Site of Drug Action: Dose Responses

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• Pharmacology is the study of the action of drugs on living tissue. Drug is an agent that interacts with specific target molecule in the body and produce a physiological effect

1. Pharmacodynamics

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   • Mechanism by which drugs exert their effect on the body to generate a therapeutic action.
   1. Types of Drugs

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      • Activity at high concentrations (non-potent). Little Structural specificity. Physical changes Drug acting at low concentrations (potent). Structural specificity, chemical interaction
   2. Receptors

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      • Site where ligand can attach. Ligands can be neurotransmitter, hormones or other factors. Activation produces a response. Receptors can be determined by Affinity or selectivity
      1. Types

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         • Most commonly G-protein coupled receptors, e.g acetylcholine, opoids, noradrenaline Ligand-Gated ion channel Kinase-lined receptors (Cytokines/growth factors) Nuclear Receptors (i.e vitamin D receptors)
         1. Subtypes

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            • Cholinergic: Either muscarinic or nicotinic Include B2, B1 or A1 (lungs, heart, blood vessels) Hence it is important to develop drugs that are specific to minimize side effects. As Receptor occurs in multiple tissues. Drugs could also be non specific, acting on more than receptors. Hence the need of trials on healthy human in the 1st phase.
2. Drug Action

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   • Many categories include: Agonists Antagonists Partial Agonist Inverse Agonist Allosteric Modulators
   1. Agonist

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      • Mimics endogenous ligands, bind to receptor and cause a secondary effect.
      1. Receptor interactions

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         • Assume that: Effect of drug is proportional to the fraction of receptors occupied Maximal effect occurs when all receptors are occupied
         1. Measurement of Receptor Binding

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            • Total receptor bound - nonspecific binding = Specific binding. 2 factors: Binding of drug to receptor: Affinity Response to binding: Efficacy (Capacity to produce an effect)
         2. ED50

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            • Effective Dose 50% (amount taken by human/animal) Effective concentration 50% ( Concentration needed for a given cell/tissue to work) Look at lecture notes for more details. Basically this is just a measurement on how to do a dose-response measurement.
   2. Antagonist

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      • Prevents action of the agonist. When an antagonist act on the receptors, nothing happens, hence you need to have a agonist for the effect to be fully noticeable.
      1. Competitive Antagonism

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         • Most common form of antagonist. Agonist and antagonist compete for the same receptor site. Maximal effect is unchanged as antagonism is surmountable. Maximum takes longer time to reach hence the graph has a parallel shift to the right
      2. Physiological Antagonism

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         • When 2 agonist had an effect of 2 opposite effects. I.e alcohol with caffeine
      3. Non-competitive Antagonism

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         • Antagonist that binds irreversibly to the receptor. Change the receptor binding site so that the agonist can no longer bind. Maximal effect is no longer produced.  Graph, lowered plus lowered slope.
         1. Spare Receptors

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            • Spare receptors are important as it allow maximum response to be reached. This means that the ED50 may not be equal to KD as there are existence of spare receptors.
      4. Inverse Agonist

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         • Opposite effect of agonist, cause an effect to be going the other way. Increase presence of inverse receptors. Effects still being researched.
   3. Partial Agonist

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      • Partial agonist is an agonist, however they have low efficacy and they never achieve maximum effect. They may act as an against a full agonist as an antagonist.
   4. Allosteric Modulators

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      • Weird interactions. Bind to the separate sites other than the agonists. Either they can increase or decrease modulation.
3. Measurement

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   • In quantitative response: Gradual changes, i.e blood pressure Quantal response: All or nothing.
   1. Therapeutic Ratio

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      • LD50/ED50 Toxic ratio: TD50/ED50
4. Receptor Numbers

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   • It is ever changing, receptors are continuously removed and replaced.  I.e if too much agonist, down regulation, increased tolerance or desensitisation. If too much antagonist, up regulation. sensitization may occur.
   1. Tolerance

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      • Tolerance: Same dose, administrated repeatedly, less effect Tachyphylaxis: Tolerance which develops too fast Desensitization: Less effect is produced the longer agonist is in contact with the receptor. Change in receptors, down regulation and the depletion of mediators or increased metabolic breakdown increases sensitization.