Pharmacodynamics Flashcards
How do Endogenous and exogenous ligands exert
effects? What are the exceptions to this?
Endogenous and exogenous ligands exert
effects by binding to a TARGET – mainly proteins
- exceptions eg. some antimicrobial & antitumour drugs bind DNA
What are GPCRs regulated by?
light, odorants, hormones, neurotransmitters, ions
What are orphan receptors?
Receptors with ligand unknown
The _____ of drug _____ around receptors is critical in determining drug action. Fill in the gaps
Concentration
Molecules
What is a ligand?
• A ligand is a substance that can interact with a target protein -
or receptor
• Ligands usually bind to a specific site(s) on the signalling protein
• Ligands can be endogenous signalling molecules e.g. hormones
neurotransmitters or ions such as Ca2+ • Ligands can be exogenous molecules -
What is the equation to work out molarity?
(molarity)M = g/L / MWt(molecular weight)(g)
What are ligand concentration at receptors usually ?
«1M
How do convert from molar to millimolar?
Times by 1000
How do convert from millimolar to micromolar?
Times by 1000
How do convert from micromolar to nanomolar?
Times by 1000
How do convert from nanomolar to picomolar?
Times by 1000
Why do we need to consider drug concentrations in molarity?
Because two drugs with the same concentration in g/L will have different concentrations in molarity due to their different molecular weights
Do most drugs bin reversibly or irreversibly to receptors?
Reversibly
What is binding governed by?
binding governed by association AND dissociation
What law does binding obey?
Binding obeys the law of mass action (related to concentrations of reactants & products)
What do most drugs do?
Most drugs either
1) block the binding of an endogenous agonist (antagonist) OR
2) activate a receptor (agonist)
What must the ligand have for it to bind to a receptor?
To bind to a receptor a ligand must have AFFINITY for the receptor
What is affinity?
- Affinity is a measure of the strength (or avidity) withwhich a ligand or drug binds to a receptor.
- Affinity can also be thought of as the likelihood of how well a ligand w
What is an agonist?
An agonist is a substance that binds to a receptor and activates the receptor to then produce a measurable biological response.
What is an antagonist?
- Antagonists are ligands that have affinity for a receptor or target protein but do not produce a biological response.
- Antagonists block the effects of agonists.
The higher the affinity?
The stringer the binding
What is receptor activation governed by?
Intrinsic efficacy
What is intrinsic efficacy?
The ability of a ligand to generate the active form of the receptor
What is ligand efficacy?
The ability of a ligand to cause a measurable biological response
Do agonists have affinity, intrinsic efficacy or efficacy?
Agonists have affinity, intrinsic efficacy (ie. can activate the receptor) and have efficacy (ie. cause a measurable response)
Do antagonists have affinity, intrinsic efficacy or efficacy?
Antagonists only have affinity.
They do not have intrinsic efficacy or efficacy so do not produce a response as can’t get the receptor in the active form.
What do antagonists do?
They Block the effects of agonists
ie. prevent receptor activation by agonists.
They Do not tun the receptor off, they prevent agonist activating the receptor
What is clinical efficacy?
Clinical efficacy is more of an indication of how well a treatment succeeds in achieving its aim.
How do we measure binding?
Often by binding of a radioactively labelled ligand (radioligand) to cells or membranes prepared from cells
What is the measurement (or parameter) used to define affinity?
Affinity is measured by Kd
dissociation constant
What is Kd
Kd is defined as the concentration of ligand at which 50% of all available receptors are bound
How does Kd affect affinity?
The lower the value of Kd
the greater the affinity
What is Bmax?
The maximum binding capacity. Information about receptor number
Why do we want drugs with higher affinity?
High affinity allows binding at low concentrations of hormones, neurotransmitters etc AND drugs.
what could a response be?
• change in a signalling pathway • change in cell or tissue behaviour (e.g. contraction)
What is Emax?
maximal effect evoked by ligand
What is EC50?
effective concentration giving 50% of the maximal response.
What is EC50 a measure of?
EC 50 = measure of agonist POTENCY
How do we define agonist potency?
Potency is defined as the concentration of a drug that evokes 50% of its maximal response (E max). The term
EC50 is used to represent this concentration.
How is potency and EC50 inked?
The lower the value for EC50, the more potent is the drug or ligand (because a lower concentration of drug is required to generate 50% of the maximal response).
What does the potency of a drug depend on?
depends on BOTH affinity and intrinsic efficacy (ie. ability to activate receptor)
PLUS cell/tissue-specific components (that allow something to happen)
What would the efficacy of an antagonist or partial agonist be?
Zero/low
What would the efficacy of an agonist be?
High
What is the difference between concentration and dose?
Concentration = known concentration of drug at site of action – e.g. in cells and tissues
Dose = concentration at site of action generally unknown
– e.g. dose to a patient in mg or mg/kg
What is asthma?
Asthma is a condition in which your airways narrow and swell and produce extra mucus. This can make breathing difficult and trigger coughing, wheezing and shortness of breath.
reversible airflow obstruction and bronchospasm
How does the sympathetic system lower the symptoms of asthma?
Releases (nor)adrenaline which activates b2-adrenoceptors (GPCR). They stimulate the relaxation of bronchioles so that there is increased airflow. This is called functionsal antagonism
What is the problem with targeting b2 -adrenoceptors?
B adrenoreceptors are not only found in the airways, they are also found elsewhere eg. b1 in heart
– increase force and rate of contraction.
How do we solve the problem of activating b1-adrenoceptors in the heart and elsewhere?
need selective/specific activation of b2-adrenoceptors (in the airways)
How do we achieve selectivity/specificity with salbutamol?
Salbutamol (agonist)- affinity to both b1 and b2 adrenoceptors are good but intrinsic efficacy at b2 adrenoceptors is better than B1 so selectivity is based on efficacy
- route of administration also has an effect - to lungs
How do we achieve selectivity/specificity with salmeterol(agonist)?
Slectivity is based on affinity because has a greater affinity to B2-adrenoceptors than B1. No selective efficacy because efficacy is the same in both B1 and B2
What is potency determined by?
Determined by affinity AND efficacy
Also affected by factors
including the NUMBER of receptors
For any ligand-receptor combination, what is fixed and what is variable?
Fixed:
- strength of interaction (affinity)
- receptor turning into active conformation (intrinsic efficacy)
Variable:
- potency - cell/tissue-dependent factors affect efficacy
What would we expect to happen to the response as the number of receptors increase?
As the number of receptors increase, the response increases. At 50% binding, 50% response. At 100%binding, 100% response
What normally happens to the response as the number of receptors increase?
As the number of receptors increase, the response increases until the maximal response. After the full response has been achieved, any further increase in receptor will not affect the response - they become spare receptors. This is because 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
What does the presence of spare receptors mean?
That in some cases <100% occupancy = 100% response. Perhaps 50%binding can evoke a 100% binding.
What is the function of having spare receptors?
Spare receptors increase sensitivity/potency
– allow responses at low concentrations of agonist
For example:
if full response requires 10,000 activated receptors/cell:
- if no spare receptors(ie. 10,000 receptors/cell), full response requires 100% occupancy
- requires»_space; Kd concentration of drug
- if spare receptors present (eg. 20,000 receptors/cell), only 50% occupancy required for full response
- ## requires Kd concentration of drug
What is the effect of changing receptor number?
Changing receptor number changes agonist potency.
and can affect the maximal response if below number needed fora full response
Are receptor numbers fixed?
Receptor numbers are not fixed:(physiological, pathological or
drug-induced changes)
• vary with cell type
• tend to increase with low activity (up-regulation)
• tend to decrease with high activity (down-regulation)
Are all agonists equal at the same receptor?
NO!
• Different affinities
• Different efficacies
What is a partial agonist?
Partial agonists are ligands that evoke responses that
are lower than the maximal response of a full agonist (ie. they have lower Emax
values).
Compared to a full agonist, a partial agonist has?
Lower intrinsic efficacy as lower efficacy than full agonists
What does maximal response indicate?
Maximal response indicates intrinsic activity
What is partial agonist dependent on?
Ligand type and receptor number
What is the effect on increasing the receptor number in partial agonists?
Increasing receptors, increases the response almost like the response of a full agonist
What is the relevance of partial agonists as drugs?
• Can allow a more controlled response
• Work in the absence or low levels of (endogenous) ligand
…..but can act as antagonist if high levels of full agonist
Give an example of a partial agonist drug
Opioids are used for pain relief and also used in recreational use as heroin as it causes euphoria. However it can cause respiratory depression and lead to death. A drug that is used to treat opioid addiction is buprenorphine which is a partial agonist with a higher affinity than the full agonist heroine. Taking buprenorphine means the full response is not achieved so doesn’t cause respiratory depression and it helps with withdrawal symptoms. Buprenorphine will also inhibit the effect of heroin as it will bind to the u-opioid receptors and prevent heroin binding:
ie. a partial agonist can provide antagonism
What are partial agonists sometimes referred to as?
Partial agonists sometimes referred to as a mixed agonist/antagonist
An addict who frequently injects heroin, injects a stolen narcotic instead of heroin which turns out to be buprenorphine. He immediately becomes very ill. Why?
- Withdrawal or abstinence syndrome
• sustained drug-taking leads to tolerance
• Turns down the sensitivity -decrease in number of receptors (down-regulation)- more heroin needed to get the same effect
• when drug is withdrawn, the endogenous ligands are now less effective – hence the withdrawal symptoms - Partial agonism
buprenorphine occupies opioid receptors but partial effect – hence withdrawal symptoms.
What are the 3 types of antagonism?
- Reversible competitive antagonism (commonest and most important in therapeutics)
- Irreversible competitive antagonism 3. Non-competitive antagonism (generally allosteric
– can even work post-receptor)
Describe Reversible competitive antagonism
Reversible competitive antagonism relies on a dynamic equilibrium between ligands and receptors
Both agonist and antagonist compete for the receptor - depends on their affinity.
the inhibition is SURMOUNTABLE
Greater [antagonist] = greater inhibition
What is IC50?
Concentration of antagonist giving 50% inhibition
IC50 gives an indication of antagonist affinity but influenced by [antagonist] AND strength of stimulus (i.e. [agonist])
What kind of shift does reversible competitive antagonist cause of the agonist concentration-response curve and why?
Reversible competitive antagonists cause a parallel shift to the right of the agonist concentration-response curve
• As more agonist needed to produce the same response as when antagonist not present - can outcompete antagonist if enough agonist present
Give an example of a competitive antagonism in the clinic?
Naloxone
How does naloxone work in out-competing opioids?
Naloxone - high affinity, competitive antagonist at μ- opioid receptors
• high affinity means it will compete effectively with
other opioids (e.g. heroin) for receptors
• reversal of opioid-mediated respiratory depression
Describe irreversible competitive antagonism
Irreversible competitive antagonism occurs when the antagonist dissociates slowly or not at all
Is irreversible competitive antagonism surmountable?
No, With increased [antagonist] or increased time more receptors are blocked by antagonist
– NON-SURMOUNTABLE - cannot be overcome with increased agonist
What kind of shift does irreversible competitive antagonist cause of the agonist concentration-response curve and why?
Irreversible competitive antagonists cause a parallel shift to the right of the agonist concentration-response curve and at higher concentrations suppress the maximal response because the spare receptors become filled by antagonist so insufficient receptors for full response
Give An example of irreversible competitive antagonism in the clinic
pheochromocytoma:
Tumour of adrenal chromaffin cells cause production of excessive adrenaline which causes vasoconstriction due to activation of a1 adrenoceptors.
phenoxybenzamine – non-selective irreversible a1 -adrenoceptor blocker used in hypertensive episodes in pheochromocytoma. Once bound, phenoxybenzamine cannot be out- competed by high levels of adrenaline/(noradrenaline)
What is the orthosteric site?
The site to which endogenous agonists bind to is named the orthosteric site. Modulators don’t bind to this site. They bind to any other suitable sites, which are named allosteric sites.
What is Non-competitive antagonism?
Where the antagonist bind to allosteric site. These antagonists can then enhance or reduce effects of agonists
- no competition for binding site - reduce orthosteric ligand affinity and/or efficacy
It is non- competitive antagonism if the binding to the allosteric site then makes it more difficult for the agonist to bind the orthosteric site - by changing conformation of the protein
Give an example of Non-competitive antagonism in clinic
Allosteric compounds for GPCRs just emerging in the clinic – inhibitors and activators
Maraviroc
- Negative allosteric modulator (NAM) of chemokine receptor 5 (CCR5) Used by HIV to enter cells.
- Used in AIDS.
Name the three main types of drug antagonism. For each type, indicate both the location of the antagonist binding site and the possible type(s) of binding at the site
- Reversible competitive antagonism
Experiments show that only 10% of muscarinic (M3) receptors in airways smooth muscle need to bind acetylcholine (ACh) to achieve maximal contraction. The EC 50 for ACh is
Spare muscarinic M3 receptors
A new drug Painex developed to reduce chronic pain acts on a subset of glutamate receptors in the CNS. With increasing concentration, Painex increases the Kd for glutamate. At higher concentrations it
reduces the E max of glutamate by 50%.
What best describes the likely pharmacodynamic action of this drug?
Non-competitive antagonist
