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避孕藥V.s用自身當避孕藥的蚵信徒之認識

獄之天者 | 2022-01-15 01:06:39 | 巴幣 0 | 人氣 152

病因學Etiology

◆去年6月時雙北廢物搞得疫情爆炸,對於那時北農爆發疫情,林靜儀也在臉書指出,台北市長柯文哲表示要替北農4,000名員工打疫苗防堵疫情,但「即使立刻打了疫苗,一樣需要隔離14天啊」!林靜儀更引用生科網友的說詞表示:「你當疫苗是事後避孕藥,事先沒戴罩,打了就有效?」強調根據英國研究顯示,遵守防疫規定能避免染疫的機率比打疫苗還高,呼籲:「重點是匡列隔離! 台北市衛生局疫調不實會害慘全台灣!」
這就是當時的慘況,偌大一個市場能匡列成這樣,無能至極!
現在證實那些行走避孕器的確只是窩在網路上互相舔剛的可憐蟲,挺誰誰倒!不管公投立委補選罷免,全都被自己創造的網路論壇沉默螺旋給迷惑了.於是我來介紹避孕的方式,讓避孕器粉們了解自己的機制與副作用 ㄏㄏ

首先先認識雌激素/FSH,LH/黃體素的綿密交織大網!
雌激素

◆Estrogen-mimetic compounds (flavonoids 類黃酮) are found in many plants, including saw palmetto 鉅棕櫚, and soybeans 黃豆 and other foods
◆Studies have shown that a diet rich in these plant products may produce slight estrogenic effects
◆Additionally, some compounds used in the manufacture of plastics 塑膠 (bisphenols, alkylphenols, phthalate phenols) have been found to be estrogenic都有雌激素作用(Ex;Cellulose acetate phthalate作為高分子膜衣)
◆It has been proposed that these agents are associated with an increased breast cancer 乳癌 incidence in both women and men in the industrialized world 塑膠製品與乳癌病因學有正相關

雌二醇Pharmacokinetics藥物動力學

◆When released into the circulation, estradiol binds strongly to an a2 globulin (sex hormone-binding globulin; SHBG) and with lower affinity to albumin雌激素與SHBG結合且與血清白蛋白親和力較低下
◆Estradiol is converted by the liver and other tissues to estrone and estriol and their 2-hydroxylated derivatives and conjugated metabolites and excreted in the bile 在肝臟及其他組織代謝後,由膽汁排泄
◆However, the conjugates may be hydrolyzed in the intestine to active, reabsorbable compounds 在小腸被水解後,又重新被吸收  enterohepatic circulation 腸肝再循環>導致Filp flop生物藥劑學現象
◆Because enterohepatic circulation ensures that orally administered estrogens will have a high ratio of hepatic to peripheral effects 由於口服後進行腸肝再循環,雌二醇在肝臟比末梢有更高的比率 be responsible for some undesirable actions such as synthesis of increased clotting factors and plasma renin substrate 與其副作用有關,例如凝血因子合成增加
◆The hepatic effects of estrogen can be minimized by routes that avoid first-pass liver exposure, ie, vaginal, transdermal, or by injection 可藉由更改劑型以改善被肝臟首渡效應代謝之問題(如陰道栓劑/穿皮貼劑/注射劑型)
◆Two genes code for two estrogen receptor isoforms 雌二醇接受器有兩種, which are members of the superfamily of steroid, retinoic acid, and thyroid receptors 與固醇類、維他命A酸及甲狀腺素接受器為同一家族
◆The estrogen receptors are found predominantly in the nucleus bound to heat shock proteins (predominantly Hsp90) that stabilize them 有一種雌二醇接受器位於細胞核,平時與Hsp90結合,使其穩定
◆Estrogen-receptor homodimers bind to estrogen response elements (EREs) on various genes 雌二醇與其接受器結合的二位體複合物會與其調控基因上的ERE結合  regulate their transcription 調控基因的轉錄作用 >proteins synthesized 合成蛋白質 genomic effects
◆Rapid estrogen-induced effects such as granulosa cell Ca2+ uptake and increased uterine blood flow do not require gene activation 雌二醇也會快速的使顆粒細胞回收鈣離子及增加子宮的血流 appear to be mediated by membrane receptors that differ from the intracellular receptor 這些作用與細胞核內的接受器無關,可能是藉由細胞膜上的雌二醇接受器

◆Most estrone and estriol are formed in the liver from estradiol or in peripheral tissues from androstenedione(ASD) and other androgens 大部分雌激素在肝臟生成或於周邊組織中經由雄二酮(ASD)為前驅物合成
◆During the first part of the menstrual cycle (follicular phase 濾泡期)  estrogens are produced in the ovarian follicle 卵巢濾泡
◆After ovulation 排卵後進入黃體期  the estrogens as well as progesterone are synthesized by the corpus luteum 黃體
◆During pregnancy 懷孕 a large amount of estrogen is synthesized by the fetoplacental unit 胎兒胎盤單位released into the maternal 母體的 circulation  excreted into the urine  
◆In normal women, estradiol is produced at a rate that varies during the menstrual cycle, resulting in plasma levels as low as 50 pg/mL 在女性體內,由月經週期交互控制雌激素濃度
◆When estrogen production is properly coordinated with the production of progesterone during the normal human menstrual cycle, regular periodic bleeding and shedding of the endometrial lining occur 雌二醇與黃體酮(助孕酮)協同性的調節月經週期子宮內膜的增生與剝落
◆Continuous exposure to estrogens for prolonged periods leads to hyperplasia of the endometrium that is usually associated with abnormal bleeding patterns 長時間持續的使用雌性素會導致子宮內膜過度增生,而有不正常出血的情況
◆雌性素增加血液中 凝血因子的濃度、減少抗凝血因子的濃度及血小板凝集,故增加血液凝固性,也會誘導助孕酮接受器的合成、影響性慾、產生水腫,使血液容積減少,造成代償性的鈉水滯留、調節交感神經調控平滑肌的功能
◆Black Box Warning: Estrogens increase the risk of Bendometrial cancer子宮內膜癌; monitor for abnormal vaginal bleeding

雌激素臨床用途

◆Primary hypogonadism 性腺功能低下—estrogen-deficient patients
Treatment attempts to mimic the physiology of puberty 模仿青春期作用,重返年少時/
It is initiated with small doses of estrogen (0.3 mg conjugated estrogens or 5-10 mcg ethinyl estradiol) on days 1-21 each month and is slowly increased to adult doses and then maintained until the age of menopause
A progestin is added after the first uterine bleeding
◆Postmenopausal hormonal therapy 更年期的賀爾蒙補充療法
Postmenopausal women  ↓estrogens
(A) acceleration of bone loss osteoporosis 骨質舒鬆;
(B) lipid changes  acceleration of cardiovascular disease 心血管疾病
If the main indication for therapy is hot flushes 熱潮紅 and sleep disturbances 睡眠干擾 or prevention of osteoporosis , therapy with the lowest dose (0.3-1.25 mg/d of conjugated estrogen or 0.01-0.02 mg/d of ethinyl estradiol) of estrogen required for symptomatic relief 症狀解除 is recommended  
◆Other uses—dysmenorrhea 經痛; hirsutism 多毛症; amenorrhea 無月經症; endometrial hyperplasia 子宮內膜增生  
黃體素Physiologic Effects  


◆Progesterone 助孕酮 is the most important progestin 黃體素 in humans 人類中最重要之性激素生理因子
◆It has important hormonal effects & serves as a precursor 前驅物 to the estrogens 雌性素, androgens 雄性素, and adrenocortical steroids 腎上腺皮質固醇 ,經由膽固醇在C-20使用Cytochrome P-450切斷側鏈而生成Pregenolone後,再把OH基用Hydroxylase水解而得本品

◆It is synthesized in the ovary 在卵巢 (corpus luteum 黃體), testis  睪丸, and adrenal 腎上腺再把PregenoloneC3'上的OH水解(Hyrdoxylation)成內脂O形成
◆Large amounts are also synthesized and released by the placenta  胎盤 during pregnancy懷孕時大量合成(母親體內之Cholesterol於胎兒之腎上腺轉變成dehydro-epinodiosterone sulfate,再由胎兒肝羥化>Sulfatase/Aromatase成Estriol
◆Promote the breast development 促進乳房的發育; causes the maturation and secretory changes in the endometrium造成子宮內膜的成熟與分泌性腺體的變化
黃體素Pharmacokinetics藥物動力學

◆口服極易被分解,可在C-17上加入Acetyl基阻止C20-one之Reduction
◆Progesterone is rapidly absorbed following administration by any route  its half-life in the plasma is approximately 5 minutes 極易被吸收半衰期僅5分鐘
◆It is almost completely metabolized in one passage through the liver (first pass effect), and for that reason it is quite ineffective when the usual formulation is administered orally  首
渡代謝幾乎100%因此無修飾藥品不可用口服劑型
{首渡代謝:口服藥物在消化道被吸收後,先進入肝門靜脈;部分藥物在通過腸黏膜與肝臟時,可能被代謝而失去活性,使得進入體循環之藥量減少、藥效下降}
[肝門靜脈血液主要源自腸繫膜,當藥物進入體循環前,會先進入肝臟代謝]
◆In the liver, progesterone is metabolized to pregnanediol and conjugated with glucuronic acid  excreted into the urine as pregnanediol glucuronide  as an index of progesterone secretion  肝臟會與葡萄醣醛酸相接合而以代謝物形式被排入尿中
黃體素臨床應用


◆A new group of third-generation 第三代 synthetic progestins has been introduced, principally as components of oral contraceptives 第三代合成之黃體素作為口服避孕藥
◆These "19-nor, 13-ethyl" steroid compounds include desogestrel, gestodene, and norgestimate>they are claimed to have lower androgenic activity than older synthetic progestins雄性素的活性較舊型的黃體素來得低
◆The remaining compounds (“19-nortestosterone” third-generation agents) produce a decidual change in the endometrial stroma  are more effective gonadotropin inhibitors, and may have minimal estrogenic and androgenic or anabolic activity   “impeded androgens”  第三代的化合物具有讓子宮內膜剝落的作用,是最有效的性腺促素抑制劑,同時雌性素及雄性素(同化作用)的作用最弱,又稱為妨礙性的雄性素
◆When used alone in large doses parenterally (eg, medroxyprogesterone acetate, 150 mg intramuscularly every 90 days), prolonged anovulation and amenorrhea result 當肌肉注射大劑量的黃體素時,會延長無排卵作用的時間即造成無月經症
◆This therapy has been employed in the treatment of dysmenorrhea, endometriosis, bleeding disorders and relieve hot flushes in some menopausal women 因此用欲治療經痛、子宮內膜異位、出血的疾病及緩解停經後的熱潮紅 when estrogens are contraindicated 當不能使用雌性素時, and for contraception 可用本品避孕
◆The major problem with this regimen is the prolonged time required in some patients for ovulatory function to return after cessation of therapy  此種療法最大的問題是當停止治療後,排卵的功能需要一段時間才能恢復


• 避孕藥物/非藥物介入措施主要分為5種

1.Combination contraception
2.Progestin-only
3.Estrogens plus progestins
4.Anti-progestin
5.Synthetic Progestins

雙重藥物避孕法Combination

(1,3)
◆Studies of progestational compounds alone and with combination oral contraceptives indicate that the progestin in these agents may increase blood pressure in some patients 單獨使用黃體素或合併雌性素的口服避孕藥都有增加血壓的機率,表示黃體素會增加血壓
◆Two recent studies suggest that combined progestin plus estrogen replacement therapy in postmenopausal women may increase breast cancer risk significantly compared with the risk in women taking estrogen alone 合併療法引發乳癌的機會較單獨使用雌性素來得高
單獨藥物避孕法Progestin-only

(2,4)
◆The combination agents are further divided into monophasic forms (constant dosage 固定劑量 of both components during the cycle) and biphasic or triphasic forms (dosage of one or both components is changed 劑量改變 once or twice during the cycle)
◆Few implantable contraceptive preparations 植入型的避孕製劑 are available at present in the USA norgestrel, also used in some oral contraceptives, is available in the subcutaneous 皮下 implant form
◆An implant containing etonogestrel, a newer progestin, is available overseas and will be marketed in the USA as Implanon  
◆Several hormonal contraceptives 賀爾蒙性質的避孕 are available as vaginal rings 陰道環 or intrauterine devices 子宮內避孕器 intramuscular injection of large doses of medroxyprogesterone also provides contraception of long duration 肌肉注射大劑量的黃體素
◆Mechanism:The combinations of estrogens and progestins exert their contraceptive effect largely through selective inhibition of pituitary function that results in inhibition of ovulation  抑制腦下腺分泌性腺促素而抑制排卵
◆The combination agents also produces a change in the cervical mucus & uterine endometrium, and in motility and secretion in the uterine tubes ↓the likelihood of conception and implantation合併使用也會造成子宮頸黏液及子宮內膜的改變,在輸卵管的移動性及分泌物也有所影響,因此降低受孕及著床的可能性
◆The continuous use of progestins alone does not always inhibit ovulation the other factors mentioned, therefore, play a major role in the prevention of pregnancy when these agents are used  單獨使用黃體素有時不能抑制排卵,但透過子宮頸、子宮及輸卵管的作用,也可達到避孕的作用
拮抗黃體素-事後避孕藥AntiProgestin

(4)
◆在性交之後,單獨使用大劑量的雌性素或合併黃體素也可達到預防受孕的效果  when treatment is begun within 72 hours, it is effective 99% of the time 通常在事後三天內使用,有99%的有效性
Mifepristone (RU 486), an antagonist at progesterone & glucocorticoid receptors, has been shown to have a luteolytic effect and is effective as a post-coital contraceptive when combined with a prostaglandin (misoprostol) it is also an effective abortifacient RU486拮抗黃體素及糖皮質素接受器,具有溶解黃體的作用,可有效的事後避孕,當合併前列腺素製劑(misoprostol)時,可有效流產
◆Mifepristone (RU 486) is a 19-norsteroid that binds strongly to the progesterone & glucocorticoid receptor  inhibit the activity of progesterone  as a contraceptive 避孕藥
A single dose of 600 mg is an effective postcoital contraceptive 事後避孕, through it may result in a delay in the following cycle  
藥物動力學(ADME)
Absorption吸收
Tmax, oral: 1 to 4 hours >>
林醫師說的事後避孕藥只需1~4小時即可超越MEC達到療效濃度產生避孕作用,智商157台大醫學系不會連這點基礎藥理都不知道吧??? 蚵憐!
Bioavailability, oral: 69%
Effects of food: increased plasma concentrations
Distribution分布
Protein binding, alpha-1-glycoprotein (AAG) and albumin: 99.2%
Vd: 1.5 L/kg
Metabolism代謝
Liver: extensive
Excretion排除
Renal: less than 0.5% unchanged
Fecal: approximately 90% changed
Elimination Half Life
20 hours to 85 hours
避孕藥副作用/意外的保護作用


◆The incidence of serious known toxicities associated with the use of these drug is low  nausea 噁心, mastalgia 乳房痛, breakthrough bleeding 突破性出血, and edema 水腫 are related to the amount of estrogen in the preparation
◆Hirsutism 多毛症 may also be aggravated by the “19-nortestosterone” derivatives, and vaginal infections 陰道感染 are more common and more difficult to treat in patients who are receiving oral contraceptives & amenorrhea 無月經症 occurs in some patients  因此使用第三代黃體素較無雄性化之副作用

        雄性素                    19-Nor雄性素衍生物品項                  雌性素樣作用雄性素樣作用
◆The risk of venous thrombosis 靜脈栓塞 or pulmonary embolism 肺栓塞 is increased among women with predisposing conditions such as stasis 鬱滯, altered clotting factors 凝血因子改變 such as antithrombin III, increased levels of homocysteine, or injury
◆The incidence of venous thromboembolism appears to be related to the estrogen but not the progestin content of oral contraceptives  and is not related to age, parity, mild obesity, or cigarette smoking靜脈血栓栓塞發生率增加與口服避孕藥中的雌性素有關,與黃體素、年齡、經產狀態、輕微肥胖、或抽菸都無關
◆The use of oral contraceptive is associated with a slightly higher risk of myocardial infarction in women who are obese, have a history of preeclampsia or hypertension, or have hyperlipoproteinemia or diabetes  在肥胖、有子癲癇前症或高血壓、高脂蛋白血症、或糖尿病的人,服用口服避孕藥發生心肌梗塞的機率會稍微增加
◆It is now clear that these compounds reduce the risk of endometrial  and ovarian cancer 子宮內膜及卵巢癌 the lifetime risk of breast cancer 乳癌 in the population as a whole does not seem to be affected  by oral contraceptive use 口服避孕藥減少子宮內膜及卵巢癌發生的機率
◆Third-generation progestins第三代合成的黃體素:
1.Desogestrel 2.Gestodene 3.Norgestimate
第三代的化合物具有讓子宮內膜剝落的作用,是最有效的性腺促素抑制劑,口服避孕藥
同時雌性素及雄性素(同化作用)的作用最弱(minimal estrogenic and androgenic or anabolic activity),
又稱為妨礙性的雄性素“impeded androgens”)
I.結構:19-nor, 13-ethyl  去除了C3的酮基可以去除男性賀爾蒙作用,並維持黃體素作用。
II.代謝:Pro-drug,肝臟代謝成活性3-ketodesogestrel
III.受體親和力:高progesterone低androgenic
IV.副作用:venous thromboembolism深層靜脈血栓
Desogestrel , Norgestimate合併ethinyl estradiol作為口服避孕藥(Oral Contraception)


結論


柯文哲跟蚵信徒還是趕緊滾回去地下室/離開電腦桌前帶風向吧!連RU486的藥物動力學藥理機制都不了解就在嘲笑別人專業見解,果然是活生生行走避孕器!
現在又改口要推三小疫苗護照,每天ABC搞平行時空的金阿北打這個銀時空阿北的臉已經層出不窮,拜託別再鬧了廢物走狗!


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