Metabolic Diaseases & Drugs Flashcards
-How the body gets energy
-Adenosine triphosphate (ATP)
*Common cellular currency of energy
Use to move things
Use to make things
-Carbohydrates
*Convert to glucose
*convert to co2 + water - capture released energy
-fats
*convert to fatty acids
*used for biosynthesis
-proteins
*convert to amino acids
Used for biosynthesis
Energy metabolism
> 50 million in USA
• Excessive weight (obesity)
• Body mass index (BMI)
• Abdominal obesity (waist circumference)
• Hypertension
• Elevated blood glucose (hyperglycaemia)
• Controlled by insulin
• Elevated blood lipids (hyperlipidemia)
• Glucolipotoxicity
Metabolic syndrome
Inefficient glucose use
• Conversion to fats
• Lowered sensitivity to insulin
• Insulin resistance
• Pancreatic dysfunction
• Loss of insulin producing cells (glucolipotoxicity)
• Blood vessel plaques
• Inflammation
Metabolic syndrome biochemistry
• Fasting blood glucose > 12.5 mg/mL
・ Hyperglycaemia
• Type 1
• Insulin-dependent
• Pancreas produces too little insulin
• Treat with insulin injections
• Type 2
• Non-insulin-dependent
・Multifactorial
• Genetics
• Diet
• Physical activity
• Can lead to Type 1 diabetes
Diabetes
• Hypertension
• 50% incidence in 60-69 year olds
• Damages vasculature
• Systolic blood pressure = force during beat
• Diastolic blood pressure = force between beats
• Sustained increase in blood pressure >
140/90 mmHg
• laeal < I<Uou mmmo
• Myocardial infarction (heart attack)
• Decreased, or loss of, blood flow to part of
neat
• Congestive heart failure
• 500,000 US deaths/yr
• $27 billion health care costs
• Decreased cardiac output
• Increased sympathetic nervous system
activallull
• Increased blood volume
• Inadequate tissue supply leads to fluid retention (oedema), fatigue, shortness of breath
• Angina (pectoris)
• Insufficient oxygen supply to heart
• Myocardial ischaemia
• > 9 million Americans
Cardiovascular disorders
• Sympathetic nervous system
• Part of autonomic (involuntary) nervous system
• Primary neurotransmitter is noradrenaline (norepinephrine)
• Same receptors as adrenaline (epinephrine)
• Released from adrenal glands
• Fight or flight response
Normal cardiovascular control
• 80% cholesterol is synthesized in body
• Hyperlipidemia (hypercholesterolemia)
• Promotes atherosclerosis
• Blood vessel plaques
• “Good” cholesterol = High density lipoproteins (HDL)
• Primarily used for cholesterol excretion/storage
• “Bad” cholesterol = Low density lipoproteins (LDL)
• Primary carrier to both peripheral and liver cells
• Lipoproteins = protein + lipid particles used to transport lipids around body
• LDL:HDL ratio important
Cholesterol control
Fat plaques build up on artery walls
• Narrows blood vessel
• Increased blood pressure
• Plaque rupture releases clotting factors
Atherosclerosis
• Type 2 diabetes
• Introduced 1979 (US FDA approval 1994)
• > 6 million patients/year
• A biguanide drug
• Not fully understood
• Increases AMP-dependent protein kinase enzyme activity
• Decreases glucose release from liver
• Increases glucose uptake into skeletal muscle and fat cells
• Decreases glucose uptake from intestines
Metformin (Glucophage)
Introduced 1984
• A sulfonylurea drug
• Block ATP-sensitive potassium channels in pancreas
• Depolarizes membrane
• Increased calcium entry
Stimulates insulin release
• Side effects
• Weight gain
• Hypoglycemia
• Other sulfonylureas
Glipizide (Glucotrol)
Introduced 1999
• A PPARy activator
• Peroxisome proliferator-activated receptor y
• PPAR = ligand activated transcription factor
• Increases transcription of insulin responsive genes
• Normally activated by fatty acids, leukotrienes, or prostaglandins
• Other PPARy activators
• Rosiglitazone (Avandia)
Pioglitazone (Actos)
A dipeptidyl peptidase-4
inhibitor
• DPP-4 = enzyme that breaks down incretins
• Incretins = peptide hormones that increase insulin release and decrease liver glucose release
Sitagliptin (Januvia)
• > 10 million patients/year
• 2006 sales - $13 billion
• Inhibit HMG CoA reductase
• Cholesterol synthesis enzyme
• Other statins
• Lovastatin (Mevacor), pravastatin
(Pravachol), simvastatin (Zocor), Fluvastatin
(Lescol), Rosuvastatin (Crestor)
• Side effects
• Can cause muscle weakness
Atorvastatin (Lipitor)
Introduced 2002
• Inhibits intestinal cholesterol uptake
• Very little drug enters blood
Ezetimibe (Zetia)
> 65 million Americans have high blood pressure
• A B-blocker
• Blocks (nor)adrenaline action at some of its receptors (B-adrenergic receptors)
• Slows heart rate, decrease force of contraction, dilates blood vessels
• Used for high blood pressure, congestive heart failure and angina
• Other ß-blockers
• > 20 e.g. propranolol (Approved 1973)
• Used as PED
Atenolol (Tenormin)
• An ACE inhibitor
• Angiotensin Converting Enzyme
• convers anglotensin I to anglotensin II
• Angiotensin Il contracts blood vessels
• Used for hypertension, myocardial infarction
(heart attacks), heart failure
• A pro-drug
•Doev convers lo ac.ve lorim
• Captopril (Capoten) = 1st (1978)
• Based on Brazilian pit viper venom
• Many others in the class
Enalapril (Vasotec)
An angiotensin receptor blocker
• Used for high blood pressure and chronic heart failure
• $2.4 billion in 2003
• Other examples
• Losartan (Cozaar - 1st to market), olmesartan (Benicar), candesartan (Atacand)
Valsartan (Diovan)
Introduced 1990
• > 6 million patients/year
• $4.7 billion in 2005
• A calcium channel blocker
• Decreases force of contraction of heart
• Dilates arteries
• Used for angina and hypertension
• Other examples
• Nifedipine (Adalat), verapamil (Calan), diltiazem (Cardizem), nicardipine (Cardene)
Amlodipine (Norvasc)
Introduced (as herbal) 1500 BCE
• 1700s - William Withering
• A cardiac glycoside
• Inhibits the sodium-potassium pump
• Increases force of contraction of heart due to increased calcium
• Used for congestive heart failure, cardiac oedema
• Based on extract of foxglove (digitalis)
• Very narrow therapeutic window
• Arrhythmia common
• Drugs with same mechanism
• Ouabain
Digoxin (Lanoxin)
Introduced 1878
• Used for angina and congestive heart failure
• A vasodilator
• Degrades in body to give nitric oxide (NO)
• Natural vasodilator
• Nobel prize 1998
Nitroglycerin
