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Breast cancer written report

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Breast Cancer Clinical Therapeutics

Breast Cancer Clinical Therapeutics

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  • 1. PROBLEM  1:  BREAST  CANCER                                                                                                                                                                                                          Yang   GOALS  OF  THERAPY:     • • The  goals  of  treatment  for  a  patient  with  metastatic  breast  cancer  are  palliation  and  prolongation  of  life.     Since  cure  is  not  the  goal  in  this  setting,  the  easiest,  least  toxic  treatment  regimen  should  be  chosen.     Screening  for  Breast  cancer       Patient  in  our  case  was  previously   diagnosed  with  stage  IIB  Breast  cancer.     In  stage  IIB  tumor:   • Larger  than  2  centimeters  but  not  larger  than  5  cm.  small  clusters  of  breast  cancer  cells  (larger  than  0.2   millimeter  but  not  larger  than  2  millimeters)  are  found  in  the  lymph  nodes   or   • Larger  than  2  centimeters  but  not  larger  than  5  centimeters.  Cancer  has  spread  to  1  to  3  axillary  lymph   nodes  or  to  the  lymph  nodes  near  the  breast  bone  (found  during  a  sentinel  lymph  node  biopsy)     or     • Larger  than  5  centimeters.  Cancer  has  not  spread  to  the  lymph  nodes.     But  now,  our  patient  has  Metastatic  Breast  Cancer     Radiation  therapy,  hormonal  therapy,  and  chemotherapy  have  all  been  used  in  the  treatment  of  metastatic   breast  cancer  to  palliate  the  patient  and  possibly  prolong  survival.         Palliation  is  the  primary  goal  of  therapy:                        the  easiest,  least  toxic  treatment  that  can  provide  the                                                              best  possible  response  is  generally  preferred.         •  metastasize  to  virtually  any  site     •  most  common  sites:  bone,  lung,  pleura,  liver,  soft  tissue,  and  the  central  nervous  system.     •  The  choice  of  therapy  for  metastatic  disease  is  based  on  the  site  of  disease  involvement  and  the  presence   or  absence  of  certain  patient  characteristics.             SECTION  3E-­‐–  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                                    1    
  • 2. Treatment:     I.  RADIATION  THERAPY:   Radiation  therapy  is  primarily  used  to  control  symptomatic  disease  such  as  bone  metastases,  metastatic  brain   lesions,  and  spinal  cord  compressions.       II.  HORMONAL  THERAPY   • goal  of  hormonal  therapy  is  to  reduce  the  stimulation  of  the  tumor  cells  by  estrogen.     • Adjuvant  hormonal  therapy  should  be  offered  to  any  patient  whose  tumor  overexpresses  hormone   receptors  [either  ER  or  progesterone  (PgR)],  regardless  of  patient  age,  nodal  status,  or  menopausal  status.     In  our  case,  patient  had  received  Tamoxifen,  a  selective  estro-­‐  gen-­‐receptor  modulator  (SERM),  (adjuvant  hor-­‐   monal  therapy  most  commonly  used)  for  five  years.       • However,  the  benefits  of  tamoxifen  must  be  weighed  against  the  side  effects  of  treatment,  particularly   when  the  drug  is  being  used  in  the  adjuvant  setting.     • The  most  common  side  effects  of  tamoxifen  include  hot  flashes  and  vaginal  discharge,  but  an  increased   risk  of  thromboembolic  events  and  endometrial  cancer  can  also  occur.       • Third-­‐generation  aromatase  inhibitors  have  been  extensively  studied  as  first  and  second-­‐line  therapy   for  metastatic  breast  cancer.       o The  ATAC  (Arimidex,  Tamoxifen  Alone  or  in  Combination)  Trialists’  Group  found  superior  disease-­‐   free  survival  for  anastrozole  as  adjuvant  therapy  in  post-­‐  menopausal  women  with  hormone-­‐ sensitive  disease  when  compared  to  tamoxifen  or  the  combination  of  tamoxifen  and  anastrozole.  As   a  result,  anastrozole  was  granted  accelerated  approval  as  adjuvant  therapy  for  breast  cancer.       • Fulvestrant,  an  injectable  pure  estrogen  antagonist,  has  also  shown  activity  in  patients  with  hormone-­‐ receptor-­‐  positive  disease  progressing  on  hormonal  therapy.       • The  choice  of  hormonal  therapy  is  patient-­‐specific  and  may  be  influenced  by  prior  therapy  in  the  adjuvant   setting,  toxicity  profiles,  cost,  and  ease  of  administration.     ***   Tamoxifen  –  acts  like  an  anti-­‐estrogen  in  breast  cells,  it  acts  like  an  estrogen  in  other  tissues,  like  the  uterus  and   the  bones   -­‐    stop  the  growth  and  even  shrink  tumors  in  women  with  metastatic  breast  cancer.  It  can  also  be  used  to   reduce    the    risk  of  developing  breast  cancer  in  women  at  high  risk   Aromatase  inhibitors:  cannot  stop  the  ovaries  from  making  estrogen,  so  they  are  only  effective  in  women  whose   ovaries  aren’t  working  (like  after  menopause)   Fulvestrant  -­‐  first  blocks  the  estrogen  receptor  and  then  also  eliminates  it  temporarily;  acts  like  an  anti-­‐estrogen   throughout      the  body   ***                            
  • 3.   Efficacy   Safety   Suitability   Cost   Anti-­‐ estrogen     Tamoxifen   +++   selective  estrogen   receptor  modulator   or  SERM   ++   Disease  flare,  hot  flashes;     rare:  thrombophlebitis,   ocular  abnormalities,   endometrial  cancer     ++   premenopausal  and   postmenopausal  women  (and   men)  with  ER-­‐positive  early-­‐ stage  breast  cancer   1,400   Aromatase   Inhibitors   3rd  gen:   anastrazole   +++   Blocking  aromatase   in  fat  tissue  that  is   responsible  for   making  small   amounts  of   estrogen  in  post-­‐ menopausal  women   +++   Hot  flashes,  nausea,   vomiting,  headache,  fatigue;     rare:  bone  fractures,   musculoskeletal  disorders     +++  No  significant  drug   interactions   initial  therapy  for  metastatic   hormone-­‐sensitive  breast   cancer   treat  postmenopausal  women   with  advanced  breast  cancer   whose  disease  has  worsened   after  treatment  with   tamoxifen   +++   2750   Pure   Estrogen   Antagonist   Fulvestrant   +++   +++   Hot  flashes,  headache,   nausea,  vomiting,  injection   site  reactions     ++    No  significant  drug   interactions   postmenopausal  women  with   metastatic  ER-­‐positive  breast   cancer  after  treatment  with   other  antiestrogens   +++   28,000       Median  duration  of  response  to  the  first  attempt  at  hormonal  manipulation  is  usually  in  the  range  of  9  to  12  mos.     First-­‐line  hormonal  therapy  should  be  administered  for  at  least  6  to  8  weeks  before  disease  response  is   assessed.    If  a  patient  becomes  refractory  to  hormonal  therapy  at  any  time,  chemotherapy  should  be  given.       III.  CHEMOTHERAPY:   Chemotherapeutic  drugs  are  most  commonly  used  as  palliative  therapy  in  patients  who  would  not  be  expected  to   respond  to  hormonal  therapy       4  GROUPS  OF  CHEMOTHERAPEUTIC  DRUGS   1.  ALKYLATING  AGENTS   The  major  clinically  useful  alkylating  agents  have  a  structure  containing  a  bis(chloroethyl)amine,  ethyleneimine,  or   nitrosourea  moiety,  and  they  are  classified  in  several  different  groups.   Mechanism  of  Action   • exert  their  cytotoxic  effects  via  transfer  of  their  alkyl  groups  to  various  cellular  constituents.     • Alkylations  of  DNA  within  the  nucleus  probably  represent  the  major  interactions  that  lead  to  cell  death.     • The  general  mechanism  of  action  of  these  drugs  involves  intramolecular  cyclization  to  form  an   ethyleneimonium  ion  that  may  directly  or  through  formation  of  a  carbonium  ion  transfer  an  alkyl  group  to  a   cellular  constituent   • a  secondary  mechanism  that  occurs  with  nitrosoureas  involves  carbamoylation  of  lysine  residues  of  proteins     through  formation  of  isocyanates.     SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        3        
  • 4. Adverse  Effects   • generally  dose-­‐related  and  occur  primarily  in  rapidly  growing  tissues  such  as  bone  marrow,  gastrointestinal   tract,  and  reproductive  system.     • Nausea  and  vomiting  can  be  a  serious  issue     • potent  vesicants  and  can  damage  tissues  at  the  site  of  administration  as  well  as  produce  systemic  toxicity.     • carcinogenic  in  nature,  and  there  is  an  increased  risk  of  secondary  malignancies,  especially  acute  myelogenous   leukemia.   Cyclophosphamide     • is  one  of  the  most  widely  used  alkylating  agents.     • One  of  the  potential  advantages:  high  oral  bioavailability     • oral  and  intravenous  routes  with  equal  clinical  efficacy.     • inactive  in  its  parent  form,  and  must  be  activated  to  cytotoxic  forms  by  liver  microsomal  enzymes     A.  NITROSOUREAS   • non-­‐cross-­‐resistant  with  other  alkylating  agents;  all  require  biotransformation,  which  occurs  by   nonenzymatic  decomposition,  to  metabolites  with  both  alkylating  and  carbamoylating  activities   • highly  lipid-­‐soluble  and  are  able  to  cross  the  blood-­‐brain  barrier   B.  NONCLASSIC  ALKYLATING  AGENTS   1. Procarbazine   2. Dacarbazine   3. Bendamustine     C.  PLATINUM  ANALOGS   Three  platinum  analogs  are  currently  used  in  clinical  practice:  cisplatin,  carboplatin,  and  oxaliplatin.     Cisplatin     • • is  an  inorganic  metal  complex  that  was  initially  discovered  through  an  observation  that  neutral  platinum   complexes  inhibited  division  and  filamentous  growth  of  Escherichia  coli.     MOA:  kill  tumor  cells  in  all  stages  of  the  cell  cycle  and  bind  DNA  through  the  formation  of  intrastrand  and   interstrand  cross-­‐links,  thereby  leading  to  inhibition  of  DNA  synthesis  and  function.   -­‐  Cisplatin  and  the  other  platinum  analogs  are  extensively  cleared  by  the  kidneys  and  excreted  in  the  urine.  As  a   result,  dose  modification  is  required  in  patients  with  renal  dysfunction.   Carboplatin     • is  a  second-­‐generation  platinum  analog     • MOA,  mechanisms  of  resistance,  and  pharmacology  are  identical  to  cisplatin.   • in  contrast  to  cisplatin,  it  exhibits  significantly  less  renal  toxicity  and  GI  toxicity   • Its  main  dose-­‐limiting  toxicity  is  myelosuppression.     • It  has  therefore  been  widely  used  in  transplant  regimens  to  treat  refractory  hematologic  malignancies.     Oxaliplatin     • • third-­‐generation  diaminocyclohexane  platinum  analog.     tumors  that  are  resistant  to  cisplatin  or  carboplatin  on  the  basis  of  mismatch  repair  defects  are  not  cross-­‐ resistant  to  oxaliplatin,  
  • 5.   2.  ANTIMETABOLITES   A.  ANTIFOLATES   Methotrexate     is  a  folic  acid  analog  that  binds  with  high  affinity  to  the  active  catalytic  site  of  dihydrofolate  reductase   (DHFR)  à  inhibition  of  the  synthesis  of  tetrahydrofolate  (THF)   Pemetrexed   Pralatrexate   •           SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        5        
  • 6. B.  FLUOROPYRIMIDINES   5-­‐Fluorouracil     inactive  in  its  parent  form;  requires  activation  via  a  complex  series  of  enzymatic  reactions  to  ribosyl  and   deoxyribosyl  nucleotide  metabolites;  cytotoxicity  of  5-­‐FU  is  thought  to  be  the  result  of  combined  effects  on   both  DNA-­‐  and  RNA-­‐mediated  events.   Capecitabine   • C.  DEOXYCYTIDINE  ANALOGS   Cytarabine     • (ara-­‐C)  is  an  S  phase-­‐specific  antimetabolite  that  is  converted  by  deoxycytidine  kinase  to  the  5'-­‐ mononucleotide  (ara-­‐CMP).  Ara-­‐CMP  is  further  metabolized  to  the  diphosphate  and  triphosphate   metabolites,  and  the  ara-­‐CTP  triphosphate  is  felt  to  be  the  main  cytotoxic  metabolite.   Gemcitabine   D.  PURINE  ANTAGONISTS   6-­‐Thiopurines   Fludarabine   Cladribine      
  • 7. 3.  NATURAL  PRODUCT  CANCER  CHEMOTHERAPY  DRUGS   A.  VINCA  ALKALOIDS   Vinblastine   • inhibition  of  tubulin  polymerization,  which  disrupts  assembly  of  microtubules,  an  important  part  of  the   cytoskeleton  and  the  mitotic  spindle.  This  inhibitory  effect  results  in  mitotic  arrest  in  metaphase,  bringing   cell  division  to  a  halt,  which  then  leads  to  cell  death.   Vincristine   • While  myelosuppression  occurs,  it  is  generally  milder  and  much  less  significant  than  with  vinblastine.   Vinorelbine   B.  TAXANES  &  RELATED  DRUGS   Paclitaxel       • • • drug  functions  as  a  mitotic  spindle  poison  through  high-­‐affinity  binding  to  microtubules  with  enhancement   of  tubulin  polymerization.     This  promotion  of  microtubule  assembly  by  paclitaxel  occurs  in  the  absence  of  microtubule-­‐associated   proteins  and  guanosine  triphosphate  and  results  in  inhibition  of  mitosis  and  cell  division   Hypersensitivity  reactions  may  be  observed  in  up  to  5%  of  patients,  but  the  incidence  is  significantly   reduced  by  premedication  with  dexamethasone,  diphenhydramine,  and  an  H2  blocker.   Abraxane     • • A  novel  albumin-­‐bound  paclitaxel  formulation  is  approved  for  use  in  metastatic  breast  cancer.    In  contrast  to  paclitaxel,  this  formulation  is  not  associated  with  hypersensitivity  reactions   B.  EPIPODOPHYLLOTOXINS   Etoposide   • The  main  site  of  action  is  inhibition  of  the  DNA  enzyme  topoisomerase  II   C.  CAMPTOTHECINS   • • inhibit  the  activity  of  topoisomerase  I,  the  key  enzyme  responsible  for  cutting  and  religating  single  DNA   strands.  Inhibition  of  this  enzyme  results  in  DNA  damage   Myelosuppression  and  diarrhea  are  the  two  most  common  adverse  events             SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        7        
  • 8. 4.  ANTITUMOR  ANTIBIOTICS   Many  of  these  antibiotics  bind  to  DNA  through  intercalation  between  specific  bases  and  block  the  synthesis  of  RNA,   DNA,  or  both;  cause  DNA  strand  scission;  and  interfere  with  cell  replication.   All  of  the  anticancer  antibiotics  now  being  used  in  clinical  practice  are  products  of  various  strains  of  the  soil   microbe  Streptomyces.   A.  ANTHRACYCLINES  among  the  most  widely  used  cytotoxic  anticancer  drugs.   The  anthracyclines  exert  their  cytotoxic  action  through  four  major  mechanisms:     (1)  inhibition  of  topoisomerase  II;   (2)  high-­‐affinity  binding  to  DNA  through  intercalation,  with  consequent  blockade  of  the  synthesis  of  DNA  and  RNA,   and  DNA  strand  scission;     (3)  generation  of  semiquinone  free  radicals  and  oxygen  free  radicals  through  an  iron-­‐dependent,  enzyme-­‐mediated   reductive  process;   (4)  binding  to  cellular  membranes  to  alter  fluidity  and  ion  transport.   Doxorubicin     • is  one  of  the  most  important  anticancer  drugs  in  clinical  practice,  with  major  clinical  activity  in  cancers  of   the  breast,  endometrium,  ovary,  testicle,  thyroid,  stomach,  bladder,  liver,  and  lung   Epirubicin     • • is  an  anthracycline  analog     initially  approved  for  use  as  a  component  of  adjuvant  therapy  in  early-­‐stage,  node-­‐positive  breast  cancer   but  is  also  used  in  the  treatment  of  metastatic  breast  cancer  and  gastroesophageal  cancer.   B.  MITOMYCIN       • undergoes  metabolic  activation  through  an  enzyme-­‐mediated  reduction  to  generate  an  alkylating  agent   that  cross-­‐links  DNA.   C.  BLEOMYCIN     •       small  peptide  that  contains  a  DNA-­‐binding  region  and  an  iron-­‐binding  domain  at  opposite  ends  of  the   molecule.  It  acts  by  binding  to  DNA,  which  results  in  single-­‐  and  double-­‐  strand  breaks  following  free   radical  formation,  and  inhibition  of  DNA  biosynthesis.  
  • 9.       The  American  Society  of  Clinical  Oncology  (ASCO)  breast  cancer  surveillance  guidelines:   • Women  with  a  history  of  breast  cancer  should  perform  monthly  BSE  and  undergo  annual  mammography  of   both  the  preserved  and  contralateral  breast.     • The  patient  should  also  have  a  complete  history  and  physical  examination  every  3  to  6  months  for  the  first   3  years  after  diagnosis,  then  every  6  to  12  months  for  2  years,  and  then  annually.       SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        9        
  • 10. NATIONAL  COMPREHENSIVE  CANCER  NETWORK                     SUMMARY:       Since  patient  was  diagnosed  6  years  ago  with  Breast  cancer:  Stage  IIB  infiltrating  ductal  carcinoma  of  the  right   breast.  Originally,  the  tumor  was  ER_/PR_  and  did  not  overexpress  HER-­‐2/neu.  The  tumor  was  staged  as  T2N1M0.   She  received  a  lumpectomy  with  axillary  lymph  node  dissection  plus  breast  irradiation,  6  cycles  of  AC  (A=   ADRIAMYCIN  an  anthracycline;  C=Cyclophosphamide),  and  tamoxifen  for  5  years.  NEXT  step  would  be  to   change  tamox  to  anastrazole  and  begin  with  chemotherapy  preferably  combination  since  patient  had  already  a   history  of  being  treated  with  a  combination  chemo  drugs  –AC.  Choice  would  depend  on  patient’s  comorbidities  and   toxicities  from  chemo  drugs.    
  • 11. PROBLEM  2:  Bone  Pain                                                                                                                                                                                                                      Zepeda     Basis  for  diagnosis:   • • • Chief  Complaint:  Severe  (7  out  of  10)  hip  pain   Bone  scan:  multiple  metastases  to  the  right  pelvis   Medications:  Ibuprofen  200  to  400  mg  PO  q4–6h  PRN,  calcium  carbonate  1,000  mg  PO  TID  with   meals     GOALS  OF  THERAPY:       • • • Decrease  the  severity  of  pain  from  severe  to  moderate   To  minimize  adverse  reactions  or  intolerance  to  pain  management  therapies     Improve  the  patient’s  quality  of  life  and  optimize  ability  to  perform  activities  of  daily  living   Bone   is   the   most   common   site   of   secondary   breast   cancer   or   breast   cancer   recurrence.   Most   commonly   affected   are   the   spine,   skull,   upper   bones   of   the   arms   and   legs   and   pelvis   which   is   the   one   affected  in  our  patient.     Pain   is   defined   as   “an   unpleasant   sensory   and   emotional   experience   associated   with   actual   or   potential   tissue   damage,   or   described   in   terms   of   such   damage”.   It   is   the   most   common   symptom   that   provokes  people  to  seek  medical  attention     Normally,   the   bone   undergoes   a   continuous   process   of   remodeling   by   the   osteoclast   and   osteoblasts   to   maintain   homeostasis.   Disruption   of   this   process,   which   occurs   in   cancer,   will   cause   the   bone  cells  to  proliferate  and  hypertrophy  causing  the  periosteum  to  stretch  or  affect  the  nerves  thereby   resulting  to  pain.     The   World   Health   Organization   developed   a   stepladder   for   relief   of   pain   management   in   adult   cancer  patient.  It  indicates  the  severity  of  pain  which  is  rated  in  1-­‐10  scale  and  will  dictate  what  type  of   medication  is  needed  or  used.     Stage  1:  Mild  (Pain  Scale:  1-­‐3)   Non-­‐opioids   are   the   first   choice   of   treatment.   Medications   include   are   Acetaminophen   or   NSAIDS   like  Ibuprofen.     Stage  2:Moderate  (Pain  Scale:  4-­‐6)   Those   who   are   not   responded   to   the   first   step   should   receive   a   weak   opioid   such   as   codeine,   oxycodone,  hydrocodone  and  Tramadol     Stage  3:  Severe  (Pain  Scale:  7-­‐10)   Those   who   have   not   been   relieved   by   the   previous   recommendation  will  receive  a  stronger  opioid  such   as  Morphine,  Methadone  and  Fentanyl.         SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        11        
  • 12. Key  Points:     • Oral  route  is  preferred  unless  contraindicated  (parenteral  therapy  may  be  required  for  refractory   pain  or  inability  to  take  per  orem)   • Cancer  pain  is  continuous.  Relief  of  pain  is  only  temporary  and  may  return  in  a  short  time   • Should  be  scheduled  at  regular  intervals  rather  than  prn     • Adjuvant  therapy  is  used  to  decrease  anxiety  and  fear  with  chronic  pain  (e.g.  antidepressants)   • Non-­‐opioids  may  be  given  in  Step  2  and  3     Treatment:     Opioids   -­‐ refers  broadly  to  all  compounds  related  to  opium,  a  natural  product  derived  from  the  poppy  plant   -­‐ reduce  moderate  to  severe  pain,  and  are  unique  in  their  ability  to  do  this  without  producing  loss  of   consciousness   -­‐ produce  analgesia,  affect  mood  and  rewarding  behavior  and  alter  respiratory,  cardiovascular,  GI,   and  neuroendocrine  function     -­‐ All  opioids  have  the  potential  for  tolerance,  habituation,  and  addiction     The  patient  experiences  a  severe  type  of  pain,  therefore  will  be  following  the  Step  3.         Drug   Morphine   Efficacy   ++++   Suitability   +++   Safety   ++   Hydromorphone   ++++   4-­‐5x  more  potent  than   morphine   +++   100x   +++   ++   ++   Only  available  in  IV,   buccal,  spinal  and   patch   +   Not  available  in  the   Philippines     ++   Fentanyl   Methadone   ++++   0.3x   ++   Cost   ++++   Tab  60's   (P1345.00/pack)   ++   Tab  28's   (P3640.00/pack)   ++   Patch  5  ×  1's   (P2513.00/box)   +   Not  available  in  the   Philippines  
  • 13. Methadone:    (Diphenylheptanes)   -­‐ long-­‐acting  mu-­‐receptor  agonist  with  properties  qualitatively  similar  to  those  of  morphine.     -­‐ relief  of  chronic  pain,  treatment  of  opioid  abstinence  syndromes,  and  treatment  of  heroin  users.   -­‐ roughly   equivalent   in   potency   to   morphine   on   a   single   dose   basis;   however,   with   repeated   administration  accumulation  in  CNS  and  lipid  tissues  occurs     Fentanyl:  (Phenylpiperidines)   -­‐ is  a  synthetic  opioid  derivative  of  the  4-­‐anilinophenyl-­‐piperidine  class     -­‐ approximately  100  times  more  potent  than  morphine   -­‐ used  clinically  as  an  analgesic;  administered  intraspinally  or  intravenously  and  as  a  preoperative   anesthetic  agent  because  of  its  potency,  rapid  onset,  and  short  duration  of  action   -­‐ Not  suitable  for  rapid  dose  filtration.  Should  be  used  for  relatively  stable  analgesic  requirement.   -­‐ Also  available  as  a  transdermal  patch  which  can  be  given  every  8  days     Hydromorphone:  (Phenanthrenes)   -­‐ Semisyntheticopioid   that   xerts   major   pharmacodynamic   effects   on   mu-­‐receptors   and   kappa-­‐ receptors   -­‐ less   potential   to   produce   nausea,   vomiting,   constipation,   sedation,   or   euphoria   and   has   a   more   rapid  onset  and  shorter  duration  of  action  than  morphine   -­‐ can  be  used  as  a  substitute  when  these  adverse  effects  warrant  a  therapeutic  alternative     Morphine:  (Phenanthrenes)   -­‐ prototype  strong  opioid  agonist  (the  gold  standard  given  for  cancer  patients  with  moderate-­‐severe  pain)   -­‐ Exert  major  pharmacodynamic  effects  on  mu-­‐receptors  (strong)  and  kappa-­‐receptors   -­‐ Interact   w/   opioid   receptors   in   the   CNS   and   GIT   causing   hyperpolarization   of   nerve   cells,   inhibition  of  nerve  firing  and  presynaptic  inhibition  of  transmitter  release     -­‐ Acts  at  κ  receptors  in  lamina  I  and  II  of  the  substantia  gelatinosa  of  the  SC  which  then  decreases   the  release  of  substance  P     -­‐ Main  indication  is  for  preoperative  pain  and  chronic  malignant  pain       *  All  are  efficacious  but  have  different  potency.  Methadone  is  not  available  in  the  Philippines.  All  opioids   have   produce   these   side/adverse   effects:   constipation   (most   common),   nausea,   vomiting,   somnolence,   mood   changes   like   euphoria,   dysphoria,   addiction,   physical   dependence   and   respiratory   depression   (most  dreaded  complication).       Drug  of  Choice:  Morphine  Sulphate     Drug  interactions:     Paroxetine  and  Morphine:  Opioids  may  enhance  effect  of  SSRI.  Additive  effect  to  sedation.   Metformin  and  Morphine:  increase  effects  of  Metformin   Lisinopril  and  Morphine:  may  have  additive  effect  causing  hypotension     *Therefore  it  is  important  to  take  the  medication  as  prescribed  and  strictly  monitor  compliance.       Plan  of  Action   • Initiate  Morphine  Sulphate  immediate  release  15mg  PO  q3-­‐4hours   • If  the  opiate  requirement  is  determined,  switch  to  a  sustained  release  formulation     SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        13        
  • 14. • • • • Start  with:   Senna  1  tablet  PO  BID  (stool  softener)   Docusate  sodium  100  mg  PO  BID  (laxative)   *   All   these   adverse   events   (nausea,   vomiting,   sedation,   confusion,   constipation,   or   itching)   except  constipation  will  be  gone.  Should  take  these  two  medications  every  day  to  prevent   constipation  from  morphine)   Ibuprofen  800mg  q8h  with  food   Pamidronate  90  mg  IV  over  2  hours  every  4  weeks  (Check  SCr  prior  to  each  dose)     Monitor   Efficacy   (decrease   pain   scale   and   opiate   requirement)   and   Toxicity   (increase   in   pain,   opiate   requirement,   nausea,   vomiting,   itching,   BP,   constipation,   confusion,   sedation,   respiratory   rate,   renal   function,   platelets,   Hct/Hgb,   signs   and   symptoms   of   bleeding,   calcium,   magnesium,   phosphate   Report  any  prolonged  adverse  events,  severe  confusion/lightheadedness,  or  difficulty  breathing   Important  to  take  the  pain  medication  around  the  clock  to  prevent  the  pain  from  recurring       Non-­‐Pharmacologic  Intervention:   • Relaxation  Techniques,  massage  therapy,  and  exercise  can  be  done   • Counsel  KF  that  the  pain  may  not  completely  resolve  but  that  it  should  substantially  decrease  and   she  should  notice  an  improvement  in  mobility     Problem  3:  Hypercalcemia  of  Malignancy  Secondary  to  Bone  Metastases          Villanueva     Hypercalcemia  in  patients  with  cancer  is  primarily  due  to  increased  bone  resorption  and  release   of  calcium  from  bone.  There  are  three  major  mechanisms  by  which  this  can  occur:  osteolytic  metastases   with   local   release   of   cytokines   (including   osteoclast   activating   factors);   tumor   secretion   of   parathyroid   hormone-­‐related  protein  (PTHrP);  and  tumor  production  of  1,25-­‐dihydroxyvitamin  D  (calcitriol).  In  this   case,     I. Basis  for  diagnosis   • • • • • • • • Breast  cancer:  commonly  associated  with  hypercalcemia   Pain  on  right  hip   Decreased  appetite   Increasing  fatigue   Constipation   More  forgetful   Confusion   Ca  level:  12.5  (N:8.5-­‐10.2)     II.  Treatment  objectives   a. To  reduce  serum  calcium  level   b. To  reverse  signs  and  symptoms  of  hypercalcemia   c. avoid  exacerbation  of  hypercalcemia   d. Reduce  gastrointestinal  calcium  absorption        
  • 15. III.  Management   A. Therapeutic   B. Non  pharmacologic     Therapeutic     Loop  diuretic   Bisphosphonat es   Calcitonin   Mechanism   of   action   enhances   urine   flow   but   also   inhibits   calcium   reabsorption   in   the   ascending   limb   of   the   loop  of  Henle   Mimic   pyrophosphat e's   structure,   inhibiting   activation   of   enzymes   that   utilize   pyrophosphat e   -­‐   binding   and   blocking   the   enzyme   farnesyldipho sphate   synthase   (FPPS)   in   the   HMG-­‐CoA   reductase   pathway   Calcitonin   lowers   plasma   Ca2+   and   phosphate   concentration s   thereby   blocking   bone   resorption,   increases   urinary   calcium   excretion   by   Indications   Adverse   effects   acute   pulmonary   edema,   other   edematous   conditions,   acute   hypercalcemia .     ototoxicity,   hypovolemia, K   wasting,   hyperuricemia Oral,  IV     ,   hypomagnese mia   osteoclast-­‐ mediated   bone   resorption,   including   osteoporosis,   steroid-­‐ induced   osteoporosis,   Paget's   disease,   tumor-­‐ associated   osteolysis,   breast   and   prostate   cancer,   and   hypercalcemia .   upset   stomach   and   inflammation   and   erosions   of   the   esophagus,   IV:   can   give   fever   and   flu-­‐like   symptoms   after   the   first   infusion,   rareosteonecr osis  of  the  jaw   Oral,  IV   50%   is   excreted   unchanged   by   the   kidney.   The   remainder  has   a   very   high   affinity   for   bone   tissue,   and   is   rapidly   adsorbed   onto   the   bone   surface   nasuea,   vomitting   effect   on   serum  calcium   is   observed   within   4–6   hours   and   lasts   for   6–10   hours,   subcutaneous,   intranasal,   oral   Paget’s   diasease,   osteoporosis   Pharmocokine tics   SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        15        
  • 16. inhibiting   renal   calcium   reabsorption   reducing   serum  calcium   nephrotoxicity   Oral,   t1/2:   1   in   cancer     hr   patients     thrombocytop decreases   enia,   Reduction   in   plasma   Ca2+   hemorrhage,     plasma   Ca2+   concentration hepatic   and   concentration hypercalcemia   s   by   inhibiting   renal   toxicity   s   occurs   bone   hypocalcemia,   within   24   to   resorption.     nausea,   and   48  hours   vomiting   IV:     short-­‐ hypocalcemia,   termcalcemic   ectopic   control   of   calcification,   some   patients   acute   renal   Binds   to   Ca   with   primary   failure,   and   Oral  and  IV   ions   hyperparathyr hypotension.   oidism   who   Oral:   ectopic   are   awaiting   calcification   surgery.     and   renal   failure   inhibiting   Gallium  Nitrate   bone   resorption     Plicamycin   (Mithramycin)   Phosphate     Rapid  reduction  of  serum  calcium  is  required.  The  first  steps  include  rehydration  with  saline  and   diuresis   with   furosemide.   Saline   rehydration   is   used   to   dilute   serum   calcium   and   promote   calciuresis.   Most  patients  presenting  with  severe  hypercalcemia  have  a  substantial  component  of  prerenal  azotemia   owing   to   dehydration,   which   prevents   the   kidney   from   compensating   for   the   rise   in   serum   calcium   by   excreting  more  calcium  in  the  urine.  Therefore,  the  initial  infusion  of  500–1000  mL/h  of  saline  to  reverse   the   dehydration   and   restore   urine   flow   can   by   itself   substantially   lower   serum   calcium.   The   addition   of   a   loop   diuretic   such   as   furosemide   following   rehydration   not   only   enhances   urine   flow   but   also   inhibits   calcium  reabsorption  in  the  ascending  limb  of  the  loop  of  Henle.  Monitoring  central  venous  pressure  is   important  to  forestall  the  development  of  heart  failure  and  pulmonary  edema  in  predisposed  subjects.       Calcitonin   Calcitonin   has   proved   useful   as   ancillary   treatment   in   a   large   number   of   patients.   Calcitonin   by   itself   seldom   restores   serum   calcium   to   normal,   and   refractoriness   frequently   develops.   However,   its   lack   of   toxicity   permits   frequent   administration   at   high   doses   (200   MRC   units   or   more).   An   effect  on  serum  calcium  is  observed  within  4–6  hours  and  lasts  for  6–10  hours.     The   drug   has   its   greatest   effect   on   spine   and   is   most   effective   in   patients   who   have   high   bone   turnover   rates.   Calcitonin   also   has   a   significant   analgesic   effect   on   acute   pain   from   vertebral   fracture   that   is   independent   of   its   effects   on   bone   metabolism.Given   by   injection   or   intranasal   spray.   Recommended   injectable   dosage   is   100IU   (SQ   or   IM)   and   the   intranasal   dosage   is   200IU   (one  spray)  per  day  in  alternate  nostrils.  Oral  formulation  is  under  investigation.   Side   effects   of   injectable   calcitonin   include   nausea   and   GI   discomfort.   This   may   be  
  • 17. minimized   by   bedtime   administration.   Pruritus   at   the   injection   site   is   also   problematic.   To   minimize  these  side  effects,  patients  should  be  instructed  to  administer  calcitonin  SQ  rather  than   IM.  Intranasal  formulation  appears  to  be  better  tolerated;  rhinitis  is  the  most  commonly  reported   side  effect.     Gallium  Nitrate   Gallium   nitrate   is   approved   by   the   FDA   for   the   management   of   hypercalcemia   of   malignancy.   This   drug  acts  by  inhibiting  bone  resorption.  Given  as  continuous  intravenous  infusion  in  5%  dextrose   for   5   days,   gallium   nitrate   proved   superior   to   calcitonin   in   reducing   serum   calcium   in   cancer   patients.   Because   of   potential   nephrotoxicity,   patients   should   be   well   hydrated   and   have   good   renal  output  before  starting  the  infusion.     Plicamycin  (Mithramycin)   Because  of  its  toxicity,  plicamycin  (mithramycin)  is  not  the  drug  of  first  choice  for  the  treatment  of   hypercalcemia.   However,   when   other   forms   of   therapy   fail,   25–50   mcg/kg   given   intravenously   usually  lowers  serum  calcium  substantially  within  24–48  hours.  This  effect  can  last  several  days.   This   dose   can   be   repeated   as   necessary.   The   most   dangerous   toxic   effect   is   sudden   thrombocytopenia   followed   by   hemorrhage.   Hepatic   and   renal   toxicity   can   also   occur.   Hypocalcemia,  nausea,  and  vomiting  may  limit  therapy.  Use  of  this  drug  must  be  accompanied  by   careful  monitoring  of  platelet  counts,  liver  and  kidney  function,  and  serum  calcium  levels.     Phosphate   Giving  intravenous  phosphate  is  probably  the  fastest  and  surest  way  to  reduce  serum  calcium,  but   it  is  a  hazardous  procedure  if  not  done  properly.  Intravenous  phosphate  should  be  used  only  after   other   methods   of   treatment   (bisphosphonates,   calcitonin,   and   saline   diuresis)   have   failed   to   control  symptomatic  hypercalcemia.  The  risks  of  intravenous  phosphate  therapy  include  sudden   hypocalcemia,  ectopic  calcification,  acute  renal  failure,  and  hypotension.  Oral  phosphate  can  also   lead   to   ectopic   calcification   and   renal   failure   if   serum   calcium   and   phosphate   levels   are   not   carefully  monitored,  but  the  risk  is  less  and  the  time  of  onset  much  longer       Biphosphonates       Alendronate   Risedronate   Ibandronate   Zoledronate   Pamidronate     Efficacy   +++   +++   +++   ++++   ++++   Safety   +++   +++   ++   ++   +++   Suitability   ++++   +++   +++   +++   +++   Cost   +++  P1100   ++  P1,800   +  P17,000   +  P24,000   ++  P1700   First-­‐generation  bisphosphonates  contain  minimally  modified  side  chains  (R1,  R2)  (medronate,  clodronate,   and   etidronate)   or   contain   a   chlorophenyl   group   (tiludronate).     They   are   the   least   potent   and   in   some   instances  cause  bone  demineralization.     Second-­‐generation  aminobisphosphonates   (e.g.,  alendronate   and   pamidronate)   contain   a   nitrogen   group   in   the  side  chain.  They  are  10  to  100  times  more  potent  than  first-­‐generation  compounds.     SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        17        
  • 18. Third-­‐generation   bisphosphonates   (e.g.,  risedronate   and   zoledronate)   contain   a   nitrogen   atom   within   a   heterocyclic  ring  and  are  up  to  10,000  times  more  potent  than  first-­‐generation  agents   Alendronate   and   ibandronate   directly   inhibit   multiple   steps   in   the   pathway   from   mevalonate   to   cholesterol   and   isoprenoid   lipids,   such   as   geranylgeranyldiphosphate,   that   are   required   for   the   prenylation   of   proteins   that   are   important   for   osteoclast   function.   The   potency   of   inhibiting   farnesyl   synthase   correlates   directly   with   their   antiresorptive   activity.   They   should   not   be   taken   with   iron   supplements,  vitamins  with  minerals,  or  antacids  containing  calcium,  magnesium,  or  aluminum  because   they  reduce  absorption  of  bisphosphonates.   Pamidronate   is   approved   for   management   of   hypercalcemia   but   also   is   effective   in   other   skeletal   disorders.  Pamidronate  is  available  only  for  parenteral  administration.  For  treatment  of  hypercalcemia,   pamidronate   may   be   given   as   an   intravenous   infusion   of   60   to   90   mg   over   4   to   24   hours.   Electrolyte   imbalances   may   occur   with   pamidronate   use.   Pamidronate   overdose   could   manifest   with   a   low   blood   calcium   level.   Twitching,   anxiety,   muscle   weakness   or   seizures   could   result.Onset:   24-­‐48   hr.   Duration:   Peak   effect:   max   5-­‐7   days.   Absorption:   Poor   absorption.   Excretion:   Elimination   half-­‐life:   21-­‐35   hr.   Excretion:  Biphasic;  urine  (approx  50%  as  unchanged  drug)  within  120  hr.   Zoledronate  has  been  associated  with  renal  toxicity,  deterioration  of  renal  function,  and  potential  renal   failure.  Thus,  the  infusion  should  be  given  over  at  least  15  minutes,  and  the  dose  should  be  4  mg.  Patients   who   receive   zoledronate   should   have   standard   laboratory   and   clinical   parameters   of   renal   function   assessed   prior   to   treatment   and   periodically   after   treatment   to   monitor   for   deterioration   in   renal   function.   It   can   be   administered   at   home   rather   than   in   hospital.   With   monitoring   of   Ca   level,   albumin,   phosphate   level,   K   level,   Mg   level,   Na   level,   hydration   status   (BUN,   SCr,   BP,   HR).   Distribution:   Protein   binding:  Low  (22-­‐56%).  Excretion:  Excreted  unchanged  in  urine  (23-­‐55%),  the  rest  sequestered  to  bone   and   eliminated   very   slowly.The   total   time   between   reconstitution,   dilution,   storage   in   a   refrigerator   at   2-­‐ 8°C  and  end  of  administration  must  not  exceed  24  hrs.   First-­‐generation   bisphosphonate   etidronate   was   associated   with   osteomalacia.   Alendronate   and   risedronate   were   well   tolerated   in   clinical   trials,   some   patients   experience   symptoms   of   esophagitis.   If   symptoms   persist   despite   precautions,   use   a   proton   pump   inhibitor   at.   Both   drugs   may   be   better   tolerated   on   a   once-­‐weekly   regimen   with   no   reduction   of   efficacy.   Patients   with   active   upper   gastrointestinal  disease  should  not  be  given  oral  bisphosphonates.     Mild   fever   and   aches   may   attend   the   first   parenteral   infusion   of   pamidronate,   likely   owing   to   cytokine   release.  These  symptoms  are  short-­‐lived  and  generally  do  not  recur  with  subsequent  administration.   All   oral   bisphosphonates   are   very   poorly   absorbed   from   the   intestine   and   have   remarkably   limited   bioavailability  [<1%  (alendronate,  risedronate)  to  6%  (etidronate,  tiludronate)].  Thus  these  drugs  should   be   administered   with   a   full   glass   of   water   following   an   overnight   fast   and   at   least   30   minutes   before   breakfast.   Oral   bisphosphonates   have   not   been   used   widely   in   children   or   adolescents   because   of   uncertainty  of  long-­‐term  effects  of  bisphosphonates  on  the  growing  skeleton.     Bisphosphonates   are   excreted   primarily   by   the   kidneys.   Adjusted   doses   for   patients   with   diminished   renal  function  have  not  been  determined;  bisphosphonates  currently  are  not  recommended  for  patients   with  a  creatinine  clearance  of  less  than  30  ml/min.   Non  pharmacologic   1. Hold  calcium  supplement   Patient  education   1. Confusion,  decreased  appetite,  constipation  are  due  to  high  calcium  level   2. Nausea  and  vomiting  are  side  effects  of  pamidronate   3. Eat  small  frequent  meals  to  help  with  the  nausea  and  vomiting  
  • 19.           Edward  Philip  I.  Villanueva                      FEU-­‐NRMF  Medical  Center         Regalado  Avenue,  West  Fairview,  Quezon  City                                                                                                                                          Room  416                                                                                                          MWF  –  10:00am-­‐11:00am                                                                                                                    Tel  no:  (02)  632-­‐1234   Patient:  Kay  Floyd                 January  30,  2014   62  years  old,  female   Address:  #4  Iris  St.,  West  Fairview,  Quezon  City       Description:  D:FEU-­‐NRMFSY  12-­‐13  2nd  semClinical  Therapeutics  3ACase  4  REPORTRx.jpg       Pamidronate                   90  mg               Sig:  initiate  pamidronateintravenouslyover  2  hours               Edward  Philip  I.  Villanueva,MD   Lic.  No.  123456                     PTR  No.  78910     PROBLEM  4:  DIABETES  MELLITUS  TYPE  2                                                                                                                                                      Zagada     Basis  for  diagnosis:   • Type  2  diabetes  mellitus    for  7  years   • 20  packs  per  year  tobacco  history   • Overweight   • HbA1c=7     Type  2  diabetes  is  characterized  by  tissue  resistance  to  the  action  of  insulin  combined  with  a  relative   deficiency  in  insulin  secretion     GOALS  OF  THERAPY:     • • Continue  control  of  blood  sugar  by  maintaining  normal  or  near-­‐normal  ranges     o Keep  HbA1C  of  <7   Prevent  disease  and  drug  related  complications   The  major  goal  of  pharmacologic  therapy  for  diabetes  is  to  normalize  metabolic  parameters,  such  as  blood   sugar,  in  order  to  reduce  the  risk  of  long-­‐term  complications.   Treatment:   The  treatment  of  Type  II  diabetes  is  multifaceted.  First,  obese  patients  should  endeavor  to  reduce  body   weight  and  increase  exercise  in  order  to  improve  insulin  sensitivity.  Some  Type  II  patients  can  achieve  good   control  of  their  diabetes  by  modifying  their  diet  and  exercise  habits.   Pharmacologically,  treatments  include  orally  available  agents  that  act  to  slow  glucose  absorption  from  the  gut   (a-­‐glucosidase   inhibitors),   to   increase   insulin   secretion   by   ß   cells   (sulfonylureas,   meglitinides,   and   GLP-­‐1   mimetics),   or   to   increase   insulin   sensitivity   at   target   tissues   (thiazolidinediones   and   biguanides).   These   agents   are   generally  ineffective  for  patients  with  Type  I  diabetes.  Patients  with  Type  II  diabetes  are  frequently  treated  with   combinations  of  these  drugs  and  are  therefore  utilizing  multiple  strategies.   SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        19        
  • 20. Class  of  Drugs  used  for  Diabetes   Drug  Class   Action   SULFONYLUREA  AND   MEGLITINIDES   Insulin  secretagogue   BIGUANIDES   Clinical   Application   Effects   Insulin  Sensitizer   • • THIAZOLIDINEDIONES     Insulin  Sensitizer   Competitive  inhibitors   • ALPHA-­‐GLUCDIDASE   of  the  intestinal   INHIBITOR   α-­‐glucosidases   • • Glucagon-­‐like  peptide-­‐ • GLP-­‐1  AGONISTS     1  (GLP-­‐1)  receptor   • agonist     reduce  circulating  glucose     increase  glycogen,fat,  and  protein  formation     Decreased  endogenous   glucose  production   Reduces  insulin  resistance   Reduce  conversion  of  starch  and   disaccharides  to  monosaccharides    reduce  postprandial  hyperglycemia   enhances  glucose-­‐dependent  insulin  secretion   inhibits  glucagon  secretion   delays  gastric  emptying,  and  decreases   appetite   DM  type  2   DM  type  2   DM  type  2   DM  type  2   DM  type  2       Class   THIAZOLIDINEDIONES   (TZDs)   BIGUANIDES   GLP-­‐1  AGONISTS     Sulfonylureas   A-­‐glucosidase   inhibitors   +++   Efficacy   +++   Safety   Suitability   ++++   ++   Cost   ++++   ++++   +++   +++   ++++   +++   +++   +++   ++++   ++++   +++   +++   ++++   ++   +++   ++     1. SULFONYLUREAS  AND  MEGLITINIDES     -­‐inhibit  the  ß  cell  K+/ATP  channel  at  the  SUR1  subunit,  thereby  stimulating  insulin  release  from  pancreatic   ß  cells  and  increasing  circulating  insulin  to  levels  sufficient  to  overcome  insulin  resistance.     First-­‐generation  sulfonylureas:   Second-­‐generation  sulfonylureas:   Acetohexamide   Glimepiride   Chlorpropamide   Glipizide   Tolazamide   Glibenclamide  (Glyburide)   Tolbutamide   Gliclazide     Gliquidone   Sulfonylureas   are   the   mainstay   of   treatment   for   Type   II   diabetes;   orally   available   and   metabolized   by   the   liver.   The   major   adverse   effect   is   hypoglycemia   resulting   from   oversecretion   of   insulin;   Thus,   these   medications   should   be   used   cautiously   in   patients   who   are   unable   to   recognize   or   respond   appropriately   to   hypoglycemia,   such   as   those   with   impaired   sympathetic   function,   mental   status   changes   (our   patient   has   depression),   or   advanced   age.   However   this   agents   can   cause   weight   gain   secondary   to   increased   insulin   activity   in   adipose   tissue;   therefore,   are   better   suited   for   nonobese   patients   (wherein   our   patient   is   already   overweight).   The   adverese   effect   of   hypoglycemia   and   weight   gain   makes   this  drugs  less  suitable  for  our  patient.   As   with   sulfonylureas,   meglitinides   stimulate   insulin   release   by   binding   to   SUR1   and   inhibiting   the   ß   cell   K+/ATP   channel.   Although   both   sulfonylureas   and   meglitinides   act   on   the   SUR1   subunit,   these   two   classes   of   drugs   bind   to   distinct   regions   of   the   SUR1   molecule.   The   absorption,   metabolism,  and  adverse  effect  profiles  of  meglitinides  are  similar  to  those   of  sulfonylureas.  
  • 21. 2. BIGUANIDES  (METFORMIN)         -­‐ activates   AMP-­‐dependent   protein   kinase   (AMPPK)   to   block   breakdown   of   fatty   acids   and   to   inhibit   hepatic   gluconeogenesis   and   glycogenolysis;   increases   insulin   receptor   activity   and   metabolic   responsiveness   in   liver   and   skeletal   muscle.   The   most   common   adverse   effect   is   mild   gastrointestinal   distress,  which  is  usually  transient  and  can   be  minimized  by  slow  titration  of  the  dose.   A   potentially   more   serious   adverse   effect   is   lactic   acidosis.   Because   biguanides   decrease   the   flux   of   metabolic   acids   through   gluconeogenic   pathways,   lactic   acid   can   accumulate   to   dangerous   levels   in   biguanide-­‐treated   patients.   This   drug   is   currently  being  taken  by  the  patient.   3. THIAZOLIDINEDIONES  (TZDS)     -­‐ bind   and   stimulate   the   nuclear   hormone   receptor   peroxisome   proliferator   activated   receptor-­‐γ   (PPARγ),   thereby   increasing   insulin   sensitivity   in   adipose   tissue,   liver,   and   muscle.   The   TZDs   do   not   affect   insulin   secretion,   but   rather   enhance   the   action   of   insulin   at   target   tissues.   Two   thiazolidinediones   are   currently   available:   pioglitazone   and   rosiglitazone.   An   adverse   effect   common   to   both   Tzds   is   fluid   retention,   which   presents   as   a   mild   anemia   and   peripheral   edema,   especially   when   the   drugs   are   used   in   combination   with   insulin   or   insulin   secretagogues.   Both   drugs   increase   the   risk   of   heart   failure.   Many   users   have   a   dose-­‐related   weight  gain  (average  1–3  kg),  which  may  be  fluid  related.   This   is   drug   (Rosiglitazone)   is   currently   being   taken   by   the   patient   but   its   adverse   effect   profile   may   warrant   its   discontinuation.       4. ALPHA-­‐GLUCOSIDASE  INHIBITORS     are  carbohydrate  analogues  that  bind  avidly  to  intestinal  brush   border  a-­‐glucosidase  enzymes,  slowing  breakdown  and  absorption  of   dietary  carbohydrates  such  as  starch,  dextrin,  and  disaccharides.   Flatulence,  bloating,  abdominal  discomfort,  and  diarrhea  are  common   adverse  effects,  all  of  which  result  from  gas  released  by  bacteria   acting  on  undigested  carbohydrates  that  reach  the  large  intestine.   The  patient  is  currently  taking  metformin  which  can  ossibly  cause  GI   distress  and  lactic  acidosis  making  this  drug    less  favorable  addition   to  the  patients  treatment.  Examples  of  this  drugs  are  Acarbose,   Miglitol  and  Voglibose   SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        21        
  • 22.   5. GLP-­‐1  (GLUCAGON-­‐LIKE  PEPTIDE-­‐1)  MIMETICS     -­‐ are  the  newest  class  of  drugs  developed  for  the  treatment   of   diabetes.   (Ex;   Exanitide   and   Sitagliptin).   Exenatide   is   Glucagon-­‐like   peptide-­‐1   (GLP-­‐1)   receptor   agonist   is   not   orally   available   and   must   be   injected   while   Sitagliptin   (available   orally)   is   a   dipeptidyl   peptidase-­‐IV   (DPP   IV)   inhibitor   that   slows   the   proteolytic   inactivation   of   GLP-­‐1   and  other  incretin  hormones.   This  agents  can  be  used  as  monotherapy  or  in  combination   with  a  TZD  or  metformin.     The  known  physiological  functions  of  GLP-­‐1  include:   • Increases  insulin  secretion   from   the  pancreas  in   a  glucose-­‐dependent  manner.   • Decreases  glucagon  secretion  from  the  pancreas  by   engagement   of   a   specific  G   protein-­‐coupled   receptor.   • increases   insulin-­‐sensitivity   in   both  alpha   cells  and  beta  cells   • Increases  beta   cells  mass   and   insulin   gene   expression,   post-­‐translational   processing   and   incretion.   • Inhibits   acid   secretion   and   gastric   emptying   in   the  stomach.   • Decreases  food  intake  by  increasing  satiety  in  brain   • Promotes  insulin  sensitivity.     Dose   adjustment   is   necessary   in   patients   with   moderate   or   severe   kidney   disease.     This   agents   may   ay   cause  hypoglycemia  in  combination  with  sulfonylureas  and  insulin.       In   this   case,   taking   into   consideration   the   patients   condition,   we   chose   to   give   a   combination   therapy   of   Sitagliptin  and  Metformin.     Drug  of  choice:  Sitagliptin  +  Metformin  (Janumet)  maintenance  50  mg/500  mg  tab  twice  a  day.       Non  pharmacologic  Intervention:   • Counsel  KF  to;   – continue  diabetes  medications  and  self-­‐monitoring.     – Remind  her  of  the  importance  of  diet/exercise  in  the  treatment  of  diabetes.     – Remind  her  to  maintain  all  follow-­‐up  appointments  for  diabetes.     – Report  any  shortness  of  breath  or  swelling  in  the  legs  to  the  physician.                            
  • 23.   PROBLEM  5:  DEPPRESSION                                                                                                                                                           Basis  for  diagnosis:   • Present  in  patients  medical  history   • Use  of  SSRI-­‐paroxetine  (controlled  under  current  regiment)   • Decreased  appetite  over  the  past  few  weeks  and  increasing  fatigue.   • Slightly  confused     Selectively  inhibit  reuptake  of  serotonin     – increase  synaptic  serotonin  levels   – also  cause  increased  5HT  receptor  activation  and  enhanced  postsynaptic  responses.       At  present,  SSRIs  are  the  most  commonly  prescribed  first-­‐line  agents  in  the  treatment  of  both  MDD  and  anxiety   disorders.  Their  popularity  comes  from  their  ease  of  use,  tolerability,  and  safety  in  overdose.     GOALS  OF  THERAPY:     • •   Continue  monitoring  for  signs  and  symptoms  of  depression   Continue  therapy  to  avoid  future  episodes   • Continue  current  regimen     – controlled  with  current  regimen   – Paroxetine,  20  mg  PO  daily     Treatment:       Non-­‐Pharmacologic  Intervention:   • Counsel  KF  to  continue  depression  medication  unless  otherwise  directed  by  her  physician.   •  She  should  seek  a  psychologist  to  discuss  her  new  diagnosis.  She  should  report  any  new/worsened   depression  symptoms  to  her  physician.         SUMMARY:     To  address  the  patients  diabetes,  we  chose  a  combination  therapy  of  Sitagliptin  and  metformin  taking  into  account   the   patients   present   condition.   Sulfonylureas   can   cause   hypoglycemia   and   weight   gain   which   is   not   favorable   since   the  patient  is  already  overweight.  Alpha  glucosidase  inhibitors  causes  abdominal  distention  and  flatulence.  TZD’s   can  cause  fluid  retention  and  edema  and  is  also  known  to  worsen  CVD’s.  Therefore  we  chose  to  retain  Metformin,  a   Biguanide  which  is  currently  used  by  the  patient  and  replace  Rosiglitazone  (TZD’s)  with  GLP-­‐1  mimetics  which  is  a   newer  class  of  drug  with  multiple  effects  mechanism  in  promoting  euglycemia.     There  were  no  changes  in  the  patient’s  medications  for  Depression  because  it  is  currently  controlled  by  the  current   regimen  thus,  paroxetine  was  retained.         SECTION  3E-­‐  CLINICAL  THERAPEUTICS  CASE  12  BREAST  CA                                                                                                                                                                                                                                                                                        23        
  • 24. CLINICAL  THERAPEUTICS     CASE  12   BREAST  CANCER                     Proctor:   Dr.  Zenaida  Maglaya         Reporters:   Villanueva,  Edward  Phillip   Yang,  Sheryl  Ray   Zagada,  Timothy   Zepeda,  Monina  Mae   3E