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					Pharmacodynamics
          PHARMACODYNAMIC CONCEPTS

Receptors:
• Specific molecules in a biologic system with which drugs
  interact to produce changes in the function of the system.
• Receptors must be selective in their ligand-binding
  characteristics.
• Receptors also must be modified as a result of binding an
  agonist molecule (so as to bring about the functional change).
• Many receptors have been identified, purified, chemically
  characterized, and cloned.
• The majority of the receptors characterized to date are
  proteins; a few are other macromolecules such as DNA.

• The receptor site or recognition site for a drug is the specific
  binding region of the macromolecule and has a high and
  selective affinity for the drug molecule.

• The interaction of a drug with its receptor is the fundamental
  event that initiates the action of the drug.
                       Effectors:
• Effectors are molecules that translate the drug-receptor
  interaction into a change in cellular activity.

• The best examples of effectors are enzymes such as adenylyl
  cyclase.

• Some receptors are also effectors in that a single molecule
  may incorporate both the drug binding site and the effector
  mechanism, eg, the tyrosine kinase effector of the insulin
  receptor, or the sodium-potassium channel of the nicotinic
  acetylcholine receptor.
         Graded Dose-Response Relationships:

• When the response of a particular receptor-effector system
  is measured against increasing concentrations of a drug,
  the graph of the response versus the drug concentration or
  dose is called a graded dose-response curve.

• Plotting the same data on semilogarithmic axes usually
  results in a sigmoid curve, which simplifies the
  mathematical manipulation of the dose-response data .

• The efficacy (Emax) and potency (ECs0) parameters are
  derived from these data.

• The smaller the EC50, the greater the potency of the drug.
      Quantal Dose-Response Relationships:

• When the minimum dose required to produce a specified
  response is determined in each member of a population, the
  quantal dose-response relationship is defined.

• When plotted as the fraction of the population that responds
  at each dose versus the log of the dose administered, a
  cumulative quantal dose-response curve usually sigmoid in
  shape, is obtained.

• The median effective (ED50), median toxic (TD50), and
  median lethal doses (LD50) are extracted from experiments
  carried out in this manner.
                          Efficacy:

• Efficacy, often called maximal efficacy, is the maximal effect
  (Emax) an agonist can produce if the dose is taken to very high
  levels.

• Efficacy is determined mainly by the nature of the receptor
  and its associated effector system.
• It can be measured with a graded dose-response curve but
  not with a quantal dose-response curve.

• By definition, partial agonists have lower maximal efficacy
  than full agonists.
                            Potency:
• The amount of a drug needed to produce a given effect.
• In graded dose-response measurements, the effect usually chosen
  is 50% of the maximal effect and the dose causing this effect is
  called the EC50.
• Potency is determined mainly by the affinity of the receptor for the
  drug.
• In quantal dose-response measurements ED50., TD50., and LD50
  are typical potency variables (median effective, toxic, and lethal
  doses, respectively, in 50% of the population studied).

• Thus. potency can be determined from either graded or quantal
  dose-response curves, but the numbers obtained are not identical.
                 Spare Receptors:
• Spare receptors are said to exist if the maximal drug response
  is obtained at less than maximal occupation of the receptors.

• In practice, the determination is usually made by comparing
  the concentration for 50% of maximal effect (EC50) with the
  concentration for 50% of maximal binding (Kd).

• If the EC50 is less than the Kd, spare receptors are said to
  exist.
• This might result from one of several mechanisms.

• First, the effect of the drug-receptor interaction may persist
  for a much longer time than the interaction itself.

• 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.
               Inert Binding Sites:
• Inert binding sites are components of endogenous molecules
  that bind a drug without initiating events leading to any of the
  drug's effects.
• In some compartments of the body (eg, the plasma), inert
  binding sites play an important role in buffering the
  concentration of a drug because bound drug does not
  contribute directly to the concentration gradient that drives
  diffusion.
• The two most important plasma proteins with significant
  binding capacity are albumin and orosomucoid (a1-acid
  glycoprotein).
                Agonists and Partial Agonists:

• An agonist is a drug capable of fully activating the effector
  system when it binds to the receptor.

• A partial agonist produces less than the full effect, even when
  it has saturated the receptors.

• In the presence of a full agonist, a partial agonist acts as an
  inhibitor.
   Competitive and Irreversible Pharmacologic
                 Antagonists:
• Competitive antagonists are drugs that bind to the receptor in
  a reversible way without activating the effector system for
  that receptor.

• In the presence of a competitive antagonist, the log dose-
  response curve is shifted to higher doses (ie, horizontally to
  the right on the dose axis) but the same maximal effect is
  reached.
• In contrast, an irreversible antagonist causes a downward shift
  of the maximum, with no shift of the curve on the dose axis
  unless spare receptors are present.

• The effects of competitive antagonists can be overcome by
  adding more agonist.

• Irreversible antagonists cannot be overcome by adding more
  agonist.
• Competitive antagonists increase the ED50; irreversible
  antagonists do not (unless spare receptors are present).
ED50
          Physiologic Antagonists:
• A physiologic antagonist is a drug that binds to a different
  receptor, producing an effect opposite to that produced
  by the drug it is antagonizing.

• Thus it differs from a pharmacologic antagonist, which
  interacts with the same receptor as the drug it is
  inhibiting.

• A common example is the antagonism of the
  bronchoconstrictor action of histamine (mediated at
  histamine receptors) by epinephrine's bronchodilator
  action (mediated at beta adrenoceptors).
                  Chemical Antagonists:

• A chemical antagonist is a drug that interacts directly with the
  drug being antagonized to remove it or to prevent it from
  reaching its target.

• A chemical antagonist does not depend on interaction with
  the agonist's receptor (although such interaction may occur).

• A common example of a chemical antagonist is dimercaprol, a
  chelator of lead and some other toxic metals.

• Pralidoxime, which combines avidly with the phosphorus in
  organophosphate cholinesterase inhibitors, is another type of
  chemical antagonist.
                           Nerve Agents
                           Organophosphate insecticides
                           Cholinesterase inhibitors
Pralidoxime

Cholinesterase generator                      Enzyme active site
Chemical antagonist
     Therapeutic Index, Therapeutic Window:

• The therapeutic index is the ratio of the TD50 (or LD50) to the
  ED50, determined from quantal dose-response curves.
• The therapeutic index represents an estimate of the safety of a
  drug, since a very safe drug might be expected to have a very large
  toxic dose and a small effective dose.

• Unfortunately, factors such as the varying slopes of dose-response
  curves make this estimate a poor safety index.
• The therapeutic window, a more clinically relevant index of safety,
  describes the dosage range between the minimum effective
  therapeutic concentration or dose, and the minimum toxic
  concentration or dose.
• For example, if the average minimum therapeutic plasma
  concentration of theophylline is 8 mg/L and toxic effects are
  observed at 18 mg/L, the therapeutic window is 8-18 mg/L.
The therapeutic index = TD50 (or LD50) / ED50
                      = 150/3
                      = 50
           Signaling Mechanisms:
• Once an agonist drug has bound to its receptor, some effector
  mechanism is activated.

• For most drug-receptor interactions, the drug is present in the
  extracellular space while the effector mechanism resides
  inside the cell and modifies some intracellular process.

• Thus, signaling across the membrane must occur.
• Five major types of transmembrane signaling mechanisms for
  receptor-effector systems have been defined:
1. Receptors that are intracellular:
• Some drugs, especially more lipid-soluble or diffusible agents
   (eg, steroid hormones, nitric oxide) may cross the membrane
   and combine with an intracellular receptor that affects an
   intracellular effector molecule.
• No specialized transmembrane signaling device is required.
2. Receptors located on membrane-spanning enzymes:
• Drugs that affect membrane-spanning enzymes combine with
   a receptor on the extracellular portion of enzymes and modify
   their intracellular activity.
• For example, insulin acts on a tyrosine kinase that is located in
   the membrane.
• The insulin receptor site faces the extracellular environment
   and the enzyme catalytic site is on the cytoplasmic side.
• When activated, the receptors dimerize and phosphorylate
   specific protein substrates.
3.   Receptors located on membrane-spanning molecules that bind
     separate intracellular tyrosine kinase molecules:

A.   Receptors have extracellular and intracellular domains and form
     dimers.

B.   After receptor activation by an appropriate drug, the tyrosine
     kinase molecules (,Janus kinases; JAKs) are activated, resulting in
     phosphorylation of "STAT" molecules (signal transducers and
     activators of transcription).

C.   STAT dimers then travel to the nucleus, where they regulate
     transcription.
Tyrosine-kinase receptors
     Structure:
     •Receptors exist as individual polypeptides
     •Each has an extracellular signal-binding site
     •An intracellular tail with a number of tyrosines
     and a single a helix spanning the membrane
4. Receptors located on membrane ion channels:

• Receptors that regulate membrane ion channels may directly
  cause the opening of an ion channel (eg, acetylcholine at the
  nicotinic receptor) or modify the ion channel's response to
  other agents (eg, benzodiazepines at the GABA channel).

• The result is a change in transmembrane electrical potential.
Ion channel receptors
     Structure:
     •Protein pores in the
     plasma membrane
5. Receptors linked to effectors via G proteins:
• A very large number of drugs bind to receptors that
   are linked by coupling proteins to intracellular or
   membrane effectors.
• The best defined examples of this group are the
   sympathomimetic drugs, which activate or inhibit
   adenylyl cyclase by a multistep process:
    – activation of the receptor by the drug results in
      activation of G proteins that either stimulate or
      inhibit the cyclase.
G protein-linked receptors

                 Structure:
                 •Single polypeptide chain
                 threaded back and forth
                 resulting in 7 transmembrane a
                 helices
                 •There’s a G protein attached to
                 the cytoplasmic side of the
                 membrane (functions as a
                 switch).
More than 20 types of G proteins have been identified;
three of the most important are listed in this table.
                      Signal transduction

1. enzyme linked
     (multiple actions)

2.   ion channel linked
     (speedy)

3. G protein linked
     (amplifier)
4. nuclear (gene) linked
     (long lasting)

				
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posted:11/10/2011
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