Drospirenone

Drospirenone is a synthetic progestin that is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity. Its molecular weight is 366.5 and its molecular formula is C₂₄H₃₀O₃.

Pharmacokinetics:

Drospirenone, a spironolactone analogue, has a unique pharmacologic profile that is similar to that of natural progesterone.

Absorption:

Drospirenone (DRSP) is taken orally with about 76% bioavailability.

Distribution:

The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4 - 5 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels).

Metabolism:

The drug is metabolized mainly in liver. The two main metabolites of DRSP found in human plasma are identified to be the acid form of DRSP generated by opening of the lactone ring and the 4, 5-dihydrodrospirenone-3-sulfate. These metabolites are shown not to be pharmacologically active. In in-vitro studies with human liver microsomes, DRSP is metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4). The half life of the drug is 30 hours.

Excretion:

DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP is nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP is extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites are observed in urine and feces. About 38-47% of the metabolites in urine are glucuronide and sulfate conjugates. In feces, about 17-20% of the metabolites are excreted as glucuronides and sulfates.

 Uses:

1) Contraception

The compound is part of certain newer oral contraceptive formulations:

1)     One preparation contains 3 mg drospirenone and 30 mcg ethinyl estradiol per tablet. It is indicated as an oral contraceptive.

2)     Other contains 3 mg drospirenone and 20 mcg ethinylestradiol per tablet and is given for 24/4 days with the same indications.

Oral contraceptives with drospirenone reportedly produce fewer side effects. Emphasis has been placed on less weight gain with a drospirenone COC. Weight gain is a significant concern for young women taking oral contraceptives. Studies have reported no significant weight gain even after 12 months of use. In fact, the investigators have noted some weight loss during the first 6 cycles with drospirenone/EE.
As a component of oral contraceptives and of HRT regimens, drospirenone may offer unique advantages. Its antimineralocorticoid effects may prevent estrogen-related bloating and weight gain secondary to water retention. (i.e., 3 mg drospirenone is comparable to 25 mg of spironolactone). It may decrease blood pressure. And its antiandrogenic effects have the potential to reduce the severity of acne, seborrhea, and related skin conditions. Drospirenone, which of the available progestins most closely resembles progesterone clinically, has data that suggest that it may be associated with improvements in quality of life. In its U.S. clinical trials, a drospirenone product produced a Pearl Index of 0.407. It was associated with a low breakthrough bleeding rate of 1%, and spotting of 9.3%. Amenorrhea occurred in only 3.2% of cycles.

2) Premenstrual dysphoric disorder (PMDD)

A new approach to treating PMDD has been developed, using a low-dose OC that contains drospirenone 3 mg plus EE 20 mcg administered for  24 days in a 28-day cycle, i.e., a 24/4 regimen (drospirenone /20EE-24/4). The efficacy of this OC has been assessed in randomized, double-blind, placebo-controlled trials in women with PMDD.

This OC has been shown to be effective in reducing mood, behavioral, and physical symptoms in women with PMDD, who also are seeking contraception, and it is comparable to sertraline in treatment outcomes. Recently, the US Food and Drug Administration approved the use of a COC containing drospirenone for treating PMDD (FDA-2006). However, the product label notes that effectiveness after three cycles is unknown.

 

3) Acne Vulgaris:

The combination is also indicated for the treatment of moderate acne vulgaris in women at least 14 years of age, who have no known contraindications to oral contraceptive therapy and have achieved menarche. However, this combination should be used for the treatment of acne only if the patient desires an oral contraceptive.

4) Menopause:

In addition to its role in a new oral contraceptive, drospirenone in combination with estradiol (0.5 mg Drospirenone and 1 mg estradiol) may provide a safer and more beneficial HRT.

Drospirenone (1 mg, 2 mg, or 3 mg) with 1 mg estradiol has also been used as an effective and safe treatment for moderate to severe menopausal vasomotor symptoms. It reduces hot flushes. Women treated with drospirenone/estradiol also experienced a greater improvement in other menopausal symptoms – including sweating episodes, sleep problems, vaginal dryness, and nocturia – than women given placebo. It also leads to relief of the symptoms of moderate to severe vulvar and vaginal atrophy associated with menopause

Studies with this HRT have shown favorable effects on lipids and on blood pressure. Estradiol on its own lowers total cholesterol by lowering LDL, but raises triglycerides and has a positive, but slight, effect on HDL. In combination with drospirenone, there is a much more significant (17-18%) reduction in total cholesterol, not only due to a more profound effect on LDL cholesterol, but also a reduction in triglycerides.
The drospirenone/EE HRT regimen also appears to lower blood pressure in women, an effect that “may well be due to its antimineralocorticoid effect.” The trend with this combination shows a reduction of roughly 9-13% in systolic blood pressure, and a small trend toward reduction in diastolic blood pressure as well. Drospirenone/ EE has all the features of a good HRT with inhibition of hot flushes, inhibition of hyperplasia, amenorrhea, a good lipid profile, and positive effects on blood pressure. And, it has shown a beneficial effect at the spine and hip compared with placebo.

Adverse drug effects:

The most frequent adverse events reported with the use of  Drospirenone-EE combination in the contraception clinical trials, which may or not be drug related, included headache, breast pain, vaginal moniliasis, leucorrhea, diarrhea, nausea, vomiting, vaginitis, abdominal pain, dysmenorrhea, accidental injury, cystitis, tooth disorder ,emotional liability, migraine, suspicious Papanicolaou smear, dyspepsia, skin disorder, inter-menstrual bleeding, decreased libido, weight gain, pain, depression, increased cough, dizziness, menstrual disorder, pain in extremity, pelvic pain, and asthenia.

Drospirenone- EE combination should not be used in patients with conditions that predispose to hyperkalemia (i.e. renal insufficiency, hepatic dysfunction and adrenal insufficiency). Women receiving daily, long-term treatment for chronic conditions or diseases with medications that may increase serum potassium (ACE inhibitors, Angiotensin II receptor antagonists, potassium sparing diuretics, potassium supplementation, heparin, aldosterone antagonists and NSAIDS) should get the serum potassium levels checked in the first cycle of treatment.