Respiratory diseases are diseases that affect the air passages, including the nasal passages, the bronchi and the lungs. They range from acute infections, such as pneumonia and bronchitis, to chronic conditions such as asthma and chronic obstructive pulmonary disease. These include diseases of the lung, pleural cavity, bronchial tubes, trachea, upper respiratory tract and of the nerves and muscles of breathing.
Respiratory disease is responsible for over 10% of hospitalizations and over 16% of deaths in Canada. The study of respiratory disease is known as pulmonology. A doctor who specializes in respiratory disease is known as a pulmonologist, a chest medicine specialist, a respiratory medicine specialist, a respirologist or a thoracic medicine specialist.
Respiratory diseases can be classified in many different ways
• by the organ involved
• by the pattern of symptoms
• by the cause of the disease
A. Obstructive lung diseases – are diseases of the lung where the bronchial tubes become narrowed making it hard to move air in and especially out of the lung.
B. Restrictive lung diseases – (also known as interstitial lung diseases) are a category of respiratory disease characterized by a loss of lung compliance, causing incomplete lung expansion and increased lung stiffness. E.g. in infant respiratory distress syndrome (IRDS)
C. Respiratory tract infections – Infections can affect any part of the respiratory system. They are traditionally divided into upper respiratory tract infections and lower respiratory tract infections.
D. Upper respiratory tract infections - The most common upper respiratory tract infection is the common cold however, infections of specific organs of the upper respiratory tract such as sinusitis, tonsillitis, otitis media, pharyngitis and laryngitis are also considered upper respiratory tract infections.
E. Lower respiratory tract infection - The most common lower respiratory tract infection in is pneumonia, a lung infection. Pneumonia is usually caused by bacteria, particularly Streptococcus pneumoniae in Western countries. Worldwide, tuberculosis is an important cause of pneumonia. Other pathogens such as viruses and fungi can cause pneumonia for example severe acute respiratory syndrome and pneumocystis pneumonia. A pneumonia may develop complications such as a lung abscess, a round cavity in the lung caused by the infection or an empyema, the spread of the infection to the pleural cavity.
F. Respiratory Tumors – Tumours of the respiratory system are either malignant or benign.
1. Malignant tumors, or cancers of the respiratory system, particularly lung cancers, are a major health problem responsible for 15% of all cancer diagnoses and 29% of all cancer deaths. The majority of respiratory system cancers are attributable to smoking tobacco.
The major types of respiratory system cancer are:
• Small cell lung cancer
• Non-small cell lung cancer
o Adenocarcinoma
o Large cell undifferentiated carcinoma
• Other lung cancers (carcinoid, Kaposi’s sarcoma, melanoma)
• Lymphoma
• Head and neck cancer
• Mesothelioma, usually caused by exposure to asbestos dust.
In addition, since many cancers spread via the bloodstream and the entire cardiac output passes through the lungs, it common for cancer metastases to occur the lung. Breast cancer may invade directly through local spread, and through lymph node metastases. After metastasis to the liver, colon cancer frequently metastasizes to the lung. Prostate cancer, germ cell cancer and renal cell carcinoma may also metastasize to the lung.
Treatment of respiratory system cancer depends on the type of cancer. Surgery (usually removal of part of the lung, a lobectomy or an entire lung, a pneumonectomy), chemotherapy and radiotherapy are all used. The chance of surviving lung cancer depends on the cancer stage at the time the cancer is diagnosed and is only about 14-17% overall. In the case of metastases to the lung, treatment can occasionally be curative but only in certain, rare circumstances.
2. Benign tumors are relatively rare causes of respiratory disease. Examples of benign tumors are:
• Pulmonary hamartoma
• Congenital malformations such as pulmonary sequestration and congenital cystic adenomatoid malformation (CCAM).
G. Pleural cavity diseases - diseases include empyema and mesothelioma which are mentioned above.
• A collection of fluid in the pleural cavity is known as a pleural effusion. This may be due to fluid shifting from the bloodstream into the pleural cavity due to conditions such as congestive heart failure and cirrhosis. It may also be due to inflammation of the pleura itself as can occur with infection, pulmonary embolus, tuberculosis, mesothelioma and other conditions.
• A pneumothorax is a hole in the pleura covering the lung allowing air in the lung to escape into the pleural cavity. The affected lung “collapses” like a deflated balloon. A tension pneumothorax is a particularly severe form of this condition where the air in the pleural cavity cannot escape, so the pneumothorax keeps getting bigger until it compresses the heart and blood vessels, leading to a life threatening situation.
H. Pulmonary vascular diseases
• Pulmonary embolism, a blood clot that forms in a vein, breaks free, travels through the heart and lodges in the lungs (thromboembolism). Large pulmonary emboli are fatal, causing sudden death. A number of other substances can also embolise to the lungs but they are much more rare: fat embolism (particularly after bony injury), amniotic fluid embolism (with complications of labour and delivery), air embolism (iatrogenic).
• Pulmonary arterial hypertension, elevated pressure in the pulmonary arteries. It can be idiopathic or due to the effects of another disease, particularly COPD. This can lead to strain on the right side of the heart, a condition known as cor pulmonale.
• Pulmonary edema, leakage of fluid from capillaries of the lung into the alveoli (or air spaces). It is usually due to congestive heart failure.
• Pulmonary hemorrhage, inflammation and damage to capillaries in the lung resulting in blood leaking into the alveoli. This may cause blood to be coughed up. Pulmonary hemorrhage can be due to auto-immune disorders such as Wegener’s Granulomatosis and Goodpasture’s syndrome.
I. Disorders of breathing mechanics
The brain co-ordinates breathing and sends messages via nerves to the muscles of respiration. The muscles produce the movements of breathing. Disorders of the brain’s control of breathing, the nerves or the muscles of respiration can affect the respiratory system. Common disorders of breathing mechanics are:
• Obstructive sleep apnea
• Central sleep apnea
• Amyotrophic lateral sclerosis
• Guillan-Barre syndrome
• Myasthenia gravis
Obesity is often associated with sleep apnea and can cause either an obstructive or a restrictive pattern on spirometry. Obesity reduces the movement of the chest wall which can, in extreme cases, result in the obesity-hypoventilation syndrome, a cause of respiratory failure.
POTENTIAL NURSING DIAGNOSIS FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND ASTHMA
1. Ineffective airway clearance
2. Impaired gas exchange
3. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR PNEUMONIA
1. Ineffective airway clearance
2. Impaired gas exchange
3. Risk for (spread) infection
4. Activity intolerance
5. Acute pain
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
7. Risk for deficient fluid volume
8. Risk for imbalanced nutrition less than body requirements
POTENTIAL NURSING DIAGNOSIS FOR LUNG CANCER: POSTOPERATIVE CARE
1. Impaired gas exchange
2. Ineffective airway clearance
3. Acute pain
4. Fear/ Anxiety
5. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR PNEUMOTHORAX/ HEMOTHORAX
1. Ineffective breathing pattern
2. Trauma/ Suffocation
3. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR RADICAL NECK SURGERY: LARYNGECTOMY (POSTOPERATIVE CARE)
1. Ineffective airway clearance
2. Risk for aspiration
3. Impaired verbal communication
4. Impaired skin or tissue integrity
5. Impaired oral mucus membrane
6. Acute pain
7. Imbalanced nutrition less than body requirements
8. Disturbed body image / Ineffective role performance
9. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR VENTILATORY ASSISTANCE (MECHANICAL)
1. Ineffective breathing pattern/ Impaired spontaneous ventilation
2. Ineffective airway clearance
3. Impaired verbal communication
4. Fear/ anxiety
5. Impaired oral mucus membrane
6. Imbalanced nutrition less than body requirements
7. Risk for infection
8. Risk for dysfunctional ventilatory weaning response
9. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR PULMONARY TUBERCULOSIS (PTB)
1. Risk for (spread/ reactivation) infection
2. Ineffective airway clearance
3. Risk for impaired gas exchange
4. Imbalanced nutrition, less than body requirements
5. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
Thursday, June 17, 2010
Cardiovascular diseases (CVDs)
Cardiovascular diseases (CVDs) are a group of disorders of the heart and blood vessels and include:
• Coronary heart disease – disease of the blood vessels supplying the heart muscle
• Cerebrovascular disease – disease of the blood vessels supplying the brain
• Peripheral arterial disease – disease of blood vessels supplying the arms and legs
• Rheumatic heart disease – damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria
• Congenital heart disease – malformations of heart structure existing at birth.
• Deep vein thrombosis and pulmonary embolism – blood clots in the leg veins, which can dislodge and move to the heart and lungs.
Heart attacks and strokes are usually acute events and are mainly caused by a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding from a blood vessel in the brain or from blood clots.
FACTS ABOUT CARDIOVASCULAR DISEASES
• CVDs are the number one cause of death globally: more people die annually from CVDs than from any other cause;
• An estimated 17.5 million people died from CVDs in 2005, representing 30% of all global deaths. Of these deaths, an estimated 7.6 million were due to coronary heart disease and 5.7 million were due to stroke.
• Over 80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women;
• By 2015, almost 20 million people will die from CVDs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death.
CAUSES OF CARDIOVASCULAR DISEASES
• The causes of CVDs are well established and well known. The most important causes of heart disease and stroke are unhealthy diet, physical inactivity and tobacco use. These are called ‘modifiable risk factors’.
• The effects of unhealthy diet and physical inactivity may show up in individuals as raised blood pressure, raised blood glucose, raised blood lipids, and overweight and obesity; these are called ‘intermediate risk factors’.
• The major modifiable risk factors are responsible for about 80% of coronary heart disease and cerebrovascular disease.
• There are also a number of underlying determinants of chronic diseases, or, if you like, "the causes of the causes". These are a reflection of the major forces driving social, economic and cultural change – globalization, urbanization, and population ageing. Other determinants of CVDs are poverty and stress.
COMMON SYMPTOMS OF CARDIOVASCULAR DISEASES
• Often, there are no symptoms of the underlying disease of the blood vessels. A heart attack or stroke may be the first warning of underlying disease.
• Symptoms of a heart attack include: pain or discomfort in the centre of the chest; pain or discomfort in the arms, the left shoulder, elbows, jaw, or back. In addition the person may experience difficulty in breathing or shortness of breath; feeling sick or vomiting; feeling light-headed or faint; breaking into a cold sweat; and becoming pale.
• Women are more likely to have shortness of breath, nausea, vomiting, and back or jaw pain.
• The most common symptom of a stroke is sudden weakness of the face, arm, or leg, most often on one side of the body. Other symptoms include sudden onset of: numbness of the face, arm, or leg, especially on one side of the body; confusion, difficulty speaking or understanding speech; difficulty seeing with one or both eyes; difficulty walking, dizziness, loss of balance or coordination; severe headache with no known cause; and fainting or unconsciousness.
• People experiencing these symptoms should seek medical care immediately.
POTENTIAL NURSING DIAGNOSIS FOR SEVERE HYPERTENSION:
1. Risk for decreased cardiac output
2. Activity intolerance
3. Acute headache pain
4. Imbalanced nutrition more than body requirements
5. Ineffective coping
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR CHRONIC HEART FAILURE (CHF)
1. Decreased Cardiac output
2. Activity intolerance
3. Excess fluid volume
4. Risk for impaired gas exchange
5. Risk for impaired skin integrity
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR ANGINA (CORONARY ARTERY DISEASE)
1. Acute pain
2. Risk for decreased cardiac output
3. Anxiety
4. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR MYOCARDIAL INFARCTION
1. Acute pain
2. Activity intolerance
3. Anxiety/ Fear
4. Risk for decreased cardiac output
5. Ineffective tissue perfusion
6. Risk for excess fluid volume
7. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR DYSRHYTHMIAS (INCLUDING DIGITALIS TOXICITY)
1. Risk for decreased cardiac output
2. Risk for poisoning, digitalis toxicity
3. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR CARDIAC SURGERY: POSTOPERATIVE CARE – CORONARY ARTERY BYPASS GRAFT (CABG), MINIMALLY INVASIVE DIRECT CORONARY ARTERY BYPASS (MIDCAB), CARDIOMYOPLASTY, VALVE REPLACEMENT
1. Risk for decreased cardiac output
2. Acute pain
3. Ineffective role performance
4. Risk for ineffective breathing pattern
5. Impaired skin integrity
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR THROMBOPHLEBITIS: DEEP VEIN THROMBOSIS (INCLUDING PULONARY EMBOLI CONSIDERATIONS)
1. Ineffective tissue perfusion
2. Acute pain
3. Impaired gas exchange (in presence of pulmonary embolus)
4. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs.
• Coronary heart disease – disease of the blood vessels supplying the heart muscle
• Cerebrovascular disease – disease of the blood vessels supplying the brain
• Peripheral arterial disease – disease of blood vessels supplying the arms and legs
• Rheumatic heart disease – damage to the heart muscle and heart valves from rheumatic fever, caused by streptococcal bacteria
• Congenital heart disease – malformations of heart structure existing at birth.
• Deep vein thrombosis and pulmonary embolism – blood clots in the leg veins, which can dislodge and move to the heart and lungs.
Heart attacks and strokes are usually acute events and are mainly caused by a blockage that prevents blood from flowing to the heart or brain. The most common reason for this is a build-up of fatty deposits on the inner walls of the blood vessels that supply the heart or brain. Strokes can also be caused by bleeding from a blood vessel in the brain or from blood clots.
FACTS ABOUT CARDIOVASCULAR DISEASES
• CVDs are the number one cause of death globally: more people die annually from CVDs than from any other cause;
• An estimated 17.5 million people died from CVDs in 2005, representing 30% of all global deaths. Of these deaths, an estimated 7.6 million were due to coronary heart disease and 5.7 million were due to stroke.
• Over 80% of CVD deaths take place in low- and middle-income countries and occur almost equally in men and women;
• By 2015, almost 20 million people will die from CVDs, mainly from heart disease and stroke. These are projected to remain the single leading causes of death.
CAUSES OF CARDIOVASCULAR DISEASES
• The causes of CVDs are well established and well known. The most important causes of heart disease and stroke are unhealthy diet, physical inactivity and tobacco use. These are called ‘modifiable risk factors’.
• The effects of unhealthy diet and physical inactivity may show up in individuals as raised blood pressure, raised blood glucose, raised blood lipids, and overweight and obesity; these are called ‘intermediate risk factors’.
• The major modifiable risk factors are responsible for about 80% of coronary heart disease and cerebrovascular disease.
• There are also a number of underlying determinants of chronic diseases, or, if you like, "the causes of the causes". These are a reflection of the major forces driving social, economic and cultural change – globalization, urbanization, and population ageing. Other determinants of CVDs are poverty and stress.
COMMON SYMPTOMS OF CARDIOVASCULAR DISEASES
• Often, there are no symptoms of the underlying disease of the blood vessels. A heart attack or stroke may be the first warning of underlying disease.
• Symptoms of a heart attack include: pain or discomfort in the centre of the chest; pain or discomfort in the arms, the left shoulder, elbows, jaw, or back. In addition the person may experience difficulty in breathing or shortness of breath; feeling sick or vomiting; feeling light-headed or faint; breaking into a cold sweat; and becoming pale.
• Women are more likely to have shortness of breath, nausea, vomiting, and back or jaw pain.
• The most common symptom of a stroke is sudden weakness of the face, arm, or leg, most often on one side of the body. Other symptoms include sudden onset of: numbness of the face, arm, or leg, especially on one side of the body; confusion, difficulty speaking or understanding speech; difficulty seeing with one or both eyes; difficulty walking, dizziness, loss of balance or coordination; severe headache with no known cause; and fainting or unconsciousness.
• People experiencing these symptoms should seek medical care immediately.
POTENTIAL NURSING DIAGNOSIS FOR SEVERE HYPERTENSION:
1. Risk for decreased cardiac output
2. Activity intolerance
3. Acute headache pain
4. Imbalanced nutrition more than body requirements
5. Ineffective coping
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR CHRONIC HEART FAILURE (CHF)
1. Decreased Cardiac output
2. Activity intolerance
3. Excess fluid volume
4. Risk for impaired gas exchange
5. Risk for impaired skin integrity
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR ANGINA (CORONARY ARTERY DISEASE)
1. Acute pain
2. Risk for decreased cardiac output
3. Anxiety
4. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR MYOCARDIAL INFARCTION
1. Acute pain
2. Activity intolerance
3. Anxiety/ Fear
4. Risk for decreased cardiac output
5. Ineffective tissue perfusion
6. Risk for excess fluid volume
7. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR DYSRHYTHMIAS (INCLUDING DIGITALIS TOXICITY)
1. Risk for decreased cardiac output
2. Risk for poisoning, digitalis toxicity
3. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR CARDIAC SURGERY: POSTOPERATIVE CARE – CORONARY ARTERY BYPASS GRAFT (CABG), MINIMALLY INVASIVE DIRECT CORONARY ARTERY BYPASS (MIDCAB), CARDIOMYOPLASTY, VALVE REPLACEMENT
1. Risk for decreased cardiac output
2. Acute pain
3. Ineffective role performance
4. Risk for ineffective breathing pattern
5. Impaired skin integrity
6. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs
POTENTIAL NURSING DIAGNOSIS FOR THROMBOPHLEBITIS: DEEP VEIN THROMBOSIS (INCLUDING PULONARY EMBOLI CONSIDERATIONS)
1. Ineffective tissue perfusion
2. Acute pain
3. Impaired gas exchange (in presence of pulmonary embolus)
4. Deficient knowledge (Learning Need) regarding condition, treatment plan, self-care, and discharge needs.
Hormones of the Reproductive System
Hormones of the Reproductive System
Females
The ovaries of sexually-mature females secrete:
• a mixture of estrogens of which 17β-estradiol is the most abundant (and most potent).
• progesterone.
Estrogens
Estrogens are steroids. They
• are primarily responsible for the conversion of girls into sexually-mature women.
o development of breasts
o further development of the uterus and vagina
o broadening of the pelvis
o growth of pubic and axillary hair
o increase in adipose (fat) tissue
• participate in the monthly preparation of the body for a possible pregnancy
• participate in pregnancy if it occurs
Estrogens also have non-reproductive effects.
• They antagonize the effects of the parathyroid hormone, minimizing the loss of calcium from bones and thus helping to keep bones strong.
• They promote blood clotting.
Progesterone
Progesterone is also a steroid. It has many effects in the body, some having nothing to do with sex and reproduction. Here we shall focus on the role of progesterone in the menstrual cycle and pregnancy [Link to a special page on progesterone].
How estrogens and progesterone achieve their effects
Steroids like estrogens and progesterone are small, hydrophobic molecules that are transported in the blood bound to a serum globulin.
• In "target" cells, i.e., cells that change their gene expression in response to the hormone, they bind to receptor proteins located in the cytoplasm and/or nucleus.
• The hormone-receptor complex enters the nucleus (if it formed in the cytoplasm) [View] and
• binds to specific sequences of DNA, called the estrogen (or progesterone) response elements
• Response elements are located in the promoters of genes.
• The hormone-receptor complex acts as a transcription factor (often recruiting other transcription factors to help) which
• turns on (sometimes off) transcription of those genes.
• Gene expression in the cell produces the response.
Regulation of Estrogen and Progesterone
The synthesis and secretion of estrogens is stimulated by follicle-stimulating hormone (FSH), which is, in turn, controlled by the hypothalamic gonadotropin releasing hormone (GnRH).
Hypothalamus → GnRH → Pituitary → FSH → Follicle → Estrogens
High levels of estrogens suppress the release of GnRH (bar) providing a negative-feedback control of hormone levels.
It works like this: Secretion of GnRH depends on certain neurons in the hypothalamus which express a gene (KiSS-1) encoding a protein of 145 amino acids. From this are cut several short peptides collectively called kisspeptin. These are secreted and bind to G-protein-coupled receptors on the surface of the GnRH neurons stimulating them to release GnRH. However, high levels of estrogen (or progesterone or testosterone) inhibit the secretion of kisspeptin and suppress further production of those hormones.
Progesterone production is stimulated by luteinizing hormone (LH), which is also stimulated by GnRH.
Hypothalamus → GnRH → Pituitary → LH → Corpus luteum → Progesterone
Elevated levels of progesterone control themselves by the same negative feedback loop used by estrogen (and testosterone).
The Menstrual Cycle
About every 28 days, some blood and other products of the disintegration of the inner lining of the uterus (the endometrium) are discharged from the uterus, a process called menstruation. During this time a new follicle begins to develop in one of the ovaries. After menstruation ceases, the follicle continues to develop, secreting an increasing amount of estrogen as it does so.
• The rising level of estrogen causes the endometrium to become thicker and more richly supplied with blood vessels and glands.
• A rising level of LH causes the developing egg within the follicle to complete the first meiotic division (meiosis I), forming a secondary oocyte.
• After about two weeks, there is a sudden surge in the production of LH.
• This surge in LH triggers ovulation: the release of the secondary oocyte into the fallopian tube.
• Under the continued influence of LH, the now-empty follicle develops into a corpus luteum (hence the name luteinizing hormone for LH).
• Stimulated by LH, the corpus luteum secretes progesterone which
o continues the preparation of the endometrium for a possible pregnancy
o inhibits the contraction of the uterus
o inhibits the development of a new follicle
• If fertilization does not occur (which is usually the case),
o the rising level of progesterone inhibits the release of GnRH which, in turn,
o inhibits further production of progesterone.
• As the progesterone level drops,
o the corpus luteum begins to degenerate;
o the endometrium begins to break down, its cells committing programmed cell death (apoptosis);
o the inhibition of uterine contraction is lifted, and
o the bleeding and cramps of menstruation begin.
Pregnancy
Fertilization of the egg takes place within the fallopian tube. As the fertilized egg passes down the tube, it undergoes its first mitotic divisions. By the end of the week, the developing embryo has become a hollow ball of cells called a blastocyst. At this time, the blastocyst reaches the uterus and embeds itself in the endometrium, a process called implantation. With implantation, pregnancy is established.
The blastocyst has two parts:
• the inner cell mass, which will become the baby, and
• the trophoblast, which will
o develop into the placenta and umbilical cord
o and begin to secrete human chorionic gonadotropin (HCG).
HCG is a glycoprotein. It is a dimer of
• the same alpha subunit (of 92 amino acids) used by TSH, FSH, and LH and
• a unique beta subunit (of 145 amino acids).
HCG behaves much like FSH and LH with one crucial exception: it is NOT inhibited by a rising level of progesterone. Thus HCG prevents the deterioration of the corpus luteum at the end of the fourth week and enables pregnancy to continue beyond the end of the normal menstrual cycle.
Because only the implanted trophoblast makes HCG, its early appearance in the urine of pregnant women provides the basis for the most widely used test for pregnancy (which can provide a positive signal even before menstruation would have otherwise begun).
As pregnancy continues, the placenta becomes a major source of progesterone, and its presence is essential to maintain pregnancy. Mothers at risk of giving birth too soon can be given a synthetic progestin to help them retain the fetus until it is full-term.
Birth
Toward the end of pregnancy,
• The placenta releases large amounts of CRH which stimulates the pituitary glands of both mother and her fetus to secrete
• ACTH, which acts on their adrenal glands causing them to release the estrogen precursor dehydroepiandrosterone sulfate (DHEAS).
• This is converted into estrogen by the placenta.
• The rising level of estrogen causes the smooth muscle cells of the uterus to
o synthesize connexins and form gap junctions. Gap junctions connect the cells electrically so that they contract together as labor begins.
o express receptors for oxytocin.
• Oxytocin is secreted by the posterior lobe of the pituitary as well as by the uterus.
• Prostaglandins are synthesized in the placenta and uterus.
• The normal inhibition of uterine contraction by progesterone is turned off by several mechanisms while
• both oxytocin and prostaglandins cause the uterus to contract and labor begins.
Three or four days after the baby is born, the breasts begin to secrete milk.
• Milk synthesis is stimulated by the pituitary hormone prolactin (PRL), and
• its release from the breast is stimulated by oxytocin.
• Milk contains an inhibitory peptide. If the breasts are not fully emptied, the peptide accumulates and inhibits milk production. This autocrine action thus matches supply with demand.
Other Hormones
• Relaxin
As the time of birth approaches in some animals (e.g., pigs, rats) , this polypeptide has been found to:
o relax the pubic ligaments
o soften and enlarge the opening to the cervix.
Relaxin is found in pregnant humans but at higher levels early in pregnancy than close to the time of birth. Relaxin promotes angiogenesis, and in humans it probably plays a more important role in the development of the interface between the uterus and the placenta that it does in the birth process.
• Activins, Inhibins, Follistatin.
These proteins are synthesized within the follicle. Activins and inhibins bind to follistatin. Activins increase the action of FSH; inhibins, as their name suggests, inhibit it. How important they are in humans remains to be seen. However the important role that activin and follistatin play in the embryonic development of vertebrates justifies mentioning them here.
Oral contraceptives: the "pill"
The feedback inhibition of GnRH secretion by estrogens and progesterone provides the basis for the most widely-used form of contraception. Dozens of different formulations of synthetic estrogens or progestins (progesterone relatives) — or both — are available. Their inhibition of GnRH prevents the mid-cycle surge of LH and ovulation. Hence there is no egg to be fertilized.
Usually the preparation is taken for about three weeks and then stopped long enough for normal menstruation to occur.
The main side-effects of the pill stem from an increased tendency for blood clots to form (estrogen enhances clotting of the blood).
RU-486
RU-486 (also known as mifepristone) is a synthetic steroid related to progesterone. Unlike the synthetic progestins used in oral contraceptives that mimic the actions of progesterone, RU-486 is a progesterone antagonist; that is, it blocks the action of progesterone. It does this by binding more tightly to the progesterone receptor than progesterone itself but without the normal biological effects:
• The RU-486/receptor complex is not active as a transcription factor.
• Thus genes that are turned on by progesterone are turned off by RU-486.
• The proteins needed to establish and maintain pregnancy are no longer synthesized.
• The endometrium breaks down.
• The embryo detaches from it and can no longer make chorionic gonadotropin (HCG).
• Consequently the corpus luteum ceases its production of progesterone.
• The inhibition on uterine contraction is lifted.
• Soon the embryo and the breakdown products of the endometrium are expelled.
These properties of RU-486 have caused it to be used to induce abortion of an unwanted fetus. In practice, the physician assists the process by giving a synthetic prostaglandin (e.g., misoprostol [Cytotec®]) 36–48 hours after giving the dose of RU-486. Use of RU-486 is generally limited to the first seven weeks of pregnancy.
RU-486 has been used for many years in some countries. However, the controversies surrounding abortion in the United States kept it from being authorized for use here until September 2000.
Menopause
The menstrual cycle continues for many years. But eventually, usually between 42 and 52 years of age, the follicles become less responsive to FSH and LH. They begin to secrete less estrogen. Ovulation and menstruation become irregular and finally cease. This cessation is called menopause.
With levels of estrogen now running one-tenth or less of what they had been, the hypothalamus is released from their inhibitory influence (bar). As a result it now stimulates the pituitary to increased activity. The concentrations of FSH and LH in the blood rise to ten or more times their former values. These elevated levels may cause a variety of unpleasant physical and emotional symptoms.
Hormone replacement therapy (HRT)
Many menopausal women elect to take a combination of estrogen and progesterone after they cease to make their own. The benefits are:
• reduction in the unpleasant symptoms of the menopause
• a reduction in the loss of calcium from bones and thus a reduction in osteoporosis and the fractures that accompany it.
It was also believed that HRT reduced the risk of cardiovascular disease. However, a recent study of 16,000 menopausal women was stopped 3 years early when it was found that, in fact, HRT increased (albeit only slightly) not decreased the incidence of cardiovascular disease.
Perhaps synthetic selective estrogen response modulators or SERMs (raloxifene is an example) will provide the protective effects without the harmful ones. Stay tuned.
Environmental estrogens
Some substances that find their way into the environment, such as
• DDE, a breakdown product of the once widely-used insecticide DDT,
• DDT itself (still used in some countries (e.g., Mexico), and
• PCBs, chemicals once used in a wide variety of industrial applications
can bind to the estrogen (and androgen) receptors and mimic (weakly) the effects of the hormone. This has created anxiety that they may be responsible for harmful effects such as cancer and low sperm counts.
However, there is as yet little evidence to support these worries.
• No epidemiological relationship has been found between the incidence of breast cancer and the levels of these compounds in the body.
• As for laboratory studies that found a synergistic effect of two of these substances on receptor binding (findings that created the great alarm), these have not been replicated in other laboratories, and the authors of the original report have since withdrawn it as invalid.
________________________________________
Males
The principal androgen (male sex hormone) is testosterone. This steroid is manufactured by the interstitial (Leydig) cells of the testes. Secretion of testosterone increases sharply at puberty and is responsible for the development of the so-called secondary sexual characteristics (e.g., beard) of men.
Testosterone is also essential for the production of sperm.
Link to diagram showing location and structure of the testes.
Production of testosterone is controlled by the release of luteinizing hormone (LH) from the anterior lobe of the pituitary gland, which is in turn controlled by the release of GnRH from the hypothalamus. LH is also called interstitial cell stimulating hormone (ICSH).
Hypothalamus → GnRH → Pituitary → LH → Testes → Testosterone
The level of testosterone is under negative-feedback control: a rising level of testosterone suppresses the release of GnRH from the hypothalamus. This is exactly parallel to the control of estrogen secretion in females. [Look back]
Males need estrogen, too!
In 1994, a man was described who was homozygous for a mutation in the gene encoding the estrogen receptor. A single nonsense mutation had converted a codon (CGA) for arginine early in the protein into a STOP codon (TGA). Thus no complete estrogen receptor could be synthesized.
This man was extra tall, had osteoporosis and "knock-knees", but was otherwise well. His genetic defect confirms the important role that estrogen has in both sexes for normal bone development.
It is not known whether this man (or any of the few other men who have been found with the same disorder) is fertile or not. However, an article in the 4 December 1997 issue of Nature reports that male mice whose estrogen receptor gene has been "knocked out" are sterile.
Anabolic steroids
A number of synthetic androgens are used for therapeutic purposes. These drugs promote an increase in muscle size with resulting increases in strength and speed. This has made them popular with some athletes, e.g., weight lifters, cyclists, runners, swimmers, professional football players.
Usually these athletes (females as well as males) take doses far greater than those used in standard therapy. Such illicit use carries dangers (besides being banned from an event because of a positive drug test): acne, a decrease in libido, and — in males — testicle size and sperm counts to name a few.
Genetic abnormalities of gonadal function.
Many things can go wrong with sexual development in both males and females; fortunately rarely. Let's look only at a few that clearly result from the inheritance of single-gene mutations.
• Inherited mutations in both copies of the gene encoding the GnRH receptor result in failure to develop at puberty.
• Mutations in the gene encoding the LH receptor prevent normal sexual development in both sexes.
• Mutations in the gene encoding the FSH receptor block development of the gonads in both males and females.
• Mutations in any of the genes encoding the enzymes for synthesis and metabolism of testosterone interfere with normal sexual function in males.
• A similar spectrum of disorders in males can be caused by mutations in the genes encoding the androgen receptor.
Females
The ovaries of sexually-mature females secrete:
• a mixture of estrogens of which 17β-estradiol is the most abundant (and most potent).
• progesterone.
Estrogens
Estrogens are steroids. They
• are primarily responsible for the conversion of girls into sexually-mature women.
o development of breasts
o further development of the uterus and vagina
o broadening of the pelvis
o growth of pubic and axillary hair
o increase in adipose (fat) tissue
• participate in the monthly preparation of the body for a possible pregnancy
• participate in pregnancy if it occurs
Estrogens also have non-reproductive effects.
• They antagonize the effects of the parathyroid hormone, minimizing the loss of calcium from bones and thus helping to keep bones strong.
• They promote blood clotting.
Progesterone
Progesterone is also a steroid. It has many effects in the body, some having nothing to do with sex and reproduction. Here we shall focus on the role of progesterone in the menstrual cycle and pregnancy [Link to a special page on progesterone].
How estrogens and progesterone achieve their effects
Steroids like estrogens and progesterone are small, hydrophobic molecules that are transported in the blood bound to a serum globulin.
• In "target" cells, i.e., cells that change their gene expression in response to the hormone, they bind to receptor proteins located in the cytoplasm and/or nucleus.
• The hormone-receptor complex enters the nucleus (if it formed in the cytoplasm) [View] and
• binds to specific sequences of DNA, called the estrogen (or progesterone) response elements
• Response elements are located in the promoters of genes.
• The hormone-receptor complex acts as a transcription factor (often recruiting other transcription factors to help) which
• turns on (sometimes off) transcription of those genes.
• Gene expression in the cell produces the response.
Regulation of Estrogen and Progesterone
The synthesis and secretion of estrogens is stimulated by follicle-stimulating hormone (FSH), which is, in turn, controlled by the hypothalamic gonadotropin releasing hormone (GnRH).
Hypothalamus → GnRH → Pituitary → FSH → Follicle → Estrogens
High levels of estrogens suppress the release of GnRH (bar) providing a negative-feedback control of hormone levels.
It works like this: Secretion of GnRH depends on certain neurons in the hypothalamus which express a gene (KiSS-1) encoding a protein of 145 amino acids. From this are cut several short peptides collectively called kisspeptin. These are secreted and bind to G-protein-coupled receptors on the surface of the GnRH neurons stimulating them to release GnRH. However, high levels of estrogen (or progesterone or testosterone) inhibit the secretion of kisspeptin and suppress further production of those hormones.
Progesterone production is stimulated by luteinizing hormone (LH), which is also stimulated by GnRH.
Hypothalamus → GnRH → Pituitary → LH → Corpus luteum → Progesterone
Elevated levels of progesterone control themselves by the same negative feedback loop used by estrogen (and testosterone).
The Menstrual Cycle
About every 28 days, some blood and other products of the disintegration of the inner lining of the uterus (the endometrium) are discharged from the uterus, a process called menstruation. During this time a new follicle begins to develop in one of the ovaries. After menstruation ceases, the follicle continues to develop, secreting an increasing amount of estrogen as it does so.
• The rising level of estrogen causes the endometrium to become thicker and more richly supplied with blood vessels and glands.
• A rising level of LH causes the developing egg within the follicle to complete the first meiotic division (meiosis I), forming a secondary oocyte.
• After about two weeks, there is a sudden surge in the production of LH.
• This surge in LH triggers ovulation: the release of the secondary oocyte into the fallopian tube.
• Under the continued influence of LH, the now-empty follicle develops into a corpus luteum (hence the name luteinizing hormone for LH).
• Stimulated by LH, the corpus luteum secretes progesterone which
o continues the preparation of the endometrium for a possible pregnancy
o inhibits the contraction of the uterus
o inhibits the development of a new follicle
• If fertilization does not occur (which is usually the case),
o the rising level of progesterone inhibits the release of GnRH which, in turn,
o inhibits further production of progesterone.
• As the progesterone level drops,
o the corpus luteum begins to degenerate;
o the endometrium begins to break down, its cells committing programmed cell death (apoptosis);
o the inhibition of uterine contraction is lifted, and
o the bleeding and cramps of menstruation begin.
Pregnancy
Fertilization of the egg takes place within the fallopian tube. As the fertilized egg passes down the tube, it undergoes its first mitotic divisions. By the end of the week, the developing embryo has become a hollow ball of cells called a blastocyst. At this time, the blastocyst reaches the uterus and embeds itself in the endometrium, a process called implantation. With implantation, pregnancy is established.
The blastocyst has two parts:
• the inner cell mass, which will become the baby, and
• the trophoblast, which will
o develop into the placenta and umbilical cord
o and begin to secrete human chorionic gonadotropin (HCG).
HCG is a glycoprotein. It is a dimer of
• the same alpha subunit (of 92 amino acids) used by TSH, FSH, and LH and
• a unique beta subunit (of 145 amino acids).
HCG behaves much like FSH and LH with one crucial exception: it is NOT inhibited by a rising level of progesterone. Thus HCG prevents the deterioration of the corpus luteum at the end of the fourth week and enables pregnancy to continue beyond the end of the normal menstrual cycle.
Because only the implanted trophoblast makes HCG, its early appearance in the urine of pregnant women provides the basis for the most widely used test for pregnancy (which can provide a positive signal even before menstruation would have otherwise begun).
As pregnancy continues, the placenta becomes a major source of progesterone, and its presence is essential to maintain pregnancy. Mothers at risk of giving birth too soon can be given a synthetic progestin to help them retain the fetus until it is full-term.
Birth
Toward the end of pregnancy,
• The placenta releases large amounts of CRH which stimulates the pituitary glands of both mother and her fetus to secrete
• ACTH, which acts on their adrenal glands causing them to release the estrogen precursor dehydroepiandrosterone sulfate (DHEAS).
• This is converted into estrogen by the placenta.
• The rising level of estrogen causes the smooth muscle cells of the uterus to
o synthesize connexins and form gap junctions. Gap junctions connect the cells electrically so that they contract together as labor begins.
o express receptors for oxytocin.
• Oxytocin is secreted by the posterior lobe of the pituitary as well as by the uterus.
• Prostaglandins are synthesized in the placenta and uterus.
• The normal inhibition of uterine contraction by progesterone is turned off by several mechanisms while
• both oxytocin and prostaglandins cause the uterus to contract and labor begins.
Three or four days after the baby is born, the breasts begin to secrete milk.
• Milk synthesis is stimulated by the pituitary hormone prolactin (PRL), and
• its release from the breast is stimulated by oxytocin.
• Milk contains an inhibitory peptide. If the breasts are not fully emptied, the peptide accumulates and inhibits milk production. This autocrine action thus matches supply with demand.
Other Hormones
• Relaxin
As the time of birth approaches in some animals (e.g., pigs, rats) , this polypeptide has been found to:
o relax the pubic ligaments
o soften and enlarge the opening to the cervix.
Relaxin is found in pregnant humans but at higher levels early in pregnancy than close to the time of birth. Relaxin promotes angiogenesis, and in humans it probably plays a more important role in the development of the interface between the uterus and the placenta that it does in the birth process.
• Activins, Inhibins, Follistatin.
These proteins are synthesized within the follicle. Activins and inhibins bind to follistatin. Activins increase the action of FSH; inhibins, as their name suggests, inhibit it. How important they are in humans remains to be seen. However the important role that activin and follistatin play in the embryonic development of vertebrates justifies mentioning them here.
Oral contraceptives: the "pill"
The feedback inhibition of GnRH secretion by estrogens and progesterone provides the basis for the most widely-used form of contraception. Dozens of different formulations of synthetic estrogens or progestins (progesterone relatives) — or both — are available. Their inhibition of GnRH prevents the mid-cycle surge of LH and ovulation. Hence there is no egg to be fertilized.
Usually the preparation is taken for about three weeks and then stopped long enough for normal menstruation to occur.
The main side-effects of the pill stem from an increased tendency for blood clots to form (estrogen enhances clotting of the blood).
RU-486
RU-486 (also known as mifepristone) is a synthetic steroid related to progesterone. Unlike the synthetic progestins used in oral contraceptives that mimic the actions of progesterone, RU-486 is a progesterone antagonist; that is, it blocks the action of progesterone. It does this by binding more tightly to the progesterone receptor than progesterone itself but without the normal biological effects:
• The RU-486/receptor complex is not active as a transcription factor.
• Thus genes that are turned on by progesterone are turned off by RU-486.
• The proteins needed to establish and maintain pregnancy are no longer synthesized.
• The endometrium breaks down.
• The embryo detaches from it and can no longer make chorionic gonadotropin (HCG).
• Consequently the corpus luteum ceases its production of progesterone.
• The inhibition on uterine contraction is lifted.
• Soon the embryo and the breakdown products of the endometrium are expelled.
These properties of RU-486 have caused it to be used to induce abortion of an unwanted fetus. In practice, the physician assists the process by giving a synthetic prostaglandin (e.g., misoprostol [Cytotec®]) 36–48 hours after giving the dose of RU-486. Use of RU-486 is generally limited to the first seven weeks of pregnancy.
RU-486 has been used for many years in some countries. However, the controversies surrounding abortion in the United States kept it from being authorized for use here until September 2000.
Menopause
The menstrual cycle continues for many years. But eventually, usually between 42 and 52 years of age, the follicles become less responsive to FSH and LH. They begin to secrete less estrogen. Ovulation and menstruation become irregular and finally cease. This cessation is called menopause.
With levels of estrogen now running one-tenth or less of what they had been, the hypothalamus is released from their inhibitory influence (bar). As a result it now stimulates the pituitary to increased activity. The concentrations of FSH and LH in the blood rise to ten or more times their former values. These elevated levels may cause a variety of unpleasant physical and emotional symptoms.
Hormone replacement therapy (HRT)
Many menopausal women elect to take a combination of estrogen and progesterone after they cease to make their own. The benefits are:
• reduction in the unpleasant symptoms of the menopause
• a reduction in the loss of calcium from bones and thus a reduction in osteoporosis and the fractures that accompany it.
It was also believed that HRT reduced the risk of cardiovascular disease. However, a recent study of 16,000 menopausal women was stopped 3 years early when it was found that, in fact, HRT increased (albeit only slightly) not decreased the incidence of cardiovascular disease.
Perhaps synthetic selective estrogen response modulators or SERMs (raloxifene is an example) will provide the protective effects without the harmful ones. Stay tuned.
Environmental estrogens
Some substances that find their way into the environment, such as
• DDE, a breakdown product of the once widely-used insecticide DDT,
• DDT itself (still used in some countries (e.g., Mexico), and
• PCBs, chemicals once used in a wide variety of industrial applications
can bind to the estrogen (and androgen) receptors and mimic (weakly) the effects of the hormone. This has created anxiety that they may be responsible for harmful effects such as cancer and low sperm counts.
However, there is as yet little evidence to support these worries.
• No epidemiological relationship has been found between the incidence of breast cancer and the levels of these compounds in the body.
• As for laboratory studies that found a synergistic effect of two of these substances on receptor binding (findings that created the great alarm), these have not been replicated in other laboratories, and the authors of the original report have since withdrawn it as invalid.
________________________________________
Males
The principal androgen (male sex hormone) is testosterone. This steroid is manufactured by the interstitial (Leydig) cells of the testes. Secretion of testosterone increases sharply at puberty and is responsible for the development of the so-called secondary sexual characteristics (e.g., beard) of men.
Testosterone is also essential for the production of sperm.
Link to diagram showing location and structure of the testes.
Production of testosterone is controlled by the release of luteinizing hormone (LH) from the anterior lobe of the pituitary gland, which is in turn controlled by the release of GnRH from the hypothalamus. LH is also called interstitial cell stimulating hormone (ICSH).
Hypothalamus → GnRH → Pituitary → LH → Testes → Testosterone
The level of testosterone is under negative-feedback control: a rising level of testosterone suppresses the release of GnRH from the hypothalamus. This is exactly parallel to the control of estrogen secretion in females. [Look back]
Males need estrogen, too!
In 1994, a man was described who was homozygous for a mutation in the gene encoding the estrogen receptor. A single nonsense mutation had converted a codon (CGA) for arginine early in the protein into a STOP codon (TGA). Thus no complete estrogen receptor could be synthesized.
This man was extra tall, had osteoporosis and "knock-knees", but was otherwise well. His genetic defect confirms the important role that estrogen has in both sexes for normal bone development.
It is not known whether this man (or any of the few other men who have been found with the same disorder) is fertile or not. However, an article in the 4 December 1997 issue of Nature reports that male mice whose estrogen receptor gene has been "knocked out" are sterile.
Anabolic steroids
A number of synthetic androgens are used for therapeutic purposes. These drugs promote an increase in muscle size with resulting increases in strength and speed. This has made them popular with some athletes, e.g., weight lifters, cyclists, runners, swimmers, professional football players.
Usually these athletes (females as well as males) take doses far greater than those used in standard therapy. Such illicit use carries dangers (besides being banned from an event because of a positive drug test): acne, a decrease in libido, and — in males — testicle size and sperm counts to name a few.
Genetic abnormalities of gonadal function.
Many things can go wrong with sexual development in both males and females; fortunately rarely. Let's look only at a few that clearly result from the inheritance of single-gene mutations.
• Inherited mutations in both copies of the gene encoding the GnRH receptor result in failure to develop at puberty.
• Mutations in the gene encoding the LH receptor prevent normal sexual development in both sexes.
• Mutations in the gene encoding the FSH receptor block development of the gonads in both males and females.
• Mutations in any of the genes encoding the enzymes for synthesis and metabolism of testosterone interfere with normal sexual function in males.
• A similar spectrum of disorders in males can be caused by mutations in the genes encoding the androgen receptor.
Migraine
Migraine
Migraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men.[1][2] The word migraine was borrowed from Old French migraigne (originally as "megrim", but respelled in 1777 on a contemporary French model). The French term derived from a vulgar pronunciation of the Late Latin word hemicrania, itself based on Greek hemikrania, from Greek roots for "half" and "skull".[3]
The typical migraine headache is unilateral (affecting one half of the head) and pulsating, lasting from 4 to 72 hours;[2] symptoms include nausea, vomiting, photophobia (increased sensitivity to light), and phonophobia (increased sensitivity to sound).[4][5][6] Approximately one-third of people who suffer migraine headache perceive an aura—unusual visual, olfactory, or other sensory experiences that are a sign that the migraine will soon occur.[7]
Initial treatment is with analgesics for the headache, an antiemetic for the nausea, and the avoidance of triggering conditions. The cause of migraine headache is unknown; the most common theory is a disorder of the serotonergic control system.
There are migraine headache variants, some originate in the brainstem (featuring intercellular transport dysfunction of calcium and potassium ions) and some are genetically disposed.[8] Studies of twins indicate a 60 to 65 percent genetic influence upon their propensity to develop migraine headache.[9][10] Moreover, fluctuating hormone levels indicate a migraine relation: 75 percent of adult patients are women, although migraine affects approximately equal numbers of prepubescent boys and girls; propensity to migraine headache is known to disappear during pregnancy, although in some women migraines may become more frequent during pregnancy.
Management
Conventional treatment focuses on three areas: trigger avoidance, symptomatic control, and prophylactic pharmacological drugs. Patients who experience migraines often find that the recommended migraine treatments are not 100% effective at preventing migraines, and sometimes may not be effective at all. Pharmacological treatments are considered effective if they reduce the frequency or severity of migraine attacks by 50%.[50]
Children and adolescents are often first given drug treatment, but the value of diet modification should not be overlooked. The simple task of starting a diet journal to help modify the intake of trigger foods like hot dogs, chocolate, cheese and ice cream could help alleviate symptoms.[31]
For patients who have been diagnosed with recurring migraines, migraine abortive medications can be used to treat the attack, and may be more effective if taken early, losing effectiveness once the attack has begun. Treating the attack at the onset can often abort it before it becomes serious, and can reduce the near-term frequency of subsequent attacks.[citation needed]
Paracetamol or non-steroidal anti-inflammatory drug (NSAIDs)
The first line of treatment is over-the-counter abortive medication.
• Regarding non-steroidal anti-inflammatory drugs, a randomized controlled trial found that naproxen can abort about one third of migraine attacks, which was 5% less than the benefit of sumatriptan.[51]
• Paracetamol (known as acetaminophen in North America) benefited over half of patients with mild or moderate migraines in a randomized controlled trial.[52]
• Simple analgesics combined with caffeine may help.[53] During a migraine attack, emptying of the stomach is slowed, resulting in nausea and a delay in absorbing medication. Caffeine has been shown to partially reverse this effect. Excedrin is an example of an aspirin with caffeine product. Caffeine is recognized by the U.S. Food and Drug Administration as an Over The Counter Drug (OTC) treatment for migraine when compounded with aspirin and paracetamol.[54] Even by itself, caffeine can be helpful during an attack,[55][56] despite the fact that in general migraine-sufferers are advised to limit their caffeine intake.[56]
Patients themselves often start off with paracetamol, aspirin, ibuprofen, or other simple analgesics that are useful for tension headaches. OTC drugs may provide some relief, although they are typically not effective for most sufferers.
In all, the U.S. Food and Drug Administration has approved three OTC products specifically for migraine: Excedrin Migraine, Advil Migraine, and Motrin Migraine Pain. Excedrin Migraine, as mentioned above, is a combination of aspirin, acetaminophen, and caffeine. Both Advil Migraine and Motrin Migraine Pain are straight NSAIDs, with ibuprofen as the only active ingredient.[57]
Analgesics combined with antiemetics
Antiemetics by mouth may help relieve symptoms of nausea and help prevent vomiting, which can diminish the effectiveness of orally taken analgesia. In addition some antiemetics such as metoclopramide are prokinetics and help gastric emptying which is often impaired during episodes of migraine. In the UK there are three combination antiemetic and analgesic preparations available: MigraMax (aspirin with metoclopramide), Migraleve (paracetamol/codeine for analgesia, with buclizine as the antiemetic) and paracetamol/metoclopramide (Paramax in UK).[58] The earlier these drugs are taken in the attack, the better their effect.
Some patients find relief from taking other sedative antihistamines which have anti-nausea properties, such as Benadryl which in the US contains diphenhydramine (but a different non-sedative product in the UK).
Serotonin agonists
Main article: triptans
Sumatriptan and related selective serotonin receptor agonists are excellent for severe migraines or those that do not respond to NSAIDs[51] or other over-the-counter drugs.[52] Triptans are a mid-line treatment suitable for many migraineurs with typical migraines. They may not work for atypical or unusually severe migraines, transformed migraines, or status (continuous) migraines.
Selective serotonin reuptake inhibitors (SSRIs) are not approved by the U.S. Food and Drug Administration (FDA) for treatment of migraines, but have been found to be effective by clinical consensus.[50]
Antidepressants
Tricyclic antidepressants have been long established as highly efficacious prophylactic treatments.[50] These drugs, however, may give rise to undesirable side effects, such as insomnia, sedation or sexual dysfunction. SSRIs antidepressants are less established than tricyclics for migraines prophylaxis. Despite the absence of FDA approval for migraine treatment, antidepressants are widely prescribed.[50] In addition to tricyclics and SSRIs, the anti-depressant nefazodone may also be beneficial in the prophylaxis of migraines due to its antagonistic effects on the 5-HT2A[59] and 5-HT2C receptors[60][61] It has a more favorable side effect profile than amitriptyline, a tricyclic antidepressant commonly used for migraine prophylaxis. Anti-depressants offer advantages for treating migraine patients with comorbid depression.[50]
Ergot alkaloids
Until the introduction of sumatriptan in 1991, ergot derivatives (see ergoline) were the primary oral drugs available to abort a migraine once it is established.
Ergot drugs can be used either as a preventive or abortive therapy, though their relative expense and cumulative side effects suggest reserving them as an abortive rescue medicine. However, ergotamine tartrate tablets (usually with caffeine), though highly effective, and long lasting (unlike triptans), have fallen out of favour due to the problem of ergotism. Oral ergotamine tablet absorption is reliable unless the patient is nauseated. Anti-nausea administration is available by ergotamine suppository (or Ergostat sublingual tablets made until circa 1992). Ergot drugs themselves can be so nauseating it is advisable for the sufferer to have something at hand to counteract this effect when first using this drug. Ergotamine-caffeine 1/100 mg fixed ratio tablets (like Cafergot, Ercaf, etc.) are much less expensive per headache than triptans, and are commonly available in Asia and Romania (Cofedol). They are difficult to obtain in the USA. Ergotamine-caffeine can't be regularly used to abort evening or night onset migraines due to debilitating caffeine interference with sleep. Pure ergotamine tartrate is highly effective for evening-night migraines, but is rarely or never available in the USA. Dihydroergotamine (DHE), which must be injected or inhaled, can be as effective as ergotamine tartrate, but is much more expensive than $2 USD Cafergot tablets.
Steroids
Based on a recent meta analysis a single dose of IV dexamethasone, when added to standard treatment, is associated with a 26% decrease in headache recurrence.[62]
Other agents
If over-the-counter medications do not work, or if triptans are unaffordable, the next step for many doctors is to prescribe Fioricet or Fiorinal, which is a combination of butalbital (a barbiturate), paracetamol (in Fioricet) or acetylsalicylic acid (more commonly known as aspirin and present in Fiorinal), and caffeine. While the risk of addiction is low, butalbital can be habit-forming if used daily, and it can also lead to rebound headaches. Barbiturate-containing medications are not available in many European countries.
Amidrine, Duradrin, and Midrin is a combination of acetaminophen, dichloralphenazone, and isometheptene often prescribed for migraine headaches. Some studies have recently shown that these drugs may work better than sumatriptan for treating migraines.[63]
Antiemetics may need to be given by suppository or injection where vomiting dominates the symptoms.
Recently it has been found that calcitonin gene related peptides (CGRPs) play a role in the pathogenesis of the pain associated with migraine as triptans also decrease its release and action. CGRP receptor antagonists such as olcegepant and telcagepant are being investigated both in vitro and in clinical studies for the treatment of migraine.[64]
[edit] Status migrainosus
Status migrainosus is characterized by migraine lasting more than 72 hours, with not more than four hours of relief during that period. It is generally understood that status migrainosus has been refractory to usual outpatient management upon presentation.
Treatment of status migrainosus consists of managing comorbidities (i. e. correcting fluid and electrolyte abnormalities resulting from anorexia and nausea/vomiting often accompanying status migr.), and usually administering parenteral medication to "break" (abort) the headache.
Although the literature is full of many case reports concerning treatment of status migrainosus, first line therapy consists of intravenous fluids, metoclopramide, and triptans or DHE.[65]
[edit] Herbal treatment
The herbal supplement feverfew (more commonly used for migraine prevention, see below) is marketed by the GelStat Corporation as an OTC migraine abortive, administered sublingually (under the tongue) in a mixture with ginger.[66] An open-label study (funded by GelStat) found some tentative evidence of the treatment's effectiveness,[67] but no scientifically sound study has been done. Cannabis, in addition to prevention, is also known to relieve pain during the onset of a migraine.
Migraine is a neurological syndrome characterized by altered bodily perceptions, severe headaches, and nausea. Physiologically, the migraine headache is a neurological condition more common to women than to men.[1][2] The word migraine was borrowed from Old French migraigne (originally as "megrim", but respelled in 1777 on a contemporary French model). The French term derived from a vulgar pronunciation of the Late Latin word hemicrania, itself based on Greek hemikrania, from Greek roots for "half" and "skull".[3]
The typical migraine headache is unilateral (affecting one half of the head) and pulsating, lasting from 4 to 72 hours;[2] symptoms include nausea, vomiting, photophobia (increased sensitivity to light), and phonophobia (increased sensitivity to sound).[4][5][6] Approximately one-third of people who suffer migraine headache perceive an aura—unusual visual, olfactory, or other sensory experiences that are a sign that the migraine will soon occur.[7]
Initial treatment is with analgesics for the headache, an antiemetic for the nausea, and the avoidance of triggering conditions. The cause of migraine headache is unknown; the most common theory is a disorder of the serotonergic control system.
There are migraine headache variants, some originate in the brainstem (featuring intercellular transport dysfunction of calcium and potassium ions) and some are genetically disposed.[8] Studies of twins indicate a 60 to 65 percent genetic influence upon their propensity to develop migraine headache.[9][10] Moreover, fluctuating hormone levels indicate a migraine relation: 75 percent of adult patients are women, although migraine affects approximately equal numbers of prepubescent boys and girls; propensity to migraine headache is known to disappear during pregnancy, although in some women migraines may become more frequent during pregnancy.
Management
Conventional treatment focuses on three areas: trigger avoidance, symptomatic control, and prophylactic pharmacological drugs. Patients who experience migraines often find that the recommended migraine treatments are not 100% effective at preventing migraines, and sometimes may not be effective at all. Pharmacological treatments are considered effective if they reduce the frequency or severity of migraine attacks by 50%.[50]
Children and adolescents are often first given drug treatment, but the value of diet modification should not be overlooked. The simple task of starting a diet journal to help modify the intake of trigger foods like hot dogs, chocolate, cheese and ice cream could help alleviate symptoms.[31]
For patients who have been diagnosed with recurring migraines, migraine abortive medications can be used to treat the attack, and may be more effective if taken early, losing effectiveness once the attack has begun. Treating the attack at the onset can often abort it before it becomes serious, and can reduce the near-term frequency of subsequent attacks.[citation needed]
Paracetamol or non-steroidal anti-inflammatory drug (NSAIDs)
The first line of treatment is over-the-counter abortive medication.
• Regarding non-steroidal anti-inflammatory drugs, a randomized controlled trial found that naproxen can abort about one third of migraine attacks, which was 5% less than the benefit of sumatriptan.[51]
• Paracetamol (known as acetaminophen in North America) benefited over half of patients with mild or moderate migraines in a randomized controlled trial.[52]
• Simple analgesics combined with caffeine may help.[53] During a migraine attack, emptying of the stomach is slowed, resulting in nausea and a delay in absorbing medication. Caffeine has been shown to partially reverse this effect. Excedrin is an example of an aspirin with caffeine product. Caffeine is recognized by the U.S. Food and Drug Administration as an Over The Counter Drug (OTC) treatment for migraine when compounded with aspirin and paracetamol.[54] Even by itself, caffeine can be helpful during an attack,[55][56] despite the fact that in general migraine-sufferers are advised to limit their caffeine intake.[56]
Patients themselves often start off with paracetamol, aspirin, ibuprofen, or other simple analgesics that are useful for tension headaches. OTC drugs may provide some relief, although they are typically not effective for most sufferers.
In all, the U.S. Food and Drug Administration has approved three OTC products specifically for migraine: Excedrin Migraine, Advil Migraine, and Motrin Migraine Pain. Excedrin Migraine, as mentioned above, is a combination of aspirin, acetaminophen, and caffeine. Both Advil Migraine and Motrin Migraine Pain are straight NSAIDs, with ibuprofen as the only active ingredient.[57]
Analgesics combined with antiemetics
Antiemetics by mouth may help relieve symptoms of nausea and help prevent vomiting, which can diminish the effectiveness of orally taken analgesia. In addition some antiemetics such as metoclopramide are prokinetics and help gastric emptying which is often impaired during episodes of migraine. In the UK there are three combination antiemetic and analgesic preparations available: MigraMax (aspirin with metoclopramide), Migraleve (paracetamol/codeine for analgesia, with buclizine as the antiemetic) and paracetamol/metoclopramide (Paramax in UK).[58] The earlier these drugs are taken in the attack, the better their effect.
Some patients find relief from taking other sedative antihistamines which have anti-nausea properties, such as Benadryl which in the US contains diphenhydramine (but a different non-sedative product in the UK).
Serotonin agonists
Main article: triptans
Sumatriptan and related selective serotonin receptor agonists are excellent for severe migraines or those that do not respond to NSAIDs[51] or other over-the-counter drugs.[52] Triptans are a mid-line treatment suitable for many migraineurs with typical migraines. They may not work for atypical or unusually severe migraines, transformed migraines, or status (continuous) migraines.
Selective serotonin reuptake inhibitors (SSRIs) are not approved by the U.S. Food and Drug Administration (FDA) for treatment of migraines, but have been found to be effective by clinical consensus.[50]
Antidepressants
Tricyclic antidepressants have been long established as highly efficacious prophylactic treatments.[50] These drugs, however, may give rise to undesirable side effects, such as insomnia, sedation or sexual dysfunction. SSRIs antidepressants are less established than tricyclics for migraines prophylaxis. Despite the absence of FDA approval for migraine treatment, antidepressants are widely prescribed.[50] In addition to tricyclics and SSRIs, the anti-depressant nefazodone may also be beneficial in the prophylaxis of migraines due to its antagonistic effects on the 5-HT2A[59] and 5-HT2C receptors[60][61] It has a more favorable side effect profile than amitriptyline, a tricyclic antidepressant commonly used for migraine prophylaxis. Anti-depressants offer advantages for treating migraine patients with comorbid depression.[50]
Ergot alkaloids
Until the introduction of sumatriptan in 1991, ergot derivatives (see ergoline) were the primary oral drugs available to abort a migraine once it is established.
Ergot drugs can be used either as a preventive or abortive therapy, though their relative expense and cumulative side effects suggest reserving them as an abortive rescue medicine. However, ergotamine tartrate tablets (usually with caffeine), though highly effective, and long lasting (unlike triptans), have fallen out of favour due to the problem of ergotism. Oral ergotamine tablet absorption is reliable unless the patient is nauseated. Anti-nausea administration is available by ergotamine suppository (or Ergostat sublingual tablets made until circa 1992). Ergot drugs themselves can be so nauseating it is advisable for the sufferer to have something at hand to counteract this effect when first using this drug. Ergotamine-caffeine 1/100 mg fixed ratio tablets (like Cafergot, Ercaf, etc.) are much less expensive per headache than triptans, and are commonly available in Asia and Romania (Cofedol). They are difficult to obtain in the USA. Ergotamine-caffeine can't be regularly used to abort evening or night onset migraines due to debilitating caffeine interference with sleep. Pure ergotamine tartrate is highly effective for evening-night migraines, but is rarely or never available in the USA. Dihydroergotamine (DHE), which must be injected or inhaled, can be as effective as ergotamine tartrate, but is much more expensive than $2 USD Cafergot tablets.
Steroids
Based on a recent meta analysis a single dose of IV dexamethasone, when added to standard treatment, is associated with a 26% decrease in headache recurrence.[62]
Other agents
If over-the-counter medications do not work, or if triptans are unaffordable, the next step for many doctors is to prescribe Fioricet or Fiorinal, which is a combination of butalbital (a barbiturate), paracetamol (in Fioricet) or acetylsalicylic acid (more commonly known as aspirin and present in Fiorinal), and caffeine. While the risk of addiction is low, butalbital can be habit-forming if used daily, and it can also lead to rebound headaches. Barbiturate-containing medications are not available in many European countries.
Amidrine, Duradrin, and Midrin is a combination of acetaminophen, dichloralphenazone, and isometheptene often prescribed for migraine headaches. Some studies have recently shown that these drugs may work better than sumatriptan for treating migraines.[63]
Antiemetics may need to be given by suppository or injection where vomiting dominates the symptoms.
Recently it has been found that calcitonin gene related peptides (CGRPs) play a role in the pathogenesis of the pain associated with migraine as triptans also decrease its release and action. CGRP receptor antagonists such as olcegepant and telcagepant are being investigated both in vitro and in clinical studies for the treatment of migraine.[64]
[edit] Status migrainosus
Status migrainosus is characterized by migraine lasting more than 72 hours, with not more than four hours of relief during that period. It is generally understood that status migrainosus has been refractory to usual outpatient management upon presentation.
Treatment of status migrainosus consists of managing comorbidities (i. e. correcting fluid and electrolyte abnormalities resulting from anorexia and nausea/vomiting often accompanying status migr.), and usually administering parenteral medication to "break" (abort) the headache.
Although the literature is full of many case reports concerning treatment of status migrainosus, first line therapy consists of intravenous fluids, metoclopramide, and triptans or DHE.[65]
[edit] Herbal treatment
The herbal supplement feverfew (more commonly used for migraine prevention, see below) is marketed by the GelStat Corporation as an OTC migraine abortive, administered sublingually (under the tongue) in a mixture with ginger.[66] An open-label study (funded by GelStat) found some tentative evidence of the treatment's effectiveness,[67] but no scientifically sound study has been done. Cannabis, in addition to prevention, is also known to relieve pain during the onset of a migraine.
Heart diseases
Heart disease
Heart disease or cardiopathy is an umbrella term for a variety of different diseases affecting the heart. As of 2007, it is the leading cause of death in the United States,[1][2] England, Canada and Wales,[3] killing one person every 34 seconds in the United States alone.
Types of heart disease
Coronary heart disease
Main article: Coronary heart disease
Coronary heart disease refers to the failure of the coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. Coronary heart disease is most commonly equated with Coronary artery disease although coronary heart disease can be due to other causes, such as coronary vasospasm.[5]
Coronary artery disease is a disease of the artery caused by the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium. Angina pectoris (chest pain) and myocardial infarction (heart attack) are symptoms of and conditions caused by coronary heart disease.
Over 459,000 Americans die of coronary heart disease every year[6]. In the United Kingdom, 101,000 deaths annually are due to coronary heart disease.[7]
Cardiomyopathy
Cardiomyopathy literally means "heart muscle disease" (Myo= muscle, pathy= disease) It is the deterioration of the function of the myocardium (i.e., the actual heart muscle) for any reason. People with cardiomyopathy are often at risk of arrhythmia and/or sudden cardiac death.
• Extrinsic cardiomyopathies – cardiomyopathies where the primary pathology is outside the myocardium itself. Most cardiomyopathies are extrinsic, because by far the most common cause of a cardiomyopathy is ischemia. The World Health Organization calls these specific cardiomyopathies[citation needed]:
o Alcoholic cardiomyopathy
o Coronary artery disease
o Congenital heart disease
o Nutritional diseases affecting the heart
o Ischemic (or ischaemic) cardiomyopathy
o Hypertensive cardiomyopathy
o Valvular cardiomyopathy – see also Valvular heart disease below
o Inflammatory cardiomyopathy – see also Inflammatory heart disease below
o Cardiomyopathy secondary to a systemic metabolic disease
o Myocardiodystrophy
• Intrinsic cardiomyopathies – weakness in the muscle of the heart that is not due to an identifiable external cause.
o Dilated cardiomyopathy (DCM) – most common form, and one of the leading indications for heart transplantation. In DCM the heart (especially the left ventricle) is enlarged and the pumping function is diminished.
o Hypertrophic cardiomyopathy (HCM or HOCM) – genetic disorder caused by various mutations in genes encoding sarcomeric proteins. In HCM the heart muscle is thickened, which can obstruct blood flow and prevent the heart from functioning properly.
o Arrhythmogenic right ventricular cardiomyopathy (ARVC) – arises from an electrical disturbance of the heart in which heart muscle is replaced by fibrous scar tissue. The right ventricle is generally most affected.
o Restrictive cardiomyopathy (RCM) – least common cardiomyopathy. The walls of the ventricles are stiff, but may not be thickened, and resist the normal filling of the heart with blood.
o Noncompaction Cardiomyopathy – the left ventricle wall has failed to properly grow from birth and such has a spongy appearance when viewed during an echocardiogram.
Cardiovascular disease
Cardiovascular disease is any of a number of specific diseases that affect the heart itself and/or the blood vessel system, especially the veins and arteries leading to and from the heart. Research on disease dimorphism suggests that women who suffer with cardiovascular disease usually suffer from forms that affect the blood vessels while men usually suffer from forms that affect the heart muscle itself. Known or associated causes of cardiovascular disease include diabetes mellitus, hypertension, hyperhomocysteinemia and hypercholesterolemia.
Types of cardiovascular disease include:
• Atherosclerosis
Ischaemic heart disease
• Ischaemic heart disease – another disease of the heart itself, characterized by reduced blood supply to the organs.
Heart failure
Heart failure, also called congestive heart failure (or CHF), and congestive cardiac failure (CCF), is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body. Therefore leading to the heart and body's failure.
• Cor pulmonale, a failure of the right side of the heart.
Hypertensive heart disease
Hypertensive heart disease is heart disease caused by high blood pressure, especially localised high blood pressure. Conditions that can be caused by hypertensive heart disease include:
• Left ventricular hypertrophy
• Coronary heart disease
• (Congestive) heart failure
• Hypertensive cardiomyopathy
• Cardiac arrhythmias
Inflammatory heart disease
Inflammatory heart disease involves inflammation of the heart muscle and/or the tissue surrounding it.
• Endocarditis – inflammation of the inner layer of the heart, the endocardium. The most common structures involved are the heart valves.
• Inflammatory cardiomegaly
• Myocarditis – inflammation of the myocardium, the muscular part of the heart.
Valvular heart disease
Valvular heart disease is disease process that affects one or more valves of the heart. There are four major heart valve which may be affected by valvular heart disease, including the tricuspid and aortic valves in the right side of the heart, as well as the mitral and aortic valves in the left side of the heart.
Heart disease or cardiopathy is an umbrella term for a variety of different diseases affecting the heart. As of 2007, it is the leading cause of death in the United States,[1][2] England, Canada and Wales,[3] killing one person every 34 seconds in the United States alone.
Types of heart disease
Coronary heart disease
Main article: Coronary heart disease
Coronary heart disease refers to the failure of the coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. Coronary heart disease is most commonly equated with Coronary artery disease although coronary heart disease can be due to other causes, such as coronary vasospasm.[5]
Coronary artery disease is a disease of the artery caused by the accumulation of atheromatous plaques within the walls of the arteries that supply the myocardium. Angina pectoris (chest pain) and myocardial infarction (heart attack) are symptoms of and conditions caused by coronary heart disease.
Over 459,000 Americans die of coronary heart disease every year[6]. In the United Kingdom, 101,000 deaths annually are due to coronary heart disease.[7]
Cardiomyopathy
Cardiomyopathy literally means "heart muscle disease" (Myo= muscle, pathy= disease) It is the deterioration of the function of the myocardium (i.e., the actual heart muscle) for any reason. People with cardiomyopathy are often at risk of arrhythmia and/or sudden cardiac death.
• Extrinsic cardiomyopathies – cardiomyopathies where the primary pathology is outside the myocardium itself. Most cardiomyopathies are extrinsic, because by far the most common cause of a cardiomyopathy is ischemia. The World Health Organization calls these specific cardiomyopathies[citation needed]:
o Alcoholic cardiomyopathy
o Coronary artery disease
o Congenital heart disease
o Nutritional diseases affecting the heart
o Ischemic (or ischaemic) cardiomyopathy
o Hypertensive cardiomyopathy
o Valvular cardiomyopathy – see also Valvular heart disease below
o Inflammatory cardiomyopathy – see also Inflammatory heart disease below
o Cardiomyopathy secondary to a systemic metabolic disease
o Myocardiodystrophy
• Intrinsic cardiomyopathies – weakness in the muscle of the heart that is not due to an identifiable external cause.
o Dilated cardiomyopathy (DCM) – most common form, and one of the leading indications for heart transplantation. In DCM the heart (especially the left ventricle) is enlarged and the pumping function is diminished.
o Hypertrophic cardiomyopathy (HCM or HOCM) – genetic disorder caused by various mutations in genes encoding sarcomeric proteins. In HCM the heart muscle is thickened, which can obstruct blood flow and prevent the heart from functioning properly.
o Arrhythmogenic right ventricular cardiomyopathy (ARVC) – arises from an electrical disturbance of the heart in which heart muscle is replaced by fibrous scar tissue. The right ventricle is generally most affected.
o Restrictive cardiomyopathy (RCM) – least common cardiomyopathy. The walls of the ventricles are stiff, but may not be thickened, and resist the normal filling of the heart with blood.
o Noncompaction Cardiomyopathy – the left ventricle wall has failed to properly grow from birth and such has a spongy appearance when viewed during an echocardiogram.
Cardiovascular disease
Cardiovascular disease is any of a number of specific diseases that affect the heart itself and/or the blood vessel system, especially the veins and arteries leading to and from the heart. Research on disease dimorphism suggests that women who suffer with cardiovascular disease usually suffer from forms that affect the blood vessels while men usually suffer from forms that affect the heart muscle itself. Known or associated causes of cardiovascular disease include diabetes mellitus, hypertension, hyperhomocysteinemia and hypercholesterolemia.
Types of cardiovascular disease include:
• Atherosclerosis
Ischaemic heart disease
• Ischaemic heart disease – another disease of the heart itself, characterized by reduced blood supply to the organs.
Heart failure
Heart failure, also called congestive heart failure (or CHF), and congestive cardiac failure (CCF), is a condition that can result from any structural or functional cardiac disorder that impairs the ability of the heart to fill with or pump a sufficient amount of blood throughout the body. Therefore leading to the heart and body's failure.
• Cor pulmonale, a failure of the right side of the heart.
Hypertensive heart disease
Hypertensive heart disease is heart disease caused by high blood pressure, especially localised high blood pressure. Conditions that can be caused by hypertensive heart disease include:
• Left ventricular hypertrophy
• Coronary heart disease
• (Congestive) heart failure
• Hypertensive cardiomyopathy
• Cardiac arrhythmias
Inflammatory heart disease
Inflammatory heart disease involves inflammation of the heart muscle and/or the tissue surrounding it.
• Endocarditis – inflammation of the inner layer of the heart, the endocardium. The most common structures involved are the heart valves.
• Inflammatory cardiomegaly
• Myocarditis – inflammation of the myocardium, the muscular part of the heart.
Valvular heart disease
Valvular heart disease is disease process that affects one or more valves of the heart. There are four major heart valve which may be affected by valvular heart disease, including the tricuspid and aortic valves in the right side of the heart, as well as the mitral and aortic valves in the left side of the heart.
Hypertension Treatment
Hypertension
Treatment
Lifestyle modifications
The first line of treatment for hypertension is the same as the recommended preventative lifestyle changes such as the dietary changes, physical exercise, and weight loss, which have all been shown to significantly reduce blood pressure in people with hypertension.[55] If hypertension is high enough to justify immediate use of medications, lifestyle changes are still recommended in conjection with medication.
Biofeedback
Biofeedback devices can be used alone or in conjunction with lifestyle changes and/or medications to reduce hypertension. One example of Biofeedback is Resperate, a portable, battery-operated personal therapeutic medical device, sold over the counter in the United States. However, claims of efficacy for this particular device are not supported by scientific studies. Testimonials are used to promote such products, while no real evidence exists that the use of
Medications
Main article: Antihypertensive drugs
There are many classes of medications for treating hypertension, together called antihypertensives, which — by varying means — act by lowering blood pressure. Reduction of the blood pressure by 5–6 mmHg can decrease the risk of stroke by 40%, decrease the risk of heart disease by 15–20%, and reduce the likelihood of dementia, heart failure, and death.
The aim of treatment should be reduce blood pressure to <140/90 mmHg for most individuals, and lower individuals with diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg).[56] Each drug reduces systolic blood pressure by about 5–10 mmHg, so often multiple drugs are combined to achieve the goal blood pressure.
Commonly used prescription drugs include:[5]
• ACE inhibitors such as captopril, enalapril, fosinopril (Monopril), lisinopril (Zestril), quinapril, ramipril (Altace)
• Angiotensin II receptor antagonists may be used where ACE inhibitors are not tolerated: e.g., telmisartan (Micardis, Pritor), irbesartan (Avapro), losartan (Cozaar), valsartan (Diovan), candesartan (Amias), olmesartan (Benicar, Olmetec)
• Calcium channel blockers such as nifedipine (Adalat)[57] amlodipine (Norvasc), diltiazem, verapamil
• Diuretics: e.g., bendroflumethiazide, chlorthalidone, hydrochlorothiazide (also called HCTZ).
Other less commonly used prescription drugs include:
• Diuretics such a furosemide or low-dosages of spironolactone
• Alpha blockers such as prazosin, or terazosin. Doxazosin has been shown to the increase risk of heart failure, and to be less effective than a diuretics.[58]
• Beta blockers such as atenolol, labetalol, metoprolol (Lopressor, Toprol-XL), propranolol. Whilst once were first line agents, now they are less commonly used because they increase the risk of diabetes.[59]
• Direct renin inhibitors such as aliskiren (Tekturna).[60]
Treatment
Lifestyle modifications
The first line of treatment for hypertension is the same as the recommended preventative lifestyle changes such as the dietary changes, physical exercise, and weight loss, which have all been shown to significantly reduce blood pressure in people with hypertension.[55] If hypertension is high enough to justify immediate use of medications, lifestyle changes are still recommended in conjection with medication.
Biofeedback
Biofeedback devices can be used alone or in conjunction with lifestyle changes and/or medications to reduce hypertension. One example of Biofeedback is Resperate, a portable, battery-operated personal therapeutic medical device, sold over the counter in the United States. However, claims of efficacy for this particular device are not supported by scientific studies. Testimonials are used to promote such products, while no real evidence exists that the use of
Medications
Main article: Antihypertensive drugs
There are many classes of medications for treating hypertension, together called antihypertensives, which — by varying means — act by lowering blood pressure. Reduction of the blood pressure by 5–6 mmHg can decrease the risk of stroke by 40%, decrease the risk of heart disease by 15–20%, and reduce the likelihood of dementia, heart failure, and death.
The aim of treatment should be reduce blood pressure to <140/90 mmHg for most individuals, and lower individuals with diabetes or kidney disease (some medical professionals recommend keeping levels below 120/80 mmHg).[56] Each drug reduces systolic blood pressure by about 5–10 mmHg, so often multiple drugs are combined to achieve the goal blood pressure.
Commonly used prescription drugs include:[5]
• ACE inhibitors such as captopril, enalapril, fosinopril (Monopril), lisinopril (Zestril), quinapril, ramipril (Altace)
• Angiotensin II receptor antagonists may be used where ACE inhibitors are not tolerated: e.g., telmisartan (Micardis, Pritor), irbesartan (Avapro), losartan (Cozaar), valsartan (Diovan), candesartan (Amias), olmesartan (Benicar, Olmetec)
• Calcium channel blockers such as nifedipine (Adalat)[57] amlodipine (Norvasc), diltiazem, verapamil
• Diuretics: e.g., bendroflumethiazide, chlorthalidone, hydrochlorothiazide (also called HCTZ).
Other less commonly used prescription drugs include:
• Diuretics such a furosemide or low-dosages of spironolactone
• Alpha blockers such as prazosin, or terazosin. Doxazosin has been shown to the increase risk of heart failure, and to be less effective than a diuretics.[58]
• Beta blockers such as atenolol, labetalol, metoprolol (Lopressor, Toprol-XL), propranolol. Whilst once were first line agents, now they are less commonly used because they increase the risk of diabetes.[59]
• Direct renin inhibitors such as aliskiren (Tekturna).[60]
Anti-diabetic drug
Anti-diabetic drug
Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.
Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected or inhaled.
Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include (1) agents which increase the amount of insulin secreted by the pancreas, (2) agents which increase the sensitivity of target organs to insulin, and (3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.
Several groups of drugs, mostly given by mouth, are effective in Type II, often in combination. The therapeutic combination in Type II may include insulin, not necessarily because oral agents have failed completely, but in search of a desired combination of effects. The great advantage of injected insulin in Type II is that a well-educated patient can adjust the dose, or even take additional doses, when blood glucose levels measured by the patient, usually with a simple meter, as needed by the measured amount of sugar in the blood.
Contents
• 1 Insulin
• 2 Secretagogues
o 2.1 Sulfonylureas
o 2.2 Meglitinides
• 3 Sensitizers
o 3.1 Biguanides
o 3.2 Thiazolidinediones
• 4 Alpha-glucosidase inhibitors
• 5 Peptide analogs
o 5.1 Incretin mimetics
5.1.1 Glucagon-like peptide (GLP) analogs and agonists
5.1.2 Gastric inhibitory peptide (GIP) analogs
o 5.2 DPP-4 inhibitors
o 5.3 Amylin analogues
• 6 Experimental agents
• 7 Alternative medicine
• 8 Notes
• 9 References
Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research is underway of other routes of administration. In acute care settings, insulin may also be given intravenously. There are several types of insulin, characterized by the rate which they are metabolized by the body.
Secretagogues
Sulfonylureas
Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" drugs are now more commonly used. They are more effective than first-generation drugs and have fewer side effects. All may cause weight gain.
Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They can not be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones. The primary side effect is hypoglycemia.
Typical reductions in A1C values for second generation sulfonylureas are 1.0-2.0%.
• First-generation agents
o tolbutamide (Orinase)
o acetohexamide (Dymelor)
o tolazamide (Tolinase)
o chlorpropamide (Diabinese)
• Second-generation agents
o glipizide (Glucotrol)
o glyburide (Diabeta, Micronase, Glynase)
o glimepiride (Amaryl)
o gliclazide (Diamicron)
Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.[1] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.[2]
They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped.
Typical reductions in A1C values are 0.5-1.0%.
• repaglinide (Prandin)
• nateglinide (Starlix)
Adverse reactions include weight gain and hypoglycemia.
Sensitizers
Insulin sensitizers address the core problem in Type II diabetes—insulin resistance. Among oral hypoglycemic agents, insulin sensitizers are the largest category.[3]
Biguanides
Main article: Biguanide
Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, metformin, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Amongst common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.
Typical reductions in A1C values for metformin is 1.5-2.0%.
• metformin (Glucophage). Metformin may be the best choice for patients who also have heart failure.[4] Should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
• phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.[5]
• buformin: also withdrawn due to lactic acidosis risk.[6]
Metformin is usually the first-line medication used for treatment of type-2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss as opposed to in the past, where Metformin was prescribed after diet and exercise had failed. Initial dosing is 500 mg once daily, then if need be increased to 500 mg twice daily up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications.
There is an extended release formulation available, but it is typically reserved for patients experiencing GI side effects.
Thiazolidinediones
Main article: Thiazolidinedione
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE [1]). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells.
Typical reductions in A1C values are 1.5-2.0%.
• rosiglitazone (Avandia)
• pioglitazone (Actos)
• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.[7]
As a result of multiple retrospective studies, there is a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease,[8] as did the DREAM trial.[9]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[10] There have been a significant number of publications since then, and a Food and Drug Administration panel[11] voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[12] Safety studies are continuing.
In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type II diabetes who have already had a heart attack.[13]
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.
Typical reductions in A1C values are 0.5-1.0%.
• miglitol (Glyset)
• acarbose (Precose/Glucobay)
These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.
Research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect,[14][15][16][17][18][19] possibly due to the fact the mushroom naturally acts as an alpha-glucosidase inhibitor.[20]
Peptide analogs
Overview of insulin secretion
Incretin mimetics
Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent Insulinotropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Glucagon-like peptide (GLP) analogs and agonists
GLP agonists bind to a membrane GLP receptor.[2] As a consequence of this, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes; thus an analogue of GLP would not be practical.
• Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist.[21][22] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[23] Typical reductions in A1C values are 0.5-1.0%.
• Liraglutide, a once daily human analogue (97% homology), is being developed by Novo Nordisk under the brand name Victoza. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[24][25][26][27][28][29]
• Taspoglutide is presently in Phase III Clinical Trials with Hoffman-La Roche.
These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs.
Gastric inhibitory peptide (GIP) analogs
• None are FDA approved
DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 (glucagon-like peptide-1) by inhibiting its degradation by dipeptidyl peptidase-4 (DPP-4).
Typical reductions in A1C values are 0.5-1.0%.
Examples are:
• vildagliptin (Galvus) EU Approved 2008.
• sitagliptin (Januvia) FDA approved Oct 2006.
• saxagliptin (Onglyza) FDA Approved July 2009.
Amylin analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces. Typical reductions in A1C values are 0.5-1.0%.
Experimental agents
Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research. Others are undergoing phase I/II studies.
• PPARα/γ ligands (muraglitazar and tesaglitazar - development stopped due to adverse risk profile, aleglitazar - under clinical development)
• SGLT2 (sodium-dependent glucose transporter 2) inhibitors increase urinary glucose.
• FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver.
Alternative medicine
A recent review article presents the profiles of plants with hypoglycaemic properties, reported in the literature from 1990 to 2000 and states that "Medical plants play an important role in the management of diabetes mellitus especially in developing countries where resources are meager."[30]
The first registered use of anti-diabetic drugs was as herbal extracts used by Indians in the Amazon Basin for the treatment of type 2 diabetes, and today promoted as vegetable insulin although not formally an insulin analog.[31] The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.[32] The usual treatment is with concentrated (root) Myrcia extracts, commercialized as "Pedra hume de kaá". Phytochemical analysis of the Myrcia extracts reported kinds of flavanone glucosides (myrciacitrins) and acetophenone glucosides (myrciaphenones), and inhibitory activities on aldose reductase and alpha-glucosidase.[33]
Walnut leaf can significantly reduce fasting blood glucose levels in rats with alloxan-induced diabetes, and rats thus treates show some evidence of regeneration of the beta cells.[34] Garlic also significantly reduces fasting blood glucose levels in rats with alloxan-induced diabetes.[35]
At least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cassia (Cinnamomum aromaticum) for oral consumption. Another study used an extract (MHCP) on laboratory rats. The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded "that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases."[36] The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone (MHCP) from cinnamon. Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[37][38] The Food and Drug Administration has not yet evaluated the use of cinnamon for the management of diabetes. It should be noted that the spice sold as cinnamon is often obtained from C. verum (true cinnamon), not C. aromaticum (cassia).
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[2] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][44] Agrocybe cylindracea[45] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Cinnamon
Though not yet evaluated by the Food and Drug Administration, at least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption. Another study used an extract (MHCP) on laboratory rats.
The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded:
The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.[51]
The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone from cinnamon. The extract was named "MHCP". Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[52][53]
Other studies have failed to reproduce these results, and, because large doses of cinnamon are not innocuous, some experts advise against treatment of diabetes with cinnamon.[54]
Chromium and vanadium
Chromium - Cholesterol and triglycerides are risk factors in heart disease and diabetes, and studies show that chromium lowers levels of total cholesterol, LDL cholesterol, and triglycerides.[55][56][57][58] Chromium supplements such as chromium picolinate have been shown to improve glucose tolerance in people with type 2 diabetes,[59][60][61] although other studies have not replicated this result.[62] A meta analysis of these trials concluded that chromium supplements had no beneficial effect on healthy people, but that there might be an improvement in glucose metabolism in diabetics, although the authors stated that the evidence for this effect remains weak.[63]
Vanadium - A form of vanadium, vanadyl sulfate, seems to improve glucose control in people with type 2 diabetes.[64][65][66][67][68]
A pilot study has also found evidence that Tai Chi and Qigong reduce the severity of type 2 diabetes.[69]
Benfotiamine, a pro-vitamin of vitamin B1 which has been in use in Europe as an over-the-counter medicine for alcoholic neuropathy for the past half century with no significant side-effects or toxicity, has recently been found to block the major metabolic pathways by which excess blood glucose in the body is transformed into the advanced glycation endproducts (AGEs) which cause diabetic complications.[70] Studies have shown that taking oral benfotiamine can prevent diabetic retinopathy,[71] diabetic neuropathy,[72] and diabetic nephropathy[73] independently of any affect on the blood sugar levels of the patient. In theory, taking benfotiamine might allow patients to be less scrupulous in trying to normalize blood sugar levels and thus free them from the danger of hypoglycemia and the stress of stringent blood sugar monitoring, while still protecting them against the negative effects of hyperglycemia. Research is ongoing to establish the full significance of benfotiamine in the treatment of diabetes.
Traditional plant treatments for diabetes
A study was made of the effects on glucose homeostasis in normal and streptozotocin (induced) diabetic mice of eleven plants that have been used as traditional treatments for diabetes. The mice were given diets containing dried leaves from the following plants: agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra). The study concluded that "The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice".[74]
Mushrooms
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[75] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][76] Agrocybe cylindracea[77] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Aloe vera Oral administration of aloe vera might be a useful adjunct for lowering blood glucose in diabetic patients as well as for reducing blood lipid levels in patients with hyperlipidaemia[citation needed]. Ten controlled clinical trials were found to reach that conclusion in four independent literature searches. However, caveats reported in each study led the researchers to conclude that aloe vera's clinical effectiveness was not yet sufficiently defined in 1999.[78]
Anti-diabetic drugs treat diabetes mellitus by lowering glucose levels in the blood. With the exceptions of insulin, exenatide, and pramlintide, all are administered orally and are thus also called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of anti-diabetic drugs, and their selection depends on the nature of the diabetes, age and situation of the person, as well as other factors.
Diabetes mellitus type 1 is a disease caused by the lack of insulin. Insulin must be used in Type I, which must be injected or inhaled.
Diabetes mellitus type 2 is a disease of insulin resistance by cells. Treatments include (1) agents which increase the amount of insulin secreted by the pancreas, (2) agents which increase the sensitivity of target organs to insulin, and (3) agents which decrease the rate at which glucose is absorbed from the gastrointestinal tract.
Several groups of drugs, mostly given by mouth, are effective in Type II, often in combination. The therapeutic combination in Type II may include insulin, not necessarily because oral agents have failed completely, but in search of a desired combination of effects. The great advantage of injected insulin in Type II is that a well-educated patient can adjust the dose, or even take additional doses, when blood glucose levels measured by the patient, usually with a simple meter, as needed by the measured amount of sugar in the blood.
Contents
• 1 Insulin
• 2 Secretagogues
o 2.1 Sulfonylureas
o 2.2 Meglitinides
• 3 Sensitizers
o 3.1 Biguanides
o 3.2 Thiazolidinediones
• 4 Alpha-glucosidase inhibitors
• 5 Peptide analogs
o 5.1 Incretin mimetics
5.1.1 Glucagon-like peptide (GLP) analogs and agonists
5.1.2 Gastric inhibitory peptide (GIP) analogs
o 5.2 DPP-4 inhibitors
o 5.3 Amylin analogues
• 6 Experimental agents
• 7 Alternative medicine
• 8 Notes
• 9 References
Insulin
Insulin is usually given subcutaneously, either by injections or by an insulin pump. Research is underway of other routes of administration. In acute care settings, insulin may also be given intravenously. There are several types of insulin, characterized by the rate which they are metabolized by the body.
Secretagogues
Sulfonylureas
Sulfonylureas were the first widely used oral hypoglycemic medications. They are insulin secretagogues, triggering insulin release by direct action on the KATP channel of the pancreatic beta cells. Eight types of these pills have been marketed in North America, but not all remain available. The "second-generation" drugs are now more commonly used. They are more effective than first-generation drugs and have fewer side effects. All may cause weight gain.
Sulfonylureas bind strongly to plasma proteins. Sulfonylureas are only useful in Type II diabetes, as they work by stimulating endogenous release of insulin. They work best with patients over 40 years old, who have had diabetes mellitus for under ten years. They can not be used with type I diabetes, or diabetes of pregnancy. They can be safely used with metformin or -glitazones. The primary side effect is hypoglycemia.
Typical reductions in A1C values for second generation sulfonylureas are 1.0-2.0%.
• First-generation agents
o tolbutamide (Orinase)
o acetohexamide (Dymelor)
o tolazamide (Tolinase)
o chlorpropamide (Diabinese)
• Second-generation agents
o glipizide (Glucotrol)
o glyburide (Diabeta, Micronase, Glynase)
o glimepiride (Amaryl)
o gliclazide (Diamicron)
Meglitinides
Meglitinides help the pancreas produce insulin and are often called "short-acting secretagogues." They act on the same potassium channels as sulfonylureas, but at a different binding site.[1] By closing the potassium channels of the pancreatic beta cells, they open the calcium channels, hence enhancing insulin secretion.[2]
They are taken with or shortly before meals to boost the insulin response to each meal. If a meal is skipped, the medication is also skipped.
Typical reductions in A1C values are 0.5-1.0%.
• repaglinide (Prandin)
• nateglinide (Starlix)
Adverse reactions include weight gain and hypoglycemia.
Sensitizers
Insulin sensitizers address the core problem in Type II diabetes—insulin resistance. Among oral hypoglycemic agents, insulin sensitizers are the largest category.[3]
Biguanides
Main article: Biguanide
Biguanides reduce hepatic glucose output and increase uptake of glucose by the periphery, including skeletal muscle. Although it must be used with caution in patients with impaired liver or kidney function, metformin, a biguanide, has become the most commonly used agent for type 2 diabetes in children and teenagers. Amongst common diabetic drugs, metformin is the only widely used oral drug that does not cause weight gain.
Typical reductions in A1C values for metformin is 1.5-2.0%.
• metformin (Glucophage). Metformin may be the best choice for patients who also have heart failure.[4] Should be temporarily discontinued before any radiographic procedure involving intravenous iodinated contrast as patients are at an increased risk of lactic acidosis.
• phenformin (DBI): used from 1960s through 1980s, withdrawn due to lactic acidosis risk.[5]
• buformin: also withdrawn due to lactic acidosis risk.[6]
Metformin is usually the first-line medication used for treatment of type-2 diabetes. It is generally prescribed at initial diagnosis in conjunction with exercise and weight loss as opposed to in the past, where Metformin was prescribed after diet and exercise had failed. Initial dosing is 500 mg once daily, then if need be increased to 500 mg twice daily up to 1000 mg twice daily. It is also available in combination with other oral diabetic medications.
There is an extended release formulation available, but it is typically reserved for patients experiencing GI side effects.
Thiazolidinediones
Main article: Thiazolidinedione
Thiazolidinediones (TZDs), also known as "glitazones," bind to PPARγ, a type of nuclear regulatory protein involved in transcription of genes regulating glucose and fat metabolism. These PPARs act on Peroxysome Proliferator Responsive Elements (PPRE [1]). The PPREs influence insulin sensitive genes, which enhance production of mRNAs of insulin dependent enzymes. The final result is better use of glucose by the cells.
Typical reductions in A1C values are 1.5-2.0%.
• rosiglitazone (Avandia)
• pioglitazone (Actos)
• troglitazone (Rezulin): used in 1990s, withdrawn due to hepatitis and liver damage risk.[7]
As a result of multiple retrospective studies, there is a concern about rosiglitazone's safety, although it is established that the group, as a whole, has beneficial effects on diabetes. The greatest concern is an increase in the number of severe cardiac events in patients taking it. The ADOPT study showed that initial therapy with drugs of this type may prevent the progression of disease,[8] as did the DREAM trial.[9]
Concerns about the safety of rosiglitazone arose when a retrospective meta-analysis was published in the New England Journal of Medicine.[10] There have been a significant number of publications since then, and a Food and Drug Administration panel[11] voted, with some controversy, 20:3 that available studies "supported a signal of harm," but voted 22:1 to keep the drug on the market. The meta-analysis was not supported by an interim analysis of the trial designed to evaluate the issue, and several other reports have failed to conclude the controversy. This weak evidence for adverse effects has reduced the use of rosiglitazone, despite its important and sustained effects on glycemic control.[12] Safety studies are continuing.
In contrast, at least one large prospective study, PROactive 05, has shown that pioglitazone may decrease the overall incidence of cardiac events in people with type II diabetes who have already had a heart attack.[13]
Alpha-glucosidase inhibitors
Alpha-glucosidase inhibitors are "diabetes pills" but not technically hypoglycemic agents because they do not have a direct effect on insulin secretion or sensitivity. These agents slow the digestion of starch in the small intestine, so that glucose from the starch of a meal enters the bloodstream more slowly, and can be matched more effectively by an impaired insulin response or sensitivity. These agents are effective by themselves only in the earliest stages of impaired glucose tolerance, but can be helpful in combination with other agents in type 2 diabetes.
Typical reductions in A1C values are 0.5-1.0%.
• miglitol (Glyset)
• acarbose (Precose/Glucobay)
These medications are rarely used in the United States because of the severity of their side effects (flatulence and bloating). They are more commonly prescribed in Europe. They do have the potential to cause weight loss by lowering the amount of sugar metabolized.
Research has shown the culinary mushroom Maitake (Grifola frondosa) has a hypoglycemic effect,[14][15][16][17][18][19] possibly due to the fact the mushroom naturally acts as an alpha-glucosidase inhibitor.[20]
Peptide analogs
Overview of insulin secretion
Incretin mimetics
Incretins are insulin secretagogues. The two main candidate molecules that fulfill criteria for being an incretin are Glucagon-like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent Insulinotropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4).
Glucagon-like peptide (GLP) analogs and agonists
GLP agonists bind to a membrane GLP receptor.[2] As a consequence of this, insulin release from the pancreatic beta cells is increased. Endogenous GLP has a half life of only a few minutes; thus an analogue of GLP would not be practical.
• Exenatide (also Exendin-4, marketed as Byetta) is the first GLP-1 agonist approved for the treatment of type 2 diabetes. Exenatide is not an analogue of GLP, but rather a GLP agonist.[21][22] Exenatide has only 53% homology with GLP, which increases its resistance to degradation by DPP-4 and extends its half-life.[23] Typical reductions in A1C values are 0.5-1.0%.
• Liraglutide, a once daily human analogue (97% homology), is being developed by Novo Nordisk under the brand name Victoza. The product was approved by the European Medicines Agency (EMEA) on July 3, 2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010.[24][25][26][27][28][29]
• Taspoglutide is presently in Phase III Clinical Trials with Hoffman-La Roche.
These agents may also cause a decrease in gastric motility, responsible for the common side effect of nausea, and is probably the mechanism by which weight loss occurs.
Gastric inhibitory peptide (GIP) analogs
• None are FDA approved
DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors increase blood concentration of the incretin GLP-1 (glucagon-like peptide-1) by inhibiting its degradation by dipeptidyl peptidase-4 (DPP-4).
Typical reductions in A1C values are 0.5-1.0%.
Examples are:
• vildagliptin (Galvus) EU Approved 2008.
• sitagliptin (Januvia) FDA approved Oct 2006.
• saxagliptin (Onglyza) FDA Approved July 2009.
Amylin analogues
Amylin agonist analogues slow gastric emptying and suppress glucagon. They have all the incretins actions except stimulation of insulin secretion. As of 2007, pramlintide is the only clinically available amylin analogue. Like insulin, it is administered by subcutaneous injection. The most frequent and severe adverse effect of pramlintide is nausea, which occurs mostly at the beginning of treatment and gradually reduces. Typical reductions in A1C values are 0.5-1.0%.
Experimental agents
Many other potential drugs are currently in investigation by pharmaceutical companies. Some of these are simply newer members of one of the above classes, but some work by novel mechanisms. For example, at least one compound that enhances the sensitivity of glucokinase to rising glucose is in the stage of animal research. Others are undergoing phase I/II studies.
• PPARα/γ ligands (muraglitazar and tesaglitazar - development stopped due to adverse risk profile, aleglitazar - under clinical development)
• SGLT2 (sodium-dependent glucose transporter 2) inhibitors increase urinary glucose.
• FBPase (fructose 1,6-bisphosphatase) inhibitors decrease gluconeogenesis in the liver.
Alternative medicine
A recent review article presents the profiles of plants with hypoglycaemic properties, reported in the literature from 1990 to 2000 and states that "Medical plants play an important role in the management of diabetes mellitus especially in developing countries where resources are meager."[30]
The first registered use of anti-diabetic drugs was as herbal extracts used by Indians in the Amazon Basin for the treatment of type 2 diabetes, and today promoted as vegetable insulin although not formally an insulin analog.[31] The major recent development was done in Brazil around Myrcia sphaerocarpa and other Myrcia species.[32] The usual treatment is with concentrated (root) Myrcia extracts, commercialized as "Pedra hume de kaá". Phytochemical analysis of the Myrcia extracts reported kinds of flavanone glucosides (myrciacitrins) and acetophenone glucosides (myrciaphenones), and inhibitory activities on aldose reductase and alpha-glucosidase.[33]
Walnut leaf can significantly reduce fasting blood glucose levels in rats with alloxan-induced diabetes, and rats thus treates show some evidence of regeneration of the beta cells.[34] Garlic also significantly reduces fasting blood glucose levels in rats with alloxan-induced diabetes.[35]
At least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cassia (Cinnamomum aromaticum) for oral consumption. Another study used an extract (MHCP) on laboratory rats. The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded "that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases."[36] The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone (MHCP) from cinnamon. Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[37][38] The Food and Drug Administration has not yet evaluated the use of cinnamon for the management of diabetes. It should be noted that the spice sold as cinnamon is often obtained from C. verum (true cinnamon), not C. aromaticum (cassia).
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[2] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][44] Agrocybe cylindracea[45] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Cinnamon
Though not yet evaluated by the Food and Drug Administration, at least two studies have shown that cinnamon can act significantly reducing some effects of diabetes. One study on people used fine ground cinnamon (Cinnamomum cassia) for oral consumption. Another study used an extract (MHCP) on laboratory rats.
The study on people published in 2003 conducted in the Department of Human Nutrition, NWFP Agricultural University, Peshawar, Pakistan concluded:
The results of this study demonstrate that intake of 1, 3, or 6 g of cinnamon per day reduces serum glucose, triglyceride, LDL cholesterol, and total cholesterol in people with type 2 diabetes and suggest that the inclusion of cinnamon in the diet of people with type 2 diabetes will reduce risk factors associated with diabetes and cardiovascular diseases.[51]
The study on laboratory rats at Department of Biochemistry, Biophysics and Molecular Biology, Iowa State University published in 2001 used purified hydroxychalcone from cinnamon. The extract was named "MHCP". Part of the study's conclusion stated that "the MHCP is fully capable of mimicking insulin" and recommended further studies.[52][53]
Other studies have failed to reproduce these results, and, because large doses of cinnamon are not innocuous, some experts advise against treatment of diabetes with cinnamon.[54]
Chromium and vanadium
Chromium - Cholesterol and triglycerides are risk factors in heart disease and diabetes, and studies show that chromium lowers levels of total cholesterol, LDL cholesterol, and triglycerides.[55][56][57][58] Chromium supplements such as chromium picolinate have been shown to improve glucose tolerance in people with type 2 diabetes,[59][60][61] although other studies have not replicated this result.[62] A meta analysis of these trials concluded that chromium supplements had no beneficial effect on healthy people, but that there might be an improvement in glucose metabolism in diabetics, although the authors stated that the evidence for this effect remains weak.[63]
Vanadium - A form of vanadium, vanadyl sulfate, seems to improve glucose control in people with type 2 diabetes.[64][65][66][67][68]
A pilot study has also found evidence that Tai Chi and Qigong reduce the severity of type 2 diabetes.[69]
Benfotiamine, a pro-vitamin of vitamin B1 which has been in use in Europe as an over-the-counter medicine for alcoholic neuropathy for the past half century with no significant side-effects or toxicity, has recently been found to block the major metabolic pathways by which excess blood glucose in the body is transformed into the advanced glycation endproducts (AGEs) which cause diabetic complications.[70] Studies have shown that taking oral benfotiamine can prevent diabetic retinopathy,[71] diabetic neuropathy,[72] and diabetic nephropathy[73] independently of any affect on the blood sugar levels of the patient. In theory, taking benfotiamine might allow patients to be less scrupulous in trying to normalize blood sugar levels and thus free them from the danger of hypoglycemia and the stress of stringent blood sugar monitoring, while still protecting them against the negative effects of hyperglycemia. Research is ongoing to establish the full significance of benfotiamine in the treatment of diabetes.
Traditional plant treatments for diabetes
A study was made of the effects on glucose homeostasis in normal and streptozotocin (induced) diabetic mice of eleven plants that have been used as traditional treatments for diabetes. The mice were given diets containing dried leaves from the following plants: agrimony (Agrimonia eupatoria), alfalfa (Medicago sativa), blackberry (Rubus fructicosus), celandine (Chelidonium majus), eucalyptus (Eucalyptus globulus), lady's mantle (Alchemilla vulgaris), and lily of the valley (Convallaria majalis); seeds of coriander (Coriandrum sativum); dried berries of juniper (Juniperus communis); bulbs of garlic (Allium sativum) and roots of liquorice (Glycyrhizza glabra). The study concluded that "The results suggest that certain traditional plant treatments for diabetes, namely agrimony, alfalfa, coriander, eucalyptus and juniper, can retard the development of streptozotocin diabetes in mice".[74]
Mushrooms
Research has shown the Maitake mushroom (Grifola frondosa) has a hypoglycemic effect, and may be beneficial for the management of diabetes.[14][15][16][17][18][19] The reason Maitake lowers blood sugar is due to the fact the mushroom naturally acts as an alpha glucosidase inhibitor.[75] Other mushrooms like Reishi,[39][40] Agaricus blazei,[41][42][43][76] Agrocybe cylindracea[77] and Cordyceps[46][47][48][49][50] have been noted to lower blood sugar levels to a certain extent, although the mechanism is currently unknown.
Aloe vera Oral administration of aloe vera might be a useful adjunct for lowering blood glucose in diabetic patients as well as for reducing blood lipid levels in patients with hyperlipidaemia[citation needed]. Ten controlled clinical trials were found to reach that conclusion in four independent literature searches. However, caveats reported in each study led the researchers to conclude that aloe vera's clinical effectiveness was not yet sufficiently defined in 1999.[78]
Huntington's disease -clinical research
Huntington's disease clinical research
There are different therapies under investigation for Huntington's disease. Huntington's disease is a is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no cure or effective treatments. Animal models help in the ongoing investigations using intrabody therapy, gene silencing, or stem cell implants, but all are at their first steps. Several clinical trials of various compounds are also in development. Many of these trials use the unified Huntington's disease rating scale (UHDRS) developed by the Huntington's Study Group.[1] This provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, backed up by a reference database of previous results provided by HSG for reference.[2] Another avenue of research is understanding the physical mechanics of protein folding, HD is one of several targets of the folding@home project,[3] one of the largest distributed computing systems on the World Wide Web.
Contents
• Animal models
• Intrabody therapy
• Gene silencing
• Stem cell treatments
• Pharmacological
Animal models
A laboratory mouse
Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Neurochemically-induced mice or monkeys were first available,[5][6] but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome, of mice (strain R6/2),[7][8]), Drosophila fruit flies,[9] and more recently monkeys.[10] Expression without insertion of a DNA repeat in nematode worms also produced a valuable model.[11]
Intrabody therapy
Genetically-engineered intracellular antibody fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in Drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell. This therapy prevented larval and pupal mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan.[14] Intrabodies have shown promise as a useful tool for drug discovery, and may potentially be used as a therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.
Gene silencing
As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT as a potential treatment. Using a mouse model, siRNA therapy achieved a 60% reduction in expression of mHTT and progression of the disease was stalled.[17] However, this study used the human form of the mHTT protein in mice, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type mouse Htt gene expression unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of Hyy is unknown, but in mice, complete deletion of the Htt gene is lethal. Thus, using RNA interference to treat HD could have unexpected effects unless knock-down of the normal Htt protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from shRNA over-expression. Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.
Stem cell treatments
Main article: Stem cell treatments
Stem cell implants are a stem cell treatment where damaged neurons are replaced by transplantation of stem cells (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, embryonic stem cells can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons; if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but stem cell treatment for HD remains highly speculative and has not been tested in clinical trials.
Pharmacological
As of August 2008, several trials of various compounds are in development or ongoing,[22] a few at the point of testing on larger numbers of people, known as phase III of clinical trials. Substances that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as creatine and CoQ10, the antibiotic Minocycline, antioxidant-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitors such as sertraline, fluoxetine, and paroxetine. A recent study suggested strong association between specific single nucleotide polymorphisms alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.
There are different therapies under investigation for Huntington's disease. Huntington's disease is a is a genetic neurological disorder characterized after onset by uncoordinated, jerky body movements and a decline in some mental abilities for which there is no cure or effective treatments. Animal models help in the ongoing investigations using intrabody therapy, gene silencing, or stem cell implants, but all are at their first steps. Several clinical trials of various compounds are also in development. Many of these trials use the unified Huntington's disease rating scale (UHDRS) developed by the Huntington's Study Group.[1] This provides an overall rating system based on motor, behavioral, cognitive, and functional assessments, backed up by a reference database of previous results provided by HSG for reference.[2] Another avenue of research is understanding the physical mechanics of protein folding, HD is one of several targets of the folding@home project,[3] one of the largest distributed computing systems on the World Wide Web.
Contents
• Animal models
• Intrabody therapy
• Gene silencing
• Stem cell treatments
• Pharmacological
Animal models
A laboratory mouse
Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of drug development. Neurochemically-induced mice or monkeys were first available,[5][6] but they did not mimic the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome, of mice (strain R6/2),[7][8]), Drosophila fruit flies,[9] and more recently monkeys.[10] Expression without insertion of a DNA repeat in nematode worms also produced a valuable model.[11]
Intrabody therapy
Genetically-engineered intracellular antibody fragments called intrabodies have shown therapeutic results, by inhibiting mHtt aggregation, in Drosophila models. This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell. This therapy prevented larval and pupal mortality (without therapy 77% died) and delayed neurodegeneration in the adult, significantly increasing their lifespan.[14] Intrabodies have shown promise as a useful tool for drug discovery, and may potentially be used as a therapy for HD and other neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions.
Gene silencing
As HD has been conclusively linked to a single gene, gene silencing is potentially possible. Researchers have investigated using gene knockdown of mHTT as a potential treatment. Using a mouse model, siRNA therapy achieved a 60% reduction in expression of mHTT and progression of the disease was stalled.[17] However, this study used the human form of the mHTT protein in mice, and was therefore only able to directly target the mHTT, leaving endogenous, wild-type mouse Htt gene expression unaffected. From a practical standpoint, it would be difficult in humans to use siRNA to target the mutant form while leaving the normal copy unaffected. The precise function of Hyy is unknown, but in mice, complete deletion of the Htt gene is lethal. Thus, using RNA interference to treat HD could have unexpected effects unless knock-down of the normal Htt protein can be avoided. Other issues include problems delivering the siRNA to the appropriate target tissue, off-target effects of siRNA, and toxicity from shRNA over-expression. Another study showed that mouse models already in late stages of the disease recovered motor function after expression of mHTT was stopped.
Stem cell treatments
Main article: Stem cell treatments
Stem cell implants are a stem cell treatment where damaged neurons are replaced by transplantation of stem cells (or possibly neural stem cells—a type of somatic [adult] stem cell) into affected regions of the brain. Hypothetically, embryonic stem cells can be differentiated into neuronal precursors in vitro, and transplanted into damaged areas of the brain to generate replacement neurons; if enough damaged neurons can be replaced and develop the correct synaptic connectivity, symptoms could be alleviated. This treatment would not prevent further neuronal damage, so it would have to be an ongoing treatment. Experiments have yielded some positive results in animal models, but stem cell treatment for HD remains highly speculative and has not been tested in clinical trials.
Pharmacological
As of August 2008, several trials of various compounds are in development or ongoing,[22] a few at the point of testing on larger numbers of people, known as phase III of clinical trials. Substances that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as creatine and CoQ10, the antibiotic Minocycline, antioxidant-containing foods and nutrients, and antidepressants, including selective serotonin reuptake inhibitors such as sertraline, fluoxetine, and paroxetine. A recent study suggested strong association between specific single nucleotide polymorphisms alleles and CAG expansion also provides an opportunity of personalized therapeutics in HD where the clinical development of only a small number of allele-specific targets may be sufficient to treat up to 88% of the HD patient population.
DIALYSIS
DIALYSIS
What is dialysis?
The kidneys are responsible for filtering waste products from the blood. Dialysis is a procedure that is a substitute for many of the normal duties of the kidneys. The kidneys are two organs located on either side of the back of the abdominal cavity. Dialysis can allow individuals to live productive and useful lives, even though their kidneys no longer work adequately. In the United States, there are over 200,000 people who use dialysis techniques on an ongoing basis.
Dialysis helps the body by performing the functions of failed kidneys. The kidney has many roles. An essential job of the kidney is to regulate the body's fluid balance. It does this by adjusting the amount of urine that is excreted on a daily basis. On hot days, the body sweats more. Thus, less water needs to be excreted through the kidneys. On cold days, the body sweats less. Thus, urine output needs to be greater in order to maintain the proper balance within the body. It is the kidney's job to regulate fluid balance by adjusting urine output.
Another major duty of the kidney is to remove the waste products that the body produces throughout the day. As the body functions, the cells use energy. The operation of the cells produces waste products that must be removed from the body. When these waste products are not removed adequately, they build up in the body. An elevation of waste products, as measured in the blood, is called "azotemia." When waste products accumulate they, cause a sick feeling throughout the body called "uremia."
When do patients require dialysis?
Patients usually require dialysis when the waste products in their body become so high that they start to become sick from them. The level of the waste products usually builds up slowly. Doctors measure several blood chemical levels to help decide when dialysis is necessary. The two major blood chemical levels that are measured are the "creatinine level" and the "blood urea nitrogen" (BUN) level. As these two levels rise, they are indicators of the decreasing ability of the kidneys to cleanse the body of waste products.
Doctors use a urine test, the "creatinine clearance," to measure the level of kidney function. The patient saves urine in a special container for one full day. The waste products in the urine and in the blood are estimated by measuring the creatinine. By comparing the blood and urine level of this substance, the doctor has an accurate idea of how well the kidneys are working. This result is called the creatinine clearance. Usually, when the creatinine clearance falls to 10-12 cc/minute, the patient needs dialysis.
The doctor uses other indicators of the patient's status to decide about the need for dialysis. If the patient is experiencing a major inability to rid the body of excess water, or is complaining of problems with the heart, lungs, or stomach, or difficulties with taste or sensation in their legs, dialysis may be indicated even though the creatinine clearance has not fallen to the 10-12 cc/minute level.
What types of dialysis are there?
There are two main types of dialysis: "hemodialysis" and "peritoneal dialysis." Hemodialysis uses a special type of filter to remove excess waste products and water from the body. Peritoneal dialysis uses a fluid that is placed into the patient's stomach cavity through a special plastic tube to remove excess waste products and fluid from the body.
During Hemodialysis, blood passes from the patient's body through a filter in the dialysis machine, called a "dialysis membrane." For this procedure, the patient has a specialized plastic tube placed between an artery and a vein in the arm or leg (called a "gortex graft"). Sometimes, a direct connection is made between an artery and a vein in the arm. This procedure is called a "Cimino fistula." Needles are then placed in the graft or fistula, and blood passes to the dialysis machine, through the filter, and back to the patient. In the dialysis machine, a solution on the other side of the filter receives the waste products from the patient.
Peritoneal dialysis uses the patients own body tissues inside of the belly (abdominal cavity) to act as the filter. The intestines lie in the abdominal cavity, the space between the abdominal wall and the spine. A plastic tube called a "dialysis catheter" is placed through the abdominal wall into the abdominal cavity. A special fluid is then flushed into the abdominal cavity and washes around the intestines. The intestinal walls act as a filter between this fluid and the blood stream. By using different types of solutions, waste products and excess water can be removed from the body through this process.
What does the patient do during dialysis?
Hemodialysis
Treatment for hemodialysis takes place in a hemodialysis unit. This is a special building that is equipped with machines that perform the dialysis treatment. Special equipment adds the proper materials to purified water for the dialysis machines. The dialysis unit is also the place where patients can receive dietary counseling and help with social needs.
Patients generally go to the dialysis unit three times a week for treatment. For example, the schedule is either on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday. Before treatment, patients weigh themselves so that excess fluid accumulated since the last dialysis session can be measured. Patients then go to assigned chairs that are like lounge chairs. The area of the graft or fistula (the connection between the artery and vein), is cleaned thoroughly. Two needles are then inserted into the graft or fistula. One takes the blood to the machine where it is cleaned. The other needle allows blood that is returning to the patient to go back into the patient's body.
Treatments last from 2 ½ to 4 ½ hours. During this time, the dialysis staff checks the patient's blood pressure frequently and adjusts the dialysis machine to ensure that the proper amount of fluid is being removed from the patients body. Patients can read, watch television, sleep, or do other work during treatment.
Peritoneal Dialysis
Peritoneal dialysis requires the patient to play a more active role in their dialysis treatment. Of primary importance is the patient's responsibility for maintaining a clean surface on the abdomen, where treatment is administered, in order to prevent infection.
In this process, the patient weighs herself/himself to determine the fluid to be used. The patient then puts on a mask and cleans the peritoneal catheter site. Fluid that has been allowed to stay in the peritoneal cavity is drained back into the plastic bag that originally contained the fluid. The patient then disconnects this bag and connects a new bag of solution that is allowed to drain into the peritoneal cavity. Once the fluid is in the body, the new bag is rolled up and placed in the patient's underwear until the next treatment. This procedure usually takes 30 minutes to accomplish and must be done four to five times a day.
As an alternative to this treatment, some patients on peritoneal dialysis use a machine called a "cycler." This cycler is used every night. Five to six bags of dialysis fluid is used on the cycler and the machine automatically changes the fluid while the patient sleeps.
What are the advantages of the different types of dialysis?
Each of the two types of dialysis, hemodialysis and peritoneal dialysis, has advantages and disadvantages. It is up to the patient to decide which of these procedures is best by considering her/his life style, other medical conditions, support systems, and how much responsibility and participation in the treatment program he/she desires. Each patient must view the two types of dialysis procedures from her/his own perspective.
Regardless of which type of dialysis is chosen , patients have certain responsibilities such as following a diet program, watching their fluid intake and taking special vitamins and other medicines to control blood pressure and calcium and phosphorus balance.
For many patients, the major advantage of hemodialysis is minimal participation in the treatment. However, patients are required to adhere to a specific schedule and travel to the dialysis unit. Hemodialysis also requires stricter diet control and fluid control than peritoneal dialysis.
For those patients preferring more independence, peritoneal dialysis allows for more flexible scheduling and can be performed at home. The patient still must undergo a certain amount of dialysis each day, but can alter the exact timing of the dialysis procedure. On the other hand, peritoneal dialysis must be done every day of the week.
The major problem with peritoneal dialysis is infection. The patient has a plastic tube that goes from the peritoneal cavity to the outside of the body and this is a potential site for the entry of bacteria into the body. Great emphasis is placed on cleanliness and technique during the training sessions.
Indications and contraindications of dialysis
Indications for Dialysis -In Chronic Renal Failure
In patients with chronic renal failure factors to be considered before initiating dialysis should include comorbid conditions and patient preference. Timing of therapy is dictated by serum chemistries and symptoms.
A) Absolute indications
Uremic Pericarditis
Uremic Encephalopathy or Neuropathy
Pulmonary edema (unresponsive to diuretics)
Severe Hypertension
Severe hyperkalemia
Intractable acidosis
Severe Bleeding diathesis
Persistent gastrointestinal symptoms
S.Creatinine more than 12 mg/dl, BUN more than 100 mg/dl
B) Relative indications
Mild encephalopathy or neuropathy
Severe edema (unresponsive to diuretics)
Progressive gastrointestinal symptoms
Recurrent GI “itis”: stomatitis, gastritis, dudenitis, pancreatitis
Ascitis without hepatic disease
Anemia refractor to Erythropoietin
Mild Bleeding diathesis
Pruritus
Infectious complications
Depression
C) Early indications
Decrease ideal body weight
Decrease in muscle mass (decrease s creatinine or its clearance)
Decrease in s.albumin to less than 4 g/l
GFR less than 15 ml/min (by I iothalamate)
S. Creatinine >10 mg/dl and bun >100 mg /dl
Decrease in s.transferrin
Low total cholesterol
Growth retardation in children
D) Specific indications for peritoneal dialysis
Patients with cardiovascular or hemodynamic instability
Hemodialysis patients with vascular access failure or can not be created (e.g. diabetic patients)
High risk of anti coagulation
Patients in the older age group (over 65) and small children
Severe hemodialysis-related symptoms or disequilibrium
Social reason
Indications for Dialysis other than chronic renal failure
1-Acute renal failure
2-Poisons and Drug intoxication
3-Hypercalcaemia
4-Hyperuricemia
5-Hypothermia
6-Metabolic alkalosis (special dialysis solution required)
Dialyzable drugs and Poisons (partial list)
a) Barbiturates : Phenobarbital -Pentobarbital -Amobarbital
b) Alcohol's : Methanol -Ethanol -Ethylene glycol -Isopropanol
c) Analgesics : Acetylsalicylic acid -Methylsalicylate
d) Metals : Calcium -Potassium -Sodium -Lithium
e) Endogenous toxins : Uric acid -Uremic toxins -Hyperosmolar state
f) Halides : Bromide
e) Miscellaneous : Theophylline -Mannitol -Radiocontrast -Thiocynate -
Boric acid -Aniline
NB 1) Dialysis for poisoning should be considered only when supportive measures are ineffective or there is impending irreversible organ toxicity.
2) Hemoperfusion is required in some cases
Factors to be considered in determine drug’s dialyzability:
1) Dialysis related factors:
Dialyzer membrane characteristics
Surface area
Blood flow rate
Dialysate flow rate
Degree of ultrafitration
Duration of dialysis
2) Drug related factors :
Availability of the drug in the plasma
Drug pharmacokinetic characteristics
Drug molecular weight (<500 cross the membrane more readily)
Drug solubility (water soluble are dialyzable than lipid soluble)
Factors Determinants for Dialysis
Factors determining the mode of chronic dialysis should include medical and non medical factors which have an impact on the treatment modality. Physicians have the responsibility to discuss the therapeutic options and offer their advice and recommendations about the choices. In general renal transplantation should be recommended as the preferred mode of renal replacement therapy in whom surgery and immunosupression is safe and feasible.
Medical Factors
1. Age
2. Comorbid medical illnesses
3. Patient survival
4. Patient rehabilitation
5. Quality of life
Non Medical Factors
1. Government-imposed Economic limitations
2. Physician and Patient bias
3. Resource availability
4. Social ,Religious ,Cultural mores
5. Availability of transplantation
6. Family support
7. Cost , race , sex , reimbursement
Contraindications of Dialysis therapy
Principally there is no absolute contraindication to dialysis therapy. Advanced age in and of itself is not a contraindication to dialysis therapy. Many elderly are physiologically equivalent to young patients.
Relative contraindications to dialysis therapy
1. Advanced malignancy (except multiple myeloma)
2. Alzheimer’s disease
3. Multi-infarct dementia
4. Hepatorenal syndrome
5. Advanced liver cirrhosis with encephalopathy
6. Hypotension unresponsive to pressors
7. Terminal illness
8. Organic brain syndrome
Contraindication for Peritoneal dialysis
Absolute
1. Peritoneal fibrosis
2. Pleuroperitoneal leak
Relative Major
1. Chronic Ostomies
2. Severe hypercatabolic state
3. Fresh aortic prosthesis
4. Recent Abdominal surgery
5. Recent Thoracic surgery
6. Extensive Abdominal adhesions
7. Quadriplegia
8. Blindness
9. Physical handicaps
10. Mental Retardation
Relative Minor
1. Polycystic Kidney disease
2. Diverticulosis
3. Obesity
4. Peripheral vascular disease
5. Hyperlipidemia
6. Social
Introduction
Background
Chronic renal failure (CRF) requiring dialysis or transplantation is known as end-stage renal disease (ESRD). In the United States, diabetic nephropathy is the most common and hypertension the second most common cause. Along with glomerulonephritis, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy. Genetic kidney disease such as polycystic kidney disease is a common cause in young adults.1
Patients with end-stage renal disease (ESRD) are commonly encountered in the ED with problems related to the metabolic complications of their renal disease or dialysis complications. Various problems related to vascular access in patients on hemodialysis and to abdominal catheters in patients using continuous ambulatory peritoneal dialysis (CAPD) are also common. Patients who have undergone renal transplantation may experience a variety of transplant-related conditions.
Patients with chronic renal failure often present to the ED with an unrelated condition. In these cases, the level of renal function may have important implications for diagnosis and treatment.
Pathophysiology
All major organ systems are affected by renal failure. Prevalence of symptoms is a function of the glomerular filtration rate (GFR), which averages 120 mL/min in a healthy adult. As the GFR falls to less than approximately 20% of normal, symptoms of uremia may begin to occur. They almost are invariably present when the GFR decreases to less than 10% of normal. Measuring GFR requires a timed urine collection as well as measurement of serum creatinine. However, it can be accurately estimated from a patient's age, weight, gender, and serum creatinine level. Online calculators are available to automate the calculation.2
Signs and symptoms of renal failure are due to overt metabolic derangements resulting from inability of failed kidneys to regulate electrolyte, fluid, and acid-base balance; they are also due to accumulation of toxic products of amino acid metabolism in the serum. Signs and symptoms include the following:
Systemic signs
Malaise, weakness, and fatigue are very common.
Gastrointestinal signs
GI disturbances include anorexia, nausea, vomiting, and hiccups. Peptic ulcer disease and symptomatic diverticular disease are common in patients with CRF.
Neurological signs
Peripheral neuropathy and restless legs syndrome are the most common neurologic complications of CRF. Seizures may occur due to uremia, and the prevalence of stroke is increased.
Hematologic signs
Anemia is inevitable in CRF because of loss of erythropoietin production. Abnormalities in white cell and platelet functions lead to increased susceptibility to infection and easy bruising.
Dermatologic signs
Pruritus is a common dermatologic complication assumed to be secondary to accumulation of toxic pigments (urochromes) in the dermis.
Metabolic/endocrine signs
Volume overload occurs when salt and water intake exceeds losses and excretion. This causes congestive heart failure (CHF) and exacerbates hypertension. Hyperkalemia is the most common immediately life-threatening metabolic complication of renal failure and may develop suddenly when GFR is severely reduced. Anion gap acidosis results from decreased hydrogen ion excretion and may exacerbate hyperkalemia. Hypocalcemia is potentially life threatening and results from loss of vitamin D and increased parathyroid hormone levels. Hypermagnesemia also may occur.
Cardiac signs
Volume overload may cause CHF and pulmonary edema. Hypertension contributes to cardiovascular disease. Dyslipidemia is a primary risk factor for cardiovascular disease and a common complication of ESRD. Uremia may also lead to pericardial effusion and, in rare cases, pericardial tamponade. Cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.
Vascular signs
Vascular access complications are similar to those seen in any patient with a vascular surgical procedure (eg, bleeding, local or disseminated intravascular infections, vessel [graft] occlusion).
Dialysis catheters
A peritoneal dialysis catheter subjects patients to the risks of peritonitis and local infection. The catheter acts as a foreign body and provides a portal of entry for pathogens from the external environment.
Infection/immunologic
Patients who have received renal transplants may experience recurrent renal failure due to rejection or other graft complications. In addition, chronic immunosuppression makes them prone to infection.
Frequency
United States
The government of the United States funds treatment of end-stage renal disease (ESRD) universally for US citizens. As a consequence, the population of patients receiving dialysis or who have had a renal transplant in the United States is large. During 2004, the last year with complete data availability, 104,364 patients (approximately 0.03% of the US population) began renal replacement therapy, an adjusted incidence rate of 339 per 1,000,000. As of 2005, more than 485,000 patients were receiving treatment for ESRD in the United States. As a result, patients with ESRD are encountered on a regular basis in US emergency departments.
International
Resources allocated for treatment of ESRD vary throughout the world, and the treatments are expensive. Untreated ESRD is rapidly fatal, and treatment is too expensive for most individuals to purchase privately. Consequently, very few patients with ESRD are encountered in countries where ESRD treatment is not funded by the government.
The morbidity and mortality of dialysis patients is much higher in the United States compared with most other countries. This is probably a consequence of selection bias. Due to liberal criteria for receiving government-funded dialysis in the United States and rationing (both medical and economic) in most other countries, US patients receiving dialysis are on the average older and sicker than those in other countries.
Mortality/Morbidity
Patients in renal failure are prone to all of the complications of any underlying condition, such as diabetes and hypertension. In addition, renal failure causes a variety of metabolic and physiologic derangements.
• The most common cause of sudden death in patients with end-stage renal disease (ESRD) is hyperkalemia, which is often encountered in patients after missed dialysis or dietary indiscretion. Serum potassium also rises when the serum is acidemic, even though total body potassium is unchanged. Hyperkalemia is usually asymptomatic and should be treated empirically when suspected and when arrhythmia or cardiovascular compromise is present.
• Iatrogenic complications related to fluid administration (fluid overload) or medications are frequently encountered in patients in renal failure.
• Cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.
• Anemia results in fatigue, reduced exercise capacity, decreased cognition, and impaired immunity.
• Renal transplant patients are prone to infection, especially in the immediate post-transplant period.
Race
Etiology of end-stage renal disease (ESRD) differs among racial groups primarily because of the prevalence of predisposing conditions, such as diabetes and hypertension. In populations with problematic access and utilization of primary medical care for treatment of predisposing conditions, ESRD often is encountered in relatively young patients. While the costs of treatment for ESRD are borne by the entire population (through government funding), relatively inexpensive preventive treatments often are funded poorly. Diseases such as diabetes and hypertension are much less likely to lead to renal failure when appropriately treated. The cost of primary care for these conditions is far lower than for dialysis or transplantation, yet primary care remains poorly funded, while ESRD treatment is reimbursed completely by the government. This conundrum is reflective of the often illogical and capricious nature of health care spending in the United States.
In the United States, racial and ethnic discrepancies in ESRD exist, with 2006 rates in the African American and Native American populations 3.6 and 1.8 times greater, respectively, than the rate among whites, and the rate in the Hispanic population 1.5 times higher than that of non-Hispanics.3
Sex
Presentation and treatment of chronic renal failure (CRF) and end-stage renal disease (ESRD) do not differ significantly between men and women. Differences in causes of renal failure are related to the types of underlying conditions prevalent in men and women.
Age
While the etiology of CRF differs among age groups, the presentations and nature of complications are similar. Young children with ESRD often are treated with transplantation rather than dialysis because of a relatively greater long-term benefit compared to that of adults, and due to difficulties related to vascular access for dialysis.
Clinical
History
Renal failure produces no symptoms early in the course of the disease. At this stage, symptoms of the underlying illness may bring the patient to medical attention and renal insufficiency is noted on laboratory testing.
• Chronic renal failure (CRF) potentially affects all organ systems. History for the presenting disorder is similar to that encountered when the same disorder exists in patients without renal failure.
• The following presentations are seen frequently in CRF. Moreover, some problems are unique to patients with CRF/ESRD; many of these are related to treatments, such as dialysis or transplantation.
• Electrolyte abnormalities include life-threatening hyperkalemia, which is usually asymptomatic.
o Dilutional hyponatremia may cause mental status changes or seizures.
o Hypocalcemia or hypermagnesemia may cause weakness and life-threatening dysrhythmias.
o Neuromuscular irritability is seen with hypocalcemia and may present as tetany or paresthesia.
o Hypermagnesemia causes neuromuscular depression with weakness and loss of reflexes.
o Acidosis may present as shortness of breath due to the work of breathing from compensatory hyperpnea.
• Pericarditis and asymptomatic pericardial effusion are common in patients with ESRD. Cardiac tamponade may occur but is rare. Presentation of pericarditis and tamponade are typical, with pleuritic chest pain being the most common presentation.
o Tamponade presents as fatigue, weakness, syncope, or dyspnea.
o Hypotension is usually present, and, if advanced, frank shock and cardiovascular collapse occur.
• Hypotension with postural weakness or syncope may occur as a complication of fluid shifts from dialysis or from any other cause. Sepsis is a serious cause of hypotension.
• Myocardial ischemia or infarction is common in patients with ESRD; consider this diagnosis in hypotensive patients along with other conditions, such as GI bleeding.
• Dialysis dysequilibrium syndrome is a common neurologic complication seen in dialysis patients.
o Syndrome is characterized by weakness, dizziness, headache, and in severe cases, mental status changes. Diagnosis is one of exclusion.
o A prime characteristic of the syndrome is that it is nonfocal.
• Peritonitis is common in patients being treated with continuous ambulatory peritoneal dialysis (CAPD), occurring approximately once per patient year. Patients present with abdominal pain, which may be mild, or complain of a cloudy effluent. Fever often is absent.
• Infection at the catheter exit site manifests as expected local pain, erythema, warmth, and/or fluctuance.
• Other abdominal conditions, such as appendicitis, pancreatitis, or diverticulitis, should be considered when patients present with abdominal pain, especially if signs and symptoms are localized.
• Vascular access problems include infections, which are usually manifest with typical signs and symptoms such as local pain, redness, warmth, or fluctuance. Fever may be present without local signs.
o Clotting of the vascular access presents as loss of normal bruit or thrill. There may be signs or symptoms of distal limb ischemia.
o Patients may present after dialysis or minor trauma with bleeding from their vascular access. Bleeding usually can be controlled with elevation and firm but nonocclusive pressure. In the immediate postdialysis period, protamine may be needed to reverse the effect of heparin (routinely used in dialysis to prevent clotting). Life-threatening bleeding may occur.
Physical
• Chronic renal failure (CRF) produces no specific physical findings.
• Patients with an arteriovenous fistula or graft should have the site examined regularly. Abnormal findings include loss of palpable thrill, overlying erythema, or active bleeding from the incisional wound of a newly placed fistula or graft.
• Physical findings of chronic renal failure complications generally are those expected with the specific complication and do not differ from those encountered when the condition occurs in patients with normal renal function.
• Certain complications are very common in renal failure.
• CAPD-associated peritonitis
o Abdominal pain and tenderness usually are generalized and relatively mild.
o Localized pain and tenderness suggest a local process, such as incarcerated hernia or appendicitis.
o Severe generalized peritonitis may be due to a perforated viscus as in any other patient.
• Transplant-related problems: Pain and tenderness over a transplanted kidney may be due to infection (pyelonephritis), obstruction (stone or extrinsic compression), or graft rejection.
• Vascular access aneurysms or pseudoaneurysms : These present as localized swelling, which may be pulsatile, and are often chronic. A rapid increase in size may indicate active bleeding.
Causes
Once chronic renal failure (CRF) has occurred, treatment options and complications are largely independent of the cause.
• In terms of broad categories of disease, glomerulonephritis and interstitial nephritis are the most common causes of CRF in adults and children.
• Chronic upper urinary tract infection causes CRF in all age groups.
• CRF also is encountered in children because of congenital anomalies such as chronic hydronephrosis, which is caused by anatomic defects that obstruct urine flow or allow reflux from the bladder (vesicoureteral reflux).
• Kidneys may be congenitally hypoplastic.
• Hereditary nephropathies also exist.
• In adults, diabetic and hypertensive nephropathies are the most common specific causes of CRF.
• Polycystic disease, renal vascular disease, and analgesic nephropathy also are common.
• In certain geographic areas, HIV-related renal disease is becoming common.
• Certain diseases such as some of the types of glomerulonephritis tend to recur in transplanted kidneys. In these cases, dialysis is the preferred treatment option.
• Consider renal transplant patients to be mildly to moderately immunosuppressed.
o In the immediate posttransplant period or during a rejection episode, intensive immunosuppression puts patients at considerable risk of infection, including disseminated viral infections such as herpes zoster.
o Degree of immunosuppression is less late in the posttransplant course when corticosteroids alone may be used.
What is dialysis?
The kidneys are responsible for filtering waste products from the blood. Dialysis is a procedure that is a substitute for many of the normal duties of the kidneys. The kidneys are two organs located on either side of the back of the abdominal cavity. Dialysis can allow individuals to live productive and useful lives, even though their kidneys no longer work adequately. In the United States, there are over 200,000 people who use dialysis techniques on an ongoing basis.
Dialysis helps the body by performing the functions of failed kidneys. The kidney has many roles. An essential job of the kidney is to regulate the body's fluid balance. It does this by adjusting the amount of urine that is excreted on a daily basis. On hot days, the body sweats more. Thus, less water needs to be excreted through the kidneys. On cold days, the body sweats less. Thus, urine output needs to be greater in order to maintain the proper balance within the body. It is the kidney's job to regulate fluid balance by adjusting urine output.
Another major duty of the kidney is to remove the waste products that the body produces throughout the day. As the body functions, the cells use energy. The operation of the cells produces waste products that must be removed from the body. When these waste products are not removed adequately, they build up in the body. An elevation of waste products, as measured in the blood, is called "azotemia." When waste products accumulate they, cause a sick feeling throughout the body called "uremia."
When do patients require dialysis?
Patients usually require dialysis when the waste products in their body become so high that they start to become sick from them. The level of the waste products usually builds up slowly. Doctors measure several blood chemical levels to help decide when dialysis is necessary. The two major blood chemical levels that are measured are the "creatinine level" and the "blood urea nitrogen" (BUN) level. As these two levels rise, they are indicators of the decreasing ability of the kidneys to cleanse the body of waste products.
Doctors use a urine test, the "creatinine clearance," to measure the level of kidney function. The patient saves urine in a special container for one full day. The waste products in the urine and in the blood are estimated by measuring the creatinine. By comparing the blood and urine level of this substance, the doctor has an accurate idea of how well the kidneys are working. This result is called the creatinine clearance. Usually, when the creatinine clearance falls to 10-12 cc/minute, the patient needs dialysis.
The doctor uses other indicators of the patient's status to decide about the need for dialysis. If the patient is experiencing a major inability to rid the body of excess water, or is complaining of problems with the heart, lungs, or stomach, or difficulties with taste or sensation in their legs, dialysis may be indicated even though the creatinine clearance has not fallen to the 10-12 cc/minute level.
What types of dialysis are there?
There are two main types of dialysis: "hemodialysis" and "peritoneal dialysis." Hemodialysis uses a special type of filter to remove excess waste products and water from the body. Peritoneal dialysis uses a fluid that is placed into the patient's stomach cavity through a special plastic tube to remove excess waste products and fluid from the body.
During Hemodialysis, blood passes from the patient's body through a filter in the dialysis machine, called a "dialysis membrane." For this procedure, the patient has a specialized plastic tube placed between an artery and a vein in the arm or leg (called a "gortex graft"). Sometimes, a direct connection is made between an artery and a vein in the arm. This procedure is called a "Cimino fistula." Needles are then placed in the graft or fistula, and blood passes to the dialysis machine, through the filter, and back to the patient. In the dialysis machine, a solution on the other side of the filter receives the waste products from the patient.
Peritoneal dialysis uses the patients own body tissues inside of the belly (abdominal cavity) to act as the filter. The intestines lie in the abdominal cavity, the space between the abdominal wall and the spine. A plastic tube called a "dialysis catheter" is placed through the abdominal wall into the abdominal cavity. A special fluid is then flushed into the abdominal cavity and washes around the intestines. The intestinal walls act as a filter between this fluid and the blood stream. By using different types of solutions, waste products and excess water can be removed from the body through this process.
What does the patient do during dialysis?
Hemodialysis
Treatment for hemodialysis takes place in a hemodialysis unit. This is a special building that is equipped with machines that perform the dialysis treatment. Special equipment adds the proper materials to purified water for the dialysis machines. The dialysis unit is also the place where patients can receive dietary counseling and help with social needs.
Patients generally go to the dialysis unit three times a week for treatment. For example, the schedule is either on Monday, Wednesday, and Friday or Tuesday, Thursday, and Saturday. Before treatment, patients weigh themselves so that excess fluid accumulated since the last dialysis session can be measured. Patients then go to assigned chairs that are like lounge chairs. The area of the graft or fistula (the connection between the artery and vein), is cleaned thoroughly. Two needles are then inserted into the graft or fistula. One takes the blood to the machine where it is cleaned. The other needle allows blood that is returning to the patient to go back into the patient's body.
Treatments last from 2 ½ to 4 ½ hours. During this time, the dialysis staff checks the patient's blood pressure frequently and adjusts the dialysis machine to ensure that the proper amount of fluid is being removed from the patients body. Patients can read, watch television, sleep, or do other work during treatment.
Peritoneal Dialysis
Peritoneal dialysis requires the patient to play a more active role in their dialysis treatment. Of primary importance is the patient's responsibility for maintaining a clean surface on the abdomen, where treatment is administered, in order to prevent infection.
In this process, the patient weighs herself/himself to determine the fluid to be used. The patient then puts on a mask and cleans the peritoneal catheter site. Fluid that has been allowed to stay in the peritoneal cavity is drained back into the plastic bag that originally contained the fluid. The patient then disconnects this bag and connects a new bag of solution that is allowed to drain into the peritoneal cavity. Once the fluid is in the body, the new bag is rolled up and placed in the patient's underwear until the next treatment. This procedure usually takes 30 minutes to accomplish and must be done four to five times a day.
As an alternative to this treatment, some patients on peritoneal dialysis use a machine called a "cycler." This cycler is used every night. Five to six bags of dialysis fluid is used on the cycler and the machine automatically changes the fluid while the patient sleeps.
What are the advantages of the different types of dialysis?
Each of the two types of dialysis, hemodialysis and peritoneal dialysis, has advantages and disadvantages. It is up to the patient to decide which of these procedures is best by considering her/his life style, other medical conditions, support systems, and how much responsibility and participation in the treatment program he/she desires. Each patient must view the two types of dialysis procedures from her/his own perspective.
Regardless of which type of dialysis is chosen , patients have certain responsibilities such as following a diet program, watching their fluid intake and taking special vitamins and other medicines to control blood pressure and calcium and phosphorus balance.
For many patients, the major advantage of hemodialysis is minimal participation in the treatment. However, patients are required to adhere to a specific schedule and travel to the dialysis unit. Hemodialysis also requires stricter diet control and fluid control than peritoneal dialysis.
For those patients preferring more independence, peritoneal dialysis allows for more flexible scheduling and can be performed at home. The patient still must undergo a certain amount of dialysis each day, but can alter the exact timing of the dialysis procedure. On the other hand, peritoneal dialysis must be done every day of the week.
The major problem with peritoneal dialysis is infection. The patient has a plastic tube that goes from the peritoneal cavity to the outside of the body and this is a potential site for the entry of bacteria into the body. Great emphasis is placed on cleanliness and technique during the training sessions.
Indications and contraindications of dialysis
Indications for Dialysis -In Chronic Renal Failure
In patients with chronic renal failure factors to be considered before initiating dialysis should include comorbid conditions and patient preference. Timing of therapy is dictated by serum chemistries and symptoms.
A) Absolute indications
Uremic Pericarditis
Uremic Encephalopathy or Neuropathy
Pulmonary edema (unresponsive to diuretics)
Severe Hypertension
Severe hyperkalemia
Intractable acidosis
Severe Bleeding diathesis
Persistent gastrointestinal symptoms
S.Creatinine more than 12 mg/dl, BUN more than 100 mg/dl
B) Relative indications
Mild encephalopathy or neuropathy
Severe edema (unresponsive to diuretics)
Progressive gastrointestinal symptoms
Recurrent GI “itis”: stomatitis, gastritis, dudenitis, pancreatitis
Ascitis without hepatic disease
Anemia refractor to Erythropoietin
Mild Bleeding diathesis
Pruritus
Infectious complications
Depression
C) Early indications
Decrease ideal body weight
Decrease in muscle mass (decrease s creatinine or its clearance)
Decrease in s.albumin to less than 4 g/l
GFR less than 15 ml/min (by I iothalamate)
S. Creatinine >10 mg/dl and bun >100 mg /dl
Decrease in s.transferrin
Low total cholesterol
Growth retardation in children
D) Specific indications for peritoneal dialysis
Patients with cardiovascular or hemodynamic instability
Hemodialysis patients with vascular access failure or can not be created (e.g. diabetic patients)
High risk of anti coagulation
Patients in the older age group (over 65) and small children
Severe hemodialysis-related symptoms or disequilibrium
Social reason
Indications for Dialysis other than chronic renal failure
1-Acute renal failure
2-Poisons and Drug intoxication
3-Hypercalcaemia
4-Hyperuricemia
5-Hypothermia
6-Metabolic alkalosis (special dialysis solution required)
Dialyzable drugs and Poisons (partial list)
a) Barbiturates : Phenobarbital -Pentobarbital -Amobarbital
b) Alcohol's : Methanol -Ethanol -Ethylene glycol -Isopropanol
c) Analgesics : Acetylsalicylic acid -Methylsalicylate
d) Metals : Calcium -Potassium -Sodium -Lithium
e) Endogenous toxins : Uric acid -Uremic toxins -Hyperosmolar state
f) Halides : Bromide
e) Miscellaneous : Theophylline -Mannitol -Radiocontrast -Thiocynate -
Boric acid -Aniline
NB 1) Dialysis for poisoning should be considered only when supportive measures are ineffective or there is impending irreversible organ toxicity.
2) Hemoperfusion is required in some cases
Factors to be considered in determine drug’s dialyzability:
1) Dialysis related factors:
Dialyzer membrane characteristics
Surface area
Blood flow rate
Dialysate flow rate
Degree of ultrafitration
Duration of dialysis
2) Drug related factors :
Availability of the drug in the plasma
Drug pharmacokinetic characteristics
Drug molecular weight (<500 cross the membrane more readily)
Drug solubility (water soluble are dialyzable than lipid soluble)
Factors Determinants for Dialysis
Factors determining the mode of chronic dialysis should include medical and non medical factors which have an impact on the treatment modality. Physicians have the responsibility to discuss the therapeutic options and offer their advice and recommendations about the choices. In general renal transplantation should be recommended as the preferred mode of renal replacement therapy in whom surgery and immunosupression is safe and feasible.
Medical Factors
1. Age
2. Comorbid medical illnesses
3. Patient survival
4. Patient rehabilitation
5. Quality of life
Non Medical Factors
1. Government-imposed Economic limitations
2. Physician and Patient bias
3. Resource availability
4. Social ,Religious ,Cultural mores
5. Availability of transplantation
6. Family support
7. Cost , race , sex , reimbursement
Contraindications of Dialysis therapy
Principally there is no absolute contraindication to dialysis therapy. Advanced age in and of itself is not a contraindication to dialysis therapy. Many elderly are physiologically equivalent to young patients.
Relative contraindications to dialysis therapy
1. Advanced malignancy (except multiple myeloma)
2. Alzheimer’s disease
3. Multi-infarct dementia
4. Hepatorenal syndrome
5. Advanced liver cirrhosis with encephalopathy
6. Hypotension unresponsive to pressors
7. Terminal illness
8. Organic brain syndrome
Contraindication for Peritoneal dialysis
Absolute
1. Peritoneal fibrosis
2. Pleuroperitoneal leak
Relative Major
1. Chronic Ostomies
2. Severe hypercatabolic state
3. Fresh aortic prosthesis
4. Recent Abdominal surgery
5. Recent Thoracic surgery
6. Extensive Abdominal adhesions
7. Quadriplegia
8. Blindness
9. Physical handicaps
10. Mental Retardation
Relative Minor
1. Polycystic Kidney disease
2. Diverticulosis
3. Obesity
4. Peripheral vascular disease
5. Hyperlipidemia
6. Social
Introduction
Background
Chronic renal failure (CRF) requiring dialysis or transplantation is known as end-stage renal disease (ESRD). In the United States, diabetic nephropathy is the most common and hypertension the second most common cause. Along with glomerulonephritis, these cause approximately 75% of all adult cases. Certain geographic areas have a high incidence of HIV nephropathy. Genetic kidney disease such as polycystic kidney disease is a common cause in young adults.1
Patients with end-stage renal disease (ESRD) are commonly encountered in the ED with problems related to the metabolic complications of their renal disease or dialysis complications. Various problems related to vascular access in patients on hemodialysis and to abdominal catheters in patients using continuous ambulatory peritoneal dialysis (CAPD) are also common. Patients who have undergone renal transplantation may experience a variety of transplant-related conditions.
Patients with chronic renal failure often present to the ED with an unrelated condition. In these cases, the level of renal function may have important implications for diagnosis and treatment.
Pathophysiology
All major organ systems are affected by renal failure. Prevalence of symptoms is a function of the glomerular filtration rate (GFR), which averages 120 mL/min in a healthy adult. As the GFR falls to less than approximately 20% of normal, symptoms of uremia may begin to occur. They almost are invariably present when the GFR decreases to less than 10% of normal. Measuring GFR requires a timed urine collection as well as measurement of serum creatinine. However, it can be accurately estimated from a patient's age, weight, gender, and serum creatinine level. Online calculators are available to automate the calculation.2
Signs and symptoms of renal failure are due to overt metabolic derangements resulting from inability of failed kidneys to regulate electrolyte, fluid, and acid-base balance; they are also due to accumulation of toxic products of amino acid metabolism in the serum. Signs and symptoms include the following:
Systemic signs
Malaise, weakness, and fatigue are very common.
Gastrointestinal signs
GI disturbances include anorexia, nausea, vomiting, and hiccups. Peptic ulcer disease and symptomatic diverticular disease are common in patients with CRF.
Neurological signs
Peripheral neuropathy and restless legs syndrome are the most common neurologic complications of CRF. Seizures may occur due to uremia, and the prevalence of stroke is increased.
Hematologic signs
Anemia is inevitable in CRF because of loss of erythropoietin production. Abnormalities in white cell and platelet functions lead to increased susceptibility to infection and easy bruising.
Dermatologic signs
Pruritus is a common dermatologic complication assumed to be secondary to accumulation of toxic pigments (urochromes) in the dermis.
Metabolic/endocrine signs
Volume overload occurs when salt and water intake exceeds losses and excretion. This causes congestive heart failure (CHF) and exacerbates hypertension. Hyperkalemia is the most common immediately life-threatening metabolic complication of renal failure and may develop suddenly when GFR is severely reduced. Anion gap acidosis results from decreased hydrogen ion excretion and may exacerbate hyperkalemia. Hypocalcemia is potentially life threatening and results from loss of vitamin D and increased parathyroid hormone levels. Hypermagnesemia also may occur.
Cardiac signs
Volume overload may cause CHF and pulmonary edema. Hypertension contributes to cardiovascular disease. Dyslipidemia is a primary risk factor for cardiovascular disease and a common complication of ESRD. Uremia may also lead to pericardial effusion and, in rare cases, pericardial tamponade. Cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.
Vascular signs
Vascular access complications are similar to those seen in any patient with a vascular surgical procedure (eg, bleeding, local or disseminated intravascular infections, vessel [graft] occlusion).
Dialysis catheters
A peritoneal dialysis catheter subjects patients to the risks of peritonitis and local infection. The catheter acts as a foreign body and provides a portal of entry for pathogens from the external environment.
Infection/immunologic
Patients who have received renal transplants may experience recurrent renal failure due to rejection or other graft complications. In addition, chronic immunosuppression makes them prone to infection.
Frequency
United States
The government of the United States funds treatment of end-stage renal disease (ESRD) universally for US citizens. As a consequence, the population of patients receiving dialysis or who have had a renal transplant in the United States is large. During 2004, the last year with complete data availability, 104,364 patients (approximately 0.03% of the US population) began renal replacement therapy, an adjusted incidence rate of 339 per 1,000,000. As of 2005, more than 485,000 patients were receiving treatment for ESRD in the United States. As a result, patients with ESRD are encountered on a regular basis in US emergency departments.
International
Resources allocated for treatment of ESRD vary throughout the world, and the treatments are expensive. Untreated ESRD is rapidly fatal, and treatment is too expensive for most individuals to purchase privately. Consequently, very few patients with ESRD are encountered in countries where ESRD treatment is not funded by the government.
The morbidity and mortality of dialysis patients is much higher in the United States compared with most other countries. This is probably a consequence of selection bias. Due to liberal criteria for receiving government-funded dialysis in the United States and rationing (both medical and economic) in most other countries, US patients receiving dialysis are on the average older and sicker than those in other countries.
Mortality/Morbidity
Patients in renal failure are prone to all of the complications of any underlying condition, such as diabetes and hypertension. In addition, renal failure causes a variety of metabolic and physiologic derangements.
• The most common cause of sudden death in patients with end-stage renal disease (ESRD) is hyperkalemia, which is often encountered in patients after missed dialysis or dietary indiscretion. Serum potassium also rises when the serum is acidemic, even though total body potassium is unchanged. Hyperkalemia is usually asymptomatic and should be treated empirically when suspected and when arrhythmia or cardiovascular compromise is present.
• Iatrogenic complications related to fluid administration (fluid overload) or medications are frequently encountered in patients in renal failure.
• Cardiovascular mortality is 10-20 times higher in dialysis patients than in the normal population.
• Anemia results in fatigue, reduced exercise capacity, decreased cognition, and impaired immunity.
• Renal transplant patients are prone to infection, especially in the immediate post-transplant period.
Race
Etiology of end-stage renal disease (ESRD) differs among racial groups primarily because of the prevalence of predisposing conditions, such as diabetes and hypertension. In populations with problematic access and utilization of primary medical care for treatment of predisposing conditions, ESRD often is encountered in relatively young patients. While the costs of treatment for ESRD are borne by the entire population (through government funding), relatively inexpensive preventive treatments often are funded poorly. Diseases such as diabetes and hypertension are much less likely to lead to renal failure when appropriately treated. The cost of primary care for these conditions is far lower than for dialysis or transplantation, yet primary care remains poorly funded, while ESRD treatment is reimbursed completely by the government. This conundrum is reflective of the often illogical and capricious nature of health care spending in the United States.
In the United States, racial and ethnic discrepancies in ESRD exist, with 2006 rates in the African American and Native American populations 3.6 and 1.8 times greater, respectively, than the rate among whites, and the rate in the Hispanic population 1.5 times higher than that of non-Hispanics.3
Sex
Presentation and treatment of chronic renal failure (CRF) and end-stage renal disease (ESRD) do not differ significantly between men and women. Differences in causes of renal failure are related to the types of underlying conditions prevalent in men and women.
Age
While the etiology of CRF differs among age groups, the presentations and nature of complications are similar. Young children with ESRD often are treated with transplantation rather than dialysis because of a relatively greater long-term benefit compared to that of adults, and due to difficulties related to vascular access for dialysis.
Clinical
History
Renal failure produces no symptoms early in the course of the disease. At this stage, symptoms of the underlying illness may bring the patient to medical attention and renal insufficiency is noted on laboratory testing.
• Chronic renal failure (CRF) potentially affects all organ systems. History for the presenting disorder is similar to that encountered when the same disorder exists in patients without renal failure.
• The following presentations are seen frequently in CRF. Moreover, some problems are unique to patients with CRF/ESRD; many of these are related to treatments, such as dialysis or transplantation.
• Electrolyte abnormalities include life-threatening hyperkalemia, which is usually asymptomatic.
o Dilutional hyponatremia may cause mental status changes or seizures.
o Hypocalcemia or hypermagnesemia may cause weakness and life-threatening dysrhythmias.
o Neuromuscular irritability is seen with hypocalcemia and may present as tetany or paresthesia.
o Hypermagnesemia causes neuromuscular depression with weakness and loss of reflexes.
o Acidosis may present as shortness of breath due to the work of breathing from compensatory hyperpnea.
• Pericarditis and asymptomatic pericardial effusion are common in patients with ESRD. Cardiac tamponade may occur but is rare. Presentation of pericarditis and tamponade are typical, with pleuritic chest pain being the most common presentation.
o Tamponade presents as fatigue, weakness, syncope, or dyspnea.
o Hypotension is usually present, and, if advanced, frank shock and cardiovascular collapse occur.
• Hypotension with postural weakness or syncope may occur as a complication of fluid shifts from dialysis or from any other cause. Sepsis is a serious cause of hypotension.
• Myocardial ischemia or infarction is common in patients with ESRD; consider this diagnosis in hypotensive patients along with other conditions, such as GI bleeding.
• Dialysis dysequilibrium syndrome is a common neurologic complication seen in dialysis patients.
o Syndrome is characterized by weakness, dizziness, headache, and in severe cases, mental status changes. Diagnosis is one of exclusion.
o A prime characteristic of the syndrome is that it is nonfocal.
• Peritonitis is common in patients being treated with continuous ambulatory peritoneal dialysis (CAPD), occurring approximately once per patient year. Patients present with abdominal pain, which may be mild, or complain of a cloudy effluent. Fever often is absent.
• Infection at the catheter exit site manifests as expected local pain, erythema, warmth, and/or fluctuance.
• Other abdominal conditions, such as appendicitis, pancreatitis, or diverticulitis, should be considered when patients present with abdominal pain, especially if signs and symptoms are localized.
• Vascular access problems include infections, which are usually manifest with typical signs and symptoms such as local pain, redness, warmth, or fluctuance. Fever may be present without local signs.
o Clotting of the vascular access presents as loss of normal bruit or thrill. There may be signs or symptoms of distal limb ischemia.
o Patients may present after dialysis or minor trauma with bleeding from their vascular access. Bleeding usually can be controlled with elevation and firm but nonocclusive pressure. In the immediate postdialysis period, protamine may be needed to reverse the effect of heparin (routinely used in dialysis to prevent clotting). Life-threatening bleeding may occur.
Physical
• Chronic renal failure (CRF) produces no specific physical findings.
• Patients with an arteriovenous fistula or graft should have the site examined regularly. Abnormal findings include loss of palpable thrill, overlying erythema, or active bleeding from the incisional wound of a newly placed fistula or graft.
• Physical findings of chronic renal failure complications generally are those expected with the specific complication and do not differ from those encountered when the condition occurs in patients with normal renal function.
• Certain complications are very common in renal failure.
• CAPD-associated peritonitis
o Abdominal pain and tenderness usually are generalized and relatively mild.
o Localized pain and tenderness suggest a local process, such as incarcerated hernia or appendicitis.
o Severe generalized peritonitis may be due to a perforated viscus as in any other patient.
• Transplant-related problems: Pain and tenderness over a transplanted kidney may be due to infection (pyelonephritis), obstruction (stone or extrinsic compression), or graft rejection.
• Vascular access aneurysms or pseudoaneurysms : These present as localized swelling, which may be pulsatile, and are often chronic. A rapid increase in size may indicate active bleeding.
Causes
Once chronic renal failure (CRF) has occurred, treatment options and complications are largely independent of the cause.
• In terms of broad categories of disease, glomerulonephritis and interstitial nephritis are the most common causes of CRF in adults and children.
• Chronic upper urinary tract infection causes CRF in all age groups.
• CRF also is encountered in children because of congenital anomalies such as chronic hydronephrosis, which is caused by anatomic defects that obstruct urine flow or allow reflux from the bladder (vesicoureteral reflux).
• Kidneys may be congenitally hypoplastic.
• Hereditary nephropathies also exist.
• In adults, diabetic and hypertensive nephropathies are the most common specific causes of CRF.
• Polycystic disease, renal vascular disease, and analgesic nephropathy also are common.
• In certain geographic areas, HIV-related renal disease is becoming common.
• Certain diseases such as some of the types of glomerulonephritis tend to recur in transplanted kidneys. In these cases, dialysis is the preferred treatment option.
• Consider renal transplant patients to be mildly to moderately immunosuppressed.
o In the immediate posttransplant period or during a rejection episode, intensive immunosuppression puts patients at considerable risk of infection, including disseminated viral infections such as herpes zoster.
o Degree of immunosuppression is less late in the posttransplant course when corticosteroids alone may be used.
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