Definition of COPD

• an inflammatory respiratory disease
• progressive airflow obstruction that is not fully reversible
• based on signs and symptoms and confirmed with spirometry
• emphysema and chronic bronchitis often make up COPD
• extrinsic and intrinsic risk factors for COPD

Emphysema and chronic bronchitis

• emphysema is a pathological term: the destruction of the alveolar-capillary membrane
• chronic bronchitis is a clinical term: cough or sputum production for 3 months in 2 consecutive years (can also have asthma component)

Extrinsic COPD risk factors

• cigarette smoke-80% of cause
• environmental tobacco smoke
• occupational dust and chemicals
• outdoor and indoor pollution

Intrinsic COPD risk factors

• Alpha-1- antitrypsin deficiency
• family history of COPD
• advancing age
• history of childhood respiratory infections

Pathophysiology of COPD

• chronic airway irritation and inflammation causing oxidative stress and increased Tlymps, macrophages and neutrophils
• causes increased mucous production and decreased muco-cilliary function and release of elastase and proteases
• this all causes cough and sputum production
• causes alveolar destruction, airway obstruction/narrowing and scarring(FEV1 down) in peripheral airways
• dyspnea occurs because air is retained(trapping RV inc) and gasses not transferred(CO2 inc)

Advanced Physical Symptos of COPD

• appears SOB
• dusky or plethoric(pinkish color
• barrel-chested
• accessory muscle use
• wheeze(expiratory
• if severe: signs of right heart failure

Chest Xray COPD

• flattened Diaphragms(lungs larger, less elastic)
• increase AP diameter(barrel chest)
• increased retrosternal air space(area behind heart)
• increased lucency(looks darker)

COPD Treatment

(Non-pharmacologic)

• smoking cessation
• pulmonary rehabilitation
• oxygen> 15 hrs daily increase survival
• bullectomy
• lung volume reduction surgery(LVRS)
• lung transplantation
• pulmonary rehabilitation(improve exercise tolerance and reduce symptoms)

COPD Pharmacologic Therapy

• Bronchodilators(B2 agonists and anticholinergics)
• phosphodiesterase 4 inhibitor
• inhaled glucocorticosteroids
• systemic glucocorticosteroids
• combinations of each
• relieves symptoms but does not prolong survival 

Beta2 agonists

• albuterol(ventolin, proair)
• increases cAMP which leads to relaxation of bronchial smooth muscle
• clinical benefit is long activing greating then short acting therapy in exacerbation rates, improvements in lung function and symptom improvement
• dose dependent side affects

Anticholinergics

• tiotropium
• competitively inhibit cholinergic receptors in bronchial smooth muscle
• increases maximum exercise performance; decreases hyperinflation

Phosphodiesterase 4 inhibitor

• roflumilast
• PDE4 inhibitors cause accumulation of cAMP within inflammatory cells
• leads to suppression of cytokine relase and inhibiton of lung infiltration by neutrophils and other leukocytes
• reduce moderate to severe exacerbations
• side effect is nausea and diarrhea

Inhaled glucocorticosteroids

• local anti-inflammatory activity and vasoconstrictive activity
• shown to decrease frequency of exacerbations and improve health status
• patien population: symptomatic COPD patients with FEV1 <50% of predicted (stage III and IV) and repeated exacerbations
• does not modifiy the long term decline of FEV1 in patients with COPD
• could lead to thrush(mouth thing from not rinsing)

oral glucocorticosteroids

• prednisone
• antiinflammatory mechanisms: reduction in capillary permeability to decease mucus
• inhibition of release of proteolytic enzymes from leukocytes
• inhibiton of prostaglandins
• symptomatic improvement
• leads to glucose intolerance and can increase bp

Pulmonary Function Tests in COPD

• TLC increase(air trapping)
• FVC normal or high if lots of air trapping
• FEV1 decrease(airway narrowing)
• FEV1/FEVC decreases
• RV increases (air trapping)
• FRC increases (air trapping)
• DLCO decreases 

Ethanol Metabolism

• uses NAD+ cofactor
• acetaldehyde to acetate using either ALDH1(cytosolic 20%) or ALDH2 (mitochondrial, 80%)
• Acetate to acetyl CoA using ACS1(cytosol in fatty acid synthesis) and ACS II (heart, muscle)
• disulfiram inhibits ALDH causing nausea and vomiting
• asian population has variant of ALDH that has high km
• CYP2E1 also used as an alternate pathway(requires NADPH) to send ethanol ot acetaldehyde

ethanol metabolism and gluconeogenesis

• cannot use alanine, lactate or glycerol because of the high NADH levels compared to NAD+
• this causes hypoglycemia
• also causes high urate levels because the left over lactate competes with it for excretion

acetaldehyde

• product of alcohol metabolism
• increases cellular damage by the formation of cellular adducts (something to do with dna)

Ethanol and liver damage

• CYP2E1 can convert ethanol to acetaldehyde which can creat ROS
• ROS cause GSH to be converted to GSSG which lowers the levels of GSH, which could cause misfolding of proteins
• acetaldehyde itself reacts with nitrogens creating a acetaldhyde-protein adduct(effects ApoB100)
• that causes lipid accumulation in liver from impaired secretion and increased TG syn from increased acetyl CoA levels

Insulin signaling

• IRS-1 adaptor protein is phosphrylated and activated by insulin receptor(tyrosine kinase rec)
• IRS-1 activates lipogenesis through activation of SREBP1(fatty acid syn) and SREBP2(cholesterol syn)
• IRS-2 inhibits gluconeogenesis by phosphorylation of cAMP binding protein CREB(FOXO)
• type II diabitis mellitus gluconeogenesis is not suprresed by insulin activation of IRS-2, while IRS-1 is active (due to inflam signals that phosph IRS-2 on serine and inactivate it)
• IGF-1 and IGF-II stimulate growth 
• blood insulin rapidly degraded by liver

Physiologic effects of glucagon

• insulin secretion from beta cells inhibits alpha cell secretion of glucagon
• proglucagon secreted by α cells of pancrease and L cells of intestine
• proglucagon cleaved to produce GLP-1 and 2
• only 60% of pancrease cleaved proglucagon makes glucagon and the rest GLP
• glucagon inhibits insulin release by paracrine mechanism 
• has halfe life of 3-6 mins

Somatostatin

• pre-pro-somatostatin produced in hypothalamus
• SS-14 inhibits insulin secretion and inhibits growth hormone release from pituitary gland
• gut also produces SS-28 that has same function but is 10X more potent
• somatostatin secretagogues are glucose, arginine and leucine, similar to insuline
• inactivates AC through Gi
• inhibits TSH and Growth hormone from pituitary 
• inhibits insulin and glucagon from pancrease
• inhibits secretion of hormones and in gut

Growth Hormone

• effects mediated through insulin like growth factor(IGF) or somatomedins
• GH 22kDa polypeptide syn in anterior pituitary
• GH direct effect on liver to syn IGF-1(not 2)
• liver GH stimulates FA oxidation, ketogenesis and gluconeogenesis, glycogen synthesis
• muscle GH amino acid transport, increaese ntrigoen retention(lean muscle) and increase energy expenditure
• adipose tissue GFR induce lipolysis and decrease lipogenesis
• GH strong influence on skel musce growth thru diversion of AA from oxidation to protein syn and positive BUN

Secretagous of GH

• Stimulate GH release: arginine, low blood glucose levels, exercise, sleep, stress, renal failure, acromegaly and anorexia nervosa
• inhibit GH release: high blood glucose, high blood fatty acids, obesity and thyroid disorders

Insulin Receptors

• insulin AA receptors binds insulin and control fuel metabolism
• insulin A and B chain bind IGF to control growth 
• different insulin receptor chain combos therefore ahve different affinities for insulin and IGFs

Catecholamines

• epinephrine from adrenal medulla
• norepinephrine adrenergic nerves
• degreaded by MAO(excessive degradation in parkinsons leads to hydrogen peroxide)
• NE converted to E by PMNT and SAM
• stimulated by stress, pain, hypoxia, hypoglycemia, hemorrhage
• excreted in urine as vanillymandelic acid

Thyroid hormone

• T3 more active then T4
• thyroid hormone controls BMR
• syn by thyroid acinar cells and stimulated by TSH
• thyroglbulin synth in thyroid follicular cella nd secreted into colloid space
• thyroid peroxidase oxidized iodide that then reacts with tyrosine residues of thyroglobulin
• lysosomes digest thyroglobulin and release T3 and T4
• thyroid synthesis stimulates syn and release
• amplifies epinephrine cortisol in adipose lipolysis
• stimulates protein syn and sensitizes cell to epinephrine
• sensitizes symp system to cold shivering and stimulate thermogenin uncouple protein in brown adipose
• stimule chol conv to bile salts, increase glycolysis, increase epi induced gluconeogensis, increase TAG syn because of glycolysis and increased adipose tissue lipolysis in liver

GI Peptides

Secretin and Ghrelin

• Secretin: from enteroendocrine S cells of small intestine inhibit gastrin and pancrease enzyme secretion (nutrient absorption)
• Ghrelin is growth hormone secretagogoue that stimulate appetite through release of Y-peptide from hypothalamus 

Incretins

• gastric inhibitory polypeptide(GIP) and glucagon like peptide(GLP-1) potentiate pancreas insulin secretion in response to glucose
• these hormones are called incretins because of their insulinotrophic effect in vivo and explains the greater insulin secretion versus IV glucose
• incretins are produced in crypt cells of the proximal duodenum and jejunum 
• 50-70% of pancreas insulin secretion to elevated blood glucose is mediated by GIP and GLP-1
• GLP-1 enhance insulin secretion and pancreas cell survival, slows gastric emptying, inhibits glucagon secretion
• GIP-enhance insulin secretion and pancreas cell survival, interacts GIP receptor on adipocytes to store energy

Incretins and Diabetes

• increased incretin secr is effective treatment for diabetes by increasing insulin secretion from beta cells and increasing beta cell survival
• DPP-4 ectoenzyme on liver, kidney  and intestine inactivates incretins, but synthetic ones are resistant
• exenatide, a GLP-1 receptor agonist
• sythetic DPP-4 inhibitor increases half life of GIP and GLP-1 (januvia)
• incretin in blood lowers blood glucose and lowers blood HbA1c
• the agonist potential immunological repsonse and pancreatitis

Secretion of insulin

• glucose enters via GLUT2 and is then sent through glycolysis
• this produces ATP that inhibits potassium channal leading to depolarization and Ca influx
• Xa causes fusion and exocytosis of insulin carrying vessicles
• sulfanylurea can also inhibit the potassium channels

Cushings syndrome

• hypersecretion of ACTH and leads to:
• hypertension, sodium retention, thinning skin
• hypokalemic, truncal obesitym muscle weakness
• bruising, glucose intolerance, osteoporosis

Addisons disease

• lack of cortisol
• weight loss, hypoglycemia, hypotension, lethargy
• weakness and pigmentation (melatonin involved)

Diabetes Mellitus

• Type I(insulin-depend)-impairment of insulin production
• Type II(insulin-indepen)- lack of insulin sensitivity
• chronic complications: atherosclerosis, small blood vessel disease(eye, kidney), nerve damage, and impaired immune system

Hypoglycemia

• common mistake taking insulin w/o meal
• blood glucose of 50-70 CNS sensitization
• 20-50 causes seizures loss of conciousnes, coma
• another symptom can be not making sense
• treatment is large amounts of glucose or epinephrine

Thiazoladine

• activates PPARY
• this stimulates lipid synthesis
• removes glucose from blood but stores excess glucose as fat 
• PPARα stimulates beta oxidation

Effects of Glucocorticoids

• stimulate gluconeogenesis and glycogen storage in liver 
• also stimulates lipolysis in excess fat in subcutaneous but lipogenesis in viscreral(cushings)(buffalohump)
• increases protein degradation and decreases synthesis and glucose utilization in muscle (uses ubiquitin ligase)

Chronic Effects of Hyperglycemia

• high glucose activates polyol pathway(aldose reductase which converts glucose or galactose to sorbitol or galactitol
• causes nephritis in kidney and artery plaques because these tissues lack Dehydrogenases to convert it to fructose
• sorbitol in lens causes osmotic swelling(cataracts)
• glucose also attaches to Hb(HbA1c) through amadori reaction involving a schiff base

Maturity Onset Diabetes of the Young

• autosomal dominant disease monogenetic diabetes
• MODY2 and 3 most common, mostly Type II diabetes but can be type I(
• MODY 4 and 6 very rare
• MODY1: HNF4α
• MODY2: Glucokinase
• MODY3:HNF1α
• MODY4:IPF1
• MODY5:HNF1β
• MODY6: NeuroD1

PKCε

• high levels of Free fatty acids(obesity) lead to high levels of DAG
• DAG activates PKCε
• this can lead to insulin resistance because PKC epsilon activates gluconeogenesis and glycogenolysis