Biochemistry - Pharmacodynamics

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					               The „receptor‟ concept




…I therefore assumed that the tetanus toxin must unite
with certain chemical groupings in the protoplasm of
cells…
As these receptors, which may be regarded as lateral
chains of the protoplasm … become occupied by the
toxin, the relevant normal function of this group is
eliminated…
               Types of drug receptors

Practically all receptors are proteins:
•   Enzymes
•   Ion channels
    • Ligand-gated channels: Ion channels that open upon
        binding of a mediator
    • Voltage-gated channels: Ion channels that are not
        normally controlled by ligand binding but by changes
        in the membrane potential
•   „Metabolic‟ receptors – hormone and neurotransmitter
    receptors that are coupled to biochemical secondary
    messenger / effector mechanisms
          Non-protein drug target sites

•   DNA: Mainly cytotoxic agents used in cancer therapy

•   DNA / RNA: Antisense oligonucleotides (experimental)

•   Membranes : Inhalation anaesthetics (?)

•   Fluid compartments: Osmotically active solutes
    •   Plasma volume expanders (dextran)
    •   Osmotically acting diuretic agents (mannitol)
    •   Laxatives (sodium sulfate; obsolete)
    How do drugs affect their receptor proteins?
Enzymes:
•    competitive inhibitors: enalapril, angiotensin convertase
•    irreversible (covalent) inhibitors: acetaminophen, cyclo-
     oxygenase
•    allosteric inhibitors: digoxin, Na+/K+-ATPase

Channels and metabolic receptors:
• allosteric agonists (activators)
• allosteric inhibitors
• allosteric partial agonists
• irreversible (covalent) inhibitors
        Drug-receptor binding

        L                                   L
                                        K
RL             R             RL                   R

                                        Rtotal

            [L][R]        [L][Rtotal - RL]
     K=              =
            [RL]                [RL]


                         [RL]               [L]
Receptor occupancy =                =
                         [Rtotal]        [L] + K
                                       Drug-receptor binding

                                                          [RL]               [L]
                            Receptor occupancy =                       =
                                                          [Rtotal]         [L] + K


                   1                                           1
[LR] / [Rtotal]




                  0.5                                        0.5



                   0                                           0
                        0     2000   4000   6000   8000            1          100    10000

                                            Ligand concentration
                       [RL]             [L]
Receptor occupancy =              =
                       [Rtotal]       [L] + K
Competitive vs. irreversible inhibition

               L

        RL          R

               L        I

        RL          R         RI

               L        I

        RL          R         RI
                    Competitive inhibition

                                                       0 = [I] < [I] < [I]
            L            I
        K                     KI
  RL              R                     RI

                Rtotal
                                                         K     K’   K’

                             [RL]               [L]                      [L]
Receptor occupancy =                     =                      =
                             [Rtotal]                    [I]        [L] + K’
                                             [L] + K 1 +
                                                         KI
          The „Schild plot‟ (1)

                               [I]
                 [A] = [A] 1 +
                               KI

                 [A]     [I]
                     =1+     = Dose ratio
                 [A]     KI
[A] [A] [A]
                 Dose ratio – 1 = [I] / KI

                 log(Dose ratio - 1) = log([I]) – log(KI)

                        y            =   x   -    b
                                   The „Schild plot‟ (2)



            log (dose ratio – 1)




                                              log([I])

- log(KI)

= “pA2”
         Irreversible (covalent) inhibition

                                             0 = [I] < [I] < [I] < [I]
                                         1
         L          I
     K
RL             R               RI


     R’total   = Rtotal - RI
                                         0




                          [RL]               [L]       [Rtotal] – [RI]
Receptor occupancy =                 =             *
                         [R’total]       [L] + K           [Rtotal]
Competitive and irreversible inhibition of a-adrenergic
    receptors: phenoxybenzamine vs. tolazoline
                                            Cl

                                            CH2

                                            CH2
                    HN         N
    H2N
                                            N
               OH        CH2          H2C        HC    CH3

                                                 CH2

                                                 O

  HO

          OH


 Norepinephrine     Tolazoline
                                   Phenoxybenzamine
The mechanism of covalent receptor blockade
          by phenoxybenzamine

               H2
               C

                    N       C    C    Cl
               H            H2   H2
      O   C    C
          H2
               CH3                                  H2
                                                    C


Cl-                                                 H
                                                         N   C
                                                             H2
                                                                  C
                                                                  H2
                                                                       N
                                                                       H
                                                                           CH3
                                           O   C    C
                                               H2
               H2           H2
               C            C                       CH3
                        +
                     N

      O   C    CH           C
          H2                H2
               CH3
        Effects of phenoxybenzamine and tolazoline
                      in a tissue model
                 Tolazoline                  Phenoxybenzamine
      100
(% of maximum)
    Tension




            0
                  2.5     20   160            2.5   20   160
                               Noradrenaline (mM)
                  0                                        0
                  10 mM                                    0.4 mM
                  20 mM                                    0.8 mM
          Drug dose-effect relationships (1)

Drug          (Receptor=Effector)
Examples:
• Enzymes – observed effect: enzyme activity
• Ion channels – observed effect: ion conductivity


Drug            Receptor           2nd Messenger           Effector
Examples:
• Enzymes – observed effect: some physiological / clinical
   readout (acetylsalicylic acid / cyclo-oxygenase / pain relief)
•   Alpha-adrenergic receptor  IP3   Ca++   increased
    muscle contraction
Drug dose-effect relationships (2)
            Receptor = effector


Receptor                          Observed
occupancy                         effect (%)
(%)

                 log [Drug]



Occupancy


                   Effect
        Receptor = effector


Receptor                      Observed
occupancy                     effect (%)
(%)

        Agonist concentration




Occupancy


                Effect
              Drug dose-effect relationships (3)
Drug                 Receptor         2nd Messenger             Effector

                     Weak maximal effect (e.g., influenced receptor is
                     only a minor player in physiological effect)


                     Threshold – physiological effect only begins at
Effect




                     finite minimum of receptor occupancy


                     Effect saturated at sub-maximal receptor
                     occupancy

         Occupancy
Cascades and dose-response characteristics

                                                 [L]
                           [RL] = [Rtotal] 
                                               [L] + KR
    L

R        RL                    [M2] = a  [RL]


pre-M2        M2                                [M2]
                         [EM2] = [Etotal] 
                                               [M2] + KM2
         E         EM2
                              Effect = F = b  [EM2]
  The effect „precedes‟ mediator binding in
               cascade systems

                [L]                                   [L]
F = F max                      [RL] = [Rtotal] 
              [L] + EC50                            [L] + KR


                 KM2
EC50 = KR 
           KM2 + a  [Rtotal]          Effect
                                                            Binding
Example:
Rat heart contractility
and b-adrenergic receptors
50% response at 1-3%
receptor occupancy                      EC50          KR
„Spare receptors‟ and irreversible inhibition

      0 = [I] < [I] < [I] < [I] < [I]




                                        reduced maximal
                                        effect
“The slope parameter of concentration-response curves used
   as a touchstone for the existence of spare receptors”
         Naunyn Schmiedebergs Arch Pharmacol. (1997) 356:283-92.




                                         spare receptors
       100
         Effect (%)




                                         no spare receptors

                                         spare fraction
             0
                      0   Receptor saturation (%) 100
“The slope parameter of concentration-response curves used
   as a touchstone for the existence of spare receptors”
         Naunyn Schmiedebergs Arch Pharmacol. (1997) 356:283-92.




                                           spare receptors
       100
         Effect




                                         no spare receptors

                                          spare fraction
          0
                  0   Ligand concentration (log scale)
                  Drug „potency‟ and „efficacy‟


                                              Efficacy:
                                              effect at
Observed effect


                                              saturating
                                              concentration



                       EC50                potency: 1 / EC50
                              log [Drug]
What if drugs that bind to the same receptor
            differ in efficacy?


                                    5-HT




                                             GDP

                                      GTP*
The allosteric model of receptor activation


                    Kintr
 inactive                            active
 state                               state




            Kintr               KA



                            active
  Inhibitors and partial agonists
      in the allosteric model

           KI                 Kintr



           inactive                    active



KI                    Kintr               KA



inactive                              active
       Beneficial and toxic drug effects
                                           toxicity
Drug         Receptor      Effector
                                           benefit



             Receptor      Effector        toxicity
Drug
             Receptor      Effector        benefit



                           Effector        toxicity
Drug         Receptor
                           Effector        benefit
The „therapeutic index‟
                                Toxic dose


     Therapeutic dose




                              Toxic dose
        Therapeutic index =
                            Therapeutic dose
                           Therapeutic dose

				
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