BIM

M11

8

Drugs for Metabolic Disorders

• Diabetes mellitus

• Hyperlipidemia

BIM

M11

8

Diabetes mellitus

Pancreas:• Islets of Langerhans: site of hormone production

– A (alpha) cells – produce Glucagon– B (beta) cells – produce Insulin

– D (delta) cells – produce Somatostatin

Insulin and Glucagon are the major regulators of blood glucose

BIM

M11

8

Diabetes mellitus

Blood glucose levels are tightly regulated:

BIM

M11

8

Diabetes mellitus

BIM

M11

8

Diabetes mellitus

Insulin:• 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 uptake

Glucagon:• 29 amino acids• Main release stimulus: hunger (= low blood sugar)

BIM

M11

8

Diabetes mellitus

Diabetis 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 drugs

BIM

M11

8

Diabetes mellitus

Complications:• Short-term

– Hyperglycemia, (hypoglycemia)– Ketoacidosis

• Long-term– Disruptions in blood flow => Cardiovascular complications => Amputations

Microvascular disease: blood flow to microvasculature lowered (kidney, eye)

– Retinopathy – blindness– Nephropathy – primary cause of morbidity and mortality– Neuropathy – nerve damage– Erectile dysfunction

BIM

M11

8

Diabetes mellitus

Insulin: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 meals

BIM

M11

8

Diabetes mellitus

Insulin: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 acting

BIM

M11

8

Diabetes mellitus

Insulin:• 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.

BIM

M11

8

Diabetes mellitus

Insulin 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 trial

BIM

M11

8

Diabetes mellitus

Oral 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 cells

First generation sulfonylureas:

• Tolbutamide (t1/2= 6-12h)

• Chlorpropamide (not used anymore)

• Tolazamide• Acetohexamide

Second generation sulfonylureas: • Glimepiride (t1/2= 18-24h), 100x more

potent than Tolbutamide

• Glipizide• Glyburide

BIM

M11

8

Diabetes mellitus

Oral 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 !

BIM

M11

8

Diabetes mellitus

Oral 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 kidney

disease (predisposition to lactic acidosis)

BIM

M11

8

Diabetes mellitus

Novel 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 insulin levels !!– Maybe useful in Type I diabetes as well?

• Acarbose– Also inhibits alpha-amylases– No significant absorption => no systemic side effects– Used to prevent postprandial hyperglycemia– Side effects: Diarrhea, flatulence (intestinal bacteria digest the carbohydrates!)

• Miglitol– Systemically absorbed– No effect on alpha-amylases

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

BIM

M11

8

Diabetes mellitus

Novel concepts (cont’d):

Incretins:– Gastrointestinal hormones: Glucagon-Like Peptide 1 (GLP1) Gastric Inhibitory Peptide (GIP)– Both are inactivated by Dipeptidyl Peptidase 4 (DPP4)– Insulin released before glucose levels become elevated– Reduce gastric emptying => slower carbohydrate absorption– Inhibit Glucagon release– Reduce food intake

Incretin mimetic:• Exenatide

– Originally identified in the saliver of the Gila Monster (“Lizard spit”)– No effect if glucose levels are normal => no risk of hypoglycemic shock– Long-term weight loss– Only for s.c.injection

DPP4-Inhibitors:No effect if glucose levels are normal => no risk of hypoglycemic shockOral administration!

• Sitagliptin• Vildagliptin

BIM

M11

8

Diabetes mellitus

Novel concepts (cont’d):

Amylin:– Pancreatic hormone (also from -Islet cells)– Reduces gastric emptying– Inhibit Glucagon release– Promotes satiety (=> decreased food intake)

Amylin mimetics:

• Pramlintide– Only drug other than insulin approved for Type I Diabetes !!– Used in combination with insulin

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

BIM

M11

8

Hyperlipidemia

Artherosclerosis:

BIM

M11

8

Hyperlipidemia

Artherosclerosis:

BIM

M11

8

Hyperlipidemia

Artherosclerosis:Initiating mechanism:

– Endothelial cells (EC) bind LDL– When activated (e.g. injury), EC and attached macrophages produce ROS– ROS oxidize LDL, which results in lipid peroxidation– This leads to the destruction of the LDL receptors which normally clear LDL– Oxidized LDL is phagocytosed by macrophages via “scavenger receptors”– Upon ingestion of oxidized LDL, macrophages become foam cells– One species of LDL, lipoprotein(a) contains apoprotein(a) which is structually

similar to plasminogen. Plasminogen activator on EC processes plasminogen into the fibrinolytic enzyme plasmin.

– LDL displaces plasminogen on EC => plasmin reduced => thrombosis promoted

BIM

M11

8

Hyperlipidemia

Lipoprotein metabolism:– Absorbed lipids released by enterocytes

in form of chylomicrones

– Chylomicrones bypass the liver, enter the

circulation via lymph and are hydrolyzed

in target tissues by lipoprotein lipases

– 60-70% of the cholesterol in the liver

stems from de novo synthesis

– Liver requires cholesterol to produce

VLDL particles, which are released into

the blood stream

– VLDL particles provide target tissues

with fatty acids => become LDL particles

– HDL particles transfer cholesterol from

tissues to LDL particles

BIM

M11

8

Hyperlipidemia

Cholesterol:– 60-70% (=1000 mg) synthesized (not from

food!): Liver, intestines, reproductive organs…

– Rate-limiting enzyme: HMG-CoA reductase

(3-hydroxy-3-methyl-glutaryl-CoA reductase)

< 200mg/dl: no risk

200-240 mg/dl: moderate risk

> 240 mg/dl: high risk

BIM

M11

8

Hyperlipidemia

Lipid-lowering drugs:HMG-CoA reductase inhibitors (Statins):

– Bear structural resemblance to HMG-CoA– Reversible competitive inhibitors of HMG-CoA reductase– Isolated from Aspergillus sp.– Side effects: Hepatotoxicity, GI disturbances, myopathy

• Simvastatin (Zocor®)• Lovastatin (Mevacor®)

– Both drugs are precursors => activated in the liver

– Lactone ring is hydrolyzed

Lovastatin

BIM

M11

8

Hyperlipidemia

Lipid-lowering drugs:HMG-CoA reductase inhibitors (Statins):

• Fluvastatin (Lescol®)• Pravastatin (Pravachol®)

– Both drugs are already in active form

• Atorvastatin (Lipitor®)– Long-lasting inhibition if HMGR Pravastatin

Atorvastatin

Fluvastatin

BIM

M11

8

Hyperlipidemia

Lipid-lowering drugs:HMG-CoA reductase inhibitors (Statins):

• Statins accumulate in the liver (usually an undesired drug effect)

• Cholesterol synthesis is predominantly effected in the liver =>

hepatocytes must meet their cholesterol requirements through

different mechanisms =>

• Hepatic upregulation of the LDL-receptors => increase in LDL

uptake => decrease in circulating LDL

BIM

M11

8

Hyperlipidemia

Lipid-lowering drugs:Fibrates:

– Fibric acid derivates– PPAR agonists: stimulate -oxidation of fatty acids– Also stimulate lipoprotein lipase activity– Reduce hepatic VLDL production– Affect predominantly VLDL levels (little effect on LDL)– Increase in HDL !– Side effects: Myositis (unusual, but severe)

• Clofibrate• Bezafibrate (Cedur®)• Fenofibrate (Tricor®)• Ciprofibrate• Gemfibrozil (Lopid®)

BIM

M11

8

Hyperlipidemia

Lipid-lowering drugs:Bile acid binding resins:

– Anion exchange resins– Prevent reabsorption and enterohepatic recirculation of bile acids

=> increase in hepatic LDL receptors => increase in hepatic LDL uptake

=> Reduced LDL in the plasma– Side effects: resins are not absorbed => no systemic side effects

mostly bloating, constipation, diarrhea

– Interfer with absorption of drugs (e.g. digoxin) and fat-soluble vitamins– Not particularly appetizing

• Cholestyramine• Colestipol

BIM

M11

8

Hyperlipidemia