pharmacodynamics Flashcards
what is the receptor theory?
the factors affecting how ligand interact with receptors to cause a response
what is the receptor theory?
the factors affecting how ligands interact with receptors to cause a response
what are drugs?
chemicals that act on specific targets to evoke a particular response
what are drug targets?
-receptors,enzymes,transporters,ion channels
what are receptors?
proteins that recognise and respond to an endogenous chemical signal called a ligand to evoke a response e.g contraction (muscle),action potential (neurone),secretion (gland)
what is specificity?
where a class of drugs binds to certain receptors (or other targets like enzymes) and certain receptors recognise only certain types of drug
what is an agonist?
-any ligand when bound to its receptor,elicits an observable response (may be endogenous or exogenous)
what is an antagonist?
any ligand,that itself may not produce any response,which interferes with the response to an agonist
what is the historical background of receptors?
-the concept of receptors originated by John Langley 1887
-the term receptor was coined by Ehrlich in 1900
-clark proposed occupation theory in 1926-this allowed prediction of the relationship between drug concentration and response
what does a dose/concentration response curve show?
the relationship between doses (if the drug is used in vivo) or concentrations (if the drug is used in vitro) of a drug and its pharmacologic effect
what is the agonist concentration-response relationship?
-where a feature of drugs acting on a specific target in a physiological system is that it will be a graded response with an increase in drug conc or dose
what is the drug-receptor relations in-vivo?
In vivo (in the body)-it is assumed the dosage of the drug provides a known conc of a drug at the target receptor
what is the drug-receptor relations in vitro?
-in vitro (out of the body)-tissues/cells are incubated in chambers of known volume and drug concentration,this enables the concentration-response relationships to be accurately measured
what are the key factors in determining drug-receptor interactions?
-Potency
-The potency of the drug is defined by the location of its concentration-response curve
on the graph and its EC50 and pD2
what is the potency of a drug?
the concentration of the drug needed to produce a defined response or effect
what is efficacy?
-it describes the way in which agonists vary in the response they produce even when they occupy the same number of receptors
-maximal response is dependant on the drug efficacy
compare high efficacy agonists to low efficacy agonists…
high-can produce their maximal response at lower concs
-low-cannot activate the receptors to the same degree and may not be able to produce the same maximal response eve when they occupy the entire receptor population and so behave as partial agonists
what is affinity?
the extent to which a ligand binds to its receptor (potency)
what is intrinsic activity?
-the maximal response of the drug (relative to the systems maximal response)
-the intrinsic activity of the drug being studied may or may not equal the system maximal response
what is the intrinsic activity of a full agonist?
-the drug produces the maximal response of the system and has an intrinsic activity of 1
what is the intrinsic activity of a partial agonist?
the drug produces a submaximal response of the system and has an intrinsic activity of >0 but <1
what is the intrinsic activity of an inverse agonist?
some systems elevated basal activity which can be decreased through drug action (inverse agonism) and this has an intrinsic activity less than 0
what is the intrinsic activity of an antagonist?
-0
what 4 factors interplay to result in agonist effects?
-two factors related to the drug
-two factors related to the system
how are drug targets coupled to cells?
-via biochemical reactions or signals
-the reactions that link cell surface signalling cytosolic responses are saturable
-the nature, capacity and sensitivity of the biochemical reactions linking stimulus and response may vary from cell to cell or tissue to tissue
what are the 2 drug factors that result in agonist effects?
-Affinity-the propensity of a drug molecule to associate closely with a target (defined by Kd)
-Efficacy-the property of the drug that causes the target to change its behaviour once the drug is bound
what does the interaction of a drug with its target provide a cell with?
-with a stimulus (controlled by concentration of the drug and its affinity for the target and its efficacy)
what are the cell based factors that result in agonist effects?
-target density
-target coupling efficiency (the efficiency with which each target is coupled to the cell response machinery)
what is relative potency?
-when using drugs that bind to the same receptor in the same tissue, we can assume that the tissue effects are common to both drugs
-this means we can compare the potency of drugs directly on the two drug factors of affinity and efficacy
how do drug affinity and efficacy relate?
-affinity and efficacy are unique properties of the drug-target interaction and are true for that target in all tissues its expressed
-we can assess these factors in one system and then apply them to another
what do we need to know to determine affinity and efficacy?
-we need to know if the drug is selective for the target
what is agonist selectivity?
-where an agonist may activate the specific biological target or activate non-specific targets
what are the two methods to determine the selectivity of agonism?
-pharmacologic selectivity test-involves the use of a specific antagonist for the target
-recombinant selectivity tst-agonist effects in presence and absence of the target
what is the occupation theory of drug receptor interactions?
-there is a bimolecular, reversible interaction between drug D and receptor R leading to the generation of a drug-receptor complex
what are the problems with the occupation theory?
-many ligand-receptor interactions are not bimolecular
-these interactions are not always reversible or independent
-response size is usually not linearly related to the proportion of coupled receptors
why are some drug-target interactions reversible?
-most ligand receptor interactions involve the formation of a few (~3) low energy bonds e.g hydrogen bonds
-the energy of the binding is low (~50-100kJ/mol) and its because of this low energy that these interactions are reversible
why are some drug-target interactions irreversible?
-some compounds bind to their receptors covalently in a much more energetic reaction
what is an example of a non-reversible drug-target interaction?
alkylating agents used as antineoplastic agents that bind to DNA of cancer cells
what do some ligands interact with their receptors to form?
tri-molecular complexes
what is the cooperativity of drug-target interactions?
-if the presence of a ligand on the receptor enhances further ligand binding there is negative cooperativity
-if the presence of the ligand decreases further ligand binding there is negative cooperativity
what is the rate of association of a drug with the target driven by?
energy changes that are energetically favourable for the drug that binds
what is the rate of dissociation of a drug from the receptor?
-the energy change when the molecule diffuses away from the receptor
-this leads to an equilibrium where the rate of the rug leaving=the rate of the drug approaching and entering binding pockets
what is the Kd equation?
-the ratio of k-1/k+1 determines the amount of drug bound to the receptor at any one time and becomes a measure of how well the drug binds to the receptor
this ratio is the equilibrium dissociation constant (Kd)
The reciprocal of Kd is the affinity constant affinity of drug for the target
what does a smaller Kd mean?
a higher affinity of the drug for its receptors
what does clarks equation tell us?
-how when the concentration of a drug equals Kd,then the drug occupies 50% of the receptor population
-Kd is the concentration of ligand D required to occupy 50% of receptors at equilibrium
-the magnitude of Kd is therefore inversely proportional to the affinity of the drug fir the receptor
what is the EC50 of a partial agonist?
-the agonist concentration producing half maximal response is the EC50 (effective concentration producing 50% response)
what does a low EC50 indicate?
a high affinity of binding
how can the EC50 of a party agonist predict Kd?
-When half of the receptors are occupied,[D]=Kd,if half of the receptors are occupied we should have half maximal response so EC50 might be used to estimate Kd
what is Kd?
-the conc of the agonist at which 50% receptor binding occurs
why can an EC50 of full agonists not predict Kd?
-using a full agonist,maximal tissue response cannot be reliably equated with 100% receptor occupation
-Changes in cellular sensitivity to full agonists results in variation of EC50
-EC50 is a complex function of both affinity and efficacy of the agonist,so no specific information about the affinity of a full agonist can be derived from the EC50
what did Stephenson discover in the 1950s?
-many systems max can be obtained without having to occupy all available receptors and this opposes the Clark’s occupation theory and resulted in the development of the concepts stimulus, efficacy and spare receptors
what is conformational selection?
the molecular mechanism underlying efficacy
-proteins are dynamic and can exist in many pre-set conformations in equilibrium with each other
what may happen if a ligand binds to one particular conformation?
-it can stabilise it at the expense of other conformations and this will eventually enrich the ligand bound conformational state
-if a cellular response is induced then the ligand is an agonist
what did Stephenson propose un 1956?
-that when an agonist occupies its receptor the drug-receptor complex provides stimulus (S) and it is the stimulus which is related to tissue response
what is the ability of a drug to provide stimulus dependent on?
-ts ability to occupy receptors (affinity) and its efficacy
-efficacy can be thought of as a measure of the ability of a drug to provide stimulus once it has occupied its receptors
what can clarks equation show?
-if e has a positive value=agonist
-if e is zero=antagonist
-if e has a negative value=inverse agonist
-if e is high,a maximal stimulus and response can be obtained only when a small proportion of receptors are occupied
why do spare receptors exist?
-only a small proportion of receptors need to be occupied to produce a maximal response and so there are extra receptors that need not be occupied which are the spare receptors
what do spare receptors do?
-help generate receptor reserve
-the number of spare receptors greatly increases sensitivity to their ligands as they become occupied the EC50 shifts to the left making the agonist appear more potent
what happens in the absence of spare receptors (partial agonist responses)?
EC50=Kd
what happens in the presence of spare receptors (full agonist responses)?
Kd>EC50 because a proportion (less than 50%) of receptors need to be occupied to achieve a half maximal response
what makes receptor number increase or decrease?
-the number of receptors a cell has is variable
-receptor numbers increase (up regulation) or decrease (downregulation) in response to many stimuli under both the physiological and pathological conditions and this can markedly affect the responsiveness to drugs
what is the formula for intrinsic efficacy?
why did furghott create the term intrinsic efficacy?
-there was a need for the classification of drug-receptor interactions to have Aterm that reflected the ability of a drug to provide stimulus but is dependent of Rt
how is intrinsic activity and receptor reserve linked?
-the intrinsic activity of each agonist is involved in the size of the receptor reserve, two different agonists of the same receptor can have different intrinsic efficacies depending on their ability to stabilise the receptors active state
what is efficacy overall dependent on?
the intrinsic efficacy of the agonist (number of receptors bound to elicit a given response) and the overall receptor number available (Rt)
how can we quantify full agonist activity-potency ratios?
-ratio’s of EC50 values can be used to quantify the relative potency of full agonists
-if the agonists produce the response by an identical mechanism of activation of the target then these ratios are system independent
-when agonists do not produce the system maximum EC50 becomes the estimate
when and who introduced the rate theory?
-it was first proposed in 1961 by Paton
what does the rate theory state?
-stimulus is provided by the initial event of occupation but does not continue with further occupation
-In order for stimulus to be continued the agonist must leave and then re-occupy the receptor
what 2 things does rate theory provide an explanation for?
-desensitisation
-tachyphylaxis
what happens in desensitisation?
when an agonist is first added (without prior exposure to an agonist) all receptors are unoccupied and since the rate of occupation depends on the concentration of free receptors, the rate of occupation is high providing a large stimulus
how does the concentration of unoccupied receptors change overtime after the addition of an agonist-desensitisation?
the concentration of unoccupied receptors declines and so the rate of occupation decreases providing a smaller stimulus
what happens in tachyphylaxis?
when and agonist is first added (without prior exposure to Ana agonist) all receptors are unoccupied and since the rate of occupation depends on the concentration of free receptors, the rate of occupation is high providing a large stimulus?
how does the concentration of unoccupied receptors change overtime after the addition of an agonist-desensitisation?
the concentration of unoccupied receptors declines and so the rate of occupation decreases providing for a smaller stimulus
what does antagonist potency depend on?
-the affinity of the antagonist for the target protein
-antagonist potency is purely chemical (no direct response is observed )
how is antagonist potency measured?
-it is measured as the equilibrium dissociation constant of the antagonist-receptor complex
-it is measured indirectly through the interference of agonist activity in functional assay
what do we look at in mechanisms?
-the location of the binding relative to the binding of the natural agonist
what are the two types of molecular mechanisms operable for antagonism?
-allosteric
-orthosteric
what happens in the allosteric mechanism?
the agonist or antagonist bind at separate binding sites on the receptor and the interaction between them occurs through a change in conformation of the protein
what happens in orthosteric antagonism?
-the antagonist binds at the same site as the agonist and precludes the agonist from binding
-it can shift the agonist conc response to the right, reduce maximal response or both
what are the two types of orthosteric antagonism?
-competitive
-non-competitive
compare the effects of competitive and non competitive orthosteric antagonism…
competitive-effects are surmountable
non-competitive-effects are insurmountable
what happens in the competitive type of orthosteric antagonism?
-at high agonist cons nearly all the receptors will be occupied by agonists in the presence of an antagonist and Emax can then be achieved
what happens if you increase the antagonist concentration in the competitive type of orthosteric antagonism?
-increasing the antagonist concentration displaces the agonist from the receptors and E decreases
-EC50 increases but Emax is unaltered
what happens in the non competitive type of orthosteric antagonism?
-the antagonist effectively decreases Rt such that it is no longer possible to occupy sufficient receptors to achieve Emax
what happens if you increase the agonist concentration in the non competitive type of orthosteric antagonism?
-increasing agonist concentration or exposure time removes more receptors
-EC50 is unaltered but Emax decreases
what are antagonist kinetics?
the persistence of antagonist binding
compare what the occupation and rate theory state..
-occupation theory states that a stimulus is generated throughout the period that the agonist occupies the receptor whilst the rate theory states that it is only provided by the initial process of occupation
what would the occupation theory believe about a high efficacy agonist?
-a high efficacy agonist would be one that remains on the receptor
-agonists with a high efficacy would be expected to have a slow rate constant
why is the occupation theory seen as more valid?
in practice efficacious agonist have a low off rate constant indicating this theory is more valid as it believes that agonists with high efficacy have a slow rate constant
what would the rate theory believe about a high efficacy agonist?
-they would rapidly leave the receptor making it available for re-ccupation
-the agonists would have a high off rate constant
what are most prescribed drugs-agonists or antagonists?
antagonists
what are the different types of antagonists?
-chemical antagonists
-physiological antagonists
-pharmacological antagonists
what do chemical antagonists do ?
give an example
-they inactivate the agonist e.g Dimercaprol which vines to heavy metals like arsenic and lead
what do physiological antagonists do?
give examples of them
-they stimulate a response that opposes the agonist e.g histamine and omeprazole
what do pharmacokinetic antagonists do?
-give examples of them
-they alter the pharmacokinetics of the agonist e.g by affecting its absorption,metabolism,excretion,it decreases the concentration of the agonist at the site of action -examples are phenobarbitone and warfarin
what do pharmacological antagonists do?
-they alter the interaction between agonist and its receptor
pharmacological antagonists bind to receptors in a similar fashion to agonist
-Unlike agonists they do not elicit an independent response when bound to the receptor,they compete with agonists for the same receptor
