Thoracic Bones & Joints

Ribs True ribs 1-7 Vertebrocostal Costal cartilage articulates directly with sternum False ribs 8-12 Vertebrochondral Costal cartilages do not attach directly with sternum Ribs 8-10 articulate with the costal cartilage above them forming the costal margin Floating/free ribs 11 & 12 Osteology Typical 3-9 Contain a head region that attaches to the vertebral body and a tubercle that articulates with the TVP of the vertebrae Atypical 1 & 2, 10-12 Misc. Fx generally occur at the weakest area just anterior to the angle of the rib Dislocation occurs when costal cartilage is displaced from sternum Seperation is dislocation of the costocondral joint Intercostal Space Named by the rib above it Vascular bundle runs in each groove and contains in order from superior to inferior: Intercostal Vein Intercostal Artery Intercostal Nerve Bundle splits and the intercostal bundle runs below the superior rib and the collateral bundle runs above the inferior rib Collateral bundle is a mirror image of intercostal bundle ("NAV") Thoracocentesis must be performed in the exact center of the intercostal space to avoid damaging either bundle

Sternal Angle Angle of Louis Between manubrium and sternum Aortic arch begins and ends behind angle Trachea bifurcates into L/R bronchi Landmark for heart sounds

Diaphragm Chief muscle of inspiration Innervated by the phrenic nerve (C3-C5; motor) and intercostal nerves (sensory) 3 openings Vena cava foramen (T8) Esophageal hiatus (T10) Aortic hiatus (T12)

Thoracic Vertebra Only T2-T9 contain demifacets (superior & inferior) T1 contains a superior costal facet AND a typical inferior demifacet T10-T12 contain bilateral costal facets Vertebral Fx due to osteoporosis `Presents as excessive thoracic kyphosis "Dowager's Hump" Treatment Kyphoplasty Inflation of a balloon within the vertebral body followed by filling cavity with bone cement Vertebroplasty Direct injection of bone cement into vertebral body (without balloon inflation)

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Thoracic Cavity & Lungs

Lymphatic Drainage Sternal/parasternal nodes (internal thoracic) Found along thoracic artery Intercostal nodes Phrenic nodes Diaphragm Pleura Parietal pleura Adhered to thoracic wall, mediastinum and diaphragm 4 parts: Costal Mediastinal Diaphragmatic Cervical Visceral pleura Adherent to lung Thoracic Cavity Has three compartments Two lateral compartments (pleural/pulmonary) Contains lungs and pleurae One central compartment (mediastinum) Contains all other thoracic structures Further divided into: Superior mediastinum Level of T4/T5 to superior thoracic aperture Contains: Thymus Can present as "sail sign" in child, looks like enlarged cardia shadow Arch of aorta Trachea etc. Left recurrent laryngeal nerve (branch of vagus n., loops under the aorta) Inferior mediastinum Anterior Middle Contains Pericardium Heart Posterior

Mesothelioma "asbestos cancer" Patients present with pleural effusion, dyspnea and chest pain Neoplastic cancer growing within the pleural space

Clinical Correlates Lacerations 2-3 cm above the medial clavical may penetrate the pulmonary cavity, causing pneumothorax Pleuritis Inflammation of pleura Upon auscultation, pleural rub is heard Can result in pain and adhesions Pleural recesses Pericardiocentesis is performed where the pericardium is in contact with the thoracic wall on the left side near the 5th rib Thoracocentesis is performed on the left side around the 9th rib

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Superficial Heart
Pericardium Double layered sac: Outer fibrous covering Double-walled serous layer Parietal layer next to fibrous covering Visceral layer next to heart Blood supply Pericardiocophrenic artery and vein Azygous vein Innervation Vagus n. Sympathetic trunks Vasomotor Phrenic Sensory/pain Serous Pericardium-Visceral Layer Transverse sinus Transverse space between the artrial and venous mesocardia Behind aorta & pulmonary trunk but in front of superior vena cava Oblique sinus Space behind the entire heart (posterior) Heart Organization Pulmonary trunk is anterior Aorta is posterior Mitral valve is left ventricle (L w/ L) Tricuspid is right ventricle Semilunar valves separate ventricles from arteries Mitral & tricuspid separate atria from ventricles

Anterior = top; posterior = bottom. P = pulmonary, A = Aorta, M = mitral, T = tricuspid.

Projection of Pericardium & Heart on Body Wall Pericardium 2nd rib - 5th intercostal space 2cm to left and right of sternum Heart 3rd rib - 5th rib Pericardiocentesis Upper left of xiphochondral junction Just to left of xiphoid process Angle needle in posterosuperior direction

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Surfaces of the Heart Coronary Arteries/Veins Sternocostal Branches of the right coronary artery Anterior Sinoatrial nodal branch Little of RA & RV (pressed during Conus branch Right marginal branch CPR) Diaphragmatic Atrioventricular nodal branch Inferior Atrial branch L & RV Posterior interventricular branch Pulmonary Branches of the left coronary artery Left Left anterior descending (LAD) LV & LA Circumflex Right Main cardiac veins RA Coronary sinus Base Anterior cardiac veins Top of the heart L & RA, great vessels Apex Bottom left (tip of left ventricle Sulcus terminalis Depression on the surface of the RA SA node resides here Coronary sulcus Seperation of atria & ventricles Interventricular sulci Anterior and posterior grooves indicating the interventricular septum Sulcus terminalis Shallow vertical groove seperating RA and superior vena cava

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Heart Interior
Primitive Circulation/Atrial Formation Umbilical vein carries oxygenated blood to the fetus Umbilical artery carries deoxygenated blood away from the fetus Heart tube folds, creating ventricles anterioinferiorly Atrium partitioning 1st atrial septum (septum primum) grows down from the top of the heart towards the cushion Endocardial cushions Develop from ant/posterior walls Divide atria and ventricles Top portion of the septum primum is obliterated Septum secundum grows down and never becomes Ventricular Partitioning complete, leaving an oval opening (foramen ovale) Muscular interventricular septum Forms one-way valve allowing blood to pass grows from apex of heart up from right to left atrium towards atria 90% of atrial septal defects are closure Stops short creating problems in the foramen ovale interventricular foramen Openings in the right atrium Closed by migratory neural Superior/inferior vena cava crest cells to form Coronary sinus (valve of Thebesius) membranous I.V. septum Fossa ovalis, located on the right, interatrial septum Ventricular septal defects are often Remnant of the fused foramen ovale seen w/ Fetal Alcohol Syndrome 90% VSD's are found in the Papillary Muscles membranous portion Three in the right ventricle (attach to tricuspid valve) Anterior attaches to anterior and posterior cusp Left Ventricle Posterior attaches to posterior and septal cusp 2-3x thicker than the right ventricle Septal attaches to septal and anterior cusp Covered by trabeculae carnae Attached through chordae tendineae Both papillary muscles in the left ventricle (anterior & Aortic sinuses house the openings to the right & left coronary arteries posterior) attach to both cusps of the mitral valve respectively (anterior & posterior)

Semilunar Valves Each cusp has a: Central nodule Lunula Curved border moving away from nodule

Right Ventricle Also covered with trabeculae carneae Septomarginal trabeculae Contains part of right conducting bundle Partially gives rise to the anterior papillary muscle

Conduction System
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Conduction System SA node is located at the junction of the SVC and the RA, above the terminal crest AV node depolarizes the Bundle of His Transfers AP from atria to ventricles Bundle of Kent Bypasses th AV node if conduction through AV node/Bundle of His isn't operating properly Wolff-Parkinson-White See a delta wave on EKG Cardiac Plexus SA node is innervated by the right half of the cardiac plexus AV node is innervated by the left half

Delta wave visible in QRS

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Posterior Mediastinum
Contents of Posterior Mediastinum Thoracic aorta and branches Esophagus & nerve plexus Azygous venous system Splanchnic nerves Thoracic duct Sympathetic trunks

Aorta Descending begins at sternal angle (T4/T5) Left of vertebral column Branches Bronchial AA. Esophageal AA. Posterior intercostal AA.
Vagus Nerve Right Vagus N. Enters thorax between brachiocephalic trunk & vein along the right side of the trachea Right recurrent laryngeal passes under the right subclavian Passes posterior to root of the right lung spreading into posterior pulmonary plexus Left Vagus N. Enters thorax between left common carotid & left subclavian AA. Left recurrent laryngeal passes under the aortic arch & ligamentum arteriosum Passes posterior to root of left lung and joins posterior pulmonary plexus Forms: Posterior pulmonary plexus Esophageal plexus Cardiac plexus Trunks Anterior Vagal trunk Forms anterior gastric plexus Posterior Vagal trunk Forms posterior gastric plexus

Esophagus Has a reverse S course Slight curve to the left high, right middle & left again in the lower thorax Relations Cervical Posterior to trachea, which is posterior to thyroid, carotids & laryngeal NN. Thoracic Posterior to aorta which is also slightly to the left, along with the thoracic duct Azygos vein is anterior and slightly right of the esophagus Abdominal Esophagus is to the left of the midline Blood supply Branches off the aorta Innervation Recurrent laryngeal Cervical sympathetics Vagus N.

Azygous System Drains posterior Thorax and abdominal walls

Splanchnic Nerves 3 Thoracic splanchnic nerves: All three pierce crus of the diaphragm Greater splanchnic N. T5-T9 Lesser splanchnic N. T10-T11 Lowest splanchnic N. T12 Ends in renal plexus

Thoracic Duct Lies between aorta & azygous vein Moves to the left of the midline at T4 Connects to left subclavian & left brachiocephalic veins Arises at T12 Union of left & right lumbar trunks Drains: Everything except right side of head & neck, & right arm (Right lymphatic duct) Cisterna chyli Dilation of distal (caudal) thoracic duct L1-L2 Posterior to esophagous in the thorax

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A. B. C. D. E.

Esophagus Aorta Azygous vein Hemiazygous vein IVC

CT at T7

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Basic Blood
RBCs are approx. 8 m in diameter RBC Maturity Hematocrit New RBCs are a bit larger and don't quite have the biconcave % of RBCs in plasma disc shape A large % of young RBCs (reticulocyte count) indicates recent hemorrhage or hemolysis and possibly pathological condition Smears vs. Sections >1.5% Smears contain better cell detail The relationship between cells in only visible on a section

Spectrin-Ankryin System on the RBC membrane that gives it it's biconcave shape Glycophorin on the outside is very hydrophilic and prevents RBCs from sticking to each other Spherocytosis is a lack of Spec-Ank system Centrifuged Blood Plasma is the liquid portion, not having clotted Serum is the liquid portion of the blood if the blood HAS clotted Buffy coat contains the WBCs and platelets

Granulocytes Neutrophils Pursue and kill bacteria Contain specific granules: Collagenase Lactoferrin Lysozyme Mostly hang onto vessel walls until stress hormones rise Can also give their lives by shooting out their DNA creating bacterial "nets" Live for about 3 days Eosinohils Kill worms Contain basic granules ("love acid" stain) Identified by saucer shaped granules Basophils Contain acidic granules ("love base" stain) Specific granules are Histamine Heparin Basophils flow in the blood, mast cells are found in the tissue

WBCs All are larger than RBCs Typically divided into two groups: Granulocytes Basophils Eosinophils Neutrophils Also called polymorphonuclear leukocytes Agranulocytes Lymphocytes Monocytes

NEUTROPHIL

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EOSINOPHIL

BASOPHIL

EOSINOPHIL NEUTROPHIL

Agranulogytes Lymphocytes Mostly B and T cells Contain one large nucleus Monocytes Precursors to tissue phagocytes and dendritic cells Nuclei are large but kidney shaped

BASOPHIL

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MONOCYTE (similar kidney shaped nuclei on EM)

LYMPHOCYTE

Platelets (Thrombocytes) Lack a nucleus Much smaller than RBCs Granulomere is the area inside the platelet cell, surrounded by the clear hyalomere zone There is also a system of canals beneath the hyalomere called the open canalicular system Platelets release their granules (clotting factors) rapidly using this system (platelet release reaction) Platelets live for about 10 days

PLATELET (arrows indicate hyalomere)

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Heart
Heart Tunics Endocardium Inside Myocardium Middle Red Epicardium Outside

Endocardium Contains three components Endothelium Innermost component Single layer of squamous endothelial cells Subendothelial connective tissue Thin layer of loose connective tissue Subendocardium Contains some vessels & nerves Purkinje fibers (conduction fibers) Purkinje fibers are paler than other myocytes Endocardium thickness differs between the atria (thick, needs more support due to less myocardium) and ventricles (thinner)

Endocardium at the top with mostly myocardium (M) at the bottom. PF = purkinje fibers; CT = connective tissue (subendothelial CT at top).

Cardiac Cell Structure Contain 1 T-tubule and one terminal cisterna of SR to form diad 40% of the cytoplasm contains mitochondria

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Epicardium (Visceral pericardium) Contains: Mesothelium Epithelium lining the walls & contents of the closed cavities of the body (in this case, the heart) Connective tissue with nerves & vessels Adipose tissue Hallmark identifier for epicardium
Cardiac Skeleton Roles: Keeps valves patent Attachments for leaflets and cusps of valves Attachment for myocardium Electrical "insulator" seperating atrial and ventricular conduction Parts: Annuli fibrosae 4 rings that surround valve openings Trigona fibrosae 2 triangular masses connected to the annuli fibrosae Septum membranaceum Dense fibrous plate that forms parts of interatrial and interventricular septa

EPICARDIUM

Valve Histology Chordae tendineae Connect cusp free edge of AV valve to papillary muscle Has a dense connective tissue core with a thin endocardium covering Papillary muscle Myocardial bundle Semilunar valve Folds of endocardium Lined by endothelium

Annuli fibrosae (circles); Trigonal fibrosae (triangles); Septum membranaceum (SM & dotted line)

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Respiratory System
Wall Structure Respiratory Epithelium Ciliated pseudostratified columnar Goblet cells Lamina propria Loose CT Seromucous glands Elastic fibers Bone/cartilage Smooth muscle Adventitia Collagen & elastic fibers Adventitia is the outermost connective tissue covering any organ Lamina Propria Seromucous glands Some cells are serous & others mucous Found from nasal cavity to bronchi Elastic fibers Increase towards alveoli Skeletal CT Prevents respiratory tube collapse Smooth muscle Regulates luminal diameter Cartilage & smooth muscle is lost as you decend while elastic fibers increase Respiratory Epithelium 5 Cell types 1. Ciliated columnar 2. Goblet cells Secrete hydrophilic glycoproteins (mucin, extrecellularly become mucus) 3. Brush cells Other columnar-shaped cells Base has afferent nerve endings 4. Basal cells Small round stem cells Give rise to ciliated columnar, goblet, & brush cells 5. Small granule cells Numerous granules of peptide hormones & catecholamines DNES cells (diffuse neuroendocrine system) Secretions (granules) exert paracrine effect on other cells Brush and granule cells are often not identifiable Primary Ciliary Dyskinesia Immotile ciliary syndrome Infertility in men, chronic respiratory infection in both sexes Cilia & flagella are immobile Smoker's respiratory epithelium Metaplasia changes cells to stratified squamous Decrease movement of mucus

1.

2. 3.

4.

Recurrent Laryngeal Nerve The left recurrent originates from the left vagus nerve at the aortic arch and loops under the it Posterior to the ligamentum arteriosum It then ascends to innervate the larynx (motor) for vocalization Due to the innervation of the larynx, if something is affecting (compressing) the nerve, patient will present with hoarseness, cough etc. Damage or tumoral involvement Lung cancer Aneurysm of aortic arch
G=Goblet; B=Basal; BM=Basement Membrane; C=Ciliated Columnar

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Trachea Diagnostic feature is 16-20 C-shaped rings Hyaline cartilage Posterior ends bridged by: Fibroelastic ligament Tracealis muscle Narrows during cough reflex Smaller diameter increases the velocity of expired air Identification Respiratory epithelium Seromucous glands Blood vessels Hyaline cartilage Chondrocytes

Trachea BALT Bronchus associated lymphoid tissue

Bronchi Main differentiation is presence of alveoli Still has cartilage & smooth muscle Each succesive branches of bronchi have less cartilage (islands of cartilage) Bronchial pulmonary segment Anatomical, structural & surgical unit of the lungs A surgeon can resect a segment w/o seriously damaging the surrounding lung

Bronchioles Differ from bronchi in the absence of cartilage and glands Terminal bronchioles NO GOBLET CELLS! Contains ciliated cuboidal Clara cells Secrete Clara cells secretory protein (CCSP) and lung surfactant Detoxify harmful substances Smooth muscle can change the airway resistance Shunt air to areas w/ good blood supply Innervation Parasympathetic fibers are from Vagus N. (CN X) and stimulate bronchial constriction (GVE) Sympathetic fibers cause dilation (GVE) GVA fibers carry pain, airway irritants & cough reflex

Dead Space Conducting airways are dead space No gas exchange occurs ~150ml of air (a breath is usually 400ml)

Respiratory Portion Alveoli start to popup in the respiratory bronchioles Followed by alveolar ducts & sacs Main differentiation of respiratory bronchioles (from terminal bronchioles) is the presence of alveoli

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Alveolar Gas Exchange Ventilation Volume of air reaching the alveoli ~4L Perfusion From right ventricle ~5L blood/min Diffusion of each gas (O2 & CO2) is independent of one another

Alveolar Ducts & Sacs Alveolar sacs are clusters of alveoli Smooth muscle is no longer present Structural support is provided by elastic & reticular fibers
DLO2 Diffusion capacity for oxygen of the lung Measure using carbon monoxide (CO) DLO2 = 1.23 x DLCO

Alveoli Alveoli are seperated by interalveolar septa that consist of two simple squamous epithelial layers w/ an interstitium (capillaries embedded in elastic tissue) between them Cell types: Type I Squamous alveolar epithelium Type II Surfactant secreting cells Surfactant creates surface tension, preventing alveolar collapse Alveolar macrophages (dust cells) Heart failure cells Alveolar macrophages that consume RBCs found in lumen due to congestive heart failure Surface area corresponds to the number of alveoli

Blood-Air Barrier Refers to the sructures that O 2 & CO2 must cross during gas exchange Includes: Cytoplasm of squamous epithelial cells Fused basal lamina of Type I alveolar cells & capillary endothelial cells Cytoplasm of capillary endothelial cells ~0.6 microns thick As distance increases diffusion rate decreases Diffusion coefficient of CO2 is 20x that of O2 O2 gas exchange will be effected pathologically much sooner than any problem with CO 2 is seen CO2 requires almost no time in a pulmonary capillary for adequate exchange O2 requires 0.25 seconds for adequate exchange Normally, it takes a RBC ~0.75 seconds to move through a pulmonary capillary, however during exercise and RBC is pushed through in 0.25 seconds If the lungs aren't in peak condition, the patient will fatigue (stress test)

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Tunics AKA layers The biggest drop in BP occurs between the arterioles & capillaries Intima Endothelium Prevents clot formation by releasing prostacyclin (vasodilator & inhibits platelet aggregation) Basal lamina Consists of type-IV collagen Subendothelial layer Media Most pronounced layer Predominantly smooth muscle Thickest in arteries Adventitia Outermost layer of collagen & elastin fibers Contains vessels and nerves Vaso vasorum Vircow's Triad "vessels of vessels" that supply the cells Factors leading to thrombosis to far from the lumen to be reached by 1. Injury diffusion 2. Turbulent Epect more vaso vasorum in veins due 3. Hypercoaguability to lower O2 content Thickest in veins Elastic Arteries Aorta & its primary branches Stretches during systole, contracts during diastole Media Smooth muscle & reticular fibers (collagen II) Adventitia Elastic & collagen I fibers Vasa vasorum ("a" for aftery) Muscular Arteries Distributing arteries Most named arteries in the body Intima Prominent internal elastic lamina Still prominent media, but not so overrun with elastic fibers (more SM)

Vascular Histology

Elastic Artery. I=intima; M=media; A=adventitia. Notice large A.

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Small Arteries Media more developed than arterioles Lumen is larger than arteriole

Arterioles Nuclei bulge into lumen 1-5 layers of smooth muscle

Arteriole Muscular Artery. Prominent internal elastic lamina (iEL).

Capillaries ~1 RBC thick Two cell types: 1. Endothelial Chief structural component Simple squamous epithelial cells 2. Pericytes Types of capillaries Continous Smooth, nonporous Cells are tightly attached Zona occludens Found in all types of muscle, brain & nerves Fenestrated Contains some pores Found where rapid exchange between tissues & blood is required Kidney, intestines etc Sinusoidal (discontinuous) Gaps between endothelial cells Abundant fenestrations Found in liver & hematopoietic organs

Large Veins
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Large Veins Superior & inferior vena cava & pulmonary veins Intima Contain valves Extensions of intima protruding into the lumen Media Sparse elastin Adventitia Best developed in large veins Veins will be flatter than arteries
Venules Media Very thin w/ few smooth muscle cells Adventitia Thickest tunic Lymphatic Vessels Look like venules May have valves CLEAR, NO RBCs!

Small/Medium Veins Intima No internal elastic lamina LOOK FOR COMPANION ARTERY!

Vein. Arrows point to valves.

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Hemoglobin
Structure Heme Group 75% -helical Composed of: Hemoglobin contains 4 globin chains (tetramer) Porphyrin ring Each globin chain contains 8 -helicies Planar and hydrophobic There is communication between chains One Fe 2+ per chain 4/hemoglobin (cooperative binding) Fetal hemoglobin contains 2 chains and 2 chains Binds oxygen Binds oxygen stronger Heme group is found between the E and F Adult hemoglobin contains 2 chains and 2 helical domains in each globin chain Adjacent histidines reduce the affinity of chains Fe for CO

Allosteric Control Regulates O2 affinity H+ (low pH), CO2 , and 2,3-bisphosphoglycerate reduce the affinity for oxygen O2 is more readily released from hemoglobin Shifts the O2 dissociation curve to the right Associated with high demand for O 2 such as in exercising muscle

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Cardiac Action Potential

1. 2. 3. 4. 5. 6.
Action Potential (AP) Review Cardiac AP Membrane potential crosses threshold Must be self generating Na+ open, Na+ enters cell Must propagate from myocyte to myocyte Rapid depolarization All or none Na+ gates close Phases of cardiac AP K+ gates open, K+ leaves cell Systole Cell repolarizes Heart is contracting Initiated by depolarization of ventricular myocytes Diastole Heart is relaxed Follows myoctye repolarization Sequence SA node Atria AV node Purkinje system Ventricles Types of cardiac APs Fast Atria, ventricles and purkinje system 5 phases 4. Resting potential 0. Rapid depolarization 1. Initial, incomplete repolarization 2. Plateau 3. Repolarization Slow SA and AV nodes Automatically depolarizes during rest phase

AP Points of Interest Usually, concentration gradients are maintained, even after several APs Changing the plasma concentration of ions usually doesn't change the net charge either because the change is usually accompanied by a equal and opposite change in the other ion species EX: most ion changes are the result of a salt, which is a positive ion attached to an equal and opposite negative ion The more beats/min, the shorter the duration of depolarization (Phase 1/2)

Fast Action Potential Caused by changes in permeability (conductance) of K+ , Na+ , and Ca+ + These changes are the result of voltage dependent gates Phase 4 Fast High K+ , low Na+ and Ca+ + permeability Phase 0 High Na+ permeability Na+ flows in Phase 1 Decreasing Na+ permeability, increasing K+ permeability K+ flows out Phase 2 High Ca+ + permeability, low K+ permeability Ca+ + gates open, K+ gates close Ca+ + flows in, offsetting repolarization by K+ Phase 3

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K+ and Ca+ + have an inverse relationship

Phase 3 High K+ permeability (causative change), low Na+ and Ca+ + permeability Timed K+ gates open, K+ flows out, repolarizing cell Duration of K+ gate timer determines length of AP/contraction force Different gates are in different areas of the heart Depolarization in Phase 0 caused the Ca+ + gates to open, the opening of the K + gates closes them Phase 4 Resting potential High K+ , low Na+ and Ca+ + permeability

Slow AP No fast Na+ gates so depolarization proceeds slowly Resting potential is closer to -60mV (vs. -80mV in fast) The amplitude of the depolarization is smaller Slow AP tissues will spontaneously depolarize slowly during Phase 4 to reach threshold without outside influence

Conduction Velocity of AP The greater the AP amplitude, the faster the depolarization in Phase 0, and the larger the cell diameter,the faster the conduction velocity Slow vs. Fast Tissue Fast type contractlie myocytes are larger diameter and have high amplitude and rapid onset AP's Fast type non-contractile myoctyes (purkinje fibers) have very large diameter with rapid upstroke Slow tissues have a small diameter with low amplitude AP's and slow depolarization

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Erythrocyte Physiology
Body Fluid Average individual contains 42L of fluid 3.5L is plasma Blood Cell Production RBCs originate: In the liver and spleen in the fetus Distal long bones and axial skeleton in the child & adolescent Axial skeleton in the adult Genesis of RBCs begins w/ the proerythrocyte Starts production of hemoglobin Progresses to erythroblast, reticulocyte (lose nucleus) and finally erythrocyte

Erythrocyte Production Each RBC contains millions of molecules of hemoglobin Stimulis for erythrocyte production: Hypoxia causes cells to form HIF (hypoxiainducible factor) HIF stimulates kidneys to produce EPO (erythropoietin) EPO stimulates bone marrow production of RBCs

Oxygen Loading Interaction among hemoglobin chains T configuration (tight) is when no O 2 is bound Converts to R configuration (relaxed) when O 2 binds Allows more O2 to bind 1 gram of Hb can transport 1.34ml O 2 (100% SO2 ) Oxygen carrying capacity (SO2 ) 1.34ml O2 x Hb (X gm/dL) = SO2 For saturation, multiply SO2 by sat. % RBCs in Solutions Hypotonic RBC size increases Isotonic Stays same Hypertonic RBC shrinks Volume change can be predicted : V 0C0 = V 1C1 V = volume; C = concentration of solution

Anemia A decreased concentration of Hb in the blood Hematocrit is linearly related to Hb concentration and is used as an index Common types: Hemorrhagic Hemolytic Aplastic Non-functional marrow Fe deficiency Pernicious B12 deficiency Energy Consumption Glycolysis Maintains electrochemical & ionic gradient Maintains membrane flexibility & integrity Resist oxidative damage through: Reduction of methemoglobin (Fe 3+) to hemoglobin (Fe 2+) Reduced glutathione protects RBC against oxidative injury to Hb and membrane

Polycythemia Excessively high RBC concentration/Hct Causes: Decreased O2 in the blood which increases the levels of EPO Genetic aberration (polycythemic vera)

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Blood-Gas Transport
O2 Dissociation Curves Fetal Hb is left shifted Addition of CO shifts curve to left Increased temperature shifts the curve to the right Higher temps in exercising tissues 2,3-bisphosphoglycerate shifts curve to the right O2 Transport in Blood 97% is attached to Hb; 3% dissolved Dissolved % is proportional to the PO2 Hemoglobin's ability to carry O2 (SO2 ) Gm Hb/dL blood x 1.34 ml O2 /gm Hb Carbon Monoxide Binds tighter than O2 to Hb CO is colorless, tasteless & odorless CO does not stimulate ventilation (unlike CO2 ) Produces a cherry-red color in the pt (versus CO2 which produces a blue color)

Solubility of Respiratory Gases PaO2 = 100mmHg in normal individual PaCO2 = 40mmHg in normal person Volume of gas dissolved is dependent on: Partial pressure of the gas Solubility of the gas Temperature Determining O2 's partial pressure: PO2 = PB x FO2 PB = barometric pressure, at sea level = 760mmHg FO2 is the decimal fraction of O 2 in the gas mixture Can be used for any gas For humidified gas subtract 47mmHg from P B

CO2 Interactions Carbamino compounds Formed as CO2 binds with amino acids of protein Reaction occurs without enzymes Unloading CO2 at the lungs (bicarbonate formation): HCO3 - in plasma is converted to CO 2 in the RBC CO2 diffuses through RBC membrane and into the alveoli at the lungs Source of CO2 evolved in the lungs: 10% dissolved CO2 30% carbamino compounds 60% bicarbonate Haldane Effect Blood w/ decreased O2 can carry CO2 better Shifts curve up Increases CO2 carrying efficiency

Haldane & Bohr Effect Interaction Oxygenated blood reaches metabolicly active tissues The Bohr effect (low pH etc.) shifts the O2 dissociation curve to the left O2 is released Release of O2 increases the CO2 carrying capacity of the blood (Haldane effect) The CO2 dissociation curve is shifted up The effectiveness of CO2 transport is increased CO2 is carried away

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Hemostasis
Steps in Hemostasis Hemostasis are the steps taken by the body to limit blood loss Four steps: 1. Vascular spasm 2. Formation of platelet plug (sometimes only need 1 & 2) 3. Formation of blood clot 4. Repair of damage Platelet Contents Actin & myosin Cell contraction Mitochondria ATP & ADP Remnants of ER Ca++ storage COX1 Fibrin stabilizing factor Platelet derived growth factor Repair Serotonin On cell membrane: Glycoproteins When activated, become sticky, adhering to other platelets

Platelets Platelets are actually cell fragments Physiological range is 150,000-300,000/um3 Production of platelets is controlled by thrombopoietin Thrombopoietin (TPO) Protein hormone (like EPO) Produced by liver & kidney Found on platelets, megakaryocytes & hematopoietic cells Increases differentiation of stem cells & maturation rate Control of TPO secretion Continually secreted Platelets bind TPO (MPL receptor) Internalize & destroy TPO A high number of platelets means a large amt of TPO is bound Very little amt of free TPO to act on megakaryocytes Little platelet production Low number of platelets has opposite effect Large platelet production

Step 1. Vascular Spasm Myogenic Direct response to injury No neurons Reflexes involved (minimally)

Step 2. Formation of Platelet Plug Collagen is exposed upon vessel damage Platelets bind to collagen in two step process 1. VonWillebrand factor Plasma protein Bind between collagen & platelet receptor 2. Binding of platelet receptor (integrin) directly to collagen Activation of platelet Platelet swells & extends podocytes Contraction releases granules from platelet Make platelets sticky Platelets bind to each other and vessel wall Thromoxane A2 & ADP

Step 3. Blood Coagulation Three steps: 1. Formation of prothrombin factor 2. Activation of thrombin Prothrombin is converted to thrombin 3. Creation of fibrin from fibrinogen Thrombin converts fibrinogen to fibrin monomer Fibrin stabilizing factor (from platelets) causes monomers to polymerize Clot retraction Excess fluid is removed from within clot Step 4. Repair of Damage Actin & myosin in platelets Platelet-derived growth factor (secreted by platelets) contract, pulling clot together stimulates fibroblast growth Requires Ca++ Fibroblasts differentiate into smooth muscle etc. to close hole

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Clot Removal Thrombin converts Protein C into Activated Protein C Activated Protein C inactivates tPA inhibitor tPA inhibitor can no longer inhibit plasminogen activator Plasminogen activator is released by damged tissue Plasminogen is converted into plasmin Plasminogen Made by liver Floating in plasma Plasmin lysis fibrin within the clot
Impaired Hemostasis Thrombocytopenia <25,000 platelets Produces spontaneous bleeding Causes: Stem cell damage Leukemia TPO or mpl gene mutation Vitamin K deficiency Genetic Hemophilia Genetic absence of clotting factor VonWillebrand's disease Congenital absence of vWF Alteration of platelet receptor of collagen molecule

Preventing Clotting Blood vessels Blood vessels have a smooth surface Prevents platelet rupture Membrane proteins Glycocalyx repels platelets Thrombomodulin changes thrombin activity Chemicals Fibrin Binds thrombin & prevents it from working Prostacyclin (PGI2) Causes vasodilation Limits platelet aggregation Antithrombin III Works as anticoagulent when bound to thrombin Heparin Derived from mast cells Increases antithrombin efficacy
Inappropriate Clotting Rough surfaces on blood vessels Blood stasis (slow moving) Thrombosis Disseminated intravascular coagulation (DIC) Clots are small/asymptomatic Clotting proteins are eventually exhausted Uncontrolled bleeding ensues

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Cardiac Electromechanical Coupling

Automaticity Some cardiac tissues will gradually depolarize during phase 4 Tissues include: SA node AV node Purkinje fibers Slow depolarization in phase 4 is due to special Na+ channels Begin opening during phase 3 Continue to open during phase 4 Cause membrane potential to gradually depolarize SA node usually depolarizes first Normal pacemaker Sinus rhythm Ectopic focus AP's originating anywhere else besides the SA node (ectopic pacemaker) In absence of ventricular depolarization, Purkinje fibers take over (overdrive suppresion) Action Potentials APs spread throughout heart as if it was one, giant cell Intercalated disks & gap junctions Termination of AP's When AP's spread throughout the tissue, they eventually meet Once they meet, they cannot proceed further as the tissue in front of them is in a refractory period Reentry When AP's never meet AP "chases it's tail" around and around the heart Fatal When AP travels from SA node through the atria, it reaches the AV node where conductance is drastically slowed down Parasympathetic further slows, sympathetic speeds up

Electromechanical Coupling AP travels along surface of myocytes AP penetrates cells via T-tubules Ca++ enters the cell from the surface and T-tubules during AP plateau The elevated intracellular Ca++ trigers more Ca++ release from the SR Different from skeletal muscle Ca++ binds to troponin & contraction proceeds
Autonomic Influences Sympathetic stimulation increases the depolarization rate Positive chronotropic effect Beta 1 receptors Norepi Increases Ca++ permeability Parasympathetic stimulation decreases depolarization rate Negative chronotropic effect Muscarinic receptors Ach Increased K+ permeability

Force of Contraction PRELOAD Frank-Starling law of the heart The more actin/myosin fibers are stretched, the stronger the force of contraction Preload is defined as the tension on the ventricular or atrial walls as contraction begins

Top is contractive force, bottom is tension force.

Physiology Page 27

Sympathetic Stimulation Causes a greater force of contraction (along w/increased speed) Increases intracellular Ca++ Norepi & cardiac glycosides (Digoxin) have same effect by inhibiting Na+/K+ pump Also increases rate of Ca++ reuptake Shortens phase 2 (systole) Parasympathetic has only a weak effect on contractile myocytes

K+/Ca++ Changes Hypokalemia Causes hyperpolarization Influences Na+/K+ pump Low K+ leads to membrane depolarization because loss of ability to pump Na+ out Needs K+ for ion exchange Hyperkalemia Partial membrane depolarization Causes a slowed AP & alters phase 3 Reduced amplitue of the AP Hypocalcemia Causes decreased contractility Hypercalcemia Increased contractility

EKG P wave AP spreading through atria QRS AP spreading through the ventricles T wave Repolarization of the ventricles Atrial repolarization is hidden in the QRS complex Repolarization in the ventricles occurs mirror-like The last cell to depolarize is the first to repolarize

Physiology Page 28

Basic EKG
EKG Characteristics Measures electrical POTENTIAL, not contraction At rest, the extracellular potential in the heart is + 90mV Different from intercellular potential, which was measures by sticking electrodes WITHIN the cell EKGs are measured from the outside Therefore, opposite During phase 2, the extracellular potential is -15mV A change in the EKG is only seen when Part of the cardiac tissue is at a different potential than the rest of the heart AND current can flow between those regions No change when atria and ventricles are different potential because they are electrically isolated

EKG Leads Standard limb leads Placement RA - Right arm LA - left arm LL - left leg Lead 1 Connects LA to RA Looks right to left through heart Lead 2 Connects RA to LL Looks from upper right to lower left Lead 3 LA to LL Upper left to lower left Lead 1, 2 & 3 form Einthoven's triangle Augmented leads aVR Between RA and combo of LA & LL Lower left to upper right aVL Between LA and combo of RA & LL Lower right to upper left aVF Between LL and combo of RA & LA Looks directly down

Cardiac Depolarization Path SA node Depolarizes atria P wave AV node Delays signal PR interval Bundle of His Purkinje fibers Ventricles depolarize Generally from right to left Apex to base QRS complex Prolonged QRS could indicate ventricular damage Action potential phase 2 delays repolarization QT interval Ventricles repolarize T wave From left to right and base to apex Last cell to depolarize is first to repolarize (due to K+ channels) Atrial repolarization is buried in the QRS complex

STANDARD LEADS

AUGMENTED LEADS

Physiology Page 29

Cardiac Output
Cardiac Output (CO) Cardiac Function CO = BP/TPR 2 ways to alter cardiac TPR (total peripheral resistance) function: CO = Q (or flow) 1. Change the HR BP = change in BP (mean arterial pressure - venous pressure) Chronotropy Assume venous pressure equals 0 2. Change the force of BP is just mean arterial pressure contraction CO also equals SV x HR Inotropy SV (stroke volume) Sympathetic regulation HR (heart rate) Sympathetics go to the SV = EDV - ESV SA & AV nodes EDV (end diastolic volume) Secrete norepi which ESV (end systolic volume) acts on Beta-1 Ejection fraction is the percentage of blood pumped out receptors Parasympathetic regulation with each beat EF = SV/EDV x 100% Vagus N. goes to both SA & AV nodes Secrete Ach which acts Vasomotor Center on muscarinic High pressure baroreceptors are located in the receptors carotid sinus & the aortic arch Sense changes in systemic arterial BP Mean firing rate is proportional to BP Inotropy Acts on vasomotor center in the medulla Contractility (inotropy) is controlled by two Chemoreceptors that are stimulated to mechanisms: increase ventilation simultaneously increase 1. Intrinsic the HR Frank-Starling Law of the heart Low pressure baroreceptors increase HR 2. Extrinsic Mediated by autonomic system

Physiology Page 30

Flow & Resistance

Velocity The greatest summed cross sectional area is in the capillaries Therefore, the velocity is the least Velocity vs. Pressure In a closed tube, the diameter and velocity are inversely proportional if flow remains constant Diameter and hydrostatic pressure are directly proportional When diameter decreases, pressure decreases and velocity increases Seen with artherosclerosis Pressure drops over clot and velocity increases Flow (Q) Resistance Q = P1-P2/R Most resistance resides in the arterioles which represent R = 8Ln/r4 the most important component in altering resistance P1 = inpt pressure through changes in vessel diameter P2 = output pressure Increasing vessel length increases diameter r = radius Adding vessels in parallel (pregnancy) decreases the n = velocity resistance L = length Laminar flow reduces resistance Poiseuille's Law Turbulent flow increases resistance R = resistance Due to high velocity Rearranged: Vessel irregularities Q = (P1-P2)r4/8Ln Stenosis Could substitute CO, TPR etc. Potentiates artheriosclerosis Radius is the most important factor influencing resistance Compliance Polycythemia How easily the vessels or heart can be stretched Increased blood Expansion in the heart & arteries stores energy viscosity Excess RBCs

Pulse Pressure Difference between systolic & diastolic pressure

Physiology Page 31

Local Control
Peripheral Circulatory Control Meant to control flow, not BP Local control of flow is mediated by altering the resistance/ vessel radius by: Mechanical force on the vessel wall change tone Increased pressure causes vasoconstriction (myogenic reflex) Reduces pressure Increased sheer stress causes vasodilation Metabolic products Myogenic reflex Increase in BP stretches walls of arterioles Stretch causes smooth muscle contraction Vasoconstriction increases R to the tissue Purpose is to maintain tissue flow, not alter TPR (although there would be a small increase) Net effect is that if central BP changes, tissue flow remains the same Sheer stress Downstream resistance decreases due to increased metabolism, flow increases Upstream this causes a drag on endothelial walls NO is secreted causing vasodilation This upstream change compliments downstream changes Metabolic regulation CO2, H+, K+, or O2 reduction causes vasodilation Reduction in resistance increases flow Special Circulations Heart ignores sympathetic stimulation of the vasculature of the heart and only responds to local control Brain also ignores sympathetic stimulation Pulmonary circulation lacks sympathetic stimulation but instead vasoconstricts to alveolar hypoxia Directs blood to areas that have O 2

Reactive Hyperemia Vascular inflow to an area is interrupted or obstructed Causes an extreme vasodilation due to accumulation of vasodilator substances When flow is returned, the area is flooded with a great than normal flow (hyperemia) possibly causing damage

Physiology Page 32

Central Control
Afterload Pressure or forcethe heart must develop to produce ejection BP = CO x TPR Increasing TPR increases afterload Low Pressure Baroreceptors Located in low pressure areas such as the atria & pulmonary vasculature Reflexes: Increased atrial volume causing increased HR Vasodilation & fluid excretion in response to increased BP Can act as "brakes" when BP may become to high Vessels As BP decreases: Baroreceptor firing decreases Sympathetic activity increases HR increases Contractility increases Vessels increase TPR BP increases In contractile tissue (heart): Norepi stimulates Beta-1 receptors In vasculature: Releases of norepi stimulates alpha receptors Venous Vasomotor center causes vein constriction Increases preload Increases contractility and SV Adrenal glands Can cause either constriction or dilation Dilation Beta-2 receptors Constriction Alpha receptors

Measuring CO Thermal dilution method Beilman Dye dilution Fick method Uses O2 High flow will dilute to greater extent than low

Physiology Page 33

Pulmonary Blood Flow

Normal Pressure Pressure in the pulmonary arteries pushes the blood towards the capillaries Wedge pressure Pressure in the pulmonary capillaries (7mmHg) Pressure in pulmonary veins is ~1-6mmHg Gravity and the Lungs The blood at the top of the lungs pushes down on the blood below Blood pressure in the capillaries at the bottom of the lungs is higher than that at the top Zones in the lung Zone 1 Capillaries at the top Closed/collapsed at rest Zone 2 Closed during diastole, open during systole Zone 3 Capillaries are always open

Resistance Pulmonary resistance is altered using two mechanisms: 1. Passive Stretching of Vascular walls Increased radius reduces resistance BP = Q x R Increase in flow causes a decrease in resistance Bronchial Artery that limits the increase in Originates from left side of the heart BP Delivers oxygenated blood to the lungs Pulmonary circulation Part of bronchial artery results in a right to left must be maintained at shunt low pressure Right to left shunt 2. Response to O2 Blood leaves the left heart and If O2 alveolar concentration returns to the left heart w/o passing falls, vessels in that area throung pulmonary circulation increase their resistance by Left to right shunt constricting (hypoxic Similar to above but starts in right vasoconstriction) ventricle and doesn't pass through systemic capillary bed Right to left shunt from bronchial artery is when Fluid Movement the venous end empties into the pulmonary Net filtration pressure is positive and venous circulation fluid continuously leaves the capillaries Alveoli don't fill w/ fluid because Surfactant Lymphatic drainage Interstitial oncotic pressure Negative interstitial hydrostatic pressure Pulmonary Edema When interstitial hydrostatic pressure is to great and fluid enters the alveoli Caused by: Capillary inflammation Pulmonary hypertension CHF Alveolar hypoxia

Gas Pressures Dry air contains: 79% Nitrogen 21% Oxygen Nasal passages saturate air w/ water 47mmHg So when calculating partial pressures (760mmHg total at sea level) must subtract 47mmHg before calculation

Physiology Page 34

Right Ventricular Function RV failure causes backup of fluid into systemic circulation Causes increased systemic pressure Seen as elevated JVP of edema (ascites)

Left Ventricular Function Normally, right heart and lungs adapt to changes induced by the systemic circulation and left ventricle Exercise RV pumps harder to increase flow through lungs Pulmonary vasculature dilates to decrease resistance and keep pressures in check LV failure If LV fails to pump all blood received from pulmonary circulation, blood backs up into the lungs Increased leakage of fluid out of pulmonary circulation and into interstitium CHF Heart failure cells

Physiology Page 35

Cell Wall Synthesis Inhibitors

-Lactams Spectrum Narrow is effective only against one (or one group of) species Extended has an intermediate range of activity Broad has a spectrum against a wide range of bugs MOA Inhibits cell wall synthesis by binding to Penicillin binding proteins (PBPs) MOR -lactamase degradation PBP alteration (MRSA, penresistant S pneumoniae (PRSP)) Decreased penetration Bacteriocidal Except against Enterococcus Time-dependent -lactamase inhibitors (anti-lactamases) Used in combo with -lactams to overcome resistance due to degradation Clavulanate Sulbactam Tazobactam Combos include: Amox/clav Amp/Sulb Pip/Sulb Ticar/Clav Some preparations of IV penicillins contain a large amount of sodium Important for patients with renal failure Cilastatin Combined with imipenem to prevent degradation of imipenem by dehydropeptidase (dehydropeptidase inhibitor) Glycopeptides & Others Vancomycin MOA Binds firmly to D-alanine-D-alanine portion of cell wall precursors Inhibits addition of peptidoglycan units to growing polymer chain Bacteriocidal (except Enterococcus) Some Enterococcus sp. show resistance (VRE) MOR Terminal D-ala replaced with D-lactate Given IV (except for C. difficile) Not absorbed via the gut Good for treating C. difficile orally because it will not be absorbed and thus stay in the gut and kill C. difficile Adverse effects Red-Man syndrome Flushing, rash etc. on face and torso Telavancin MOA D-ala-D-ala (like Vanco) but also depolarizes cell membrane Concentration dependent Adverse effects Metallic taste Foamy urine BLACK-BOX warning Abnormal fetal development, do NOT take while pregnant Daptomycin Cyclic lipopeptide MOA Causes rapid depolarization of cell membrane Concentration dependent IV only DO NOT use to treat pneumona Death, serious complications Reserved for serious infx caused by resistant bacteria Adverse effects Myopathy and CPK elevation Bacitracin Inhibits incorporation of AAs and nucleotides into cell wall Bacteriostatic Causes nephrotoxicity when used systemically (topically only)

Pharmacology Page 36

CLASS

FAMILY

PRE/ SUFFIX

NAME(S)

SPECIAL/DOC

Penicillins Penicillins

Natural penicillins Penicillinaseresistant penicillins

-cillin -cillin

Penicillin G, Penicillin VK Nafcillin, Dicloxacillin, Oxacillin, Methicillin Ampicillin, Amoxicillin

Ticarcillin, Piperacillin

Syphillis, Neisseria meningitidis, pen-susceptible S. pneumoniae Anti-Staphylococcal (MSSA), especially skin & soft tissue; can cause renal failure (methicillin & nafcillin) Greater action against gram (-) aerobes; Enterococcal infections
Pseudomonas aeruginosa, Bacteroides, Clostridium (not difficile)

Penicillins
Penicillins

Aminopenicillin -cillin
AntiPseudomonal penicillins -cillin

Cephalosporins 1st Gen.

Cef-

Cefazolin, Cephalexin, Cefadroxil Cefuroxime, Cefoxitin, Cefotetan, Cefprozil Cefdinir,Cefixime, Cefotaxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone
Cefepime

Best against gram (+) aerobes; do not penetrate the CNS; surgical prophylaxis Better than 1st Gen. against gram (-) aerobes; some anaerobes

Cephalosporins 2nd Gen.

Cef-

Cephalosporins 3rd Gen.

Cef-

Greater against gram (-) aerobes; SOME are best for gram (+) aerobes including PRSP (Ceftriaxone & cefotaxime); P. aeruginosa (ceftazidime); can cross BBB
Extended spectrum gram (+) & (-); P. aeruginosa & Enterobacter sp.; cross BBB

Cephalosporins 4th Gen.

Cef-

Carbapenems

-enem

Imipenem/cilastin, Most broad spectrum of activity of Ertapenem, all antimicrobials; hospital-aquired Meropenem infx, polymicrobial infx & empiric therapy; NOT covered include MRSA, VRE, coag (-) staph., C. difficile, S maltophilia, Nocardia; cross BBB; Imipenem can cause seizures
Aztreonam Gram (-), including P. aeruginosa; Penicillin-allergic patients who need gram (-) coverage; cross BBB

Monobactams

-LACTAMS

Pharmacology Page 37

CLASS

NAME(S)

SPECIAL/DOC MRSA, gram (+) bacteria (especially those with allergies to lactams

Glycopeptide Vancomycin s

Glycopeptide Telavancin/Vibativ MRSA, gram (+) s

Other Other Daptomycin Bacitracin Gram (+), MRSA, VRE, Enterococcus faecalis Gram (+) & (-); Used topically

GLYCOPEPTIDES & OTHER

Pharmacology Page 38

Protein Synthesis Inhibitors

Selection of Antimicrobial Drugs Host factors Pregnancy Tetracycline produces tooth discoloration and enamel hypoplasia Age Older people have lower clearance rates Can't give tetracycline to kids under 8 (teeth) Antimicrobial activity Pharmacokinetic properties Sites not easily penetrated by drugs CNS Drugs that do penetrate include: Chloramphenicol Tetracyclines TMP-SMZ Bone Prostrate Ocular tissue Adverse effects Cost

Tetracyclines MOA Inhibit bacterial protein synthesis by binding to 30S subunit Bacteriostatic MOR Efflux of tetracycline Decreased permeability Enzymatic inactivation Distribution Good tissue penetration Minimal CSF penetration Adverse effects Photosensitivity Discoloration of teeth in children
Glycylcyclines Tigecycline is only drug MOA Similar to other tetracyclines Binds 30S subunit (5x higher than other tetracyclines) Macrolides/Ketolides Inhibit protein synthesis by binding to 50S subunit Bacteriostatic Time-dependent MOR S. pneumoniae Active efflux Mef gene encodes for efflux pump Altered target sites Erm gene alters binding site Distribution Minimal CSF penetration Adverse effects (Macrolides) GI effects Elongation of QT interval Adverse effects (Ketolides) CNS Dizziness, headache Hepatotoxicity Severe liver injury Blurred vision Contraindicted for patients w/myasthenia gravis Worsening symptoms Elongation of QT interval

Aminoglycosides MOA Inhibition of protein synthesis Binds to 30S subunit Bacteriocidal Concentration dependent MOR Decreased penetration Aminoglycoside-modifying enzymes Alteration in binding site Adverse effects Ototoxicity Vertigo, hearing loss etc. Nephrotoxicity Acute tubular necrosis Neuromuscular blockade Hypersensitivity reactions

Streptogramins

Chloramphenicol
Pharmacology Page 39

Streptogramins MOA Combo agent that acts on 50S subunit Protein synthesis inhibitor Bacteriostatic MOR Alterations in binding sites Enzymatic inactivation Clindamycin MOA Binds 50S subunit Bacteriostatic MOR Altered target sites Erm gene Active efflux Mef gene encodes for effllux pump Adverse effects GI C. difficile colitis

Chloramphenicol MOA Binds to 50S subunit Penetrates CNS Limited usee due to adverse effects Adverse effects Hematologic Bone marrow suppression Anemia, leukopenia etc. Aplastic anemia (fatal) Hemolytic anemia Gray baby syndrome Newborns have a decreased ability to conjugate drug High serum concentrations CNS Optic neuritis Headache, depression & confusion Oxazolidinones Only Linezolid MOA Binds 50S subunit Bacteriostatic Time-dependent Moderate CSF penetration PRE/ SUFFIX -cycline SPECIAL/DOC Community-aquired pneumonia (doxycycline); Rickettsial Infx (RMSF); Chlamydia; Anthrax; Lyme disease (DOC for Borrelia burgdorferi) Gram (+) & (-) aerobes, MRSA & VRE; Doesn't cover P. aeruginosa; Both types of pneumonia; intraabdominal infections

CLASS Tetracyclines

NAME(S) Demeclocycline, Doxycycline, Minocycline, Tetracycline Tigecycline

Glycylcyclines

NA

Macrolides/ Ketolides

Azithromycin, -thromycin Gram (+) & (-) aerobes; Intracellular organs Clarithromycin, (STDs); Mycobacterium; Telithromycin covers Erythromycin, all macrolides PLUS multi-drug resistant Telithromycin (Ketolide) Streptococcus pneumoniae -mycin/ -micin Gram (+) & (-) aerobes, not streptomycin; Mycobacteria (tuberculosis)

Aminoglycosides Amikacin, Gentamicin, Neomycin, Streptomycin, Tobramycin

Streptogramins
Oxazolidinones Clindamycin

Quinopristin/ NA Dalfopristin (Synercid)

Linezolid Clindamycin NA NA NA

VRE, MRSA, MSSA or Streptococcus pyogenes; not active against E. faecalis

MRSA, VRE & E. faecalis; Gram (+) & (-) Anaerobes outside of the CNS Gram (+) & (-) aerobes & anaerobes; spirochetes; Rickettsia; chlamydia,

Chloramphenicol Chloramphenicol

Pharmacology Page 40

Nucleic Acid Synthesis & Metabolic Inhibitors

Flouroquinolones MOA Inhibit topoisomerases Concentration-dependent Bacteriocidal MOR Altered target sites Altered cell wall permeability Active efflux Adverse effects GI CNS Headache, hallucinations, insomnia Cardiac Extended QT interval Articular damage Tendonitis Metronidazole MOA Inhibits DNA synthesis Given as a prodrug Concentration-dependent bacteriocidal Adverse effects GI CNS Avoid during pregnancy Sulfonamides Metabolic inhibitor MOA Inhibits dihydrofolate reductase (DHFR) TMP-SMX Individually are bacteriostatic, together are bacteriocidal MOR Point mutations in DHFR Adverse effects GI Hematologic Skin disorders Agents for C. difficile Glycopeptides Vanco Teicoplanin Telavancin Metronidazole DOC for C. diff colitis Carbapenems Doripenem Ertapenem Imipenem Meropenem

Anti-pseudomonal Antibiotics Penicillins Ticarcillin Piperacillin Carbapenems Aztreonam Cipro Cephalosporins Ceftazidime Cefepime Aminoglycosides Gentamicin Tobramycin Amikacin
DOCs Penicillin Syphilis Neisseria meningitidis Tetracycline Lyme disease Borrelia burgdorferi Macrolides & Flouroquinolones Legionella pneumophila Vanco MRSA hospital aquired Metronidazole Pseudomembranous colitis due to C. difficile TMP-SMX Pneumocystis jirovecii pneumonia

Anti-MSSA Antibiotics Penicillins Nafcillin/Oxacillin Dicloxacillin Amox/Clavulanate Ticar/Clav Pip/Tazo Carbapenems Imi, dori, erta, mero

Anti-MRSA Antibiotics Vanco DOC for hospital aquired MRSA Teicoplanin Dapto Linezolid TMP-SMX Clindamycin Tigecycline

Pharmacology Page 41

CLASS

FAMILY NAME(S)

PRE/ SPECIAL/DOC SUFFIX NA -xacin Gram (+) & (-); atypicals; DOC for Legionella pneumophilia; RTIs; UTIs; STDs "

Flouroquinolones 1st Gen. Nalidixic acid Flouroquinolones 2nd Gen. Ciprofloxacin, Norfloxacin, Ofloxacin

Flouroquinolones 3rd Gen. Levofloxacin

Flouroquinolones 4th Gen. Moxifloxacin, Gatifloxacin Metronidazole NA Metronidazole

-xacin
-xacin NA

"
" Protozoa; anaerobes (including CNS); DOC for pseudomembranous colitis due to C. difficile

Sulfonamides

NA

Trimethoprim/ Sulfamethoxazole (TMP-SMX)

NA

RTIs; DOC for Pneumocystis jirovecii pneumonia; traveler's diarrhea (Salmonella & Shigella)

Pharmacology Page 42

Respiratory System
Lung Development Early and late phases Early Positioning of lung primordium and primary lung bud formation Late Mechanism of bronchial branching and cytodifferentiation Early Phase Location determined by TBX4 Linked to an increase in retinoic acid produced by adjacent splanchnic mesoderm Development begins in week 4 w/ formation of laryngeotracheal diverticulum Originates from the foregut Stems from endoderm Outgrowth of foregut grows into the surrounding mesoderm

Tracheoesophageal Fistula Most common malformation Abnormal connection between trachea & esophagus Caused by improper formation of tracheoesophageal septum Development of the Bronchi Left & right bronchial buds form around week 5 Trachea & bronchi are endoderm, everything else is mesoderm Cell Types Type I pneumocyte Form part of blood-air barrier Type II Secretory cells Produce surfactant Terminal sacs (alveoli) develop from respiratory bronchioles

Stages in Lung Development Embryonic (weeks 4-7) Formation of laryngeotracheal diverticulum & all major bronchopulmonary segments Glandular stage (weeks 8-16) Major formation of duct systems No respiratory components Canalicular stage (weeks 17-26) Formation of respiratory bronchioles & terminal sacs (primitive alveoli) Begin of POSSIBLE viability Premature birth before this stage is deadly Postnatal Up to 90% of alveoli form after birth Primarily through septation of existing alveoli

Congenital Neonatal Emphysema Over distention w/ air of one or more lobes of the lung Caused by collapsed bronchi Bronchial cartilage doesn't develop

Respiratory Distress Syndrome Occurs primarily in immature lungs Labored breathing Deficiency/absence of surfactant

Pulmonary Agenesis Complete absence of lungs, bronchi & vasculature Bronchial buds don't develop

Embryology Page 43

Pulmonary Hypoplasia Poorly developed bronchial tree Polyhydramnios During normal development, amniotic fluid enters Fetus also swallows amniotic fluid the lungs through fetal breathing Polyhydramnios develops if fetus is unable This provides lung distention & is necessary to swallow for normal development Associated w/ CNS abnormalities & Pulmonary hypoplasia is a result of lack of esophogeal atresia distention of lungs & increased amniotic fluid pressure from the OUTSIDE IN (versus correct pressure from within the lungs) Potter syndrome Congenital Diaphragmatic Partitioning of the Body Cavity Hernias Pleuropericardial membrane Herniation of abdominal Forms between heart and lungs contents into the pleural Grows lateral to medial cavity Phrenic nerve (C3-5) grows with formation Pleuroperitoneal membrane Seperates lungs and abdominal cavity Sheets of somatic mesoderm from dorsolateral wall Septum transversum Seperates heart and abdominal cavity Sources of the diaphragm Septum transversum forms central tendon Pleuroperitoneal membranes

Embryology Page 44

Normal Heart
Most common clinical component/symptom is Five Finger Method History pain Follow OLDCARTSMP3 Art of taking a good history is everything Physical EKG Physical X-Ray Check jugular venous pressure Lab (JVP) Precordial palpation PMI (point of maximal History impact) Fatigue, dyspnea, chest pain, palpations, syncope Apex of heart found lower Non-specific left (5th intercostal) Always consider: Percusion Underlying etiology will usually be one of the Not to useful following: Heart sounds Hypertensive Grading system of murmurs Ischemic Perform the proper sequence: Infection Inspection Congenital Palpation Valves Percussion Anatomical abnormalities Auscultation Which chamber is involved Which valve Scale for Risk of Heart Disease Pericardium Development Listen while patient leans forward to 4 stages: hear friction between visceral and A. People who have risk factors, parital pericardium but at this time do not have MI? any impairment Physiological disturbance B. People with structural Arrythmia changes but no symptoms yet CHF C. Patient with current Functional disability symptoms of disease How strenuous is the physical activity D. Advanced disease necessary to elicit symptoms Class I Murmurs Grading System No physical limitations 1. Barely audible Class II 2. Soft Slight limitation 3. Loud, without thrill Ordinary activity causes symptoms 4. Loud with thrill Class III 5. Loud with minimal contact of Marked limitation stethescope & thrill Less than ordinary activity elicits 6. Loud, can be heard w/o stethoscope, symptoms thrill Asymptomatic at rest Class IV Thrills can be felt Symptomatic at rest

Internal Med Page 45

Jugular Venous Pressure S1 1st heart sound Mitral, tricuspid closure S2 2nd heart sound Aortic, pulmonic closure Systole S1 - S2 Diastole Beginning of S2 A wave Atrical contraction Tricuspid valve is open Giant A waves seen: Obsruction between RA & RV Increased pressure in RV Pulmonary hypertension A-V dissociation Atria contracts against a closed valve Complete heart block "Cannon A waves" C wave Backward push by the closure of the tricuspid valve X wave Passive atrial filling Atria is relaxed Steep X descent indicates constrictive pericarditis Tricuspid valve is still closed V wave Atria is filling as pressure increases Tricuspid valve is still closed Y Slope Open tricuspid valve Rapid RV filling Kussmauls Sign Venous column rises during inspiration, rather than falls Seen in R heart failure

Measuring JVP Place patient in supine position to allow veins to engorge, then raise patient to 30-45 Measure from sternal notch up to level of waveform in jugular vein Add 5cm (due to RA 5cm below sternal notch) Normal is 0-9cm Most common cause of elevated JVP is elevated RV diastolic pressure Also: SVC obstruction HF Constrictive pericarditits Hepatojugular reflex (HJR) Positive indicatesproblems
Heart Sounds Mitral Apex of heart Tricuspid 4th left intercostal space (ICS) Aortic valve 2nd right ICS Pulmonary valve 2nd left ICS

Internal Med Page 46

Chest X-Ray Interpretation

Shades of Gray Dark to light Air Fat Water Bone Metal Rib Fx can lead to pneumothorax Best visualized with an expiration chest view Most chest views are inspiration

Cardiac Size Should be 50% of less of entire chest diameter

Cardiac Landmarks. 1.SVC 2.RA 3.Aortic arch 4.Main pulmonary artery 5.Left atrial appendage 6.Left ventricle

Etiologies of Alveolar Disease Acute Hemorrhagic Pneumonia Edema Aspiration Chronic Lots Round Pneumonia Infiltrate visible Symptoms Cough 5 days Fever 102 Elevated WBC Bronchogenic carcinoma Infiltrate Symptoms Cough 5 weeks Fever 99 WBC ok An good history is the difference in diagnosis between cancer and pneumonia

X-Ray Signs of Interstitial Disease Ground glass pattern Nodular patterns Kerley B's Interstitial edema Honeycombing Interstitial fibrosis Acute etiologies Interstitial edema Viral or mycoplasma pneumonia Pneumocystis carinae pneumonia Chronic etiologies Lots
Kerley B's visible above diaphragm. Interstitial edema.

Radiology Page 47