PPT 9- Adrenergic Agonists

Question 1

Differentiate between direct acting and indirect-acting adrenergic agonists

Answer 1

Direct agonist - bind to receptors and illicit response
Indirect agonist - Increase amount of catecholamines in synapse; either facilitating removal or preventing reuptake

Question 2

What is the structure of catecholamines?

Answer 2

Catechol group + amine group
Benzene ring with adjacent hydroxyl groups at positions 3 & 4 (catechol) and an amine group on side chain

Question 3

How are catecholamines inactivated?

Answer 3

In the gut by catechol-O-methyltransferase (COMT) - can’t take epinephrine or NE orally

Question 4

Why can non-catecholamines be taken orally?

Answer 4

Non-catecholamines (ephedrine) not inactivated in gut because they lack catechol hydroxyl group

Question 5

Changes in the alpha carbon of catecholamines affect the activity of which enzyme?

Answer 5

monoamine oxidase (MAO) - prolonged action by blocking oxidation

Question 6

Changes in the benzene ring of catecholamines affect the activity of which enzyme?

Answer 6

catechol-O-methyltransferase (COMT) - greatly reduces potency

Question 7

List the affinity for binding of epinephrine, NE, and isoproterenol at alpha receptors

Answer 7

Epinephrine = Norepinephrine
>Isoproterenol

Question 8

List the affinity for binding of epinephrine, NE, and isoproterenol at beta receptors

Answer 8

Isoproterenol > Epinephrine ≥ Norepinephrine
B1 (heart): Equal affinity for Epi and Norepi
B2 (lungs): Epi > Norepi

Question 9

Alpha 1 vs alpha 2 effects

Answer 9

• α1: Gq → phospholipase C → increases IP3 and DAG
  
  • contracts vascular smooth muscle, prostate contraction, heart - increases force of contraction
• α2: Gi → decreases cAMP
  
  • inhibited transmitter release at adrenergic and cholinergic nerve terminals

Question 10

Compare the effects of beta 1, 2, 3

Answer 10

Gs - all increase cAMP
- β1: increases force and rate of contraction (heart) and increases renin release (juxtaglomerular cells)
- β2: promotes smooth muscle relaxation at respiratory, uterine, and vascular smooth muscle
- β3: activates lipolysis in fat cells

Question 11

Describe the mechanism of action for alpha 1 receptors

Answer 11

Question 12

Describe the mechanism of action for G inhibitory vs G stimulatory receptors

Answer 12

Question 13

What are the 3 monoamine transporters?

Answer 13

1. NET: transports back to presynaptic terminal (NE, dopamine)
2. DAT: dopamine transporter
3. ST: serotonin transporter

Question 14

Differentiate the mechanism of actions of amphetamines vs cocaine

Answer 14

Amphetamines - increasing NE released
Cocaine - blocking reuptake NE

Question 15

What effect does D1 receptor have?

Answer 15

Dilates renal blood vessels in smooth muscles

Question 16

Describe what happens in the cardiovascular system after the administration of an alpha-agonist

Answer 16

• Increases vascular resistance/tone
• HR decreases (indirect effect)
• BP increases

Question 17

Describe what happens in the cardiovascular system after the administration of a beta-agonist

Answer 17

• Decreases vasculature resistance/tone
• Increased contractility and HR
• BP decreases overall

Question 18

Describe what happens in the cardiovascular system after the administration of a mixed agonist

Answer 18

• Mixed vascular resistance
• Increased contractility and HR
• Increased BP

Question 19

Describe the effects of epinephrine

Answer 19

• Potent vasoconstrictor
  
  • α receptors
• Cardiac stimulant (β1)
  
  • Positive inotropic (force)
  • Positive chronotropic (rate)
• β2 activation in some vessels
  
  • Dilation of skeletal muscle vessels
  • Dilation in bronchioles

Question 20

Describe the effects of norepinephrine

Answer 20

• Effects on α and β1
• Little effect on β2
• Results
  
  • Increase in systolic and diastolic
  • Vagal reflexes overcome chronotropic effects

Question 21

Describe the effects of isoproterenol

Answer 21

• Potent β agonist - vasodilator - heart
• Little effect on α receptors
• Results
  
  • Increase cardiac output
  • Fall in Mean arterial pressure
  • Slight decrease or increase in systolic BP

Question 22

Describe the effects of dopamine

Answer 22

Triphasic response:
- Low dose: Activates D1 receptors - vasodilation,
decrease in peripheral resistance
- Higher dose: mimics action of epinephrine; β1 receptors in the heart
- Highest dose: activates alpha, increases BP

Question 23

Describe the effects of dobutamine

Answer 23

• β1 selective agonist
• Cardiac shock, acute heart failure

Question 24

Define non-catecholamine

Answer 24

Not targets for COMT

Question 25

What are the effects of phenylephrine

Answer 25

- Pure α agonist, non-catecholamine - Decongestant, raise blood pressure - push blood back into systemic - Tetralogy of Fallot

Question 26

What are the 4 issues of the heart in TOF?

Answer 26

1. overarching aorta 2. pulmonic stenosis 3. VSD 4. right ventricular hypertrophy

Question 27

What is Midodrine used for? What receptors is it selective for?

Answer 27

- α1 receptor selective - Primarily – postural hypotension (orthostatic) - Can cause hypertension in primarily supine patient

Question 28

What is ephedrine used for? How does it work?

Answer 28

- Orally active, OTC - Releases stored catecholamines (indirect) - Mimics epinephrine (direct) - Does cross BBB - Nasal decongestant (pseudoephedrine)

Question 29

How do amphetamines work?

Answer 29

- Readily enter CNS - Mood elevator, appetite suppressant

Question 30

How does cocaine work?

Answer 30

Readily enters CNS - Amphetamine-like effects Inhibits dopamine reuptake into neurons in the pleasure centers (and addictiveness) of the brain

Question 31

What is tyramine and how does it work?

Answer 31

- Tyrosine by-product, increases PANS - High concentrations in fermented foods - Indirect action - Releases stored catecholamines - Metabolized by MAO - MAOIs may increase blood pressure significantly after eating fermented foods (increased NE)

Question 32

What questions should you ask before picking a sympathomimetic?

Answer 32

- Which receptor activation is required? - Route of administration? - Dosing – monitoring therapeutic response

Question 33

What are the 6 major clinical applications of adrenergic agonists?

Answer 33

Hypotension, shock, reduce blood flow, cardiac, respiratory, anaphylaxis

Question 34

What is a pressor agent?

Answer 34

Increases blood pressure

Question 35

How are adrenergic agonists used to treat hypotension?

Answer 35

Enhance blood flow or pressure (direct acting α agonists - NE, phenylephrine) - most important thing is to maintain cerebral, renal, and cardiac perfusion

Question 36

What is the treatment for shock?

Answer 36

volume replacement (underlying cause) and vasoconstrictors or dilators (depends on if cardiogenic shock of non-MI cause)

Question 37

How are adrenergic agonists used to reduce blood flow? What is the drug target?

Answer 37

Hemostasis in surgery Reduce diffusion of local anesthetics away from the desired site Reduce mucous membrane congestion Drug target - α receptor agonist (epinephrine and lidocaine)

Question 38

How are adrenergic agonists used to treat cardiac issues?

Answer 38

complete heart block and cardiac arrest (isoproterenol and epinephrine); target vasodilation of coronary arteries

Question 39

How are adrenergic agonists used to treat respiratory issues?

Answer 39

Bronchial asthma - β2 selective agonists

Question 40

List the most common toxicities associated with sympathomimetic and the adverse effects

Answer 40

Pressor agents - Elevated blood pressure - Cerebral hemorrhage - Pulmonary edema - Angina - Cardiac tamponade - MI CNS Toxicity - Catecholamines - rare, but can cross BBB at high levels - Cocaine - cross BBB - Convulsions - Cerebral hemorrhage - Arrhythmias - MI

Question 41

What are the two commonly used α2 agonists and how do they work?

Answer 41

Clonidine and dexmedetomidine; decrease BP by shutting down NE Increase firing of vagal nerve - decrease in SV and HR Decrease firing of sympathetic nerves - vasodilation