Session 6 Flashcards
- The target site for drugs are mainly proteins , give examples of protein targets.
- What are the exceptions?
- R - receptor
I - ion channel
T - Transporters?
E - enzyme
- some antimicrobial & antitumour drugs bind DNA
Give examples of receptors which can be targeted
K - tyrosine kinase
I - ion channel
N - Nuclear hormone receptors
G - GPCRs
State the prefixes for concentration
How do you work out molarity?
Why we need to consider drug concentrations in molarity
- Most drugs bind ? to receptors -binding governed by association AND dissociation
- Most drugs either ?
- reversibly
- block the binding of an endogenous agonist (antagonist) OR
- activate a receptor (agonist)
- block the binding of an endogenous agonist (antagonist) OR
- To do anything they must BIND to the receptor. To bind to a receptor a ligand must have ? for the receptor
- AFFINITY
- Binding governed by affinity higher affinity = ?
- Does an antagonist have affinity?
- An agonist has bound to its receptor due to its affinity for the receptor. What happens next?
- stronger binding
- Yes
- Beyond the activated receptor THINGS have to happen to evoke a response – dependent on the response and the cell/tissue
The ability of a ligand to cause a response is an indication of the ligand’s EFFICACY
Efficacy governed by intrinsic efficacy PLUS other things that influence the response:
- Agonists have …
- Antagonists have… • affinity ONLY
- • affinity
- have intrinsic efficacy (ie. can activate the receptor)
- have efficacy (ie. cause a measurable response)
- • affinity ONLY
- How do we measure drug-receptor interactions by binding?
Often by binding of a radioactively labelled ligand (radioligand) to cells or membranes prepared from cells
- What is Bmax
- What is Kd
- Bmax (max. binding capacity – information about receptor number)
- concentration of ligand required to occupy 50% of the available receptors
Kd (or KD) = dissociation constant
Kd= index of AFFINITY
LOWER value = HIGHER affinity
i.e. Kd = is actually the reciprocal of affinity
[Drug] – usually logarithmic not linear:
Relation between [drug] and RESPONSE nb. response requires drug efficacy agonist
- Response could be e.g. ?
- What graph do we use to determine the relationship between [drug] and RESPONSE?
- What is EC50
- • change in a signalling pathway
• change in cell or tissue behaviour (e.g. contraction)
- Concentration-response curve
- effective concentration giving 50% of the maximal response
- Concentration –
- Dose –
- known concentration of drug at site of action – e.g. in cells and tissues
- concentration at site of action unknown – e.g. dose to a patient in mg or mg/kg
What is EC50 ?
POTENCY
effective concentration giving 50% of the maximal response
This is a measure of agonist POTENCY -
it depends on BOTH affinity and intrinsic efficacy (ie. ability to activate receptor)
PLUS cell/tissue-specific components (that allow something to happen)
ie. for a ligand to have potency (generate a measurable response) requires:
Note that the same potency could occur with ?
different combinations of affinity and efficacy
What is the effect of adrenaline in asthmatics
Adrenaline (noradrenaline) -> B2 adrenoceptor agonists -> relaxation
HOWEVER
but other b-adrenoceptors elsewhere eg. b1 in heart – increase force & rate
need selective/specific activation of B2 adrenoceptors (in the airways) to treat asthma
Which agent is better to use for asthmatics and why. Salbutamol or salmeterol
What is the problem with using salbutamol?
angina
b1-adrenoceptor – speed up heart
Potency depends on BOTH affinity & intrinsic efficacy PLUS cell/tissue-dependent factors including
the NUMBER of receptors
How do cell/tissue dependent factors such as receptor number influence agonist potency?
often the response is controlled or limited by other factors eg.
• a muscle can only contract so much • a gland can only secrete so much
Spare Receptors
- Often seen when receptors catalytically active eg.
- Exist because of:
- tyrosine kinase or G-protein coupled receptors
- • amplification in the signal transduction pathway
• response limited by a post-receptor event
Give an example where signal amplification is seen
- Adrenaline
- B - adrenoceptor
- Gs protein
- adenylyl cyclase
- cAMP
- PKA
Why have spare receptors?
increase sensitivity – allow responses at low concentrations of agonist
Changing receptor number changes?
agonist potency and can effect the maximal response
Explain why receptor no’s are not fixed
- tend to increase with low activity (up-regulation)
- tend to decrease with high activity (down-regulation) (for drugs this can contribute to tolerance/tachyphylaxis)
physiological, pathological or drug-induced changes
What does the statement Not all agonists elicit maximal responses in the same assay mean
Partial agonist
- Maximal response indicates ?
- intrinsic activity
Describe the intrinsic activity of partial agonists
Partial agonists have lower intrinsic activity as they have lower efficacy than full agonists (– usually lower intrinsic efficacy)
Relevance of partial agonists: (3)
- Can allow a more controlled response
- Work in the absence or low levels of (endogenous) ligand
- Can act as antagonist if high levels of full agonist
Opioids are clinically used for?
Unfortunately are also used for?
ADR?
Action primarily through?
- Pain relief
- Recreational use (eg. heroin) - euphoria
- BUT respiratory depression – can lead to death
- μ-opioid receptor (GPCR)
Along with the graph explain how buprenorphine can be used clinically
buprenorphine – higher affinity (ie. lower K efficacy (inability to produce full response) than morphine
buprenorphine can be advantageous to morphine in some clinical settings
e.g. pain control – adequate pain control, less respiratory depression
Partial agonists and the treatment of opioid addiction
e.g. buprenorphine to enable gradual withdrawal and prevent use of other illicit opioids
Heroin (diamorphine) addict (heroin - full agonist at μ-opioid receptor)
Addiction related to physical and psychological dependence.
The addict frequently injects heroin but injects a stolen narcotic instead of heroin – turns out to be buprenorphine. Immediately become very ill. Why?
- Withdrawal or abstinence syndrome – generally opposite to acute drug effects - contributes to continued drug taking.
- Partial agonism
Withdrawal symptoms as buprenorphine antagonizes the effect of heroin – low efficacy at receptor
Partial agonism is compound AND SYSTEM dependent. Increasing receptor number can change a partial agonist into a ?
full agonist
Partial agonist still has low intrinsic efficacy at each receptor BUT - sufficient receptors to generate a full response.
- Partial agonists have lower efficacy than full agonists
- BUT full agonists with identical intrinsic activities may have different efficacies
Draw a diagram to represent this information
How would you describe the compounds in terms of agonism?
Rank in terms of efficacy.
Rank in terms of potency.
- What is an antagonist?
- What are the three ways in which they can act?
- Block the effects of agonists ie. prevent receptor activation by agonists
- Reversible competitive antagonism (commonest and most important in therapeutics)
- Irreversible competitive antagonism
- Non-competitive antagonism (generally allosteric or even post-receptor)
- Reversible competitive antagonism (commonest and most important in therapeutics)
- What is IC50
- Competitive antagonists compete with agonists for binding – the inhibition is ?
- Concentration of antagonist giving 50% inhibition
index of antagonist potency determined by strength of stimulus (i.e. [agonist])
Kd used to describe antagonist affinity
KB when derived pharmacologically
(50% occupancy - reciprocal of affinity)
- SURMOUNTABLE
How do reversible competitive antagonists effect the agonist concentration-response curve?
cause a parallel shift to the right
Naloxone is a high affinity, competitive antagonist at μ-opioid receptors. Why might such a compound be useful clinically?
Reversal of opioid-mediated respiratory depression
- high affinity means it will compete effectively with
other opioids (e.g. heroin) for receptors
- Irreversible competitive antagonism occurs when the antagonist ?
- Effects are?
- How do Irreversible competitive antagonists effect the concentration-response curve
- dissociates slowly or not at all
- With increased [antagonist] or increased time more receptors are blocked by antagonist – NON-SURMOUNTABLE
- Irreversible competitive antagonists cause a parallel shift to the right of the agonist concentration-response curve and at higher concentrations suppress the maximal response
Give an example of a Irreversible competitive antagonists and where it is used clinically
Pheochromocytoma e.g. phenoxybenzamine – non-selective irreversible a
-adrenoceptor blocker used in hypertension episodes in pheochromocytoma
Allosteric sites Provide binding sites for:
Allosteric compounds for GPCRs just emerging in the clinic
Maraviroc - Negative allosteric modulator (NAM) of chemokine receptor 5 (CCR5)
Used by HIV to enter cells. - Used in AIDS.
Allosteric compounds more established in other areas eg. ion channels and enzymes
