Pharmacodynamics Flashcards
Adjusted body weight formula
adjusted body weight = ideal body weight + 0.4 x (actual body weight - ideal body weight)
What does adjusted body weight correspond to?
The weight of metabolically active tissue
Outline the 4 different mechanisms by which a drug may act?
- Action on receptors
A. Alteration of ionic permeability
B. GPCR
C. Receptors acting as enzymes
D. Regulation of gene transcription - Effects on enzymes
A. Inhibition either reversible or non reversible
B. Activation - Action on ion channels
- Action dependent on physicochemical properties - osmotic activity, acid-base activity, chelation, oxidation, reduction
What 4 receptors subtypes might a drug act at?
- Action on receptors
A. Alteration of ionic permeability
B. GPCR
C. Receptors acting as enzymes
D. Regulation of gene transcription
Outline using a graph how drug concentration and effect are related? What equation might be used?
In an idealised system the relation between drug concentration and effect is described by a hyperbolic curve according to the following equation; where only a single subject studied and used to measure efficacy (Emax)and potency (EC50)
E = Emax x C / C + EC50
Y axis a continuous variable; quantal is where it is categorical
E = effect observe at concentration C
E max = maximal response of the drug
EC50 = concentration of the drug that produces 50% of maximum effect
This describes the mass action law, which describes association between two molecules of a given affinity
Using the law of mass action illustrate how receptor bound drug is related to drug concentration? Use an equation in addition to descrbe this?
When does response data is plotted why is it linear?
It should be logarithmic but using logarithm of dose or concentration (X axis) allows for hyperbolic curve transformation into a sigmoid curve with a linear midpoint explaining low dose scales iof effect changing rapidly and compresses it at high doses where effect is changing slowly
What is coupling in the context of drugs and receptors?
The transduction process that links drug occupancy of receptors and pharmacological response is often termed coupling
What is the term for The transduction process that links drug occupancy of receptors and pharmacological response
coupling
What two factors determining coupling efficiency in drug effect?
- Initial confirmation change - full agonists are more efficiently coupled to receptor occupancy than a partial agonist
- Drug effect relationship to receptor occupancy - for ion channels this may be more linear, but for enzymatic signal cascades this can be more disproportionate
What is the concept of spare receptors?
where maximal biologicalresponse is achieved without maximum receptor occupancy e.g. even under conditions where 90% of Beta adrenorecpeotrs are occupied by irreversible antagonist maximal response can still be achieved i.,e. Heart has heaps of spare beta receptorsas does the NMJ
Why do spare receptors exist
Provide protection against failure of transmission in the presence of toxins
At what point does the concept of spare receptors get overridden?
75% receptor occupancy of the antagonsit and then maximal response is unable to occur
What is the affinity of agonist binding denoted as
Kd
The Kd of the agonist receptor interaction determines what fraction of total receptors will be occupied at a given concentration of agonist regardless of receptor concentration
How would you denote receptor occupancy fraction compared to Kd
B/Bmax = C / (C + Kd)
Draw 4 curves representing the relationship between drug dose and response?
Drug A should have moderate potency, high maximal efficacy.
Drug B will have higher potency than drug A but lower maximal efficacy
Drug C will have equal maximal efficacy to Drug A but lower potency
Drug D will have equal maximal efficacy to Drug A, lower potency than drug C or A, but a steep dose response curve
Describe these curves
Drug A should have moderate potency, high maximal efficacy.
Drug B will have higher potency than drug A but lower maximal efficacy
Drug C will have equal maximal efficacy to Drug A but lower potency
Drug D will have equal maximal efficacy to Drug A, lower potency than drug C or A, but a steep dose response curve
How do you describe drug potency in a drug dose vs effect curve?
EC50 or ED50 required to produce 50% of the drugs maximum effect
◦ I.e. a drug is potent if not much of it is needed to reach maximum effect even where another drug may have a higher maximum effect in large concentrations ◦ So drug B is more POTENT than drug A —> ◦ Dependent on ‣ Kd - affinity of receptors for binding the drug ‣ EFificency in which drug receptor binding is coupled to response
What two factors determine drug potency?
Kd - affinity of receptors for binding the drug
‣ EFificency in which drug receptor binding is coupled to response
How is drug potency different to maximal efficacy?
Potency is related to ◦ EC50 (concentration) or ED50 (dose) of a drug required to produce 50% fo the drugs maximum effect
◦ I.e. a drug is potent if not much of it is needed to reach maximum effect even where another drug may have a higher maximum effect in large concentrations
Maximal effect is the limit of the dose response axis
i.e. Drug B is more potent than Drug A, but Drug A has a greater maximal effect
Explain using Drugs C and D what effect a dose response cruve shape has?
◦ extremely steep curves may mean the probability of undesirable over-effects occur easily and may occur where cooperative interactions of different effect sites e.g. heart, brain and kidney dose effect sites contributing to very significant and rapid overall clinical effect
Define drug efficacy?
a measure of the maximal response achievable by a drug once it is bound to its recpetor (often described as eMax - the drug concentration at which maximal effect is achieved)
What is EC50
- Median effective concentration (EC50) - the concentration fo a drug required to induce 50% of a maximal effect
What is ED50
- Median effective dose ED50 - the dose of a drug required to produce a response in 50% of the population to whom it is administered
Illustrate how a quantal effect plot diferse from a dose effect plot?
Why is this more useful for some drugs than other?
What characteristics of a drug do both curves represent?
How are the axes different on the graph?
What characteristics of the curves are similar between the two graphs?
(all or nothing, and population based)
- Graded response curves do not work if there is an either-or response e.g. termination of a seizure; and will not reflect the variability in drug response between people
◦ Both dose response curves show - potency and selectively
◦ Graded dose response shows maximal efficacy
◦ Quantal dose response curve indicates potential variability among individuals
Y axis instead shows cumulative frequency instead of effect potency; plotted against log (dose)
- Characteristics of the log dose-response curve
◦ Sigmoid curve
◦ X axis the logarithmic section
◦ Middle 1/3 is linear
◦ Steep curve = increased potency (i.e. slope = potency) - Has the
◦ Median effective dose ED50 -50% of individuals get the quantal effect
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
What are cardinal characteristics of a quantal dose response cruve
- Characteristics of the log dose-response curve
◦ Sigmoid curve
◦ X axis the logarithmic section
◦ Middle 1/3 is linear
◦ Steep curve = increased potency (i.e. slope = potency) - Has the
◦ Median effective dose ED50 -50% of individuals get the quantal effect
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
What is Ld50 vs TD50
◦ Median toxic dose TD50 (if this is death - LD50 - lethal dose)
What is therapeutic index? If you were to measure this what is the equation?
- A measure of a the margin of safety which can be expected to produce a certain effect
- The TI is the ratio of the TD50 to the ED50 for some therapeutically relevant effect
TI = LD50/ED50
Drugs that have a low therapeutic index have what relationship between Ld50 and ED50
Close in value
Narrow safety margin
Draw a dose response curve representing LD50 and ED50
What is an idiodysncratic reaction?
Unusual drug response not usually observed, may be due to genetic differences in metabolism
Why might variability in drug response occur - describe in terms of mechanisms by which drug effect could be altered (4)
◦ Alteration in concentration that reaches receptor
‣ Affected by: Absorption, Distribution, Clearance
‣ Age,weight,sex, disease state,liver and kidney function
‣ Genetic differences in drug processing e.g. drug metabolism enzymes OR active transport of drug from cytoplasm (MDR - multi drug resistances genes - membrane transporters upregulation increases drug resistance)
◦ Variation in concentration of endogenous receptor ligand
‣ E.g. catecholamine surges being dampened but during normal physiology heart rate unaffected by beta blockade
◦ Alterations in number of function of receptors
‣ Other hormonal action, thyroid hormones affecting number of Beta receptors and sensitivity to catecholamines
‣ Endogenous tolerance or tachyphylaxis + withdrawal overshoot of endogenous ligand response are explained by natural responses to stimulation or lack thereof \
◦ Changes in component of response distal to the receptor
Clinical selectivity refers to? What drugs do we commonly use that have poor clinical selectivity? What strategies do we use to try and avoid adverse effects in these circumstances? (3)
- Selectivity usually considered in beneifical/therapeutic effects versus toxic/adverse effects
- Beneficial and toxic effects mediated by the same receptor/effector system
◦ E.g.anticoagulation,insulin —> means that avoidance of other things that increase the risk of complications,increased monitoring or careful weighting of risk/benefit in weak indications is necessary - Sometimes it is caused by single receptor type action in different tissues
◦ E.g. digoxin, glucocorticoids
◦ Strategy to use can include
‣ Minimum possible dose
‣ ADjunctive drugs
‣ Optimise drug delivery to reduce exposure to other organ systems - Sometimes it is mediated by different types of receptors
◦ ALpha and beta selective adrenoreceptors agonists and antagonist,histamine and nicotine blocking drugs
Define antagonist. What two varieties of this are there? How are they different in terms of their ability to be overcome
a drug with high affinity for a receptor but no intrinsic activity, binding to active sites or allosteric sites
reversible antagonists can be overcome antagonist action whereas irreversible binding means agonist concentration becomes independent of receptor function
What is an allosteric agent
◦ Allosteric binding are drugs that bind to the same receptor molecule but at a differing location to agonists and affect either agonist/antagonist binding at other sites via confirmational change enhancing or inhibiting receptor affinity. Not overcome by increasing the dose of the agonist and non competitive
What is the effect on Emax of a competitive antagonist? Why? What does this depend on (2)
Unaltered
You can still acheive the same maximal effect with increased drug concentration
The amount of drug required to acheive this will depend on the dose of the antagonist and its receptor affinity
Draw a dose response curve for an agonist, agonist + competitive inhibitor, agonist + allosteric activator, and agonist + allosteric inhibitor or irreversible compeititve inhibitor
Describe what each of these must correlate to
What is the equation which describes the relationship between agonist and antagonist effect?
What two important therapeutic considerations does this equation raise
- Degree of inhibition produced by a competitive antagonist depends on its concentration
A. Fixed doses result in wildly different concentrations amongst patients - Clinical response to a competitive antagonist depends on the concentration of the agonist that is competing for binding to its receptors
A. E.g. in beta blockade the beta blocker may suppress adrenergic response under normal physiological conditions but with exercise, postural change or emotional stress this may overcome competitive antagonism
How are potency and efficacy affected by competitive antagonists?
a drug whose antagonistic effect can be reversed by higher concentration of the agonist
* Efficacy is unaffected (Emax) while potency is reduced (ED50 is increased)
A competitive antagonists function is much the same as a less potent full agonist
What is a non competitive antagonist?
- Don not bind at the same site as agonist and classically are thought not to alter the binding of the agonist however this is now known to be untrue
- Their antagonism comes from preventing receptor activation through conformational distortion - cannot be overcome by increasing agonist concentration
- e.g. ketamine at NMDA receptors
Allosteric modulation is?
- Non competitively by binding to a site that separate to the agonist binding site modulating receptor activity without blocking agonist binding
- Actions usually reversible if they do not bind covalentely e.g. Benzo at GABA A receptors
What is an irreversible inhibitor? What mechanism might they act by? What effect do they have on efficacy and potency? What does this depend on? Advantages of this style of drug? Disadvantages?
- A drug whose antagonistic effect cannot be reversed by a higher concentration of the agonist
- Either via a covalent bond or binding so tightly that is receptor for all practical purposes is unavailable
- The effect on Emax for agonists will depend on the dose of the antagonist as well as the degree of spare receptors; but in general potency and efficacy are decreased (EMax and ED50 decrease)
- Advantages of this style of drug
◦ Duration of action independent of elimination , instead it is dependent on receptor turnover
◦ Effect is independent of swings in agonist concentration if the agonist is prone to this e.g. alpha blacked in pheochromocytoma - Disadvantage
◦ Overdose - you need to counteract it without using the receptor
E.g. Clopidogrel metabolite binds irreversibly to Gi protein coupled ADP Py2Y12 receptors
Advantages of an irreversible antagonist? Disadvantages?
- A drug whose antagonistic effect cannot be reversed by a higher concentration of the agonist
- Either via a covalent bond or binding so tightly that is receptor for all practical purposes is unavailable
- The effect on Emax for agonists will depend on the dose of the antagonist as well as the degree of spare receptors; but in general potency and efficacy are decreased (EMax and ED50 decrease)
- Advantages of this style of drug
◦ Duration of action independent of elimination , instead it is dependent on receptor turnover
◦ Effect is independent of swings in agonist concentration if the agonist is prone to this e.g. alpha blacked in pheochromocytoma - Disadvantage
◦ Overdose - you need to counteract it without using the receptor
E.g. Clopidogrel metabolite binds irreversibly to Gi protein coupled ADP Py2Y12 receptors
What are the 2 main factors in determining a drugs pharmacological effect
- Intrinsic activity/efficacy
- Affinity
Describe agonists, partial agonsits, antagonsits and inverse agonists in terms of affinity and effiacy>
- Full agonist - high affinity = full IA (IA = +1)
- Antagonist - high affinity, no IA (IA =0)
- Partial agonist - high affinity, fractional IA (O<IA<1)
- INverse agonist (-1<IA<0
What is intrinsic actitivty/efficacy?
- A measure of the ability of a drug to produce an effect once it is bound to its receptor
What is affinity with reference to drug to receptor binding?
How well or avidly a drug binds to the receptor - determined by Kp or Ka
What is Bowmans principle?
- Weaker antagonists at the NMJ have a more rapid onset of action
- This is because they are given at a higher dose for the same maximal effect so that more molecules are available to occupy receptors —> receptor occupancy required for full effect is achieved more rapidly
- Rocuronium 1/5 of the effect of vecuronium but given at 5x the dose it acts quicker
How do you explain Rocuronium being faster in onset than Vecuronium?
Bowmans principle
* Weaker antagonists at the NMJ have a more rapid onset of action
* This is because they are given at a higher dose for the same maximal effect so that more molecules are available to occupy receptors —> receptor occupancy required for full effect is achieved more rapidly
* Rocuronium 1/5 of the effect of vecuronium but given at 5x the dose it acts quicker
How does a non competitive inhibitor effect maximum effect
reduces it, reduces maximal efficacy. However fractional response remains the same, so the dose response curve is not shifted to the right
What is Kd
The dissociation constant, unaltered by inhibitor
A competitive inhibitor will result in a lower maximum response, but the dose at which this maximal response is unaltered. (i..e no inhibitor may have a higher maximal response but the 50% of maximal response dose is the same; even though with an inhibitor the total maximal response is lower)
Draw a dose response curve illustrating the effect of a partial agonist
A is a full agonist, C is a partial agonsit
Dotted line - shows dose response for A in the presence of submaximal dose of C
At low concentrations of A the combintion results in a greater effec tthan would be seen with A alone, but as the dose of A is increased the total effect is lower until very high doses than A+C = A maximal effect
Therefore in the middle concentrations C acts as a COMEPTITIVE ANTGONIST
Draw a graph representing change in receptor activity to dose for agonist, partial agonist, antagonist and inverse agonist where there is constitutive activity
What is Ka? Demonstrate how it is derived from first principles?
