CV Autonomic Pharmacology

Question 1

What autonomic system & respective receptors respond to norepinephrine? Epinephrine? Acetylcholine?

Answer 1

• Sympathetic
  
  • norepinephrine
    
    • alpha₁, alpha₂, beta₁
  • epinephrine
    
    • alpha₁, alpha₂, beta₁, beta₂
• Parasympathetic
  
  • Acetylcholine
    
    • M, N

Question 2

Cardiovascular response to activation of the autonomic nervous system depends on what factors?

Answer 2

• location adn proportoin of the receptors
• baroreflex and adjustments
• predominant tone

Question 3

Fill out the provided table with regards to receptor location and proportion on CV response to activation of parasympathetic nervous system (M₂)

Answer 3

Question 4

Fill out the provided table with regards to receptor location and proportion on CV response to activation of sympathetic nervous system

Answer 4

Question 5

Describe the sympathetic, parasympathetic & physiolgical responese to baroreceptors

Answer 5

• Baroreceptor response occurs in reaction to acute changes in pressure - (Blood Pressure)
  
  • purpose is to maintain acceptable blood pressure
• direct relationship w/ parasympathetic & indirect relationship with sympathetic
• Increase in pressure
  
  • decrease sympathetic activity
  • increase sympathetic
  • = decrease in HR & contractility
• Decrease in pressure
  
  • increase in sympathetic
  • decrease in parasympathetic
  • = increase in HR & contractility

Question 6

What is the predominant ANS tone for the following structures:

arterioles

veins

heart & ventricular muscle

SA node

Answer 6

• arterioles
  
  • SNS
• veins
  
  • SNS
• heart & ventricular muscle
  
  • SNS
• SA node
  
  • PNS

Question 7

How does this graph demonstrate the concept of predominant tone?

What happens when a medication blocks innervation by either sympahetic or parasympathetic systems?

Answer 7

If the intrinsic heartrate without any autnomic innervation is around 100-110 bpm, but our normal resting heart rate is 60-80 bpm, then our normal resting heart rate is mostly controlled by the parasympathetic nervous system

• Parasympthetic blocked
  
  • heart rate will increase
• Sympathetic blocked
  
  • heart rate will decrease

Question 8

What are 2 examples of clinical uses of atropine? What type of drug is this?

Answer 8

• Muscarinic antagonist
• Clinical uses
  
  • sinus bradycardia or AV block in patients with MI
  • severe bradycardia and syncope caused by hyperative carotid sinus reflex

Question 9

Explain how the different type of indirect adrenergic agonists work & provide examples for each type

Answer 9

• cocaine & tricyclic antidepressants
  
  • inhibiting NE reuptake into presynaptic nerve
• tolcapone
  
  • blocking metabolism of NE by catechol methyltransferase
• rasagiline
  
  • blocking the metabolism of NE by monoamine oxidase in presynaptic neuron
• amphetamine tyramine
  
  • promoting release of NE by presynaptic nerve terminals
• ephedrine
  
  • mixed acting
  • indirect agonist: promote release of NE by presynaptic nerve terminals
  • can also bin to post synaptic nerve

Question 10

Fill out the provided table regarding clasfication of adrenergic agonists based on receptor selectivity

Answer 10

• Selectivity is dose dependent
  
  • become less selective as dosage increases
    *

Question 11

What are the 3 clinical uses of alpha₁-selective receptor agonists?

Name of the drugs?

Answer 11

• Phenylephrine (alpha₁>alpha₂) and midodrine (alpha₁)
• Through vasoconstriction, can be used for the following clinical uses:

1. Reduce bleeding
2. Hypotension
   
   • via increasing blood pressure
3. Nasal congeestion
   
   • via increased nasal cavity

Question 12

What are the clinical uses of alpha₂ agonists?

Drugs & mechanism of action?

Answer 12

• Methyldopa – pro-drug (alpha-methyl-NE)
  
  • decreases sympathetic outflow by stimulating alpha₂ receptors in the CNS
  • this decreases blood pressure
  • clinical use: hypertension
  • ** safe for pregnant women
• Clonidine
  
  • SAME as methyldopa
  • ALSO, stimulates alpha₂ receptors on neurons to decrease NE release
  • decreasing blood pressure
  • Clinical use: hypertension

Question 13

Clinical uses of beta-adrenergic receptor agonists?

Drug names?

Answer 13

• Dobutamine: beta₁ receptors (beta₁ > beta₂, alpha)
  
  • Low cardiac output states
    
    • severe decompensated heart failure
    • cardiogenic shock
  • AV block
• Dopamine (D₁=D₂>B₁>a₁) – dose dependent
  
  • low dose
    
    • activation D_A1 in kidneys
    • induces diuresis
  • intermediate dose
    
    • activation B₁ reeptors in heart
    • increase in contractile force
  • high dose
    
    • alpha receptors = increase peripheral resistance
    • increases work of the heart
    • could lead to arrhythmias
  • Clinical uses
    
    • septic shock
    • severe decompensated heart failure
    • cardiogenic shock
    • AV block
• Fenoldopam- DA-1 agonists
  
  • ​Hypertensive crisis
  • may cause reflex tachycardia

Question 14

Clinical uses of nonselective beta-receptor agonists?

Drug names?

Answer 14

• Isoproterenol (B₁=B₂)
  
  • severe decompensated heart failure
  • cardiogenic shock
  • AV block
  • In conjuction with others: septic shock
  • bronchospasm occurring during anesthesia
    
    • stimulation B₂ can open airway

Question 15

Explain the clinical uses of epinephrine & mechanism of action

Answer 15

• Epinephrine (a₁, a₂, B₁, and B₂, B>a)
  
  • co-administered with local anesthetics to prolong the duration of anesthesia
    
    • activate alpha₁ receptors & constric blood vessels at site of local injection to prevent the body from carryign the anesthesia to different parts of the body
  • anaphylactic shock: the drug of choice
    
    • allergic attack = production IgE – will bind to surface of mast cells & basophils
      
      • leads to degranulation & release of histamine, cytokines & leukotrienes
      • Respiratory system
        
        • increase bronchospasm, mucus secretion, pulmonary edema (b/c capillary permeability)
        • obstruction of airway
      • Cardiovascular system
        
        • increase capillary permeability (fluid loss) & vasodilation, decrease cardiac contractility
        • hypotensive shock
• Mechanism of Action
  
  • (1) by activating vascular a₁ receptors, decrease capillary permeability
    
    • relieve pulmonary edema & reduce fluid loss
  • (2) by activating vascular a₁ in smooth muscle can cause vasoconstriction
    
    • increase blood pressure (prevent shock)
  • (3) B₁ receptors in heart increasing contractility
    
    • increase heart rate & cardiac output
    • increase blood pressure (prevent shock)
  • (4) activating B₂ in ariway, can cause vasodilation
    
    • increase airway
  • (5) activating a₁ in mucus gland can reduce mucus secretion
    
    • clear airway
  • (6) activate B₂ receptors on the surface of mast cells & basophils, inhibiting their degranulation

Question 16

Explain the clinical uses of norepinephrine & mechanism of action

Answer 16

• Norepinephrine (a₁>a₂>B₁)
  
  • Clinical uses: cardiogenic shock & septic shock
  • Stimulate B₁
    
    • _​increase cardiac contractility (increase cardiac output)
      
      • increase blood pressure
  • Stimulate a₁
    
    • increase vascular resistance
      
      • increase blood pressure

Question 17

Why is Norepinephrine not used to treat anphlactic shock?

Answer 17

It does not stimulate B₂ receptors, so it does not cause bronchodilation

Question 18

What are the adverse effects of adrenergic agonists & the associated receptor to each effect?

Answer 18

• Tachycardia (B₁)
• Cardiac Arrhythmias (B₁)
• Hypertenzive Crisis (a₁)
• Dry mouth, sedation, mild depression (a₂)
• Exacerbate urinary retention in patients with benign prostatic hyperplasia (BPH, a₁)
• exacerbate closed-angle glaucoma (a₁)
  
  • iris has circular muscle (M) & radial (a₁)
  • stimulating a₁ will pull muscle back to trabecular meshwork & open pupil
  • closed-angle glaucoma, can be caused by the iris muscle being pathologically positioned against the trabecular meshwork, this prevents an outflowof vitreous humor to the venous system don’t have outflow of atreous humor to venous system
    
    • this will increase intraocular pressure, leading to glaucoma

Question 19

Adverese effects of Methyldopa & Fenoldopam? What receptors do they stimulate?

Answer 19

• Methyldopa (a₂):
  
  • autoimmune response (positive direct coombs test, rarely hemolytic anemia, systemic lupus erythematosus)
• Fenoldopam (D₁):
  
  • increases aqueous humor production
    
    • intraocular pressure
  • induces reflex tachycardia

Question 20

Describe the mechanism of action for non-selective alpha eceptor antagonists

Answer 20

• Blocking a₁ in smooth muscle will prevent lead to vasodilation
  
  • decrease blood pressure
  • the decrease in blood pressure stimulate baroreceptors in the brain to stimulate the sympathetic nervous system to release more NE
• Blocking a₂ receptors in presynaptic nerve terminals, interrupting the synaptic feedback control of NE, and can lead to increased NE release
• NE will act on the heart to increase HR contractility
• Clinical Results
  
  • vasodilation & cardiatc stimulation

Question 21

What are the two major non-selective a receptor antagonists?

What are their clinical uses?

Answer 21

• Phenoxybenzamine: Pheochromocytoma
  
  • competitive, irreversible
  • normal adrenal medulla: EPI:NE= 80:20
  • Pheochromocytoma: EPI:NE=20:80
    
    • major problem is hypertension
  • Receptor selectivity of NE: a₁=a₂, B₁>B₂
• Phentolamine
  
  • Phentolamine
  • Reversal of local soft tissue anesthesia
    
    • compete with the epinephrine that was injected with the anesthesia, causing relaxation & blood flow
  • a₁ agonist overdose
  • hypertensive crisis associated with monoamine oxidase inhibitor (MAOI)
    
    • NE can be metabolized by MAO in presynaptic nerve terminals
    • Tyrosine can be used to synthesize NE via dopamine
    • Tyrosine can also be converted to tyramine (indirect adrenergic agonist) via bacterial decarboxylation
      
      • have MAO in GI that converts tyramine to P-hydroxyphenylacetic acid
    • MAOI will inhibit MAO in both the presynaptic nerve terminals & in the GI system
      
      • release of a lot of NE in the blood stream which can leave to hypertensive crisis

Question 22

What are the a₁-selective receptor antagonist drugs?

Describe their mechanism of action.

Answer 22

• All are competitive, reversible antagonists
  
  • Prazosin
  • Terazosin
  • Doxazosin
  • Tamsulosin
• Mechanism of Action
  
  • block peripheral a₁ receptors
    
    • vasodilation, leads to decrease in BP
  • decrease baroreflexive response, so does NOT stimulate sympathetic system & does NOT induce NE release
    
    • since a₂ are not blocked, NE concentration decreases
  • Decreased heart rate & decreased cardiac contractility
    
    • ​further decreases blood pressure
  • Also reduce LDL & TG and increase HDL levels, but mechansim is not uderstood

Question 23

Clinical uses of a₁-selective receptor antagonists

Adverse effects?

Answer 23

• Clinical uses
  
  • Pheochromocytoma
  • Chronic hypertension: not commonly used
  • Chronic hypertension with benign prostatic hyperplasia (BPH)
  • Urinary retention in men with benign prostatic hyperplasia (BPH)
    
    • block a₁ in urinary tract, relaxing urinary track improving urination & reducing urinary retention
• Adverse effects
  
  • Apply to all: hypotension, dizziness, fainting
  • Reflex tachycardia
    
    • mainly apply to non-selective
  • First-dose syncope (selective a₁)
    
    • prevented by:
      
      • reducing dose, increasing dose slowly, and add additional antyhypertensive drug cautiously

Question 24

What are the B-receptor antagoinstic drugs?

Answer 24

• All are competitive reversible
• Non-selective (B₁ and B₂)
  
  • Propranolol
  • pindolol
  • timolol
• Cardioselective (B₁)
  
  • atenolol
  • acebutolol
  • betaxolol
  • bisoprolol
  • esmolol
  • metoprolol
• Vasodilatory with ISA (in addition to B₁ or B₁ & B₂)
  
  • B₃ activity: endothelial NO production: nebivolol
  • B₂ activity: pindolol

Question 25

Describe the mechanism of action for the B-receptor antagonists

Answer 25

• Physiological effect
  
  • lower BP and reduce O₂ consumption
• By blocking B₁ receptors in the heart, ​
  
  • heart reate contractility decreases
    
    • decreasing cardiac work load & decreasing O₂ consumption
  • CO consumption decreases
  • BP decreases
• Blocking B₁ in the renal system can block the release of Renin, preventign the vasoconstriction & aldosterone production that increases BP

Question 26

What are the clinical uses of all B-receptor antagonists?

Answer 26

• Apply to all B-receptor antagonists
  
  • Hypertension
    
    • CO reduction and RAAS inhibition
    • prejunctional B blockade – NE release decrease
    • CNS – sympathetic outflow decrease
  • Ischemic heart disease
    
    • angina (decrease O₂ demand)
    • Myocardial infarction (decrease arrhythmia, O₂ demand, cardiac remodeling, reinfarction)
  • Arrhythmias: supraventricular & ventricular
  • Chronic Heart Failure

Question 27

Specifc clinical uses of Propanol?

Answer 27

• non-selective B receptor antagonist
• Hemangiomas:
  
  • inhibits the growth & induces the regression of infantile hemangiomas by
    
    • induciton vasoconstriction (blocking B₂ receptors on vasculature)
    • inhibiting expression of VEGF and bFGF and/or triggering apoptosis

Question 28

Specific clinical uses of Labetalol & Carvedilol?

Answer 28

• alpha & B-adrenergic receptor antagonists
• Appy to all
  
  • block a₁ and B receptors
  • potency for B receptors blockade > a₁ receptor blockade
  • reversible, competitive blockade
• Carvedilol
  
  • antioxidant
  • anti-proliferative
  • NO production
• Clinical uses
  
  • Hypertension
    
    • Labetalol can also be used to treat hypertensive crisis
    • Ischemic heart diseases
    • chronic heart failure: Carvedilol

Question 29

What are the adverse effects of all B-receptor antagonists & non-selective B-receptor antagonists?

Answer 29

• All B receptor antagonists
  
  • Bradycardia
  • Precipitation of acute heart failure
  • metabolic effects
    
    • augmenttion of hypoglycemic action of insulin
      
      • blocks beta receptors, messing with the B₃/B₂ glucose feedback system
      • not able to monitor heart rate as indicator insulin overdose b/c tachycardia is blocked by blocking B receptors
    • altered plasma lipid levels
      
      • worsen serum lipid profile (VLDL and HDL)
  • CNS: mental depression, insomnia, fatigue, and dreams
  • Sudden discontinuation of B receptors can exacerbate angina and cause death
    
    • ALWAYS taper
• Non-selective B receptor antagonists
  
  • Bronchospasm (blocking B₂​ in lungs)
    
    • in patients with asthma or COPD
  • cold extremities (blocking B₂ in vasculature)
  • Raynaud’s disease (blocking B₂​ in vasculature)
  • Metabolic effects
    
    • selective B₁ = improve serum lipid profile

Question 30

What are the contraindications to starting B receptor antagonists

Answer 30

• Asthma and chronic obstructive pulmonary disease (nonselective)
• AV block
• Cardiogenic shock
• uncompensated heart failure
• Propanolol:
  
  • premature infants with corrected age <5weeks
  • infants weighing <2kg