Oral contraceptives Seminar

Oral contraceptives :

Oral contraceptives Submitted to Mr. Kumaraswamy M Asst. Professor By Prasanna Dahal Pharm D (P.B) Department of Clinical Pharmacy AH & RC, SACCP

History:

History 1939 Russell marker Progesterone (Plant steroid , sapogenins ) synthetic progesterone , diosgenin ( mexican yam) 1956 “ evonoid 10” trail (9.85 mg norethynodrel and 150 µg mestranol ) nausea , vomiting , breakthrough bleeding 1957- FDA approval menstrual disorder 1960 - FDA approval for contraception Extensive use by over 1 milliion womens over few years 1960-1970 - Epidimological study Many problems of venous thrombosis, MI/ stroke, blood clot ,etc concerned with contraceptives use reported 1970- Till date Many change in formulation Decrease in doses , reduce side effect More than 100 million women are currently using contraceptives En wikepedia

Menstrual cycle, hormonal and other Physiological changes:

Menstrual cycle, hormonal and other Physiological changes

Hormones involved for contraception:

Hormones involved for contraception Estrogen Mainly ethinyl estradiol and mestranol . Mestranol is a “ prodrug ” that is converted in vivo to ethinyl estradiol Progestins Various types C21 Progestin, 19-nor testosterone, spironolatone

The gonane progestins appear to be more potent than the estrane derivatives :

The gonane progestins appear to be more potent than the estrane derivatives

Inhibition of Ovulation:

Inhibition of Ovulation Estrogen Inhibits ovulation by suppressing FSH and LH Alters endometrium secretions Progestin Suppresses LH secretion Thickens cervical mucus preventing/hindering sperm transport Thins endometrium preventing ovum implantation Interferes with secretory /peristaltic function inside fallopian tubes

Types of Oral Contraceptives Pills:

Types of Oral Contraceptives Pills Combined Oral Contraceptives Phased regimen Mini Pills (Progesterone Only Pills) Post- cointal (Emergency Contraceptives) Pills

Oral Contraceptives Generation:

Oral Contraceptives Generation Progestin Derivatives 1st Generation Norethindrone Norethynodrel -derivative of Norethindrone 2nd Generation Norgesterl Levonorgestrel 3rd Generation Desogestrel Norgestimate Gestodene Estrogen Derivatives Mestranol Ethinyl Estradiol (Diana 2003)

Cont…:

Cont… First generation oral contraceptives ; products containing 50ug or more of ethinyl estradiol Second generation oral contraceptives ; products containing levonorgestrel , norgestimate and other members of northindrone family and 30 or 35ug ethinyl estradiol Third generation oral contraceptives ; products containing desogestrel or gestodene with 20 or 30ug ethinyl estradiol

Present COCs :

Present COCs low dose than 1960s 2-5 times decrease dose of estrogen i.e 50-150 µg vs 20-40µg 5-10 time decrease in Progestins i.e 10mg vs. 0.15-1.5mg Decrease in adverse effects with dose ( Thorogood 1993)

Combine Oral Contraceptives (COCs):

Combine Oral Contraceptives (COCs) Contains estrogen ( ethinylestradiol ) dose 20-50µg Progestin ( levonorgestrel , desogestrel ) dose 0.15- 1.5mg Both synergise to inhibit ovulation, Progestin ensures prompt bleeding at end of cycle and blocks the risks of endometrium carcimona due to estrogen 21 days schdule starting from 5 th day of menstruation and gap of 7 days Most Popular and efficacious methods

Phased Regimens:

Phased Regimens Biphasic and Triphasic Estrogen step down and Progestin Step up type regimens Estrogen kept constant or slightly changed while Progestin is high in 2 nd and 3 rd phase. uses for better menstrual cycle control and increase efficacy Recommended for women > 35 yrs or other risk factors present like massive menstrual bleeding

Minipill (progesterone only Pill):

Minipill (progesterone only Pill) eliminates the long term effect of estrogen 28 days schedule without gap less efficacious than COCs about 3-5% Risk of ectopic pregnancies among users not so common Recommended for Smokers, breast feeding , older women's and other health problems

Postcoital (emergency) contraception:

Postcoital (emergency) contraception 3 regimen usually available levonorgestrel 0.5mg + ethinylestradiol 0.1 mg ( Yuzpe method) Levonorgestrel along 0.75 mg Should be taken as early as possible within 72 hours of unprotected intercourse and repeated after 12 hrs Mifepristone 600mg single dose within 72 hrs of intercourse High failure rate and side effects

Adverse Effects:

Adverse Effects Common nausea, vomiting, breast tenderness,breakthrough bleeding (progestin) , migrane precipitation etc. frequent in 1-3 cycles and gradually disappear Long term use effect weight gain, chloasma , carbohydrate intolerence , mood swing increase body hair Newer contraceptives have less effects

Risk Factors / Complication:

Risk Factors / Complication Venous Thromboembolism Hypertension and CV disorders Myocardial Infraction/Stroke Migrane Breast cancer and cervical cancer Fertility Others

Venous Thromboembolism:

Venous Thromboembolism 3-4 fold increase in risk in users of new contraceptives (low dose estrogen) Older contraceptives more significant risk 2-11 fold >50µg estrogen use at high risk 3 rd generation containing desogestrel or gestodene have more risk than 2 nd generation levonorgestrel by 1.5-1.8 Presence of Protein C,S or factor V leiden ( thrombophilia ) is at 6-40 fold risk ( Rachel 2002; Thorogood 1993; Diana 2003)

Hypertension and CV Disorders:

Hypertension and CV Disorders COCs cause rise in diastolic BP- 2mm Hg , systolic – 5mmHg elevate risk of cerebral haemorrhage , cerebral infraction, coronary heart disease by 1.7, 1.5 and 1.2 fold. ( Rachel 2002; Thorogood 1993)

Myocardial infraction/Stroke:

Myocardial infraction/Stroke 2- 4 times more prone than non users more than 7 times in smokers and above 35 years High dose estrogen >50µg at high risk POCs do not increase the risks COCs – increase coagulability by increasing levels of factors VIIc and fibrinogen (mainly estrogen effects) Increased of VT/MI/ stroke Risks with COCs: Smoking Age >30 (2-3 fold) Hyptertension (10 fold) Estrogen Level (>30µg) Hypercholesterolemia Obesity Migraines if over 35y ( Rachel 2002; Thorogood 1993; Diana 2003)

Migrane :

Migrane May be related to estrogen effects ( vasodilation ) Progestin generation does not influence migrane Migrane considered linked to stroke (conflicting) High prevalence in women> 35 yrs (Diana 2003)

Breast cancer and cervical cancer :

Breast cancer and cervical cancer Prolong use at younger age may increase 2-4 fold risk. (conflicting results) women strong family history of breast cancer or BRCA1 ,BRCA2 at high risk Increased risk if used >35y due to increase risk of breast cancer with age Estrogen users > 35µg high risk small increase in risk of cervical cancer for those having HPV positive DNA ( Rachel 2002; Thorogood 1993; Diana 2003)

Fertility:

Fertility COCs considered to delay fertility for 1-12 months Newer low dose contraceptives less effect Never cause Permanent infertility. (Huggins 1990, lynn 1999)

Others:

Others COCs slightly tends to rise small increase in LDL/ decrease in HDL Prolong exposure may leads to disturbed carbohydyate metabolism. Progesterone tends to increase glucose and insulin level Gall stones Combined OC use increases the secretion of cholic acid in bile, potentially leading to a higher incidence of gallstone formation ( Rachel 2002)

BENEFITS :

BENEFITS Ovarian and endometrial Cancer Anemia / Menstual disorders Pelvic Inflammatory Diseases Benign Breast cancer Acne/ hirustism others

Ovarian and Endometrial cancer:

Ovarian and Endometrial cancer benefits probably due to inhibition of ovulation and Progestin mediated suppresion of estrogen induce endometrium cancer 1.5-2 fold less risk for non users Protection increases with increase duration Nonusers 5 times more prone than users for 10 yrs. Effects remains for10-15 yrs later after discontinuation ( Rachel 2002; Thorogood 1993; Diana 2003)

Anemia and menstrual disorders:

Anemia and menstrual disorders controls and reductionof blood loss on menstrual flow upto 50%-60%. increase blood iron level COC regulate: Irregular cycles Dysmenorrhea Menorrhagia Amenorrhea

Pelvic inflammatory disorders:

Pelvic inflammatory disorders Risk of PID is half than that of non users Mechanism COCs increasing the thickness of cervical mucus. Preventing bacteria from moving up the reproductive system Acne / hirustism Improvement due to Decreases bio-available testosterone Decreases o varian and adrenal androgen secretion ( Rachel 2002; Thorogood 1993; Diana 2003

Benign breast cancer:

Benign breast cancer Long Term uses causes Half likely to develop fibroadenoma & fibrocystic breast disease than nonusers Considered as Progesterone effect ( Rachel 2002)

Contraindication:

Contraindication < 6 weeks postpartum if breastfeeding Smoker over the age of 35 (≥ 15 cigarettes per day) Hypertension (systolic ≥ 160mm Hg or diastolic ≥ 100mm Hg) Current or past history of venous thromboembolism (VTE) Ischemic heart disease History of cerebrovascular accident Complicated valvular heart disease Migraine headache with focal neurological symptoms Breast cancer (current) Diabetes with retinopathy/nephropathy/neuropathy Severe cirrhosis Liver tumour (adenoma or hepatoma )

Interaction:

Interaction Enzyme Inducers Rifampin , carbamazepin , barbiturates etc GI flora Conversion of ethinylesrtadiol to active form Should take precautions while taking antibiotics Some common drugs Decreased effects of contraceptives: Ampicillin,Anticonvulsants,Griseofulvin.NNRTIs,PIs,Rifampicin , Phenytoin , Pioglitazone ,Sulfonamides Tetracyclines , Theophylline , paracetamol , tolbutamide , methyldopa etc.

Practical Consideration:

Practical Consideration Avoid conception within 2-3 cycle after discontinuation Posibility of rebound increase in fertility –multiple pregnancy Missed dose- 2 tablets next day and continua as usual More than 2 dose missed then discontinue –take in next cycle Accidential pregnancy during use should be terminated Risk of malformation and genital carcinoma in offspring

Cont….:

Cont…. Dose adjusment for obese For Breakthrough bleeding Swith to pill containing higher estrogen Selection of OCs More estrogenic preparation preferred for women with acne and hirustism Progestin preparation for women having excessive menstrual bleeding Newer Progestin ( desogestrel ) prefer for women who develop weight gain, acne raised LDL.

Patients councelling:

Patients councelling Instructions on how to take the combined OC Information on potential side-effects Non-contraceptive benefits of the combined OC Addressing common myths and misconceptions Discussing risks and warning signs, including when to seek medical care Discussing what to do if pills are missed Emphasizing dual protection (the combined OC with condom use to prevent STIs and HIV infection) Information about emergency contraception in the event of missed pills

Recent Advancement in Oral Contraceptives:

Recent Advancement in Oral Contraceptives Drospirenone (DRSP)- newest generation Progesterone 30 g ethinylestradiol (EE) and 3 mg DRSP ( Yasmin ®; Bayer AG, Leverkusen, Germany), which improved water retention symptoms and bleeding pattern. 20 g EE and 3 mg DRSP in a novel 24/4 regimen (Yaz; Bayer AG), improved symptoms of premenstrual dysphoric disorder. oestradiol valerate (E2V) and dienogest in a multiphasic regime ( Qlaira ®; Bayer AG), optimised to provide good efficacy and cycle control. -1 st preparation using natural estradiol . (Li 2010)

References:

References KD Tripathi The Essential of Medical Pharmacology 6 th edition Katzung BG Basic and Clinical Pharmacology 10 th edition Thorogood M , Villard-Mackintosh T Contraceptives risks and benefits , British Medical Bulletin (1993) fal 49. No 1. pp 124-139 Diana B. Petitti (2003) Combination Estrogen–Progestin Oral Contraceptives The new England Journal of Medicines . 349: 1143-50

Slide 38:

Rachel E.D (2002) Risk and Benefit of Oral Contraceptives Pill . Best Practice and Research clinical obstretics and Gynaecology : 16: pp- 133-154 Huggins GR, Cullins VE. 1990 Fertility after contraception or abortion Fertil Steril . 1990;54(4):559-73 . Lynn Borgatta 1999 The effect of oral contraceptives on conception . Journal Of Family Planning :59 :29s-33s Li H R , Anderson RA (2010) Recent Advances in Hormonal Contraception Med Reports2010, 2 :58 Am J Obstet Gynecol 180: S343-8.

Slide 39:

Questions?? Thank you !!!