PHARMACOTHERAPY OF DYSLIPIDEMIA

HMG-CoA Reductase Inhibitors
Lovastatin, pravastatin, simvastatin fluvastatin atorvastatin (Lipitor) and cerivastatin are HMG-CoA reductase inhibitors, or statins, that inhibit cholesterol synthesis. To varying degrees, all of these agents lower total, LDL and triglyceride cholesterol components and slightly raise the HDL fraction. While these agents are generally well tolerated, a small percentage of patients (less than 1 percent) may develop elevated hepatic transaminase levels, which may necessitate discontinuation of the drug.21 Other adverse effects include myopathy (fewer than 0.1 percent of cases) and gastrointestinal complaints. The gastrointestinal effects often subside with continued therapy. Evidence suggests that these agents reduce untoward cardiovascular events and work by mechanisms beyond the simple reduction in the LDL cholesterol level. The results of the Primary Prevention of Coronary Heart Disease with Pravastatin trial demonstrated reductions of 31 percent in first myocardial infarctions, 32 percent in cardiovascular mortality, 22 percent in total mortality and 37 percent in the need for revascularization procedures (Shepherd J, Cobbe SM, 1995) HMG-CoA reductase inhibitors, or statins, are well tolerated and cost-effective, and have been shown to reduce coronary events as well as the need for revascularization procedures. There are differences among the statins. For example, atorvastatin has a slightly different side effect profile than the other statins. It may exert a greater effect on lowering LDL cholesterol, total cholesterol and triglycerides, but higher doses of other statins may produce the same response. However, atorvastatin as a single agent may obviate the need for multiple drug therapy in high-risk patients. (Nawrocki JW, Weiss SR, Davidson MH, 1995). In view of the numerous other mechanisms being investigated, such as plaque stabilization, antiplatelet aggregation activity and anti-arterial spasmodic effects, this particular difference may be less important than other factors. To date, no comparative studies of the statins have been performed to delineate all of the clinically important differences. However, analysis of the Scandanavian Simvastatin Survival Study showed that hospitalization costs for patients hospitalized because of cardiovascular disease were reduced by approximately 31 percent, making statins quite cost-effective. (Pedersen TR, Kjekshus J, Berg K, 1996) Statins should generally be taken in a single dose with the evening meal or at bedtime to maximize the LDL lowering effect.
Bile Acid Binding Resins
The anion exchange resins cholestyramine (Questran) and colestipol (Colestid) bind cholesterol-containing bile acids in the intestines, producing an insoluble complex that prevents reabsorption. This results in increased hepatic oxidation of cholesterol to bile acids, fecal cholesterol excretion and LDL receptor activity. (Snyder S. 1990)These agents decrease LDL cholesterol levels by up to 20 percent. They may be a good choice in patients with hepatic disease because they do not affect hepatic metabolism. They are also a good choice in very young patients and women of childbearing age.. (Atkins D, Garber AM. 1996)

Nicotinic Acid
Nicotinic acid, or niacin, decreases the synthesis of LDL cholesterol by reducing the hepatic synthesis of VLDL cholesterol, by increasing the synthesis of HDL cholesterol, by inhibiting lipolysis in adipose tissue and by increasing lipase activity. This agent increases the HDL level by 15 to 35 percent, reduces total and LDL cholesterol levels by 10 to 25 percent, and decreases the triglyceride level by 20 to 50 percent. Side effects of nicotinic acid include flushing, pruritus, gastrointestinal discomfort, hyperuricemia, gout, elevated liver function tests and glucose intolerance. Taking 325 mg of aspirin 30 minutes before the drug is ingested may minimize flushing. (Jungnickel PW, Maloley PA, 1997).
Fibric Acid Derivatives
Fibric acid derivatives, or fibrates, increase the clearance of VLDL cholesterol by enhancing lipolysis and reducing hepatic cholesterol synthesis. These agents have been reported to lower triglyceride levels by 20 to 50 percent, raise HDL levels by up to 20 percent and reduce LDL levels by approximately 5 to 15 percent.( Carlson LA, Rosenhamer G. 1988) Some patients with hypertriglyceridemia may have an increase in LDL levels, so such patients should be very closely monitored if fibrates are used. Gemfibrozil is particularly useful in patients with diabetes and familial dysbetalipoproteinemia.
Side effects of gemfibrozil include nausea, bloating, flatulence, abdominal distress and mild liver-function abnormalities. Myositis, gallstones and elevation of the LDL cholesterol level have also been reported. Clofibrate has been associated with formation of gallstones and serious gastrointestinal disease, including hepatic malignancy, (Cohen JD, Pearson TA, 1996) and therefore should only be used in certain select patients with types II, IV or V hyperlipidemia. In addition, clofibrate has not been shown to prevent coronary heart disease. Fibrates should generally not be used with HMG-CoA reductase inhibitors because the risk of severe myopathy is greatly increased. (National Cholesterol Education Program. Cholesterol lowering in the patient with coronary heart disease 1997).
COMPLEMENTARY AND ALTERNATIVE THERAPIES FOR THE MANAGEMENT OF DYSLIPIDEMIA
Randomized controlled trials were found for omega-3-fatty acids, policosanol, plant stanols and sterols, flaxseed, red yeast rice, guggulipid, garlic, fiber, almonds, and soy. Studies for each of these agents report varying degrees of lipid reduction. Based on published data, effective therapeutic options for lipid-lowering include intake of fiber, intake of plant stanols/sterols, replacement of animal protein with soy protein, and substitution of foods high in saturated fat with those with monounsaturated fatty acids (e.g., dry roasted almonds). Adding omega-3-fatty acids is effective for reducing triglycerides in patients with hypertriglyceridemia. Well-designed studies with long-term outcome data are necessary to further define the role for guggul, red yeast rice, policosanol, garlic, and flaxseed in the management of dyslipidemia.

Oral Agents for Type 2 Diabetes

Sulphonylureas
With the labeling of tolbutamide by the U.S. Food and Drug Administration in 1962, the sulfonylurea class of drugs quickly became the mainstay of treatment for type 2 diabetes. Although newer agents have recently entered the marketplace, sulfonylureas still play a primary role in pharmacologic management of type 2 diabetes. Patients who respond best to treatment with sulfonylureas include those with a diagnosis of type 2 diabetes before 40 years of age, duration of disease less than five years before initiation of drug therapy and a fasting blood glucose level of less than 300 mg per dL (16.7 mmol per L) Approximately two thirds of patients who begin therapy with a sulfonylurea respond, although up to 20 percent of them eventually require additional medication. Few patients with uncontrolled diabetes receive clinical benefit when switched from one sulfonylurea agent to another. (Mooradian AD. 1996). The use of agents with a longer half-life e.g., chlorpropamide in the elderly and in patients with renal impairment is discouraged because the risk of hypoglycemia is increased.
Metformin
Metformin is a biguanide agent that lowers blood glucose primarily by decreasing hepatic glucose output and reducing insulin resistance. Metformin is used as monotherapy or in combination with sulfonylureas for management of type 2 diabetes. When used as monotherapy, metformin does not cause hypoglycemia and is thus termed an "antihyperglycemic." The use of metformin is contraindicated in patients with renal insufficiency (i.e., a serum creatinine level of 1.5 mg per dL [130 µmol per L] in men and 1.4 mg per dL [120 µmol] in women, or abnormal creatinine clearance) or acute or chronic metabolic acidosis. Metformin should be temporarily withheld before any procedure involving intravascular administration of iodinated contrast media. Normal renal function should be confirmed 48 hours after the procedure before restarting metformin therapy. There is no known reason to discontinue metformin therapy during other parenteral contrast studies. Extreme caution should be used in patients with severe hepatic dysfunction, hypoxemic states (e.g., severe chronic obstructive pulmonary disease, congestive heart failure), moderate to severe illness and excessive alcohol intake. In these patients, the use of metformin may contribute to the development of lactic acidosis, a condition that is fatal in about 50 percent of patients who develop it (one episode per 100,000 patient-years). Cimetidine decreases the renal clearance of metformin and may potentiate its effects. Patients receiving oral anticoagulant therapy and metformin may require a higher dosage of warfarin to achieve a therapeutic antithrombotic effect. (Melchior WR, Jaber LA. 1996) Hemogloblin, hematocrit, red blood cell indexes and renal function should be monitored at least annually in patients taking metformin.
Alpha-Glucosidase Inhibitors
Alpha-glucosidase inhibitors, such as acarbose and miglitol are indicated as monotherapy or in combination with sulfonylureas for management of type 2 diabetes. These agents inhibit the breakdown of complex carbohydrates and delay the absorption of monosaccharide from the gastrointestinal tract. Acarbose and miglitol should be titrated over two to three weeks to minimize flatulence and other gastrointestinal side effects that commonly lead to discontinuation of these agents. Alpha-glucosidase inhibitors are contraindicated in patients with inflammatory bowel disease, partial intestinal obstruction, a predisposition to intestinal obstruction, colonic ulceration and other gastrointestinal disorders. (Campbell LK, White JR, 1996). Dose-dependent hepatotoxicity is associated with this drug class, so liver function tests should be carefully monitored in patients receiving higher dosages of these medications (e.g., more than 50 mg three times daily). Transaminase elevations are reversible with discontinuation of the drug and are often asymptomatic. Serum transaminase levels should be checked every three months for the first year patients take the medication and periodically thereafter. Drugs that are susceptible to binding with other agents (e.g., cholestyramine [Questran]) should be taken two to four hours apart from alpha-glucosidase inhibitors to avoid drug interactions. Intestinal absorbents and digestive enzyme preparations should not be administered with acarbose. Near-normal or improved glycemic control has been shown to significantly diminish the risk of microvascular complications in patients with type 2 diabetes mellitus.
Troglitazone
The thiazolidinediones are a unique drug class of "insulin sensitizers" that promote skeletal muscle glucose uptake Troglitazone is the first agent of this drug class to be introduced in the U.S. market and, like metformin, it reduces insulin resistance. Troglitazone is beneficial in patients requiring large daily amounts of insulin (more than 30 units per day) whose diabetes is still uncontrolled. A reduction of up to 50 percent in total daily insulin dosage is possible with drug titration. Troglitazone is also effective when used in combination with other oral agents thereby potentially delaying the need to start insulin therapy. The U.S. Food and Drug Administration recently ruled that troglitazone should only be used in combination with other diabetic therapies. The effectiveness of oral contraceptives may be decreased with troglitazone administration. Over 150 case reports of hepatotoxicity have been reported with troglitazone, so liver function must be monitored every month for the first eight months of treatment and every other month for four months thereafter. (Sparano N, Seaton TL. 1998). Periodic transaminase measurements should be obtained as long as the patient is taking troglitazone.
Repaglinide
Repaglinide is a benzoic acid derivative and the first of the non-sulfonylurea meglitinides introduced in early 1998. The mechanism of action and side effect profile of repaglinide are similar to those of the sulfonylureas. (Scheen AJ. 1997) This agent has a rapid onset of action and should be taken with meals two to four times daily. Repaglinide is a suitable option for patients with severe sulfa allergy who are not candidates for sulfonylurea therapy. The drug is used as monotherapy or in combination with metformin. It should be titrated cautiously in elderly patients and in those with renal or hepatic dysfunction.

INSULIN RESISTANCE

A second category of causation is insulin resistance. Many investigators place a greater priority on insulin resistance than on obesity in pathogenesis. They argue that insulin resistance, or its accomplice, hyperinsulinemia, directly causes other metabolic risk factors. Identifying a unique role for insulin resistance is complicated by the fact that it is linked to obesity. Insulin resistance generally rises with increasing body fat content, yet a broad range of insulin sensitivities exists at any given level of body fat. Most people with categorical obesity (body mass index [BMI] 30 kg/m2) have postprandial hyperinsulinemia and relatively low insulin sensitivity, but variation in insulin sensitivities exists even within the obese population. Overweight persons (BMI 25 to 29.9 kg/m2) likewise exhibit a spectrum of insulin sensitivities, suggesting an inherited component to insulin resistance. In some populations (e.g., South Asians), insulin resistance occurs commonly even with BMI <25 kg/m2 and apparently contributes to a high prevalence of type 2 diabetes and premature CVD. South Asians and others who manifest insulin resistance with only mild-to-moderate overweight can be said to have primary insulin resistance. Even with primary insulin resistance, however, weight gain seems to enhance insulin resistance and metabolic syndrome. Thus, dissociation of obesity and primary insulin resistance in patients with metabolic syndrome is difficult.
This is not to say that insulin resistance per se does not play a significant role in causation of metabolic syndrome. When insulin-resistant muscle is already overloaded with lipid from high plasma NEFA levels, some excess NEFA presumably is diverted to the liver, promoting fatty liver and atherogenic dyslipidemia. Hyperinsulinemia may enhance output of very-low-density lipoprotein triglycerides, raising triglycerides. Insulin resistance in muscle predisposes to glucose intolerance, which can be worsened by increased hepatic gluconeogenesis in insulin-resistant liver. Finally, insulin resistance may raise blood pressure by a variety of mechanisms.

PROBLEM STATEMENT OF METABOLIC SYNDROME

With the formulation of NCEP/ATP III guidelines some uniformity and standardization has occurred in the definition of metabolic syndrome and has been very useful for epidemiological purposes. At present, metabolic syndrome is an all or none diagnosis. The study results based on third National Health and Nutrition Examination Survey (NHANES III), indicate that approximately one fourth of the US adults 20 years or older meet the diagnostic criteria for metabolic syndrome. The prevalence of the metabolic syndrome depends on age, ethnic background, and gender. It rises linearly from 20 to 50 years and plateaus thereafter. Looking at various studies around the world, which included population samples, aged from 20 to 25 and upwards, the prevalence varies from 8% (India) to 24% (United States) in men and from 7% (France) to 46% (India) in women. Metabolic syndrome prevalence rates as described earlier vary among ethnic groups as defined by the ATP III criteria among Finnish and Native American men. These studies involved subjects with comparable age ranges (42-60 and 44-49 years, respectively), with the Finnish study showing prevalence of only 14% compared with the prevalence in the Native American study of 43.6%. The prevalence varies from a low of 13.9% in black men to a high of 27.2% in Mexican American women

HISTORY OF METABOLIC SYNDROME

Although the modern era of what we now call the 'metabolic syndrome' or the 'insulin resistance syndrome' seems to have started less than two decades ago with the description of syndrome X by G.M. Reaven (Banting lecture 1988) in the late 1980s, the history of this syndrome is much longer. In particular, a considerable number of scientists, starting as early as almost 90 years ago, have described the very common coexistence of the various components of the syndrome, including hypertension, and some of them gave several names to this clustering. On the other hand, during the past few years several international organizations have tried to form a reference context of what is included under the terms 'metabolic syndrome' and 'insulin resistance syndrome', proposing various 'definitions' for them. The various synonyms exist for metabolic syndrome are Syndrome X, Beer Belly syndrome, Dysmetabolic syndrome, Reaven syndrome.
The term "metabolic syndrome" dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes, that had been noted as early as the 1920s.

PATHOGENESIS OF DIABETES

TYPE I DIABETES
Type I or IDDM is basically an autoimmune disorder in which autoantibodies are formed against beta cells of pancreas which synthesise insulin. This leads to beta cell depletion and absolute insulin deficiency. This manifest early in onset hence called juvenile onset diabetes. There is also some genetic predisposition for the development of type I diabetes. Many viuses are also implicated in causing beta cell depletion such as coxakie B virus.
TYPE II DIABETES
Type II diabetes is mainy due to insulin resistance. Insulin level may be normal or low. There is strong genetic predisposition for the development of type II diabetes. Varios genes for glucose uptake are defective so that glucose entry into the cells is defective in spite of presence of insulin.
Apart from these causes diabetes may be caused by diseases of pancreas, drugs or pregnancy induced diabetes or gestational diabetes.

TYPES OF DIABETES

Type I or Insulin dependent diabetes mellitus (IDDM)
Type II or non insulin dependent diabetes mellitus (NIDDM)
Type III or drugs mediated diabetes
Type IV or gestational diabetes

RECENT ADVANCES IN MANAGEMENT OF DIABETES

There are many new treatment options available to a diabetic patient. Type I diabetes is mainly treated by diet control and insulin while type II diabetes or adult onset diabetes is treated by diet and oral hypoglycemic drugs. Recently varios clinical trials are in phase III or phase IV for many new drugs. These new treatment options are inhaled insulin, exenatide, incretins. Recently various new preparations are available in market which are long acting so as to avoid repeated insulin injections such as insulin glargine. Insulin lispro is used to avoid immediate post meal hyperglycemia. Various new insulin delivery system have been devised such as pen injector, automatic digital injector, continious subcutaneous insulin infusion and artificial pancreas.

ROLE OF PAIN CLINIC IN THE MANAGEMENT OF CHRONIC PAINFUL DISORDERS

Pain is a very distressing symptom. It is important to treat pain especially if it become chronic. Chronic pain can be very effectively managed in pain clinic by an anaesthesiologist.Before going into details first of all I am trying to explain the basic pathophysiology of pain.Pain is of two types somatic and visceral. Somatic pain is sharp and well localised while visceral pain is dull and poorly localised. Pain has two components one is nociceptive other is affective. Nociceptive components can be treated by both narcotic and non steroidal antiinflammatory agents while affective components can be only treated by opioid or narcotic analgesics. Analgesics are of two types one is narcotic or opioid or morphine like analgesic. They act mainly on central nervous system. Another is non narcotic or aspirin like or non steroidal antiinflammatory agents, they act mainly on peripheral nervous system. There are various painful disorders that can be treated in pain clinic eg. cancer pain, degenerative neurological dysorders, muscle dystonia, diabetic neuropathy,trigeminal neuralgias and viral neuralgias.

COMORBID DISEASES ASSOCIATED WITH METABOLIC SYNDROME

There are various comorbid conditions that are associated with metabolic syndrome. The underlying cause may be insulin resistance, any harmonal abnormalities. These conditions are :
Fatty liver
Polycystic ovarian disease
gout

DRUG DELIVERY SYSTEMS

Now a days various drug delivery systems have been developed. These systems enabled to use more drug selectively at a particular target organ at relatively lower side effects. The various drug delivery systems are liposomes coated drug particles such as Amphoterecin B, various anticancer drugs, Ocusert for delivering drugs in the eye, monoclonal antibodies for a particular target organs, transdermal drug delivery systems for harmonal drugs such as contraceptives, testosterone etc. Liposomes are molecules which are lipophilic and cross blood brain barrier easily. So the drugs which have poor blood brain barrier penetration can be coated with liposomes and can be delivered easily without increasing the drug toxicity.

MONOCLONAL ANTIBODIES

Now a days Monoclonal antibodies are used for the treatment of various diseases. These antibodies are developed by fusing myeloma tumour cell with B lymphocytes. These cells have the combined property of producing an antibody against a particular antigen and proliferating property of tumour cell. These antibodies have an important therapeutic use in the treatment of cancers, autoimmune diseases and as an antiplatelet agent.The various antibodies that are used now a days are :
Trastuzumab for the treatment of carcinoma breast
Absciximab as an antiplatelet agent
Etanercept for Rheumatoid arthritis
Infliximab for rheumatoid arthritis

STUDIES ON NIGELLA SATIVA OR BLACK CUMIN OR KALONJI

Nigella sativa had been intensively studied all over the world for its various therapeutic uses. A lot of animal and clinical studies have been conducted across the world. Most of the studies have shown that it can be used as a natural add on remedy for treatment of various disorders such as diabetes, hypertension, dyslipidemia and obesity.

HOW NIGELLA SATIVA IS HELPFUL IN THE TREATMENT OF METABOLIC SYNDROME ?

Nigella sativa or black cumin or "kalonji" is an annual herbacious plant. Its oil is extracted from seeds and used for the treatment of various disordes. It has got various chemical compounds which help in metabolic syndrome by various ways
1. Its insulin sensitising action
2. Improving lipid profile
3. Maintain normal blood pressure
4. Its antiobesity action
5. Its antioxidant action
It can be taken in the form of seeds as well as in the oil form. Its oil is available in the markets.

ROLE OF DIET IN THE MANAGEMENT OF METABOLIC SYNDROME

The diet has very vital role in the management of metabolic syndrome. Low calory and low fat diet should be used. Highly condensed food and fatty meal should be avoided. The diet should be supplemented with plenty of high fibre diets such as salads, fruits, vegetables. High fibre diet help by reducing the absorption of cholesterol and carbohydrates, improving bowel transit time. High fibre diet also have a lots of other benefits such as reducing the risk of colorectal cancer and constipation. The diet should also be supplemented with various mono and polyunsaturated fatty acids such as fish oils. A recent clinical trial showed that regular consumption of fish oils helpped in lowering hypertriglyceridemia. Hypertriglyceridemia is associated with various fatal diseases such as Acute pancreatitis. Alcohol restriction also help in reducing hypertriglyceridemia

DRUGS USED FOR THE TREATMENT OF INSULIN RESISTANCE

1. Metformin
2. Thiazolidinediones e.g. Rosiglitazone, Piaglitazones
Glitazones act via nuclear superfamily receptors Peroxysome proliferator activated receptors (PPAR gamma ) which increase the expressions of various transporter proteins which help in the uptake of glucose in adipose tissues

ROLE OF COMPLEMENTRY AND ALTERNATIVE MEDICINE IN THE MANAGEMENT OF METABOLIC SYNDROME

The various agents that are used for the treatment of metabolic syndrome are
1. Red rice
2. Policosanol
3. Coenzyme Q
4. Nigella sativa ( Black cumin )
5. Fish oils
6. High fibre diet

PHARMACOLOGICAL INTERVENTIONS

The various pharmacological interventions are
1. Oral hypoglycemic agents eg. Metformin which also help to reduce insulin resistance
2. Antihyperlipidemic drugs e.g. Atorvastatin, Rosuvastatins
3. Antihypertensive druge e.g. Atenolol
4. Antiplatelet agents e.g. Aspirin

MANAGEMENT OF METABOLIC SYNDROME

NONPHARMACOLOGICAL INTERVENTIONS
1. LIFESTYLE MODIFICATION
2. EXERCISE
3. ALCOHOL RESTRICTION
4. SMOKING RESTRICTION
5. DIET

PATHOGENESIS OF METABOLIC SYNDROME

The following factors are implicated in the pathogenesis of metabolic syndrome

1. Insulin resistance
2. Proinflammatory state
3. Oxidative stress
4. Obesity
5. Dyslipidemia

ROLE OF EXERCISE IN THE MANAGEMENT OF METABOLIC SYNDROME

Exercise has very important role in the management of metabolic syndrome
It help in the following ways
1. Redistribution of body fat
2. Reduces insulin resistance

ALCOHOL

Drinking alcohol is very hazardous for health because it damage almost all body systems. So it should be avoided strictly.

CIRCUMCISION

Now it is confirmed scientifically that circumcised people have a very low incidence and prevalence of developing cancer penis. So circumcision has very protective role in the prevention of cancer penis. It was observed that cancer penis was very rare in Muslims and jews because they are circumcised at an early age.

HEALTH QUERIES

This blog was made to provide the solutions, queries and information about common health problems and various medical issues. This blog was made only for educational purpose and the information provided in the blog should not be used for medicolegal purpose