antihyperlipidemia and hypothalamic hormones

Pharmacology of the Endocrine System

Hypothalamic & Pituitary Hormones

Spinal cord

Posterior pituitary
Cerebellum
Pineal gland
Anterior pituitary
Hypothalamus
Pituitary gland
Hypothalamus
Thalamus
Cerebrum

The Pituitary Gland

The Pituitary Gland is divided into 2 areas, with separate types of hormone production. The anterior pituitary makes and releases H under regulation of the hypothalamus Growth Hormone (GH) Thyroid-stimulating Hormone (TSH) Adrenocorticotropin (ACTH) Follicle-stimulating Hormone (FSH) ), Leutinizing Hormone (LH), Prolactin The posterior pituitary stores and secretes H that are made in the hypothalamus: oxytocin and antidiuretic hormone (ADH)


Hypothalamic hormones:
Growth hormone (somatotropin) Somatotropin is a large polypeptide that is released by the anterior pituitary in response to growth hormone (GH)-releasing hormone produced by the hypothalamus. Secretion of GH is inhibited by another hypothalamic hormone, somatostatin. GH Synthetic human GH (somatropin) is produced using recombinant DNA technology. Therapeutic uses: Somatropin is used in the treatment of GH deficiency or growth failure in children. Somatropin is also indicated for growth failure due to Prader-Willi syndrome, management of AIDS wasting syndrome, and GH replacement in adults with confirmed GH deficiency

Hypothalamic hormones:

Somatostatin (Growth hormone-inhibiting hormone) In the pituitary, somatostatin binds to receptors that suppress GH and thyroid-stimulating hormone release. Somatostatin not only inhibits the release of GH but also that of insulin, glucagon, and gastrin. Octreotide and lanreotide are synthetic analogs of somatostatin. Their half-lives are longer than that of the natural compound, and depot formulations are available, allowing for administration once every 4 weeks.

Hypothalamic hormones:

Somatostatin (Growth hormone-inhibiting hormone) They have found use in the treatment of acromegaly and in diarrhea and flushing associated with carcinoid tumors. An intravenous infusion of octreotide is also used for the treatment of bleeding esophageal varices. Adverse effects of octreotide include diarrhea, abdominal pain, flatulence, nausea, and steatorrhea.

Gonadotropin-releasing hormone Pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is essential for the release of the gonadotropins folliclestimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. Continuous administration of synthetic GnRH analogs, such as leuprolide, goserelin , nafarelin, and histrelin is effective in suppressing production of the gonadotropins Suppression of gonadotropins, in turn, leads to reduced production of gonadal steroid hormones (androgens and estrogens). Thus, these agents are effective in the treatment of prostate cancer, endometriosis, and precocious puberty


Gonadotropin-releasing hormone In women, the GnRH analogs may cause hot flushes and sweating, as well as diminished libido, depression, and ovarian cysts. They arecontraindicated in pregnancy and breast-feeding. In men, they initially cause a rise in testosterone that can result in bone pain. Hot flushes, edema, gynecomastia, and diminished libido may also occur.


Gonadotropins The gonadotropins (FSH and LH) are glycoproteins that are produced in the anterior pituitary. The regulation of gonadal steroid hormones depends on these agents. They find use in the treatment of infertility. Menotropins (also known as human menopausal gonadotropins or hMG) are obtained from the urine of postmenopausal women and contain both FSH and LH. Urofollitropin is FSH obtained from postmenopausal women and is devoid of LH. Follitropin alfa and follitropin beta are human FSH products manufactured using recombinant DNA technology. Human chorionic gonadotropin (hCG) is a placental hormone that is excreted in the urine of pregnant women. The effects of hCG and choriogonadotropin alfa (made using recombinant DNA technology) are essentially identical to those of LH.

Gonadotropins All of these hormones are injected via the IM or subcutaneous route. Injection of hMG or FSH products over a period of 5 to 12 days causes ovarian follicular growth and maturation, and with subsequent injection of hCG, ovulation occurs. Adverse effects include Ovarian enlargement and possible ovarian hyperstimulation syndrome, which may be life threatening. Multiple births are not uncommon.



HORMONES OF THE POSTERIOR PITUITARY Oxytocin: is used in obstetrics to stimulate uterine contraction and induce labor. Oxytocin also causes milk ejectionby contracting the myoepithelial cells around the mammary alveoli. Although toxicities are uncommon when the drug is used properly, hypertension, uterine rupture, water retention, and fetal death have been reported. Vasopressin Vasopressin (antidiuretic hormone) is structurally related to oxytocin. Vasopressin has both antidiuretic and vasopressor effects. In the kidney, it binds to the V2 receptor to increase water permeability and reabsorption in the collecting tubules. Thus, the major use of vasopressin is to treat diabetes insipidus. It also finds use in the management of cardiac arrest and in controlling bleeding due to esophageal varices.

HORMONES OF THE POSTERIOR PITUITARY Vasopressin Other effects of vasopressin are mediated by the V1 receptor, which is found in liver, vascular smooth muscle (where it causes constriction), and other tissues. Desmopressin , an analog of vasopressin, has minimal activity at the V1 receptor, making it largely free of pressor effects. This analog is longer acting than vasopressin and is preferred for the treatment of diabetes insipidus and nocturnal enuresis. For these indications, desmopressin may be administered intranasally or orally.

THYROID HORMONES The thyroid gland facilitates normal growth and maturation by maintaining a level of metabolism in the tissues that is optimal for their normal function. The two major thyroid hormones are triiodothyronine (T3; the most active form) and thyroxine (T4). Inadequate secretion of thyroid hormone (hypothyroidism) results in bradycardia, poor resistance to cold, and mental and physical slowing. In children, this can cause mental retardation and dwarfism. In contrast, excess secretion of thyroid hormones (hyperthyroidism) can cause tachycardia and cardiac arrhythmias, body wasting, nervousness, tremor, and heat intolerance.

Thyroid hormone synthesis and secretion

Pharmacokinetics Both T4 and T3 are absorbed after oral administration. Food, calcium preparations, and aluminum-containing antacids can decrease the absorption of T4. Deiodination is the major route of metabolism of T4. T3 also undergoes sequential deiodination. The hormones are also metabolized via conjugation with glucuronides and sulfates and excreted into the bile.


Treatment of hypothyroidism Hypothyroidism usually results from autoimmune destruction of the gland or the peroxidase and is diagnosed by elevated TSH. Levothyroxine (T4) is preferred over T3 (liothyronine) or T3/T4 combination products for the treatment of hypothyroidism. It is better tolerated than T3 preparations and has a longer half-life. Levothyroxine is dosed once daily, and steady state is achieved in 6 to 8 weeks. Toxicity is directly related to T4 levels and manifests as nervousness, palpitationsm and tachycardia, heat intolerance, and unexplained weight loss. Drugs that induce the cytochrome P450 enzymes, such as phenytoin, rifampin, and phenobarbital, accelerate metabolism of the thyroid hormones and may decrease the effectiveness.


Treatment of hyperthyroidism (thyrotoxicosis) Graves disease, an autoimmune disease that affects the thyroid, is the most common cause of hyperthyroidism. The goal of therapy is to decrease synthesis and/or release of additional hormone. This can be accomplished by removing part or all of the thyroid gland, inhibiting synthesis of the hormones, blocking release of the hormones from the follicle. 1. Removal of part or all of the thyroid: This can be accomplished either surgically or by destruction of the gland with radioactive iodine (131I), which is selectively taken up by the thyroid follicular cells. Most patients become hypothyroid as a result of this drug and require treatment with levothyroxine.


2. Inhibition of thyroid hormone synthesis: The thioamides, propylthiouracil (PTU) and methimazole, are concentrated in the thyroid, where they inhibit both the oxidative processes required for iodination of tyrosyl groups and the condensation (coupling) of iodotyrosines to form T3 and T4. PTU also blocks the peripheral conversion of T4 to T3. [Note: These drugs have no effect on thyroglobulin already stored in the gland. Therefore, clinical effects of these drugs may be delayed until thyroglobulin stores are depleted. Methimazole is preferred over PTU because it has a longer half-life, allowing for once-daily dosing, and a lower incidence of adverse effects. However, PTU is recommended during the first trimester of pregnancy due to a greater risk of teratogenic effects with methimazole.


3. Blockade of hormone release: A pharmacologic dose of iodide inhibits the iodination of tyrosines, but this effect lasts only a few days. More importantly, iodide inhibits the release of thyroid hormones from thyroglobulin by mechanisms not yet understood. Iodide is employed to treat thyroid storm or prior to surgery, because it decreases the vascularity of the thyroid gland. Iodide is not useful for long-term therapy, because the thyroid ceases to respond to the drug after a few weeks. Iodide is administered orally. Adverse effects include sore mouth and throatswelling of the tongue or larynx, rashes, ulcerations of mucous membranes, and a metallic taste in the mouth.


4. Thyroid storm: Thyroid storm presents with extreme symptoms of hyperthyroidism. The treatment of thyroid storm is the same as that for hyperthyroidism, except that the drugs are given in higher doses and more frequently. β-blockers, such as metoprolol or propranolol, are effective in blunting the widespread sympathetic stimulation that occurs in hyperthyroidism.

Agents Used in the Treatment of Hyperlipidemia

* Chylomicrons- transport dietary lipids from the gut to the adipose tissue and liver Chylomicron remnants- produced from Chylomicrons by lipoprotein lipases in endothelial cells and transport cholesterol to the liver VLDL-made in the liver and secreted in to plasma deliver triglycerides to adipose tissue in the process get converted to IDL and LDL LDL- (bad cholesterol) delivers cholesterol to peripheral tissues via receptors and is phagocytosed by macrophages thus delivering cholesterol to the plaques (atheromas) HDL- (good cholesterol) produced in gut and liver cells, HDL transports cholesterol from atheromas to the liver (reverse cholesterol transport)

Classification of Hyperlipidemics

HMG-CoA reductase inhibitors (HMGs or statins) Fibric acid derivatives Niacin (nicotinic acid) Bile acid sequestrants Cholesterol absorption inhibitor

1. HMG CoA reductase inhibitors 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (commonly known as statins) lower elevated LDL-C, resulting in a substantial reduction in coronary events and death from CHD. They are considered first-line treatment for patients with elevated risk of ASCVD. Therapeutic benefits include 1.Plaque stabilization 2.Improvement of coronary endothelial function 3.Inhibition of platelet thrombus formation 4.Anti-inflammatory activity.


1. HMG CoA reductase inhibitorsMechanism of action: Lovastatin, simvastatin , pravastatin, atorvastati, fluvastatin, Pitavastatin and rosuvastatin are competitive inhibitors of HMG CoA reductase, the rate-limiting step in cholesterol synthesis. By inhibiting de novo cholesterol synthesis, they deplete the intracellular supply of cholesterol. Depletion of intracellular cholesterol causes the cell to increase the number of cell surface LDL receptors that can bind and internalize circulating LDLs. Thus, plasma cholesterol is reduced, by both decreased cholesterol synthesis and increased LDL catabolism. Pitavastatin, rosuvastatin, and atorvastatin are the most potent LDL cholesterol–lowering statins, followed by simvastatin, pravastatin, and then lovastatin and fluvastatin. [Note: Because these agents undergo a marked first-pass extraction by the liver, their dominant effect is on that organ.] The HMG CoA reductase inhibitors also decrease triglyceride levels and may increase HDL cholesterol levels in some patients.

1. HMG CoA reductase inhibitors Therapeutic uses: These drugs are effective in lowering plasma cholesterol levels in all types of hyperlipidemias. Pharmacokinetics: Absorption of the statins is variable (30% to 85%) following oral administration. All statins are metabolized in the liver, with some metabolites retaining activity. Excretion takes place principally through bile and feces, but some urinary elimination also occurs. Their half-lives are variable.

1. HMG CoA reductase inhibitors Adverse effects: 1. Elevated liver enzymes may occur with statin therapy. Therefore, liver function should be evaluated prior starting therapy and if a patient has symptoms consistent with liver dysfunction. 2. Myopathy and rhabdomyolysis (disintegration of skeletal muscle; rare) have been reported. In most of these cases, patients usually had renal insufficiency or were taking drugs such as erythromycin, gemfibrozil, or niacin.


2. Niacin (nicotinic acid)
Niacin can reduce LDL-C by 10% to 20% and is the most effective agent for increasing HDL-C. It also lowers triglycerides by 20% to 35% at typical doses of 1.5 to 3 grams/day. Niacin can be used in combination with statins, and a fixed-dose combination of lovastatin and long-acting niacin is available. Mechanism of action: At gram doses, niacin strongly inhibits lipolysis in adipose tissue, thereby reducing production of free fatty acids. The liver normally uses circulating free fatty acids as a major precursor for triglyceride synthesis. Reduced liver triglyceride levels decrease hepatic VLDL production, which in turn reduces LDL-C plasma concentrations. to hyperuricemia and gout.

2. Niacin (nicotinic acid)

Therapeutic uses: Since niacin lowers plasma levels of both cholesterol and triglycerides, it is useful in the treatment of familial hyperlipidemias. It is also used to treat other severe hypercholesterolemias, often in combination with other agents. Adverse effects: The most common side effects of niacin are an intense cutaneous flush (accompanied by an uncomfortable feeling of warmth) and pruritus. Administration of aspirin prior to taking niacin decreases the flush, which is prostaglandin mediated. Some patients also experience nausea and abdominal pain. Niacin inhibits tubular secretion of uric acid and, thus, predisposes to hyperuricemia and gout.

3.Fibrates

Fenofibrate and gemfibrozil are derivatives of fibric acid that lower serum triglycerides and increase HDL levels.Mechanism of action: The peroxisome proliferator–activated receptors (PPARs) are members of the nuclear receptor family that regulates lipid metabolism. PPARs function as ligand-activated transcription factors. Upon binding to their natural ligands (fatty acids or eicosanoids) or antihyperlipidemic drugs, PPARs are activated. They then bind to peroxisome proliferator response elements, which ultimately leads to decreased triglyceride concentrations through increased expression of lipoprotein lipase and decreasing apolipoprotein (apo) CII concentration. Fenofibrate is more effective than gemfibrozil in lowering triglyceride levels. Fibrates also increase the level of HDL cholesterol by increasing the expression of apo AI and apo AII.

3.Fibrates

Therapeutic uses: The fibrates are used in the treatment of hypertriglyceridemias. Pharmacokinetics: Gemfibrozil and fenofibrate are completely absorbed after oral administration and distribute widely, bound to albumin. Fenofibrate is a prodrug, which is converted to the active moiety fenofibric acid. Both drugs undergo extensive biotransformation and are excreted in the urine as glucuronide conjugates. Adverse effects: The most common adverse effects are mild gastrointestinal (GI) disturbances. Myositis (inflammation of a voluntary muscle) can occur, and muscle weakness or tenderness should be evaluated. Patients with renal insufficiency may be at risk. Myopathy and rhabdomyolysis have been reported in patients taking gemfibrozil and statins together. The use of gemfibrozil is contraindicated with simvastatin.

4.Bile acid–binding resins Bile acid sequestrants (resins) have significant LDL cholesterol–lowering effects, although the benefits are less than those observed with statins.Mechanism of action: Cholestyramine, colestipol, and colesevelam are anion-exchange resins that bind negatively charged bile acids and bile salts in the small intestine. The resin/bile acid complex is excreted in the feces, thus lowering the bile acid concentration. This causes hepatocytes to increase conversion of cholesterol to bile acids, which are essential components of the bile. Consequently, intracellular cholesterol concentrations decrease, which activates an increased hepatic uptake of cholesterol-containing LDL particles, leading to a fall in plasma LDL-C.

4.Bile acid–binding resins Therapeutic uses: The bile acid–binding resins are useful (often in combination with diet or niacin) for treating type IIA and type IIB hyperlipidemiasCholestyramine can also relieve pruritus caused by accumulation of bile acids in patients with biliary stasis. Colesevelam is also indicated for type 2 diabetes due to its glucose-lowering effects.Pharmacokinetics: Bile acid sequestrants are insoluble in water and have large molecular weights. After oral administration, they are neither absorbed nor metabolically altered by the intestine. Instead, they are totally excreted in feces.

4.Bile acid–binding resins Adverse effects: The most common side effects are GI disturbances, such as constipation, nausea, and flatulence. Colesevelam has fewer GI side effects than other bile acid sequestrants. These agents may impair the absorption of the fat-soluble vitamins(A, D, E, and K), and they interfere with the absorption of many drugs (for example, digoxin, warfarin, and thyroid hormone). These agents may raise triglyceride levels and are contraindicated in patients with significant hypertriglyceridemia (≥400 mg/dL).

5.Cholesterol absorption inhibitor

Ezetimibe selectively inhibits absorption of dietary and biliary cholesterol in the small intestine, leading to a decrease in the delivery of intestinal cholesterol to the liver. This causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood. Ezetimibe lowers LDL cholesterol by approximately 17%. Due its modest LDL-lowering effects, ezetimibe is often used as an adjunct to statin therapy or in statin-intolerant patients. Ezetimibe is primarily metabolized in the small intestine and liver via glucuronide conjugation, with subsequent biliary and renal excretion. Patients with moderate to severe hepatic insufficiency should not be treated with ezetimibe.


Thank you