Drugs for Metabolic DisordersDiabetes mellitusSlide 3Slide 4Slide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17HyperlipidemiaSlide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28BIMM118Drugs for Metabolic Disorders•Diabetes mellitus•HyperlipidemiaBIMM118Diabetes mellitusPancreas:•Islets of Langerhans: site of hormone production–A (alpha) cells – produce Glucagon–B (beta) cells – produce Insulin–D (delta) cells – produce SomatostatinInsulin and Glucagon are the major regulators of blood glucoseBIMM118Diabetes mellitusBlood glucose levels are tightly regulated:BIMM118Diabetes mellitusBIMM118Diabetes mellitusInsulin:•First protein whose sequence was identified (1955)•51 amino acids; synthesized as proinsulin (84 aa)•6-10 mg stored in the pancreas•~ 2 mg released per day•Liver, brain and red blood cells do not require Insulin for glucose uptake (only muscle and fat cells depend on insulin)•Main release stimulus: elevated blood sugar•Main effect: promote storage of glucose (increase in glucose uptake (GLUT4) and glycogen synthesis)•Also inhibits lipolysis, and promotes lipogenesis and amino acid uptakeGlucagon:•29 amino acids•Main release stimulus: hunger (= low blood sugar)BIMM118Diabetes mellitusDiabetis mellitus:•Group of metabolic diseases characterized by high blood sugar•Elevated levels of blood glucose (hyperglycemia) lead to spillage of glucose into the urine (diabetes mellitus means “sweet urine”)Two distinct clinical forms:•Type I (= insulin-dependent diabetes = juvenile onset diabetes)–Caused by destruction of the B cells–Generally appears in childhood–Absolutely dependent on insulin replacement•Type II (= insulin-independent diabetes = adult onset diabetes)–Caused by target cell resistance to insulin (InsR decreased, signaling defect)–Mostly obese patients (likely genetic predisposition)–Obesity appears to reduce the number of insulin receptors–Can be treated with oral hypoglycemic drugsBIMM118Diabetes mellitusComplications:•Short-term–Hyperglycemia, (hypoglycemia)–Ketoacidosis•Long-term–Disruptions in blood flow => Cardiovascular complications => AmputationsMicrovascular disease: blood flow to microvasculature lowered (kidney, eye)–Retinopathy – blindness–Nephropathy – primary cause of morbidity and mortality–Neuropathy – nerve damage–Erectile dysfunctionBIMM118Diabetes mellitusInsulin:Therapeutic insulin used to be purified from porcine or bovine pancreas => functionally active, but many patients developed an immune responseToday, human insulin is produced by recombinant DNA technologyMain side effect: Hypoglycemia (requires immediate attention!)“Natural” insulin and four modified insulins are used clinically:•Regular (Natural) Insulin–Unmodified human insulin –rapid acting with short duration (half-life 9 min)–Only one that can be given IV (infusions, since injections are too brief acting)–Useful for emergencies (hyperglycemic coma)•Insulin Lispro (Humalog®)–reversal of the order of the 28th and 29th amino acids of the Beta-chain–Mutation prevents dimer formation–more rapid acting – effects 5-15 minutes–Usually given right before mealsBIMM118Diabetes mellitusInsulin:Main problem with using natural and rapid acting insulin: wide fluctuations in concentration=> Longer lasting formulations:•Insulin Lente–mixed with zinc => forms micro-precipitates => takes longer to absorb => longer acting –Only for s.c. administration–Ultra-lente: longest acting•NPH Insulin–regular insulin mixed with protamine (large positively charged protein) => delayed absorption–NPH = neutral protamine Hagedorn–Long actingBIMM118Diabetes mellitusInsulin:•Insulin Glargine (Lantus®)–amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain–low aqueous solubility at neutral pH, but it is completely soluble at pH 4 (as in the LANTUS injection solution). After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak.BIMM118Diabetes mellitusInsulin administration:•Subcutaneously (oral application impossible due to degradation)•Only Regular Insulin can be given IV if needed•Jet injectors•Pen injectors•Implantable insulin pumps•Intranasal insulin - mucosal atrophy (abandoned)•Pulmonary insulin (inhalation) - in clinical trialBIMM118Diabetes mellitusOral hypoglycemic agents:Useful only in Type II diabetes!SulfonylureasStimulate insulin release (increase sensitivity of B cell towards glucose: block ATP-gated K+ channel => membrane depolarization => Ca++ increase => insulin secretion), reduce serum glucagon levels, increase insulin binding on target cellsFirst generation sulfonylureas: •Tolbutamide (t1/2= 6-12h)•Chlorpropamide (not used anymore)•Tolazamide•AcetohexamideSecond generation sulfonylureas: •Glimepiride (t1/2= 18-24h), 100x more potent than Tolbutamide•Glipizide•GlyburideBIMM118Diabetes mellitusOral hypoglycemic agents:-glitazones (Thiozolidinediones)Increase insulin sensitivity of target cells:function as PPAR agonists => promote transcription of insulin receptor signaling components and of glucose transportersMain side effect: hypoglycemia•Troglitazone–First of its class–Hepatotoxic!–No longer in use•Rosiglitazone•Pioglitazone–Half-life ~ 7hrs–Half-life of active metabolites up to 150 hrs !BIMM118Diabetes mellitusOral hypoglycemic agents:Biguanides•Metformine–Only drug in this class in use–Increase glucose uptake and inhibit gluconeogenesis in the liver–Mechanism unclear–Also lowers LDL and VLDL–Adverse side effects: Diarrhea, nausea–Benefitial side effect: appetite suppressant!–Does not cause hypoglycemia–Not for patients with liver or kidneydisease (predisposition to lactic acidosis)BIMM118Diabetes mellitusNovel concepts:Alpha-Glucosidases:–Intestinal enzymes in the small intestine–Break down complex carbohydrates (Starch, Glygogen)Alpha-Glucosidase Inhibitors:–Inhibit carbohydrate breakdown => less monosaccherides available for absorption–Saccharides that act as competitive enzyme inhibitors–DO NOT increase
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