PHARMACODYNAMICS

dr. Dwi Indria Anggraini, MSc., SpKK.

Pharmacology and Pharmacy Dept.
Lampung University
Introduction

Pharmacodynamics
Ø The study of biochemical and physiological effects of
drugs and their mechanism of action

Ø What the drugs do to the body

How  drugs  act?

PDs
General  principles:
Interaction  between  drug  with  living  systems
• binding  drugs  to  the  cells
• desensitization  and  tachyphilaxis

Molecular  aspects:
• target  for  the  drug  action
• receptor  protein
• ion  channels  as  drug  targets
• control  for  receptor  expression
• receptor  and  disease
Binding of drug molecules to the cells
• drugs act on target protein:
• receptors
• ion channels
• enzymes
• carriers

• drug  specificity:  individual  classes  of  drug  bind  ONLY  to  

certain  target,  and  individual  targets  recognize  ONLY  
certain  classes  of  drugs

• No one drugs COMPLETELY specific in their actions.

Increasing the dose à can lead to side-­‐effects
(exp: TCA à can block various receptors à lot of SE)
RECEPTOR:
Is  target  molecules,  present  on  the  cell  surface/intra-­‐
cellularly,  that  bind  a  drug  and  mediates  its  
pharmacologic  actions    (elicit  specific  effect)

• D + R à D-­‐R complex à effect

• Drug – Receptor interaction Efficacy

• D – R à activation à response (agonist)
• in between (partial agonist)
• D – R à no activation à no response (antagonist)

• Tendency of D to bind R : affinity

Agonists,  antagonists  and  efficacy:
D  acting  on  the  physiologic  R  :  agonist  or  antagonist
• Agonists:
• agent  that  can  bind  a  R  and  mimic  the  regulatory  effect  of  
endogenous  substance  /elicit  response/effect
• the  potency  depends  on  
• affinity  (tendency  to  bound  to  the  R)
• efficacy  (ability  to  initiate  the  changes  à effect)
• Antagonists:
• bind  a  R  without  the  regulatory  effect  of  endogenous  
substance  ;  block  the  binding  of  endogenous  substance
Graded dose-­‐response curve
• Magnitude  of  the  drug  effect  depends  on  conc.  at  receptor  
• drug  dose  
• characteristic  of  drugs  (rate  of  A,  D,  M)
• efficacy: maximal response produced by a drug à
• Σ D-­‐R complex and efficiency of the cellular action
• potency:  how  much  drug  is  required  to  elicit  a  given  
response
• << the dose needed for a given response à >> potent
• determined by affinity of R to the D
• slope of the dose-­‐response curve
Binding of D to the R:
• If >2 D compete for the same R à each will reduce affinity of the
other
• Drug antagonism
if  the  effect  of  one  drug  is  diminished  in  the  presence  of  another  drug
a. chemical  antagonism  (interaction  in  solution)
b. PK  antagonism  (affecting  A,D,M,E)
c. antagonism  by    R  block  (  both  drugs  bind  to  the  same  R);  
d. non-­‐competitive  antagonism  (drug  interrupt  R  -­‐ effector)  
e. Physiological  antagonism  (2  drugs  produce    opposing  physiologic  effect)  
Antagonists  will  reduce   affinity  AND  efficacy                                                  
of  other  drugs
Desensitization & Tachyphylaxis
•The  loss  of  a  drug’s  effect,  esp.  if  it’s  given  repeatedly  
/continuously
• It  takes  time  to  happen  &  to  recover  (days  – weeks)
• Mechanism  involved:
a. changes  in  R
b. loss  of  R
c. exhaustions  of  mediators
d. enhanced  D  metabolism
e. compensatory  physiological  mechanism
f. extrusion  of  D  from  the  cells  (resistance)
Molecular  aspects
Targets for drug actions:
a. Receptors
b. Ion  channels
c. Enzymes
d. Carrier  molecules
Receptors:
Ion channels:
a. ligand-­‐gated ion channels (= ionotropic receptors)
it’s open only if R is occupied by the agonist
exp: vasodilators (Ca-­‐channel blockers)
b. voltage-­‐gated ion channels
it’s open when cell membrane is depolarized
exp: sulfonylurea (release insulin)
Enzymes:
• Drugs  is  substrate  analogue  à competitive  inhibitor  of  
certain  enzyme
exp: aspirin (COX inhibitor)
• Drug as false substrate à abnormal metabolite produced
exp: 5FU (anti cancer, replace uracil)
• Pro-­‐drug à active drug (catalyzed by enzyme)
Transporters/carrier molecules:
• Normal transport
• Drug inhibit NE uptake (exp: reserpine)
• Drug as false substrate (exp: methyldopa)
Type of Rs:
1. Ligand-­‐gated ion channels:
• = ionotropic receptors
• Involved mainly in fast synaptic transmission
• Time scale: milliseconds
• Exp: GABA-­‐R, nicotinic Ach-­‐R

2. G-­‐protein-­‐coupled receptors:
• = metabotropic receptors
• G-­‐protein is a membrane protein (consist of αβγ subunit)
• Drug binds to α-­‐subunit à activates other subunit
• Time scale: seconds
• Exp: muscarinic Ach-­‐R
3. Kinase-­‐linked & related receptors:
• à gen transcription and protein synthesis
• Main effect: control cell growth & differentiation
• Time scale: hours
• Exp: some hormone (e.g. insulin) –R

4. Nuclear receptors:
• R is intranuclear à D must enter the cell first
• Effect: gene transcription à protein synthesis
• Time scale: hours
• Exp: receptor for steroid hormone, thyroid hormone
Receptors  for  Physiological  Regulatory  Molecules
2  functions  of  R:
• Ligand  binding
• Message  propagation  (signaling)  à to  effector  protein  OR
to  transducer  (intermediary  cellular  signaling  molecules:  second  
messenger  ,  exp:  cAMP,  NO,  Ca++,   etc)

Receptor-­‐effector  system  is  called  by  signal-­‐transduction   pathway

But….not  all  the  drugs  work  through  the  R

à antacid,  mannitol
Regulation  of  R:
Regulation  of  synthesis  &  degradation
• Multiple  mechanism
• From  other  R  OR  from  feedback  regulation  by  their  own  signaling  output
Includes:
• Desensitization:    cont stimulation  of  cells    by  agonist
• =  down  regulation  =  adaptation  =  refractoriness
• The  phenomenon  is  called  by  TACHYPHILAXIS  !!!

Disease  caused  by  R  malfunction:

• Type  2  diabetes  à insulin  resistance
• Myasthenia  gravis  à autoimmune  depletion  of  nicotinic  Ach-­‐R
• Deficiency  of  androgen  à loss  of  R
• Graves’  Disease  (hyperthyroidism)  à auto-­‐Ab  to  TSH-­‐R
Concentration-­‐effect relationship
4 characteristic variables:
• Potency Pharmacodynamic
• Maximal efficacy variability
• Slope
• Individual variation

PD variability:
• Between subjects AND Within subject
• Factors affecting: internal and external
• Genetic Alter  PK  of  the  drug  à effect
• Age • sub-­theraputic
• Disease • therapeutic
• toxicity
• Other drugs
The Therapeutic Index

ED50 :
dose of the drug required to produce specified effect in 50% of
population
LD50 :
dose of the drug required to produce death in 50% of
experimental population

TI = LD50/ED50
The bigger is the TI à the safer is the drug
ADR and DRUG TOXICITY

ADR (Adverse Drug Reaction)

> any drug has potential to do harm

> it is the common cause of iatrogenic disease!

> idiosyncratic: if it’s encountered infrequently

-­‐ mechanism-­‐based (angioedema) OR

-­‐ off-­‐target action (anaphylaxis to penicillin)

ADR and DRUG TOXICITY
Therapeutic  Drug  Monitoring

Many  factors  that  alter  drug  disposition  …need  TDM  (in  special  case)
• drug  with  narrow  therapeutic  window  (range  of  plasma  conc.  between  required  for  
efficacy  – toxicity  occurs)

• drug  with  low  TI

• drug  with  effect  (+  or  -­‐)  that  is  difficult  to  monitor

• drug  with  large  variability  of  plasma  conc.