456  Cardiac  Stimulants  and  Depressants.   |Ao'ctobeJ'  So™' 
to  the  Charybdis  of  uncertain  reaction.  It  is  a  well  known  fact 
of  physiology,  that  the  stronger  the  stimulus  the  more  nearly  in 
accord  are  the  results  obtained  on  different  individuals.  This  is 
particularly  true  of  drug  action.  If  Vie  of  a  grain  of  morphine 
be  given  to  each  of  a  series  of  persons,  it  will  cause  sleep  in  this 
person,  nausea  in  that,  wakefulness  in  a  third,  and  perhaps  a  head- 
ache in  a  fourth.  If,  however,  several  grains  are  given  to  the 
same  persons,  it  will  cause  narcosis  in  all.  The  same  difference 
in  reaction  to  small  doses  of  medicine  is  seen  in  the  effect  of 
blood-pressure-raising  drugs  on  different  individuals.  For  this 
reason  it  is  necessary  to  give  first  to  the  animals  on  which  the 
tests  are  being  carried  out,  a  dose  of  a  standard  preparation,  and 
then  to  determine  how  much  of  the  preparation  to  be  tested  is 
required  to  bring  about  the  same  rise.  The  elimination  of  most 
drugs  is  so  slow  as  to  render  this  method  valueless.  With  the 
exception  of  such  drugs  as  amyl  nitrite,  which  is  eliminated 
within  a  few  minutes,  and  adrenal  principle,  which  is  destroyed 
as  rapidly,  the  effect  of  the  first  dose  cannot,  under  the  ordinary 
conditions  of  experiment,  be  allowed  to  pass  off  entirely  before 
the  next  dose  is  administered,  and  there  is  for  this  reason  a  cumula- 
tive action,  each  dose  adding  to  the  effect  of  the  previous  one  and 
rendering  a  true  comparison  impossible. 
We  thus  come  by  a  process  of  exclusion  to  the  third  method, 
the  determination  of  the  amount  of  a  drug  required  to  cause  death. 
This  amount  is  ordinarily  determined  by  injecting  into  a  series 
of  animals  progressively  larger  doses  of  the  drug  under  con- 
sideration, and  noting  the  smallest  dose  required  to  cause  death. 
The  method  is  therefore  known  as  a  minimal  lethal  (fatal)  dose 
method.  A  large  series  of  experiments  show  that  by  basing  the 
dose  on  the  weight  of  the  animal,  the  activity  of  the  preparation 
can  be  determined  to  within  10  per  cent.  That  is  to  say,  if  a 
given  dose  is  the  smallest  which  will  kill  a  given  animal,  11 /10  of 
this  amount  will  kill  almost  any  individual  of  the  same  species, 
and  9/10  of  this  amount  will  hardly  ever  kill.  This  fact  bears 
out  what  has  been  said  above  concerning  the  agreement  in  the 
effects  of  large  doses. 
Granting  then  that  the  method  gives  concordant  results,  can  we 
be  at  all  sure  that  the  toxic  power  which  is  estimated  in  this  way 
is  in  accord  with  the  therapeutic  activity  of  the  preparation?  The 
