drugs for metabolic disorder. lecture 11

7/28/2019 Drugs for Metabolic Disorder. Lecture 11

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Drugs for Metabolic Disorders

Diabetes mellitus

Hyperlipidemia


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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


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Diabetes mellitus

Blood glucose levels are tightly regulated:


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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)


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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


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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


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Insulin:Therapeutic insulin used to be purified from porcine or bovine pancreas =>

functionally active, but many patients developed an immune response

Today, human insulin is produced by recombinant DNA technology

Main 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


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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


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Diabetes mellitus

Insulin: Insulin Glargine (Lantus)

amino acid asparagine at position A21 is replaced by glycine and two argininesare 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 theLANTUS injection solution). After injection into the subcutaneous tissue, the acidic

solution is neutralized, leading to formation of microprecipitates from which smallamounts of insulin glargine are slowly released, resulting in a relatively constantconcentration/time profile over 24 hours with no pronounced peak.


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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


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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 morepotent than Tolbutamide

Glipizide

Glyburide


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Oral hypoglycemic agents:

-glitazones (Thiozolidinediones)Increase insulin sensitivity of target cells:

function as PPARg agonists => promote transcription of insulin receptor signalingcomponents and of glucose transporters

Main 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 !


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Oral hypoglycemic agents:

Biguanides

Metformine Only drug in this class in use

Increase glucose uptake and inhibit gluconeogenesis in the liver Mechanism unclear (AMPK?)

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)


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Novel concepts:

Alpha-Glucosidases: Intestinal enzymes in the small intestine

Break down complex carbohydrates (Starch, Glygogen)

Alpha-Glucosidase Inhibitors: Inhibit carbohydrate breakdown => less monosaccharides 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

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Diabetes mellitus

Novel concepts (contd):

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 shock

Oral administration!

Sitagliptin

Vildagliptin


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Diabetes mellitus

Novel concepts (contd):

Amylin:

Pancreatic hormone (also from b-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) decompres sorare needed to see this picture.

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Hyperlipidemia

Artherosclerosis:


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Hyperlipidemia

Artherosclerosis:


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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 phagocytosedby 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 intothe fibrinolytic enzyme plasmin.

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


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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


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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


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Hyperlipidemia

Lipid-lowering drugs:

HMG-CoA reductase inhibitors (Statins): Bear structural resemblance to HMG-CoA

Reversible competitive inhibitors of HMG-CoA reductase Isolated fromAspergillus sp. Side effects: Hepatotoxicity, GI disturbances, myopathy

Simvastatin (Zocor)

Lovastatin (Mevacor) Both drugs are precursors =>

activated in the liver

Lactone ring is hydrolyzed

Lovastatin


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Hyperlipidemia


HMG-CoA reductase inhibitors (Statins):

Fluvastatin (Lescol)

Pravastatin (Pravachol)

Both drugs are already in active form

Atorvastatin (Lipitor)

Long-lasting inhibition of HMGRPravastatin

Atorvastatin

Fluvastatin


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Hyperlipidemia


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


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Fibrates: Fibric acid derivates

PPARa agonists:stimulate b-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)


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Hyperlipidemia


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


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drugs for metabolic disorder. lecture 11

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