ENDOCRINE SYSTEM

Endocrine System

The nervous system sends electrical messages to control and coordinate the body. The endocrine system has a similar job, but uses chemicals to “communicate”. These chemicals are known as hormones. A hormone is a specific messenger molecule synthesized and secreted by a group of specialized cells called an endocrine gland. These glands are ductless, which means that their secretions (hormones) are released directly into the bloodstream and travel to elsewhere in the body to target organs, upon which they act. Note that this is in contrast to our digestive glands, which have ducts for releasing the digestive enzymes.
Pheromones are also communication chemicals, but are used to send signals to other members of the same species. Queen bees, ants, and naked mole rats exert control of their respective colonies via pheromones. One common use for pheromones is as attractants in mating. Pheromones are widely studied in insects and are the basis for some kinds of Japanese beetle and gypsy moth traps. While pheromones have not been so widely studied in humans, some interesting studies have been done in recent years on pheromonal control of menstrual cycles in women. It has been found that pheromones in male sweat and/or sweat from another “dominant” female will both influence/regulate the cycles of women when smeared on their upper lip, just below the nose. Also, there is evidence that continued reception of a given man’s pheromone(s) by a woman in the weeks just after ovulation/fertilization can significantly increase the chances of successful implantation of the new baby in her uterus. Pheromones are also used for things like territorial markers (urine) and alarm signals.
Each hormone’s shape is specific and can be recognized by the corresponding target cells. The binding sites on the target cells are called hormone receptors. Many hormones come in antagonistic pairs that have opposite effects on the target organs. For example, insulin and glucagon have opposite effects on the liver’s control of blood sugar level. Insulin lowers the blood sugar level by instructing the liver to take glucose out of circulation and store it, while glucagon instructs the liver to release some of its stored supply to raise the blood sugar level. Much hormonal regulation depends on feedback loops to maintain balance and homeostasis.
There are three general classes (groups) of hormones. These are classified by chemical structure, not function.

• steroid hormones including prostaglandins which function especially in a variety of female functions (aspirin inhibits synthesis of prostaglandins, some of which cause “cramps”) and the sex hormones all of which are lipids made from cholesterol,
• amino acid derivatives (like epinephrine) which are derived from amino acids, especially tyrosine, and
• peptide hormones (like insulin) which is the most numerous/diverse group of hormones.

The major human endocrine glands include:
(clipart edited from Corel Presentations 8)

1. the hypothalamus and pituitary gland
   The pituitary gland is called the “master gland” but it is under the control of the hypothalamus. Together, they control many other endocrine functions. They secrete a number of hormones, especially several which are important to the female menstural cycle, pregnancy, birth, and lactation (milk production). These include follicle-stimulating hormone (FSH), which stimulates development and maturation of a follicle in one of a woman’s ovaries, and leutinizing hormone (LH), which causes the bursting of that follicle (= ovulation) and the formation of a corpus luteum from the remains of the follicle.
   There are a number of other hypothalamus and pituitary hormones which affect various target organs.
   One non-sex hormone secreted by the posterior pituitary is antidiuretic hormone or ADH. This hormone helps prevent excess water excretion by the kidneys. Ethanol inhibits the release of ADH and can, thus, cause excessive water loss. That’s also part of the reason why a group of college students who go out for pizza and a pitcher of beer need to make frequent trips to the restrooms. Diuretics are chemicals which interfere with the production of or action of ADH so the kidneys secrete more water. Thus diuretics are often prescribed for people with high blood pressure, in an attempt to decrease blood volume.
   Another group of non-sex hormones that many people have heard of is the endorphins, which belong to the category of chemicals known as opiates and serve to deaden our pain receptors. Endorphins, which are chemically related to morphine, are produced in response to pain. The natural response to rub an injured area, such as a pinched finger, helps to release endorphins in that area. People who exercise a lot and push their bodies “until it hurts” thereby stimulate the production of endorphins. It is thought that some people who constantly over-exercise and push themselves too much may actually be addicted to their own endorphins which that severe exercise regime releases.
2. the thyroid gland
   Thyroid hormones regulate metabolism, therefore body temperature and weight. The thyroid hormones contain iodine, which the thyroid needs in order to manufacture these hormones. If a person lacks iodine in his/her diet, the thyroid cannot make the hormones, causing a deficiency. In response to the body’s feedback loops calling for more thyroid hormones, the thyroid gland then enlarges to attempt to compensate (The body’s plan here is if it’s bigger it can make more, but that doesn’t help if there isn’t enough iodine.). This disorder is called goiter. Dietary sources of iodine include any “ocean foods” because ocean-dwelling organisms tend to accumulate iodine from the seawater, and would include foods like ocean fish (tuna) and seaweeds like kelp. Because of this, people who live near the ocean do not have as much of a problem with goiter as people who live inland and don’t have access to these foods. To help alleviate this problem in our country, our government began a program encouraging salt refiners to add iodine to salt, and encouraging people to choose to consume this iodized salt.
3. the pancreas
   This organ has two functions. It serves as a ducted gland, secreting digestive enzymes into the small intestine. The pancreas also serves as a ductless gland in that the islets of Langerhans secrete insulin and glucagon to regulate the blood sugar level. The -islet cells secrete glucagon, which tells the liver to take carbohydrate out of storage to raise a low blood sugar level. The -islet cells secrete insulin to tell the liver to take excess glucose out of circulation to lower a blood sugar level that’s too high. If a person’s body does not make enough insulin (and/or there is a reduced response of the target cells in the liver), the blood sugar rises, perhaps out of control, and we say that the person has diabetes mellitus.
4. the adrenal glands
   These sit on top of the kidneys. They consist of two parts, the outer cortex and the inner medulla. The medulla secretes epinephrine (= adrenaline) and other similar hormones in response to stressors such as fright, anger, caffeine, or low blood sugar. The cortex secretes corticosteroids such as cortisone. Corticosteroids are well-known as being anti-inflammatory, thus are prescribed for a number of conditions. However, these are powerful regulators that should be used with caution. Medicinal doses are typically higher than what your body would produce naturally, thus the person’s normal feedback loops suppress natural secretion, and it is necessary to gradually taper off the dosage to trigger the adrenal glands to begin producing on their own again. Because the corticosteroids suppress the immune system, their use can lead to increased susceptibility to infections, yet physicians typically prescribe them for people whose immune systems are hard at work trying to fight off some pathogen. For example, back when I was in grad school, I was diagnosed with mono, and the campus doctor prescribed penicillin and cortisone. Since mono is a virus and penicillin only is effective against some bacteria, about all it did was kill off the friendly bacteria in my body, therefore causing me to develop a bad case of thrush. At the same time, the cortisone was supressing my immune system so my body could not as efficiently fight off the mono and the thrush. People with high blood pressure should be leery of taking prescription corticosteroids: they are known to raise blood pressure, thus can cause things like strokes. My mother-in-law had high blood pressure and was being treated with diuretics. Her physician also had her on large doses of cortisone for her arthritis. While he was on vacation, she started having significant back pain and was referred to an orthopedic surgeon. This man decided the back pain was just due to arthritis, and without carefully checking on what dosage she was already taking, prescribed more cortisone. Simultaneously, because of difficulty walking due to her arthritis, she decided to decrease the amount of diuretics she was taking so she didn’t have to make as many “long” trips to the other end of the house. The combination of lowered dose of diuretics and high dose of cortisone raised her blood pressure to the point where a blood vessel in her brain burst, causing a stroke. When the EMTs took her blood pressure, as I recall the systolic was way over 200 mm Hg.
5. the gonads or sex organs
   In addition to producing gametes, the female ovaries and male testes (singular = testis) also secrete hormones. Therefore, these hormones are called sex hormones. The secretion of sex hormones by the gonads is controlled by pituitary gland hormones such as FSH and LH. While both sexes make some of each of the hormones, typically male testes secrete primarily androgens including testosterone. Female ovaries make estrogen and progesterone in varying amounts depending on where in her cycle a woman is. In a pregnant woman, the baby’s placenta also secretes hormones to maintain the pregnancy.
6. the pineal gland
   This gland is located near the center of the brain in humans, and is stimulated by nerves from the eyes. In some other animals, the pineal gland is closer to the skin and directly stimulated by light (some lizards even have a third eye). The pineal gland secreted melatonin at night when it’s dark, thus secretes more in winter when the nights are longer. Melatonin promotes sleep (makes you feel sleepy). It also affects reproductive functions by depressing the activity of the gonads. Additionally, it affects thyroid and adrenal cortex functions. In some animals, melatonin affects skin pigmentation. Because melatonin production is affected by the amount of light to which a person is exposed, this is tied to circadian rhythm (having an activity cycle of about 24 hours), annual cycles, and biological clock functions. SAD or seasonal affective disorder (syndrome) is a disorder in which too much melatonin is produced, especially during the long nights of winter, causing profound depression, oversleeping, weight gain, tiredness, and sadness. Treatment consists of exposure to bright lights for several hours each day to inhibit melatonin production. It has also been found that melatonin levels drop 75% suddenly just before puberty, suggesting the involvement of melatonin in the regulation of the onset of puberty. Studies have been done on blind girls (with a form of blindness in which no impulses can travel down the optic nerve and reach the brain and pineal gland), which showed that these girls tended to have higher levels of melatonin for a longer time, resulting in a delay in the onset of puberty. While some older people, who don’t make very much melatonin, thus don’t sleep well, might benefit from a melatonin supplement, I’m skeptical of the recent melatonin craze in this country. When so many people apparently are suffering from SAD, I question the wisdom of purposly ingesting more melatonin, especially since the pineal gland is one of the least-studied, least-understood of the endocrine glands.

Local regulators are hormones with target cells nearby or adjacent to the endocrine gland in question. For example, neurotransmitters are secreted in the synapses of our nervous system and their target cells are in the same synapses.

GLUCOMA

Glaucoma is not a single eye disorder but a group of disorders that affect the eye. The optic nerve is made up of 1 million nerve fibers. It carries visual images from the retina, the layer of light-sensitive tissue at the back of the eyeball, to the brain. Untreated glaucoma may lead to vision loss or even complete blindness. In most cases of glaucoma, the optic nerve is damaged by increased fluid pressure inside the eyeball. However, reduced blood supply to the optic nerve, caused by the increased pressure, can also be a factor.

Glaucoma is often categorized as either primary or secondary. Primary glaucoma refers to glaucoma that is not triggered by an injury or other medical condition. It accounts for about 90 percent of cases. There are several major types of primary glaucoma:
• Open-angle glaucoma. This term refers to the angle in the front portion of the eye where the cornea meets the iris. In normal circumstances, fluid flows in and out of the front of the eye through a meshwork of tissue at the angle that acts like a drain. In openangle glaucoma, the angle remains open and fluid continues to pass through the meshwork, but not quickly enough. As a result, fluid builds up inside the eye, and the fluid pressure may rise high enough to damage the optic nerve. Open-angle glaucoma is the most common type of primary glaucoma.
• Closed-angle glaucoma. Closed-angle glaucoma is a disorder in which the angle between the iris and the cornea is blocked, usually because the iris becomes swollen from pressure and moves forward to touch the meshwork directly, thus preventing fluid from draining out of the eye. Closed-angle glaucoma can develop either gradually or suddenly. Acute closed-angle glaucoma is a medical emergency.
• Congenital glaucoma. This is a type of glaucoma that is present at birth and is usually noticeable within the first year of life. It is more common in boys than in girls. In congenital glaucoma, there is a defect in the structure of the baby’s eye that slows down the normal drainage of fluid.
• Normal-pressure glaucoma. Also called normal-tension glaucoma, this is a type of primary glaucoma in which the optic nerve is damaged even though the fluid pressure within the eye is within normal range. Doctors do not yet understand the causes of this type of glaucoma, although one theory suggests that the optic nerve is damaged by normal fluid pressure because its blood supply has been reduced.
• Pigmentary glaucoma. This is a type of glaucoma that develops when pigment granules from the iris flake off and block the drainage meshwork in the angle between the iris and cornea. About 10 percent of cases of glaucoma are secondary, meaning that they develop as a result of injury to the eye or another disease, most commonly diabetes, leukemia, or sickle cell anemia. Secondary glaucoma may result from a blow to the eye, a tumor, cataract surgery, or the use of corticosteroid medications.

People’s experience of glaucoma varies considerably depending on which type they have and whether it is chronic (developing slowly) or acute (sudden onset). In addition, glaucoma can affect both eyes or only one.

Children with congenital glaucoma are usually diagnosed within the first few months after birth because their eyes look cloudy, are unusually sensitive to light, and secrete large amounts of tears. Chronic open-angle glaucoma, the single most common type, develops over a period of years and is related to the aging of the drainage meshwork in the angle between the iris and cornea. In the early stages, patients with this type of glaucoma may have no symptoms at all. Gradually, however, they find it more difficult to see objects to the side or on the edges of their visual field. They may also develop tunnel vision, in which they can see only objects straight in front of them.

Closed-angle glaucoma can come on suddenly, often in dim light, with eye pain, reddening of the eye, a sudden severe headache, and nausea and vomiting. The person may also see colored or rainbow-like halos around lights.

Glaucoma is largely an eye disorder of adults. Congenital glaucoma is rare and childhood glaucoma is also unusual. Glaucoma in middle-aged adults, however, is a common eye disorder and the second leading cause of blindness in the United States. According to Prevent Blindness America, more than 2.2 million Americans over age forty have open-angle glaucoma, but only half of them know that they have it. In North America and Europe, glaucoma affects one person in every two hundred aged fifty or younger, but one in ten over the age of eighty.

Some people are at increased risk of glaucoma:
• Those with increased fluid pressure in the eye, sometimes called ocular hypertension. A high level of fluid pressure inside the eye is the greatest single risk factor for glaucoma. However, as noted earlier, some people develop the disorder even though their eye fluid pressure is normal.
• Age. The risk of glaucoma increases over age sixty for most Americans; it rises over age forty for African Americans.
• Race and ethnicity. African Americans have six to eight times the risk of glaucoma as Caucasians. Mexican Americans over the age of sixty are also at increased risk. Asian Americans and Alaskan Inuit have a higher than average risk of acute closed-angle glaucoma, and Japanese Americans have an increased risk of normal-pressure glaucoma. The reasons for these differences are not yet understood.
• Family history of glaucoma.
• Certain diseases or conditions, including high blood pressure, diabetes, heart disease, hypothyroidism, and sickle cell anemia.
• Myopia (nearsightedness).
• A history of injury to the eye, inflammation of the eye, tumors in the eye, or cataract surgery.
• Long-term use of corticosteroid medications.

Signs and Symptoms

The most important cause of glaucoma is increased fluid pressure within the eye resulting from overly slow drainage of fluid through the meshwork in the angle between the iris and cornea or complete blockage of the angle. This buildup of fluid pressure damages the optic nerve. In some cases inadequate blood supply to the optic nerve is also a factor.

There is some evidence that genetic factors are also involved in glaucoma because the disorder is known to run in some families. Several genetic mutations have been linked to primary open-angle glaucoma, but no single gene has been shown to cause the disorder. The symptoms of the various types of glaucoma were described earlier.

Diagnosis

The diagnosis of chronic primary glaucoma is usually made during a routine eye examination by an ophthalmologist, who is a doctor specializing in the diagnosis and treatment of eye disorders. A complete eye examination, depending on the individual patient’s history and risk factors, will include most or all of the following tests:
• Dilation of the eye. The doctor will dilate the pupil of the eye by placing drops in the eyes that keep the iris from narrowing the pupil when the doctor shines a bright light directly into the eye. The doctor will then be able to see directly to the back of the eye to check for damage to the optic nerve.
• Tonometry. This is a test for measuring the level of fluid pressure inside the eye. It can be performed either by resting an instrument briefly on the surface of an anesthetized eye, or by blowing a puff of air onto the surface of the eye while the patient’s chin is held steady. The fluid pressure is estimated by measuring the response of the eye to the puff of air.
• Tests of peripheral vision. Since open-angle glaucoma often starts with gradual loss of side vision, doctors may measure whether such loss has occurred by asking patients to look at a set of blinking lights and indicate when they can see the lights. The patients’ answers allow doctors to map how much, if any, of the patients’ visual field has been lost.
• Tests to measure the thickness of the cornea. This test is done to rule out the possibility that a cornea that is either unusually thick or unusually thin is affecting the measurement of the fluid pressure inside the eye.
• Gonioscopy. This is a test than uses a gonioscope, an instrument with a mirror as well as a light source. It allows the doctor to tell whether the angle between the iris and the cornea is open or closed.

A patient with acute closed-angle glaucoma will usually be treated by an ophthalmologist in a hospital emergency department. Emergency treatment consists of medications to quickly reduce the fluid pressure inside the eye and laser surgery to cut a drainage hole in the iris.

Treatment

Glaucoma can be treated with medications, surgery, or both. The medications used include special eye drops or oral medications. In some cases the patient may be asked to use more than one type of eye drop. There are several different types of drugs that may be prescribed; some work to lower the fluid pressure inside the eye by decreasing the amount of fluid produced. Other drugs work by increasing the outflow of fluid. All of these medications have side effects, however, and must be used exactly according to the doctor’s instructions. Surgery is usually used to treat congenital glaucoma and acute closed angle glaucoma. The procedure used to treat closed-angle glaucoma is called an iridotomy. The surgeon uses a laser to cut a hole in the iris to relieve the increased pressure inside the eye. Surgery can also be performed to treat open-angle glaucoma. There are two major types of laser surgery that can be done. One technique involves using the laser to open clogged portions of the drainage network.

Another approach is called filtering surgery. The surgeon uses the laser to cut a small hole in the sclera (white part of the eyeball) and remove a small portion of the clogged meshwork. The extra fluid can then leave the eye through the hole in the sclera. Children with glaucoma and adults with secondary glaucoma can be treated with drainage implant surgery. The implant is a small silicone tube that the doctor inserts inside the eye to help drain the excess fluid.

Prognosis

The prognosis of glaucoma depends on its type and the stage at which it is diagnosed. Vision that has been lost to any type of glaucoma cannot be restored. Without treatment, acute glaucoma results in permanent vision loss within days. Untreated chronic glaucoma can progress to blindness within several years.

Prevention

The best prevention for glaucoma is regular eye exams. Anyone over age eighteen should be screened periodically for glaucoma. The schedule of eye examinations recommended by the National Eye Institute (NEI) is as follows:
• Eighteen to sixty years of age: Every two years.
• Over sixty: Every year.
• One or more risk factors other than age: Every year before and after age sixty. Other preventive steps that people can take include getting treatment
(special eye drops) if diagnosed with high fluid pressure inside the eye; controlling one’s

ANEMIA

Anemia

Introduction

The function of red blood cells is to transport oxygen to tissues. This is accomplished by the hemoglobin. The hemoglobin protein is composed of two alph and two beta subunits. Each of the subunits contains a central iron containing protein called a heme protein. It is the iron atom in the heme protein that binds to molecular oxygen. As a result of the four iron-containing heme groups, each molecule of hemoglobin can carry four atoms of oxygen.

Definition

Anemia is a condition in which there is a reduced number of red blood cells or decreased concentration of hemoglobin in those cells or both.

Pathophysiology

Anemia can be caused by:

1-      Decreased red cell production, which may  be due to lack of nutrient (B₁₂, folic acid, iron)  or bone marrow failure.

2-      Increased red cell destruction secondary to hemolysis.

3-      Increased red cell loss caused by acute or chronic bleeding.

Morphologic classification of  anemias by red blood cell size (microcytic, normocytic, macrocytic) and hemoglobin content (hypochromic, normochromic, hyperchromic) is as follows (see figure-1):

Macrocytic (Megaloblastic) anemia: Vitamin B₁₂ deficiency (pernicious) and folic acid deficiency anemia.

Microcytic, hypochromic anemia: Iron deficiency

Normochromic, normocytic: Recent blood loss and Hemolysis

Figure-1: illustrating microcytic hypchromic and macrocytic hyperchromic anemia

Signs and Symptoms

Onset of anemia can be acute or can develop slowly, resulting in tissue hypoxia caused by the decreased oxygen-carrying capacity of the reduced red cell mass.

Slowly developing anemias can be asymptomatic initially or include symptoms such as slight exertional dyspnea, and fatigue. In severe anemia, heart rate, and stroke volume often increase in an attempt to improve oxygen delivery to tissues. These changes in heart rate and stroke volume can result in angina pectoris and high output congestive heart failure.

Microcytic hypochromic anemias (Iron Deficiency Anemia)

Iron deficiency is the most common cause of anemia worldwide. Iron deficiency is a state of negative iron balance in which the daily iron intake and stores are unable to meet the RBC and other body tissue needs.

Only about 0.5 to 1 mg/day of iron is lost from urine, sweat, and the sloughing of intestinal mucosal cells that contain ferritin. Menstruating women lose approximately 0.6% to 2.5% more iron per day.

Iron is absorbed from the duodenum and upper jejunum by an active transport mechanism. Dietary iron, which is primarily in the ferric state, is converted to the more readily absorbable ferrous form in the acid environment of the stomach.

Animal sources of iron are better absorbed than plant sources. A gastrectomy may decrease the conversion of the ferric form of iron to the ferrous state, thereby diminishing iron absorption.

Etiology and pathophysiology

Iron deficiency anemia can be caused by:

1-      Chronic blood loss due to peptic ulcer disease, hemorrhoids, menstruation and ingestion of GI irritants such as NSAIDs.

2-      Decreased absorption due to gastrectomy, or ingestion of medications that complex with iron, decreasing its absorption.

3-      Increased requirement during infancy, pregnancy and lactation.

4-      Inadequate dietary intake of iron (less than 1 to 2 mg/day), as in prolonged non supplemented breast-feeding or bottle-feeding of infants.

Because iron is the functional component of hemoglobin, lack of available iron will result in a decreased hemoglobin synthesis and subsequent impairment of red blood cell oxygen-carrying capacity.

Treatment (Iron Therapy)

Oral Administration

The goals of iron therapy are to normalize the Hb concentrations and to replete iron stores.

The preferred route of iron administration is oral route. Oral iron is most readily absorbed in the absence of food,

The ferrous form of iron is absorbed three times more readily than the ferric form. Although ferrous sulfate (contain 20% of elemental iron ), ferrous gluconate (contain 11% of elemental iron), and ferrous fumarate (contain 33% of elemental iron) are absorbed almost equally, each contains a different amount of elemental iron.

The usual adult dose of ferrous sulfate is 325 mg (one tablet) administered three times daily, between meals.

Hematologic response is usually seen in 2 to 3 weeks with a 1 g/dL increase in hemoglobin, anemia can be resolved in 1 to 2 months; however, iron therapy should be continued for 3 to 6 months after the hemoglobin is normalized to replete iron stores.

Side effects

Oral iron therapy produces dark stools. Gastric side effects, which occur in 5% to 20% of patients, include nausea, epigastric pain, constipation, abdominal cramps, and diarrhea.

Drug-drug interactions

Food, especially dairy products, decreases the absorption of iron by 40% to 50%. Drugs that increase the pH of the stomach (antacids, proton pump inhibitors, and H2 blockers) will decrease the solubility of ferrous salts and thus reduce iron absorption.

Because the absorptions of both iron and tetracycline are decreased when administered concomitantly, the iron should be taken 2 hours before or 3 hours after the tetracycline and drugs that increase gastric pH.

Parenteral Iron Therapy

Parenteral iron therapy is indicated when there is failure to respond to oral therapy (due to nonadherence, or malabsorption). Iron can be given parenterally in the form of ferric gluconate, iron dextran, and iron sucrose.

Iron dextran can be administered undiluted intramuscularly or by very slow intravenous infusion  after dilution in 0.9% NaCl.

Ferric gluconate  and iron sucrose can be administered undiluted as a slow IV injection or as an IV infusion after dilution in 0.9% NaCl.

Side effects of parentral iron

Anaphylactoid reactions can occur in about 1% of patients treated with parenteral iron therapy. Other side effects seen with parenteral iron agents include hypotension, nausea and vomiting, cramps, and diarrhea.

Megaloblastic Anemias

Megaloblastic anemia is a common disorder that caused by either vitamin B₁₂ deficiency or folic acid deficiency. Megaloblastic anemia results from impaired DNA synthesis in replicating cells, which is signaled by a large immature nucleus.

Folic Acid Deficiency Anemia

Etiology

Folate deficiency can result from decreased intake or increased requirement (during pregnancy). Folate deficiency also can occurs due to ingestion of drugs that alter folate metabolism (e.g., trimethoprim, pyrimethamine, methotrexate, sulfasalazine anticonvulsants)

Pathogenesis and symptoms

Once absorbed, the inactive dihydrofolate  is methylated and reduced to methyl tetrahydrofolate (folinic acid) by dihydrofolate reductase. Within the cells the methyl group is removed (in a reaction requiring vitamin B₁₂) to form the active  tetrahydtofolate  which acts as a coenzyme involved in a number of reactions including DNA and RNA symthesis. Defect in DNA synthesis mainly affect cells with rapid turnover such as red blood cells and gastrointestinal cells, hence sore tongue and anemia seen in folate deficiency. 

Treatment

Folate deficiency is usually managed by replacement therapy. The normal daily requirement of folic acid is about 100 mcg/ day. Despite this, the usual treatment doses given are 1-5 mg /day of oral folic acid. Even in malabsorption states sufficient folate is absorbed because of these large doses.

The RBC morphology should begin to revert back to normal within 24 to 48 hours after therapy is initiated, and  the anemia should be corrected in 1 to 2 months.

Large doses of folate can partially reverse hematologic abnormalities caused by vitamin B₁₂ deficiency; however, folate cannot correct neurologic damage caused by vitamin B₁₂ deficiency. Therefore, folate deficiency absolutely must be differentiated from vitamin B₁₂ deficiency before folate therapy is initiated. Otherwise, the progression of the neurologic sequelae of vitamin B₁₂ deficiency can occur.

Vitamin B₁₂ Deficiency Anemia

The typical diet contains 5 to 15 mcg/day of vitamin B₁₂, an amount sufficient to replace the 2 mcg lost daily. The total body stores of vitamin B₁₂ range from 2,000 to 5,000 mcg. Because body stores are extensive, 3 to 4 years are required before symptoms of vitamin B₁₂ deficiency develop (the onset of the vitamin B₁₂ deficiency anemia is slow).

In the stomach, the vitamin B₁₂  bound to intrinsic factor, which protects it from degradation by GI microorganisms. Intrinsic factor is essential for the absorption of vitamin B₁₂. Specific mucosal receptors in the distal ileum allow for attachment of the intrinsic factor-B₁₂ complex.  In the liver, vitamin B₁₂ is converted to coenzyme B₁₂, which is essential for hematopoiesis, maintenance of myelin throughout the entire nervous system, and production of epithelial cells.

Aetiology

Vitamin B₁₂ deficiency can result from decreased intake or malabsorption. Malabsorption occur if the distal ilium is removed. In addition, the gastric mucosa may be unable to produce intrinsic factor under conditions such as total and partial gastrectomy or autoimmune destruction (Pernicious anemia).

Pathogenesis and symptoms

Vitamine B12 is acoenzyme for the removal of a methyl group from methyltetrahydrofolate. Lack of vitamin B₁₂ traps the folate as methyltetrahydrofolate and prevents DNA synthesis. So vitamin B₁₂ is a coenzyme essential for hematopoiesis, maintenance of myelin throughout the entire nervous system, and production of epithelial cells. Therefore, vitamin B₁₂ deficiency is associated with sore tongue, and numbness or tingling in the extremities (peripheral neuropathy)

Treatment

Parenteral vitamin B₁₂ in a dose sufficient to provide the daily requirement of approximately 2 mcg,  and to replenish tissue stores (about 2,000 to 5,000 mcg;) is given for treatment of vitamin B₁₂ deficiency anemia. To replete vitamin B₁₂ stores, cyanocobalamin (1,000 mcg) IM once a week for 4 to 6 weeks followed by 1,000 mcg/month for lifetime maintenance therapy in case of pernicious anemia .

Sickle Cell Anemia

Patients with sickle cell anemia have HbS (normal Hb is HbA). HbS has  valine substituted for  glutamic acid  as the sixth amino acid in the beta chain of Hb.

The hemoglobin produced from such a substitution has a more negative charge than normal HbA, and the deoxygenated state favors hemoglobin aggregation and polymerization, which forms sickled RBC. Sickled RBCs are more rigid and may become “lodged” when passing through microvasculature, resulting in vascular occlusions. In addition, the sickled RBCs surface contains aminophospholipids, which augments the ability of the RBC to initiate coagulation and adhere to vascular endothelium leading to vaso-occlusive episodes and multiorgan damage.

Symptoms and treatment

The kidney is commonly affected by microinfarction. Although, vaso-occlusive events are uncommon. If they do occur, they usually are caused by hypoxic conditions resulting from excessive exercise or high altitudes.

Treatment of sickle cell anemia is largely directed toward prophylaxis against infections and supportive management of vaso-occlusive crises.

The following are symptoms and complications of sickle cell disease

Hemolytic Anemia

Hemolytic anemia in patients with sickle cell disease is caused by splenic sequestration of abnormal RBC. Sequestration reduces the RBC life span from 120 days to 15 to 25 days. Management of the underlying anemia may include splenectomy following the first splenic sequestration event. Alternatively, patients can be treated with transfusions and careful observation.

Infections

Patients with sickle cell disease have a high incidence of infections especially pneumococcal infections, due to altered B-cell immunity  and granulocyte function.

Pneumonia caused by S. pneumoniae can worsen hypoxia, causing progression to vaso-occlusion. Because of such complications, the prophylactic administration of penicillin has significantly reduced morbidity and mortality from pneumonia in children <3 years of age, but prophylaxis is recommended to be continued through age 5.

Vascular Occlusion Episodes

Vascular occlusion episodes, or “sickle cell crises,” cause severe pain and organ damage. The pain typically lasts 2 to 6 days and should be managed with narcotic analgesics.

Treatment for Frequent Vaso-occlusive Crises

Hemoglobin F (HbF) has a protective effect against hemoglobin polymerization. Hydroxyurea has been found to increase HbF synthesis, which, in turn, may decrease sickling of RBC and the occurrence of disease-related complications. Hydroxyurea is used prophylactically in patients with recurrent vaso-occlusive crises, but not in treatment of the crises.

Thallasemia.

Pathophysiology

Patients with α-thalassemia have a decrease in α-globin chain production relative to β-globin chain, with the formation of β₄ (HbH) inclusion bodies. Red blood cells bearing these inclusion bodies are removed rapidly from the circulation by the reticuloendothelial system, shortening their survival. The resulting mild anemia is compensated partially by an increase in red blood cell production.

In contrast, patients with β-thalassemia have a decrease in β-globin chain production relative to α-globin chain production, which leads to an excess of α-globin chains. Unbound α-globin chains are extremely insoluble and precipitate in red blood cell precursors leading to defective erythroid maturation (ineffective erythropoiesis). The few cells that do emerge into the peripheral circulation are removed rapidly in the spleen and liver.

Clinical manifestation

The resulting profound anemia increases circulating levels of erythropoietin and causes a massive expansion of bone marrow. In sever cases this lead to bone abnormalities and growth retardation. The spleen is actively involved in removing the abnormal mature cells from the circulation and become enlarged (spleenomegaly).

Treatment

There is currently no effective treatment for thalassemia. Many patients with sever forms are blood transfusion dependant from early age. Although intensive blood transfusion programs have led to markedly improved survival, patients die from iron overload unless chelation therapy is instituted and maintained. Desferrioxamine and deferiprone are used for chelation of iron.

Glucose-6-phosphate dehydrogenase  (G6PD) deficiency anemia

Pathophysiology

G6PD is essential for the production of the reduced form of NADPH in erythrocytes. NADPH is needed to keep glutathione in a reduced form. Reduced glutathione maintain Hb in a reduced form and help erythrocytes deal with oxidative stress. In G6PD deficiency, if the erythrocytes are exposed to an oxidizing agent, the Hb becomes oxidized and forms what are known as Heinz bodies. The cell membrane damaged and some red cells hemolysed and removed from ciculation by the spleen.

Clinical manifestations

The milder form of  G6PD deficiency that occurs in black population results in an acute self limiting hemolytic anemia following exposure to an oxidizing agent  e.g. infection, acute illness, fava beans or some drugs. The hemolytic anemia is self limiting because the younger cells produced by the bone marrow have higher level of G6PDactivity than older cells.

In the Mediterranean form of G6PD deficiency, the enzyme activity is very low and the hemolysis is not usually self limiting and so some patients have chronic hemolytic anemia despite the absence of an obvious causative factor 

Drugs to be avoided in all types of G6PD deficiencies include ciprofloxacine, nalidixic acid, sulphonamides including trimethoprim,  dapsone and primaquine,

Drugs to be avoided only in sever type of G6PD deficiencies are aspirin, chloramphenicol, chloroquine, probenicid, quinidine and quinine.    

Treatment

There is no specific  treatment for this disorder. It is important to avoid  known precipitating factors to prevent acute episode. During the acute episode the causative factor should be stopped and the patient must kept well hydrated to ensure good urine flow and prevent renal damage. Some times blood transfusions may be necessary.

Renal Insufficiency-Related Anemia

The cause of the anemia is complex but involves reduced erythropoietin (EPO) production and a shortened RBC life span. Because EPO is secreted in the kidney in response to anoxia and is responsible for normal differentiation of RBC from other stem cells, EPO is used to treat anemia in patients with renal failure.

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liposome drug delivery system

SAMARTH PHARMA

 

Liposomal drug delivery system

What is liposome:
Liposomes are small vesicles made up of phospholipids , the very similar constituent of cell membrane, so that the pospholipid vesicles behave more or less as a micro cell inside which drug molecules can be loaded .
The phospholypid molecule is made up of hydrophylic head( containing choline, phosphate, and glycerol) , to which two long lypopylic chains(essential fatty acid chain) are attached, because of which these molecule aline themselves together in water in a very peculiar manner so as to form a membrane like bilayer.

Formation of phospholypid bilayer.
When phospholypid come in contact with aqueous solution,first they form film like alignment, water soluble head of molecule (hydrophylic ) aline and attache with water molecule, the fat soluble (hydrophobic fatty acid chains ) part of molecule is stay away from water molecules , projecting outwards.
This is a peculiar monolayer formation , up on which anther layer of phospholypid molecule aline themselves , hydrophobic chains attache to hydrophobic chains in first film , now in second layer of phospholypid hydrophobic heads are projecting outwards , this is a peculiar billayer of phospholypid.

All lypopilic heads of pospholipid molecule are aligned inside forming a spherical capsules of varying size, these vesicles may be single layered pospholipid or multi layered pospholipid.They are further categorised in to MLV (multilamellar vesicles) SUV (Small Unilamellar Vesicles) and LUV (Large Unilamellar Vesicles) each one has its unique application, depending up on the requirements of drug delivery and required targeting.

Application of liposome:
1) Drug delivery: Both water soluble and water insoluble, and peptide drug molecules can be delivered with the help of liposome. Liposome’s are used for delivering drug directly in to cells, owning to the property of liposomal membrane which is similar in properties with that of cell wall, liposome’s tend to fuse with the cell wall and can deliver a drug directly inside the cells.

How drug is carried by liposome:
Hydrophilic drug (water soluble) can be encapsulated inside the hydrophilic inner core of liposome, from where it can not come out easily as outer core is hydrophobic , which serves as a protective membrane. A hydrophobic drug can be trapped inside the lipid bi layer of liposome.

Targeted drug delivery system:
Liposome’s can be attached with antibodies against particular cells or tissue, these antibodies along with liposome’s wherein drug is loaded are then attracted by those cells or tissue against which the antibodies work, after attachment of the antibodies with the particular cell, liposome membrane fuses with cell wall and drug molecules entrapped inside the liposome are delivered inside the cell.

Application of liposome’s in anticancer drug delivery system:
Liposome’s of size smaller than 200 nm can enter cancer cells in the tumor and deliver anticancer drug directly in to affected cells, by mechanism explained above.
Liposome’s can be tagged with antibodies against cancerous tissue , and a drug against those cancer cell can be entrapped inside the liposome , these antibody tagged liposome’s get attracted to cancerous cells wall get fused with liposomal wall, and anticancer drug entrapped inside liposome’s is delivered directly inside affected cells.

Application of liposome’s in gene therapy in gene delivery RNA, DNA peptide drug delivery:
Liposomes have great application in gene therapy, as genes can be successfully delivered inside cells for desired incorporation of a gene. Also DNA and RNA and peptide drugs can be delivered directly in to cells for their desired effect on those cells.

Application of liposome’s in protecting drug from external environment:
Drugs which are highly sensitive for external environment, like PH and oxygen, and get degraded easily can be formulated in to liposome’s, for example vitamins can be formulated in liposome’s, which enhances self life of these drugs.

Optimization of cytotoxic drug treatments:
Some drugs are very toxic , for example anticancer drugs like doxorubicin, cisplatin, cytarabine, these drugs when given in conventional dosage form also have cytotoxic side effect on other body tissues and cells, therefore produce more undesired toxic side effects, with liposomal drug delivery systems , the concentration of drug required for desired effect is reduced to very low concentration , which also keeps other body tissue and cells away from such drugs harmful cytotoxic effects.

Long circulation Liposome’s:
Liposome’s can be treated with polyethylene glycol , so that they keep them selves intact for long time in blood circulation with which we can achieve long duration of drug delivery.

Phospholipids used in liposome formulation:
Natural origin: Sphingomyelin , Egg yolk Phospholipids , Soybean Phospholipids
Synthetic origin: Phosphatidylcholine, Lyso-Phosphatidylcholine , Phosphatidylserine ,Phosphatidylethanolamine , Phosphatidic Acid,

SKIN PENETRATION

ANTI HERPS Agent/ anti viral drugs

Like antibiotics for bacteria, antiviral drugs are a class of antimicrobials used specifically for treating viral infections. They are relatively harmless to host because they inhibit the development of pathogens instead of destroying them. Most of the antiviral agents need to be activated by viral and cellular enzymes before exerting antiviral effect. Hence, activity of enzymes and concentration of substrates will influence the efficacy of these drugs.
In majority of acute infections, viral replication is already at its peak when symptoms appear. To be effective, antiviral therapy has to be started in the incubation period, i.e has to be prophylactic.

Antiviral

CLASSIFICATION:
1. Anti-herpes virus: Idoxuridine, acyclovir, valacyclovir, famciclovir, ganciclovir, forscarnet
Except forscarnet which is an inhibitor of DNA polymerase and reverse transcriptase, others are purine and pyrimidine anlaogues.
2. Anti-retrovirus:
a. Nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine (AZT), Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir
b. Non-nucleoside reverse transcriptase inhibitors (NNRTIs):Nevirapine, Efavirenz, Delaviridine
c. Protease inhibitors: Ritonavir, Indinavir, Nelfinavir, Saquinavir, Lopinavir
3. Anti-influenza virus: Amatidine, Rimantadine
4. Nonselective antiviral drugs: Ribavirin, Lamivudine, Interferon alpha
General Mechanism of Action of Nucleoside Analogues:
1. Taken up by cells
2. Converted by viral and cellualr enzymes to the triphosphate form
3. The triphosphate form inhibits:
a. DNA polymerase
b. Reverse transcriptase
c. RNA polymerase
4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.

ANTI-HERPES VIRUS DRUGS:

1. Acyclovir and Valaciclovir: These are guanine analogues with antiviral activities against Herpes group only.
Mechanism of action:
Acyclovir –viral thymidine kinase–> AcycloGMP –cellular kinases–> AcycloGTP
AcycloGTP performs 2 functions:
a. Inhibits viral DNA polymerase competitively
b. Termination of DNA synthesis by incorporation into DNA
Mechanism of resistance development:
a. Reduced activity of viral thymidine kinase
b. Altered DNA polymerase
Use:
The activity of acyclovir on herpes group:
Herpes simplex type I > Herpes simplex type II > (Varicella-zoster virus = Epstein-Barr virus)
Cytomegalovirus (CMV) are practically not affected.
a. Genital Herpes simplex (type II)
b. Mucocutaneous H. simplex (type I) : remains localized to lips and gums
c. H.simplex encephalitis (type I)
d. H. simplex (type I) keratitis : because of good corneal penetration
e. Herpes zoster
f. Chickenpox
Adverse effects:
a. Topical: stinging and burning sensation
b. Oral: headache, nausea, malaise
c. Intravenous: rashes, sweating, emesis and fall in BP
d. Other toxicities:
i. Renal insufficiency (normalization on discontinuation of drug)
ii. Encephalopathy : tremors, lethargy, disorientation, hallucinations, convulsions and coma
Valaciclovir is an ester prodrug of acyclovir with improved oral bioavailability. It is the drug of choice in herpes zoster.
2. Famciclovir: It is used an alternative to acyclovir for genital or orolabial herpes and herpes zoster.
3. Ganciclovir:
a. Analogue of acyclovir
b. Active against all herpes viruses including CMV
c. CMV can develop ganciclovir resistance by mutation
d. Low oral bioavailability given I.V.
e. Drug of choice for CMV infection in immunosupressed patients (eg. AIDS) : pneumonia, colitis, retinitis
Adverse effects:
a. Bone marrow supression : leukopenia and thrombocytopenia
b. CNS effects: headache, behavioral psychosis, coma, convulsions
c. Rashes, fever, vomiting
4. Idoxuridine and Trifluridine:
a. Topical agent for Herpes keratitis
b. Triflurdine (also for CMV) is better for H.simplex II keratoconjunctivits
5. Forscarnet:
a. Direct inhibitor of DNA polymerase and reverse transcriptase
b. An inorganic pyrophosphate analogue
ADR:
a. Nephrotoxicity (Renal diabetes like condition, acute renal failure)
b. Hypocalcemia, hypokalemia and hypomagnesemia
c. Anemia
d. Tremor, convulsions
e. Phlebitis (administered i.v.)
Use:
a. CMV retinitis and other CMV infections resistant to gancyclovir
b. H.simplex and Varicella Zoster resistant to acyclovir
c. HIV



Read more ANTIVIRAL DRUGS: Classification and Anti-Herpes Virus drugs | Medchrome

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