INTRAUTERINE DRUG DELIVERY SYSTEMS

 

Introduction.

  • Most of today's global problems are due to increased population.

  • It is important to create new, more effective birth control methods that are simple to use, have few side effects, and don't need to be constantly monitored or applied before every sexual act. 

  • The solution to this problem is to use long-acting contraceptives that do not require such daily activity and only require a small amount of action during coitus. However, creating a novel form of contraception is extremely difficult. 

  • New intrauterine drug delivery products are intended to offer better birth control options, better methods for the prevention and treatment of gynecological conditions, and higher levels of safety, acceptability by users, compliance, and quality of life for women. 

  • A drug with progestogenic activity is released under controlled circumstances over an extended period of time and at a concentration necessary for contraception using an intrauterine drug delivery system (IUDDS).

  • Appropriate in vitro test methods that guarantee a predictable in vivo performance are crucial for safe use because IUDs are intended for the controlled delivery of hormones, i.e., drugs with a narrow therapeutic index, over a very long period of time.

Advantages of IUDDS 

  1. They have a success rate of over 98% in preventing unwanted pregnancy.

  2. They possess a long lifespan.

  3. If you are breastfeeding, you can use them safely. 

  4. No medications stop them from working.

  5. It provides another contraceptive choice if there is difficulty taking the hormone estrogen.

  6. There is no vaginal bleeding at all or a light regular period after use.

Disadvantages of IUDDS 

  1. It offers no protection from STIs (sexually transmitted infections).

  2. IUDDS is useless in cases of pelvic infection and abnormal uterus shape.

  3. It is not recommended if you have endometriosis, heavy periods, or low iron levels.

  4. The chance of an ectopic pregnancy may rise as a result.

  5. During insertion and removal, there are risks.

  6. IUDDS have the potential to result in systemic contraindications such as copper allergy, immunodeficiency disorders, immunosuppressive therapy, Wilson's disease, acute liver disease, liver cancer, and breast cancer, particularly for hormonal IUDs, as well as multiple sexual partners for the patient or her partner.

Anatomy of Uterus:

  • The uterus, also known as the womb, has an inverted pear shape. It has a glandular lining known as the endometrium and is a hollow muscular organ with thick walls

  • The uterus weighs between 30 and 40 gm and is approximately 7.5 cm long, 5 cm wide at its upper part, and nearly 2.5 cm thick. 

  • The fundus is the portion of the body that is located above a plane that runs through the points where the uterine tubes enter, and the body is the portion that is located below that plane. 

  • The isthmus, a slight external constriction that marks the point where the body and cervix meet, is where the body narrows toward the cervix. It is the short narrowed portion of the uterus located inferior to superior to the cervix and above the body. 

  • Uterus consists of mainly 3 parts such as 

    • Fundus,

    •  body 

    • Cervix.

Fundus

  • The peritoneum covering the fundus is continuous with that on the vesical and intestinal surfaces, and it is convex in all directions. 

  • The margins on the sides are slightly convex. 

  • Each uterine tube pierces the uterine wall at its upper end. 

  • The round ligament of the uterus is fixed below and in front of this point, and the ovary's ligament is attached behind it. 

  • These three structures are contained within the broad ligament, a fold of peritoneum that extends from the uterine rim to the pelvic wall.

Body:

  • On its way from the fundus to the isthmus, the body gradually narrows. The peritoneum flattens and covers the vesical or anterior surface, which is reflected onto the bladder to form the vesicouterine excavation. 

  • The surface is in contact with the bladder. 

  • The intestinal or posterior surface is convex transversely and is covered by peritoneum, which extends down onto the cervix and vagina.

Cervix:

  • The cervix is the uterus's lower constricted segment. 

  • It has a slightly conical shape with a blunted apex that faces backward and downward, but it is wider in the middle than both above and below. 

  • The cervix has a firmer consistency than the uterus's body because it is made of fibrous connective tissue. 

  • It can move less easily than the body. 

  • The vagina is divided into an upper, supravaginal portion and a lower, vaginal portion by the cervix, which protrudes through the anterior wall of the vagina.

Structure.

  • The uterus is composed of three coats like an external or serous, a middle or muscular, and an internal or mucous. 

  • The peritoneum gives rise to the serous coat, which covers the vesical surface only up to the junction of the body and cervix while covering the fundus and the entire intestinal surface of the uterus. 

  1. The muscular coat / Myometrium: 

  • The bulkiest component of the uterus' substance is its muscular coat. 

  • Myometrium, the muscular middle layer of tissue that makes up the majority of the organ's bulk. 

  • It is made up of tightly packed, striped smooth muscle fibers and is very firm. 

  • During pregnancy, the cells in this layer expand and contract in order to prepare for the delivery of the fetus.

  1. The mucous membrane/ Endometrium: 

  • The mucous membrane is smooth and firmly attached to the tissue around it. 

  • The mucous membrane, or endometrium, is the uterus' innermost layer of tissue. 

  • It merges with the lining of the cervical canal to completely enclose the uterine cavity up to the uterus' isthmus. 

  • Endometrium can be further subdivided into 2 parts: 

    •  Deep stratum basalis: 

      • little changes during the menstrual cycle and is not shed during the period.

    •  Superficial stratum functionalis: 

      • Oestrogens cause it to multiply, while progesterone causes it to secrete.

      • It regenerates from cells in the stratum basalis layer and sheds during menstruation.

  1. Vessels and Nerves: 

  • The uterine and ovarian arteries enter the uterus from the hypogastric and abdominal aorta, respectively. 

  • The ovarian artery terminates where it meets the uterine artery, forming an anastomotic trunk from which branches supply the uterus in a circular pattern. 

  • The veins are large in comparison to the arteries. 

  • They come to an end in the uterine plexuses. 

  • The arteries in the impregnated uterus transport blood to, and veins away from, the placental intervillous space. 

  • The nerves branch off the hypogastric and ovarian plexuses, as well as the third and fourth sacral nerves.

Development of Intrauterine Device (IUD).

  • Intrauterine Device (IUD) is a small object that is inserted through the cervix and placed in the uterus to prevent unwanted pregnancy. 

  • IUDs typically consist of a small, flexible plastic frame with a small string hanging down into the upper vagina. 

  • During the act of sexual contact, the IUD is not visible. 

  • Depending on the type, IUDs can last 1 to 10 years. 

  • To stop fertilization, they interfere with sperm and egg motion. 

  • Additionally, they alter the uterine lining and stop the fertilized egg from implanting. 

  • IUDs are 99.2–99.9% effective at preventing pregnancy. 

  • They are not able to fend off sexually transmitted diseases like HIV/AIDS. 

  • Insertion of an IUD is very simple, usually painless and takes only about 5 to 10 minutes. 

Advantages of IUDs.

  1. It has a great deal of success in preventing pregnancy. 

  2. It is affordable. 

  3. Sex is not disrupted. 

  4. It doesn't need a partner to participate. 

  5. It's functional for a protracted period of time.

  6. It is a birth control option that can be used in an emergency. 

  7. An IUD offers cost-effective long-term contraception for three to five years.

Disadvantages of IUDs.

  1. Sexually transmitted infections (STIs) are not prevented. 

  2. It may increase the chances of ectopic pregnancy (pregnancy outside the uterus). 

  3. It may result in more painful and heavier bleeding. 

  4. Cramping and discomfort happen during insertion and for 24-48 hours afterwards. 

  5. Both insertion and removal involve risks.

Time of using an IUD.

  • An IUD is usually inserted during a menstrual period, when the cervix is slightly open and pregnancy is least likely to occur. 

  • There is however a greater chance of expulsion if a device is introduced early in the cycle because the uterus can squeeze the device back out. 

  • Therefore, the best time for insertion is just after a period. 

  • However, an IUD may be inserted at any time. 

  • The best timing for IUD insertion for women in different situations is given as follows,

Types of intrauterine systems:

  • Most widely used IUDs are as following,

  1. copper-bearing IUDs: 

  • These are made of plastic with copper sleeves and copper wire on the plastic, such as TCu-380A and MLCu-375 

  1. Hormone-releasing IUDs: 

    1. These are made of plastic and steadily release small amounts of progesterone or other progestin hormones, such as LNG-20 and Progestasert.

  2. Inert or non medicated IUDs: 

    1. These are made of plastic or stainless steel only, such as Lippes Loop and Chinese stainless steel rings. 


  1. Copper IUDs 

    •  Copper wire or copper sleeves are put on the plastic frame (polyethylene frame). 

    • Examples include Copper T, CuT380A, Multiload 375 etc. 

  • The various types of Copper IUDs differ from each other by the amount of copper. 

  • The initial Copper IUDs were wound with 200-250 mm2 wire (CopperT 200). 

  • The modern copper containing devices contain more copper and a part of copper in the form of solid tubal sleeves rather than wire. 

  • This increases the efficacy and lifespan (Cu T-380 A). 

  • Mechanisms of action:

  • The copper IUD functions as a contraceptive (inhibiting fertilization). 

  • CuT-380A IUD inhibits sperm motility and block activation of acrosomal enzymes in the sperm head needed for the sperm to penetrate through the zona pellucida to enable union of the gametes. 

  • The copper slows down the movement of sperm within the woman's uterus and so prevents them from reaching the fallopian tubes and fertilizing the egg. 

  • The device also stimulates a strong reaction in the wall of the uterus, which prevents implantation of the egg (even if it is fertilized). 

Advantages of the Copper T 380A IUD:

  1. IUDs are a highly effective, secure, and long-acting method of birth control. 

  2. It only requires one decision from the woman to use it, unlike the pill, condoms, and spermicides, which require decisions for each act of sexual activity. 

  3. Copper-bearing or inert IUDs have no negative hormonal effects. 

  4. It is the best option for people taking antiepileptic or antituberculosis medications because it does not interact with any other drugs the client may be taking. 

  5. The IUD works best for people who want a quick and long-lasting reversible method. 

  6. Additionally, the Copper T 380A IUD aids in preventing ectopic pregnancies. 

  7. Lactating women may use the copper T 380A IUD because it has no effect on the quantity or quality of breast milk. 



Disadvantages of the Copper T 380A IUD:


  1. Pelvic inflammatory diseases (PID): 

    1. The risk of PID development is one of the main issues with IUD use. 

    2. At the time of insertion, there is the greatest risk of pelvic infection related to IUD use. 

  2. Menstrual problems: 

    1. IUD use may be accompanied by increased menstrual pain (dysmenorrhoea). 

  3. Expulsions: 

    1. It's possible for an IUD to exit the uterus without the woman's knowledge. 

    2. This happens more frequently when the IUD is put in place soon after giving birth, when there is abnormally heavy menstrual flow, or when there is severe dysmenorrhoea (painful cramping during the menstrual cycle). 

  4. Pregnancy: 

    1. When an IUD is present, spontaneous abortion occurs in 50% of intrauterine pregnancies. 

    2. Early pregnancy IUD removal reduces spontaneous abortion rates to about 25%.

2. Hormone-Releasing IUDs:

  • Levonorgestrel (LNG), a progestin, is a hormone that is released in small amounts by hormonal IUDs. 

    • Brand names Skyla, Liletta, and Mirena

  • The main mechanism of action is to render the uterus' interior lethal to sperm. 

  • Their primary purpose is not to thin the endometrial lining or possibly hinder implantation. 

  • Once pathologic causes of menorrhagia, such as uterine polyps, have been ruled out, they can be used to treat menorrhagia (heavy menses) because they thin the endometrial lining, which reduces or even stops menstrual bleeding.  

  • When Mirena is used compared to other very-low-dose progestogen-only contraceptives, systemic progestin levels are significantly lower. The progestin released by hormonal IUDs primarily acts locally.

  • e.g 

    • Progestasert:

  • It is a T shaped IUD made of ethylene and vinyl acetate copolymer containing titanium dioxide. 

  • The vertical stem contains a reservoir of 38 mg progesterone together with barium sulfate dispersed in silicone fluid. 

  • The progesterone is released at the rate of 65 µg per day.

  • LNG-releasing IUDs:

    •  There are two similarly sized IUDs with 52 mg LNG and one is smaller with 13.5 mg LNG. 

    • The release rates of LNG were measured at different times following the placement, which initially led to some confusion in naming conventions. 

3. Inert or non medicated IUDs: 

  • These IUDs do not have a bioactive component. 

  • The Lippes Loop, which can be inserted through the cervix with a cannula and takes on a trapezoidal shape inside the uterus, is one example of an inert material that is used to make it. Stainless steel is used in the stainless steel ring (SSR), a flexible ring of steel coils that can deform to be inserted through the cervix. 

  • It has similar side effects to copper IUD and is less effective than hormonal or copper IUD. 

  • Inducing a localized foreign body reaction serves as the mechanism of action, making the uterine environment hostile to both sperm and embryo implantation.  

  • These IUDs have higher rates of preventing pregnancy after fertilization, instead of before fertilization, compared to copper or hormonal IUDs. 

  • Inert IUDs are not approved for use in the United States, UK, or Canada. 

  • But in China, these IUDs are the most common form of contraception.

Applications of IUD:

  1. IUD is effectively useful in contraception similar or better than female sterilization.

  2. IUDs are safe to use for many years. 

  3. They may even remain somewhat effective past their recommended end date. 

  4. It provides long term contraception. 

  5. For people with severe health conditions that make pregnancy dangerous, an IUD can be life-saving.

  6. IUDs can be safely placed immediately after abortion or 6 weeks

  7. postpartum with high contraceptive benefits. 

  8. Copper IUD is recommended as the most effective option for emergency contraception. 

  9. IUDs include the treatment of menorrhagia, anemia, dysmenorrhea and pelvic pain associated with endometriosis, and endometrial protection during hormone replacement.

Commonly Asked Questions.

  1. Write in detail about the Intrauterine drug delivery system.

  2. What are IUDs? Enlist different types. Give their advantages and disadvantages.

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