The role of tadalafil in treated hypertensive patients with erectile dysfunction
Does Cialis Lower Blood Pressure?
Cialis®, known in its generic form as tadalafil, is one of the most commonly prescribed erectile dysfunction medications on the market today.
While other erectile dysfunction drugs such as Viagra® (sold generically as sildenafil) and Levitra® (sold generically as vardenafil) are taken as needed immediately before sex, tadalafil’s long half-life — the amount of time it takes to eliminate 50 percent of the drug from your system — renders it effective for up to 36 hours.
Tadalafil can also be taken at a low dose on a daily basis, which allows those on the medication to be ready for sexual encounters as they come up organically, rather than having to take a pill and wait for it to kick in.
But like any other medication, tadalafil can have side effects and may not be right for everybody — particularly those with certain medical conditions or those taking certain medications.
Below, we’ll talk about how Tadalafil (Cialis) works and the impact it can have on blood pressure.
How Cialis Works
Tadalafil belongs to a class of medications known as phosphodiesterase type 5 inhibitors, or PDE5 inhibitors.
PDE5 inhibitors are so named because they block an enzyme called cGMP-specific phosphodiesterase type 5 (PDE5) that breaks down cyclic guanosine monophosphate (cGMP), a molecule that relaxes smooth (or involuntary) muscles.
When PDE5 is blocked, cGMP can relax smooth muscles, widen blood vessels and increase blood flow without interference — particularly in the penis and lungs, where PDE5 is highly concentrated.
This, in turn, makes it easier for the erectile tissue in the penis to become engorged with blood and stiffen, causing an erection.
Cialis’ Effect on Blood Pressure
Because tadalafil and other PDE5 inhibitors have vasodilating effects — meaning they open blood vessels — they make it easier for blood to flow, which can lower blood pressure.
These decreases in blood pressure are typically temporary and unlikely to cause significant health issues in most patients.
A clinical study found that healthy men taking 20 mg of Cialis® versus a placebo experienced an average decrease of up to 1.6 Hg in systolic blood pressure and 0.8 mm Hg in diastolic blood pressure when lying down, and 0.2 Hg in systolic blood pressure and 4.6 mm Hg in diastolic blood pressure when standing.
For context, people may begin to feel negative effects after a sudden blood pressure drop of 20 mm Hg.
Tadalafil can more substantially lower pulmonary blood pressure, or the pressure of the blood flowing in your lungs, because of the lungs’ high concentration of PDE5.
As a result, tadalafil is sometimes used as a treatment for pulmonary hypertension — or elevated blood pressure in the lungs — under the brand name Adcirca®. It should be noted, though, that pulmonary blood pressure is different than systemic (overall) blood pressure.
While tadalafil by itself isn’t likely to cause a dangerously low drop in systemic blood pressure in healthy men, there are certain medical conditions and drugs that can potentially heighten its hypotensive effects.
genuine cialis has your back all weekend
Contraindicated Conditions
Patients with the following conditions were not included in clinical safety or efficacy trials, so tadalafil is not currently recommended for them:
Severe, uncontrolled arrhythmia (irregular heartbeat)
Other groups that tadalafil may not be well suited for include those with:
Obstructions of outflowing blood from the left ventricle (such as aortic stenosis and idiopathic hypertrophic subaortic stenosis)
Severely impaired autonomic control of blood pressure
Not healthy enough for sexual activity
Kidney problems, or those who require dialysis
Retinitis pigmentosa (a rare genetic eye disease)
Severe vision loss, including non-arteritic anterior ischemic optic neuropathy (NAION)
Penis deformations or Peyronie’s disease
Priapism (erections lasting more than 4 hours)
Blood cell problems such as sickle cell anemia, multiple myeloma or leukemia
Contraindicated Drugs
There are also drugs that can increase the hypotensive effects of tadalafil to a dangerous level, including:
Other medicines that treat erectile dysfunction
Substantial amounts of alcohol (5 units [50 millilitres/40 grams at a time] or more)
The role of tadalafil in treated hypertensive patients with erectile dysfunction
This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
In this issue, Kloner and colleagues showed in a pooled safety analysis that tadalafil—a phosphodiesterase type 5 (PDE‐5) inhibitor—is safe in treated hypertensive patients and is not associated with increased hypotension‐related treatment adverse events and major cardiovascular (CV) events. 1 The safety data were extracted from 72 Phase II–IV clinical studies of tadalafil used for erectile dysfunction (ED) or benign prostate hypertrophy. PDE‐5 inhibitors are vasodilating drugs that work by blocking the degradation of cyclic GMP by PDE‐5 in the smooth muscle cells lining the blood vessels supplying various tissues. The increase of the intracellular cyclic GMP prolongs its duration of action resulting in increase in nitric oxide bioavailability, smooth muscle relaxation, vasodilation and increased blood flow in the corpora cavernosa, and penile erection. The main PDE‐5 inhibitors are sildenafil, vardenafil, avanafil, and tadalafil. They differ in their pharmacodynamic and pharmacokinetic properties allowing targeting the treatment to the patients’ needs. Avanafil has the fastest onset of action and tadalafil has the longest duration of action (half‐life of 17.5 h and duration of action up to 36 h). 2
ED impairs the quality of life of affected individuals and may be a prognostic marker for the development of CV disease. 3 The prevalence of ED in the general population is around 15–20% and it is significantly higher in patients with hypertension, 2 , 4 probably due to vascular changes. Hypertension is a major modifiable risk factor for CV disease and lowering blood pressure is beneficial. Lowering blood pressure may cause or aggravate ED and it is not clear whether it is a side effect of the antihypertensive treatment or a result of the blood pressure decrease. The development of ED is one of the major reasons to withdraw antihypertensive treatment leading to inadequate blood pressure control. PDE‐5 inhibitors improve ED and improve adherence to antihypertensive therapy, improve blood pressure control, and thereby may reduce CV risk in hypertensive patients with ED.
The effect of PDE‐5 inhibitors is not limited to the corpora cavernosa and they also vasodilate other vascular beds thereby reducing blood pressure. There was a concern that blood pressure decrease may cause CV side effects particularly in patients with CV risk factors. Kloner and colleagues in this issue showed that in subjects not receiving antihypertensive medications the incidence of hypotension related treatment emergent adverse events was low, but it was significantly higher in the tadalafil group than in the placebo group. 1 Most subjects (>90%) not receiving antihypertensive medications were normotensives, and in this group, lowering blood pressure by tadalafil may increase the incidence of hypotension‐related events. However, in hypertensive patients on antihypertensive medications tadalafil does not increase the hypotension related events.
The co‐administration of tadalafil with doxazosin, a blood pressure lowering alpha blocker is associated with a remarkable blood pressure decrease that maybe deleterious. 5 However, with other antihypertensive agents tadalafil is not associated with hypotensive related side effects.
The co‐administration of PDE‐5 inhibitors with various antihypertensive drugs, except alpha blockers, is safe. This was observed even in those who used several antihypertensive agents. 1
It has been shown that all PDE‐5 inhibitors are safe in treated hypertensive patients. 2
The hypotensive effect of PDE‐5 inhibitors should be exploit to treat resistant hypertension, particularly in those with ED. Since tadalafil has the longest duration of action it will probably be the best PDE‐5 inhibitor to use for lowering blood pressure. Low dose tadalafil (5 mg daily) can improve blood pressure control and erectile function. The fact that PDE‐5 inhibitors can lower blood pressure and improve erectile function suggests that lowering blood pressure by itself does not cause ED and it is probably related to the antihypertensive medications.
The safety profile of tadalafil presented by Kloner in this issue may justify wider use of the drug in hypertensive patients. Wide use of tadalafil in hypertensive patients may improve erectile function and blood pressure control leading to a decrease in CV events. Further long term studies should be done to prove this concept.
CONFLICT OF INTEREST
Notes
Grossman E. The role of tadalafil in treated hypertensive patients with erectile dysfunction . J Clin Hypertens . 2022; 24 :182–183. 10.1111/jch.14434 [CrossRef] [Google Scholar]
Editorial to manuscript # JCH‐ 21‐0330R1 entitled “Analysis of integrated clinical safety data of tadalafil in patients receiving concomitant antihypertensive medications”
REFERENCES
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Influence of a single dose of 20 mg tadalafil, a phosphodiesterase 5 inhibitor, on ambulatory blood pressure in subjects with hypertension
Correspondence Dean Patterson, Clinical Lecturer, Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Tel: + 013 8266 0111, ext 33531, pager 4100 Fax: + 013 8263 2333 E-mail: [email protected]
Abstract
To test the non-inferiority of a single dose of tadalafil 20 mg compared with placebo with respect to 26-h mean ambulatory systolic and diastolic blood pressure in treated and untreated hypertensive subjects.
Methods
A multicentre, randomized, double-blind, placebo-controlled crossover study in 114 subjects with hypertension (36 subjects on no therapy with daytime mean ambulatory blood pressure ≥ 140/85 mmHg; 38 subjects on two to four classes of antihypertensive agents with daytime mean ambulatory blood pressure ≥140/85 mmHg and 40 subjects on two to four classes of antihypertensive agents with ambulatory blood pressure < 140/85 mmHg).
Results
Overall tadalafil reduced mean ambulatory blood pressure monitor systolic and diastolic blood pressure by 4.8 mmHg [95% confidence interval (Cl) 3.7, 5.9; P < 0.01] and 2.9 mmHg (95% CI 1.9, 3.6; P < 0.01), respectively, compared with placebo. In hypertensive subjects with uncontrolled blood pressure on two to four classes of antihypertensive agents (n = 36) tadalafil reduced mean ABPM systolic and diastolic blood pressure by 7.5 mmHg (95% CI 5.4, 9.6; P < 0.01) and 4.3 mmHg (95% CI 6.1, 8.9; P < 0.01) compared with placebo.
Conclusions
In patients with uncontrolled hypertension on multiple agents the addition of tadalafil 20 mg lowered mean 26-h blood pressure.
Introduction
Although hypertension itself is asymptomatic, it is often associated with severe erectile dysfunction (ED) [1]. This link can be partially explained by the recognized association between traditional vascular risk factors and ED [2, 3]. In the USA, for example, approximately 36% and 20% of men in their 5th decade have hypertension and ED, respectively, while both these figures increase to over 60% by the age of 70 years [4–6].
With the global increase in life expectancy, obesity rates and the associated vascular disease, one can foresee a burgeoning health burden from both hypertension and ED [7, 8]. Addressing these linked vascular disorders with a single agent is a novel yet logical approach, particularly when considering that antihypertensive drug treatment has often been implicated as a cause of ED.
Sildenafil citrate, the first agent in the class of phosphodiesterase-5 (PDE5) inhibitors to receive regulatory approval, has been shown to have mild transient peripheral vasodilatory and hypotensive effects [9], in addition to its beneficial effects in the penile vasculature. In contrast with sildenafil and its half-life of 4 h, tadalafil, a newer PDE5 inhibitor, has a 17.5-h half-life and the potential to provide prolonged pharmacotherapeutic benefits in subjects with both hypertension and ED. Tadalafil has been proven to be efficacious in the treatment of ED in patients with a variety of clinical conditions, including hypertension [10]. In addition, its effect on ED when taken as an alternate day therapy has been assessed [11].
Various data from studies in both normotensive and hypertensive subjects available at the time of the study design suggested a significant but small antihypertensive effect when tadalafil was taken alone and an additive effect with other monotherapies for hypertension. Significant additive office blood pressure (BP)-lowering effects of between 6 and 8 mmHg systolic and 4–5 mmHg diastolic BP have been demonstrated with tadalafil 10 mg in conjunction with metoprolol (25–200 mg) and bendrofluazide (2.5 mg) and with 20 mg tadalafil and angiotensin II receptor antagonists when compared with placebo [12].
Studies using both sildenafil and tadalafil have suggested that there is a shallow dose–response curve for haemodynamic effects. However, the effect of 20 mg tadalafil in hypertensive subjects on multiple antihypertensive therapies and in hypertensive subjects on no antihypertensive therapy had not been tested in a large study assessing ambulatory blood pressure.
Methods
This study was conducted by the Scottish Hypertension Academic Research Collaboration (SHARC) at three centres. Local ethics committees approved the study, which was designed to test the hypothesis that in hypertensive subjects the effect on BP of tadalafil 20 mg was no different from that of placebo. The study was conducted in accordance with the declaration of Helsinki and Good Clinical Practice guidelines. All subjects gave written voluntary informed consent and continued on their usual medication throughout the study.
Outcomes
The primary and secondary outcomes were changes from screening in ambulatory blood pressure monitor (ABPM) mean systolic (SBP) and diastolic BP (DBP), respectively.
Participants
Subjects were recruited from outpatient clinics at the three affiliated hospitals. Exclusion criteria included active substance abuse, major organ disease (apart from drug treatment for diabetes mellitus, acid indigestion, osteoarthritis, hypercholesterolaemia or anxiety/depression), nitrate use or PDE5 inhibitor allergy.
Subjects ≥ 18 years of age with normal laboratory test and ECG results (apart from left ventricular hypertrophy) were randomized into the double-blind, placebo-controlled, crossover phase if their screening mean daytime ABPM BP fulfilled one of the following group criteria:
Interventions
Screening
Subjects ingested no grapefruit-containing products and 2 units (1 unit =a drink with 10 ml of ethanol/ethyl alcohol) or less of alcohol per day from 1 week before randomization until the study end. Subjects attended fasted for an initial full medical examination and laboratory indices (ECG, haematology, biochemistry and urinalysis). An ABPM device was then fitted and subjects completed a standardized breakfast within 30 min and consumed only water during a 6-h period of observation for hourly monitoring of vital signs. Smoking was not allowed during this time. Subjects returned the following day for ABPM removal, 26 h after fitting.
Crossover study
The procedure for treatment periods 1 and 2 was identical to that during the screening period. Subjects were dosed with either tadalafil 20 mg or placebo 30 min after ABPM fitting. On day 2 subjects returned for removal of the monitor, inquiry about adverse events and blood sampling for electrolytes.
Blood pressure
m anual bp . A trained nurse measured blood pressure in the seated position in the dominant arm according to British Hypertension Society guidelines with a well-calibrated mercury sphygmomanometer [13].
abpm . Between 08.00 and 10.00 h, an ABPM (Spacelabs 90207, Issaquah, WA, USA) was fitted on the nondominant arm and then calibrated using five manual BP readings via a T-piece. The ABPM device was programmed to record for 26 h with 15-min measurement intervals, apart from 22.00−08.00 h when the interval was 30 min. Upon return of the ABPM, data were downloaded via a modem link to Biomedical Systems Corporation (Brussels, Belgium) for blinded analysis. The screening mean daytime BP results were faxed back to the study centre for categorization of subjects into Group A, B or C. On treatment results were analysed at the end of the study.
Clinically significant blood pressure changes
Adverse event monitoring
Subjects were asked to keep a study diary recording the time and details of daily activities, medication taking and adverse events. Subjects were also questioned about adverse events at study visits.
Sample size
For each population a non-inferiority hypothesis with a limit of non-inferiority of 4 mmHg was tested. Using this criterion and assuming a within-subject standard deviation for maximum post-baseline difference in ambulatory mean SBP of 7.77 mmHg, a population size of 36 subjects per group provided 90% power to declare non-inferiority.
Randomization and blinding
Eli Lilly and Company Ltd (Windlesham, UK) entered anonymized subjects into a stratified randomization after assigning each a kit number, kits containing matching tadalafil 20 mg and matching placebo having previously been allocated to each study site. The randomization code remained unbroken throughout the study.
Statistics
For each group, the change from the screening in both 26-h ambulatory BP was calculated for each time point post dose. Least squares (LS) means, mean differences and the upper 95% confidence interval (CI) for differences were calculated using a mixed effects model where the period and treatment were fixed effects and the subject was a random effect. Non-inferiority was confirmed if the upper 95% CI was < 4 mmHg.
The change from the screening mean 26 h ambulatory BP was calculated for periods 1 and 2. These data were analysed using repeated measures anova (SPSS v 11.5; SPSS Inc., Chicago, IL, USA) with change in mean 26 h ABPM BP as the dependent variable, screening mean SBP as a covariate and antihypertensive treatment as a between-subject factor.
Results
Study subjects
A total of 114 caucasian subjects were randomized (112 completed; 41 females, 71 males): 36 subjects in population A, 38 subjects in population B and 40 subjects in population C. Two subjects in population B were withdrawn following dosing in treatment period 1 due to protocol violations (administration of five classes of antihypertensive medication and change of antihypertensive medication during the study). Both subjects were dosed in treatment period 1 (one received 20 mg tadalafil and one received placebo). Available data for all subjects were included in the safety and pharmacodynamic evaluations ( Tables 1 and and2 2 ).
Table 1
| Group | A | B | C |
|---|---|---|---|
| Age, years | 53 (10) | 57 (10) | 57 (10) |
| Weight, kg | 85 (15) | 87 (17) | 87 (16) |
| Height, cm | 170 (9) | 170 (10) | 167 (11) |
| Body mass index, kg m −2 | 29 (4) | 29 (4) | 31 (5) |
| Number | 36 | 38 | 40 |
| Male | 26 | 25 | 22 |
| Female | 10 | 13 | 18 |
| LVH | 3 | 7 | 7 |
| HC (no. on treatment) | 6 (4) | 16 (10) | 10 (7) |
| DM | 2 | 2 | 4 |
LVH, Left ventricular hypertrophy from ECG or echocardiography; HC, hypercholesterolaemia; DM, diabetes mellitus.
Table 2
Concomitant antihypertensive therapy for Groups B and C
| Drug | Antihypertensive therapy | |
|---|---|---|
| Group B | Group C | |
| ACE-inhibitors | 15 (39) | 11 (28) |
| Angiotensin II antagonist | 13 (34) | 13 (32) |
| β-Blocker | 22 (58) | 18 (45) |
| Calcium antagonist | 16 (42) | 19 (47) |
| Thiazide | 29 (76) | 29 (73) |
| Loop diuretic | 3 (8) | 1 (2.5) |
| Doxazosin | 7 (18) | 4 (10) |
| Spironolactone | 1 (2.6) | 1 (2.5) |
| Moxonidine | 2 (6) | 0 |
Blood pressure
An initial analysis using least squares means demonstrated that tadalafil-induced changes from screening BP were non-inferior to placebo only for DBP in Group A and for SBP in Group C. All other BP differences failed non-inferiority testing ( Table 3 ).
Table 3
Summary results for each of the groups for the change from the screening in ambulatory blood pressure (mmHg) calculated for each time point post dose and analysed by least squares means
| Group | A | B | C | ||
|---|---|---|---|---|---|
| 26-h screening blood Pressure | 144/90 | 144/86 | 127/77 | ||
| SBP | Change from screening | Tadalafil | −7.2 (3–22) | −11.2 (0–22) | −5.7 (3–13) |
| Placebo | −3.2 (8–11) | −3.8 (5–17) | −2.4 (6–11) | ||
| Tadalafil–placebo LSM | −4.9 [8.1] | −8.3 [13.6] | −1 [3.6] | ||
| DBP | Change from screening | Tadalafil | −5.1 (1–19) | −7.6 (1–14) | −3.8 (7–7) |
| Placebo | −2.9 (5–13) | −3.3 (6–19) | −0.9 (6–19) | ||
| Tadalafil–placebo LSM | −0.8 [3.1] | −6.0 [8.7] | −4.1 [6.3] | ||
| HR | Change from screening | Tadalafil | 3 | 1 | 2 |
| Placebo | −1 | −2 | 0 |
Data are mean (range); [upper 95% CI]; LSM, least squares means; SBP, systolic blood pressure; DBP diastolic blood pressure; HR, heart rate.
The secondary analysis using anova demonstrated statistically significant 26-h ambulatory BP changes for Groups A, B and C (see below). An analysis of 24-h ambulatory data revealed results similar to the 26-h monitoring analysis.
Group A (uncontrolled hypertension on no drug therapy)
Mean changes from baseline 26-h ambulatory mean SBP and DBP on tadalafil compared with placebo were − 3.9 mmHg (95% CI 2.2, 5.6; P < 0.01) and − 2.2 mmHg (95% CI 0.6, 3.8; P < 0.01), respectively.
Group B (uncontrolled hypertension on two to four classes of antihypertensive)
Mean changes from baseline 26-h ambulatory mean SBP and DBP on tadalafil compared with placebo were −7.5 mmHg (95% CI 5.4, 9.6; P < 0.01) and −4.3 mmHg (95% CI 2.9, 5.6; P < 0.01), respectively.
Group C (controlled hypertension on two to four classes of antihypertensive)
Mean changes from baseline 26-h ambulatory mean SBP and DBP on tadalafil compared with placebo were −3.3 mmHg (95% CI 1.5, 5; P < 0.01) and −2.8 mmHg (95% CI 1.5, 4; P < 0.01), respectively.
In addition changes in SBP and DBP for all subjects combined were significant when compared with anova ( Table 4 ).
Table 4
Summary of blood pressure (mmHg) results for the whole group (A + B + C)
| n = 112 | Screening | Tadalafil | Screening-tadalafil | Placebo | Screening-placebo | P-value |
|---|---|---|---|---|---|---|
| SBP | 137 | 129 | −7.9 | 134 | −3.1 | |
| (135, 140) | (127, 131) | (6.7, 9.1) | (132, 137) | (1.8, 4.3) | – | |
| DBP | 84 | 78 | −5.4 | 82 | −2.3 | |
| (82, 85) | (77, 80) | (4.6, 6.2) | (80, 83) | (1.3, 3.2) | – | |
| HR | 68 | 69 | 1 | 67 | −1 | NS |
Data are mean (95% CI); SBP, systolic blood pressure; DBP diastolic blood pressure; HR, heart rate; data analysed using anova (SPSS v 11.5) with change from screening in mean 26-h ambulatory blood pressure monitor BP as the dependant variable, screening mean SBP as a covariate and antihypertensive treatment as a between-subject factor.
Mean daytime and night time data are shown in Table 5 .
Table 5
Mean day time and night time peak and trough ambulatory blood pressure data per treatment group
| Day time | Night time | |||||
|---|---|---|---|---|---|---|
| Tadalafil 20 mg | Placebo | Tadalafil 20 mg | Placebo | |||
| Group A | SBP | Peak | 173 (168, 177) | 177 (173, 182) | 150 (145, 154) | 152 (147, 156) |
| Trough | 117 (114, 120) | 120 (116, 123) | 102 (99, 106) | 107 (103, 111) | ||
| DBP | Peak | 110 (108, 112) | 113 (110, 115) | 92 (90, 95) | 96 (93, 99) | |
| Trough | 69 (67, 72) | 72 (69, 74) | 56 (54, 58) | 61 (58, 63) | ||
| Group B | SBP | Peak | 166 (163, 170) | 178 (172, 184) | 150 (145, 155) | 156 (151, 161) |
| Trough | 109 (106, 112) | 117 (114, 121) | 102 (98, 105) | 108 (104, 112) | ||
| DBP | Peak | 104 (101, 107) | 109 (106, 112) | 91 (88, 95) | 93 (90, 97) | |
| Trough | 61 (59, 64) | 67 (64, 70) | 53 (51, 56) | 58 (56, 61) | ||
| Group C | SBP | Peak | 153 (150, 156) | 159 (156, 163) | 132 (128, 135) | 134 (131, 137) |
| Trough | 101 (98, 103) | 104 (102, 106) | 95 (92, 98) | 96 (94, 98) | ||
| DBP | Peak | 94 (92, 97) | 98 (96, 101) | 82 (79, 85) | 84 (81, 87) | |
| Trough | 56 (54, 58) | 59 (57, 62) | 51 (48, 53) | 53 (51, 55) | ||
mmHg (95% CI); day time 08.00–20.00 h; night time 20.00–08.00 h.
Clinically significant BP changes
More subjects experienced clinically significant decreases in ambulatory systolic and diastolic BP following administration of tadalafil compared with placebo, but this was statistically significant only for Group B (P= 0.041). No decreases in BP were associated with hypotensive symptoms ( Table 6 ).
Table 6
Numbers of clinically significant decreases in ambulatory blood pressure (BP)
| Number of subjects with a CSD in ambulatory BP | ||||
|---|---|---|---|---|
| Group | A | B | C | |
| SBP | Screening | 1 (9) | 1 (2) | 3 (6) |
| Tadalafil | 29 (170) | 33 (310) | 28 (130) | |
| Placebo | 27 (96) | 28 (153) | 25 (90) | |
| DBP | Screening | 2 (4) | 1 (3) | 7 (17) |
| Tadalafil | 35 (195) | 35 (273) | 37 (162) | |
| Placebo | 31 (175) | 29 (152) | 32 (120) | |
CSD, Clinically significant decrease; (number of clinically significant decreases); SBP, systolic blood pressure; DBP diastolic blood pressure.
Tolerability
The total number of adverse events that were thought to be drug related was 120 and 30 for tadalafil and placebo, respectively. Of the adverse events attributable to tadalafil, 33% were mild, 53% were moderate and 14% were severe. There was a similar distribution of adverse event severity for placebo (30%; 50%; 20%) No serious adverse events were reported ( Table 7 ).
Table 7
Frequencies of drug-related adverse events by type
| Overall | Group A | Group B | Group C | |||||
|---|---|---|---|---|---|---|---|---|
| n = 114 | n = 36 | n = 38 | n = 40 | |||||
| Tadalafil | Placebo | Tadalafil | Placebo | Tadalafil | Placebo | Tadalafil | Placebo | |
| Headache | 23 (41) | 4 (6) | 25 (12) | 3 (1) | 21 (16) | 8 (4) | 23 (13) | 3 (1) |
| Myalgia | 10 (18) | 2 (3) | 14 (9) | 0 | 11 (7) | 0 | 5 (2) | 5 (3) |
| Back pain | 11 (16) | 0 | 8 (3) | 0 | 11 (6) | 0 | 13 (7) | 0 |
| Flushing | 7 (9) | 0 | 8 (1) | 0 | 5 (3) | 0 | 8 (3) | 0 |
| Dyspepsia | 4 (8) | 0 | 3 (1) | 0 | 3 (1) | 0 | 8 (6) | 0 |
Percentage of subjects with adverse event (number of adverse events).
The adverse events reported (listed in order of frequency observed in the study), namely headache, dyspepsia, back pain, myalgia and flushing were consistent with the data sheet on tadalafil. In total, 65 of the 114 subjects were adverse event free after tadalafil dosing and 96 subjects were adverse event free on placebo only. Thus, 57% of subjects experienced no adverse events after tadalafil dosing and the figure for placebo was 84%. Of the total headache incidents reported following tadalafil, 42% were mild, 53% moderate and 5% severe. Of the total myalgia incidents reported following tadalafil, 16% were mild, 56% moderate and 28% severe. Of the total back pain incidents reported following tadalafil, 13% were mild, 50% moderate and 37% severe. Adverse events either resolved spontaneously or responded to paracetamol or other simple analgesia as required.
Discussion
This study has proved that a single dose of tadalafil 20 mg results in a significant BP reduction in subjects with hypertension. These BP-lowering effects are in keeping with other interaction studies in both hypertensive and coronary artery disease subjects [12, 15]. Taken as a whole, these effects are clinically important as systolic BP is recognized to be the major risk predictor in hypertension [16, 17] and is generally unsatisfactorily managed, with only small proportions of patients reaching target BP [18].
The mechanism responsible for the haemodynamics effect of tadalafil requires clarification. The vasodilatory mechanism is known to interact with both nitrate and α-blocker therapy. PDE5 inhibitors are contraindicated with nitrates due to the substantial potentiation of hypotensive effects. Tadalafil augments the vasodilatory action of doxazosin by up to 9.8 mmHg and currently may only be used with caution for patients on this drug [19]. Peripheral vasodilation secondary to PDE5 inhibition is known to occur during periods of augmented nitric oxide drive [20]; despite this, the dose–response at the doses used for ED is shallow. Incremental dosages do not significantly lower blood pressure further in otherwise healthy subjects [9]. The hypotensive action of tadalafil may depend upon a balance between nitric oxide and renin bioavailability in relation to the degree of constriction/dilation of the peripheral circulation. Sildenafil citrate has been shown to increase renin production in normotensive men [21], a possible mechanism limiting its vascular vasodilatory effect. This generates a hypothesis for the limited blood pressure responses seen in the untreated hypertensive subjects in study group A, in which the effects of reflex PDE5 inhibitor-induced renin secretion (not blocked by drug therapy such as ACE-inhibitors) could limit the blood pressure-lowering effects of tadalafil. In contrast, subjects with uncontrolled hypertension on multiple therapies (Group B) demonstrated the largest blood pressure fall, probably due to the relatively vasoconstricted vasculature in the presence of antihypertensive therapy inhibiting the effects of any reflex renin secretion upon the angiotensin–aldosterone axis. Subjects with controlled BP (Group C) on therapy, on the other hand, tend to be relatively vasodilated [22] and less prone to further BP reduction from PDE5 inhibition. Unfortunately, we did not measure renin values during this study to confirm this hypothesis.
The use of tadalafil and other PDE-5 inhibitors in subjects at risk of cardiovascular disease has to date not been associated with adverse effects on cardiovascular morbidity or mortality [15, 23]. Data from clinical trials performed in the general population of men with ED, including those with cardiovascular disease, show that the incidence of cardiovascular adverse events is not increased in men taking tadalafil or sildenafil and is similar to that observed in the general population of men with ED [11, 22]. Additionally, the myocardial infarction rate across 29 double-blind and open-label tadalafil clinical trials in patients with ED was 0.43 per 100 patient years in tadalafil-treated patients compared with 0.6 per 100 patient years in placebo-treated patients [15], while in a meta-analysis, sildenafil citrate was found to have a favourable effect on mortality [24].
One question that remains unanswered is whether the antihypertensive effects of tadalafil persist at the dosages and frequency of use in ED subjects. Certainly, tolerability is not a problem with chronic use for ED [25]. One of the remaining challenges for modern therapeutics is the maintenance of a good quality of life when treating hypertensive patients. This study has demonstrated that tadalafil may be useful in reducing some of the excess risk attributable to BP in uncontrolled hypertension, with little reduction in quality of life. Indeed, men with resistant hypertension are more likely to have severe ED and may have an improved quality of life on tadalafil. Patients on antihypertensive therapy often implicate drug therapy as a major contributor to ED, whilst clinicians implicate risk factors. The ideal antihypertensive drug should have a neutral or positive effect on erectile function. Tadalafil could fulfil such a role. This, however, was a single dosing study and at present little is known of its blood pressure effects when taken chronically in hypertensive subjects, although in healthy subjects it has been shown to reduce SBP by 2.79 mmHg compared with 0.63 mmHg by placebo when taken over 26 weeks at the 20-mg dose [15]. Additionally, the side-effect profile in the present study may not be insignificant for the average patient with hypertension. Tadalafil is, however, well tolerated when used chronically in the ED setting [26]. Patients with both hypertension and ED may be more inclined to tolerate side-effects in lieu of improved erectile function. It is also possible that tolerance to side-effects may occur [27].
We have demonstrated an incremental antihypertensive effect of a single dose of tadalafil in uncontrolled hypertensive subjects. An additional mortality and morbidity benefit may be brought about by the chronic use of tadalafil in subjects with both ED and uncontrolled hypertension and, more specifically, in diabetic subjects who are at increased cardiovascular risk [28], more likely to suffer severe ED [29] and require more aggressive blood pressure-lowering therapy than the general hypertensive population [13, 30].
Acknowledgments
A presentation of this work has been made at the British Hypertension Society, September 2003, Cambridge. This study was supported financially by Lilly ICOS LLC.
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Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society
How Does Cialis Work?
Is it safe to take Cialis if you have high blood pressure?
What are the effects of Cialis on blood pressure?
Cialis may cause a slight decrease in blood pressure. Cialis’s effect on blood pressure is exaggerated if it is taken with a nitrate drug, but this is not a problem for most men.
| Is Cialis good for blood pressure? | Does cialis lower blood pressure? |
| Can Cialis cause high blood pressure? | Is Cialis good for high blood pressure? |
| Does Cialis affect blood pressure? |
Does Cialis help urine? Cialis is the first ED drug approved to treat benign prostatic hyperplasia (BPH), commonly known as enlarged prostate. Symptoms include difficulty starting to urinate, a weak urine stream, sudden urge to urinate, and frequent urination at night.
What are the effects of Cialis on blood flow?
Cialis contains the active drug ingredient tadalafil, which belongs to a group of medications called phosphodiesterase 5 (PDE5) inhibitors. For erectile dysfunction, Cialis relaxes the blood vessels leading to the penis so that more blood can flow into it.
Is Cialis generic now? You’re going to love what we have in store for you! Tadalafil, also known as Generic Cialis, is now available at pharmacies. This is the second erectile dysfunction drug to go generic in the past year.
What is the relationship between Cialis and nitric oxide?
Nitric oxide can improve your erection quality, if you’re a guy. In fact, the two most popular erectile dysfunction medications, Viagra and Cialis, work by stimulating nitric oxide pathways in the penis. This relaxes blood vessel muscles so more blood can flow through. [1]
Can I take 2 5mg Cialis instead 10mg? If this dosage does not work for the patient, the doctor may prescribe taking 10 mg of Cialis simultaneously. The dose will be increased to 10 mg. If the 10-mg dose of Cialis is not effective, your doctor may increase the dosage to 20 mg. The maximum recommended dose of Cialis is one pill per day.
What is the effect of Cialis on blood pressure?
What is the effect of caffeine on blood pressure? Cialis may cause a slight drop in blood pressure. The effect of Cialis on blood pressure is exaggerated if it is taken with a nitrate drug, but this is not a problem for most men. Nitrates are a type of medication that doctors prescribe for angina.
Is it safe to take out of date Cialis? Even though a drug’s expiration date has passed, it is often still safe to take. There are very few people who would have Cialis stocks several years old. You can safely use a tablet that is a few months expired.
What is the average decrease in blood pressure when taking Cialis?
On average, the Cialis group’s blood pressure decreased by 1.6/0.8 mm Hg more than the placebo group’s. If you’re taking Cialis along with other medications that can also lower blood pressure, a decrease in blood pressure may be more likely. Dizziness can be a symptom of low blood pressure.
Does Cialis cause blood clots? The popular impotence drug Viagra may have the opposite effect of what it is meant to do. The drug affects blood-clotting cells, known as platelets, by making them clump together and form clots. 20 issue of the Journal of Experimental Medicine The Jan. 20 issue of the Journal of Experimental Medicine features a study.
What is the average blood pressure reduction for cialis?
The results are in. Overall, tadalafil reduced mean ambulatory blood pressure monitor systolic and diastolic blood pressure by 4.8 mmHg and 2.9 mmHg respectively, compared with placebo. This reduction was significant, with a 95% confidence interval of 3.7 to 5.9 for systolic blood pressure, and a 95% confidence interval of 1.9 to 3.6 for diastolic blood pressure. [2]
Is it safe to take Cialis if you have high blood pressure?
You shouldn’t take sildenafil (Revatio, Viagra), tadalafil (Adcirca, Cialis), or vardenafil (Levitra, Staxyn) if you’re also taking ritonavir (Norvir). If you take any of these drugs with certain alpha blockers such as alfuzosin (Uroxatral), doxazosin (Cardura), terazosin (Hytrin), tamsulosin (Flomax), or prazosin (Minipress), your blood pressure could suddenly drop. [3]
Why would Cialis become less effective?
Offending causes of prostate cancer treatment side effects include surgery, radiation therapy, and low testosterone levels. The main reason the medications don’t work is because there is not enough blood flow to the penis, regardless of the cause. [4]
What are the benefits of Cialis for depression?
A study done in Canada shows that Viagra not only improves symptoms of minor depression in men, but also helps with impotence. Smith is fifty years old Dr. Smith is 50 years old. [5]
What are the effects of Cialis on erectile dysfunction?
Erectile dysfunction can often be reversed. A study published in the Journal of Sexual Medicine found that 29 percent of people went into remission after 5 years. It’s important to remember that even though erectile dysfunction can’t be cured, the right treatment can minimize or eliminate symptoms. [6]
Is it possible to develop a tolerance to Cialis?
Tolerance to the therapeutic effect of tadalafil does not occur during 6 months of treatment. This was shown in a randomized, double-blind, placebo-controlled study in men with erectile dysfunction. [7]
Does cialis work for everyone?
How effective is Cialis? Clinical studies have shown that Cialis and the other drugs in the same class result in significant improvement in erectile function when compared to placebo. Cialis is a safe and effective drug, but it may not work for everyone and it is not appropriate for all people. [8]
What if cialis is ineffective?
Some drugs such as Cialis are most effective 2-3 hours after being taken as recommended by doctors. Giving up too soon is not an option. It is impossible to tell how your body is going to respond to a drug – any drug – so don’t be discouraged if your ED drug doesn’t work the first time. Try it a few times, then increase the dosage if necessary.
