ADRENERGIC

 DRUGS!  
 
Drugs  that  affect  catecholamine  SYNTHESIS  
• Metyrosine  
o Competes  with  tyrosine  for  a  binding  site  on  tyrosine  hydroxylase,  which  
decreases  its  activity  
o Since  TH  is  the  rate-­‐limiting  step,  this  effectively  decreases  the  amount  of  
catecholamines  made  
o Used  in  the  management  of  tumors  that  secrete  catecholamines,  called  
phenochromocytomas  
• L-­‐DOPA  
o Increases  synthesis  of  all  catecholamines  in  the  CNS  
o Provides  a  substrate  beyond  the  rate-­‐limiting  step  
o Allows  increase  in  synthesis  of  DA,  NE  and  EPI  
o Used  in  the  treatment  of  Parkinson’s  
§ Why  not  just  use  dopamine?  
§ Because  Dopamine  does  not  cross  BBB  well  but  L-­‐DOPA  does!  
 
Drugs  that  affect  catecholamine  STORAGE  
• Reserpine  
o Drug  that  is  used  to  interrupt  the  storage  process  
o Prevents  synthesized  NE  from  being  pumped  by  the  VMATs  (VMAT2)  
o NE  then  remains  in  the  cytoplasm,  is  degraded,  and  therefore  release  of  NE  is  far  
less  
§ Degraded  most  prominently  by  MAO  
o Not  used  in  USA  
o Used  to  treat  psychotic  conditions,  but  also  lowered  BP  
§ Less  NE  à  Decreased  tone  on  BV  à  Lower  BP  
§ Was  the  first  anti-­‐hypertensive  drug  in  US!  
o Too  many  side-­‐effects  now  –  depression,  stomach  ulcers,  etc.  
§ DA  and  other  NT  are  also  transported  into  vesicles  via  the  transporter,  and  
thus  degraded  when  taking  this  drug  
 
Drugs  that  INHIBIT  catecholamine  RELEASE  
• Botulinum  Toxin  (ACh)  and  Tetanus  Toxin  (GABA)  
o Blocks  coupling  of  VAMPs  and  SNAPs,  preventing  the  release  of  ACh  and  GABA  
respectively  (NOT  NE  –  just  examples  of  drugs  that  affect  release)  
o Botulinum  leads  to  paralysis  of  muscles  
§ Used  in  Botox  
o Tetanus  blocks  inhibitory  GABA  transmission,  so  seizures  may  result  
• Clonidine  
o This  affects  release  of  NE  
o Stimulates  presynaptic  alpha-­‐2  receptors  that  hyperpolarize  the  NE  axon  
termine,  leading  to  DECREASED  NE  release  
o Also  stimulates  postsynaptic  alpha-­‐2  receptors  on  smooth  muscle  of  blood  vessels  
which  leads  to  vasoconstriction  
 o BUT,  this  is  an  ANTI-­‐hypertensive  drug!  
§ Low  doses  –  clonidine  goes  into  the  brain  and  acts  on  the  vasomotor  
system,  decreasing  SNS  outflow  
§ Has  specificity  for  pre-­‐synaptic  alpha-­‐2  receptors  in  the  brain  
§ Remember:  Neuronal  control  of  BP  is  only  through  the  SNS!  
 
Drugs  that  ENHANCE  catecholamine  RELEASE  
• Amphetamine  
o Increases  the  release  of  NE,  DA  and  5-­‐HT  
o Competitively  binds  to  the  reuptake  pumps    
§ Allows  NT  to  have  more  prolonged  effects  in  the  synapse  
o Also  enters  the  nerve  ending  
o Allows  more  release  in  two  ways  
§ Binds  MAO  in  cytoplasm  to  prevent  it  from  degrading  NT  
§ Inhibits  the  VAMT  from  allowing  them  to  enter  the  vesicles,  increases  NT  
in  the  cytoplasm  
§ Now  the  concentration  in  the  cytoplasm  is  HIGHER  than  at  the  synapse,  so  
the  reuptake  pumps  that  usually  clear  out  NT  are  reversed  
• Now  NT  is  pumped  into  the  synapse!!  
• This  does  not  require  calcium  –  non-­‐physiologic  release  
§ Over  an  extended  period,  tolerance  develops  because  the  high  
concentrations  of  DA  and  NE  cause  feedback  inhibition  of  synthesis  
• Tyramine  
o Increases  release  of  NE  by  causing  it  to  be  released  from  vesicles  
o Not  used  clinically  anymore  
o Always  around  us  and  inside  of  us  
o Bacteria  in  our  gut  converts  tyrosine  à  tyramine  
§ Usually  quickly  metabolized  by  MAO  
§ Inhibiting  MAO,  however,  will  cause  buildup  of  tyramine  
§ Enters  nerve  endings,  displaces  NE  from  cytoplasm(releases  NE)  and  
causes  hypertensive  crisis  
• Too  much  NE  à  HIGH  sympathetic  tone  à  HIGH  
vasoconstriction  à  HIGH  BP!  
o Unable  to  cross  BBB  
o Found  in  fermented  foods  –  yogurt,  wine,  beer,  aged  cheese,  etc.  
§ Can  cause  cheese-­‐reaction  à  hypertensive  crisis!  
• Ephedrine  (Ephedra)  
o Enters  nerve  terminal  where  it  increases  release  of  NE  
o Has  been  used  in  OTC  decongestants  –  vasoconstrictive  actions  
o Treats  asthma  –  bronchodilator  
o Weak  agonist  of  alpha1,  beta1,  and  beta2  receptors)  
o Can  be  diverted  to  the  synthesis  of  methamphetamine  
o Tolerance  develops  
 
Drugs  that  block  REUPTAKE  of  catecholamines  
• Amphetamine  
o See  above,  one  of  its  many  mechanisms  
• (Selective)  Serotonin  Reuptake  Inhibitors  (SSRIs)  
 o Used  to  treat  depression  
• Cocaine  
o Blocks  the  reuptake  of  NE,  DA,  and  5-­‐HT  
o Leads  to  CNS  excitation,  energy  and  euphoria  
o Vasoconstriction  and  cardiac  stimulation  
• Desipramine  
o Tricyclic  anti-­‐depressant  
o Selectively  blocks  only  NE  reuptake  in  CNS  and  periphery  
o These  drugs  aren’t  abused  –  the  abused  ones  have  to  do  with  dopamine  
 
Drugs  that  inhibit  DEGRADATION  by  MAO  
• Phenelzine  &  Tranylcypromine  
o MAO  inhibitor  
o Allows  concentration  of  these  NT  in  cytoplasm  to  increase,  which  eventually  leads  
to  their  release  
o Useful  for  depression  
• Selegiline  (Deprenyl)  
o MAO  inhibitor  used  as  an  adjunct  in  the  treatment  of  PD  
o MAO-­‐B  selective  
§ MAO-­‐A  breaks  down  NE,  EPI  and  5HT  
§ DA  broken  down  by  both  
§ Tyramine  is  primarily  broken  down  by  MAO-­‐B  
• But  because  it  is  selective  for  only  MAO-­‐B,  MAO-­‐A  will  take  over  
and  continue  its  metabolism  of  tyramine  and  other  drugs  
 
Drugs  that  act  INDIRECTLY  on  POST-­‐synaptic  cell  
Phosphodiesterase  Inhibitors  –  Increase    levels  of  cAMP/cGMP  in  the  post-­‐synaptic  cell  once  
NT  bind  (PDE  breaks  down  cAMP  and  cGMP)  
 
• Aminophylline  (theophylline)  
o Non-­‐selective  inhibitor  of  PDE  that  is  used  to  treat  asthma  –  causes  
bronchodilation  and  inhibits  the  release  of  pro-­‐inflammatory  cytokines  
o Also  stimulates  cardiac  muscle  –  similar  to  those  of  beta-­‐adrenergic  agonists  (such  
as  EPI  an  NE)  
§ Can  cause  excess  CNS  stimulation  
o Can  also  block  denosine  receptors  (different  mechanism)  and  increases  histone  
acetylation  to  decrease  inflammation  
• Sildenafil  (Viagra)  
o Selective  PDE-­‐5  inhibitor  that  increase  cGMP  stimulated  by  the  release  of  NO  
o These  drugs  relax  penile  smooth  muscle  to  cause  erections,  
o Also  relaxes  vascular  smooth  muscle  in  the  lungs    to  alleviate  pulmonary  
hypertension  and  respiratory  distress  syndromes  
o May  also  increase  cerebral  blood  flow  –  could  be  used  to  treat  cerebrovascular  
dementias  and  AD  in  the  future  
 
 
 
 
Adrenergic  Receptor  AGONISTS  
• DA,  NE,  EPI  
o Pretreatment  with  what  drugs  would  result  in  NE  increasing  HR  and  CO?  
o DOPAMINE!  
§ DA  stimulates  D1  >>>  Beta-­‐1  >>  Alpha-­‐1  
§ Renal  smooth  muscle  dilates  at  low  doses  
§ Higher  dose  à  Beta-­‐1  effects  –  
increase  heart  contractility  and  CO  
§ Highest  dose  à  Alpha-­‐1  effects  à  
vasoconstriction  
o Combine  DA  with  NE  
§ Increase  in  renal  blood  flow  and  
decrease  in  renal  resistance  
§ Increase  in  CO  via  an  increase  in  HR  
§ Increase  in  the  ratio  of  renal  blood  flow  
to  CO  
o Why?  
§ DA  may  be  a  better  substrate  for  
reuptake  at  the  NE  neurons  
§ Therefore  DA  will  buildup  into  the  cell,  
reverse  the  pump  and  allow  for  
increased  NT  in  the  synapse  
§ DA  increases  CO  somehow  
o NE  is  not  widely  used,  but  anesthesiologists  
sometimes  use  it  because  of  the  vascular  
effects  while  not  increasing  CO  
§ Use  in  severe  septic  shock  and  sever  hypotensive  states  because  even  
though  it  doesn’t  increase  CO  much,  it  increases  cardiac  force  and  BP  
increase  perfusion  pressure  without  increasing  HR  
o EPI  and/or  DA  used  more  than  NE  because  they  produce  better  CO  outcomes  
and  organ  perfusion  
§ NE  use  is  also  limited  because  of  its  rapid  reuptake  and  potent  
vasoconstrictive  effects  
 
 
• Dobutamine  
o DOES  NOT  have  dopamine  activity  
o Stimulates  beta-­‐1  >  beta-­‐2  with  weak  alpha-­‐1  stimulation  
o Because  there  is  less  activation  of  vasodilator  beta-­‐2  receptors  and  modest  alpha-­‐1  
receptors,  there  is  less  reflex  tachycardia  via  baroreceptors  
o Results  in  favorable,  relatively  selective  increase  in  force  of  cardiac  contraction  
compared  to  rate  increase  
o Used  in  short  term  IV  infusion  during  cardiac  failure  

 
 o Why  does  HR    go  down  &  CO  go  up?  
§ DB  relieves  SNS  of  workload  by  acting  directly  on  the  CO  
§ So,  SNS  is  not  firing  the  way  it  was  before  DB  was  administered  
• Initially,  very  high  vascular  resistance  lead  to  the  decreased  CO  
§ If  the  SNS  is  relieved,  then  a  decrease  in  vascular  resistance  in  turn  an  
increase  in  CO  will  occur  
o Downregulation  of  receptors  and  sensitivity  to  the  drug  occurs  over  time  –  why  it  
isn’t  used  chronically  in  patients  with  heart  failure  
§ Also  short-­‐lived  (T1/2  of  2  minutes)  
• Isoproterenol  
o Potent  beta-­‐1  and  beta-­‐2  selective  agonist  (see  above)  
o Not  a  substrate  for  reuptake  or  for  MAO,  so  it  has  a  longer  duration  of  action  
than  NE  or  EPI  
§ Still  broken  down  by  COMT  
 
 
BETA-­‐2  Adrenergic  Agonists  (selective)  
• Albuterol,  Terbutaline,  Ritodrine  
o Beta-­‐2  Agonists  
o Used  in  asthma  –  bronchodilators  
o How  is  this  an  advantage  over  isoproterenol  and  epi?  
§ Albuterol  et  al.  is  selective  
§ Less  cardiac  stimulating!  
o Also  reduce  premature  contractions  of  a  pregnant  uterus  (ritrodine  especially),  
leading  to  a  delay  in  labor  and  allows  more  development  of  the  fetal  respiratory  
system  
 
ALPHA-­‐1  Adrenergic  Agonists  (selective)  
• Phenylephrine  
o Selective  for  alpha-­‐1  
o Causes  vasoconstriction  of  arteries  and  veins,  leading  to  an  increase  in  BP  with  
subsequent  decrease  in  HR  
o Used  as  a  nasal  decongestant  
§ Too  much  can  cause  rebound  hyperemia  (eye  redness)  –  engorgement  of  
blood  vessels  (smooth  muscles  constricting  the  vessels  end  up  weakening)  
o See  above  notes/graph  
 
Alpha-­‐2  Adrenergic  Agonists  (selective)  
• Clonidine  
o Alpha-­‐2  partial  agonists  
o Given  IV,  stimulates  postsynaptic  alpha-­‐2  receptors  in  peripheral  vasculature  
causing  vasoconstriction  
§ It  also  decreases  NE  release  via  a  pre-­‐synaptic  mechanism  
§ Acts  on  presynaptic  terminal  ends  of  NE  neurons,  causing  hyperpolarizing  
effects  and  decreasing  NE  release  (inhibitory!)  –  causes  decrease  in  HR  
 o Given  orally,  it  decreases  peripheral  sympathetic  outflow  by  stimulating  
postsynaptic  alpha-­‐2  receptors  in  the  brainstem  CV  centers  –  and  is  thus  used  
as  an  antihypertensive  drug  
o See  graph  below  
§ Stimulate  heart  before  administration  of  drug,  increase  NE  and  HR  
§ Administer  clonidine  –  HR  decreases,  plasma  NE  decreases!    
§ Administer  phentolamine  –  competitive  antagonist  (blocks  alpha-­‐1  and  
alpha-­‐2  receptors,  focus  on  alpha-­‐2),  response  is  more  than  double  of  1  Hz  
stimulation  alone  
§ Evidence  that  these  receptors  are  physiologically  active  and  relevant  to  
cardiac  function  

 
o Alpha-­‐Methyl-­‐DOPA  is  another  antihypertensive  drug  –  probably  works  in  a  
similar  manner  
 
Therapeutic  Uses  of  Beta-­‐Agonists  (Recap)  
• Heart  Failure  –  beta-­‐1  agonists  
• Cardiac  arrest  –  beta-­‐1  agonists  
• Shock/Low  perfusion  –  beta-­‐1  and  alpha  agonists  
• Anaphylactic  Shock  –  alpha  and  beta  agonists  (EPI  dramatically  increases  CO  because  it  
increases  firing  at  SA,  conduction  at  AV,  and  contractility  in  the  ventricles)  –  due  to  its  
bronchiole  dilation  (beta-­‐2  at  high  doses)  AND  cardiac  effects,  it  is  used  for  shock  
• Vasoconstrictors  –  alpha  agonists  
• Asthma/Bronchospasm  –  beta-­‐2  effects  
• Glaucoma  –  decrease  aqueous  solutions  –  alpha-­‐2  agonists  
 
 
Beta-­‐Adrenergic  Receptor  ANTAGONISTS  (Beta-­‐Blockers!)  
• Therapeutic  Uses  of  Beta-­‐Blockers  
o Hypertension  –  decrease  CO  
o Angina  (insufficient  coronary  blood  flow)  –  decrease  work  of  heart  
o Cardiac  Arrhythmias  –  decrease  conduction  and  stabilize  heart  rhythm  
o Chronic  Heart  Failure  
§ Used  cautiously,  beneficial  effects  may  derive  from  decreased  sudden  
death  due  to  arrhythmia  
§ Decreased  catecholamine  stimulation  of  heart  
§ Possibly  less  remodeling/increasing  in  size  of  myocardium  
§ Possible  preservation  of  heart  muscle  cells  (via  anti-­‐apoptotic  effects)  
 • Key  points  
o 80%  Beta-­‐1  in  heart,  20%  Beta-­‐2  
§ Number  of  Beta-­‐1  in  heart  decreases  during  heart  failure  since  so  much  
more  NE  is  flooding  in  
o Beta-­‐1  selective  blockers  should  usually  allow  exercise  tolerance  
§ Better  blood  flow  to  muscles,  less  block  of  K+  uptake  (beta-­‐2  effects  in  
muscle)  
o Beta-­‐1  blockers  should  produce  less  blockade  of  liver  Glycogenolysis  
• Propranolol  
o Non-­‐selective  beta-­‐1  and  beta-­‐2  blocker  
o Give  Epi  alone,  there  will  be  an  increase  in  contractility,  arterial  pressure,  and  
heart  rate  (acts  on  all  receptors)  
o FIRST  add  propranolol,  then  administer  EPI  à  EPI  is  only  able  to  do  its  alpha  
effects  because  of  the  beta-­‐blockade  

 
• Metoprolol  
o Beta-­‐1  selective  drug  
o Patients  should  never  leave  without  being  placed  on  a  beta-­‐blocker  
• Pindolol    
o Beta-­‐1  and  Beta-­‐2  
o Weak  partial  agonist  à  good  for  better  exercise  tolerance  
§ Intrinsic  sympathomimetic  activity  (ISA)  
§ Doesn’t  slow  resting  heart  rate  as  much  as  other  beta-­‐blockers,  but  still  
blocks  increase  in  HR  and  CO  produced  by  SNS  stimulation    
§ Less  likely  to  cause  severe  bradycardia  in  hypertensive  patients  with  low  
resting  HR  
• Don’t  want  to  use  beta-­‐blockers  in  asthmatic  patients,  even  beta-­‐1  selective  ones  can  be  
problematic  
 
Alpha-­‐Adrenergic  Receptor  ANTAGONISTS  
• Phentolamine  
o Alpha-­‐1  and  alpha-­‐2  antagonist  
o Lowers  vasoconstriction,  decreases  BP  
o Management  of  pheochromocytomas  (NE/EPI  releasing  tumors)  
o Competitive  Antagonist  
o Reversible  
o Can  cause  orthostactic  hypotension  and  reflex  tachycardia  (high  heartbeat  due  to  
low  blood  pressure)  
• Phenoloxybenzamine  
o Non-­‐competitive  alpha-­‐1  and  alpha-­‐2  antagonist  
o Irreversible  
 o Used  in  cases  of  extreme  vasoconstriction  
o Can  be  used  to  block  catecholamine  effects  at  alpha-­‐adrenergic  receptors  before  
surgery  to  remove  catecholamine  secreting  tumors  (pheochromocytomas)  or,  in  
cases  where  tumors  are  inoperable,  to  attenuate  their  effects  
• Prazosin  
o Competitive  antagonist  approximately  100x  more  potent  at  alpha-­‐1  than  at  alpha-­‐
2  receptors  
o Useful  antihypertensive  –  produces  less  reflex  tachycardia  than  nonselective  drugs  
o Orthostatic  hypotension  is  a  side-­‐effect,  but  only  the  first  few  times  
• Tamsulosin  
o Useful  for  treating  benign  prostatic  hyperplasia  (BPH)  because  they  cause  
relaxation  of  the  smooth  muscle  in  the  prostate  
o Alpha-­‐1A  selective  –  usually  produces  less  orthostatic  hypotension  
• Epinephrine  Reversal  
o When  EPI  is  given  normally,  it  acts  on  all  receptors  and  increases  BP  
o When  given  after  phentolamine,  a  non-­‐specific  alpha  antagonist,  BP  
DECREASES  
o This  is  known  as  epinephrine  reversal  
o Demonstrates  that  there  are  multiple  catecholamine  receptors  with  different  
functions  

 
 
 
Alpha  AND  Beta  Receptor  ANTAGONISTS  
• Carvedilol  
o Alpha  AND  beta-­‐receptor  antagonist  
o Shown  to  decrease  mortality  and  morbidity  in  patients  with  moderate  heart  
failure  
o Also  has  anti-­‐oxidant  and  anti-­‐proliferative  properties  
• Labetalol  
o Alpha  AND  beta-­‐receptor  antagonist  
o Used  to  treat  hypertension  in  pregnancy  
 
 
  
 
Sympathetic  Response  from  Head  to  Toe  (KNOW  THIS  COLD)  
Organ   Sympathetic  Effect   Adrenergic  Receptor  
Eyes   Dilation  -­‐  Mydriasis  (+)   α1  
Bronchi   Dilation  (-­‐)   β2  (Epi)  
Heart   Increased  HR  from  SA  (+)*   β1  (80%)  
Increased  Conduction  Velocity  AV  node  (+)*   β2  (20%)  
Increased  Contractility  A/V  myocytes(+)  
Some  α1  for  contractility  
Increased  Automaticity  other  pacemakers  (+)  
GI/Bladder   Decreased  Motility/Decreased  Contraction  (-­‐)   Lots  of  receptors  reverse  
Contraction  of  Spinchters  (+)   PSNS  tone,    
α1  for  sphincters  
Kidney   Increased  Renin  (Inc.  angio,  inc.  aldos,   β1  
increased  Na+  and  H2O  retention,  increase  
BP)  (+)  
Liver   Increased  Glycogen  Breakdown   β2  (Epi)  
Skeletal  Muscles   Increased  K+  Uptake,  Increased  glycogen   β2  (Epi)  
breakdown  
Uterus  (Pregnant)   Relaxation   β2  (Epi)  
Skin   Piloerection   α1  
Blood  Vessels   Constriction   α1,  α2  
Dilation  (liver  and  skeletal  muscle)   β2  (Epi)  
Dilation  (Renal  BV)   D1  (Dopamine)  
Fat  Cells   Lipolysis  stimulated   β3  
Sweat  Glands   Profusely  Sweating   M3  Muscarinic  Receptors  
(ACh)  
Prostate   Contraction   α1  
*  =  The  PSNS  controls  the  top  of  the  heart  at  rest  (AV  and  SA  node)  –  thus,  these  two  effects  are  in  
opposition  to  the  PSNS  when  the  SNS  is  in  effect,  but  the  contractility  is  strictly  under  SNS  
control.  Under  resting  conditions,  PSNS  predominates  to  keep  heart  in  resting  state.  
 
  
Reviewing  the  Effects  of  Catecholamines  on  Blood  Vessels  
 
Receptor   Action   Neurotransmitters  
    Skin  Blood  Vessels  
Alpha-­‐1   Vasoconstriction   NE/Epi  
Alpha-­‐2   Vasoconstriction   NE/Epi  
Muscarine   Vasodilation   ACh  
Activated  by  EXOGENOUS  ACh  
Skeletal  Muscle  Blood  Vessels  
Alpha-­‐1   Vasoconstriction   NE/Epi  
Alpha-­‐2   Vasoconstriction   NE/Epi  
Beta-­‐2   Vasodilation  at  low  dose  (Epi   Epi  
selectivity)  
Renal  and  Mesenteric  Blood  Vessels  
Alpha-­‐1   Vasoconstriction   NE/Epi  
Alpha-­‐2   Vasoconstriction   NE/Epi  
D1  (Dopamine)   Relaxation   Dopamine