CVS Pharmacology

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• INTRODUCTION TO CVS PHARMACOLOGY
  Brief-Physiology of the Heart and Regulation of
  Cardiovascular Function

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• Lecture objectives
• Brief-physiology of the heart and review of
  regulation of cardiovascular function necessary
  for CVS pharmacology
• Identify locations of ANS receptors and their
  neurotransmitters
• Predict the cardiovascular and non cardiovascular
  effects
• of activation or antagonism of these receptors.
• Describe the effects of the baroreceptor reflex
  on response
• to autonomic drugs)

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Brief-Physiology of the Heart
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What are the 3 parts of the cardiovascular system?
heart blood blood vessels
What do arteries do? Take blood AWAY from the
heart What do veins do? Bring blood TOWARD the
heart

• What are the 4 chambers of the heart?
• Right Atria
• Left Atria
• Right Ventricle
• Left Ventricle
• What does the septum do?
• Divides the heart into right and left sides

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• PHYSIOLOGY OF THE HEART

• The Conducting System (electric)

• called an intrinsic conduction or nodal
  system of specialized tissue

1. Sinoatrial Node (SA)

• PACEMAKER OF HEART starts each heartbeat

• located in wall of right atrium

• made of specialized myocardial cells

• sends impulse to both atria, causing them to
  contract

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SA Node
AV Node
2. Atrioventricular Node (AV node)

• located at base of right atrium receives
  impulse from SA node

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• Atrioventricular Bundle

• Location middle of septum

Atrioventricular Bundle

• impulse from AV node goes down bundle to base
  of heart

• Direction of Heart Beat

• it then travels up the sides of the ventricles
  through the PURKINJE NETWORK causing the
  ventricles to contract from the bottom up

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• RATE OF HEART BEAT

• Factors affecting heart rate

• age, sex, physical activity, temperature,
  thought processes, chemicals (natural and
  otherwise)

• rate high at birth (100 140 bpm) then
  declines steadily until average is reached (70
  80 bpm)

• heart rate faster in females slower in
  trained athletes

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• CARDIAC CYCLE

• the events of one complete heartbeat

• length of cycle (heartbeat) is about 0.8 sec

• atria contract at the same time as they
  relax, the ventricles contract

• SYSTOLE

• contraction of ventricle

• DIASTOLE

• relaxation of ventricle

• amount of blood pumped out of each side of the
  heart in 1 minute

• Cardiac Output

• heart rate X stroke volume

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• PULSE BLOOD PRESSURE

• pulse can be found at many sites on the body

• Pulse

• expansion contraction of an artery as the
  left ventricle contracts

• normal is 70 80 bpm (there are exceptions to
  this)

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• Blood Pressure

• pressure blood exerts on the inner walls of
  blood vessels

• Measuring BP

• BP is a measure of the systolic pressure
  (ventricles contracting) OVER the diastolic
  pressure (ventricles relaxing)

• Example

• 110/70 is in normal range

• Factors affecting BP

• nervous system, blood volume (kidneys), temp,
  chemicals, diet, exercise

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• The Electrocardiogram (EKG or ECG)

• amplifies electric current of heart producing
  distinct wave patterns

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QRS Complex
P wave
T wave

• P wave

• depolarization of atria

• QRS Complex

• depolarization of ventricles

• T wave

• repolarization of ventricles

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Autonomic Innervation of the Heart and Vasculature
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• Neural Activation of the Heart and Blood Vessels
• Medulla
• It is located in the brainstem and a major site
  for regulating autonomic nerve outflow to the
  heart and blood vessels
• It contains cell bodies for the two main
  divisions of the ANS- sympathetic and parasympathe
  tic.
• Sympathetic nerves exit the medulla and travel
  down the spinal cord and synapse with
  preganglionic fibers.
• Postganglionic efferent fibers from ganglia
  travel to the heart and vasculature.
• Parasympathetic nerves exit the medulla and form
  synapses with postganglionic fibers within the
  heart or vascular tissue.

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• Nucleus Tractus Solitarius (NTS)
• NTS of the medulla receives sensory input from
  different receptors (e.g., baroreceptors and chemo
  receptors).
• NTS modulate the activity of sympathetic neurons
  and vagus nerves (X cranial nerves).
• The hypothalamus and higher centers modify the
  activity of the medullary centers and are
  particularly important in stimulating
  cardiovascular responses to emotion and stress
  (e.g., exercise, thermal stress).

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• Innervation within Heart and vasculature
• Sympathetic efferent nerves are present
  throughout the atria (especially in the SA node)
  and ventricles, including the conduction
  system of the heart.
• Their activation increases HR, contractility
  and conduction velocity.
• The vagus nerve innervates SA node, AV node and
  atrial muscle is also innervated by vagal
  efferents and the ventricular myocardium is only
  sparsely innervated by vagal efferents (Therefore
  parasympathetic effect on inotropy is weak in
  ventricle but relatively strong in atria)

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• Sympathetic activation constricts arteries and
  arterioles (resistance vessels) increases
  vascular resistance and decreases distal blood
  flow leading to increase in arterial pressure
• Also constrict veins (capacitance vessels)
  thereby increasing venous pressure.
• Most blood vessels do not have parasympathetic
  innervation but innervate salivary glands,
  gastrointestinal glands, and genital erectile
  tissue where they cause vasodilation.

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Sympathetic Receptors effects Responsible for basal control of vasculature tone Sympathetic Receptors effects Responsible for basal control of vasculature tone Sympathetic Receptors effects Responsible for basal control of vasculature tone Sympathetic Receptors effects Responsible for basal control of vasculature tone
Receptor Location Effect Mechanism GPCR
a1 Vascular smooth muscle Vasoconstriction a1 Gq (phospholipase C)
a2 Presynaptic SNS nerve terminals Negative feedback (decreases NE release) a2 Gi (adenylyl cyclase inhibition)
ß1 SA node AV node Atrial ventricular myocytes Increased heart rate Increased AV conduction Increased contractility All ß Gs (adenylyl cyclase)
ß2 Vascular smooth muscle Vasodilation
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Parasympathetic Receptors effects Responsible for basal control of heart rate Parasympathetic Receptors effects Responsible for basal control of heart rate Parasympathetic Receptors effects Responsible for basal control of heart rate Parasympathetic Receptors effects Responsible for basal control of heart rate
Receptor Location Effect Mechanism GPCR
M2 SA Node AV Node Atrial myocytes Decreased HR Decreased conduction Decreased atrial contractility M2 Gi (adenylyl cyclase inhibition)
M3 Vascular endothelium Vasodilation (not innervated) Effected by drugs M1/M3 Gq (phospholipase C
NN Ganglia Mediates ganglionic transmission (sympathetic and parasympathetic) Ligand-gated ion channels
Adapted from Katzung, Basic and Clinical
Pharmacology, 12th ed. Table 6-3.
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Neurotransmitters

• Sympathetic receptor endogenous ligands
• Norepinephrine
• Epinephrine (hormone)
• At physiological concen- all SNS receptors
  activated
• At pharmacological concen- receptor specificities
  vary- also vary based on dose
• Parasympathetic receptor endogenous ligand
• Acetylcholine (Ach)
• Reminder All autonomic ganglionic transmission
  mediated by nicotinic (NN) receptors and ACh

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BaroReceptor Reflex
VMC vasomotor center
Increases vagal outflow
Stretch receptors
(MAP)
Brenner, Pharmacology (2000), Fig. 5-4.