Lecture 9 Flashcards
MUST LEARN FROM NOTES AND THEN USE THIS TO TEST OR USE THIS TO LEARN AND SOLIDIFY BY LOOKING AT NOTES - BECAUSE EVERYTHING LINKS - IT IS HARD TO SHOW THIS USING FLASHCARDS
What is pharmacodynamics?
Pharmacodynamics: (what a drug does to the body) - the biochemical, physiologic, and molecular effects of drugs on the body and involves receptor binding (including receptor sensitivity), post-receptor effects, and chemical interactions.
What is pharmokinetics?
Pharmacodynamics, along with pharmacokinetics (what the body does to a drug, or the fate of a drug within the body), helps explain the relationship between the dose and response, ie, the drug’s effects.
What does pharmocodynamics and pharmokinetics allow?
- Helps us to better understand physiology and pathology
- Helps us to understand drug action
- Informs clinical decisions
- Allows development of new drug
Where does ligands mostly bind?
Endogenous and exogenous ligands exert effects by binding to a TARGET – mainly proteins
Some key concepts - exceptions eg. some antimicrobial & antitumour drugs bind DNA
What are the molecular targets responsible for the therapeutic effects of drugs?
Briefly how to GPCRs work?
What is a superfamily? What is the potential for GPCRs?
What receptor does sulbutomal act on?
β2 adrenoreceptor (it is a selective agonist)
- Asthma
What is a ligand?
Ligand something that binds to a receptor eg. drug, hormone, neurotransmitter
- applicable to targets other than GPCRs
Drug action is determined by:
The concentration of drug molecules around receptors is critical in determining drug action (at the site of action)
Molarity - description and units
M (units for molarity) MOLARITY IS NOT MOLES!
It is the molar concentration
The number of moles of solute per liter of solution
It’s units: mol/dm3 (this is the same as mol/L as dm3=L)
What is MWt (molecular weight)
This is the atomic number, e.g. the larger number you see in the periodic table e.g. for oxygen it is 16, for water (H2O) it is 18
What is the molarity formula?
This is changing number of g/L (i.e. concentration in grams) to concentration in moles, using the molecular weight
Another formula for molarity
molarity (M) = moles
Volume (either dm3 or L)
The MWt of the drug simvastatin is 418.57. How many grams are required in 1 mL to make a 0.5 M solution?
- Formula to use is: molarity (M) = g/L
MWt - 0.5 = g/L
- 57
- 0.5 x 418.57 = 209.285g/L
- Changing g/L into g: 209.285 / 1000 = 0.209g
What is cm3 in dm3?
1000cm3 = 1dm3
Need to learn the conversion unit table
What are the main bits to remember from the conversion table?
What is the Avagadro’s constant?
The Avogadro constant = 6.022 × 10 23 atoms per mole.
What is the Avagadro’s formula?
Why is it important to consider drug molarity?
Recap, why do we need to consider drug concentration in molarity?
Describe what happens when a drug binds reversibly
Association
Dissociation
-binding governed by association AND dissociation
Draw at a visible representation of drugs binding reversibly
Binding to the receptor requires ______?
To do anything, a ligand (such as a drug) must BIND to the receptor
To bind to a receptor a ligand must have AFFINITY for the receptor
binding governed by affinity
Higher affinity =
Higher affinity = stronger binding
How can binding be measured?
A common method measures the binding of a radioactively labelled ligand (radioligand) to intact cells or cell membranes. Many cells/many receptors (e.g. 10,000-100,000 per cell)
Incubate radioligand and receptors -> binding
At equilibrium (not instant!), separate bound and free: usually measure bound
What the graph that is used to measure affinity, what else is on the graph, what do the values mean?
What is Bmax?
Maximum binding capacity - information about receptor number
What is Kd?
Dissociation constant
Kd = the concentration of drug that leads to half of the receptors being bound. Measure of AFFINITY
What does a lower Kd value mean?
Lower Kd = higher affinity
Describe what a ligand is
• 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 – drugs
Describe the meaning of affinity and how is it measured?
- Affinity is a measure of the strength (or avidity) with which a ligand or drug binds to a receptor.
- Affinity can also be thought of as the likelihood of how well a ligand will optimally ‘fit’ the receptor or target molecular binding site.
- Affinity is measured by Kd (dissociation constant)
What is the definition of Kd and how can it be determined from a radioligand saturation binding curve?
Kd is defined as the concentration of ligand at which 50% of all available receptors are bound. This can be determined from a saturation binding curve as 50% binding can be determined and the concentration giving this 50% binding then determined.
What of the following drugs has the highest affinity and why?
A drug has a Kd of 6.5 x 10-9 M at the b2-adrenoceptor. Under conditions of equilibrium binding to this receptor in airways smooth muscle, how many receptors would be occupied per cell at 6.5 x 10-9 M if there were 12,000 receptors per cell?
Binding of the same drug at the b2-adrenoceptor is examined in another tissue with only 5,000 receptors per cell. How many receptors would be occupied per cell at 6.5 x 10-9 M?
2500
Why do we often plot drug concentration vs binding using a semi-logarithmic plot? What is the shape of this curve? Can you still derive Kd and Bmax?
When we plot eg drug concentration vs. binding – usually a semi logarithmic plot – sigmoidal plot (rather than the rectangular hyperbola shown previously)
Understanding logs - drug concentration vs binding
How to convert/interpret log graph REALLY IMPORTANT IN THIS - AS NEARLY ALL GRAPHS SHOWN WILL BE LOG SIGMOIDAL GRAPHS
Log question:
-6
10-6M
How to antagonists work?
Bind to the receptor and simply block the binding other ligands (endogenous or exogenous)
By themselves, these drugs do not cause the receptor to do anything – they are ANTAGONISTS
THEY ONLY HAVE AFFINITY
How do agonists work?
Some drugs bind and then activate the receptor – they are agonists
Agonists have affinity PLUS intrinsic efficacy as they can generate/stabilize an active form (shape) of the receptor
R* - represents the active receptor
Agonist has bound to the receptor and caused it to chnage it’s conformation
What is intrinsic efficacy?
Generating the active form of the receptor
Difference between antagonists and agonists?
Agonists have AFFINITY and EFFICACY
Antagonists only have AFFINITY (don’t have efficacy, as they don’t have intrinsic efficacy i.e. don’t change the conformation of the receptor, so don’t make ‘things happen’)
What are the three factors involved in agonism?
Affinity
Intrinsic efficacy
Intrinsic efficacy leading to things happening in the cell (cell/tissue-dependent factors, e.g. number of receptors)
Lock and key analogy for agonists and antagonists
Caution with language when working on the wards -pharmocological efficacy and clinical efficacy
Pharmocological efficacy = i.e. does the drug successfully cause relaxation/dilation
Clinical efficacy = i.e. does the drug cause lowering blood pressure, does it cure a headache, MEASURE OF HOW WELL A TREATMENT IS WORKING
Left box = pharmacological efficacy
Right box = clinical efficacy
Define agonist
• An agonist is a substance that binds to a receptor and activates the receptor to then produce a measurable biological response.
Define 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
Define intrinsic efficacy
Generate the active form of the receptor (R*)
Define ligand efficacy
Cause a measurable biological response
In medicine, (clinical) efficacy relates to a response with therapeutic value
• Without therapeutic value the intervention is not justified !
How is affinity important for a herion overdose? What drug is used?
morphine or heroin (agonists of µ-opioid receptors) overdose -> respiratory depression -> death
naloxone used to treat overdose - high affinity antagonist of µ-opioid receptors (GPCRs) - out-competes opioid
What fentanyl?
fentanyl driving opioid crisis
- very high affinity agonist
- naloxone ineffective
naloxone has a much lower affinity compared to fentanyl, so naloxone will be ineffective
Concentration-response curve, what can be derived?
Emax
Emax = Emax is the maximal effect at high drug concentrations when all the receptors are occupied by the drug
EC50
Effective concentration giving 50% of the maximal response. Also known as drug POTENCY.
A ligand curve that is more potent will be more to the…
Left
Concentration and dose - difference
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
Define intrinsic efficacy
Degree at which a lignad enables the receptor to conformationally change to create an active receptor and cause things to happen
MUST GO THROUGH AND TRY AND ANSWER GROUP WORK QUESTIONS
