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    Pcol 2

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    Alfie16
    The document discusses several theories of drug-receptor interactions including simple occupancy theory, modified occupancy theory, and dose-response relationships. Key concepts covered include affinity, intrinsic activity, potency, efficacy, graded vs quantal dose-response curves, and definitions of terms like median effective dose. The document also classifies drugs based on their intrinsic activity as full agonists, partial agonists, inverse agonists, or antagonists (competitive, irreversible, allosteric).

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    Pcol 2

    Uploaded by

    Alfie16
    127 views6 pages
    The document discusses several theories of drug-receptor interactions including simple occupancy theory, modified occupancy theory, and dose-response relationships. Key concepts covered include affinity, intrinsic activity, potency, efficacy, graded vs quantal dose-response curves, and definitions of terms like median effective dose. The document also classifies drugs based on their intrinsic activity as full agonists, partial agonists, inverse agonists, or antagonists (competitive, irreversible, allosteric).

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    The document discusses several theories of drug-receptor interactions including simple occupancy theory, modified occupancy theory, and dose-response relationships. Key concepts covered include affinity, intrinsic activity, potency, efficacy, graded vs quantal dose-response curves, and definitions of terms like median effective dose. The document also classifies drugs based on their intrinsic activity as full agonists, partial agonists, inverse agonists, or antagonists (competitive, irreversible, allosteric).

    Copyright:

    © All Rights Reserved
    Download as DOCX, PDF, TXT or read online from Scribd
    Download as docx, pdf, or txt
    127 views6 pages

    Pcol 2

    Uploaded by

    Alfie16
    The document discusses several theories of drug-receptor interactions including simple occupancy theory, modified occupancy theory, and dose-response relationships. Key concepts covered include affinity, intrinsic activity, potency, efficacy, graded vs quantal dose-response curves, and definitions of terms like median effective dose. The document also classifies drugs based on their intrinsic activity as full agonists, partial agonists, inverse agonists, or antagonists (competitive, irreversible, allosteric).

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    © All Rights Reserved
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    of 6

    Theories of drug-receptor interaction

    Simple occupancy theory

    - Intensity of the response to a drug is directly proportional to the number of receptors occupied
    by that drug.
    Notes: occupancy of receptor by drug
    intensity of response
    - Maximal response will occur when all available receptors have been occupied.
    - Several limitations:
    o Does not account for the potency and maximal efficacy of drugs
    o Does not give consider the effect of partial agonists.

    Modified occupancy theory

    - Recognized the fact that drugs differ in several aspects:


    o Ability to bind to the receptor function once binding has taken place (Intrinsic activity)

    Affinity

    - Strength of attraction b/w drug and its receptor


    - The higher the affinity, the greater the strength of attraction
    - Reflected in the drugs potency
    o Drugs with high affinity are effective in low doses.

    Notes: affinity strength of attraction dose

    Intrinsic activity

    - Ability of a drug to activate a receptor upon binding


    - Drugs with high intrinsic activity cause intense receptor activation
    - Reflected in drugs maximal efficacy
    o Drugs with 1 intrinsic activity have 1 maximal efficacy
    Dose-response relationships

    - The magnitude of the drug effect depends on the drug conc. at the receptor site
    - Types:
    o Graded Dose-Response
    o Quantal Dose-Response

    Graded Dose-receptors

    - As the conc. of a drug , its pharmacologic effect also gradually until all the receptors are
    occupied (the maximum effect)
    - Plotting the magnitude of response against increasing dose of a drug produced a graded dose-
    response curve
    o Rectangular hyperbola
    - Limitations:
    o Difficult to construct for a pharmacological response that us quantal (i.e. present/absent
    or all-or-none), Example: death, arrhythmia, convulsions
    o May not be applicable to other patients
    Potency

    - Measure of the amount of a drug necessary to produce an effect of a given magnitude


    - Determined based on the conc. of drug producing 50% of the maximum effect (EC50)

    Efficacy

    - Magnitude of response a drug causes when it interacts with a receptor


    - Dependent on the no. of drug-receptor complexes formed and the intrinsic activity of the drug
    - Maximal efficacy (EMAX)
    o Assume that all receptors are occupied by the drug
    o No increase in response is observed if a higher conc. of drug is obtained
    o Main point of difference b/w a full vs partial agonist
    - More clinically useful than drug potency
    o Drug with efficacy is more therapeutically beneficial than a drug with potency

    Quantal dose-response relationship

    - A dose of drug reqd to produce a specified magnitude of effect in a large number of individual
    patients is determined first
    - The cumulative frequency of distribution of responders is plotted against the logarithm of the
    dose
    - Plot of dose of the drug and the proportion of a population that responds to it
    - Graded response can be transformed to quantal responses by designating a predetermined level
    of the graded response as the point at which a response occurs or not.
    - Useful for determining doses to which most of the population responds.
    - Important in determining the ff:
    o Median effective dose (ED50)
    o Median toxic dose (TD50)
    o Median lethal dose (LD50)
    o Therapeutic index
    o Therapeutic window

    Definition of terms

    - Median effective dose (ED50)


    o Dose that produces a clinically desired or effective response (ED50) in half the population
    - Median toxic dose (TD50)
    o Dose required to produce a particular toxic effect in half of the population
    - Median lethal dose (LD50)
    o If the toxic effect produced above is death

    Therapeutic index

    - Ration of the dose that produces toxicity in half the population (TD50) to the dose that produces
    a clinically desired of effective response (ED50) in the half of the population
    - TI = (TD50)/ (ED50)
    - Measure of a drugs safety
    o A larger value indicates a wide margin b/w doses that are effective and toxic.

    Therapeutic window

    - The concentration range range over which drug produce its therapeutic effect.

    Drug classification based on intrinsic activity

    - Intrinsic activity: ability of drug to activate a receptor binding


    - Drug types:
    o Agonist
    Full/ Strong agonist
    Partial/ Weak agonist
    Inverse agonist
    o Antagonist
    Competitive antagonist
    Irreversible antagonist
    Non-competitive/ Allosteric antagonist
    Other types:
    Chemical antagonist
    Functional antagonist

    Full agonist

    - Agonist: drug that binds to a receptor and produce a biologic response


    - Full agonist
    o Drug that binds to a receptor and produces a maximal biologic response (EMax) similar to
    the response of the endogenous ligand
    o Bind to a receptor, stabilizing it in its active state
    o Have an intrinsic activity = 1
    o Cause maximal effect despite occupying a small no. of receptors in a cell

    Side concept: Spare receptors

    - Stephen (1965), while studying the action of acetylcholine, found that full agonists were capable
    of eliciting EMax despite occupying a small fraction of receptors, often < 1%
    o The largely unoccupied receptors are termed spare receptors or receptor reserves
    Common with drugs that elicit smooth muscle contraction

    Partial agonist

    - Produce lower response at full receptor occupancy than do full agonists


    o Even if all the receptors are occupied, partial agonists cannot produce the same EMax as a
    full agonist
    - Intrinsic activity > 0 but < 1

    Inverse agonists

    - Have a relative affinity for inactive (R) receptor states and will shift the equilibrium from R* to R
    o Unlike full agonist, stabilize the inactive (R) form and cause R* to convert to R
    o Decrease the no. of R* to below that observed in the absence of drug
    - Have an intrinsic activity < 0
    - Reverse the activity of receptors
    - Exert the opposite pharmacological effect of agonists

    Antagonist

    - Inhibit or block responses cause by agonists


    - Bind to a receptor with high affinity but possess zero intrinsic activity
    - Types:
    Competitive antagonist
    Irreversible antagonist
    Non-competitive/ Allosteric antagonist
    Other types:
    Chemical antagonist
    Functional antagonist

    Competitive antagonist

    - Competes with the agonist fir the same binding site a reversible manner
    o By binding a receptor, it maintains the receptor in an inactive state and hence prevents
    an agonist from binding to the receptor
    - The inhibition can be overcome by increasing the concentration of agonist relative to antagonist
    o Hence competitive antagonism is surmountable
    - Thus, competitive antagonist characteristically shift the agonist dose-response curve to the right
    (increased EC50) without affecting EMax

    Irreversible antagonist

    - Binds covalently to the active site of the receptor, thereby reducing the number of receptors
    available to the agonist
    - Cause a downward shift of the EMax, with no shift of EC50 values (unless spare receptors are
    present)
    - The effect of irreversible antagonists cannot be overcome by adding more agonist
    o Hence called Insurmountable
    o The rate of antagonist is bound to a receptor, it can no longer be reclaimed by agonist
    o According to Lippincott Book: a form of non-competitive antagonist

    Allosteric antagonist

    - Other books: true non-competitive antagonist


    o Binds to a site (allosteric site) other than the agonist-binding site and prevents the
    receptor from being activated by the agonist
    o Induce a conformational change in the receptor -> agonist no longer recognizes the
    agonist-binding domain
    - Also cause a downward shift of the EMax, with no shift of EC50 values

    Chemical antagonism

    - Aka. Neutralization or complexation


    o Drugs that binds together when taken at the same time, regarding one or both drugs
    inactive
    - Example:
    o Non-beneficial:
    Ca/Mg/Al antacids when taken with tetracycline
    o Beneficial:
    Chelation therapy (e.g EDTA) during heavy metal poisoning (Pb)
    Antidotal therapy of Protamine sulfate (basic) in heparin (acidic) overdose

    Functional antagonism

    - An antagonist may act at a completely separate receptor, initiating effects that are functionally
    opposite those of the agonist
    - Example functional antagonism by epinephrine to histamine induced bronchoconstriction:
    o Histamine binds to H1 histamine receptors on bronchial smooth muscle, causing
    bronchoconstriction.
    o Epinephrine agonist at 2-adrenoreceptors on bronchial smooth muscle, causing
    bronchodilation
    - Aka. Physiological antagonism

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