Download Lecture 11

Drugs for Metabolic Disorders
• Diabetes mellitus
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• Hyperlipidemia
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
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Insulin and Glucagon are the major regulators of blood glucose
Diabetes mellitus
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Blood glucose levels are tightly regulated:
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Diabetes mellitus
Diabetes mellitus
Insulin:
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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
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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
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Glucagon:
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29 amino acids
Main release stimulus: hunger (= low blood sugar)
Diabetes mellitus
Diabetis mellitus:
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Group of metabolic diseases characterized by high blood sugar
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Elevated levels of blood glucose (hyperglycemia) lead to spillage of
glucose into the urine (diabetes mellitus means “sweet urine”)
Two distinct clinical forms:
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Type I (= insulin-dependent diabetes = juvenile onset diabetes)
– Caused by destruction of the B cells
– Generally appears in childhood
– Absolutely dependent on insulin replacement
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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)
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– Obesity appears to reduce the number of insulin receptors
– Can be treated with oral hypoglycemic drugs
Diabetes mellitus
Complications:
• Short-term
– Hyperglycemia, (hypoglycemia)
– Ketoacidosis
• Long-term
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– 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
Diabetes mellitus
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
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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®)
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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
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
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– regular insulin mixed with protamine (large positively charged protein)
=> delayed absorption
– NPH = neutral protamine Hagedorn
– Long acting
Diabetes mellitus
Insulin:
• Insulin Glargine (Lantus®)
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– 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.
Diabetes mellitus
Insulin administration:
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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
Diabetes mellitus
Oral hypoglycemic agents:
Useful only in Type II diabetes!
Sulfonylureas
Stimulate insulin release (increase sensitivity of B cell towards glucose: block ATPgated K+ channel => membrane depolarization => Ca++ increase => insulin secretion),
reduce serum glucagon levels, increase insulin binding on target cells
First generation sulfonylureas:
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Tolbutamide (t1/2= 6-12h)
Chlorpropamide (not used anymore)
Tolazamide
Acetohexamide
Second generation sulfonylureas:
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Glimepiride (t1/2= 18-24h), 100x more
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potent than Tolbutamide
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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 signaling
components and of glucose transporters
Main side effect: hypoglycemia
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Troglitazone
– First of its class
– Hepatotoxic!
– No longer in use
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Rosiglitazone
Pioglitazone
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– Half-life ~ 7hrs
– Half-life of active metabolites up to 150 hrs !
Diabetes mellitus
Oral hypoglycemic agents:
Biguanides
• Metformine
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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 kidney
disease (predisposition to lactic acidosis)
Diabetes mellitus
Novel concepts:
Alpha-Glucosidases:
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Intestinal enzymes in the small intestine
Break down complex carbohydrates (Starch, Glygogen)
Alpha-Glucosidase Inhibitors:
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Acarbose
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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
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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?
Systemically absorbed
No effect on alpha-amylases
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Diabetes mellitus
Novel concepts (cont’d):
Incretins:
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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:
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Exenatide
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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:
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No effect if glucose levels are normal => no risk of hypoglycemic shock
Oral administration!
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Sitagliptin
Vildagliptin
Diabetes mellitus
Novel concepts (cont’d):
Amylin:
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Pancreatic hormone (also from b-Islet cells)
Reduces gastric emptying
Inhibit Glucagon release
Promotes satiety (=> decreased food intake)
Amylin mimetics:
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Pramlintide
– Only drug other than insulin approved for Type I Diabetes !!
– Used in combination with insulin
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Hyperlipidemia
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Artherosclerosis:
Hyperlipidemia
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Artherosclerosis:
Hyperlipidemia
Artherosclerosis:
Initiating mechanism:
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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
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
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– HDL particles transfer cholesterol from
tissues to LDL particles
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)
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< 200mg/dl: no risk
200-240 mg/dl: moderate risk
> 240 mg/dl: high risk
Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
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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®)
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– Both drugs are precursors =>
activated in the liver
– Lactone ring is hydrolyzed
Lovastatin
Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
Fluvastatin
• Fluvastatin (Lescol®)
• Pravastatin (Pravachol®)
– Both drugs are already in active form
• Atorvastatin (Lipitor®)
– Long-lasting inhibition of HMGR
Pravastatin
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Atorvastatin
Hyperlipidemia
Lipid-lowering drugs:
HMG-CoA reductase inhibitors (Statins):
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Statins accumulate in the liver (usually an undesired drug effect)
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Cholesterol synthesis is predominantly effected in the liver =>
hepatocytes must meet their cholesterol requirements through
different mechanisms =>
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Hepatic upregulation of the LDL-receptors => increase in LDL
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uptake => decrease in circulating LDL
Hyperlipidemia
Lipid-lowering drugs:
Fibrates:
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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®)
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
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• Cholestyramine
• Colestipol
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Hyperlipidemia