Understanding Drug Targets and Mechanisms of Action

RESPONSE
 
altering their biochemical &/or biophysical activity
Depress
Activate
Replace
Irritate
Destroy
PHARMACODYNAMICS
PHARMACODYNAMICS
Absorb
Distribute
Metabolize
Excrete
PHARMACOKINETICS
PHARMACOKINETICS
Interacts with biological  molecules
TARGETS
Exceptions
 Osmotic Diuretics
 Purgatives
 Antacids
MOLECULAR  MECHANISMS  OF  DRUG  ACTION
ilo
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By the end of this lecture you will be able to :
 
 Differentiate between their patterns of
       action; agonism versus antagonism
 
 Identify  different targets of drug action
 
 Elaborate on drug binding to receptors
TARGETS
 
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Tubulin
Tubulin
  
is target for:
               
Vincristine
                   
Colchicine
REGULATORY
TARGETS
REGULATORY
ENZYME
 
The drug competes with the natural substrate
for the enzyme
REVERSIBLE
IRREVERSIBLE
Organophosphates 
irreversibly competes with ACH for 
cholinestrase
Neostigmine 
reversibly compete with ACH
 for 
cholinestrase
TARGETS
REGULATORY
CARRIER
MOLECULE
 
Responsible for transport of ions and small organic
molecules between intracellular compartments,
through cell membranes or in extracellular fluids.
Antiporter
Symporter
 
The drug binds to such molecules
altering their transport ability
Cocaine  
 blocks transport of 
catecholamines
 at synaptic cleft
TARGETS
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CARRIER
MOLECULE
Digitalis
 blocks efflux of Na by 
Na pump
Digitalis
TARGETS
REGULATORY
ION
CHANNEL
 
Responsible for  influx or out-flux  of ions through
cell membranes along their concentration gradients.
They are activated by alteration in action potential
and are controlled by gating machinery.
 
Drugs bind to alter channel  function by block or
modulation
 
Local Anesthetics 
block Na influx through 
Na channel
in nerve fibers. They are 
Na channel Blockers.
L.Anaesthesia
TARGETS
REGULATORY
ION
CHANNEL
 
Sulfonylurea drugs  
block   K
+
 
out flux via the 
K channels 
in pancreatic
cells . They are 
K
 Channel  Modulator
TARGETS
REGULATORY
 
Drugs bind and alter R signal transduction machinery.
 
Responsible for selectively sensing and binding  of a
stimulus (ligand) and its coupling to a response  via a
set of signal transduction machinery
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QUANTIFY  ASPECTS OF  DRUG  ACTION
 
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Explore the intricate world of pharmacokinetics and pharmacodynamics, from drug absorption to their interaction with biological molecules. Learn about different drug targets, such as proteins and ions, and how drugs alter their biochemical and biophysical activities. Dive into molecular mechanisms of drug action, including how drugs bind to receptors and compete with natural substrates for enzymes. Gain insights into the regulatory and structural roles of proteins in drug interactions, and understand how various drugs target specific molecules to elicit therapeutic responses.


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  1. PHARMACOKINETICS Absorb Distribute Metabolize Excrete Osmotic Diuretics Purgatives Antacids Exceptions Interacts with biological molecules TARGETS altering their biochemical &/or biophysical activity Depress Activate Replace Irritate Destroy RESPONSE PHARMACODYNAMICS

  2. ilos By the end of this lecture you will be able to : Identify different targets of drug action Differentiate between their patterns of action; agonism versus antagonism Elaborate on drug binding to receptors MOLECULAR MECHANISMS OF DRUG ACTION

  3. TARGETS > Proteins REGULATORY STRUCTURAL Tubulinis target for: Vincristine CARRIER MOLECULE ION RECEPTOR ENZYME Colchicine CHANNEL Tubulin Structure

  4. TARGETS Proteins REGULATORY The drug competes with the natural substrate for the enzyme ENZYME REVERSIBLE REVERSIBLE Neostigmine reversibly compete with ACH for cholinestrase IRREVERSIBLE IRREVERSIBLE Organophosphates irreversibly competes with ACH for cholinestrase Neostigmine Organophosphorsphates

  5. TARGETS Proteins REGULATORY MAO_cocaine Responsible for transport of ions and small organic molecules between intracellular compartments, through cell membranes or in extracellular fluids. CARRIER MOLECULE The drug binds to such molecules altering their transport ability Cocaine blocks transport of catecholamines at synaptic cleft Antiporter Symporter

  6. TARGETS > Proteins REGULATORY CARRIER MOLECULE Digitalis blocks efflux of Na by Na pump Digitalis

  7. TARGETS > Proteins REGULATORY ION Responsible for influx or out-flux of ions through cell membranes along their concentration gradients. They are activated by alteration in action potential and are controlled by gating machinery. Local Anesthetics block Na influx through Na channel in nerve fibers. They are Na channel Blockers. Drugs bind to alter channel function by block or modulation CHANNEL L.Anaesthesia

  8. TARGETS > Proteins REGULATORY ION CHANNEL Sulfonylurea drugs block K+out flux via the K channels in pancreatic cells . They are K Channel Modulator

  9. TARGETS > Proteins REGULATORY Responsible for selectively sensing and binding of a Drugs bind and alter R signal transduction machinery. stimulus (ligand) and its coupling to a response via a set of signal transduction machinery Bind Occupy RECEPTOR Initiate Activate Physiological RESPONSE L L LR* R EFFICACY AFFINITY ENDOGENOUS LIGAND Pharmacological RESPONSE R A drug that possesses both affinity and efficacy Agonist A A R AR* ACh DRUGS A drug that possesses an affinity but no efficacy Antagonist Tubocurarine NO RESPONSE B B R

  10. The tendency of a drug to bind to the receptors is governed by its affinity. AFFINITY The ability for it, once bound, to activate the receptor is denoted by its efficacy. EFFICACY Agonist A drug that possesses both affinity and efficacy Is that inherent property intrinsic to the agonist that determines how "good" an agonist is. high intrinsic efficacy a full agonist low intrinsic efficacy a partial agonist. Antagonist A drug that possesses an affinity but no efficacy

  11. Ligand Agonist Ligand High intrinsic efficacy low intrinsic efficacy Submax response agonist. Max response Agonistic-Antagonistic Potentials A Full Agonist A Partial Agonist Pindolol, a beta blocker which is a partial agonist, produces less decrease in heart rate than pure antagonists such as propranolol.

  12. The tendency of a drug to bind to the receptors is governed by its affinity. AFFINITY The ability for it, once bound, to activate the receptor is denoted by its efficacy. EFFICACY QUANTIFY ASPECTS OF DRUG ACTION Initiate Activate Bind Occupy D + R D R RESPONSE[R] DR* Relate concentration [C] of D used (x- axis) to the binding capacity at receptors (y-axis) Relate concentration [C] of D used (x- axis) to the R produced (y-axis) Concentration-Binding Curve Dose Response Curve AFFINITY EFFICACY POTENCY

  13. Concentration-Binding Curve Initiate Activate Bind Occupy association rate constant k1 D + R D R RESPONSE[R] DR* k2 dissociation rate constant At equilibrium the equilibrium dissociation constant (KD) is presented by ratio (k2/k1) The relationship between drug binding & drug concentration is expressed mathematically by the following equation Bmax xC B = ----------- C+ KD50

  14. Concentration-Binding Curve (Bmax): Total density of receptors in the tissue KD KD (kD ) = [C] of D required to occupy 50% of receptors at equilibrium Concentration-Binding curves are used to determine: 1. The binding capacity (Bmax) total density of receptors in the tissues. 2. The affinity of D for receptor The higher the affinity of D for receptor the lower is the KD i.e. inverse relation

  15. DOSE RESPONSE CURVE How does response vary with C? See full size image A continuous response BP, HR, FBG, Cholesterol, GRADED DOSE RESPONSE CURVE An all-or-non response prevention of convulsion, arrhythmias or death .. Relate C to % of patients eliciting the : * specified therapeutic response * adverse response * lethal outcome QUANTAL DOSE RESPONSE CURVE How the therapeutic window of a drug is defined ?

  16. L L G G U U O O C C O O K K D D

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