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Self-Study of Cardiovascular Pharmacology

Download CardioPharm(TM) to start self-study of Cardiovascular Pharmacology

Download the zipped file for CardioPharm(TM) setup.

Student Information:

 
  First Name:
   Last Name:
      E-mail:
        ID #:
Please fill out your name above and then put the .zip file in a temporary subdirectory and unzip the "cvsim.zip" file. A group of setup files will be created and you can install CardioPharm(TM) by double-clicking on "setup.exe". When the program has been installed you can run the program in Windows 9X or Windows 2000/XP.

Self-assessment questions:

A SIMULATION OF CARDIOVASCULAR PHARMACOLOGY
AND AUTONOMIC REGULATION

Adapted for the Web and USC School of Pharmacy, PHAR 545, Therapeutics III Course
by Michael B. Bolger, Ph.D.

One of the best ways to learn autonomic pharmacology, is to become involved in the administration of autonomic drugs and monitoring of cardiovascular endpoints. In the past, students could participate in live demonstrations of cardiovascular pharmacology by using mongrel dogs. The use of animals in medical research and education was a highly valued priviledge and a serious responsibility. Those animals always received the best in humane care. In spite of the value of this type of real life experience, problems were always apparent during the conduct of such experiments. Catheters would become misplaced and not read correctly, the dogs might have an unusual response to the drugs administered, electronic connections would become disconnected, etc.

Today, we have the benefit of high speed computers capable of producing a realistic simulation of blood pressure, heart rate, peripheral resistance, and cardiac output in real time. The simulation model that drives such a simulation is cabable of responding to the administration of autonomic drugs in much the same way that a real animal responds. In order to get the most out of this simulated individual lab experience, you should run the simulation program, "CardioPharm(TM)", (sorry PC's only for now, until I finish a platform independent JAVA version) and follow the instructions below.

CardioPharm(TM) installation files can be found on the internet at LabSoft Solutions . After installing CardioPharm(TM) you can run the program by double-clicking on its icon. When you are looking at the CardioPharm(TM) window, standard MS-Windows buttons are used to administer various drugs and to perform a variety of invasive procedures. In addition the following Alt-Key combinations can be used with CardioPharm(TM):

  • Alt-C = Start/Stop
  • Alt-A = Alpha-1 agonist
  • Alt-B = Beta agonist
  • Alt-M = Muscarinic agonist
  • Alt-p = Alpha antagonist
  • Alt-e = Beta antagonist
  • Alt-u = Muscarinic antagonist
  • Alt-t = Angiotensin
  • Alt-V = Vasodilator
  • Alt-n = Epinephrine
  • Alt-o = Norepinephrine
  • Alt-I = Isoproterenol
  • Alt-g = Vagal Section
  • Alt-R = Reset simulation to normal values.


Return to A Programmed Introduction to Autonomic Nervous System

AGONISTS
  • Alpha-1 = Pure Alpha Adrenergic (mainly A1 arteriolar constriction)
  • Beta-(1&2) = Pure Beta Adrenergic (mixed B1 and B2)
  • Muscarinic = Pure Muscarinic
ANTAGONISTS
  • Alpha-1 = Pure Alpha Adrenergic Blocker
  • Beta-(1&2) = Pure Beta Adrenergic Blocker
  • Muscarinic = Pure Muscarinic Blocker
ANS DRUGS
  • Epinephrine = (Mixed beta and alpha agonist)
  • Norepinephrine = (Mostly alpha agonist)
  • Isoproterenol = (Mostly beta agonist)
  • Acetylcholine = (Muscarinic and Nicotinic agonist)
DIRECT ACTING
  • Angiotensin = Potent Endogenous Vasoconstrictor
  • Vasodilator = Direct Acting Arteriolar Vasodilator
PHYSIOLOGICAL
  • Vagal Section (cut the parasymathetic influence on the heart)
  • Carotid Occlusion (decrease blood pressure in the carotid sinus)
  • Carotid Release (restore blood flow to carotid sinus)
  • Hemorrahage (serious consequences, you might loose the dog)
HOUSEKEEPING
  • Start / Stop CardioPharm = Suspend computation (freeze the current screen)
  • Reset = Restart (Clear Everything)
GRAPH LEGEND
  • - = Cardiac Output
  • + = Peripheral Resistance
  • black line = Systolic and Diastolic Blood pressure.
  • blue line = Relative degree of sympathetic tone in arterioles.
  • green line = Relative amount of agonists present.
  • red line = Relative amount of antagonists present.
KEY TO VITAL STATISTICS
  • HR = Heart Rate (beats / m)
  • CO = Cardiac Output (L / m)
  • SV = Stroke Volume (L)
  • SP = Systolic Pressure (mm Hg)
  • DP = Diastolic Pressure (mm Hg)
  • PP = Pulse Pressure (SP - DP, mm Hg)
  • MAP = Mean Arterial Pressure (DP + (PP / 3), mm Hg)
  • TPR = Total Peripheral Resistance (mm Hg m / L)
INITIAL CONDITIONS
  • CO = 5.5 L/min
  • HR = 75 beats /min
  • DP = 90 mm Hg
  • SP = 115 mm Hg
  • Mean arterial pressure = 98 mm Hg
  • TPR = 0.36
  • Initial Stroke Volume = 0.078 L
IMPORTANT EQUATIONS
  • BP = CO x TPR (Ohm's law: E = I * R)
  • CO = SV * HR
  • TPR = MAP / CO

When a drug is administered, the response can usually be divided into three phases:

  1. The direct action of the drug on the target tissue and subsequent responses of other components.
  2. Reflex actions which attempt to restore the normal conditions.
  3. The gradual diminution in response as the drug is degraded.

Look for these phases when you simulate the administration of drugs. You inform the computer that you wish to simulate the administration of a drug or perform a procedure by pressing a command button. It is best to administer drugs, etc. when the trace is near the left edge of the screen so that you can observe the entire response.

Questions are posed throughout the experimental protocol. You should answer all of the questions and submit this form with your name and ID number when you are finished. You may possibly see some of these questions again sometime.

We will start this laboratory session by administering some theoretically pure autonomic agents. In reality, most drugs do not have "pure" autonomic actions. Typically, an alpha adrenergic agonist will have some beta adrenergic effects and vice versa. A selective beta-1 adrenergic antagonist might have 100 times higher affinity for beta-1 receptors compared to beta-2 receptors, but there is usually some residual effect at other sites. With the computer, we can create pure alpha and beta agonists in order to learn the expected results when the drug induced changes in cardiovasular parameters occur from the action of a drug on only one site of action followed by the reflex response and then by the degradation of the administered drug.

  1. Run the CardioPharm(TM).EXE program as described above. Allow the blood pressure oscillations to smooth out and then record the normal values of HR, CO, SV, SP, DP, PP, MAP, and TPR. You will be able to compare these baseline values to those you observe later in the laboratory.

  2. Now use your mouse to press the "alpha-1 agonist" button once when the trace is close to the left side of the screen to administer a pure alpha-1 agonist. If you do not see the following cardiovascular response please ask your TA for assistance.

    In time zone 1, the most immediate response of an agonist is to peripheral resistance (see + symbols) causing an increase in mean arterial pressure and a decrease in cardiac output (see - symbols).
    One consequence of this increase in arterial pressure is increased stretching of the carotid sinus (click for image). Stretch of the baroreceptors in the carotid sinus increases the firing rate of the depressor nerve causing stimulation of alpha-2 receptors in the cardiovascular control center of the CNS. This causes increase parasympathetic outflow and decreased sympathetic outflow.

  3. In time zone #2 the heart rate is due to the reflex action of the system. The change in heart rate is caused by the action of on the receptors of the SA node of the heart.

  4. Assuming the alpha agonist is an intravenous dose of norepinephrine,in time zone #3 the cardiovascular parameters are returning to normal due to of the administered drug.

  5. Now press the Reset menu item to reset initial condition and then press "Beta-(1&2)" for a pure beta adrenergic agonist (Note: this is a mixed beta-1 and beta-2 agonist. The first actions of a pure beta agonist are to peripheral resistance (beta-2 response on skeletal muscle) and to increase heart rate (direct action of a beta-1 agonist on the SA node of the heart. This causes an increase in stroke volume and cardiac output. Note that the inital decrease in peripheral resistance is rapidly eliminated as the reflex action of NE (alpha-1 agonist) causes arteriolar vasoconstriction. Finally, the parasympathetic reflex causes an decrease in heart rate and eventual decrease in stroke volume as the peripheral resistance returns to normal.

  6. Now press the the Reset menu item to reset the simulations and then press "Muscarinic" for a pure muscarinic agonist. Notice that the response is very minor and terminates quickly. Now press "Muscarinic" five times rapidly. This is a very strong muscarinic effect on the heart producing a large in heart rate. Again, the action is terminated rapidly.

  7. Next we will compare the action of NE to the action of Isoproterenol and Epinephrine. First, Reset the computer screen and then press "Norepinephrine" to administer norepinephrine. Next, Reset the computer screen again and then "Epinephrine" to administer epinephrine. Which drug has the greater alpha-1 adrenergic activity? (Ans: ). Now, Reset the computer screen and then "Isoproterenol" to administer isoproterenol. The primary action of isoproterenol is . Be sure you can explain the three phases of each drugs action, (1) direct, (2) reflex, and (3) termination.

  8. We can now administer an alpha-adrenergic antagonist and retest NE and EPI to check their relative degrees of beta-adrenergic action. Reset the simulation and then press "alpha-1 antagonist" for an alpha antagonist and wait for the trace to return to normal. Now press "Norepinephine", "Epinephrine", or "Isoproterenol" to see their relative degree of beta-adrenergic action. Notice that the effect of NE and EPI are similar in their beta activity and that the standard dose of isoproterenol produces a beta effect that is approximately five times the beta effect of EPI or NE.

  9. In order to clearly see the direct effects of adrenergic agonists you can administer a a muscarinic blocker to screen out the reflex bradycardia caused by the parasympathetic system. Reset the simulation and then "Muscarinic Antagonist" for a muscarinic blocker like . Now, when "Epinephrine" or "Norepinephrine" are pressed the parasympathetic reflex decrease in heart rate does not occur and the mean arterial pressure oscillates up and down due to the sympathetic reflex only.

  10. Now compare the effect of a muscarinic blocker to the result of a surgical procedure that cuts the vagus. Reset the simulation and then "Vagal Section" to cut the vagus. Now repeat the administration of EPI or NE as in the previous question. Do the responses look similar? (ANS: )

  11. Finally, experiment with the effects of a very strong vasoconstrictor like "Angiotensin" or a pure "Vasodilator" on the action of EPI and NE. Notice that the alpha-1 vasoconstrictor effect of NE is enhanced with angiotensin on board and the reflex bradycardia induced by the parasympathetic system tries to keep the mean arterial pressure low.

Questions? Comments?

  • bolger@usc.edu - Content and Web Page Administration

    Last updated 8/27/02
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