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  • Definition: - Study of Drugs on biological process
  • Effect of drug on body (what drug dose to body)

Drug acts on: - Specific Receptors on;

  1. Plasma membrane
  2. Cytoplasm
  3. Nucleus
  1. Types
  • If mimic the effect of natural receptor Agonist
  • If blocking it: - Antagonist
  • If opposing it: - Inverse agonist


  • Binding is highly specific
  • Binding –    
  1. Usually reversible
  2. Sometimes irreversible – covalent linkage of aspirin with COX
  1. Combined with Enzymes – Methotextrate: - DHFR
  2. Transport proteins – Na+K+ATPase: - digitalis
  3. Structural proteins- tubulin colchicine

Receptors and signal transduction

  1. Efficacy – on drug response curve
  2. Potency – dose required to produce maximal response

Receptors classification

  1. Earlier classified on basis of relative potencies of agonist & antagonist
    e.g. Isoprenaline ˃ Adrenaline˃ NA on Cardiac muscle
    NA ˃ Adrenaline ˃ Isoprenaline on vasoconstriction in skin
  2. Radiolabelled ligand binding studies
  • Beta receptors B1, B2, B3
  • Alpha-receptors A1, A2

Method: -

  1. Label the receptor with irreversible antagonist
  2. Receptor solubilization & purification
  3. Use of oligonuecleotide probes based on deduced sequence
  4. Extract full length of DNA sequnce

Adv: -

  1. More receptor subtype, isoenzeymes (especially in CNS)
  2. Orphan receptors – newly discovered receptors whose ligand is presently unknown

Signal transduction

-         Despite much complexity of receptors, these are 4 superfamily of receptors linked to a particular signal transduction





  1. Transmembrane Ion Channels
  2. G protein coupled receptors (GPCR)
  3. Ligand Regulated Transmembrane enzymes
  4. Intranuclear Receptors

Transmembrane Ion Channels

  • Fastest (within milliseconds)
  • Direct depolarization by flow of current due to movement of ions resulting in cellular response

Responsible for:

  1. Neuroconduction (Voltage gated Na channels)
  2. Cardiac conduction
  3. Muscle contraction
  4. Synaptic plasticity

* No Second Messenger Is Involved

e.g. Nicotinic Receptors ( by Ach), GABA receptors ( chloride receptor by Benzodiazepines), CCB (verapamil), Glutamate receptors.


  • Pentamer with 2 Alpha. Beta, Gamma and a Delta subunit
  • Each subunit approx. weighs 43000-50000 kDa
  • Ligand binds to alpha subunits and opens channel to promote conduction of ions


Structure: -

  1. Extracellular: Receptor (ligand binding site)
  2. Trans membrane: Serpentine polypeptide chain
  3. Intracellular: G-Protein Active C terminal
  4. Largest family of receptors: -
  5. Mainly work as monomers (exceptions) 1. GABA-B, 2. Glutamate

e.g. Adrenergic system, muscarinic ach system, serotonin, Peptide hormones, odorants visual receptors, etc.

Method of functioning: -

  1. Receptor – ligand interaction
    1. Spare receptors
    2. Promiscuity of ligand
    3. ∆: - X ray crystallography
  2. Activation of G proteins
    1. Concept of Desensitization
    2. Types of G proteins
  3. Modify enzymes/Channel K+ Channels
  4. 2nd messenger
    1. cAMP System
    2. Phosphoinositides & Ca2+
    3. cGMP System

Receptor ligand Interaction: -

  1. Activate G protein by converting GDPGTP bound to G protein
  2. Activation of G protein is not time related to ligand – receptor binding
  3. Amplification of signal/Longer duration of action
  4. Hence only some receptor occupied by ligand can produce desired action, whilst other are spared receptors

Promiscuity of ligand

Some ligand receptor is attached to different subset of G protein and hence may illicit different response


  1. Beta1 Heart rate
  2. Alpha2 Vasoconstriction

Type of G-Protein


Effector Pathway


Beta adrenergic, glucagon, histamine, serotonin

cAMP by adenyl cyclase


Alpha2 adrenergic, Ach muscarinic, opioid, serotonin

cAMP by Adenyl cyclase
Open K+ Channel is heart



adenyl cyclase→↑CAMP


A-ch muscarinic, Bombesin-?  Serotonin

Phospholipase C→↑1P3/DAG Ca2+



cGMP phosphodiestrase causes
cGMP (Phototransduction)


Desensitization of Receptors

  1. Development of tolerance
  2. Diminish responsiveness of receptor over time in continued presence of agonist
  3. Re-sensitization – by removal of agonist
  4. Mechanism: - continued G protein activation causes Phosphorylation of C terminal serine/threonine

    Attachment of beta arrestin
  5. receptor-G protein interaction
  6. Endocytosis of receptor
    1. Degradation of receptor in lysosomes
    2. Removal of agonist & positioning of receptor on plasma membrane

2nd Messengers of GPCR:

  1. cAMP pathway
    1. Versatile And Ubiquitous Pathway
    2. Gs & Go type

MOA: GDP GTP →↑adenyl cyclase→↑cAMP (cAMP dependant protein kinase avctivation) Degraded to 5-AMP by Phosphodiesterase (termination of action)

  • PDE/Phosphodiesterase – terminate the response
  • PDE inhibitors:- Milrinone – heart failure Caffeine / theophylline/ methylxanthines
  1. Phosphoinositides & Calcium
  • More complex than CAMP pathway

MOA: GDP GTP phospholipase C Acts on Membrane phospholipids IP3 and DAG IP3 release Calcium and activates Ca dependent enzyme; DAG activates Phosphokinase C and cause phosphorylation of proteins

  1. Termination:
    1. IP3 – dephosphorylation
    2. DAG -
      1. Phosphorylated: - Phosphatitic acid      
      2. Deacylated – Arachidonic acid
    3. Ca2+ - active removal into vesicles by pumps
  2. cGMP system
    -    Only few areas – (a) Intestinal mucosa (b) vessels of smooth muscles
    MOA: GDP GTP →↑guanyl cyclase→↑cGMP (Formation of NO; causes dephosphorylation of Myosin light chain kinase resulting relaxation of smooth muscles) Degraded to 5-GMP by Phosphodiesterase (termination of action)
    e.g Nitrates/ Nitroglycerines/Nitroprussides used in IHD/ hypertension

PDE Θ →↑ Blood flow e.g. Sildenafil

  1. Erectile dysfunction
  2. Pulmonary hypertension
  3. Lymphangiomas

Ligand Regulated Transmembrane Enzymes

-         Signaling of trophic (growth promoting) ligand e.g Insulin, PDGF, EGF, TGF-B etc.


  1. Extracellular: - Trophic ligand binding domain
  2. Cytoplasmic: - Enzyme domain like:
  3. Tyrosine kinase – Insulin
  4. Serine Kinase – TGF-B
  5. Guanyl cyclase – ANP

Activation of receptor

By dimerization – phosphorylation of tyrosine residues (each other) + also downstream phosphorylation

  1. Growth factor receptor antibody: - Trastuzumab/ cituximab/ Antineoplostic drugs
    Tyrosine kinase inhibitors: - gefitinib / erlotinib/ imatinib mesylale (CML)
  2. Desensitization: - endocytosis (mutation-causes cancer)

*Cytokine Receptors

-     Similar to above but uses JAK-STAT pathway (janus kinase signal transduction & activation of transcription)

  • Growth Hormone, erythropoietin, Interferon’s, cytokines

Intranuclear Receptors

  • Slowest,
  • But effect persist longer than any other type
  • 30 minutes to several hours

E.g. glucocorticoids do not relieve asthma immediately


MOA: Ligand diffuses into cyotplasmHSP-90 protein detaches from 2nd Messenger (activation) complex diffuses into nucleus Gene transcription


* Significance: - Amplification of signal

                             Flexible regulation – differential activation of kinases)


-   Activate receptor like endogenous mediator

Consequence: -        

  1. Excitation – Beta1 on heart
  2. Inhibition - Beta2 on bronchial smooth muscle

Inhibition by excitation

-    Suxamethonium:- Inhibit N-M junction Na channel resulting long lasting depolarization


  1. Full agonist – maximal response
  2. Partial agonist – submaximal response
  3. Inverse Agonist – opposite response

 Full Agonist--Maximum biological response like endogenous ligand e.g. Phenylephrine
 Partial agonist – Submaximal response (see after antagonist) e.g. Aripiprazole, Buprenorphine
 Inverse Agonist--Stabilizes the inactive from of receptors e.g. beta cabergolines.


*[Constitutively some receptors can spontaneously convert to active form]



  1. Competitive Antagonism
    1. Structure is like endogenous agonist but fail to activate it
    2. Act on same endogenous receptor
    3.  Also prevent assess of endogenous agonist
    4. Surmountable antagonism – Agonist can be used to produce maximum effect but with higher concentration
    5. Dose ratios A’/A (Amount of new dose of agonist to produce maximum response)
  2. Non-Competitive Antagonism
    1. Do not combine with same receptor / receptor site
    2. the slope of maximal response (vs. competitive antagonism)
    3. Non – surmountable antagonism

Dose Ratio in Competitive antagonism

The dose of agonist (say A) causes defined effect when used alone, than dose (say A’) needed to produce same effect in presence of antagonist is a multiple of A’/A k/s Dose Ratio


Gaddum and schildt plot

r= dose ratios

B= conc. of competitive antagonist

KB= dissociation equilibrium constant of reversible reaction of

Antagonist to its receptor

KB= conc. of antagonist needed to occupy half of receptors in absence of agonist.

Adv.: provide relative potencies of antagonism for receptor classification

  1. Physiological antagonism
    Situation where two drugs have opposite effects
    1. Adrenaline vs. histamine on bronchial smooth muscles
    2. Glucocorticoids vs. insulin on blood sugar
  2. Chemical antagonism
  • No involvement of receptor
    E.g. Protamine          vs. Heparin
    (Positively charged)          (Negatively charged)
    at physiological pH            at physiology pH

Partial Agonist

  • Agonist incapable of eliciting maximal response
  • Low efficacy agonist                  

E.g.: Buprenorphine --- partial agonist at mu opioid receptors

Oxprenolol --- partial agonist at Beta receptor


 Difference from full agonist

1.  Spare receptor: Full agonist act on small proportion of receptors and produce maximal response—others left (spare receptor) while Partial against occupy substantial receptor for submaximal response

2.  Effect of partial agonist is difficult to reverse with competitive antagonist

3.  Partial agonist antagonizes the effect of full agonist. E.g. naloxone vs. morphine (effective)

4.  Naloxone vs. buprenorphine (not effective)


Slow Process

Slow process: down regulation/desensitization of receptors (prolonged agonist exposure)


  1. Internalization of membrane receptor
  2. Delinking of G proteins from effectors enzyme/or receptor

Heterologous Desensitization: G protein link several receptors to same effector molecule. E.g. morphine, BZDs, alcohol causes cross tolerance and desensitization  

  1. Desensitization/down regulation of receptors-----TOLERANCE
  2. Therapeutics advantage of tolerance: Goserelin/buserelin (GnRH continuous administration) in prostatic carcinoma


  1. Due to prolonged use of antagonist
  2. Decrease expression of agonist
  3. Denervation

Therapeutics: Sudden withdrawal of beta-blockers in ischemic heart disease causes worsening of angina, tachycardia due to super sensitivity of receptor towards endogenous catecholamines 

Non-receptor mechanism of Drug action

  • Due to simple physical property, chemical reactions etc.        

Antacids—neutralize pH  

  1. Osmotic diuretics, bulk laxatives--- physical action
  2. Oxygen
  3. Chelators
  4. GA----low specificities: low molar potency determined by oil water partition coefficients

Dose response relationship


Graded Dose response relationship

Quantal Dose response relationship

Increase in dose causes increase in response

Response only in subset of quantal dose (range)

  • Estimation of efficacy
  • Estimation of potency
  • Effect of conc. On receptor binding  
  • Effect of conc. on degree of response
  • Determination of therapeutic index


*Some curves are very steep---undesirable due to cooperative interaction of different action of drug e.g.: coma due to opioid, barbiturates

  1. Max efficacy (Emax): degree of maximum response. *Concept hold true if no spare receptor is found (practically impossible effect)
  2. Potency (EC 50): effective conc. at which 50% of maximal response is generated
  3. Effect of conc. on receptor binding

Assumption made that binding of molecule does not alter subsequent binding

[DR] /R = D / KD+D                                              
DR: drug occupancy

R: receptor conc. total.

D: conc. of free drug

KD: dissociation constant at which 50% of receptor are occupied

KD is inversely proportional to affinity of a drug towards receptor

  1. Effect of conc. to degree of response
    Assumption made - magnitude of response to proportional to drug bound (Not considering the relevance of spare receptors)
    E/Emax = D/D+Kd 
  2. Therapeutic index
    1. Dose producing toxicity (TD50)/dose producing desired effect (ED50)
    2. TOXIC DOSE50: dose at which 50% people experience toxic effect
    3. EFFECTIVE DOSE 50: dose at which 50% people experience therapeutic effect
      if ratio is high than WIDE THERAPEUTIC INDEX
      if ratio is low than NARROW THERAPEUTIC INDEX (e.g. warfarin, theophylline)


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