December 19, 2017 | Author: ckmeesha | Category: Heart, Vasodilation, Circulatory System, Cardiovascular System, Angiology
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  Subject:   PHARMACOLOGY    

First  Semester  A.Y.  2015-­‐2016  

2.2  VASODILATORS  &  TREATMENT  OF  ANGINA   Topic:   Lecturer:   Dr.  Paguirigan    

PATHOPHYSIOLOGY  OF  ANGINA   A.  DETERMINANTS  OF  CARDIAC  OXYGEN  REQUIREMENT   • The  treatment  of  coronary  insufficiency  is  based  on  physiologic   factors  that  control  myocardial  oxygen  requirement    


the  double  product    


MYOCARDIAL  FIBER  TENSION   • Major  determinant  of  cardiac  oxygen  requirement   o The  higher  the  tension,  the  greater  the  oxygen  requirement   • Several  variables  contribute  to  fiber  tension:   o Preload   o Afterload   o Heart  rate   o Cardiac  contractility     PRELOAD   • Diastolic  filling  pressure   • Function  of  blood  volume  and  venous  tone   • Because  venous  tone  is  mainly  controlled  by  sympathetic   outflow,  activities  that  increase  sympathetic  activity  usually   increase  preload     AFTERLOAD   • Arterial  blood  pressure   • One  of  the  systolic  determinants  of  oxygen  requirement   • Arterial  blood  pressure  depends  on  peripheral  vascular   resistance,  which  is  determined  by  sympathetic  outflow  to  the   arteriolar  vessels  and  other  factors     HEART  RATE   • Contributes  to  time-­‐integrated  fiber  tension   o At  fast  heart  rates,  fibers  spend  more  time  at  systolic  tension   levels   o At  faster  rates,  diastole  is  abbreviated  and  constitutes  the   time  available  for  coronary  flow   § Coronary  blood  flow  is  low  or  nil  during  systole   • Systolic  blood  pressure  and  heart  rate  may  be  mutiplied  to  yield   the  double  product   • DOUBLE  PRODUCT   o Measure  of  cardiac  work  and  oxygen  requirement   o In  patients  with  atherosclerotic  angina,  effective  drugs  reduce   Trans  By:  Milka  Maddara,  Arianne  Tamaray  and  Krisha  Turingan   Edited  By:  Tony  Tagacay  II  

CARDIAC  CONTRACTILITY   • Force  of  cardiac  contraction   • Another  systolic  factor  controlled  mainly  by  sympathetic   outflow  to  the  heart   • EJECTION  TIME  for  ventricular  contraction   o Inversely  related  to  force  of  contraction   o Influenced  by  impedance  to  outflow   • Increased  ejection  time  increases  oxygen  requirement     B.  TYPES  OF  ANGINA   • There  are  three  forms  of  angina  pectoris:   o Atherosclerotic  angina   o Vasospastic  angina   o Unstable  angina     ATHEROSCLEROTIC  ANGINA   • Also  known  as  ANGINA  OF  EFFORT  or  CLASSIC  ANGINA   • Associated  with  atheromatous  plaques  that  partially  occlude   one  or  more  coronaries   • When  cardiac  work  increases,  for  example,  in  exercise,   o Obstruction  of  flow  results  in  accumulation  of  acidic   metabolites   o Ischemic  changes  stimulate  myocardial  pain-­‐mediating  nerve   endings   • Constitutes  90%  of  angina  cases   • Depending  on  the  rate  of  progression  of  atheromas,  it  may  last   for  years  with  little  change     VASOSPASTIC  ANGINA   • Also  known  as  VARIANT  ANGINA  or  PRINZMETAL’S  ANGINA   • Involves  reversible  spasm  of  coronaries  usually  at  the  site  of  an   atherosclerotic  plaque   o Spasm  may  occur  at  any  time,  even  during  sleep   • May  deteriorate  into  unstable  angina     UNSTABLE  ANGINA   • Also  known  as  CRESCENDO  ANGINA   • Caused  by  diminished  coronary  flow  that  results  from  a   combination  of   o Athersclerotic  plaques   o Platelet  aggregation  at  fractured  plaques   o Vasospasm   • Immediate  precursor  of  a  myocardial  infarction   • Treated  as  medical  emergency     C.  THERAPEUTIC  STRATEGIES   • CORONARY  OXYGEN  DELIVERY  INADEQUATE  FOR   MYOCARDIAL  OXYGEN  REQUIREMENT   o The  defect  that  causes  anginal  pain   • This  defect  can  be  corrected  in  two  ways  by:   Page  1  of  5  

o Increasing  oxygen  delivery   o Reducing  oxygen  requirement   • Pharmacologic  therapies  include  nitrates,  calcium-­‐channel   blockers,  beta-­‐blockers   o These  three  groups  reduce  oxygen  requirement  in   atherosclerotic  angina     o Nitrates  and  calcium-­‐channel  blockers  can  also  increase   oxygen  delivery  by  reducing  vasospasm   § But  only  in  the  vasospastic  form   • MYOCARDIAL  REVASCULARIZATION   o Corrects  coronary  obstruction  either  by   § Bypass  grafting   § Angioplasty   • Enlargement  of  the  lumen  by  means  of  a  special   catheter     NITRATES     CATEGORY   EXAMPLE   DURATION  OF   ACTION   Very  short   Short  

Inhaled  amyl  nitrite   Sublingual  nitroglycerin  or   isosorbide  dinitrate  

Intermediate   Oral  regular  or  sustained-­‐ release  nitroglycerin  or   isosorbide  dinitrate  


Transdermal  nitroglycerin   patch  

3  –  5  minutes   10  –  20  minutes   (for  nitroglycerin)   10  –  30  minutes   (for  isosorbide   dinitrate)   4  –  6  hours   (for  oral  regular)   4  –  8  hours   (for  oral  sustained-­‐ release)   8  –  10  hours  

  NITROGLYCERIN   • CLASSIFICATION  AND  PHARMACOKINETICS:   o Active  ingredient  in  dynamite   o Most  important  of  the  nitrates   o Available  in  forms  that  provide  a  range  of  durations  of  action   from  10  –  20  minutes  (sublingual)  to  8  –  10  hours   (transdermal)   o Also  known  as  GLYCERYL  TRINITRATE   o Rapidly  denitrated  in  the  liver   § First  to  the  dinitrate  (glyceryl  dinitrate),  which  retains  a   significant  vasodilating  effect   • Active   § Then,  more  slowly  to  the  mononitrate,  which  is  less  active   o Because  of  the  high  enzyme  activity  in  the  liver,  first-­‐pass   effect  is  large  –  90%   o Efficacy  of  oral  nitroglycerin  results  from  high  levels  of   glyceryl  dinitrate  in  the  blood   o Effects  of  sublingual  nitroglycerin  are  mainly  the  result  of  the        

unchanged  drug   • CLINICAL  USES:   o SUBLINGUAL  TABLET:  duration  of  action  of  10  –  20  minutes   o ORAL  NORMAL-­‐RELEASE:  duration  of  4  -­‐6  hours   o ORAL  SUSTAINED-­‐RELEASE:  duration  of  4  –  8  hours   o TRANSDERMAL:   § Placed  on  anterior  chest  wall  for  steady  release  of   nitroglycerin  for  24  hours   § Tolerance  develop  after  about  8  hours  with  markedly   decreasing  effectiveness   § Patches  should  be  removed  after  8  –  10  hours  to  allow   recovery  of  sensitivity  to  the  drug     ISOSORBIDE  DINITRATE   • CLASSIFICATION  AND  PHARMACOKINETICS:   o Available  in  sublingual  and  oral  forms   o Rapidly  denitrated  in  the  liver  to  isosorbide  mononitrate   o ISOSORBIDE  MONONITRATE   § Active   § Available  as  a  separate  drug  for  oral  use   • CLINICAL  USES:   o SUBLINGUAL  ISOSORBIDE  DINITRATE   o ORAL  NORMAL  RELEASE  ISOSORBIDE  DINITRATE   o ORAL  SUSTAINED-­‐RELEASE  ISOSORBIDE  DINITRATE     AMYL  NITRITE   • CLASSIFICATION  AND  PHARMACOKINETICS:   o Volatile   o Rapidly-­‐acting  vasodilator  that  was  used  for  angina  by   inhalation   o No  longer  prescribed   • CLINICAL  USES:   o INHALED  AMYL  NITRITE:  duration  of  action  of  3  –  5  minutes     MECHANISM  OF  ACTION   • Denitration  of  the  nitrates  within  the  smooth  muscle  cells   o Releases  nitric  oxide  (NO),  which  stimulates  guanylyl  cyclase   that  causes  an  increase  of  the  second  messenger  cGMP  and   leads  to  smooth  muscle  relaxation  by  dephosphorylation  of   myosin  light  chain  phosphate     CARDIOVASCULAR  SYSTEM  EFFECTS   • Smooth  muscle  relaxation  leads  to  peripheral  venodilation,   which  results  in  reduced  cardiac  size  and  cardiac  output   through  reduced  preload   • Reduced  afterload   o From  arteriolar  dilation   o May  contribute  to  an  increase  in  ejection  and  a  further   decrease  in  cardiac  size   • Venodilation   o Leads  to  decreased  diastolic  heart  size  and  fiber  tension   • Arteriolar  Dilation   o Leads  to  reduced  peripheral  resistance  and  blood  pressure   Page  2  of  5  

• Overall  reduction  in  myocardial  fiber  tension,  oxygen   consumption  and  double  product     PRIMARY  MECHANISM  OF  THERAPEUTIC  BENEFIT   • ATHEROSCLEROTIC  ANGINA   o Reduction  of  the  oxygen  requirement   o Increase  in  coronary  flow  in  ischemic  areas  is  less  likely   • VASOSPASTIC  ANGINA   o Reversal  of  coronary  spasm  and  increased  blood  flow   • Reflex  tachycardia  often  occurs  when  nitroglycerin  reduces  the   blood  pressure     ORGAN  SYSTEM  EFFECTS   • Nitrates  relax  the  smooth  muscle  of  the  bronchi,  gastrointestinal   tract,  and  genitourinary  tract   • Intravenous  nitroglycerin,  sometimes  used  in  unstable  angina,   reduces  platelet  aggregation     TOXICITY   • NITRATE  TOXICITY   o Most  common  toxic  effects  of  nitrates  are  responses  evoked   by  vasodilation   § Tachycardia   • From  baroreceptor  reflex   § Orthostatic  hypotension   • Direct  extension  of  the  venodilator  effect   § Throbbing  headache   • From  meningeal  artery  vasodilation   o Do  not  cause  methemoglobinemia   o In  the  past,  nitrates  were  responsible  for  several  occupational   diseases  in  munitions  plants  in  which  workplace   contamination  by  these  volatile  chemicals  was  severe   o “MONDAY  DISEASE”   § most  common  form  of  these  diseases   § alternating  development  of  tolerance  (during  the  work   week)  and  loss  of  tolerance  (over  the  weekend)  for  the   vasodilating  action,  resulting  in  headache,  tachycardia  and   dizziness  every  Monday   • NITRITE  TOXICITY   o Cause  methemoglobinemia  at  high  concentrations   o Has  potential  antidotal  action  in  cyanide  poisoning     NITRITES  IN  THE  TREATMENT  OF  CYANIDE  POISONING   • Cyanide  ion  rapidly  complexes  with  the  iron  in  the  cytochrome   oxidase  resulting  in  a  block  of  oxidative  metabolism  and  cell   death   • Iron  in  methemoglobin  has  a  higher  affinity  for  cyanide  than  the   iron  in  cytochrome  oxidase   • Nitrites  convert  the  ferrous  iron  in  hemoglobin  to  the  ferric   form,  yielding  methemoglobin   • Cyanide  poisoning  can  be  treated  by:   o Immediate  exposure  to  amyl  nitrite,  followed  by   o Intravenous  administration  of  sodium  nitrate,  which  rapidly        

increases  the  methemoglobin  level  to  the  degree  necessary   to  remove  a  significant  amount  of  cyanide  from  cytochrome   oxidase,  followed  by   o Intravenous  sodium  thiosulfate,  which  converts   cyanmethemoglobin  to  thiocyanate  and  methemoglobin   • THIOCYANATE   o Less  toxic  than  cyanide   o Excreted  by  the  kidney     CALCIUM  CHANNEL  –  BLOCKING  DRUGS   CLASSIFICATION  &  PHARMACOKINETICS   • Typified  by:   o NIFEDIPINE   o DILTIAZEM   o VERAPAMIL   • All  are  orally  active   • Most  have  half-­‐lives  of  3  –  6  hours     NIMODIPINE   • Another  member  of  dihydropyridine  family  with  similar   properties   • Approved  only  for  management  of  stroke  associated  with   subarachnoid  hemorrhage     BEPRIDIL   • Drug  somewhat  similar  in  structure  to  verapamil   • Has  a  longer  duration  of  action  but  greater  cardiovascular   toxicity  than  the  other  calcium  channel  blockers   • May  induce  torsade  de  pointes  and  other  arrhythmias     MIBEFRADIL   • Newest  calcium  blocker   • Not  a  dihydropyridine   • Blocks  cardiac  “T-­‐type”  calcium  channels  as  well  as  “L-­‐type”   calcium  channels     MECHANISM  OF  ACTION   • Almost  all  of  these  drugs  block  voltage-­‐dependent  “L-­‐type”   calcium  channels,  the  most  important  calcium  channels  in   cardiac  and  smooth  muscle   • Decreasing  calcium  influx  during  action  potentials  in  a   frequency-­‐  and  voltage-­‐dependent  manner  will  reduce   intracellular  calcium  concentration  and  muscle  contractility   • None  of  the  calcium  channel-­‐blockers  interfere  with  calcium-­‐ dependent  neurotransmitter  or  hormone  release  because  these   processes  does  not  utilize  “L-­‐type”  or  “T-­‐type”  channels     EFFECTS  &  CLINICAL  USE   • Relax  blood  vessels,  uterus,  bronchi  and  gut   • All  calcium  channel-­‐blockers  reduce  blood  pressure  and  double   product  in  patients  with  angina     • Effective  as  prophylactic  therapy  in  angina     Page  3  of  5  

• In  atherosclerotic  angina,  these  drugs  are  effective  if  combined   with  nitrates     • These  drugs  are  used  in:   o Angina   o Hypertension   o Supraventricular  tachycardia   o Migraine   o Preterm  labor   o Stroke   o Raynaud’s  phenomenom   • DILTIAZEM  and  VERAPAMIL   o Reduce  rate  of  heart  contractility  and  block  levels  of  calcium   conduction  in  the  heart     o Can  treat  AV  nodal  arrhythmias     • NIFEDIPINE   o Evoke  greater  vasodilation   § The  resulting  sympathetic  reflex  prevents  bradycardia  and   may  actually  increase  the  heart  rate   o Can  be  used  to  abort  an  acute  anginal  attack     TOXICITY   • Can  cause:   o Constipation   o Edema   o Nausea   o Flushing   o Dizziness   • More  serious  adverse  effects:  (more  common  with  verapamil)   o Congestive  heart  failure   o Atrioventricular  blockade   o Sinus  node  depression   • Bepridil  may  induce  torsade  de  pointes  and  other  arrhythmias     BETA-­‐BLOCKING  DRUGS   MECHANISM  OF  ACTION   • Include:   o Propranolol   o Timolol   o Nadolol   o Carvedilol   o Labetalol   o Metoprolol   o Atenolol   o Osmolol   o Butoxamine   • Effective  in  the  prophylaxis  of  atherosclerotic  angina  attacks   • Actions  include  both:   o Beneficial  effects:   § Decreased  heart  rate   § Decreased  cardiac  force   § Decreased  blood  pressure   o Detrimental  effects:   § Increased  heart  size        

  • • • • •

§ Longer  ejection  period   o Reduced  double  product   CLINICAL  USE   Used  only  for  prophylactic  therapy  of  angina   Are  of  no  value  in  an  acute  attack   Effective  in  preventing  exercise-­‐induced  angina   Ineffective  against  vasospastic  form  of  angina   Combination  of  beta-­‐blockers  with  nitrates  is  useful   o Because  the  undesirable  compensatory  effects  evoked  by  the   nitrates  (tachycardiac  and  increased  cardiac  force)  are   prevented  or  reduced  by  beta-­‐blockade  

  NONPHARMACOLOGIC  THERAPY  FOR  ANGINA   • MYOCARDIAL  REVASCULARIZATION  BY   o CORONARY  ARTERY  BYPASS  GRAFT  (CABG)   o PERCUTANEOUS  TRANSLUMINAL  CORONARY  ANGIOPLASTY   (PTCA)   § Important  therapies  in  severe  angina   § Only  methods  capable  of  consistently  increasing  coronary   flow  in  atherosclerotic  angina  and  increasing  double   product                                       PRAYER  BEFORE  STUDYING     Holy  Spirit,  Giver  of  all  good  gifts,  enter  into  my  mind  and  heart.   Give  me  the  gift  of  knowledge  and  the  grace  to  use  it  wisely.   Help  me  in  all  my  endeavors.   Give  me  perseverance  and  fortitude.   Help  my  memory,  that  I  may  remember  what  I  learn   and  recall  it  when  necessary.   Guide  me  in  the  classroom.   You  who  are  the  Way,  the  Truth,  and  the  Life,   Let  me  not  be  deceived  by  false  teaching.   Our  Lady  of  Good  Studies,  pray  for  me.   Amen.     Page  4  of  5  

  Subject:   PHARMACOLOGY    

First  Semester  A.Y.  2015-­‐2016  

2.2  VASODILATORS  &  TREATMENT  OF  ANGINA   Topic:   Lecturer:   Dr.  Paguirigan     APPENDIX          

Nitrates  Alone  

Beta-­‐blockers  or  Calcium   channel-­‐blockers  Alone  

Combined  Nitrate  and  Beta-­‐ blockers  or  Calcium  channel-­‐ blockers  

Heart  Rate   Reflex  increase   Decrease   Decrease   Arterial  Pressure   Decrease   Decrease   Decrease   End-­‐diastolic  Pressure   Decrease   Increase   Decrease   Contractility   Reflex  increase   Decrease   No  effect  or  Decrease   Ejection  time   Reflex  decrease   Increase   No  effect   Table  1  –  Effects  of  nitrates  alone  and  with  beta-­‐blockers  or  calcium  channel-­‐blockers  in  angina  pectoris                   DRUG   SELECTIVITY   PARTIAL  AGONIST   LOCAL  ANESTHETIC   LIPID  SOLUBILITY   ELIMINATION   APPROXIMATE   ACTIVITY   ACTION   HALF-­‐LIFE   BIOAVAILABILITY   Acebutolol   Atenolol   Esmolol   Carvedilol   Labetalol   Metoprolol   Nadolol   Pindolol   Propranolol   Timolol  

Beta-­‐1   Beta-­‐1   Beta-­‐1   None   None   Beta-­‐1   None   None   None   None  

Yes   Yes   Low   3  –  4  hours   No   No   Low   6  –  9  hours   No   No   Low   10  minutes   No   No   No  data   7  –  10  hours   Yes   Yes   Moderate   5  hours   No   Yes   Moderate   3  –  4  hours   No   No   Low   14  –  24  hours   Yes   Yes   Moderate   3  –  4  hours   No   Yes   High   3.5  –  6  hours   No   No   Moderate   4  –  5  hours   Table  2  –  Properties  of  several  beta  receptor-­‐blocking  drugs  

Trans  By:  Milka  Maddara,  Arianne  Tamaray  and  Krisha  Turingan   Edited  By:  Tony  Tagacay  II  

50%   40%     25  –  35%   30%   50%   33%   90%   30%   50%  

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