EFFECTS OF SYMPATHOMIMETICS ON CARDIOVASCULAR DISEASES

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PREREQUISITE Sympathetic Nervous
System PHYSIOLOGY Needed for studying SNS
PHARMACOLOGY
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• ?Differ in
• Site of ganglia
• Length of pre postganglionic fiber
• Mediators of postganglionic fiber
• Ramifies adrenal medulla and its mediator
  circulate in blood

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PREDOMINANT TONES OF MAJOR ORGAN SYSTEMS

• Heart - parasympathetic
• Arterioles/arteries - sympathetic
• Veins - sympathetic
• Iris - parasympathetic
• Ciliary muscle - parasympathetic
• GI tract (ENS) - parasympathetic
• Smooth muscle - parasympathetic
• Bladder - parasympathetic
• Sweat glands - sympathetic
• Salivary glands parasympathetic
• Lacrimal glands parasympathetic

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• Transmitter is
• Mainly norepinephrine NE
• Rarely Ach ? M2
• or Dopamine ? D1

• Transmitter is
• Mainly epinephrine E ? circulates and
  acts a1, a2, b1 , b2 , b3

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POSTGANGLIONIC SYMPATHETIC NERVE ENDING
Na
Norepinephrine (NE)
Tyrosine
Dopa
Tyrosine
SYNTHESIS
DA
STORAGE
NE
RELEASE
Ca
ACTION
REUPTAKE
NET
DEGRADE
COMT
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ADRENOCEPTORS ADRs
D1
Postsynaptic
Presynaptic
a1 ADRs. a2 ADRs. b1 ADRs. b2 ADRs. b3 ADRs.
a2
b2
a1
b1
b3
Autoregulatory Function
a2
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ADRENOCEPTORS ADRs
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ADRENOCEPTORS ADRs
a1 ADRs couple to Gq to stimulate PLC ??Ca
intracellular. a2 ADRs couple to Gi to inhibit
AC ? ?cAMP . B1,2 3 ADRs couple to Gs to
stimulate AC ? ?cAMP
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ADRs
Coupled to Gq ?Activates PLC ?? IP3 ??Ca PKC
a1 ADRs

• Some smooth muscles SMC ?
• Vascular VSMC
• N-VSMC Lung / GIT UB (sphincters) / eye
  (dilator) .etc

Adr
?Ca
At VSMCs ?VASOCONSTRICTION
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Couple to Gi ? Inhibit AC ? ?cAMP
ADRs
a2 ADRs

• At presynaptic nerve ending
• At some VSMCs N-VSMC GIT motility
• In pancreas ? ? insulin

Adr
?cAMP
At VSMCs ?a2 ADRs activation postsynaptic ??cAMP
?leaves Ca signaling unopposed ? Vasoconstriction
At Presynaptic Nerve Ending ??NE release ?????
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ADRs
b1,2 ,3 ADRs
Adr
Couple to Gs ? stimulate AC ? ?cAMP

?cAMP
b1 ADRs
b2 ADRs
b3ADRs

• CARDIAC STIMULATION
• Renal (renin release)

• VSMCs ?Vasodilatation (cardiac,skeletal)
• N-VSMCs ? RELAXATION Bronchodilatation
• GIT, UB, pregnant uterus,
  (?motility)
• ? glucagon secretion (glycogenolysis, glycolysis)

Adipose T. (Lipolysis)
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SNS ACTIVATION on VSMCs
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1
2
NET SUMMATION will dictate the FINAL ACTION
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SNS actions at b receptors in organs
controlling metabolism
b2 ADRs
b3ADRs
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Eye
Mydriasis
IOP
Kept by a balance between formation drainage
Paralysis of constrictor pupilli (M) Contraction
of dilator pupilli (a1)
Accomodation
If balance disturbed by increasing formation or
decreasing drainage ? ?IOP ?glaucoma
Parasymp mimetics ?? glucoma (trabecular) Parasymp
lytics ? ? glucoma Sympathomimetics ? ???
effect b blockers ?? glucoma (uveoloscleral)
For near vision (M) For far vision (b2)
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SYMPATHETIC ACTIONS Fight Flight
a receptors
b1 receptors
b2 receptors
EYE Relax Ciliary m.
EYE Contract Dilator Pupilli
SALIVARY GLANDS ? Salivation
VESSELS Vasodilatation
BLOOD VESSELS Vasoconstriction

• HEART
• ? Force Inotropic
• HR Chronotropic
• ?AV conduction
• Dromotropic

BRONCHUS Bronchodilatation
GIT Contraction of sphincters
GIT G. Bladder ?Motility
LIVER ? Glucose
PANCREAS ? Insulin secretion
KIDNEY ?Renin from Juxta-glomerular cells
URINARY BLADDER Contraction of sphincters
BLADDER Detrusal m.Relax
UTERUS Relax Tocolysis
PENIS Ejaculation
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Sum up of physiological actions of Epinephrine
(adrenaline)
Acts on all ADR b /gt a

• Heart ? inotropic, chronotropic, dromotropic
  lusiotropic (?excitability)(b1)
• BP ?? systolic (b1) / diastolic ? ? low dose
  (b2) ? ?high dose (a1)
• Vascular SMC constrict skin peripheral (a1) /
  dilate coronaryskeletal (b2)
• Non vascular SMC
• Lung ? bronchiodilatation (b2)
• GIT ? ?motility (b2) / contract
  sphincter (a1)
• Bladder ? ? detrusor m. (b2) / contract
  trigone sphincter (a1)
• Pregnant uterus ? tocolytic (b2)
• Eye ? mydriasis (a1)
• ? accommodation for far
  vision little effect on IOP
• Metabolism ??insulin (a2) , ?glucagon (b2), ?
  liver glycogenolysis sk. m. glycolysis
  (b2) / ? ? adipose lipolysis (b3 /b2)
• CNS ?little, headache, tremors restlessness

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GOOD LUCK
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Adrenergic receptor subtypes and actions

• Alpha
• GPCRs
• Two subtypes
• A1 Gq protein coupled
• A2 Gi protein coupled
• Beta
• GPCRs
• Three subtypes
• B1-3 Gs protein coupled

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Autonomic regulation of organ systems
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Autonomic regulation of CVS function

• Baroreceptor reflex
• Increase in MAP
• Increased baroreceptor firing
• Increase parasympathetic tone
• Decrease sympathatic tone
• Decrease in MAP
• Decreased baroreceptor firing
• Decrease parasympathetic tone
• Increase sympathetic tone

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Regulation of the heart
Dominant tone parasympathetic
Sympathetic Increases heart rate and
contractility via beta-1 and 2 (primarily beta-1)
Parasympathetic Decreases heart rate and atrial
contractility via M2
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Regulation of the blood vessels
Veins Dominant tone parasympathetic
Arterioles/arteries Dominant tone
sympathetic Contraction via alpha1 Relaxation
via beta-2
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Regulation of bronchi

• In autonomic ganglia there is cholinergic N and
  M1 receptors
• At postganglionic parasympathetic fibres there is
  M2 receptors and is also controlled by B2 ADRs
  fibres
• On bronchiolar SMCs there is M3 and B2 ADRs

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Regulation of bronchi
Vagus n.
AD
AD
Adrenaline is coming to bronchi mainly humoral
AD
Epithelial Irritation Shedding
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Enteric Nervous System

• Large and highly organized system of neurons
  located in the walls of the gastrointestinal
  system
• It is often considered a third division of the
  autonomic nervous system
• Includes the myenteric plexus (of Auerbach) and
  the submucous plexus (of Meissner)

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Enteric nervous system
Parasympathetic
Longitudinal muscle
Myenteric plexus
Circular muscle layer
Submucosal plexus

• Walls constricted and sphincters relaxed via M3
• Secretions increased via M3

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Autonomic regulation of eye structures
Dominant tone Parasympathetic
Iris radial contracted via alpha-1 Iris
circular contracted via M3 Ciliary muscle
contracted via M3
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Regulation of the liver

• Sympathetic
• Increase gluconeogenesis and glycogenolysis
• Provide glucose to fuel flight or fight
  response
• Primarily beta-2, possibly alpha-1

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Control of stomach acid

• Parasympathetic
• Increase histamine release from ECL cell via M3
• Increase H production from parietal cell in
  fundus via M3
• Decrease somatostatin release from D cell in
  antrum
• Increases gastrin release from G cell

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Regulation of the bladder

• Parasympathetic
• Bladder wall
• Constriction via M3
• Relaxation via beta-2
• Sphincter
• Relaxation via M3
• Constriction via alpha-1

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Glandular secretion
Sweat
Salivary
Increased via M3
Appocrine increased via alpha-1 Eccrine
increased via M
Lacrimal gland (tear production) increased via M
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PHYSIOLOGICAL EFFECTS OF ANS INNERVATION AND
RECEPTORS THAT GOVERN SUCH EFFECT
PARASYMPATHETIC
SYMPATHETIC

• Contracts the iris radial muscle via alpha-1
• Relaxes the ciliary muscle via beta
• Accelerates the sinoatrial node via beta-1,2
• Accelerates ectopic pacemakers via beta-1,2
• Increases cardiac contractility via beta-1,2
• Relaxes bronchiolar smooth muscle via beta-2
• Relaxes GI walls via alpha-2, beta-2
• Contracts GI sphincters via alpha-1
• Relaxes bladder wall via beta-2
• Contracts bladder sphincter via alpha-1
• Contracts uterus via alpha, relaxes uterus via
  beta-2
• Contracts pilomotor smooth muscle via alpha
• Activates sweat glands via alpha, M
• Increases gluconeogenesis and glycogenolysis in
  liver via beta-2 and alpha
• Induces lipolysis via beta-2
• Increases renin release from kidney via beta-1
• Semine ejaculation alpha-1

• Contracts the ciliary muscle via M-3
• Decelerates the sinoatrial node via M-2
• Decreases heart contractility via M-2
• Releases EDRF in the endothelium via M-3, M-5
• Contracts bronchiolar smooth muscle via M-3
• Contracts GI walls via M-3
• Relaxes GI sphincters via M-3
• Increases GI secretions via M-3
• Contracts the uterus via M-3
• Causes erection of the penis via M