Antihyperlipidemic, Glycemic, & Thyroid Drugs PDF

Lecture 4: Antihyperlipidemic, Glycemic, & Thyroid Drugs Antihyperlipidemic Drugs Hyperlipidemias • Primary o Single gene defect o Combination of genetic and environmental factors • Secondary (acquired) o Generalized metabolic disorder o DM o ETOH (alcohol use) o Hypothyroidism o Primary biliary cir...

Lecture 4: Antihyperlipidemic, Glycemic, & Thyroid Drugs Antihyperlipidemic Drugs Hyperlipidemias • Primary o Single gene defect o Combination of genetic and environmental factors • Secondary (acquired) o Generalized metabolic disorder o DM o ETOH (alcohol use) o Hypothyroidism o Primary biliary cirrhosis Classification • Type I: Familial hyperchylomicronemia • Type IIa: Familial hypercholesterolemia • Type IIb: Familial combined (mixed) hyperlipidemia • Type III: Familial dysbetalipoproteinemia • Type IV: Familial hypertriglyceridemia • Type V: Familial mixed hypertriglyceridemia Goals of Treatment • Decrease the production of lipoproteins • Increase the catabolism of lipoproteins • Increase the removal of cholesterol • Treatment leads into a decline in the progression of plaques and regression of preexisting lesions Desired Levels • Cholesterol: below 200 mg/dl • LDL “bad”: below 130 mg/dl • HDL “good”: higher than 60 mg/dl Nicotinic Acid- Niacin (Vitamin B-3) • MOA: inhibits a hormone-sensitive lipase in adipose tissue which reduces its breakdown o Results in a decreases in: Fatty Acids, Triglycerides, VLDL synthesis (liver), LDL synthesis, cholesterol o Results in an increase in HDL o Promotes plasminogen secretion o Lowers plasma fibrinogen • Broadest lipid lowering drug • Most potent agent for raising HDL • Therapeutic uses: effectively lowers cholesterol and triglycerides • Side effects limits its use o Intense cutaneous flush, pruritus, and feeling of warmth (attenuated w the use of asprin) o Nausea, abdominal pain o Predisposition to hyperuricemia and gout o Impairs glucose tolerance o Hepatotoxic HMG-CoA Inhibitors (“STATINS”) (hydroxy-methyl-glutaryl Coenzyme A) • Lovastatin, Pravastatin, Simvastatin, Fluvastatin, Atorvastatin, and Rosuvastatin • Competitive inhibitors of the first committed step of sterol synthesis (HMG-CoA reductase) • • • o Rate limiting step in cholesterol synthesis Inhibit de Novo cholesterol depleting its intracellular supply Therapeutic use: effectively lowers plasma cholesterol in all types of hyperlipidemias Side Effects o Hepatotoxic o Rhabdomyolysis CI in pregnancy, and children • Fibrates • Fenofibrate and Gemfibrozil • MOA: mediated by gene expression, decreased triglycerides by increasing expression of lipoprotein lipase and decreasing apo C II concentration • Stimulates lipoprotein lipase (hydrolyzes triglycerides into chylomicrons and VLDL promoting their removal from the plasma) • Indirectly HDL levels increase moderately • Decrease plasma fibrinogen • Therapeutic use o Particularly useful in Type III o May be used in Type IV and V when diet or other drugs have failed • Pharmacokinetics o Well absorbed orally o Strongly binds to albumin o Excreted in urine as glucuronide conjugate • Adverse Effects o GI disturbances o Formation of gallstones o Malignancies (specifically clofibrate) o Myositis: immune system attacks your muscles • Drug Interactions o Elevates Coumarin levels o Transient elevation of sulfonylureas • CI: o Hepatic and renal dysfunction o Preexisting gallbladder disease Bile Acid Binding Resins • Cholestyramine and Colestipol • Resins binds bile acids and bile salts in the small intestine • Complex is excreted in feces and avoids enterohepatic circulation • Consequently, intracellular cholesterol is used to produce new bile acids and salts, thus reducing total cholesterol concentration • Therapeutic use: DOC w diet and combination with niacin for Type II • Adverse Effects o GI Disturbances o Impaired absorption of § Lipid soluble vitamins (A, D, E, K) § Folic Acid § Ascorbic Acid o Interfere w intestinal absorption of drugs (will be less effective) § Tetracycline, phenobarbital, digoxin, warfarin, prevastin, Fluvastatin, aspirin, and thiazide diuretics o Resins should be taken 2 hours prior or 6 hours prior to food intake Cholesterol Absorption Inhibitors • Ezetimibe o Inhibits intestinal cholesterol absorption o Reduces serum LDL and triglycerides o Less impairment in absorption of fat soluble vitamins Glycemic Drugs Diabetes Mellitus • Type 1: Genetic, younger patients o Commonly undernourished at time of onset o 5-10% of diagnosed diabetics o Moderate genetic predisposition o Beta cells are destroyed, eliminating the production of insulin • Type II: due to diet, usually later in life (>35 years old) o Commonly obese at time of onset o 90-95% of diagnosed diabetics o Very strong genetic predisposition o Inability of Beta cells to produce appropriate quantities of insulin; insulin resistance; oth er defects Insulin • Protein composed of 2 polypeptides linked by a disulfide bond • Produced by the pancreatic Beta cells as the precursor protein known as pro-insulin • When secreted it cleaves into Insulin and Protein C Rapid Action Insulin • Regular Insulin o Short acting crystalline zinc insulin o Peak levels are acquired between 50-120 minutes after administration § SC and IV (emergencies) o Sources: recombinant and animal • Lispro, Glulisine, and Aspart Insulins o Modified insulin molecule that allows for a quicker time of absorption after SC administration o Should be used 15 min prior to meal § Peak levels are seen between 30-90 minutes after administration o Usually used in combo w longer action insulin for appropriate control of glucose levels Intermediate Action Insulin • Lente Insulin o Mixture of semilente (30%) and ultralente (70%) insulin o Onset and peak of action is slower than rapid action but longer than prolonged action o Only use SC • Isophane Insulin o Suspension or neutral protamine Hagedorn (NPH) o Intermediate duration of action o Only use SC Prolonged Action Insulin • Ultralente Insulin o Suspension of pork and recombinant insulin o Composed of large particles that dissolve slower o Produce a slow onset of action w prolonged hypoglycemic effect Intensive Treatment • Seeks glucose level normalization w more frequent insulin injections • Goal is to achieve glucose levels of 175 mg/dl w total HbA1c of 7% • This intensive therapy shows a 60% reduction of long term complications of diabetes if compared with those using standard therapies Standard Treatment • Relies on insulin injections twice a day • Maintaining glucose levels between 225-275 mg/dl w total HbA1c of 8-9% Complications of Therapy • Coma • Seizures • Hypoglycemia (tachycardia, confusion, vertigo, diaphoresis) • Lipodystrophy • Hypersensitivity Diabetes Mellitus Type II • T1: resistance of peripheral tissue absorption of glucose • T2: B cells do not secrete insulin in the pancreas Oral Hypoglycemic Drugs • Useful in the treatment of NIDDM in which glucose levels are NOT controlled soley by diet • Most effective in young patients (<40) which has had NIDDM for <5 years? o Patients w long standing NIDDM need a combo therapy w insulin injection and oral hypoglycemic drugs is the standard • NEVER use in Type I DM Sulfonylureas • Agents o 2nd generation: Tolbutamide, Glyburide, Glipizide o Rarely used today: Glimepiride, Acetohexamide, Tolazamide • MOA: o Stimulate insulin secretion from B cells o Reduction of serum Glucagon levels o Increase insulin binding to target receptors • Metabolized by the liver • Excreted by the liver and kidney • CI: Hepatic or renal disease (accumulation leads to hypoglycemia), Pregnancy (cross BBB and may deplete the fetal pancreas of insulin) • Drug Interactions o Reduce Effectiveness (loss of glucose control): atypical antipsychotics, corticosteroids, diuretics, Niacin, Phenothiazines, Sympathomimetics o Potentiate Effectiveness (hypoglycemia): Azole antifungals, beta-blockers, chloramphenicol, clarithromycin, monoamine oxidase inhibitors, probenecid, salicylates, sulfonamides Meglitinide Analogs • Repaglinide and Nateglinide • Stimulates insulin secretion by binding to ATP sensitive K+ channel of pancreatic cells • It is used orally and taken 3 times per day in combo w sulfonylurea (synergistic effect providing better glucose control) • Postprandial glucose regulator • The incidence of hypoglycemia is lower than that of the sulfonylureas • Inhibits CYP 3A4 isoenzyme Biguanides • Metformin o DOC in newly diagnosed diabetics o MOA: reduction of hepatic gluconeogenesis, as well as hyperlipidemia (results in better control of cholesterol, LDL, and VLDL) with weight loss o Doesn’t stimulate insulin secretion, possess a lower risk for hypoglycemia o May be used in combo w sulfonylureas o No drug metabolism o Excreted in the urine o Adverse effects: § Mainly GI § May interfere with Vit. B12 § Potentially fatal lactic acidosis o CI: avoid in hepatic and renal impairment patients Alpha-Glucosidase Inhibitors • Acarbose o Inhibits this enzyme in the brush border, decreasing the absorption of starch and disaccharides, and as such post-prandial rise of glucose is blunted o It doesn’t increase insulin action on Peripheral tissue (no hypoglycemia) o May be used in monotherapy, in those with controlled diet or in combination with other oral hypoglycemic agents and even insulin o Adverse effects: § GI disturbances § Flatulence, Diarrhea, abdominal pain Thiazolidinediones • Troglitazone, Pioglitazone, and Rosiglitazone o Act by enhancing insulin actions in the liver and skeletal muscle o Reduces hepatic gluconeogenesis o Improves hyperglycemia, and hyperinsulinemia, and elevated HbA1c o Counteracts insulin resistance o Usually used in patients receiving insulin injections, and may lower their dose to achieve glucose control o Oral absorption is enhanced when taken with food o Extensively bound to albumin o Metabolized in the liver (induces CYP-450) o Excreted in feces o Adverse effects: URI, HA, Anemia, Edema, Weight Gain, increase metabolism of OC and interference of drugs metabolized through CYP-450 Thyroid Drugs Hyperthyroidism (most commonly secondary to autoimmune disease or hormone producing tumor) • Ionizing Radiation (ablation) • Propylthiouracil Hypothyroidism (Primary (congenital), or secondary (most commonly autoimmune disease or ablation)) • Hormone replacement • Oral Levothyroxine