our seven-year open marriage was no longer for her. In the blink of an eye, her secondary partner became her primary partner, and I was her ex. Together, they committed to monogamy and, a year or two later, procreation.

Given that non-monogamy was something she’d persuaded me to try, I was pretty miffed, but as there was no recourse, I decided to step aside with minimal fuss. Within weeks, I’d moved back across the continent, and on the face of it, it was like our marriage had never happened. Now, what I maybe ought to have done at that point is spoken with a mental health professional. Instead, I went on a 24-month, full-throttle fucking spree that ended up with me afraid to leave the house without a bottle of Afrin Severe Congestion spray on my person. Allow me to explain.

My two-year bender wasn’t about promiscuous sex—though admittedly there was a little of that at first—but instead a headlong dive into polyamory. Though sex was an important part of the three relationships I was juggling as ethically and transparently as I could, I was just as excited to boyfriend. In fact, I made boyfriending my job. I made up for the shortfall in profits from my actual job by using the money I received from my ex-wife buying me out of the condo we owned. Wise.

There were elaborate excursions, dinners, and trips out of town. Six or seven nights a week, I was a mixologist, chef, Zagat guide, Netflix co-binger, experience curator, and sexual fantasy fulfillment specialist. I wanted to be a gatekeeper to every kind of fun imaginable, like a horny, heartbroken Willy Wonka.

In retrospect, I can see that I was working out some serious issues, but all I knew at the time was that I was fucking exhausted and needed pharmaceuticals to keep up with the life I’d created. Don’t get ahead of me. I’m not talking about nasal spray just yet. I’m talking about boner pills which were a sort of gateway drug, I suppose.

A friend had been buying generic sildenafil—the active ingredient in Viagra—from a company in India (not an endorsement, btw) and was happy to sell me as many as I wanted. The pills were $5 each, but my friend told me I’d only need to take a third to a half of a pill on the days when I felt that my energy reserves were unusually low. I used them sparingly at first, but when six out of every seven nights was a date night—replete with one or two morning rounds followed by me whipping up a pancake breakfast—I began to rely on the pills. Hard.

The thing is, sildenafil has side effects. “It’s a vasodilator, meaning that it opens blood vessels and increases blood flow,” explains Michael Reitano, New York-based sexual health specialist and doctor-in-residence at health startup, Ro. “Sildenafil is something users really do well to titrate.” Reitano refers, here, to adjusting the dosage accordingly. How much you need in order to feel better is dependent on a number of factors that could include how much you’ve had to drink, how tired you are, your state of mind, and a host of other things besides. “If you were experiencing side effects, it might have been that you were using more than the minimum effective dose,” he tells me.

Sildenafil can be great for giving you a crowbar-hard erection that’s impervious to alcohol, cocaine, exhaustion, and episodic indifference, but it gave me flushed cheeks, bright red ears, and a very stuffy nose because it turns out that blood vessels are everywhere. The blushing and ear thing I could deal with, but when you can’t breathe through your nose, performing oral sex becomes virtually impossible—dangerous, even. Moreover, how my partners’ hair, skin, and various other parts’ smell is an extraordinary turn-on for me. So while I was sporting an indomitable, four-hour erection that I could hammer nails with after popping a quarter of a pill, I couldn’t smell, so I was paradoxically less turned on and less effective than I was au naturel.

During one early sildenafil-fueled session, I realized that the tradeoff was becoming untenable. But instead of admitting that my self-inflicted schedule was too much for me, I made a 2 AM run to the bodega to pick up some nasal spray. I’d never used it before, but friends with occasional nasal congestion swore by it.

I tore open the package and administered a mega dose on the 30-second walk back from the bodega. By the time I got my clothes back off, it felt like a fresh, minty breeze was whistling through every nook and cranny of my skull.

The funny thing is that I’d always thought that the stuffing in a stuffy nose was snot, but it’s chiefly the swelling of tissues in the nose. “Oxymetazoline is the active ingredient in most over-the-counter nasal sprays,” says Raj Sindwani, vice chairman of the rhinology, sinus & skull base surgery at the Cleveland Clinic. “It’s a vasoconstrictor, meaning that it has the opposite effect on blood vessels than sildenafil does.”

From the next several months, I reached for the miraculous nasal spray whenever the sildenafil caused congestion, though I sometimes noticed that I was often stuffy before date night got underway. I figured this had to do with the half-life (the amount of time it takes for your body to metabolize 50 percent of a drug) of the sildenafil. It wasn’t until I went home to visit my parents—and took a couple of much-needed weeks off from boyfriending—that I noticed my nose still felt as though a wet California king duvet had been stuffed into it. A little poking around online revealed that I should have read the nasal spray packaging I chucked into a garbage can while running back to my place to resume having sex. I’d done far too much, far too often. I was hooked.

“Yeah, you really shouldn’t use a topical decongestant for more three days,” Sindwani says. “It says that on the label.” Oxymetazoline, he tells me, works well in the short term but after a while, it can make the tissue inside your nose swell even more, something he calls a “rebound effect.” Known medically as rhinitis medicamentosa, this self-inflicted rebound congestion will often cause people—um, people like me—to use even more oxymetazoline, unwittingly making the problem much worse.

I ended up going cold turkey and, after a few uncomfortable days and nights of mouth-breathing, the situation improved. However, Sindwani says there are alternatives to going either cold turkey or gradually weaning yourself off oxymetazoline. “You’ll see three classes of over-the-counter nasal spray in the drug store,” he says “Topical decongestants that contain oxymetazoline, saline nasal sprays, and steroid sprays [like Flonase] which are often effective at relieving the rebound effect.”

Once I got back home to New York, I decided to stop putting so much pressure on myself to host, entertain, and perform for my partners. My chemical mishap led me to engage in a little introspection and soon afterward, I realized I’d worked out whatever was compelling me to make dating my number-one priority. Though I remain resistant to the trappings of monogamy on a philosophical level, I’m happy to be down to one girlfriend, no boner pills, and zero decongestant.

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Side effects of tadalafil – Brand names: Cialis, Adcirca

Like all medicines, tadalafil can cause side effects in some people, but many people have no side effects or only minor ones.

Common side effects

Common side effects of tadalafil happen in more than 1 in 100 people.

If you’re taking it for erection problems you’re unlikely to get side effects as you’re only taking it for a short time.

If you’re taking tadalafil for pulmonary hypertension and get these side effects, there are things you can do to help cope with them:

Make sure you rest and drink plenty of fluids. Do not drink too much alcohol. Ask your pharmacist to recommend a painkiller.

Headaches should usually go away after the first week of taking tadalafil. Talk to your doctor if they last longer than a week or are severe.

It may help if you stick to simple meals and avoid rich or spicy food. If you’re taking tadalafil for pulmonary hypertension, it may help to take it after a meal or snack.

Try cutting down on coffee, tea and alcohol. It might help to keep the room cool and use a fan. You could also spray your face with cool water or sip cold or iced drinks.

The flushing should go away after a few days.

If you need something to ease the discomfort, try taking an antacid, but do not put off going to the doctor if it bothers you. They may be able to prescribe an extra medicine to protect your stomach.

Speak to a pharmacist or doctor. They may be able to recommend a nasal spray that helps.

If you get unusual muscle ache that is not from exercise or physical work, ask your pharmacist to recommend a suitable painkiller. Talk to your doctor if the aches continue.

Side effects will usually go away when you stop taking the tablets. Talk to a doctor or pharmacist if the advice on how to cope does not help and a side effect is still bothering you or does not go away.

Serious side effects

Serious side effects are rare and happen in less than 1 in 1,000 people.

Urgent advice: Go to A&E straight away if:

• you have sudden loss of vision or sudden problems with your hearing – stop taking tadalafil if this happens
• you have a prolonged or painful erection, especially if it lasts for more than 2 hours

Immediate action required: Call 999 now if:

Stop taking tadalafil if you get any of these symptoms.

If you get chest pain during or after sex and you usually use nitrates, such as glyceryl trinitrate (GTN), do not take them to treat your chest pain.

Serious allergic reaction

In rare cases, tadalafil can cause a serious allergic reaction (anaphylaxis).

Immediate action required: Call 999 or go to A&E now if:

• you get a skin rash that may include itchy, red, swollen, blistered or peeling skin
• you’re wheezing
• you get tightness in the chest or throat
• you have trouble breathing or talking
• your mouth, face, lips, tongue or throat start swelling

You could be having a serious allergic reaction and may need immediate treatment in hospital.

Other side effects

These are not all the side effects of tadalafil. For a full list, see the leaflet inside your medicine packet.

You can report any suspected side effect using the Yellow Card safety scheme.

More in Tadalafil

Page last reviewed: 11 November 2022
Next review due: 11 November 2025

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Oxytocin Nasal Spray

Endogenous oxytocin is a hormone secreted by the supraoptic and paraventricular nuclei of the hypothalamus and stored in the posterior pituitary. It stimulates contraction of uterine smooth muscle during gestation and causes milk ejection after milk has been produced in the breast. Oxytocin has been associated with mating, parental, and social behaviors. Oxytocin is released during intercourse in both men and women, which has led to the belief that it is involved in sexual bonding. There is speculation that in addition to facilitating lactation and the birthing process, the hormone facilitates the emotional bond between mother and child.1 Oxytocin has also been studied in autism and have some sort of relation to the social and developmental impairments associated with the disease.2 Clinically, oxytocin is used most often to induce and strengthen labor and control postpartum bleeding. Intranasal preparations of oxytocin, used to stimulate postpartum milk ejection, are no longer manufactured in the U.S. Oxytocin was approved by the FDA in 1962.

Mechanism of Action

Synthetic oxytocin elicits the same pharmacological response produced by endogenous oxytocin, with cervical dilation, parity, and gestational age as predictors of the dose response to oxytocin administration for labor stimulation.3 Oxytocin increases the sodium permeability of uterine myofibrils, indirectly stimulating contraction of the uterine smooth muscle. The uterus responds to oxytocin more readily in the presence of high estrogen concentrations and with the increased duration of pregnancy. There is a gradual increase in uterine response to oxytocin for 20 to 30 weeks gestation, followed by a plateau from 34 weeks of gestation until term, when sensitivity increases.3 Women who are in labor have a greater response to oxytocin compared to women who are not in labor; only very large doses will elicit contractions in early pregnancy. In the term uterus, contractions produced by exogenous oxytocin are similar to those that would occur during spontaneous labor. Oxytocin increases the amplitude and frequency of uterine contractions, which transiently impede uterine blood flow and decrease cervical activity, causing dilation and effacement of the cervix.

Oxytocin causes contraction of the myoepithelial cells surrounding the alveolar ducts of the of the breast. This forces milk from the alveolar channels into the larger sinuses, and thus facilitates milk ejection. While oxytocin possesses no galactopoietic properties, if it is absent the milk-ejection reflex in the breast fails.

Oxytocin causes dilation of vascular smooth muscle, thus increasing renal, coronary, and cerebral blood flow. Blood pressure usually remains unaffected, but with the administration of very large doses or high concentration solutions blood pressure may decrease transiently. This transient decrease in blood pressure leads to reflex tachycardia and an increase in cardiac output; any fall in blood pressure is usually followed by a small, but sustained, increase in blood pressure.

Oxytocin does possess antidiuretic effects, but they are minimal. If oxytocin is administered with an excessive volume of electrolyte-free IV solution and/or at too rapid a rate, the antidiuretic effects are more apparent and water intoxication can result.

Pharmacokinetics

Oxytocin administered effectively by parenteral injection or nasal inhalation. Steady state, following parenteral administration, is usually achieved in plasma by 40 minutes.3 Oxytocin’s plasma half-life is between 1 and 6 minutes. The drug distributes throughout the extracellular fluid, with minimal amounts reaching the fetus.

Oxytocinase, a glycoprotein aminopeptidase that is capable of degrading oxytocin, is produced during pregnancy and is present in the plasma. Enzyme activity increases gradually until term approaches, when there is a sharp rise in plasma levels and activity is high in the plasma, placenta and uterus. After delivery enzyme activity declines. Oxytocinase most likely originates from the placenta and regulates the amount of oxytocin in the uterus; there is little or no degradation of oxytocin in men, nonpregnant women, or cord blood. Oxytocin is rapidly removed from plasma by the liver and the kidneys, with only small amounts being excreted unchanged in the urine. Oxytocin is metabolized in the lactating mammary gland and is distributed into breast-milk.

Contraindications/Precautions

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.3

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breast-feeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breast-milk, but is not expected to have adverse effects in the infant.4

Parenteral oxytocin should be used only by qualified professional personnel in a setting where intensive care and surgical facilities are immediately available. Furthermore, according to the manufacturer, oxytocin should only be used when induction of labor is necessary for medical reasons. It should not be used for elective induction of labor as available data are insufficient to evaluate the risk-benefit ratio in this indication. During oxytocin administration, uterine contractions, fetal and maternal heart rate, maternal blood pressure, and, if possible, intrauterine pressure should be continuously monitored to avoid complications. If uterine hyperactivity occurs, oxytocin administration should be immediately discontinued; oxytocin-induced stimulation of the uterine contractions usually decreases soon after discontinuance of the drug. The induction or continuance of labor with oxytocin should be avoided when the following conditions or situations are present: evidence of fetal distress, fetal prematurity, abnormal fetal position (including unengaged head), placenta previa, uterine prolapse, vasa previa, cephalopelvic disproportion, cervical cancer, grand multiparity, previous surgery of the uterus or cervix (including 2 or more cesarean deliveries), active genital herpes infection, or in any condition presenting as an obstetric emergency requiring surgical intervention. Use of oxytocin in any of these settings can aggravate the condition or cause unnecessary fetal or maternal distress.

Oxytocin may possess antidiuretic effects, and prolonged use can increase the possibility of an antidiuretic effect. Prolonged use of oxytocin and administration in large volumes of low-sodium infusion fluids are not recommended, particularly in patients with eclampsia or who have unresponsive uterine atony. Antidiuretic effects have the potential to lead to water intoxication and convulsive episodes due to hypertension.

Pregnancy

Oxytocin is indicated during pregnancy to induce labor; it precipitates uterine contractions and abortion.3

Breastfeeding

Endogenous oxytocin is involved in the process of lactation and therefore, oxytocin has been used in mothers having difficulty with engorgement and breastfeeding. Because several small studies have failed to show a beneficial effect, oxytocin is not used for this indication. Oxytocin is excreted in the breastmilk, but is not expected to have adverse effects in the infant.4

Interactions

In certain cases, oxytocin can be used in combination with other oxytocics for therapeutic purposes. There is a risk, however, of severe uterine hypertony occurring, with possible uterine rupture or cervical laceration. The concurrent use of dinoprostone, prostaglandin E2 and oxytocin is considered contraindicated; following the removal of the dinoprostone vaginal insert, an interval of at least 30 minutes is recommended prior to the use of another oxytocic agent. These products should be used sequentially only under adequate obstetric supervision.5

Adverse cardiovascular effects can develop as a result of concomitant administration of oxytocin with general anesthetics or with spinal or epidural anesthetics, especially in those with preexisting valvular heart disease. Cyclopropane, when administered with or without oxytocin, has been implicated in producing maternal sinus bradycardia, abnormal atrioventricular rhythms, hypotension, and increases in heart rate, cardiac output, and systemic venous return.6 In addition, halothane decreases uterine responsiveness to oxytocics (e.g., oxytocin, ergonovine, methylergonovine) and, in high doses, can abolish it, increasing the risk of uterine hemorrhage. Halothane is a potent uterine relaxant.7 It is not clear if other halogenated anesthetics would interact with oxytocics in this manner.

The administration of prophylactic vasopressors with oxytocin can cause severe, persistent hypertension, as the 2 drugs may have a synergistic and additive vasoconstrictive effect. This interaction was noted when oxytocin was given 3—4 hours after prophylactic vasoconstrictor in conjuction with caudal anesthesia. The incidence of such an interaction may be decreased if vasopressors are not administered prior to oxytocin.6 This interaction can include certain other sympathomimetics such as ephedra, ma huang.

Do not take this medicine with any of the following medications:

This medicine may also interact with the following medications:

• dinoprostone, prostaglandin E2
• medicines for blood pressure
• medicines used for sleep during surgery
• other medicines to contract the uterus

This list may not describe all possible interactions. Give your health care provider a list of all the medicines, herbs, non-prescription drugs, or dietary supplements you use. Also tell them if you smoke, drink alcohol, or use illegal drugs. Some items may interact with your medicine.

Adverse Reactions/Side Effects

Some patients can experience a hypersensitive uterine reaction to the effects of oxytocin. Excessive doses can have the same effect. This can produce increased, hypertonic uterine contractions, possibly prolonged, resulting in a number of adverse reactions such as cervical laceration, postpartum hemorrhage, pelvic hematoma, and uterine rupture.8

Oxytocin-induced afibrinogenemia has been reported; it results in increased postpartum bleeding and can potentially be life-threatening. Neonatal retinal hemorrhage has been reported. Also, intracranial bleeding including subarachnoid hemorrhage has been reported in patients receiving oxytocin.8 In one case, subarachnoid hemorrhage mimicked acute water intoxication and delayed the diagnosis of hemorrhage after an oxytocin assisted labor.9

Adverse maternal cardiovascular effects from oxytocin may include arrhythmia exacerbation, premature ventricular contractions (PVCs), and hypertension. In the fetus or neonate, fetal bradycardia, PVCs, and other arrhythmias have been noted.8

Oxytocin has an antidiuretic effect, and severe and fatal water intoxication has been noted and may occur if large doses (40—50 milliunits/minute) are infused for long periods. For example, water intoxication with seizures and coma has occurred in association with a slow oxytocin infusion over a 24-hour period. Management of water intoxication includes immediate oxytocin cessation and supportive therapy. In the fetus or neonate, fetal death, permanent CNS or brain damage, and neonatal seizures have been noted with oxytocin.8 The rare complications of blurred vision, ocular hemorrhage (of the conjunctiva), and pulmonary edema have been associated with oxytocin induced water intoxication.

Oxytocin administration has been associated with anaphylactoid reactions.8

Oxytocin-induced labor has been implicated in an increased incidence of neonatal hyperbilirubinemia, about 1.6 times more likely than after spontaneous labor. This can lead to neonatal jaundice.8

Nausea and vomiting have been noted with oxytoxin.8

Side effects that you should report to your doctor or health care professional as soon as possible:

• allergic reactions like skin rash, itching or hives, swelling of the face, lips, or tongue
• breathing problems
• excessive or continuing vaginal bleeding
• fast, irregular heartbeat
• feeling faint or lightheaded, falls
• high blood pressure
• seizures
• unusual bleeding or bruising
• unusual swelling, sudden weight gain

Side effects that usually do not require medical attention (report to your doctor or health care professional if they continue or are bothersome):

This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.

Storage

• 1. Cabanac M, Pfaff DW, Ogawa S, et al. Neural oxytocinergic systems as genomic targets for hormones and as modulators of hormone-dependent behaviors. Results Probl Cell Differ 1999;26:91-105.
• 2. Modahl C, Green L, Fein D, et al. Plasma oxytocin levels in autistic children. Biol Psychiatry 1998;43:270-277.
• 3.a.b.c.d.e. American College of Obstetrics and Gynecology (ACOG). ACOG Practice Bulletin Number 10: Clinical Management Guidelines for Obstetrician-Gynecologists. Induction of labor. Washington, DC: American College of Obstetricians and Gynecologists; November 1999.
• 4.a.b. Mangesi L, Dowswell T. Treatments for breast engorgement during lactation. Cochrane Database Syst Rev. 2010;9:CD006946.
• 5. Cervidil® (dinoprostone vaginal insert) package insert. St. Louis, MO: Forest Laboratories, Inc.; 1997 Jul.
• 6.a.b. Pitocin® (oxytocin injection, USP) package insert. Rochester, MI: Monarch Pharmaceuticals; 2003 Jan.
• 7. Halothane, USP package insert. North Chicago, IL: Abbott Laboratories; 1998 Mar.
• 8.a.b.c.d.e.f.g. Pitocin (oxytocin) package insert. Rochester, MI: JHP Pharmaceuticals, LLC; 2014 Sept.
• 9. Curless RV, Beaumont DM, Sinar EJ, et al. Subarachnoid hemorrhage mimicking acute water intoxication during labour augmented by oxytocin infusion. Br J Clin Pract 1990;44(12):637-638.