A™ ctobe r' i9iaorm' }  Cardiac  Stimulants  and  Depressants.  457 
physiologic  action  of  these  drugs,  on  which  their  therapeutic  value 
depends,  is  mainly  a  stimulation  of  the  heart,  shown  by  more 
forcible  contraction  of 'its  wall.  The  drugs  kill  either  by  inducing 
a  state  of  constant  contraction  (death  in  systole)  or  by  over- 
working the  heart  muscle  to  such  an  extent  that  it  gives  way  to 
a  more  or  less  sudden  exhaustion  with  relaxation  (death  in 
diastole).  In  either  case,  the  effect  is  primarily  due  to  stimulation 
of  the  heart,  and  thus  varies  in  accord  with  the  physiologic  or 
therapeutic  activity.  In  this  connection  it  may  be  as  well  to  men- 
tion that  occasionally  in  mammals,  the  respiration  ceases  before 
the  heart  has  come  to  a  standstill.  This  does  not  indicate  any 
direct  action  of  the  drug  on  the  respiratory  centres,  but  is  due  to 
interference  with  the  function  of  the  medulla,  dependent  on  the 
disturbance  of  its  blood  supply.  The  death  is  thus  due  to  the 
stimulating  action  on  the  heart,  however  it  may  eventually  occur. 
Granting  then  that  the  lethal  dose  method  is  not  only  exact,  but 
also  determines  the.  physiologic  activity,  what  animal  is  the  best 
to  use?  It  is  often  stated  that  as  the  drug  acts  on  the  medulla 
in  mammals,  as  shown  by  respiration  occasionally  ceasing  before 
the  cardiac  contractions,  the  drugs  should  be  tested  on  frogs,  in 
which  it  acts  on  the  heart.  As  we  have  seen,  the  respiratory  failure 
is  really  due  to  beginning  cardiac  exhaustion,  and  in  reality  there  is 
no  essential  physiologic  difference  between  the  action  of  the  drugs  on 
the  frog  and  on  the  guinea  pig.  The  action  of  digitalis  is  largely 
exerted  on  the  cardiac  ganglia.  In  the  frog  these  ganglia  are  in 
the  heart,  as  may  be  demonstrated  by  the  continuance  of  contrac- 
tions after  the  removal  of  the  organ  from  the  body.  In  birds  they 
are  in  the  spinal  cord,  as  is  shown  by  the  cardiac  action  continuing 
after  the  head  is  cut  off.  In  mammals,  however,  the  cardiac  ganglia 
are  in  the  base  of  the  brain  and  any  stimulus  acting  on  these 
ganglia  acts  of  course  on  the  brain. 
The  frog  is  an  unsatisfactory  animal  for  the  purpose  of  stand- 
ardization, as  its  reaction  to  stimulation  is  markedly  influenced 
by  external  surroundings,  temperature,  amount  of  moisture  present 
in  the  cage,  relation  of  time  of  injection  to  time  of  feeding,  etc. 
The  species  of  frog  also  makes  a  difference  and,  according  to 
many  authors,  the  time  of  year.  Certain  writers  believe  that  season 
has  of  itself  no  influence,  but  that  the  differences  found  are  de- 
pendent on  different  species  being  used,  or  on  temperature.  Al- 
