pathophysiology wk 2

pathophysiology of COPD

emphysema

chronic bronchitis

increase AWR

inhaled toxins (eg smoking)

emphysema

destruction of the alveoli

loss of radial traction on the small airways

chronic bronchitis

excessive mucus production

increase AWR

dynamic compression of the airways → decrease FEV 1.0 or PEF

symptoms of COPD

wheezing, coughing, SOB (dyspnea)

often low PaO2 by PaCO2 is somewhat normal

progressive disease → often fatal

classification of COPD

mild → very severe

drug targets for COPD

bronchiole smooth muscle

immune cells

bronchiole smooth muscle

block Gq coupled receptors (M3)

stimulate Gs coupled receptors (beta-2)

block PDE → increase cAMP/ pka effects

bronchodilators _ in copd compared to asthma

help less

immune cells

inhibits inflammation

in copd, immune involvement is

different (mast cells not important); ICS help less compared to asthma

bronchodilators

beta-2 agonist

SABA

LABA (indacaterol only for COPD)

LABA can be used as monotherapy

muscarinic antagonist for copd

ipatropium (SAMA)

tiotropium (LAMA)

anti inflammatory for copd

ics

theophylline

roflumilast

roflumilast moa

oral pde inhibitor only for COPD

copd has no _ component, therefore

allergy; lt modifiers, cromology not used in COPD

gastroesophageal reflux disease (GERD) clinical findings (classical)

pyrosis (heartburn)

regurgitation

dysphagia

water brash

belching

gastroesophageal reflux disease (GERD) clinical findings (atypical)

chest pain

cough

asthma

recurrent sore throat

dental enamel loss

worrisome “alarm” symptoms of GERD

dysphagia (trouble swallowing), vomiting blood, unexplained weight loss, anemia

pathophysiology of GERD

transient lower esophageal sphincter (LES) relaxation

hypotensive LES

hiatal hernia

complications of GERD

esophagitis

barrett’s esophagus

diagnosis of GERD

• history

• improvement of responds in response to therapeutic trial of acid suppressing rx

• GI referral for upper endoscopy

  • 24 hrs continuous pH monitors

treatment of GERD

lifestyle modifications

weight loss

increase head of bed 6 inches

avoid post prandial recumbency

avoid large meals

avoid certain foods (eg fatty acids, chocolate, carbonated beverages, EtOH, citrus juices)

smoking cessation

antacids types

magnesium containing: Mg(OH)2

aluminium containing: Al(OH)3

calcium containing: CaCO3

Sodium containing: Na+HCO3

Antacids MOA

neutralize HCl in the lumen

also inhibit pepsin activation/ activity

Mg2+, Al3+ inhibit H pylori

NAHCO3

NAHCO3 + HCl → NaCl + H2O + CO2

CaCO3

CaCO3 + 2 HCl → CaCl2 + H2O + CO2

Mg(OH)2

Mg(OH)2 + 2Hcl → MgCl2 + 2H2O

Al(OH)3

Al(OH)3 + 3HCl → AlCl3 + 3H2O

adverse effects of NaHCO3

gastric distension, belching (due to CO2)

Na+ reabsorption → fluid retention problematic in HF, HTN, kidney disease

CaCO3 adverse effects

gastric distention, belching (due to CO2)

ca2+ absorption may → hypercalcemia in patients with increase dairy ingestion, kidney disease)

ca2+ → increase gastric H+ secretion

Mg(OH)2 adverse effects

Mg2+ → diarrhea

Mg2+ absorption may → hypermagnesemia (in pts w/ kidney disease)

Mg2+ can chelate drugs in intestine → decrease drug absorption

Al(OH)3 adverse effects

Al3+ → constipation

Al3+ absorption may → Al3+ accumulation in bones, tissues (in pts with kidney disease)

Al3+ can chelate drugs in intestine → decrease drug absorption

DDI of antacids

may alter absorption of drugs with gastric pH-dependent bioavailability

H2 receptor antagonists (H2RAs) MOA

block H2 receptors on parietal cells → decrease cAMP/ pka → decrease K+-H+ ATPase activity → decrease H+ secretion (basal> meal stimulated, especially nocturnal H+ secretion)

H2 receptor antagonists example

cimetidine, ranitidine

AEs of H2RA

miscellaneous adverse effects (usually minor, relatively uncommon)

headache, diarrhea, dizziness, drowsiness

hypergastrinemia: discontinuation after prolonged use → rebound acid hypersecretion; also explains tolerance

tolerance

drug becomes less effective over time

for cimetidine additional side effects

H2RA

hyperprolactinemia (reproductive dysfunction, galactorrhea, gynecomastia/ reproductive dysfunction in males, fron antiandrogen effects)

DDI of H2RA

may alter absorption of drugs w/ gastric pH-dependent bioavailability

DDI for cimetidine

inhibit CYPs

competes with other drugs (and creatinine) for secretion into the kidney tubes

can increase plasma creatinine (which looks like renal function has decreased, but renal function is not affected)

proton pump inhibitors (PPIs) ex

omeprazole

PPI MOA

absorbed from small intestine → enter parietal cell basolaterally → secreted into lumen cavity → protonated to active form → irreversible blockade of H+ -K+ ATPase activity → decreased H+ secretion (most efficacious at basal and meal stimulated)

takes 30-60 minutes before meals

requires several days for maximal effect

aes of PPI

minor (headache, abdominal pain, nausea, diarrhea)

nutritional concerns

H+ releases B12 from food, promotes absorption of ca2+, Mg2+. chronic use may decrease vitamin B12 levels, increase risk of fractures, hypomagnesemia → muscle spasms, seizures, arrhythmias

infection concerns

increase risk of enteric and respiratory infections in certain patient populations

kidney function concerns, increase risk of chronic kidney disease and aki

hypergastrinemia (worse with PPIs than with H2RAs), discontinuation after prolonged use → rebound acid hypersecretion

can cause hyperplasia of enterochromaffin like (ECC) cells

DDIs of PPI

may alter absorption of drugs with gastric pH-dependent bioavailability

for omeprazole: inhibits certain CYPs and induces other CYPs

reticulocyte count

% of RBCs that are reticulocyte

reticulocyte count =

%RBCs that are reticulocytes

steady state of reticulocyte

replaces RBC, bone marrow reproduce 1% per day

normal reticulocyte count

around 1%

first correction of reticulocyte count

reticulocyte count x patient’s [hgb] or [hct]/ normal [hgb] or [hct]

normal hgb

14

normal hct

45

increase marrow →

increase reticulocyte = erroneous reticulocytes hanging out for 2x as long

nucleated RBCs in peripheral smear =

reticulocytes are coming out too soon

when hgb is really low, can assume this is happening

second correction of reticulocyte count

reticulocyte production index (RPI)

= corrected retic count/ correction factor

regulation of erythropoiesis

bone marrow erythropoiesis + → reticulocyte + → RBC mass (hgb or hct) + → o2 delivery to kidney (-) → erythropoietin + → bone marrow erythropoiesis

increase PaO2 →

decreases erythropoietin

Fe,b12, folate impact

bone marrow erythropoiesis

anemias differentiate by

retic %

megablastic anemia

decrease DNA synthesis → ineffective hematopoiesis

maturation defect: cells stay big → increase RBC size

decrease B12

trap N5 methyl THF → depletes the cycle as if you had folate deficient

can resupply w/ folic acid can recover DNA synthesis

odd chain FAs

odd chain FAs → (FAO) → propionyl coA → methmalonic acid (mma) (b12 dependent) → succinyl coA

drugs that block thymidylate synthase/ DHFR

mess up this cycle → RBC precursors not go through normal maturation process

anemia

RPI <2

macrocytosis

>110 MCV

pancytopenia

other cell lines are down

other causes of anemia

hypersegmented neutrophils

increase homocysteine

hemolytic products (increase LDH, increase unconjugated bilirubin)

B12 →

increase MMA (neurological changes/ damage to places in nervous system, polyneuropathy)

nitrous oxide

megaloblastic anemia

has effect on b12

symptoms of anemia are

often non-specific (eg fatigue dyspnea, dizziness/ lightheadedness, palpitations, headaches) and asymptomatic if mild

MCV

average size of the RBCs

reticulocyte count is should increase substantially in response to anemia

if the problem is not affecting EPO or bone marrow

reticulocytes

immature RBCs that still have ribosomal RNA and other organelles that get eliminated normally within 24 hrs

3 major types of anemia

hypoproliferative

ineffective hematopoiesis

hemolytic

hypoproliferative anemia

decrease RBC production

causes of hypoproliferative anemia

kidney disease resulting in diminished EPO production

decreased hgb production from iron deficency or iron sequestration in macrophages

iron deficency results from

blood loss along with inadequate diet

2 major causes are menstrual bleeding or GI blood loss (cancer or ulcers)

anemia of chronic inflammation (disease)

inflammatory cytokines (tumor necrosis factor) are released that ultimately cause increase storage of iron in macrophages and decreased delivery of iron to the bone marrow

eg of prolonged inflammatory states

tb, malignancies, rheumatologic disorders

in all hypoproliferative anemias

reticulocyte % should be low

low MCV (microcytic)

iron deficiency and sometimes anemia of chronic inflammation

normal MCV (normocytic)

anemia of chronic inflammation and kidney disease

megaloblastic anemias are primarily caused by

folate deficiency or vitamin B12 deficiency

in both folate deficiency and b12 deficiency

MCV is high = macrocytic

reticulocyte count to be low

b12 is involved in

myelination

particularly of large diameter neurons in peripheral nerves, dorsal columns, lateral corticospinal tracts, optic nerves, and other cortical neurons

if give a b12 deficient patient folate

their anemia will improve but will not fix neurological damage

common cause of b12 deficiency

GI malabsorption

• patient receives b12 intramuscular injections

folate deficiency can occur

relatively quickly from dietary deficiency (months)

b12 deficiency develops

much longer (years), because most people have 3-5 years of b12 stores in their liver

problem in hemolytic anemia

RBC lifespan is shortened due to increased destruction

both sickle cell anemia and g6pd deficiency are

genetic diseases

sickle cell disease

substitution of valine for glutamine in the beta-hemoglobin chain

hemoglobin S has a strong tendency to form aggregates when deoxygenated

heterozygotes for hemoglobin S

sickle cell trait and dont have a lot of RBC sickling

complications of sickle cell anemia

vascular “sludging” and thrombosis (widespread tissue infarction)

G6PD deficiency

NADPH produced from pentose phosphate shunt in RBC is used to keep glutathione reduced → reduced glutathione prevents oxidative damage to RBC membrane

patients with g6pd deficiency

may not even know they have it until they are exposed to something that increases oxidative load on RBC

eg. infection, rx, food (fava beans)

in all cases of hemolytic anemia

reticulocyte % should be increased

RBC oxidized are

targeted by spleen for destruction