CONTRACEPTIVE PHARMACOLOGY

Michael Katz, Pharm.D.

College of Pharmacy
CONTRACEPTIVE CHOICES
 ESTROGENS
• Steroidal and non-steroidal
▫ 17b-estradiol most potent
human natural estrogen
▫ Most estrogens used in therapy
are steroidal
 Conjugated equine estrogen in
HRT (equilin-predominant)
• Non-steroidal compounds
▫ Estrogenic and anti-estrogenic
▫ Plant and fungal derived
 Isoflavones, coumestans
▫ Environmental
 Polychlorinated bisphenyls,
insecticides, plasticizers
 Long-term effects on
humans, animals?
▫ OTC phytoestrogens
 Mexican yam, others
PHYSIOLOGIC/PHARMACOLOGIC
ACTIONS
• Developmental actions
▫ Sexual development, bone growth in girls
▫ Bone growth, counterbalancing of testosterone in boys
• Neuroendocrine control of the menstrual cycle
▫ Hypothalamic/pituitary/ovarian axis
• Reproductive tract effects
▫ Endometrial proliferation, myometrial contractility
▫ Fallopian tube proliferation, contractility
▫ Increase amount cervical mucus, decr viscosity
PHYSIOLOGIC/PHARMACOLOGIC
ACTIONS
• Metabolic effects
▫ Decreased osteoclast, increased osteoblast activity
▫ Bone growth, epiphyseal closure in both sexes
▫ Lipids
 Increase HDL, decrease LDL
▫ Biliary
 Increased bile acid saturation, decreased bile volume
▫ Sl decrease in blood glucose, insulin levels
▫ Increase synthesis of hormone-binding proteins
(cortisol, thyroxine, sex hormones)
PHYSIOLOGIC/PHARMACOLOGIC
ACTIONS
• Cardiovascular
▫ Increase clotting factor synthesis (II, VII, IX, X,
XII); decrease protein C and S, antithrombin
▫ Increased fibrinolysis
▫ Decrease plasma renin, ACE, endothelin-1,
expression of angiotensin II AT1 receptor
▫ Increased endothelial NO production, vasodilation
• CNS
CELLULAR MECHANISMS OF ACTION
• Estrogen receptors ER a, ER b
▫ Estrogen-dependent nuclear transcription factors
▫ Different tissue distributions (many cells express
both)
 ER a most in female reproductive tract, breast,
hypothalamus, vascular smooth muscle
 ER b most in prostate, ovaries, less in lung, brain,
bone, vasculature
▫ Transcriptional effects on a wide variety of genes
▫ ER polymorphism exists, but not clearly linked to
disease (breast CA, endometrial CA, osteoporosis,
CV disease)
CELLULAR MECHANISMS OF ACTION
• Passive diffusion through cell membrane, bunds to
nuclear ER
▫ Inactive ER monomer bound to heat shock proteins
• Estrogen binding to ER causes dissociation of heat
shock protein, dimerization
▫ Increases affinity, rate of binding to DNA
• ER dimer binds to estrogen response element of
target gene
• ER/DNA complex recruits cascade of co-activators,
other proteins to target genes
• Ultimate effect is altered transcription
ESTROGEN PHARMACOKINETICS
• Oral, injectable, transdermal, topical
• Oral estrogens undergo 1st pass metabolism
▫ Ethinyl estradiol more bioavailable
▫ Enterohepatic recirculation
• Circulating estradiol strongly bound to sex hormone-
binding globulin (SHBG)
▫ Ethinyl estradiol bound primarily to albumin
▫ Only free fraction physiologically active
• Estradiol metabolized in liver to active estrone, estriol
and inactive metabolites
▫ Mestranol prodrug for ethinyl estradiol
▫ Induction, inhibition of metabolism by other drugs,
environmental agents (tobacco smoke)
PROGESTINS
• All steroidal compounds
• 3 main chemical classes
• 19-nortestosterone derivatives
have androgenic activity
• Gonanes have more specific
affinity for progesterone
receptors
• Drosperinone is spironolactone
derivative
▫ Some mineralocorticoid
activity
PHYSIOLOGIC/PHARMACOLOGIC
ACTION
• Neuroendocrine control of menstrual cycle
▫ Luteal phase progesterone decreases frequency of
GnRH pulses
• Reproductive tract
▫ Production of secretory endometrium
 Sudden decrease of progesterone at end of cycle
initiates menstruation
▫ Decrease cervical mucus, increased viscosity
▫ Maintenance of pregnancy
▫ Breast gland proliferation
PHYSIOLOGIC/PHARMACOLOGIC
ACTION
• CNS
▫ Increased basal body temperature
▫ Increased minute ventilation
▫ ? CNS depressant effect
• Metabolic
▫ Increase basal insulin, no net effect on fasting BG
▫ May decrease HDL, increase LDL (19-nor)
▫ Decreases effect of aldosterone at renal tubule
CELLULAR MECHANISM OF ACTION;
PHARMACOKINETICS
• Single gene encodes 2 progesterone receptors,
PR-A (inhibitory) and PR-B (stimulatory)
• After binding of PG to PR, similar basic
sequence of events as ER
• Pharmacokinetics
▫ Oral, injectable, vaginal, device (IUD, implants)
▫ PG has extensive 1st pass metabolism
▫ PG, MPA bound to plasma albumin; 19-nor bound
to SHBG
▫ Liver metabolized
HORMONAL CONTRACEPTION
• Hormones
▫ Combination estrogen-progestin
▫ Progestin-only
• Route of administration
▫ Oral (“the pill”)
▫ Transdermal (patch)
▫ Injectable
▫ Devices
 Implants
 IUD—not discussed in this lecture
 Vaginal ring
• Emergency contraception
MECHANISMS OF CONTRACEPTIVE
ACTION
• Well-established
▫ Thickening of cervical mucus preventing sperm
entry to upper genital tract
▫ Suppression of ovulation by negative feedback to
HP axis
 Decreased frequency of GnRH pulses
 Decreased responsiveness to GnRH stimulation
 Suppression of LH and FSH production
 Inhibition of mid-cycle LH surge
 “Breakthrough” ovulation dose-dependent
 ~8% with low dose OCs
OC ADVANTAGES AND DISADVANTAGES
• Advantages
▫ Effectiveness
▫ Safety if proper patient selection
▫ Option throughout reproductive years
▫ Rapid reversibility
• Disadvantages
▫ Daily administration
▫ Expense and access
▫ Need for storage, ready access
▫ No STD protection
NON-CONTRACEPTIVE BENEFITS
• Ovarian cancer risk reduction
• Endometrial cancer risk reduction
• Improved regulation of menstruation
• Decreased menstrual blood loss, Fe deficiency
anemia
• Decreased dysmenorrhea
• Reduction in PMS/PMDD
• Decreased risk of benign breast disease
• Improvement of acne, hirsutism
CHOICES FOR INITIATION
• Quick start (same day start)
▫ Preferred method by most to assure adherence, persistence
▫ Take 1st pill on same day OC received
 R/O pregnancy, need for emergency contraception
▫ Use back-up method at least 7 days
▫ Next menses will follow completion of active pills in pack
• First day start
▫ 1ST pill on 1st day of next period (assuming normal period
▫ No back-up method needed
• Sunday start
▫ 1st pill on 1st Sunday of period (not Sunday after period is
over)
▫ Used to be preferred method; some patient instructions still
recommend
▫ Use back-up for at least 7 days if period started more than 5
days prior to pill start
PATTERNS OF PILL USE
• Monthly cycling 21/7
▫ 7 days placebo pills, allows for withdrawal
bleeding
▫ With low dose formulations, sl higher risk of
ovulation vs shortened pill-free interval
• Shortened pill-free interval
▫ 4-5 days placebo (e.g. Mircette, Yaz, Loestrin-24)
• Extended cycle use
▫ 91 day (84 active)—Seasonale, Seasonique
▫ 365 day--Lybrel
BICYCLES AND TRICYCLES
• Monophasic products have same hormone content
throughout cycle
• Multiphasic products developed to lower total
monthly progestin dose
▫ Increased progestin later in cycle, simulates normal
hormone pattern
▫ No evidence for overall better efficacy and safety vs
monophasic
 Useful for pts with progestin-related ADEs
▫ Heavily marketed for acne benefit (Ortho Tri-Cyclen)
▫ Missed pill handling more complex
Ortho Tri-Cyclen Lo
ADVERSE EFFECTS
• Overall ADE rates in clinical trials same as
placebo
• 59-81% who stop, do so d/t ADEs
• Most ADEs manageable either by improved
patient tolerance or altering formulation
• Menstrual
▫ Absence of withdrawal bleeding
▫ Vaginal spotting or breakthrough bleeding
 Dose-related, usually stops after 2-3 months
A
C
H
E
S
PROGESTIN-ONLY PILLS
• Used when pt cannot take estrogen (hx
thromboembolic disease, etc.)
• Lower contraceptive efficacy than combination
products
• 28 active pills/cycle
• Increased rates of spotting, break-through
bleeding
• Strict adherence
▫ Increased pregnancy risk if dose 3 hours late
 TRANSDERMAL PATCH
• Ortho Evra—delivers 20mcg ethinyl estradiol,
150mcg norelgestromin (metabolite of
norgestimate) per day
▫ Convenience
▫ Theoretical benefit of less hepatic effect on
clotting factors, lipoproteins
• One patch per week X 3 weeks, no patch 4th
week
• Efficacy similar to combination OCs
• Newer evidence
▫ 60% higher exposure to estrogen vs OC
 No first pass metabolism of EE
▫ Increased risk of vascular complications, ?death
▫ FDA warning 2005
INJECTION
• Depot medroxyprogesterone acetate (Depo-Provera,
DMPA)
▫ 150mg IM or or 104mg SC q3 months
 SC form not widely available, more $
▫ Highly effective
▫ Used in patient unwilling/unable to use other forms
▫ ADES
 Breakthrough bleeding
 Weight gain
 Bone mineral density loss if used >2 years
 Delay in return to fertility mean 10-12 months
• Lunelle (depot MPA/estradiol no longer available in
US
 IMPLANTS
• Norplant original product, removed from US
market 2002 due to ADE concerns, lawsuits
▫ Jadelle (Norplant II), not marketed in US
• Implanon approved in US 2006
▫ Etonogestrel-impregnated plastic rod, inserted in
forearm
▫ Up to 3 years efficacy
▫ ADEs similar to other
progestin methods
 Long-term not known yet
▫ Insertion-site complications
▫ Insertion timed to cycle, previous
method
VAGINAL RING
• NuvaRing—delivers 15mcg EE, 120mcg
etonogestrel
▫ Intravaginal drug absorption
▫ Insertion similar to diaphragm
▫ Inserted for 21 days, removed, new ring inserted
7 days later
 Timed insertion
▫ Comparable efficacy to COCs
▫ May come/fall out
 >3hrs, use back-up method
▫ ? Increase risk thromboembolism
EMERGENCY CONTRACEPTION
• Prevent pregnancy after known or suspected
unprotected sex
▫ 75-89% effective if taken within 120 hours
▫ Large dose of progestin or progestin/estrogen
▫ Mechanisms of action
 Inhibition or delay of ovulation
 Thickening of cervical mucus
 Alteration of corpus luteum function
 Alteration of tubal transport
 NOT ABORTION
EMERGENCY CONTRACEPTION
• 1-888-NOT2LATE, www.not-2-late.com
• Plan B available without Rx to women, men 18 or older
▫ Pharmacists can prescribe in at least 9 states
▫ Best if 1st dose taken within 72 hours of unprotected sex
▫ Problems of access, availability
▫ Cost $25-50, about same as 1 month OC
• Can use higher dose of combination OC—2 doses 12
hours apart
▫ # of pills depends on product—see chart
• High incidence of N/V with combo—pretreat with
antiemetic
▫ Repeat dose if vomiting within 1 hr
▫ 2nd dose can be given intravaginally
• Pt may need STD evaluation
• Initiate ongoing contraception