Pharmacodynamics

Lec 5/  2hrs
Dr.  Raz  Muhammed
PhD  Pharmacology
 Pharmacodynamics
• Pharmacodynamics  describes  the  actions  of  a  
drug  on  the  body.  
• Most  drugs  exert  effects,  both  beneficial  and  
harmful,  by  interacting  with  specialized  target  
macromolecules  called  receptors,  which  are  
present  on  or  in  the  cell.
• The  drug–receptor  complex  initiates  alterations  in  
biochemical  and/or  molecular  activity  of  a  cell  by  
a  process  called  signal  transduction
The  recognition  of  a  drug  by  a  receptor  triggers  a  
biologic  response.
 The  drug–receptor  complex
• Cells  have  many  different  types  of  receptors,  each  
of  which  is  specific  for  a  particular   agonist  and  
produces  a  unique  response.  
• Cardiac  cell  membranes,  for   example,  contain  β-­‐
adrenergic  receptors  that  bind  and  respond  to  
epinephrine  or  norepinephrine.  
• Cardiac  cells  also  contain  muscarinic  receptors  
that  bind  and  respond  to  acetylcholine.  
• These  two  receptor  populations  dynamically  
interact  to  control  the  heart’s  vital  functions.
• The  magnitude  of  the  cellular  response  is  
proportional  to  the  number  of  drug–receptor  
complexes.  
• Not  all  drugs  exert  effects  by  interacting  with  a  
receptor.  
• Antacids,  for  instance,  chemically  neutralize  
excess  gastric  acid,  thereby  reducing  stomach  
upset.
 Receptor  states
• Receptors  exist  in  at  least  two  states,  inactive  (R)  and  active  
(R*),  that  are  in  reversible  equilibrium  with  one  another,  
usually  favoring  the  inactive  state.  
• Binding  of  agonists  causes  the  equilibrium  to  shift  from  R  to  
R*  to  produce  a  biologic  effect.  
• Antagonists  are  drugs  that  bind  to  the  receptor  but  do  not  
increase  the  fraction  of  R*,  instead  stabilizing  the  fraction  
of  R.  
• Some  drugs  (partial  agonists)  shift  the  equilibrium  from  R  
to  R*,  but  the  fraction  of  R*  is  less  than  that  caused  by  an  
agonist.  
• The  magnitude  of  biological  effect  is  directly  related  to  the  
fraction  of  R*.  
 Receptors
• If  drug-­‐receptor  binding  results  in  activation  of  
the  receptor  molecule,  the  drug  is  termed  an  
agonist;  
• If  drug-­‐receptor  binding  results  in  inhibition  of  
the  receptor  molecule,  the  drug  is  considered  
an  antagonist.
• A  receptor  molecule  may  have  several  binding  
sites.
Mechanisms  of  drug  interaction  with  a  
receptor
• Drug  A  is  agonist
• Drug  B  is  a  pharmacologic   antagonist  that  competes  
with   the  agonist  for   binding   to  the   receptor  site.
• The   dose-­‐response   curve   produced  by  increasing   doses  
of   A  in   the   presence   of   a  fixed   concentration  of   B  is  
indicated   by  the   curve  A+B.
• Drugs  C  and  D  act  at  different  sites  on   the   receptor  
molecule;  they   are  allosteric activators  or  inhibitors.
• Allosteric   inhibitors  do   not  compete   with   the  agonist  
drug   for   binding   to  the   receptor.
• Pharmacologic  antagonist:  A  drug  that  binds  to  the  
receptor  without  activating  it  and  prevents  activation  
by  an  agonist.
• Allosteric  agonist/antagonist:  A  drug  that  binds  to  a  
receptor  molecule  without  interfering  with  normal  
agonist  binding  but  alters  the  response  to  the  normal  
agonist.
• Partial  agonist:  A  drug  that  binds  to  its  receptor  but  
produces  a  smaller  effect  (Emax)  at  full  dosage  than  a  
full  agonist.
• Constitutive  activity:  Activity  of  a  receptor-­‐effector  
system  in  the  absence  of  an  agonist.
• Inverse  agonist:  A  drug  that  binds  to  the  non-­‐active  
state  of  receptor  molecules  and  decreases  constitutive  
activity.  
 Major  receptor  families
A.  Transmembrane  Ligand-­‐gated  ion  channels
B.  Transmembrane  G  protein-­‐coupled  receptors
C.  Enzyme-­‐linked  receptors
D.  Intracellular  receptors
E.  JAK/STAT  receptors
 A.  Transmembrane Ligand-­‐gated  ion  
channels
• These  are  responsible  for  regulation  of  the  
flow  of  ions across  cell  membranes.
• The  activity  of  these  channels  is  regulated  by  
the  binding  of  a  ligand to  the  channel.
• Example:  (GABA)  receptor
• Benzodiazepines,  enhance  the  stimulation  of  
the  GABA  receptor  by  GABA,  resulting  in  
increased  chloride  influx  and  
hyperpolarization  of  the  respective  cell.  
GABA  receptor
B.  Transmembrane G  protein-­‐coupled  
receptors
• These  receptors  consist  of  a   single  peptide  that  
has  seven  membrane-­‐spanning  regions.
• Intracellularly,  these  receptors  are  linked  to  a  G  
protein
• The  intracellular  G  protein  becomes  activated  and  
modulates  cytoplasmic  effectors.
The  effectors  synthesize  second  messengers  such  
as  cAMP,   inositol    triphosphate  (IP3)  and  
diacylglycerol (DAG).
• GPCRs  are  the  most  common  type  of  receptors  
in  the  body.
• Example  of  receptors:
α and  ß  adrenergic  receptors
muscarinic receptors
 C.  Enzyme-­‐linked  receptors  (Receptor  
Tyrosine  kinase)
• These  receptors  have  cytosolic enzyme  activity  as  an  integral  
component  of  their  structure  or  function.
• Binding  of  a  ligand to  an  extracellular  domain  activates  this  cytosolic
enzyme  activity.
• Example  of  receptor:  insulin.
• These  receptors  have  a  tyrosine  kinase activity  as  part  of  their    
structure.
• Upon  binding  of  the  ligand to  receptor  subunits,  the  receptor  
undergoes  conformational  changes,  converting  from  its  inactive  form  
to  an  active  kinase form.  
 D.  Intracellular  receptors
• The   fourth   family  of  receptors   is  different  from  the  
other   three   in   that  the  receptor  is  entirely  intracellular
and  the   ligand must  diffuse   into  the   cell   to  interact  
with   the  receptor.
• The   ligand in  that  it   must  have  sufficient   lipid   solubility  
to  be   able   to  move  across  the   target  cell   membrane.
• For   example,  steroid  hormones  exert   their   action   on  
target  cells   by   this  receptor   mechanism.
• The   ligand  binds  with   its  receptor,   and  the   receptor  
becomes   activated
Mechanism  of  
intracellular  receptors
 E.  JAK/STAT  receptors  

• Many  cytokines  activate  receptor  molecules  that  

bind  separate  intracellular  tyrosine  kinase  
enzymes  (Janus  Kinases,  JAKs)  that  activate  
transcription  regulators  (signal  transducers  and  
activators  of  transcription,  STATs)  that  migrate  to  
the  nucleus  to  produce  the  final  effect.
 Characteristics  of  signal  transduction
• Signal  transduction  has  two  important  
features:  
• 1)  the  ability  to  amplify  small  signals  and  
• 2)  mechanisms  to  protect  the  cell  from  
excessive  stimulation.
 1.  Signal  amplification
• A  characteristic  of  G  protein–linked  and  enzyme-­‐
linked  receptors  is  the  ability  to  amplify  signal  
intensity  and  duration  via  the  signal  cascade  
effect.  
• Additionally,  activated  G  proteins  persist  for  a  
longer  duration  than  does  the  original  agonist–
receptor  complex.  
• The  binding  of  albuterol  ,  for   example,  may  only  
exist  for   a  few   milliseconds,  but  the  subsequent  
activated  G  proteins  may  last  for  hundreds  of  
milliseconds.  
 Spare  receptors
• Because  of  this  amplification,  only  a  fraction  of  the  total  
receptors  for  a  specific  ligand  may  need  to  be  occupied  to  
elicit  a  maximal  response.  
• Systems  that  exhibit  this  behavior  are  said  to  have  spare  
receptors.  
• About  99%  of  insulin  receptors  are  “spare,”  providing  an  
huge  functional  reserve  that  ensures  that  adequate  
amounts  of  glucose  enter  the  cell.  
• On  the  other  hand,  only  about  5%  to  10%  of  the  total  β-­‐
adrenoceptors in  the  heart  are  spare.  
• Therefore,  little  functional  reserve  exists  in  the  failing  
heart,  because  most  receptors  must  be  occupied  to  obtain  
maximum  contractility.
 Spare  Receptors
• This  might  result  from  1  of  2  mechanisms.
• First,  the  duration  of  the  effector   activation  may  
be  much  greater  than  the  duration  of  the  drug-­‐
receptor  interaction.
• Second,  the  actual  number  of  receptors  may  
exceed  the  number  of  effector  molecules  
available.
• The  presence  of  spare  receptors  increases  
sensitivity  to  the  agonist  because  the  likelihood  
of  a  drug-­‐receptor  interaction  increases  in  
proportion  to  the  number  of  receptors  available.
2.  Desensitization  and  down-­‐regulation  of  
receptors
• Repeated  or  continuous  administration  of  an  
agonist  or  antagonist  often  leads  to  changes  in  
the  responsiveness  of  the  receptor.  
• The  receptor  may  become  desensitized  due  to  
too  much  agonist  stimulation,  resulting  in  a  
diminished  response.  
• This  phenomenon,  called  tachyphylaxis,  is  
often  due  to  phosphorylation  that  renders  
receptors  unresponsive  to  the  agonist.  
 Down-­‐regulation
• In  addition,  receptors  may  be  internalized  
within  the  cell,  making  them  unavailable  for  
further  agonist  interaction  (down-­‐regulation).  
• Some  receptors,  particularly  ion  channels,  
require  time  following  stimulation  before  they  
can  be  activated  again.  
• During  this  recovery  phase,  unresponsive  
receptors  are  said  to  be  “refractory.”
Desensitization  of  receptors.
 Up-­‐regulation
• Repeated  exposure  of  a  receptor  to  an  
antagonist,  on  the  other  hand,  results  in  up-­‐
regulation  of  receptors.
• Receptor  reserves  are  inserted  into  the  
membrane,  increasing  the  number  of  
receptors  available.  
• Up-­‐regulation  of  receptors  can  make  cells  
more  sensitive  to  agonists  and/or  more  
resistant  to  effects  of  the  antagonist.