Phys Lab Protocols BLOCK 2. Pharmacokinetics, Compartments ECG Blood Pressure and Heart Spirometry. v

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1 Phys Lab Protocols BLOCK 2 Pharmacokinetics, Compartments ECG Blood Pressure and Heart Spirometry v. 0.1 PhysLabs@lf1.cuni.cz Labs aim: Explore biology in context through brain and hands PLS NOTE: For ECG, BP and Spirometry students are advised to find the principles in textbooks and plentiful internet resources. The labs cover basics of the methods. For these labs, just the list of tasks is currently available. ver. 02 (2007) 1

2 List of tasks: Blood pressure (BP) and heart: 1. arterial pressure a. compare results of auscultation, palpation and oscilometry measurement b. compare reading from left and right artery c. demonstrate effect of gravity on BP d. check pressure during and after exercise 2. venous pressure, central venous pressure (CVP) a. perform aspection of jugular veins (sitting and lying object) b. invrease CVP voluntarily and observe jugular veins b. estimate CVP by observing emptyiing of peripheral veins during elevating hand 3. heart - perform physical examination of the heart if the time allows a. asection b. palpation c. percussion d. auscultation ECG: 1. record 12 lead ECC: (label the record with patients name and activities performed) a. in resting laying subject b. during increased ventilation c. during patient movement d. in max inspiration and max expiration 2. describe ecg record from task 1: a. rhythmh b. regularity c. HR d. AV conduction e. cardiac el. axix f. waves and intervals SPIRO 1. perform FVC and FEV1 measurement, compare to norm. (everyone) 2. estimate PEF, compare to norm (everyone) 3. perform thorough spirometry examination using flowscreen students exmined a. static spirometry (VT,IRV,ERV) b. dynamic spirometry (flow-volume curve) 4. perform physical examination of lungs (if the time allows) a. asection b. palpation c. percussion d. auscultation ver. 02 (2007) 2

3 Compartments, modeling Pharmacokinetics What? compartment is a substance quantity (Q(t)) within a distribution space in which the substance has a uniform kinetics of transport and transformation. In easy words: a substance in a black box : We know what gets in (sources) and/or out (sinks) and do not see (neither care) what happens inside (the black-box). sources P 1 P 2 k 2 P m k m incomes employer mom k 2 lottery k m k 1 (Backbox) Compartment Q(t) k 1 my bank balance $$$ sinks k 1 k n spendings Why? Modeling using compartments is a method that enables us to simulate (mathematically) biological events and thus can help us to predict what would happen in reality Labs example: Pharmacokinetics (= distribution and metabolization of a drug in the body) Calculations enable us to find dosing of drugs, specifically in cases where metabolization is altered by additional diseases. How? As a result of simulations, we can get a time-course of a drug in various body regions/fluids, (e.g. blood, target organ/tissue etc) see the pic. below. Once the desired amount of drug in target organs is known (therapeutical level), parameters such as onset (A) of the effect, duration (B), peak concentration etc. can be estimated. Pic: Simulation result: Time course of drug amount in target tissue after one tab. ver. 02 (2007) 3

4 HOW? 1. how does that work? reality is simplified i.e. a model created Such model is mathematically described Math allows for calculation of a model behavior - i.e. simulation simulated events can help us to predict what would happen in reality calculated prediction can be much more accurate and quantitative than our guess 2. how a model is built? Let s see through an example used in the labs. The tasks are also illustrated by the scheme below Task example 0 System of interest described Pharmacokinetics 1 Compartments are identified GIT, blood, liver,... 2 Relevant Inputs / outputs for Absorption from GIT into blood, each compartment identified 3 Kinetics of i/o reactions is described elimination... Linear / non-linear Zero / First/second... order Rate constants Based on experimental findings 4 Initial conditions found i.e. amount of drug in the body before the simulation 5 simulation Just press magical button simnulate Labs example and task: 4-compartmental model of Pharmacokinetics after oral administration of a drug. step 0: Our drug travels just among certain organs (Thus not all are included) ver. 02 (2007) 4

5 step 1: organs with similar kinetics are black boxed. (E.g. Further details of processing in GIT are not studied as in our case it can here be assumed that it is same for stomach, duodenum, ileum,... ) step 2: just relevant transportations are considered (E.g. no gastric secretion of our drug is expected / possible) step 3: Calculation of transports (flows) between compartments requires the knowledge of reaction kinetics and rate constants. Constants are obtained from biological experiments. FLOWS: In our example, flows are first-order kinetics and can be easily calculated: Actual flows (amount of drug per time) between compartments depend on two parameters: Amount in source ( how much is available ) Rate constant ( how fast it could flow ) Thus: FLOW ~ Q(GIT) x k 1 Rate constants reflect the ability of the mechanisms transporting the substance (drug). Their values are obtained from experiments. QUESTIONs: Can rate constants vary? Which biological features are included in rate constants? 3. how a model is used INPUT: Once a model is constructed (i.e. compartments are identified and equations written) it requires initial data: initial conditions (amount of substance at time of simulation beginning) i. originally no drug in the body, just the tablet in GIT rate constants (see above) OUTPUT: Time-courses of compartments as mentioned earlier. Allows us to: see amount of drug in the body (blood, tissues, urine) after our virtual administration of a drug, see the effect of changes in transportation and metabolization (phys and pathophys) suggest administration strategies TASKS For all tasks assume effective concentration in tissues 0.26 (arb. Units) 1. physiology. Identify in tissues: a. onset b. duration c. maximum and time of maximum ver. 02 (2007) 5

6 2. simulated renal disorder a. see the effect of progressive decrease of renal elimination (in steps 20%), notice and record parameters 1.a.b.c. b. plot a graph of the relationship between renal dysfunction and tissue maximum c. suggest dose refinement for 60% decrease in renal elimination 3. chronical therapy suggest periodical oral administration of the drug so that tissue level never falls below effective amount ver. 02 (2007) 6

7 Compartments Software interface (v.2005) The whole interface is squeezed into one screen see the screenshot below. Simulation checklist: 1. Check the time info (start, end time, step) 2. Type or load equations for all compartments. (name to the left column, right-hand side to respective right one. 3. define constants (name to the left column, value in the right one) 4. Fill in initial conditions (values at time zero ) 5. See the results and read values with the help of a cursor. Troubleshooting hints 1. For context hints - hold the mouse over the input fields 2. If no graphical results can be obtained - reload the app. 3. If you cannot Load, Save or you see little response - see Running Mode info. 4. If problems persist, check that: a. equal number of a) compartments names, b) expressions and c) init cond. are filled b. all other cells MUST BE FADED. To fade the cell, right-click and in context menu select 'Data Opreation' -> 'Delete Element/Row'. 5. Up to 6-compartmental model and 8params can be defined. For more, other tool is available. Running Mode Info In order to allow for interactivity the model is permanently running. This means that after any change the data are recalculated and re-plotted automatically (sometimes faster than one can notice). This is called Run continuously, it is selected by default when software is opened. To reactivate continuous run (i.e. after previous STOP) hit button (top left). For major changes required to solve some tasks it is usefull to STOP the running, do the chabges and start calculation again. Hit STOP button and once the changes are done hot Run continuously ver. 02 (2007) 7

8 DATA INPUT AREA (left half-screen) RESULTS AREA (right half-screen) 1. Check Time: set start and end time for the simulation. PC does not know how long to calculate if nod said so. (default start=0, end=24 hr). also step (time intervals how often the calculation is repeated) must be defined (default step=05h) 4. Graph see results see the legend at top right axes can be rescaled by directly retyping the desired value additional display functions are available after right-clicking the graph 2. Fill in Equations: comp name of the compartment, usually a, b, c,. Max of six compartments can be defined in this model equation expression to calculate respective compartment (max. of 6) 5. Cursor results more detailed allows for accurate reading data from graphs snaps to the curves by default additional display functions are available after right-clicking the graph 3. Set Parameters Init. condition size of the compartment in the beginning of simulation ( time zero ) rate constants names and values of respective rate constants from the eqns. (usually k1, k2, k3, ) 8 constants can be defined at max. LOAD/SAVE instead of typing all the values, default eqns and params can be loaded. Also custom model can be saved (but just in certain folder) ver. 02 (2007) 8