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342 Cards in this Set

  • Front
  • Back
What do the M2 muscarinic receptors do to the nodal tissue of the heart?
Slow the heart rate.
What do Alpha-1 receptors in the systemic veins do?
Constrict veins to increase venous return/ preload.
What do beta-1 receptors do in the heart?
Stimulate heart rate and contractility
What do Beta-2 receptors doe in the large arteries?
Vaso dilation
What do M3 muscarinic receptors do to the entire circulatory system?
Vasodilation via NO
What do alpha-one receptors in the arterioles do?
Constrict to regulate tissue blood flow.
What breaks the actin and myosin crossbridges in cardiac muscles?
When Ca binds to troponin on actin.
How are cardiac muscle fibers different from skeletal muscle fibers?
They contract spontaneously/ myogenic and they are coupled by gap junctions at the intercalated discs to form syncytia.
How does the signaling move in the heart?
Begins at pacemaker the SA nodes then travel to atrial syncytium via intermodal fibers and then go to atrioventricular nodes to the bundle of His to the ventricular syncytium that then pumps the heart…
What are the three yagiela classification for abnormal cardiac function?
Arrythmias (automaticity, refractoriness, and conduction velocity), Heart Failure (defects in contraction process), and Angina (pain due to oxygen deficiency)
What is the membrane permeable to in a resting state of a muscle cell?
Permeable to K but not Na and the cell is inherently negative inside the cell.
What happens to the charge along the membrane as K diffuses out?
The negative (anions) accumulate along the inner surface of the membrane and at the equilibrium potential for K (-90) mV further diffusion stops. This is the pump-leak model
What happens during phase 0 of a cardiac action potential?
Na permeability increases and the membrane depolarizes and can approach 60 mV (the equilibrium potential for sodium)
Why are changes in membrane potential so rapid?
The phospholipid bilayer is effective in separating charges so very few ions actually have to move across the membrane.
What occurs to repolarize the cell membrane?
K permeability increases again and K enters and Ca in the cytosol is moved back into the SR and also out of the cell to relax the muscle cell.
What is the resting potential of a pacemaker cell?
Usually around -60 mV due to permeability to Na.
In cardiac tissue, what is the Ca concentration like?
It is 10^-7 < vs. 1.2 mM in the ECF creates a large gradient for Ca to diffuse back into the cell, so if Ca channels are activated the cell membrane can become depolarized.
What do many antiarrythmic drugs target in the heart?
The different types of Na, Ca and K channels.
What happens in the cardiac cell when Na depolarization occurs?
Ca channels are activated and Ca entry stimulate the activation of Ca channels in the SR to release more Ca into the cytosol which binds troponin and allows crossbridging to occur (contraction/systole)
How does the resting potential of the nodes compare to those of the conducting or contracting fibers?
It is more depolarized. -60 vs. -90.
Which phase is depolarization and which is repolarization?
Phase 0 is depolarization and phase 3 represents repolarization.
Which phases are not seen in nodal phases but represent important events in contractile tissue?
Phase 1 and 2.
How do channel blockers work in the heart?
They slow down the depolarization and thus the conduction velocity is slowed.
How are sinoatrial fibers depolarized?
By way of funny Na channels (if) that are slowly activated at membrane voltages below -55 mV.
Why are funny channels funny?
Because they become activated as the membrane replarizes unlike most ion channels that are activated upon depolarization
What is another term for funny channels?
Hyperpolarizing, cyclic nucleotide activating channels or HCN
What gives the automatic continual rhythm to the heart?
As the cell repolarizes the funny channels are activated and they begin to depolarize the membrane to produce this cycle and become the pacemaker…
How does sympathetic stimulation work to increase the heart rate?
Via B1 receptors cAMP is produced to make the funny channels more sensitive to repolarization and so the rate of depolarization increases also Ca channels become more sensitive which lowers their threshold activation….to increase the rate.
What controls the heart rate?
The autonomic nervous system.
How does the parasympathetic/vagus nerve lower the heart rate?
Via muscarinic receptors that activate K channels in the SA and AV nodal cells to hyperpolarize the membrane and reduce the rate of spontaneous depolarization.
How does the rate of depolarization of the atrial fibers compare that of the SA nodes?
It is faster mediated by fast Na channelsthese channels is what begins the Action potential in contractile fibers.
What do small transitional fibers in the heart do?
They slow conduction by delaying the conduction of impulses from the atria to the ventricles, they can break and cause an A-V block.
What is the name of the fibers the bundle branches that rapidly conduct impulses to the ventricular myocytes?
The perkinje fibers.
Why are the SA nodes the pacemakers?
Because they have a less negative resting potential than the other fibers of the heart so they reach their threshold more quickly and thus set the pace.
How do Ca channels compare to the Na chanels in conducting and contracting fibers of the heart?
The Ca channels are long acting and the Na channels are very fast acting.
How does the sympathetic nervous system control the force of contraction?
Catecholamines stimulate the release of Ca from the SR and increases turnover of Ca-troponin binding.
How is cytosolic Ca reduced?
Pumped back into SR with Ca pump and then pumped out of cell with a 3Na : 1 Ca antiport driven by inward gradient for Na.
How does digitalis work?
It inhibits the Na-K pump and intracellular Na increases which reduces the gradient for Na so the Na-Ca antiport doesn’t happen and Ca concentration in the cell remains high to effect a stronger contraction.
Why is voltage form the heart on the left side more positive as the atria and ventricles contract?
Because the heart sits at about 60 degrees and the left ventricle is larger.
Who pioneered the EKG?
Willem Einthoven in 1913 using a three lead system that form Einthoven’s triangle.
What is lead 1?
RA- : LA+
What is lead 2?
RA- : LL+
What is lead 3?
LA- : LL+
Which lead best approximates the anatomical axis of the heart?
Lead II.
How are depolarizations viewed in an Lead II EKG?
They are seen as positive deflections like the P wave or the QRS complex.
How are repolarization events viewed in the Lead II EKG?
As negative deflections.
What do the waves mean on the ECG?
T=atrial depolarization, QRS = ventricular depolarization, and T = ventricular repolarization.
What does an extended PR interval represent?
A first degree heart block…a delay in AV node conduction
What would indicate a second degree block?
Two p waves per QRS
What does the Q-T interval represent?
The duration of action potentials in the ventricles.
What is Q-T syndrome?
It allows ventricular fibers to remain depolarized beyond their refractory period and initiate premature depolarization and uncoordinated heart contractions.
What is the refractory period?
During depolarization and most of repolarization the Na and Ca channels aren’t electrically excitable and the heart relaxes (diastole) until the next signal from the pacemaker. This prevents a second heart beat during contraction of the ventricles.
What is sinus tachycardia?
Increased automaticity that causes depolarization as the fibers emerge from refractory period and a premature contraction occurs.
What do many antiarrythmia drugs target?
They attempt to prolong the refractory period.
What type pattern might you see with long QT syndrome?
Torsade de pointes
What are 4 conditions that can cause re-entry that can lead to multiple action potentials and fibrillation?
Enlarged heart, Reduced conduction velocity, shortened refractory period, and ischemic cells can become more excitable and become pacemakers that depolarize faster than the normal sinus rhythm.
What is technically happening during re entry?
Conduction along a purkinje fiber is blocked and it returns and takes another path to the muscle cell and can cause a second premature depolarization of the muscle cells.
What is the aim of defibrillators?
To put the entire heart into a refractory state to allow the heart to resume a normal sinus rhythm.
Where do arrhythmias occur in the heart?
Can result from abnormal SA node or atria (supraventricular arrhythmias) or in the ventricles themselves (ventricular arrhythmias)
What do class I anti arrhythmia drugs target?
They target Na channels but also may block K channels and be vagolytic.
What does lidocaine do?
It blocks fast Na channels in the closed state.
What is vagolytic action?
It blocks parasympathetic stimulation that would normally slow the heart rate and can actually increase the heart rate.
What do beta 1 blockers and Ca channel blockers do to the heart rate?
They slow it down.
What do Na channel blocker and Ca channel blockers do in the heart?
They delay conduction through the AV node.
What do Class1a, B, and Class IV drugs do?
Prolong the P-R interval.
What do class 1B drugs do?
They block Na channels in ischemic tissues to offset high sympathetic tone that might cause arrhythmias.
What do class 1a drugs do?
They delay phase O and also block K channels to delay repolarization
What do class III drugs do?
They act on K channels to delay repolarization.
If you inhibit K channels with a class III drugs, what will be the effect on the EKG?
It will give a longer QT interval.
How does the CO of the R and L ventricles compare?
It is equal
How does the pulmonary pressure compare to the systemic pressure?
The pulmonary pressure is lower owing to a much smaller resistance.
What does left ventricular insufficiency lead to?
Fluid accumulation in the lungs/pulmonary edema to cause congestive heart failure.
What is the volume of blood circulated per minute by the heart?
5 L/min
What is the function of the systemic circulation?
Respiratory gas exchange with the tissues.
What do class I drugs do?
Na channel blockers that slow the heart rate
What do Class 2 drugs do?
Beta blockers that slow the heart rate and force of contraction
What do Class 3 drugs do?
K channel blockers that prolong depolarization
What do Class 4 drugs do?
Block Ca channels to relax smooth muscle.
What do ACE inhibitors do?
They block the synthesis of angiotensin II and relax vascular smooth muscle.
What do Alpha-1 blockers do?
Relax smooth muscle and reduce vascular resistance.
Do you understand the graph from Guyton and Hall fig. 9.5?
Get on it!!
What is preload?
The forces that lead to ventricular filling during diastole measured as end diastolic volume (EDV).
What is afterload?
The forces that oppose ejection of the blood by the ventricles. Lower the after load to reduce the workload on the heart.
Are the atria responsible for ventricular filling?
During diastole the mitral valve is open and blood from the pulmonary veins can enter the left atrium and the atria contribute little to ventricular filling
What is isovolemic contraction?
The period between depolarization and contraction where the pressure develops in the ventricles and the mitral valve closes but the aortic valve is still closed.
What is the first hear sound?
The mitral valve closing
What opens the aortic valve?
The pressure develops in the left ventricle and becomes larger than the pressure in the aorta.
What is the second heart sound?
Is the closing of the aortic valve
What causes the ventricles to relax?
Ca is sequestered in the SR and pumped out of the cell.
What is the incisura?
A drop in aortic pressure that results from elastic recoil in the aorta
What maintains the BP in the the aorta during diastole?
The elastic recoil.
What happens when ventricular pressure declines to the level of the atria?
The mitral valve opens and ventricular filling begins….most filling occurs without atrial contraction.
What is the third sound of the heart?
The opening of the mitral valve….it is weak
What is CO?
HR X SV it is normally around 5L/min it can be 35L/min in athletes during exercise due to increased HR and SV.
What is starlings law of the heart?
The more the ventricles fill during diastole, the more cardiac muscle fibers are stretched and the more forceful the contraction will be.
What is Ohms law?
Pressure = Flow X Resistance
Where does the most rapid drop in pressure occur in the CV system?
Arterioles
What is the pressure in the veins?
Near zero in large veins
How do you calculate total peripheral resistance (TPR)?
MAP/CO at rest it is around .02PRU and during exercise it is .003 PRU….This reduction allows for increased CO during exercise.
How does ATH affect TPR?
Arterial elasticity is reduced and so MAP is increase and TPR and work of the heart will increase.
Where does the increase in blood flow during exercise go?
The skeletal muscle and skin
What controls the blood flow to the capillary beds?
The smooth muscle sphincters in the arterioles controlled by the sympathetic NS via alpha-1 receptors and local tissue factors (CO2, Low pH, and Temp). These two contribute to the vasomotor tone.
How do M3 receptors mediate vasodilation?
G proteins activating PLC to release Ca, bind calmodulin and activate NO synthase in EC’s, the NO enters SMC’s to catalyze the synthesis of cGMP that promotes smooth muscle relaxation and dilation to increase arterial blood flow.
How does nitroglycerin work?
It is a substrate for NO and helps to relax the arteries.
What part of the brain controls heat and blood vessels?
Autonomic centers in the medulla.
What initiates the sympathetic and parasympathetic regulation of the heart and blood vessels?
Baroreceptors and chemorecptors in the CV system.
What is the orthostatic reflex?
It preserves the blood pressure to the head, via pressure receptors in the coratid sinus that send input to medulla to coordinate peripheral vasoconstriction and heart rate to maintain blood pressure when a patient gets out of your dental chair.
What is vagal escape?
A reduction in blood pressure by muscarinic stimulation is compensated by for a sympathetic reflex to stimulated heart rate and blood pressure. Sympathetic and parasympathetic reflexes can offset the effects of drugs.
Where are there baro and chemoreceptors found together that activate the autonomic NS to control heart rate and blood pressure?
In the aorta.
How does resistance and vessel diameter related?
smaller vessels have more resistance. A small change in diameter can have a large effect on blood flow.
How will halfing the size of the diameter of a vessel affect the resistance?
It will be 2^4 or 16 times the amount of resistance.
How many branches one half the diameter of the original would have the same resistance to flow?
16 even though the total cross sectional areao fo the 16 branches will be four times greater than the original.
What occurs in shock?
Capillaries dilate and there is not enough blood for there rest of the body…this is why sympathetic regulation of blood flow is so important.
How much of the systemic blood is in the veins?
64%.
How does blood return to the heart?
Due to pressure from skeletal muscle contraction and the valves are one way and prevent backflow. Also negative thoracic pressure during inspiration. People who sit or stand for long periods can have venous return issues.
What does sympathetic stimulation do to the veins?
It can contract the large veins to increase blood preload, this also allows large veins to serve as a reserve to permit cardiac output during period of blood loss.
How does Nitroglycerin affect the venous return?
It reduces venous return and pre-load so cardiac output and the workload on the heart will decrease.
How much fluid leaks out of the capillaries each day?
Around 3 liters….this almost equals the entire plasma volume.
What are starling forces?
The blood pressure that drives blood through the capillaries and small solutes out into the interstial fluid, albumen remains in the blood and exerts the colloid osmotic pressure to retain water in the blood, normally there is a net loss of fluid fromt eh capillaries.
What is the process of fluid and small solutes diffusing out of the capillaries into the interstium?
Capillary ultrafiltration……most of which will enter the lymphatics to be returned to the venous system.
What is the total outward force from the capillaries vs the total inward forces?
28.3 outward vs. 28.0mm Hg inward to give a net outward of .3 mmHg which will produce about 3 liters/day of fluid moving out of the capillaries per day.
What does substance P do following an injury?
It will increase capillary pressure and protein loss to the fluids both of which increase the fluid loss from capillaries and produce edema.
How is fluid taken up into the lymphatics?
They are collapsed during exercise, then when they are relaxed they generate a negative pressure to draw fluid into the lumen.
What can occur with excess edema due to injury?
They lymphatics can become overwhelmed and tissue swelling will occur.
Are there valves in the lymphatics?
Yes one way valves…
What is the generalized edema seen in the malnourished caused by?
It is called PEM and is caused by reduced plasma proteins so there is little or no colloid osmotic pressure to draw fluids back into the capillaries are decreased and generalized edema /ascites is noted…..Kwashikor.
How can liver cirrhosis affect the fluid loss at the capillaries?
Can cause ascites due to htn or due to reduced blood proteins.
What is the lymphatic drainage from the lungs like?
It can compensate for a limited amount of excess blood flow due to lower left ventricular output.
Where does gas exchange occur in the respiratory system?
In the respiratory bronchioles and the alveoli.
How do pulmonary capillaries differ from systemic capillaries?
The pulmonary capillaries are more permeable to protein than the systemic…this leads to a larger net fitration pressue in the lungs.
When does pulmonary edema occur?
When the left ventricle is weakened and the right side pumps more than the left.
What are the first branches off the aorta?
The right and left coronary arteries that emerge from within the aortic valves at the level of the coronary sinus.
When is coronary blood flow greatest?
As opposed to systemic arteries, blood flow is greatest during diastole.
Cardiac output to the left coronary arteries is maximal during what?
The beginning of diastole.
What can lead to DVT?
Dehydration and inactivity as in a long airplane ride.
What are the major causes of morbidity and mortality in developed countries associated with?
Failure to maintain normal fluid status.
What 3 pathologic lesions in western society are caused by abnormal fluid stasis?
MI, Pulmonary embolism, and CVA.
What is inappropriate clotting?
Thrombosis.
What does the inability to clot lead to?
Hemorrhage.
What happens when a blood vessel is damaged?
Vasoconstriction, platelet aggregation and Coagulation
What causes the vasoconstriction after initial injury?
Reflex neurogenic mechanisms augmented by local factors like endothelin….this gives time to activate the platelet and coagulation systems.
What activates the platelets to secrete products to recruit additional platelets?
The exposure to subendothelial ECM via injury.
What does vWF do?
It binds to collagen and other ECM proteins in the sub endothelium and also binds the platelets via glycoprotein 1bs of the platelets.
What happens when the platelets begin to aggregate?
They release ADP and thromboxane A2 that activate intigrins that can bind fibrinogen.
What is the primary hemostatic plug formed by?
Platelet aggregation.
How does aspirin exert its effects?
It is a cyclooxygenase inhibitor that inhibits the formation of PFH2 which is a precursor for thromboxane A2.
What do non-injured endothelial cells secrete to prevent platelet aggregation?
NO and prostacyclin.
What does thrombomodulin do?
It binds to thrombin to prevent fibrin formation.
Where are thromoembolisms especially problematic?
In pooled venous blood and turbulent flow around atherosclerotic plaques where local concentration of clotting factors can occur.
What tow products activate platelets?
Thromboxan A2 and ADP which activate fibrinogen….the platelets extend pseudopodia to flatten and increase the membrane area for greater aggregation.
What does plavix do?
It inhibits ADP binding toe the platelets.
What is tissue factor?
A membrane bound coagulation factor made by the blood vessels. It activates the extrinsic side of the clotting cascade by activating thrombin which takes fibrinogen to fibrin. This is part of secondary hemostasis which takes longer than the primary hemostasis.
What limits the hemostatic plug to the site of injury?
Tissue plasminogen activator (t-pa)
What is the intrinsic pathway?
The hagemen factor (factor XII) in blood binds negatively charged collagen and this initiates the pathway that converts prothrombin to thrombin.
What causes hemophilia B?
a defect in factor IX
What causes hemophilia A?
a defect in factor VIII
What are the steps of the clotting cascade?
Prothrombin to thrombin which converts fibrinogen to fibrin that can cross link and polymerize.
Where do the intrinsic and extrinsic pathways merge?
With the activation of factor X.
What are factors VII, XII, XI, IX, X, and II?
They are serine proteases made in the liver as inactive zymogens and they become activated when cleaved.
What initiate the clotting cascade?
Collagen exposure to factor XII on the intrinsic side or release of an extrinsic factor (tissue factor) from the endothelium.
Why is the clotting cascade so complex?
Each protease can activate many molecules down stream to become a true cascade that can form a clot very quickly.
Where does the clotting reaction occur?
On the platelet membranes so more platemembranes gives more area for the rxn to occur.
What is need for the binding of factors IX, X and other factors to the platelet membrane where the rxn will occur?
Ca ions.
What accelerates the activation of factor X?
Factor VIIIa holds factor X close to Factor IXa which will activate it.
What is stabilized by von Willibran’s factor?
Factor VIII, so vWF disease may show hemophilia type symptoms that result from a defective factor VIII or factor IX.
What are normal concentrations of intra and extracellular K+?
4mM outside and 139mM inside
What are normal concentrations of intra and extracellular Na+?
139 mM outside and 12 mM inside.
Where are Cl ions and HCO3 concentrated more highly?
Extracellularly
Where are Mg++, PO4 and organic anions and Protein higher concentration?
Intracellularly
Is Ca+ concentrated more highly inside or outside of cells?
Outside, but very little exists in either place.
What are the primary ions of the extracellular fluid?
Na and Cl
What are the primary ions of the cytosol?
K, PO4, organic ions, and proteins.
How do Beta 2 and M3 receptors affect preload?
They relax the vessels to reduce preload.
What do alpha 1 receptors in the vessels do?
Instigate vessel constriction.
What do M2’s do to the heart rate?
They decrease the heart rate
What is mean arterial pressure?
Cardiac output X Peripheral resistance
What are some complications associated with HTN?
Pulmonary edema due to decreased systemic CO, increased afterload = greater work for the heart and weakened heart has reduced CO, Aneurysm and stroke, Blood pools in lower extremities, increased lymph formation, edema, and thrombosis.
What is the primary cause of HTN?
Excessive volume in the vascular system
What regulates plasma volume and composition?
The kidneys.
What is the total fluid volume in the body?
41L and of that only 3 L make up the plasma.
How much volume of the blood is RBC’s?
2L or 40%
How much of the CO goes to the kidneys?
About 25% via the renal arteries and about 60% of that is plasma.
How much of the plasma that is received by the kidneys gets filtered?
About 20%....the rest goes via the efferent vessels at the glomerlus.
How much of the filtered plasma is excreted as urine?
Only about 1%....1.5 L/day
What might be worse than a hangover after binge drinking?
Exploding bladders
What is the pattern of renal blood flow?
Renal artery  Segmental arteries Interlobar ateries  Arcuate arteries  interlobular arteries…these feed into the afferent arterioles to the glomerulus bowmans capsule  tubular segments of the nephrons.
What are the two types of nephrons and which type is the most common?
Cortical (85%), and Juxtamedullary (15%) JM’s are about 40mm in length.
To where does the final urine go from the collecting ducts?
Into the ducts of Bellini
Where does the efferent arteriole go after leaving the glomerulus?
It becomes the peritubular capillaries and the vasa recta that surrounds the nephron to enable resorption and secretion.
How much water, Na, and Cl are reabsorbed into the peritubular capillaries?
99%.
What is normal GFR?
125 ml/min or 180 L/day.
Is inulin reabsorbed or secreted?
Neither, for inulin the amount filered = the amount excreted and so it can be used to determine GFR.
What is renal clearance?
The volume of plasma from which you remove a given amount of solute.
What is creatinine?
A natural occurring metabolite present in the plasma, it is only marginally secreted so it can give an estimate of GFR. Usually about 140 ml/min vs. the actual GFR of 125 ml/min.
What is the equation for calculating GFR with Creatinine?
Ucr X V/Pcr Ucr= urinary Creatinine, and Pcr = plasma creatinine.
What might the accumulation of creatinine in the plasma indicate?
A decline in GFR which can be diagnostic of renal disease.
At what point does a decrease in GFR become problematic?
The kidney compensates very well and nothing is noticed until it is less than half of normal.
How much glucose is excreted in the kidneys?
Normally none…it is completely reabsorbed so clearance = 0.
What happens to clearance vs. GFR if a solute is secreted?
Clearance is greater than the GFR.
What occurs to most solutes in the kidney?
They are partially reabsorbed so the clearance is greater than 0 but less than GFR.
What is PAH used for?
It is almost completely secreted so it can be used to estimate the renal plasma flow.
What is the filtration fraction?
The GFR/renal plasma flow.
What happens to the colloid osmotic pressure in the peritubular capillaries?
It increases due to the large percentage of plasma that is filtered through the glomerulus….this increase in pressure facilitates the reabsorption of solutes and water to the circulation.
What effect will high concentrations of mannitol have on the kidney?
It will draw more water into the tubular lumen and have a diuretic effect.
Where are 67% of Na and H2O and 100% of glucose reabsorbed?
In the proximal tubule
Where are 25% and 15% of H2O reabsorbed setting up an omotic gradient in the peritubular fluid?
In the Loop of Henle.
What occurs in the distal tubule?
7% of NaCl and 8-17% of H2O is reabsorbed and Na/K balancing occurs
What happens in the collecting duct?
Final urine concentration, the reabsorption of water and NaCl is regulated by ADH.
Where do Osmotic diuretics work?
On the proximal tubule and descending limb of Henle.
Where do Loop diuretics work?
On the ascending limb of henle.
Where do Thiazides work?
On the distal convoluted tubules.
Where do Na channel blocker type diuretics like spiranolactone work?
Block Na channels in the collecting duct.
What % of the filter load is reabsorbed in the collecting ducts?
1-5%
What disorder do diuretics treat?
HTN.
When are osmotic diuretics used in practice?
Rarely, but in cases of cerebral edema or for brain surgery, they are used to draw fluid out of cells
What are carbonic anhydrase inhibitos used for?
To produce metabolic acidosis to offset respiratory alkalosis in people with altitude sickness….thiazides can also do this.
What do thiazides and K+ sparing diuretics do?
Reduce the ability to acidify the urine.
How could you describe the reabsorption of Na, Cl, and water in the proximal tubule?
It is isoosmotic…they are removed in the same amounts as in the filtrate….glucose and amino acids are also completely removed at this point.
What is the mechanism that Na is reabsorbed from the tubular lumen across the epithelial cells and BM into the peritubular capillaries?
It crosses the apical side of the tubular cells down its gradient passively and then it crosses the BM via the Na and K pump actively through the basolateral membrane.
How is glucose reabsorbed from the proximal tubule?
Via a Na-glucose exchange protein (SGLT) into the tubular cells and then it diffuses out of the basolateral membrane via a glucose transport protein the glut family.
What is the believed mechanism for Cl reabsorption?
Thought to diffuse via the paracellular pathway drawn by the positive charge of Na+.
What occurs when there are more solutes to be reabsorbed than there are available SGLT molecules?
A transport maximum will be exceeded and glucose will appear in the urine as with DM.
Why is the urinary pH usually around 5.5-6.5 (acidic)?
Because of the need to eliminate acidic metabolites and retain bicarbonate.
What happens to CO2 in the tubular lumen?
It diffuses in with carbonic anhydrase and reacts to form carbonic acid which dissociates into bicarbonate which diffuses into the interstial fluid and the H+ is secreted into the tubular lumen with a Na-H antiport membrane on the apical membrane.
What does reduced H+ secretion cause?
Metabolic acidosis.
What do Carbonic Anhydrase inhibitors like acetozolamide do?
Inhibit carboinic acid formation so less H+ is available for secretion and the urine becomes more alkaline…
What might the K+ sparing diuretics also inhibit?
Na-H+ exchange….leading to more alkaline urine.
Where is the active transport component of the loop of Henle?
The ascending thick limb, this is specialized for this purpose with numerous Na-K pumps.
What type of transport occurs in the descending limb and the ascending thin loop?
Passive transport
What type of diuretics inhibit the Na-K-2Cl cotransport proteins in the ascending thick limbs?
Loop diuretics like furosemide.
What does the active transport of solutes out of the thick ascending loop of Henle cause?
It cause more water to diffuse out of the thin loop areas to offset the increase solutes in the peritubular space.
What is counter current multiplication?
It is what occurs between the descending and thin ascending portions of the loop of Henle and the ascending thick portion. The active transport in the ascending thick portion increasesolute concentration in peritubular space which draws more water out of the other portions…this concentrates the fluid delivered to the ATL which is transported out and round and round we go….
What maintains the concentration gradient between the peritubular space and the tubules?
Salt becomes concentrated in the descending vasa recta and water is absorbed and is then tranfered to the closely associated ascending vasa recta and returned to the circulation…This is called Counter Current Exchange.
What is important for the final concentration of urine by the collecting ducts?
The interstitial fluid osmotic gradient from the cortex to the inner medulla.
What occurs in the early distal tubule?
Na Cl reabsorption via Na-Cl exchange protein that is inhibited by thiazide diuretics.
What occurs in the late distal tubule/early collecting duct?
Na is reabsorbed and K is secreted via apical channels and then Na is transported across the basolateral membrane via Na-K pump.
Where do mineralcoticoids like aldosterone work?
Stimulates both steps of Na resorption in the collecting ducts and so they increase Na resorption and thus water retention.
What do blockers of aldosterone and Na channel blockers do for Blood pressure?
They reduce salt retention and thus HTN.
Where are aquaporins found?
They are water conducting proteins found in the proximal tubule, descending loop of Henle and in the medullary collecting ducts. The specific type in the apical membrane of the collecting duct are expressed in response to ADH.
What happens to urea in the nephrons?
It becomes concentrated by the time it reaches the collecting duct and ADH increases the permeability to urea, this leaks into the peritubular fluid, and back into the loop of Henle another counter current exchange to help draw more water and concentrate the final urine.
What is the maximal urine concentrating ability of the human kidney?
1200 mOsm/L….600 due to NaCl and another 600 due to urea.
What is antidiuresis?
The production of a small volume of concentrated urine.
What stimulates the release of ADH?
It is made in the supraoptic and paraventricular nuclei in the hypothalamus and stimulated when osmoreceptors detect dehydration or a decrease in blood pressure.
What occurs with low ADH?
A diuretic condition
Where do thiazides work?
They prevent salt retention by inhibiting the cotransport protein of Na and Cl in the early distal tubules causing natriuresis and diuresis.
How are diuretic states and coagulation related?
If you lose too much water then your blood will be thicker and so the procoagulation molecules will be in closer proximity, this puts the person at risk for thrombosis.
What does aldosterone do?
Stimulates salt retention which cause water retention.
What do diuretics do in general?
They reduce the gradient for solute and water resorption which interferes with the ability to concentrate the urine and thus urine is dilute and high volume.
How do loop diuretics work?
They reduce the Na, K, 2Cl transport decreasing the osmotic gradient needed for water absorption in the collecting ductscausing diuresis.
Where does K+ secretion occur?
The late distal tubule.
What stimulates Na resorption and K secretion?
Aldosterone stimulates both, K + secretion is stimulated by Na resorption.
What are two common K+ sparing diuretics?
Amiloride and Spironolactone
What else stimulates K+ secretion?
Thiazides and loop diuretics because Na enhances K secretion.
What might K+ secretion cause?
Hypokalemia
Where do K+ sparing diuretics work?
In the collecting duct.
How do K+ sparing diuretics like amiloride work?
They inhibit Na reabsorption by blocking ENaC’s, decreasing the charge gradient for K+ secretion….these are often used in conjuction with other diuretics that cause K+ to be lost.
How does spironolactone work?
It binds a cytosolic receptor that inhibits aldosterone from increasing Na absorption which it normally does by stimulating Na-K pumps and increasing ENaC
What type of drug interactions might be predicted with loop diuretics and thiazides?
Concentration of blood clotting factors (anticoagulants) and hypokalemia (digoxin toxicity, arrhythmias---cells can’t depolarize)
What type of issues might occur if taking a K+ sparing diuretic?
Hyperkalemia
What is mannitol?
It can be used as an osmotic nonelectrolyte to reduce the osmotic pressure/reabsorption of water.
What happens to membrane potential with hypokalemia?
Extracellular K+ decreases, outward diffusion gradient is larger and the membrand potential will be more negative -112mv vs. -90 mv under normal concentrations. This is harder to depolarize.
What is can be given with thiazide to prevent hypokalemia?
K+ sparing diuretics like Amiloride, Spironolactone or triamterene.
Where is the macula densa?
It is part of the distal tubule that passes between the afferent and efferent arterioles and contacts juxtaglomerular cells of the arterioles.
What does the macula densa do?
It detects changes in the composition of the distal tubular fluid and then communicates the juxta glomerular cells to regulate the GFR and tubular function. This autoregulation limits GFR at elevated blood pressure while maintaining it as renal blood flow and GFR decrease.
Where on the in the kidney does angiotensin II work?
It constricts the efferent arteriole
What happens to the amount of solute reabsorption when the GFR is normal and fluid moves quickly through the nephron?
Reabsorption is less because there is less time.
What occurs with reduced GFR?
Tubular fluid moves more slowly and so more solute reabsorption occurs, the macula densa will detect that the solute concentration is less and the afferent arterial will dilate to increase the GFR.
Which cells release renin?
The juxtaglomerular cells release renin if the macula densa detects dilution of fluid in response to low GFRthis causes an increase in aldosterone levels
How does renin release control aldosterone levels?
Renin is released then it converts angiotensinogen to angiotensin in the liver, from there angiotensin travels to the lungs where it is converted by ACE to angiotensin II which acts to raise BP.
In what three ways does angiotensin II affect the GFR?
It acts directly on the kidney constricting the efferent arteriole, It acts on the brain to release ADH which decrease Na and H2O excretion, and it actions on the adrenal gland to make aldosterone which decrease Na and H2O excretion.
How big are angiotensinogen, angiotensin I, and angiotensin II?
Angiotensinogen is larger, renin snips a 10 amino acid fragment which is angiotensin I, ACE cleaves 2 aa’s from angiotensin I to give the 8 aa protein, angiotensin II.
What effect does angiotensin II have on the vascular smooth muscle?
It cause vasoconstriction and thus HTN.
Besides its effects on the kidneys and the vaculature, how else does angiotensin II work to increase BP?
It is a powerful dipsinogen (thirst producer).
What are 5 ways to relax the vessels and lower BP?
NO, alpha receptor antagonists, ACE inhibitors, ATII receptor antagonists, and Ca channel blockers.
What is the primary effect of ACE inhibitors, Angiotensin II receptor antagonists and Ca channel blockers?
Promote vasodilation and reduce blood pressure.
How does Ca play a role in vasoconstriction/ elevated BP?
The signal for contraction of smooth muscle is the activation of myosin light chain kinase by increased cytosolic Ca. So Ca channel blocker will prevent smooth muscle from contracting.
What do drugs that end in opril do?
They are ACE in hibitors
What do drugs that end in artin do?
They are receptor agonists
What are the three ways to relax the smooth muscles of the vasculature?
1. Ace inhibitors, 2. Angiotensin II receptor antagonists, and 3. Ca channel blockers.
What are 5 drugs and an endothelial cell product that act on the SMC to relax vascular smooth muscle?
1. Alpha-adrenergic antagonist, 2. Activators of the NO/guanylate pathway, 3. Ca channel blockers, 4. K+ channel activators, 5. Angiotensin II receptor antagonists….and NO is the endothelial cell product that relaxes the vasculature.
As far as pharmacokinetics go, how is the systemic route of administration different from Parenteral?
Parenteral?
What are the pharmacokinetic considerations dealing when dealing with antibacterials?
Access of antibiotics to the site of infection, route of administration, Absoption, and Distribution.
What does penetration rely on?
Lipid and water solubility and protein biding. Lipophilic antibiotics (like tetracycline, macrolides) diffuse better than hydrophilics (B-lactams)
How does protein binding affect drug penetration?
If they are tightly bound in the plasma they won’t diffuse through capillary walls.
What are GI absorption, Permeability, Protein binding, Lipophilicity and the effects of dietary factors like for tetracycline?
GI absorption is 77-88%, Permability is low, protein binding is 55-64%, lipophilicity is low and absorption is inhibited by food, Ca, Fe…peanutbutter.
How does doxycycline compare to tetracycline in the above areas?
It is higher in all areas except dietary factors don’t affect absorption as much.
How does liver function relate to drug metabolism?
Some antibiotics are metabolized here and you can have drug toxicity if the pt has liver insufficiency, or in underdeveloped liver of the very young or w/reduced rates in the elderly.
How are most antibiotics excreted?
Via the urine in their active forms, so lower doses are needed to treat a UTI as the drug is very targeted/concentrated in these areas.
What is the therapeutic index?
The ratio of toxic dosage to the effective dosage (LD50/ED50)
What is the therapeutic range?
It falls between the toxic dose and the effective dose
What does the therapeutic index indicate?
The greater the ratio the easier it is to find a dosage that kills the bug but doesn’t harm the host.
What are the adverse effects of antibacterials?
GI disturbances (most common), Allergy (penecillins, sulfonamides, and cephalosporins), superinfections(Candida, antibiotic-associated colitis), and teratogenicity.
What are the 6 targets of antibacterial agents?
Cell wall synthesis, DNA replication, RNA synthesis, Folic Acid Synthesis, Protein synthesis 30s, and Protein synthesis 50s.
How do Penicillin and cephalosporins and vancomycin work?
They inhibibit petidoglycan synthesis by binding and inhibiting transpeptidase, so the bacteria can’t for a cell wall and they die => bactericidal.
What might enhance the effectiveness of Beta Lactams like penicillin or cephalosporin?
The use of beta-lactamase inhibitors like Clavulanic acid, Sulbactam, and Tazobactam.
Which beta lactamase inhibitor is most commonly used?
Clavulanic acid is used with amoxicillin as Augmentin.
What is the primary cause of antibiotic allergies?
Penicillin …note that 10% of patients with penicillin allergies show cross reactivity to cephalosporins.
What are three general types of penicillin?
There are narrow spectrum types like penicillin G and procaine penicillin that target most oral anaerobes, There are broad spectrum types like ampicillin or amoxicillin, and there are penicillinase/ beta-lactamase resistant penicillins like Methicillin.
What are the newer cephalosporin generations working to improve?
Increased spectrum, beta-lactamase resistance, and CNS penetrance
What is ceftriaxone?
The DOC for N. gonorrhea…a third generation cephalosporine.
What are the pharmacokinetics like for penicillin?
They are poorly lipid soluble, and don’t cross the BBB unless inflames as in meningitis, excreted by the kidney in active form so dose should be reduced in renal failure.
What are the pharmacokinetics of cephalosporins like?
Lipophilic, well aborbed w/good distribution, newer agents penetrate the CSF.
How do Vancomycin, Bacitracin, and Cycloserine work?
They interrupt petidoglycan synthesis.
How is Bacitracin taken?
Topical use only.
What is cycloserine?
A TB drug that works by inhibiting peptidoglycan synthesis.
What is Vancomycin like?
It is a hospital drug that is broad spectrum with high toxicity, can cause direct histamine release from mast cells to give Red Man syndrome. (looks like an allergic reaction, but isn’t)
What are the 30s protein synthesis inhibitors?
Aminoglycosides and Tetracyclines
What are some common aminoglycosides and what can they cause?
Streptomycin, Neomycin, gentamycin can cause Ear or Kidney issues.
What are tetracycline and doxycycline?
30s protein synthesis inhibitors that bind reversibly (bacteriostatic) can cause tooth staining and are used for Chlamydia, Rickettsia, and Mycoplasma.
What are the drugs that bind the 50s subunit to inhibit protein synthesis?
Macrolides (Erythromycin, azythromycin) and Chloramphenicol….these all bind reversibly and are bacteriostatic.
What is the first choice for penicillin allergic patients?
Erythromycin
What can Chlorampheicol cause and what is it used for?
It is used for Typhoid and could cause Aplastic Anemia or Gray Baby syndrome.
What are the pharmacokinetics of aminoglycosides?
Poorly lipid soluble, not absorbed orally so they must be injected, excreted in active form by the kidneys and can cause toxic tubular damage.
What are the pharmacokinetics like for tetracyclines?
Bind heavy metal ions, absorption is greatly reduced if taken with food, milk, antacids, or Fe tablets.
What are the pharmacokinetics like for macrolides?
Erythromycin is acid labile and so it is given as an enteric coated tablet.
What is unique about Linezolid?
It binds the 50s and inhibits the binding of 30s subunits, it can be bacteriostatic vs. enterococci and staph or bactericidal vs. strept, can have adverse side effects, used in serious infections (MRSA)
Are Fusidic Acid and Liconsamides (clindamycin) bactericidal or bacteristatic?
They are bacteriostatic
What side effect is clinamycin associated with?
It is broad spectrum and can cause psuedomembranous colitis via a superinfection with C. difficile.
What mechanism do quinolones, Rifampin, and Daptomycin use?
They are nucleic acid inhibitors and are all bactericidal.
What is the number one drug for uncomplicated UTI’s?
Septra
Which drugs are DNA gyrase inhibitors?
Quinolones
What is Rifampin used for?
TB and prophylaxis for N. meningitides
What is Daptomycin like?
It inhibits everything and is used for MRSA and VRSA skin infections and is bacticidal vs. enterococcus faecalis.
What is Metronidazole?
It is a DNA synthesis inhibitor that is bactericidal and is the DOC for ANUG and for Mild antimicrobial-induced enterocolitis.
What is unique about Metronidazole?
It can be used to treat mild antimicrobial-induced enterocolitis, but it can also cause that disorder. It also creates a state of alcohol intolerance and so can be used to help alcoholics quit.
What would you treat a severe case of antimicrobial-induced enterocolitis with?
Vancomycin.
What type of drugs are sulfonamides and trimethoprim?
They inhibit folic acid synthesis.
What is Septra the DOC for?
Pneumocystis jiroveci pneumonia, and most UTI’s (E. coli)
What is the second most common cause of antibiotic allergy?
The sulfonamides….they can also cause blood dyscrasias.
How does dapsone work and what is it used for?
It competes with PABA to inhibit folic acid synthesis and is used to tx leprocy…and brown recluse spider bites.
What are the 1st line drugs you would take if you seroconvert on your TB test?
1st Isoniazid (INH) that inhibits the synthesis of Mycolic acid
What is para-aminosalicylic acid (PAS)?
Works like sulfonamides and are bacteriostatic
What is the anti-leprosy drug?
Moxifloxacine
What are three possible interactions between antibacterials?
Additive, Synergistic, and Antagonistic
What are the indications for combining drugs?
Prevent resistant strains, treat polymicrobial infections, empirical therapy (just throw everything you have at it), and due to proven synergy of combo drugs.
When should we use antibacterials to manage an odontogenic infections?
Acute onset of fever or chills, spreading abscess, diffuse swelling or cellulitis, involvement of fascial spaces, or immunodeficient.
When don’t you need an antibiotic for an odontogenic infection?
In a chronic well localized abscess or in a minor vestibular abscess.
Which drugs would you usually prescribe for odontogenic management?
Penicillin or amoxicillin…if no improvement in 48-72 hours then metronidazole. Give clindamycin if allergic to penicillin….this is different than infections in the rest of the body where erythromycin is the DOC for penicillin allergic patients.
Who should get antibiotics before dental tx?
Prosthetic cardiac valves, Previous infective endocarditis, surgically placed shunts or implanted devices, and cardiac transplants with valve regurgitation.
Who doesn’t need antibiotic coverage for dental tx?
Rheumatic heart disease, mitral valve prolapsed, mitral or aortic valve stenosis, and congenital heart conditions n/c VSD or ASD.
If a patient requires antibiotic coverage what is usually prescribed?
A single dose of 2gm Amoxicillin for adults or 50mg Amoxicillin for kids 30-60 minutes prior to procedure.
As of 2009, what are the AAOS recommendations on antibiotic prophylaxis for those with joint replacements?
We are to administer a cephalosporin or amoxicillin 2 g orally 1 hour prior to procedure and they started a study in 2010 but there is still no change to this recommendation.