​PHARMACOLOGY (4 PRE MID TERM/5 POST MID TERM)
I e-mailed Summary and Chart...

Pharmacology Thursday 11/5/09 10:00 and 11:00
Antibiotics Dr. McRae

Types of Kill
  1. Concentration Dependent - (peak MIC)
  2. Time Dependent - Time concentration is above MIC
  3. Post Antibiotic Effect (PAE)- Persistant effect on growth after drug is removed (Aminoglycosides)
Pregnancy - penicillins and cephalosporins are relatively safe
Tetracyclines=tooth discoloration under 8
Sulfonamides=kernicterus (neonates) =brain damage caused by unconjugated bilirubin not being able to bind serum albumin (wiki)
CNS, Bone, Prostate, Ocular tissue - not easily penetrated by antibiotics
Antibiotics which cross Blood/Brain Barrier
  1. Do Not Cross- 1st and 2nd generation Cephalosporins, Clindamycin
  2. Cross Menengitis-Penicillin, 3rd gen cephalosporins, metronidazole, axtreonam, meropenem, imipenem(seizures)
  3. Readily Cross- Chloramphenicol, Tetracyclines, TMP-SMZ (Trimethoprim/Sulfamethoxazole)
Bacteria By Source (site of infection)
  1. Mouth - Peptococcus, Peptostreptoccus, Actinomyces
  2. Abdomen - E. coli, Klebsiella, Enterococcus, Bacteroides sp.
  3. Lower Respiratory Community - S. pneumoniae, H. influenzae, K. pneumoniae, Legionella, Mycoplasma, Chlamydia
  4. Lower Respiratory Hospital - K. pneumoniae, P. aeruginosa, Enterobacter sp., Serratia sp., S. aureus
  5. Skin/Soft Tissue- S. aureur, S. pyogenes, S. epidermidis, Pasteurella
  6. UTI - E. coli, Proteus, Klebsiella, Enterococcus, Staph saprophyticus
  7. Upper Respiratory - S. pneumo, H. influenzae, M. catarrhalis, S. pyogenes
  8. Meningitis - S. pneumoniae, N. meningitidis, H. influenza, Group B strep, E. coli, Listeria
ANTIMICROBIALS
  • ß-Lactams-
    • Leukopenia, Thrombocytopenia, Neutropenia when > 2 weeks
    • Pseudomembranous Colitis (C. diff)
    • Interstitial Nephritis (methicillin and nafcillin especially)
    • Cephalosporins - cefamandole, defotetan, defmetazole, defoperazone, moxalactam -
      • bleeding due to lack of Vit K producing bacteria in gut (decreased thrombin)
      • Ethanol intolerance (disulfuram like rxn -headache, flushing,violent vomiting, dizziness, etc.)
      • Na+ overload
    • Hypersensitivity (3-10%)
    • Most Renally eliminated
    • MOA-Cell Wall Synthesis Inhibitor
    • Bacteriocidal (except Enterococcus)
    • MOR-Mechanism of Resistance
      1. B-Lactamase Enzyme from bug inactivates
        1. Secreted - Staph, Gonococci (Nisseria sp.), Gram - , H. influenzae, E. coli, Klebsiella pneumonaie, Bacteriodes (ana)
      2. Reduced affinity of binding proteins (MRSA and PRSP)
      3. Decreased penetration of cell wall through the Porins
    • Penicillins (10 total)
      • Narrow Spectrum-single species or group (ie-Gram +)
        • (2) Penicillin G (shot), Penicillin V(oral) - Natural Penicillins
          • Strep, S. pneumoniae, Viridans strep., Enterococcus,
          • Gram - = Nisseria (Penicillin G),
          • Ana - Clostridium (not C. diff) above diaphram
          • Treponema pallidum (syphilis)
      • Penicillinase-Resistant Penicillins - developed to overcome B-lactamase enzymes from Staph
        • (4) - Nafcillin(liver), Dicloxacillin, Oxacillin(liver), Methicillin(not used for treatment only ID MRSA)
          • MSSA, Strep A-B-C-G, Viridans strep
      • Extended Stectrum (ESBL) - Intermediate (can be used w/ B-Lactamase inhibitors)
        • (2) Amoxicillin & Ampicillin=aminopenicillins (better G - aerobes)
          • MSSA, strep, viridans, enterococcus, listeria
          • Clavulanate(Amoxicillin) PO {Augmentin® discolored Seth's teeth}, Sulbactam(Ampicillin) IV-all inhibit Class A B-LactamASE Enzyme (used w/ antibiotics)
        • (2) Piperacillin(some liver) & Ticarcillin=antipseudomonal penicillins (further G- aerobes)
          • proteus, Salmonella, Shigella, E. coli, H. influenzae, Enterobacter, Pseudomonas aeruginosa, Serratia marcescens, some Klebsiella sp.
          • Tazobactam(Piperacillin)IV, Clavulanate(Ticarcillin) - all inhibit Class A B-LactamASE Enzyme (used w/ antibiotics)
      • Broad Spectrum - wide range of pathogens (not really any drugs in this class???)
    • Cephalosporins-(16)
      • 1st Generation (3) - Gram +, some Gram -, No anaerobe, NO CNS penetration
        • Cefadroxil, Cefazolin, Cephalexin
        • Gram (+) MSSA, S. pneumoniae (penicillin susceptable), Strep A,B,C,G, Viridans
        • Gram (-) E. Coli, K. pneumoniae, P. mirabilis
      • 2nd Generation (4) - slightly less Gram (+), Better Gram (-), several cover Ana NO CNS penetration
        • Cefaclor, Cefprozil, Cefuroxime, Cefoxitin
        • Gram (+) MSSA, S. pneumoniae (penicillin susceptable), Strep A,B,C,G, Viridans
          • Additionally - None
        • Gram (-) E. Coli, K. pneumoniae, P. mirabilis
          • Additionally - H. influenzae, M. catarrhalis, Neisseria sp.
        • Ana - Cefotetan, cefoxitin -
          • Bacteriodes, Clostridia (not C. diff)
      • 3rd Generation (8) - Less Gram (+), Higher Gram (-), DO cross BB barrier, good for GNR meningitis
        • Cefdinir, Cefixime, Cefotaxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone (liver), Cefoperazone (liver)
        • Ceftriaxone/Cefotaxime - Gram (+) aerobes, penicillin resistant Strep pneumo
        • Gram (-) E. Coli, K. pneumoniae, P. mirabili, H. influenzae, M. catarrhalis, Neisseria sp.(including B-lactamase producing)
          • Additionally - Citrobacter sp., Acenitobacter sp.,Enterobacter sp., Morganella morganii, Serratia marcescens, Providencia
        • Pseudomonas aeruginosa=ceftizidime specifically
      • 4th Generation (1) - Cefepime
        • Covers Gram (+), Gram (-), pseudomonas
    • Carbapenems (4)- Ertapenem, Imipenem(cilastatin-prevents elimination renal brush border), Meropenem, Doripenem
      • Broad Coverage - Gram (+), Gram (-), Ana, hospital acquired infections, empiric therapy
        • No MRSA, Coag- staph, VRE, Coag (-) staph, C. diff, S. maltophilia, Nocardia
    • Monobactams (1) - Aztreonam (*Allergy to one B-Lactam = allergy to ALL B-lactams EXCEPT Aztreonam)
      • Gram (-) Only
  • Glycopeptides (2)
    • Vancomycin - Gram (+) including MRSA, No Gram (-)
      • Parenternall (orally when refractory C. diff colitis and trying to get rid of that)
      • MRSA
      • B-Lactam allergic patients
      • Red Man Syndrome - rash on upper torso and head, due to too rapid infusion, goes away with discontinuation or pretreat w/ antihistamines
      • Nephrotoxicity/Ototoxicity - usually when given w/ other Nephrotoxic/Ototoxic drugs
      • Renal Elimination
      • Widely distributed (fat soluble) use TBW for dosing
      • D-alanine-D-alanine cell wall synthesis inhibitor
      • Bacteriocidal (except Enterococcus)
      • Resistance change D-Alanine to B-lactate and Vanc cannot bind bacterial cell wall
    • Telavancin - similiar to Vanc. w/ the following differences
      • MOA=depolarizes cell wall (and D-Ala-D-Ala)
      • Metallic taste, foamy urine, abnormal fetal development
  • Daptomycin - misc cell wall synthesis
    • Depolarizes cell membrane and gums up work
    • Concentration Dependent Bacteriocidal
    • Gram (+), MRSA, VRE, Enterococcus faecalis, Gram (-) relatively ineffective
    • IV administered, Renal elimination base dose on Creatinine clearance
    • NOT for pneumonia, serious cardiovascular side effects
    • Statins-HmGCoA Reductase Inhibitor interaction
  • Bacitracin -
    • Bacteriostatic (topically almost exclusively)
    • Inhibits aa incorporation into cell wall, damages cell membrane
    • Good Gram (+) and Gram (-)
    • Nephrotoxicity


Monday 11/9/09 Antibiotics III 8:00
Dr. McRae
Tetracyclines(4) -doxycycline(rickettsia), demeclocycline (renal)-{not used as antibiotic}, minocycline, tetracycline(renal)
  • 30S ribosomal subunit (reversably bind) - inhibits tRNA from binding on mRNA
  • Bacteriostatic
  • MOR - efflux mechanism, protective proteins around ribosome (tet gene), Enzymatic Inactivation
  • Cross-Resistance occurs except minocycline
  • Gram (+) aerobes, Gram (-) aerobes{resistance is common}, Anaerobes, Mycoplasma, Chlamydia, Rickettsiae
  • Doxycycline (PO and IV) - community acquired pneumonia
  • Cations (Di-and Tri-valent effect absorption)- 2 hrs separate antacid, calcium, etc.
  • Poor CNS penetration
  • Community acquired pneumonia (no specific Drug of Choice), Borgellia Burgdorforia DOC, Rickettsia (rocky mtn. spotted fever, Q fever), Chalymidia infections, Anthrax, SIADH-demeclocycline- increased Anti-Diuretic Hormone (retain H2O) so adverse effect of excess urination used to rid H2O
  • Adverse Effects - GI (dose related), hypersensitivity (rare), photosensitivity(sunburn), hepatotoxicity
  • Contraindicated - pregnancy/children under 8 (teeth discoloration)
  • Drug Interactions-Calcium, Magnesium, Aluminum, Iron, sodium, Bicarbonate, cimetidine(Tagament), milk products, milk - antibiotic should be taken 2 hours before
Glycylcyclines - (1) Tigecycline (tetracycline modified to improve binding)
  • 5X higher affinity for 30S subunit - specifically for VRE, MRSA,
  • Skin infections, intra-abdominal,
Ketoldes (1) - Telithromycin (binds 50S @ 2 different sites)
Macrolides (3) -
  • 1-Azithromycin(Z-Pak)
  • 2- Clarithromycin (broad spectrum, adverse effects), newest limited use
  • 3- Erythromycin (1st in class-topical acne treatment, bowel stimulation), diarrhea, acid degredation,
  • Ketolides//Macrolides - 50S ribosomal subunit, all given PO
  • Bacteriostatic/Time Dependent Kill
  • MOR - usually w/ S. pneumo but can occur in other bugs as well
    • Efflux of drug (mef gene)
    • Alters 50S binding site
  • Gram (+), little Gram (-), Chlymadia, Legionella, Mycoplasma - good for upper respiratory (S. pneumo, )
    • Telithromycin - same plus Resistant S. pneumo
  • All Hepatic elimination (except Azithro)
  • 1/2 Life
    • 1.4 hrs E, 3-7 Hrs C, 68 Hrs Az, 10 Hrs T
  • Otitus media, penicillin allergy, HIV-Opportunistic/CD4 lower than 50 Azithro-prophalactic and clarithromycin-treatment of infection (mycobacterium avium complex - MAC)
  • Side Effects - GI (1/3 pts) mostly erythro,
    • Hepatitis (Erythro, long therapy)
    • Ototoxicity - rare, QTc elongation-rare but fatal
    • Ketolides-
      • Contriaidicated Myasthenia Gravis (worsening of symptoms)
    • All Macrolides but Azithro inhibit P450 system

Monday 11/9/09 Antibiotics IV 9:00
Dr. McRae

Aminoglycosides

  • Amikacin, gentamicin, neomycin, streptomycin, tobramycin
  • Bactericidal—concentration dependant
  • Exhibits post antibiotic effect (stays in system a while)
  • Binds to 30S ribosome—oxygen dependant
  • MOR—decreased penetration/uptake; enzymes modify structure; alteration of ribosomal binding sites
  • Activity—most S. aureus, coagulase- staph viridans, strep, entero, gram- aerobes (not streptomycin) including pseudomonas aeruginosa, mycobacterium
  • Distribution—widely in body fluids, no CSF, poor adipose (use LBW for dose), poor GI absorption
  • Elimination—renal; ½ life dependant renal fxn—normal 2.5-4hr
  • Adverse Reactions
    • Ototoxicity—8th cranial nerve damage cochlear (hearing difficulty) and/or vestibular (irreversible inability to walk or stand)
    • Nephrotoxicity—acute tubular necrosis, starts in 5 days, usually reversible
    • Neuromuscular blockade—infrequent, reverse with calcium gluconate
    • Hypersensitivity and/or local injection site inflammation

Streptogramins—Quinupristin + Dalforpristin = Synercid (mix is 30:70)
  • Bacteriostatic (cidal against some bacteria)
  • Acts on 50S ribosome to inhibit protein synthesis
  • Developed for resistant positive bacteria (VRE)
  • MOR—altered binding sites, enzymatic inactivation
  • Activity—Gram+ VRE & MRSA, gram- aerobes (not Neisseria sp. & Maraxella), mycoplasma, legionella
  • Adverse Reactions
    • Venous irritation—requires slow IV, central line preferred
    • Myalgias, arthralgias

Oxazolidinones—Linezolid
      • Bacteriostatic
      • Binds to 50S ribosome which inhibits 70S initiation complex which inhibits protein synthesis
      • Developed for resistant gram+ MRSA, VRE, enterococcus faecalis
      • MOR—altered binding site (rare)
      • Activity—above, mycoplasma, Chlamydia, legionella
      • Distribution—100% available, CSF~30%
      • Elimination—primarily metabolized; renal & non-renal
      • Adverse Reactions—thrombocytopenia 2-4%

Clindamycin
  • Bacteriostatic
  • Binds to 50S ribosome
  • MOR—altered binding site (erm gene); active efflux (mef gene)
  • Activity—Gram+ & - anaerobes, MSSA, strep pneumonia, group and viridans strep, NOT—enterococcus, MRSA or gram- aerobes (resistant)
  • Distribution—90%, good tissue penetration, minimal CSF
  • Elimination—metabolized by liver
  • Adverse Reactions
    • C. difficile colitis (treat with metronidazole)
    • Hepatotoxicity (rare)

Chloramphenicol - not widely used due to toxcicity
  • MOA - 50S ribosome
  • Activity - Gram (+), Gram (-), aerobes, anaerobes, spirochetes, good coverage, CNS penetration
  • Adverse Effects
    • Hemolytic - Bone marrow suppression and aplastic anemia(not dose related) resulting in death
    • *Gray Baby Syndrome - Newborns unable to conjugate the drug (associated w/ hich concentrations
Fluorquinolones
  • Nucleic Acid Inhibitors - inhibit DNA topoisomerase-4 (help DNA release tension from supercoiling during replication)
  • Bactericidal/Concentration Dependent Killing
  • ALL PO/ ALL IV EXCEPT Gemifloxacin
  • MOR - Alter target site, cell membrane less permeable, increase efflux, ALL exhibit cross resistance
  • Spectrum - descent G(+), little enterococcus, Good G(-), Legionella pneumonae - DOC (w/ macrolides)
    • Ciprofloxacin=only one w/ pseudemonal coverage
    • UTI's due to good concentration in urine
    • Upper Respiratory, Sinusitis, Chronic Bronchitis, Community Acquired Pneumonia (Lower Rt)
    • Good bone penetration (osteomyelitis)
  • Well Absorbed, Good penetration
    • Not all Renally eliminated (Moxi, Gemi - liver)
  • Adverse Effects - GI, CNS, adverse effect on QTc interval,
    • Halmark-articular damage-arthralgias and tendonitis(black box warning) leading to tendon rupture
    • Di/Trivalent Cations - 2 hrs before taking cation/4 hrs after cations
  • 1st Generation - Nalacixic Acid
    • Not used, first isolated, all are structural modifications
  • 2nd Generation - Ciprofloxacin, Norfloxacin, Ofloxacin
  • 3rd Generation - Levofloxacin
  • 4th Generation- Moxifloxacin, Gatifloxacin, Gemifloxacin
Metrodiazole
  • Inhibits DNA synthesis-pro-drug converted to active by anerobic bacteria
  • Bactericidal/Concentration Dependent Killing
  • ANAEROBES, And Protazoa (trichimonas-std)
  • CSF Penetration
  • Liver elimination (6-8hrs Half life)
  • DOC - C. difficil colitis
  • Adverse Effects
    • GI, CNS (rare),
    • Contraindicated - Pregnancy/Breastfeeding - animal testing caused cancer
  • Drug interactions
    • Warfarin - huge increase of anticoagulant effect of Warfarin
    • Alcohol - disulfam like rxn
Sulfonamides -
  • Folate Synthesis Inhibitors > Make Tetrahydrofolate>DNA precursor>which in turn inhibits DNA synthesis
    • Dihydropterate Synthase - inhibited by Sulfamethoxazole (PABA Analog) - Bacteria Only
    • Dihydrofolate Reductase - inhibited by Trimethoprim(bacterial only) - Bacteria and Humans
  • Bacteriostatic Individually/Bacteriostatic together
  • MOR - point mutations and enzymes become less sensitive to the drugs
    • Combination Therapy- slows development of resistance
    • Resistance Common
  • Good Gram (+) and Gram (-)
    • Good Urine distribution (UTI's)
    • DOC - Pneumocistis jirovecci (HIV Pneumonia)-treatment and prophalaxis, also toxoplasmosis prevention
  • Hypersensitivity is Common
  • Renal Elimination,
  • IV and PO
  • Adverst Effects -
    • Hematologic (most serious) - leukopenia, thrombocytopenia, eosinophelia
    • Steven's Johnson - skin reaction, head to toe rash and skin flakes off - life threatening
  • Sulfamethoxazole, Trimethoprim (TMP-SMX)
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PHYSIOLOGY (11 PRE-MID TERM/9 POST-MID TERM)
  • ----
Dr. Ballam CardioPulmonary Drawing (1st day) - 1 slide

Right Heart - low pressure, failure leed to backup into tissues (systemic edema) chest pain and dyspnea (cannot catch breath)
Lungs - Air pump/Gas exchange, CNS Controls, extracts CO2 and loads O2 (and N2), malfunction=chest pain and dyspnea
  • Ventilation = Rate X Tidal Volume
Left Heart - High Pressure, CNS controls (sympathetic and parasympathetic), preload controls (favorite term!=how much blood in ventricle when it contracts)
  • CNS + Preload = maintain BP
  • Failure=backup into lungs (pulmonary edema), chest pain, and dyspnea
Arteries=high O2
Veins = Low 02 (except pulmonary!)
Tissues
  • Extract O2 and load CO2
  • Flow Regulated by resistance - 2 controls for blood pressure
    • CNS - sympathetic only (very little parasympathetic)
    • Hormones-

Histology & Gas Exchange Physiology (Cole & Karius Wed 11/4)

  • Bronchiole smooth muscle contracts at expiration (parasympathetic) and relaxes at inspiration
  • Asthma has prolonged contraction—steroids and beta-2 agonists relax contraction
  • Segmental bronchi each have their own arterial branch so can be surgically removed (like cancer) without taking out other segments (modular)
  • Lymphatic drainage follows bronchial pattern IN REVERSE, from peripheral lungs to central. Important for cancer spread by lymphatics.
  • Neuroepithelial bodies (80-100 cells) in bronchioles are probably gas composition chemoreceptors
  • Clara cells in terminal bronchioles
    • protect bronchiolar epithelium by secreting clara cell secretory protein (CCSP) and a component of the lung surfactant
    • detoxify harmful substances that make it this far with cytochrome P450 enzyme
    • differentiate into ciliated cells to regenerate bronchiolar epithelium
  • Airway diameter adjusts to induce airway resistance and controls where the air is heading in a given section of the lung—wherever there is the most blood
  • A small change in radius (by smooth muscle) has a large impact on airway resistance
  • parasympathetic GVE constrict (vagus nerve)
  • sympathetic fibers dilate (spinal nerve roots)
  • all of the space up until the respiratory bronchioles and alveoli is anatomical dead space--gas exchange does not take place (trachea; bronchi; bronchioles)
  • A normal inspiration at rest~ 350-450ml; 150ml is in dead space (incr. age)
  • Alveolar ventilation—volume of air in alveoli per min (Vdot) 4L/min avg
  • Perfusion (Q) blood pumped from right ventricle 5L/min
  • In resting conditions 250ml O2 exchanged/min—200ml CO2/min—diffusion of O2 and CO2 are INDEPENDANT of each other
  • Surface area of alveolus (#of) and thickness (distance) of alveolar wall directly impact ability to exchange gas—J=(SA)xDx(P1-P2)/distance
  • J (diffusion rate) is also a factor of the number of open capillaries 70ml at rest up to 200ml in exercise
  • In congestive heart failure blood backs up into lung and RBCs end up in alveoli where macrophages phagocytize them—reduces ability to exchange gases
  • Emphysema decreases surface area due to loss of alveoli—gas exchange issue
  • The distance in the equation is made up of the capillary endothelium, alveolar basal lamina, interstitial space and surfactant layer (avg .6 microns)
  • Interstitial fibrosis is collagen in this layer which increases distance and lowers diffusion rate (J)
  • D (equation) diffusion coefficient based on gas solubility and molecular weight
  • D of CO2 is 20x higher than O2—O2 is harder to exchange than CO2
  • O2 deficit (not CO2 overload) is first sign of COPD, emphysema, etc. Increase O2 concentration to help compensate (P1-P2)
  • Increase difference between P1 and P2 will give you more of a tendency for gas to diffuse through to where you want (ie alveoli to capillary)
  • As low oxygen blood travels through capillary bed of alveolus it has a given amount of time to pick up the needed oxygen. Faster heartbeat=less time
  • Increased diffusion distance or reduced surface area can prevent the blood cells from being able to become fully oxygenated especially with exercise
  • Normal person at rest diffusion capacity of lung (DLo2) is 21ml/min/mm Hg
  • DLo2 is 1.23xDLco (carbon monoxide—used to test oxygen capacity)
  • We can move an estimated 400ml/CO2/min/mm Hg, so its never a problem
  • Surfactant keeps surface tension the same for smaller and larger alveoli so that smaller alveoli don’t collapse in the interface from capillary to alveolar membrane—this is confusing, I hope to clarify it when they finish the lecture.


Cardiac Action Potential--Dr. Ballam
  • KNOW HOW AN ACTION POTENTIAL WORKS IN SKELETAL MUSCLE
  • Requirements of a Cardiac AP
    • self generating
    • prolonged, lengthens twitch for appropriate contraction
    • propagates from one myocyte to another
      • proper sequence
      • change rate in different areas
  • Phases of cardiac cycle
    • Systole: mechanical contractile phase
      • initiated by depolarization of the ventricular myocytes
    • Diastole: relaxed phase
      • follows myocyte repolarization
  • Cardiac contraction sequence
    • SA Node (normal origin)
    • Atrial muscle
    • AV Node
    • Purkinje system (ventricles)
    • Ventricular muscle
  • Types of AP's
    • Remember: K concentrated inside, Na/Ca concentrated outside the cell membrane
      • concentration gradients are maintained as constant
      • high rates of depolarization/pathology changes can alter resting membrane potential
      • changing of ion concentration does not alter net charge, parallel ion change
    • Fast: atria, ventricles, Purkinje fibers
      • rapid conduction/contractile (chambers)
      • very rapid/non-contractile (Purkinje)
      • high amplitude (100 mV)
      • 5 phases
        • 4: resting potential
          • High K, Low Na/Ca conductance
        • 0: rapid depolarization
          • High Na conductance
        • 1: initial, incomplete repolarization
          • Decreasing Na, Increasing K conductance
        • 2: plateau
          • High Ca, Low K conductance
            • due to special voltage gated K gates that close for a set period of time
        • 3: repolarization
          • High K (causative), Low Na/Ca conductance
            • Due to timed K gates reopening
            • K dates are different in different parts of the heart--reason for different timing of contractions
        • 4: back to resting potential
          • High K, Low Na/Ca conductance
    • Slow: SA/AV Nodes
      • spontaneous depolarization (automaticity)
        • more rapid in SA Node
      • slow conduction, delays AP transmission to ventricles
        • Ca generated AP, not Na
      • low amplitude (60 mV)
  • Conduction velocity
    • greater the amplitude the faster the conduction velocity
    • larger the cell diameter the faster the conduction velocity
  • Refractory period
    • impossible to generate another AP--effective refractory period
    • another AP can be generated, takes greater than normal stimulus--relative refractory period
    • altering refractory period causes the heart to be more susceptible to the production of arrhythmia
    • the faster ion channels/gates return to phase 4, the shorter the refractory period and vice-versa
  • Cycle length
    • as frequency of depolarization increases (increasing HR), the duration of the AP decreases
      • previous mechanisms for AP are still active, causing a shortening of following AP

Friday 11/6/09 11:00 Dr. Ballam
Cardiac and Electromechanical Coupling
Automaticity- the ability of some healthy tissues to depolarize on their own
  • Phase 4 automatic contraction, SA node, AV node, and Purkinje fibers
  • Rhythmicity-determined by the rate of depolarization
  • Depolarize slowly so an outside influence causes contraction first (SA node causes others to contract first)
  • Na+ channels (special type) begin opening during phase 3 and continue opeing during phase 4 causing depolarization
Sinus Rhythm - generated when SA node depolarizes and creates and AP (normal pacemaker)
Ectopic Focus - ANYWHERE other than SA(usually AV node or purkinje system) generate AP
(+) Chronotropic Effect - during phase 4; sympathetic NS increases SA depolarization ONLY (NOREPI >Beta 1>increased Ca++ conductance)
(-) Chronotropic Effect - during phase 4; parasympathetic NS decreases SA depolarization AND increases the membrane potential-hyperpolarization (ACH>muscarinic>Increased K+ conductance)
ECG-normal SA node>atrial muscle>AV node> purkinje system>Ventricular Contraction- route dictates shape of ECG
ReEntry- when AP continously spreads around heart over and over never stopping Atria=dangerous/ Ventricles=deadly quickly
AV - slow conduction velocity (more than 1/10th of a second)
  • small cells, Low Amplitude of AP, and slow rate of depolarization during excitation
  • Parasympathetic/Sympathetic can also act on AV node slowing/increasing speed
Phase 2 AP=extracellular Ca++ enters cell>more Ca++ to be released from SR (Different than Skeletal muscle)
  • Skeletal = depolarization, Cardiac = Ca++ entering>then Ca++ in from SR
  • Ca++/Na+ diffuses Na+ in and Ca++ out; Na+ closes Ca++ channels; Ca++ pump (not Na+ in cell membrane) resequesters Ca++ in SR
Force of Contraction=Preload + amount of Ca++ in cells
Preload - tension on ventricular or atrial walls when contraction begins
  • Related to Ventricular Pressure and Volume (good indicators)
Frank-Starling Law of Heart - the more Actin-myosin are stretched, the more force they will generate during contraction
(-) Ionotropic Effect - Parasympathetic IGNORE IT
(+) Ionotropic Effect -Sympathetic increases force of contraction via increase intracellular Ca++, also shortens systole (contraction)
  • Norepinephrine - from sympathetic increases intracellular Ca++
  • Cardiac Glycosides (Digoxin) - inhibit Na+/K+ pump (increases intracellular Ca++ by blocking Na+/Ca++ transporter)
Hypocalemia = low extracellular K+- inhibits the Na+/K+ pump>leads to depolarization because Na+ cannon be pumped out=ectopic beat or abnormal beat of heart
Hypercalemia - high extracellular K+ - Causes partial depolarization via reducing concentration gradient and cell cannot repolarize
Hypocalcemia - low extracellular Ca++ - decreased contractility
Hypercalcemia - high extracellular Ca++ - increased contractility
EKG - P=atria depolarization, QRS=Ventricular depolarization/Atria repolarization, T=Ventricular repolarization

Dr. Morril- Erythrocyte Physiolgy (11/5/09)

-Average person (70kg) 60% water, 42L of body fluids
-Erythrocytes- 45% of whole blood (hematocrit- formed elements)
-Most of plasma is water (91%), but also contains albumins, globulins, fibrinogen
-Buffy layer- WBC, platelets- layer between plasma and RBC’s
-Most of red RBCs produced in red marrow- ribs, pelvis
-Genesis of RBC- proerythroblast, basophil erythroblast, polychromatophil erythroblast, Orthochromatic erythroblast, reticulocyte, erythrocyte
-Reticulocytes do not have nucleus- exist in circulation for 1-2 days, then converted to erythrocyte
-RBCs don’t create proteins, don’t utilize mitochondria
-Each RBC can carry a billion Oxygen molecules
-stimulus for erythrocyte production- hypoxia causes many cells to produced hypoxia-inducible factors (HIF) Cells in the kidneys and other tissues (liver) are stimulated by HIF to produce Erythropoietin (EPO)
-decreasing blood levels of O2 content progressively stimulates production of more EPO
-Rate of RBC production in marrow is directly related to level of EPO in plasma
-Takes 2-3 days for increased EPO to increase levels of RBC
-Interaction among Hb chains- the T to the R interconversion- helps to explain the Sigmoidal curve
-T configuration- tight; R indicates more open structure (relaxed)
-When 1st oxygen binds, T can change to R- heme group less guarded = cooperativity

-1 gram of Hb can maximally transport 1.34 ml O2- this is the oxygen capacity of Hb (100%)
-the O2 capacity for blood that contained 15 g Hb in a deciliter would thus be:
15g/dL X 1.34 ml O2/g Hb = 20 mL/dL
-If the Hb were 70% saturated then a dL of blood would be carrying 20mL x 0.7 = 14 mL O2
-Anemia- decreased Hb in blood
-an individual having a Hb of 10 g/dL would be anemic
-since an individual’s hematocrit is linearly related to Hb conc, Hct is typically used as an anemic index
-common types of anemia- hemorrhagic, hemolytic (SCA), aplastic (non-functional marrow, radiation), iron-deficiency (most common- small RBC, decreaced Hb- hypochromatic), pernicious (vitamin B12 deficiency, macrocytic, have trouble getting DNA produced for RBC)
-Macrocytic- large, Microcytic- small, hypochromatic- decreased Hb
-solutions: if solution is Hypotonic, RBC volume increases, Isotonic- no change, Hypertonic, RBC vol decreases
-V0C0 = V1C1
-V0 = volume in isotonic solution
-C0 = conc of soln (i.e. 300 mOsm = osmolality of plasma)
-C1 = soln conc that is not 300
-V1 = cell’s relative volume after change
-Polycythemia- due to excessively high RBC conc or Hct
-causes- decreased O2 conc in blood which causes increased levels of EPO
-genetic aberration- polycythemic vera
-Glucose metabolism in RBC- all of RBC’s ATP obtained by glycolysis
-branch points off glycolysis provides for: pentose shunt (aka hexose monophosphate pathway
-2,3 BPG formation
-RBC use ATP to maintain electrochemical and ionic gradient; maintains membrane flexibility and integrity
-reduction of met hemoglobin to hemoglobin (mainly by NADH-dependent reaction catalyzed by Cytochrome b5 reductase

-defense of RBC against oxidative injury to Hb and cell membrane- reduced glutathione is also important

Dr. Morrill- Gas Tranport (11/6/09)


-O2 transport in blood- combined with Hb 97%, dissolved 3%
-Partial pressure of O2 promotes release of O2 from alveoli (100 mm Hg), to lung capillary (40 mm Hg)
-15 g/dL X 1.34 ml/g = 20.1 ml/dl
-% SO2 = volume of O2 bound to Hb / O2 capacity of Hb
-Volume of a gas dissolved in a liquid is dependent upon: partial pressure of the gas, solubility of the gas in the liquid, temperature
-Solubility of gases at normal body temp: O2- .30ml/dl = PO2 = 100 mm Hg
CO2 = 6.55 ml/dl at PCO2 = 100 mm Hg
generally PaCO2 = 40 mm Hg
-Dalton’s Law- PB (total barometric pressure) = PN2 + PO2 + PCO2 + PH2O + Pz + Px +…
-determining O2’s partial pressure PO2 = PB X FO2 (altitude?0
-where FO2 is the decimal fraction of O2 in the gas mixture and equals 0.21 in ambient air
-160 mm Hg = 760 mm Hg X 0.21
-In Denver, partial pressure would be different (due to PB) but 0.21 would remain the same.
-Partial pressure of humidified gases- for a wet gas which is fully saturated with H2O vapor at 37 deg C, subtract 47 mm Hg (# wouldn’t change with altitude) for PH2O: PO2 = (PB-47 mm Hg) X FO22
150 = (760 – 47) X 0.21
-Bohr effect- has to do with O2- as Ph decreases, curve shifts to the right, as you increase the temp, curve shifts to the right as well. Environment of the tissues is acidic and hi in CO2, which encourages O2 to unload from Hb
-2,3 BPG also shifts curve to the right.
-Carbon Monoxide poisoning
-CO combines on Hb where O2 normally does
-A CO-Hb combo cannot transport O2
-Hb combines more tightly with CO than with O2
-colorless, tasteless, odorless, doesn’t stim ventilation, produces cherry red color
-CO2- dissolves in plasma, as carbamino compounds, as bicarbonate ions
-9:38- he lost me- calculations. (Start to re-listen)
-Carbamino compounds- formed as CO2, binds with amino acids of protein (could be Hb)
-reaction occurs without an enzyme
-The largest portion of CO2 that evolved into lungs (60%) is transported in blood as bicarbonate
-Carbonic anhydrase- in RBC- helps speed up the removal of CO2
-Law of Mass Action: CO2 + H2O
ßà (w/CA) H2CO3 ßà HCO3- + H+
In tissues
à ßIn lungs
-Chloride shift- as the concentration of bicarbonate builds in RBC, exchanged with extracellular anion exchanger
-Source of CO2 evolved in lungs:
-10% from dissolved CO2
-30% from carbamino compounds
-60% from bicarbonate ions
-Haldane effect- deoxygenated blood is able to transport a greater volume of CO2 per volume
-Respiratory Exchange Ratio ( R ) = rate of CO2 output/rate of O2 uptake
-If the volume of CO2 produced and O2 consumed were equal, then the resp. exchange ratio would be 1.00
-Average R is 0.82




Dr. Karius 11/6/09 Friday
Online - Hemostasis
Hemostasis- steps taken by body to limit blood loss (not confined only to blood clot production!!)
  1. Vascular Spasm
  2. Platelet Plug formation
  3. Blood Clot formation (don't always have this step)
  4. Repair of Damage
Platelets-megakaryoblast>megakeryocyte>platelet
  • Thrombopoetin-protein hormone, amine terminal similiar to Erythropoetin/carboxyl terminal - prolongs half-life
    • Chromosome 3
    • Liver and Kidney produce (Erythropoetin mostly kidney)
    • Continually secreted>MPL receptor on platelets binds thrombopoetin>internalize receptor/TPO complex>destroyed
    • More platelets=Less TPO-Injury=Low platelets=high TPO>binds MPL (CD-110)>JAK2/STAT5 pathway>Megakaryoblast>megakaryocyte>platelets produced
    • TPO-has effects on ALL blood cells
    • Polycythemia Vera-where MPL receptor on platelets is mutated and TPO isn't destroyed thus constantly telling cells to be produced causing viscous blood
    • May increase platelet function (when internalized)
  • Actin and Myosin - contraction to empty vesicles*
  • Mitochondria - (ATP and ADP*)
  • ER - Calcium storage
  • Cyclooxiginase (COX1) -> Thromboxane A2*
  • Fibrin Stabilizing Factor* (clot stability)
  • Platelet Derived Growth Factor* (repair)
  • Serotonin (5-HT) - in platelets and in vesicles
  • Glycoproteins on membrane (make them sticky)
  • Phospholipids - platelet factor 3
  • Collagen Receptors
Hemostasis - Damage>Vascular Spasm>Platelet Plug>Blood Coagulation (clotting)>Repair of Damage
  • Vascular Spasm-Smooth Muscle Contraction - MYOGENIC - no neurons or reflexes involved
    • Serotonin (from Platelet) 5-HT
    • Thromboxane A2
    • Slight neural reflex - not necessary nor sufficient to stimulate spasm-(not most important factor-ever!)
  • Platelet Plug - collagen exposed
    • 1 - Von Willebrand Factor (plasma protein) - links collagen to platelet
    • 2 - Platelet binds directly to collagen (integrin-platelet receptor for collagen)
    • Platelet Activation - swells, contraction(actin and myosin), release granules
      • Causes more platelets to bind the other platelets
  • Blood Coagulation (clotting)
    • Step 1 - Pro-thrombin activator
      • Intrinsic(1%) blood cell only/Extrensic (99%)
    • Step 2 - Activation of thrombin
    • Step 3 - Creation of fibrin from fibrinogen
      • Fibrin Stabalizing Factor from Platelet - causes fibrin monomer to polymerize
    • Clot Retraction- getting rid of fluid in a clot, bind fibrin and squeeze w/ actin and myosin (requires Ca++)
    • RBC's, Platelets, Fibrin, WBC's
  • Repair of Damage-platelet derived growth factor stimulates fibroblast to differentiate into whatever it needs to close hole (s. muscle, etc.)
  • Getting Rid of Clot - Plasminogen (pro-enzyme) - made in liver, always in blood
    • Tissue Plasminogen Activator - tPA - released from tissue at time of damage
      • Inhibitor which inhibits activation
      • Thrombomodulin expressed by endothelial cell>binds thrombin>enzyme complex activates Protein C (blood)> Inactivates the Tissue Plasminogen Activator Inhibitor (WTF???)>Plasminogen converted to Plasmin>Lysis of Fibrin
Prevention of Clotting -
  • Smooth BV surface prevents rupture of platelets
  • Glycocalyx - repels the platelet surface
  • Thrombomodulin - changes thrombin into an anti-coagulant
  • Fibrin - allosterically binds thrombin and prevents it from working
  • Prostacyclin - (PGI2) - made from endothelial cell, causing vasodilation (from COX pathway), also limits platelet aggregation
  • Antithrombin III + thrombin = anticoagulant
  • Heparin - mast cells, increases antithrombin efficacy
  • Activated Protein C - inactivates clotting Factors 5-A,(and 8-A)>which inhibits fibrin formation
Impaired Hemostasis-
  • Thrombocytopenia (low platelets) <25,000- normal 150,000-spontaneous bleeding
    • Bone Marrow- stem cells not making them
    • Leukemia - marrow now overproducing one at expense of another
    • TPO and mpl - gene mutations
  • Vitamin K Deficiency - (frequent in infants) - Fat soluble made by gut bacteria, required for prothrombin
    • Adult - gallstones, anything prevents absorption of fat
  • Genetic
    • Hemophelia-Genetic Abscense of clotting factor (VIII most common)
    • Von Willebrands Disease - congenital absence of vWF, impairs platelet function and clot production (several forms)
    • Alteration of Platelet receptor to collagen/collagen molecule - don't bind together
Inappropriate Clotting -
  • Blood Vessels Rough Surface(atherosclerosis)
  • Blood Stasis (slow moving)
  • Disseminated Intervascular Coagulation-
    • Bacterial infection + complement activation>tissue damage releases thromboplastin>clots small and asymptomatic>exhausts clotting proteins> uncontrolled bleeding
  • Protein C Deficency - child dies in infancy due to clotting
  • APC - Activated Protein C Resistance -
    • Leiden Mutation (most common form) - single point mutation for Factor V, first signs often in pregnancy, then suffer from clots, and end of pregnancy does not stop clots
      • Can also cause clotting during pregnancy and death of fetus
*GO TO SLIDE 40 FOR GOOD REVIEW OF ALL LEARNING OBJECTIVES

Basic ECG Dr. Ballam Tues. 11-10-09 10:00am

  • The ECG measures the extracellular potential which is opposite of intracellular so resting potential is +90mV
  • Deflection occurs when the cardiac tissue is at a different membrane potential than the rest of the heart—you have one part of the heart depolarized and the other parts are not
  • There is no deflection if atrium and ventricles are different potentials because they are electrically shielded from each other.
  • During phase 2 the extracellular potential swings to negative (-15mV)
  • SA node causes atrium depolarization from right to left—P wave
  • AV node delays signal—PR interval
  • Ventricles depolarize right to left; apex to base—QRS complex
  • Action potential phase 2 delays repolarization of ventricles—QT interval
  • Ventricles repolarize left to right base to apex (last first; first last)
  • We can’t see atria repolarization because it is “buried” in QRS
  • An interval encompasses a wave and a segment does not
  • 12 leads--Each electrode of an ECG lead looks at changes in voltage of different parts of the heart, basically a different “view” of what is happening in the heart
    • Standard leads 1--left to right arm, 2--right arm to left leg, 3--left arm to left leg
    • Augmented leads aVR—right arm to comb. Left arm & leg, aVL—left arm to combo right arm left leg, aVF—left leg to combo right and left arm
    • Think cardinal and secondary points on a compass as the viewing angles of the heart that these leads provide
    • The same 3 leads provide the 6 listed views of the heart (machine adjusts the polarity automatically for the printout)
  • V1-6 are surrounding heart from right to left side—look at a diagram
  • V1-6 let us look at specific regions of the heart
  • Normal—P wave positive, PR interval 3-4 squares (.12-.16sec)
  • First negative wave is Q
  • First positive wave is R
  • First negative AFTER a positive is S—seldom are all three present (usually Q gone)
  • QRS normal duration ~.12 seconds
  • QT interval—from the beginning of a QRS wave to the end of the T wave
  • Normal QT interval (60 beats/min) is 12 squares (.48sec)--shorter for faster heart rate and longer for slower
  • Prolonged QT could mean potassium channels not opening at the correct time
  • Anything that shortens the action potential, shortens the QT interval


Cardiac Output - Contractility and Heart Rate
11/10/09 11:00 Dr. Ballam

What we do to the heart to maintain BP constant
FLOW = (Arterial Pressure - Venous Pressure) / Resistance of Tissue
  • Q=delta P/R (memorize)
  • Q=flow
  • R=resistance=ml/second
Cardiac Output (systemic circulation)
  • CO=BP/TPR (memorize)-be intimately familiar w/ this!!!
    • CO=Q=flow=cardiac output
    • BP=average Arterial Pressure (assume Venous = 0)
    • TPR=total peripheral resistance (all tissues of the body)
Systemic Pressures - 120 systolic/80diastolic=average about 93mmHg
  • Large Arteries= 93mmHg
  • Arterioles=60-60mmHg
  • Capillaries=18mmHg
  • Vena Cava= 0-4mmHg (Central Venous Pressure/Filling Pressure of R. Atria)
  • Pulmonary
    • Arteries- 24 systolic / 16 diastolic (about 19mmHg)
    • Capillaries - 8 mmHg
    • Veins - 6mmHg = Left Atrial Filling Pressure
Do Not Need to Know how to Calculate Resistance!
Resistance through the lungs is 1/4 or 1/5 the entire Systemic system
Control of BP BP=CO X TPR
  • Autonomic Nervous System
    • Cardiac Rate (BP)
    • Cardiac Force (BP)
    • Vascular Diameter (TPR)
    • Venous Return
  • Hormones - long term via renin/angiotensis system
CO=Stroke Volume X Heart Rate
  • SV=blood out of the heart per beat
*Ejection Fraction=blood pumped into aorta/max ventricular volume(max ventricular volume=preload=end diastolic volume)
    • SV/End Diastolic Volume (100/150=67%)
Autonomic Innervation of Heart
  • Sympathetic-Norepi + Beta-1 receptors
    • Go to SA and AV nodes (and entire ventricular mass)
    • Positive Chronotopic Effect=increased heart rate
  • Parasympathetic - Ach + muscarinic receptors
    • Vagus to SA and AV nodes(almost exclusively)
    • Rest = High Para/Low Symp
  • Vasomotor Center - hind brain
    • Outputs - Sympathetic/Parasympathetic
    • Increased Para=Decreased Sympa (and vice versa)
    • High Pressure Baroreceptors - located in regions sampling high blood pressure
      • Can INCREASE AND DECREASE BP (not in response to just High BP)
      • Always sending a signal at rest (baseline firing rate)
      • Carotid SINUS (not bodies)
      • Aortic Arch (more important)
      • BP High>Sensed Baroreceptors>Increase Firing Rate >Inhibits Pressor (sympathetic) and Stimulates the Depressor (parasympathetic)
      • BP Low>Sensed Baroreceptors>Decrease Firing Rate (to vasomotor)>Stimulates Pressor Region (sympathetic) and Inhibits the Depressor Region (parasympathetic)
      • Reflexes eventually will recalibrate to habitual low/high bp's
    • Low Pressure Sensors (located in areas of Low BP)
      • Can increase heart rate when preload is increased
    • Respiratory Sinus Arrhythmia
      • Inspiration=HR increases
      • Expiration=HR Decreases
      • Rapid Breathing=Increased Stimulation of HR
    • Endocardial Receptors
      • Fever, Shock, Cardiac Failure, Hemorhage, Tachycardia - ALL influence
    • Other Factors (Urination)- everything else
Inotropy (change in FORCE of Contraction)
  • Frand Starling Law - more blood in=more forceful contraction (preload)
    • Overstretching-too much blood in heart (acute) decreases contractile strength
    • Dilation-long term anatomical change of the heart (becomes larger)
  • Autonomic Innvervation and Hormones (external)
    • Norepinephrine/Epinephrine - adrenal gland - Sympathetic stimulation of heart + adrenal gland = epi in blood
    • Sympathetic - always increases inotropy and chronotropy (heart rate)
    • Parasypathetic - always decreases inotropy and chronotropy (verry little on contractility)
  • Treppe - condition where Ca++ retained in cardiac tissue(Ca++Pumps not able to keep up)=more forceful contraction
  • Gas - (CO2) -
    • Low levels = increased respiration=increased heart rate via respiratory center
    • High levels = decreased heart rate (pH, O2 levels, etc.)


Vascular System Dr. Ballam 11/11/09 9:00am

  • Hemodynamics Velocity
    • Greater crolls sectional area the lower the velocity (V=Q/A)
    • Greatest summed cross sectional area is the capillaries (slowest)
    • Aorta and vena cava have greatest velocity

  • In closed tube, diameter decreases but flow constant, velocity increases but the hydrostatic pressure decreases—doesn’t alter total vessel resistance
  • Arterial plaque can decrease diameter 10-30%,
  • aortic stenosis of a valve-- total resistance could increase significantly
  • pressure on either side of the plaque has higher outward pressure while the section by the plaque decreases outward wall pressure which can make the wall want to collapse exacerbating the problem of plaque
  • Q=(P1-P2)/R R=8nL/r^4pie n=viscosity, p1=input pressure, P2=output pressure, r=radius, L=length
  • Increased radius means an increased flow if pressure stays the same
  • Increase viscosity of blood will decrease flow (Q)
  • Most resistance resides in the arterioles, so this is the place where resistance can be altered with a diameter change
    • Large % smooth muscle in walls allows changability
    • Increase diameter would increase flow through an organ
    • Vasomotor tone influenced by circulating hormones, local and central

  • Increasing length of vessel increases resistance
  • Adding vessels in parallel decreases resistance—pregnancy is a good example
  • Laminar flow reduces resistance, turbulent flow produces increased resistance
  • Turbulence is caused by
    • high velocity
    • Vessels irregularities, branching, plaque, stenosis
    • Increases resistance
    • Potentiates arteriosclerosis

  • Compliance is the function of how easily vessels or heart stretch (changeV/changeP)
  • Stretching vessel walls stores energy in the walls
  • Allows more blood to enter a vessel without increasing pressure much
  • Energy in walls is dissipated during diastole
  • Heart does not have to generate as high a systolic pressure, decreasing work load
  • If the system is stiffer, it takes much more work for the heart to create needed pressure—you want a system to be able to expand relatively easily
  • Arteriosclerosis makes the system stiffer, so the heart works much harder
  • Pulse pressure is difference between systolic and diastolic pressure
    • Increased with decreased vascular compliance—arteriosclerosis
    • Increased with greater stroke volume
  • Mean arterial pressure is closer to diastolic pressure due to time in this state
  • Cardiac index is a way of comparing cardiac output between individuals of different body sizes—take cardiac output and divide by body surface area (CI=CD/BSA) avg is 3

Thursday 11/12/09
Dr. Ballum Central Control ov CV 9:00
Central Control of Cardiovascular System

Originates in Vasomotor Center of Brain (influences the Heart + Vasculature)

TPR - dependent on sympathetic tone - pressor region is either increased or decreaed
Afterload - pressure needed to eject blood from ventricle (during systole-NOT systolic pressure) - varies throughout contraction
  • Dependent Largely on TPR (some pharmacologists relate TPR=Afterlaod)
Neural Control - changes vessel caliber to change BP via barroreceptors
  • Baroceptor Reflexes -
    • Act in Seconds
    • Reset w/in a few days (habituate to new high BP)
  • Limits Increases and Decreases in BP
Can control Venous vasculature
  • Venous constriction=increase preload=increase contractility=increase SV=increase BP
  • Small % change significantly changes preload (does impact TPR but not significantly)
    • Main impact of Constriction Arterioles is TPR (does impact Preload but not significantly)
Decrease BP>Decreased Baroreceptor Firing>Reduced Pressor Inhibition=(increase activity)>arteriole/venous constriction
Increase BP>Increased Baroreceptor Firing>Increased Pressor Inhibition=decrease activity>arteriole/venous dilation
Sympathetic Stimulation (vasculature)
  • Release of Norepinephrine/Epinephrine>Alpha Receptors>contraction of arterioles
Parasympathetic - little control of TPR
Adrenal Glands - Nor/Epi - Beta 2 = dilation, Alpha Receptors=vasoconstriction (depends on tissue), also Beta-1 of Heart (high concentrations)
Low Pressure Baroreceptors - atria and pulmonary circulation
  • Increase Atrial Volume>Increase HR
  • Vasodilation and renal fluid excretion (different from atrial receptors)-may "put on brakes" when other reflexes are to strong
Imputs to Vasomotor Center (reflexes from tissues to CNS) - local vs central control - tissue needs are generally overriddein by BP regulation (not in heart or brain)
  • Autoregulation (myogenic)-
  • Shear Stress
  • Metabolic (reactive hyperemia)
Measurement of Measuring Blood Flow
  • Dilution of the substance is measured over a certain distance
    • Thermal Dilution (most often) -temperature
    • Dye Dilution - dye - change in color
    • Fick (O2) - O2 level-before and after lungs (O2 put in before lungs/lungs add O2/ Level measured w/ lung addition taken into consideration)
Increase HR=reduced duration of Action Potential - allows heart time to adequately fill
  • 75 beats/min and greater heart doesn't have time to adequately fill (reduced preload)
Baroreflex - simultaneously stimulates
  • HR, Cardiac contractility, TPR, and Preload
Venous Pooling
  • Reduced preload>decreases BP
  • Reduced by muscle movement and valves in veins of legs
Cardiac Index - Normals
  • Adult-3.5
  • Child-5
  • Neonate/Elderly - 2.5

Physiology- Pulmonary Blood Flow
Ballam- 11/13/09- 9am
Ballard- 11/13/09- 9am
-Highest pressures of the pulmonary CV system are found in the right ventricle and pulm artery.
-Pressure in R ventricle max at 24mm Hg- lowest between 0-4 mmHg
-Pressure changes less in the pulm artery with maximum the same (24mm Hg), but min is 10-16 mm Hg
-Pressure in the pulm arteries pushes blood toward capillaries, so pressure in capillaries,
-measure wedge pressure- block flow in artery with canula- pressure measured through hole in canula- actually measuring pressure on capillary end of one artery = capillary wedge pressure
-not measuring upstream pressure, but downstream capillary beds of system
-indicative of pressure in venous side of pulmonary circuit, as well as pressure in L atrium
-A further drop in pressure occurs in getting the blood through the pulm veins to L atrium
-gravity weighs blood in lungs- blood at top of lungs puts pressure on blood below, so pressure on bottom greater than pressure on top- influences capillary pressure
-Capillaries at top of lungs have least pressure, when too small, capillaries will remain collapsed during cycle
-This is called Zone 1
-Region of lung below Zone 1 has greater blood pressure- if pressure is sufficient to open capillaries during part of the cycle, called Zone 2
-At bottom of lungs, pressure sufficient to keep caps open always- Zone 3 due to increasing CO increasing pulmonary BP with vascular dilation.
-Can reverse Zone 1 to a Zone 3 with exercise
-Resistance through lungs altered using 2 primary mechanisms
1- passive involves stretching of vascular walls as pressure increases (exercise) pulmonary vascular dilates- dilation causes a decrease in resistance in lungs which decreases major increases in pulmonary BP which needs to happen to prevent edema
2- responsiveness to airway (alveolar) oxygen concentration; If O2 conc falls, vessels in that region increase resistance by constricting (hypoxic vasoconstriction) which decreases blood flow thru the affected region of the lung; If entire lung becomes hypoxic, will have global vasoconstriction, make it difficult for R heart to get blood through lungs
-Bronchial Artery- originates from L side of heart, responsible for delivering oxygenated blood to various structures of the lung.
-Part of venous end of bronchial artery empties into pulm venous circulation
-This causes a small right to left shunt (blood never went through lungs).
-Right to left shunt- when blood leaves L heart, and releases O2 at tissues, then re-enters systemic circulation w/o passing through pulmonary regions to release CO2 and take up O2 (happens with some branches of the Bronchial arteries.
-Left to Right shunt- blood travels to R ventricle without passing through a systemic capillary bed- No release of O2, and obtaining CO2
-Review fluid movements, Starlings forces, capillary fluid dynamics from previous lectures
-Fluid movement- net filtration pressure is positive and fluid continuously leaves the capillaries
-In normal conditions, fluid would be carried away by the lymphatic system
-Alveoli don’t fill with fluid because:
-surfactant lining of the lungs repels water
-interstitial oncotic pressure
-negative interstitial hydrostatic pressure in lungs- sucks fluids out of alveoli
-combined pressure favors flow of fluids out of capillaries- tends to accumulate in interstitial space
-normally, this fluid picked up by lymphatics
-in alveoli, pressures favor fluids staying out of alveoli- which is good- need to keep dry
-Normally, R heart and lungs adapt to changes induced by systemic circulation and L ventricle
-during Exercise, CO increases- R heart pumps harder to get increased flow through lungs
-pulmonary vasculature dilates to decrease resistance and keep pressures in check.
-If the left ventricle fails to pump, excess blood in lungs- can lead to increased leakage of fluid out of pulm circulation into lung interstitium
-CHF is the result of L heart failing, leading to fluids congesting into lungs, as backup worsens, R heart becomes compromised, which ultimately leads to edema in systemic circulation
-Pulmonary edema- if interstitial hydrostatic pressure becomes too great, fluid will enter alveoli
-can be caused by capillary wall inflammation, pulmonary hypertension, CHF, alveolar hypoxia
-Right heart failure- fluid backup into systemic circulation
-right ventricular failure can be either the result of defect in right heart, or L heart failure
-backup causes increased pressures expressed as elevated jugular venous pressure or edema in limbs or abd
-Pressure at sea level = 760 mm Hg. Since O2 is 21% present in atmosphere, 760 (.21) = 159.6 mm Hg
-Inspired air needs to account for water vapors, so subtract 47 mm Hg from atmospheric pressure
-Alveolar air- need to account for presence of CO2
-In expired air, O2 increases from 104 in alveolus to 120
-CO2 drops from 40 to 27 in airways, due to mixing of air upon expiration


Pulmonary Function Volumes and Flows Dr. Ballam 11/18 11:00

  • Total lung capacity is made up of a combination of volumes—tidal volume, inspiratory reserve volume, expiratory reserve volume, residual volume
  • Tidal volume is your normal resting in and out
  • Difference between tidal volume and: take a deep breath—inspiratory reserve; forced exhale—expiratory reserve
  • Vital capacity—sum of all inspired or exhaled volumes—total amount that can be moved
  • Inspiratory capacity—sum of volumes above resting capacity
  • Functional residual capacity—sum of volumes below resting capacity—from end of expiration to 0
  • Minute ventilation—breaths per minute x tidal volume
  • Alveolar ventilation—(minute ventilation) minus (dead space plus alveoli ventilated but not perfused with blood)
  • Obstructive disease—harder to blow air out than to breath it in; asthma, emphysema
    • Lungs expand beyond normal capacity
    • Increases resting volume and func. resid. vol. may increase total lung cap.
    • Breathing level is at a higher overall volume both inspiration and exhalation—your exhale doesn’t go as low as it should
  • Restrictive disease—less capable of bringing air in, less expansion; pulmonary fibrosis
    • Decrease residual volume, IRV, TLC and VC
    • Changes in support structures or ventilatory muscles
  • Diagnostic procedures
    • Measure how rapidly a person can inspire or expire
    • Measure patterns of inspiration or expiration
    • Expiratory patterns are especially useful as many diseases characterized by impact on expiration
  • Maximum Expriatory Flow/Volume Curve—measures how great of flow is produced at various points in maximum forced expiration and inspiration
    • determining at what points the air is moving most quickly
    • obstructive disease—after deep inspiration, expiration flow is highest early and decreases below normal late—curve shift left
    • restrictive disease—expiratory peak flow is less than normal since you don’t have as much air in the system to start—we do not have to interpret this curve
  • FEV—Forced Expiratory Volume
    • How long it takes to blow out all possible air after max. inspiration
    • Volume expired after 1 second is FEV1; 2 sec FEV2, etc.
  • FEV1/FVC(forced vital capacity)—volume of air out in 1 sec divided by total amount of air expired—that % is compared to normal known values
    • Obstructive disease FEV1 reduced; FEV1/FVC reduced
    • Restrictive disease FEV1 normal; FEV1/FVC normal or above normal

BIOCHEMISTRY (1 PRE-MID TERM/1 POST-MID TERM)


Biochem- 11/3/09- Siedler
RBC's ATP - for Na+ (swell up and explode /Ca+=activate proteases and degrades
  • -Erythropoeisis- 13 steps through bone marrow to make RBC's
  • Erythropoetin - hormone from kidney that stimulates erythropoesis
  • -After 120 days, new round of blood cells regenerated.
  • -Outer surface membrane must be deformable, because it’s larger than vessels-
  • -Hemoglobin- four polypeptide chains = tetramer (RBC's are 37% hemoglobin)
  • -75 % alpha helix- most stable secondary structure
  • -Beta strands- think sticky- would not want stickiness in hemoglobin because they contact
each other frequently.
  • -4 structures communicate to bind oxygen quickly (cooperativity)
  • -4 porphoryn ring structures where Oxygen actually binds
  • -Types of subtypes of globin chains- on different chromosomes
  • -Alpha like chains: Alpha(4 alleles) and Zeta (2 alleles)
  • -Beta like chains- Epsilon, Gamma, Delta, Beta
    • Very mutable-hundreds identified
    • Beta Thalasemia - too few hemoblobin synthesized (wiki)
    • Sickle Cell- beta chain "misspelling" of sequence
  • -Fetal hemoglobin (HbF)- Alpha-2 Gamma-2 (memorize!)
  • -tetromers consist of two alphas and two betas
  • -Hemoglobin A(HbA1)- Alpha 2- Beta 2 (adult hemoglobin)
  • -Hemoglobin A2- Alpha 2, Delta 2 (1% or less)
  • -Hemoglobin A1C – sugar reacts with hemoglobin- glycosylated hemoglobin- injury to protein- elevated in diabetics- accumulates over months
  • -Porphyrin rings structure- contains iron for O2 binding- released in tissues in mitochondria
  • -Heme- heterocyclic (made of C and N) tetrapyrrole (plate); planar and hydrophobic- sticks into hydrophobic inner portion of molecule, bound to globin chain (noncovalently, but very tight) =Coordination Complex
  • -One Iron atom per chain, four per tetrameric molecule
  • -conjugation system of heme allows for binding of light, giving it red color.
  • -Iron held by four nitrogens- Iron only in 2+ form ;
  • -Iron builds up in mens systems, can contribute to aging process, builds up without removal.
  • -When Iron goes from 2+ to 3+, it becomes toxic- met-hemoglobin
  • -Met hemoglobin repaired fairly quickly. (by met-hemoglobin reductase in our cells)
  • -Histidines at F8 (proximal) and E7 (distal)- (8 aa on F helix and 7 aa on E helix)
  • -CO can easily compete with O2 for the iron- histidines were developed to prevent binding of CO
  • -Proximal histidine binds to iron, pulls out of plane
  • -Nitrogen forms kelation bonds to iron- forces iron to pop out of plane, 6th bond (when O2 binds) pulls Fe back into plane.
  • -No oxygen- Iron out of plane, O2 comes in, pulls iron into plane, drags histidine with it, shifts F,G along C- significant conformational change occurs- all depends on movement of iron into and out of plane
  • -conformational communication, changes affinity of other subunits to bind oxygen.
  • -changes at the alpha 1 beta 2 interface- ???
  • -Myoglobin- monomer in muscle- one Heme Fe 2+; myoglobin curve hyperbolic, hemoglobin sigmoidal (for cooperativity)
  • -Function of Hemoglobin- allosteric control- binding of O2 controlled by other chemicals (protons, CO2, BPG)
  • -2,3 BPG = DPG- (bisphosphoglycerate)- comes from shunt off of glycolysis (1,3 BPG)- isomerizes to 2,3 BPG
  • -Presence of BPG determined by altitude.
  • -RBC environment- H+ drops, CO2 increases; as you burn fuel, oxygen driven off of molecule (allosteric regulation)
  • -Allosteric control- binding of substances to sites other than active sites which regulates control of active site- CO2 doesn’t bind to iron, but changes affinity of iron to Oxygen
  • -Cooperativity- multi-subunit proteins only (not myoglobin), conformational change in one subunit induces change in another.
  • -Dynamic contact points- F/C to G subunits of adjacent molecules ???.
  • -Effects of H+, CO2, 2,3 BPG- allosteric control, bind to distant sites, regulate O2 affinity, all shift curve to R
  • -Fetal Hg doesn’t bind BPG, so it shifts the curve to the left.

Biochem- Acid-Base Balance
Dr. Chang- 11/17/09

Remember these numbers:
  • pH of blood: 7.4
  • PaCO2: 40 mm Hg
  • HCO3: 25 mEq/L or mol/L (MM)
-Changes in pH affect protein function and enzyme activity, CV function, tissue oxygenation
-Normal metabolism generates CO2
-kidneys maintain bicarbonate and excrete H+ in urine- regulate RBC production
-Acids release H+ ions, bases accept H+ ions
  • strong acids like H2SO4 and HCl dissociate completely in solution
  • a weak acid is a conjugate acid, dissociates into H+ and anionic component (A-) = conjugate base
  • Ka is the equilibrium constant for a dissociation of a weak acid

-pH = -log [H+] in units of molarity
  • pH 7 = 1 X 10^-1 M
  • -0.1 HCl, [H+] = 10^-1 M, so pH =1
Ka = [H+] [A-]/[HA]
pH = pKa + log [A-]/[HA] Henderson- Hasselbach Equation
When pH = pKa, at halfway point on titration curve
-Zwitterionic form- overall charge is 0, one positive and one negative balace out
-Buffers
  • Hb- main bufereing action: Erythrocytes
  • proteins: Intracellular
  • Phosphate buffer: Intracellular
  • Bicarbonate: Extracellular
-Bicarbonate Buffer system:
  • CO2 major source of metabolic acid- reaction occurs spontaneously in plasma
  • Catalyzed by carbonic anhydrase in RBC
  • CO2 + H20 (with carbonic anhydrase) <--> H2CO3 (carbonic acid) <--> HCO3- + H+ (bicarbonate)
  • ph = pKa + log [Bicarbonate]/PaCO2 X 0.03
    • pKa: 6.1: buffer acid equals 0.03 X the PaCO2 in mmHg
    • Approximate Plasma normal
      • ph 7.4, [Bicarb] = 25, PaCO2 = 40mm Hg
-With excess H+ (pH falls), excess CO2 is eliminated through lungs (breath faster)
-With Excess OH (pH rises), decrease in H2, decreasing PaCO2, compenstate by breathing slower to retain blood (breath slow)
-Plasma bicarbonate concentration is controlled by the kidneys and RBCs because both contain carbonic anhydrase
  • Acidemia- excess H+, buffered by phosphates or proteins , exchanges K+ ions to maintain charge
  • Alkalemia- same, but with K+ entering cells to maintain charge
-70% of CO2 produced in tissues dissolves in water and esbablishes equilibrium with carbonic acid/bicarb
  • 20% carried as carbamino groups on Hb molecules, 10% travel dissolved in plasma
  • same reaction occurs in RBc, but much faster due to carbonic anhydrase
  • H+ ion resulting from dissocaition of H2CO3 is buffered by Hb and HCO3- moves to plasma in exchange for Cl- ion
  • This is called the chloride shift
Acidosis- increased H+, decreased pH
  • decreased HCO3- metabolic acidosis
    • compensate by decreasing pCO2- hyperventilation in minutes/hours
  • increased pCO2- respiratory acidosis
  • both of these take minutes to hours to occur
Alkalosis- decreased H+, increased pH
  • increased HCO3- metabolic alkalosis (compensate with hypoventilation takes minutes/hours)
  • decreased pCO2- respiratory alkalosis
Acid/Base disorder
Primary change
Compensatory Change
Timescale of compensatory change
Metabolic Acidosis
Decrease in plasma bicarbonate concentration
Decrease PaCO2
(hyperventilation)

Minutes/hours
Metabolic Alkalosis
Increase in plasma bicarbonate concentration
Increase PaCO2
(hypoventilation)

Minutes/hours
Respiratory Acidosis
Increase in PaCO2
Increase in renal bicarb reabsorption
Increase in plasma bicarb concentration

Days
Respiratory Alkalosis
Decrease in PaCO2
Decrease in renal bicarb reabsorption
Decrease in plasma bicarb concentration

Days
Kidney- Acid base balance
  • made up of millions of tubular structures known as nephrons
  • 3 parts to remember- proximal convoluted tubule, glomerulus, and distal convoluted tubule
    • glomerulus filters ensure Bicarb stays in your system, absorbed by proximal renal tubule
    • bicarbonate absorbed from glomerulus, converted to CO2 and H20 (with carbonic anhydrase)
      • CO2 enters PRT, combines with water to form carbonic acid
      • H+ splits off leaves PRT, and re-enters glomerulus to convert more bicarbonate
      • remaining bicarbonate re-enters blood stream
      • general function to reabsorb bicarbonate
      • Hydrogen ions used to regenerate more bicarbonate
    • at DRT, CO2 enters combines with water to form acid again, which splits
      • carbonic acid splits into bicarb which goes back into blood
      • general function to expel H+ ion that results, exhanged with Na+ to maintain neutrality
-Anion Gap- defined as the amount of anions not balanced by cations
  • calculation necessary in all cases of metabolic acidosis
  • Anion Gap = [Na+] - ([CL-] + [HCO3-])
  • Normal is 8-16 with a mean of 12
  • High anion gap indicates presence of unaccounted for anions

-Osmolal Gap- (measured osmolality - calculated osmolality)
  • 2X Na+ (mEq/L) + glucose (mg/dL)/18 + BUN (mg/dL)/2.8 BUN = WTF
  • seriously? we learned this after the freaking bell



Control of Breathing--Dr. Karius
  • Innervation of the diaphragm is by the phrenic nerve (C3-5)
  • The brain controls the frequency and pattern of breathing
    • medullary centers
      • DRG: dorsal respiratory group
        • nucleus of the solitary tract
        • responsible for inspiration
        • 95% premotor to phrenic--mainly sensory information
      • VRG: ventral respiratory group
        • responsible for both inspiration and expiration
        • rostral portion--premotor to phrenic nerve
        • caudal portion--premotor to upper airway
          • expiration is passive for the ribs and diaphragm
          • expiration is active for airway musculature
      • PRG: pontine respiratory group
        • located in the pons
        • responsible for both inspiration and expiration
        • responsible for the transition time between
        • lesions to this area produce apneutic changes in the respiratory rhythm (cannot release inspiration)
      • Botzinger Complex
        • expiratory nuerons
        • do not really need to know this--only for location purposes
      • Pre-Botzinger Complex
        • located in the gap between the Botzinger Complex and the VRG
        • believed to be the site that generates the time of the respiratory rhythm
    • effectors--respiratory muscles
    • controlled variables--CO2, O2, pHa (arterial pH)
    • Sensors
      • normal response for respiratory neuron to increase in CO2/decrease in O2
        • decrease in activity, causes a decrease in ventilation, a decrease in gas exchange
          • this only makes the problem worse
      • chemoreceptors are designed for the opposite
        • increase their firing rate in hypoxic or hypercapnic situations
        • this will activate the respiratory centers and increase respiration
      • 2 types of chemoreceptors
        • central (brain)
          • ventral surface of the medulla
          • indirectly sensitive to CO2 in the blood (crosses the blood brain barrier)
            • as CO2 reacts with water, carbonic anhydrase changes it to H and HCO3
            • this receptor detects the H ion
            • drive to breathe--makes you breathe regularly
          • not sensitive to O2 or arterial H (pH changes)
          • only sensitive to pH changes in the local CSF
          • slow responders
        • peripheral (carotid and aorta)
          • directly sensitive to O2, CO2, and H
          • quick responders
          • increase the firing rate of afferent nerves
          • increases the tidal volume
      • stretch receptors
        • slowly adapting pulmonary stretch receptors
          • located in the airways
          • sensitive to the stretch of airways
          • affects the vagus nerve
          • causes inhibition of inspiration (causes termination) and prolongation of expiration
          • when the volume is too big, the lungs are stretched too far
            • reflex is to stop inspiration and increase the expiration to get rid of the air
          • important for controlling respiration in infants and adults during exercise
            • not important for controlling tidal volume in adults at rest
        • rapidly adapting pulmonary stretch receptors
          • located in the airways
          • sensitive to irritation or foreign bodies in the airway
            • also sensitive to stretch
          • fibers travel to the vagus nerve
          • causes the cough reflex
            • cough is also created by receptors at the larynx
        • J receptors
          • located near blood vessels of the alveoli
          • sensitive to pulmonary edema
          • fibers travel to the vagus nerve
          • causes the cough reflex and tachypnea
        • rapidly adapting pulmonary receptors and J receptors are protective reflexes that OVERRIDE the normal respiratory control system
          • VERY IMPORTANT FOR SURVIVAL!!
      • cortex also influences breathing by bypassing the medullary centers and sending input directly to the muscles of respiration
        • reason you can take a breath/hold your breath voluntarily


INTERNAL MEDICINE (1 PRE-MID TERM/10 POST-MID TERM)

Normal ECG Dr. Johnston 11/17/09 8:00am

  • ALL waves on AVR are inverted when normal
  • P wave is a result of atrium depolarization--it is upright on ECG 1,2,V4-6, AVF, inverted for AVR, variable on others. If AVR upright think AV node rhythm
  • PR Inverval from start of P wave to QRS complex--.12-.20 seconds—short is indication of pre-excitation, conduction of signal is not right
  • QRS Complex is ventricular depolarization .05-.10 sec; Q .03 sec.—small 1-2mm Q normal in 1, AVL, AFV, V5, V6
  • ST segment after QRS
    • Usually isoelectric to baseline
    • Normal is up no more than 1mm leads 1-3; 2mm V1-6 or down more than ½ mm
    • some populations have different “normal”—black healthy athlete
    • more than ½ mm depression (subendocardial injury) or elevation (subepicardial injury)
  • T Wave is ventricular depolarization—upright rounded; 1,2,V3-6; variable 3, AVL, AVF, V1-2—not more than 5mm standard leads, 10mm chest leads
  • QT Interval starts with Q to end of T wave (ventricular systole)
  • Know the pattern for how the electrical impulse travels through the heart
  • Each bold black line on ECG is 5mm .20 sec.
  • Prominent U wave associated with low potassium
  • 11 EKG features
    • Rate
    • Rhythm
    • Axis
    • P-Wave
    • PR Interval
    • QRS Interval
    • QRS Complex
    • ST Segment
    • T-Wave
    • U-Wave
    • QT Interval
  • QT Interval varies with age, race, gender—charts to help interpret these—usually less than ½ of the R to R interval
  • There are variations—be sure to look at several beats and different leads to determine a pattern
  • Short PR Interval—pre-excitation; long PR Interval--AV block
  • Broad, notched, fat P-wave can be a problem with L atrial enlargement (mitral valve disease, stenosis, regurgitation, rheumatic fever)
  • Tall, pointed P-wave on 2, 3, AVF—P Pulmonali; right atrial disease (COPD, Emphysema, pulmonary emboli)
  • Huge upward T-wave across several leads probably telling you about MI
  • To calculate the rate find QRS on dark line and count blocks (5mm) to the next QRS; take 300 and divide by that number (i.e. 300/3.5=85 bpm)
  • Inverted P-wave in lead 2, variable in 3, upright AVR—another pacemaker has taken over; the SA node is not determining the rhythm (nodal rhythm)
  • Wolf-Parkinson-White syndrome—genetically disposed to fast arrhythmia; pre-excitation syndrome; the AV node is being bypassed
  • R, S, Rprime, Sprime—bundle branch block; interfering with conduction
  • Don’t treat the paper, treat the patient