Drugs for Metabolic Disorders

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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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Diabetes mellitus
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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)

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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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Diabetes mellitus

• Complications
• Short-term
• Hyperglycemia, (hypoglycemia)
• Ketoacidosis
• Long-term
• Disruptions in blood flow gt Cardiovascular
  complications gt 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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Diabetes mellitus

• Insulin
• Therapeutic insulin used to be purified from
  porcine or bovine pancreas gt 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
• gt Longer lasting formulations
• Insulin Lente
• mixed with zinc gt forms micro-precipitates gt
  takes longer to absorb gt longer acting
• Only for s.c. administration
• Ultra-lente longest acting
• NPH Insulin
• regular insulin mixed with protamine (large
  positively charged protein) gt 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 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.

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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

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Diabetes mellitus

• Oral hypoglycemic agents
• Useful only in Type II diabetes!
• Sulfonylureas
• Stimulate insulin release (increase sensitivity
  of B cell towards glucose block ATP-gated K
  channel gt membrane depolarization gt Ca
  increase gt 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

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Diabetes mellitus

• Oral hypoglycemic agents
• -glitazones (Thiozolidinediones)
• Increase insulin sensitivity of target cells
• function as PPARg agonists gt promote
  transcription of insulin receptor signaling
  components 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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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 kidneydisease
  (predisposition to lactic acidosis)

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Diabetes mellitus

• Novel concepts
• Alpha-Glucosidases
• Intestinal enzymes in the small intestine
• Break down complex carbohydrates (Starch,
  Glygogen)
• Alpha-Glucosidase Inhibitors
• Inhibit carbohydrate breakdown gt 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 gt no systemic side
  effects
• Used to prevent postprandial hyperglycemia
• Side effects Diarrhea, flatulence (intestinal
  bacteria digest the carbohydrates!)
• Miglitol
• Systemically absorbed

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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 gt 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 gt no risk
  of hypoglycemic shock
• Long-term weight loss
• Only for s.c.injection
• DPP4-Inhibitors
• No effect if glucose levels are normal gt no risk
  of hypoglycemic shock

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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 (gt decreased food intake)
• Amylin mimetics
• Pramlintide
• Only drug other than insulin approved for Type I
  Diabetes !!
• Used in combination with insulin

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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 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 gt plasmin
  reduced gt thrombosis promoted

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Hyperlipidemia

• Lipoprotein metabolism
• Absorbed lipids released by enterocytesin form
  of chylomicrones
• Chylomicrones bypass the liver, enter
  thecirculation via lymph and are hydrolyzedin
  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 intothe blood
  stream
• VLDL particles provide target tissueswith fatty
  acids gt 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)
• lt 200mg/dl no risk200-240 mg/dl moderate
  riskgt 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 from Aspergillus sp.
• Side effects Hepatotoxicity, GI disturbances,
  myopathy
• Simvastatin (Zocor)
• Lovastatin (Mevacor)
• Both drugs are precursors gt activated in the
  liver
• Lactone ring is hydrolyzed

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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

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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 gt hepatocytes must meet their
  cholesterol requirements through different
  mechanisms gt
• Hepatic upregulation of the LDL-receptors gt
  increase in LDL uptake gt decrease in circulating
  LDL

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Hyperlipidemia

• Lipid-lowering drugs
• 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

• Lipid-lowering drugs
• Bile acid binding resins
• Anion exchange resins
• Prevent reabsorption and enterohepatic
  recirculation of bile acids
• gt increase in hepatic LDL receptors gt increase
  in hepatic LDL uptake
• gt Reduced LDL in the plasma
• Side effects resins are not absorbed gt 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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Hyperlipidemia