Adrenergic Pharm

Question 1

SNS Anatomy

Answer 1

• Pre-ganglionic neurons- run from lateral horns in SC —> through white rami —> sympathetic chain OR directly on adrenal gland chromaffin cells
  
  • Shorter
  • “thoracolumbar” (T1-L2)
  • All release acetylcholine (nicotinic receptors on post-ganglionic body)
• Post-ganglionic neurons- run from sympathetic chain —> organ it innervates
  
  • Longer
  • All release norepinephrine (except those that innervate sweat glands - acetylcholine)

Question 2

Steps of Noradrenergic Neurotransmission

Answer 2

• Biosynthesis of catecholamines
  
  • Made by post-ganglionic sympathetic nerve endings AND chromaffin cells
  • L-tyrosine —> L dopa —> dopamine —> norepinephrine
    
    • Dopamine —> norepinephrine occurs INSIDE vesicle (NE is neuroT)
    • Adrenal cont to make epinephrine (80%) - secretes NE and epic into bloodstream directly
• Storage
  
  • Stored w/ co-transmitters (neuropeptide Y and ATP)
• Release
  
  • AP —> exocytosis
• Termination (MAO, COMT)

Question 3

5 Fates of NE

Answer 3

• 1- Interact w/ post-synaptic receptor (neurotransmission)
• 2- Interact w/ pre-synaptic receptor (auto-regulation)
• 3- Diffuse out of synaptic cleft —> circulation (NE spillover)
• 4- Taken up back into sympathetic nerve (neuronal uptake - via Uptake 1)
  
  • Higher affinity, lower max rate, selective for NE
  • Most common fate
• 5- Taken up by other tissues (extra neuronal uptake - via Uptake 2)
  
  • Lower affinity, higher max rate, non-selective
  • Then metabolized by monoamine oxidase (MAO) or catechol-o-methyl transferase (COMT) —> end product is vanillylmandelic acid in urine

Question 4

alpha- methyltyrosine

Answer 4

Inhibit tyrosine hydroxylase

Depletion of NE

Inhibit biosynthesis

Question 5

How do cocaine and TCAs affect NE?

Answer 5

Inhibit reuptake at nerve terminal –> accumulation of NE at receptor site

Question 6

How do amphetamines and tyramine affect NE?

Answer 6

Increase transmission by promoting NE exocytosis or displacement from vesicles

Indirect sympatho-mimetics

Question 7

Bretilium and Guanethidine

Answer 7

Replace NE in vesicles and prevent NE release from storage vesicles

Anti-hypertensive/sympatho-lytic

Question 8

What drugs inhibit NE metabolism?

Answer 8

Non-selective MAO inhibitors (anti-depressants)

COMT Inhibitors (anti-Parkinson)

Question 9

Overall SNS Goals (7)

Answer 9

• Redistribute blood flow; inc blood to heart and skeletal muscle; reduced blood to splanchnic organs and skin
• Inc blood gas exchange inc respiratory rate and bronchodilation
• Reduce secretion of salivary and GI tract glands; reduce peristalsis
• Reduce micturition
• Constrict skin blood vessels; sim sweat glands (evaporation of secreted sweat —> heat dissipation and cold/clammy/pale skin)
• Inc availability of glucose/FAs; prevent insulin secretion (HYPERGLYCEMIA)
• Dilate pupils

Question 10

SNS and BP Control

Answer 10

• BP normally regulated by sympathetic NS —> inc tension in vessels
• If high BP - this is detected as stretch of vessels by baroreceptors —> afferent signal to vasomotor center —> inhibits sympathetic NS —> dec tension in vessels
  
  • Baroreceptors mainly in carotid sinus and aortic arch
• Antihypertensive drugs can inhibit the sympathetic NS (sympatho-inhibitory)

Question 11

SNS and CVD

Answer 11

• If CVD —> dec in cardiac output —> sympathetic NS tries to compensate via norepinephrine acting on beta receptors
• BUT these beta 1 receptors are down-regulated
  
  • Why? failing myocardium fails in NE reuptake so more NE around —> desensitization (less mRNA, more BARK —> endocytose receptors, G protein uncouples, etc)
• Leads to chronic cardiac stimulation —> inc resistance and inc activation of renin-angiotensin —> more heart damage (hypertrophy of muscle)

Question 12

Adrenergic Crisis

Answer 12

• Sudden, marked inc in circulating, extracellular levels catecholamines (usually NE or epic NOT dopamine)
• Source - from adrenal gland or spillover from nerve terminals
• Effects - life-threatening tachycardia, extremely elevated BP, axillary sweating (diaphoresis)
• Causes- cocaine OD, intoxication w/ amphetamines, pheochromocytoma (tumor in adrenal), ingesting Tyramine in food when on MAO-inhibtors, clonidine/beta blocker/opiate/alcohol withdrawal. MI, subarachnoid hemorrhage, panic attack, etc

Question 13

Overall Classes of Adrenergic Drugs

Answer 13

• Sympatho-mimetic - adrenergic agonists
  
  • Direct-acting
    
    • Non-selective
    • Selective
  • Indirect-acting
  • Mixed-Acting
• Sympatho-lytic - adrenergic antagonists
  
  • Alpha 1 selective
  • Alpha 2 selective
  • Alpha non-selective
  • Beta 1 selective
  • Beta non-selective
  • Alpha + Beta antagonist

Question 14

What signaling mechanism does each adrenergic receptor use?

Answer 14

• Alpha 1 - G q (inc PLC - inc Ca++ -inc Na/K+, inc MAPK)
• Alpha 2- G i (inhibition of adenylyl cyclase, dec cAMP, dec PKA)
• Beta 1,2 and 3- G s (activate adenylyl cyclase, inc cAMP, inc PKA, inc Ca++)

Question 15

Where are alpha 1 and alpha 2 receptors found?

Answer 15

Alpha 1-
Periphery
Eye
CNS

Alpha 2-
Periphery/post-synp
Periphery/pre-synp
CNS/pre-synp

Question 16

Where are beta 1, 2, and 3 receptors found?

Answer 16

Beta 1-
Heart, Kidney

Beta 2 -
Heart, vessels, GI, bronchial, uterus

Beta 3-
Adipose tissue, GI, heart

Question 17

What is the general physio affect of each adrenergic receptor?

Answer 17

• Alpha -generally constrict and psychostimulant in CNS
• Beta 1- cardiac effects (5 positive tropic effects)
• Beta 2- generally dilate and inc secretion
• Beta 3- metabolic effects

**A2 and B2 pre-synaptic receptors involved in auto-regulation and dec in sympathetic outflow from vasomotor center

Question 18

Which catecholamines are most likely to work on which adrenergic receptor?

Answer 18

• alpha- Norepinephrine > Epinephrine > Isoproterenol

- beta- Isoproterenol > Epinephrine > Norepinephrine