drugs for metabolic disorder. lecture 11
TRANSCRIPT
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
1/28
BIMM11
8
Drugs for Metabolic Disorders
Diabetes mellitus
Hyperlipidemia
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
2/28
BIMM11
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
3/28
BIMM11
8
Diabetes mellitus
Blood glucose levels are tightly regulated:
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
4/28
BIMM118
Diabetes mellitus
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
5/28
BIMM118
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)
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
6/28
BIMM118
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
7/28BIMM118
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
8/28BIMM118
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
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
9/28BIMM118
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
10/28BIMM118
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.
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
11/28BIMM118
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
12/28BIMM118
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
13/28BIMM118
Diabetes mellitus
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 !
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
14/28BIMM118
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 (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)
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
15/28BIMM118
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 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
QuickTime and aTIFF (Uncompressed) decompressor
are needed to see this picture.
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
16/28BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
17/28BIMM1
18
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.
QuickTime and a
TIFF ( Uncompressed) decompressorare needed to s ee this picture.
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
18/28BIMM1
18
Hyperlipidemia
Artherosclerosis:
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
19/28
BIMM1
18
Hyperlipidemia
Artherosclerosis:
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
20/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
21/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
22/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
23/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
24/28
BIMM1
18
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 of HMGRPravastatin
Atorvastatin
Fluvastatin
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
25/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
26/28
BIMM1
18
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)
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
27/28
BIMM1
18
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
-
7/28/2019 Drugs for Metabolic Disorder. Lecture 11
28/28
MM1
18
Hyperlipidemia