SN4 - Pharmacodynamics Flashcards
Define pharmacodynamics
What the drug does to the body - the mechanism of action,
Mechanisms of actions of drugs - name 2
Specific: Specific molecular targets - low doses (most drugs)
Non specific: most drugs at high doses. (not binding to specific targets) eg bicarb
Name some drugs that don’t bind to specific targets
- Osmotic drugs laxatives, diuretics
- Buffers
- Oxidants
- reducing agents
- chelating agents
What is the pharmacological dogma
Most drugs interact with specific molecular targets to induce biological response - mutual recognition
Name 6 receptor properties
- sensitivity
- selectivity
- specificity - depends on the cell where it is
- saturability
- pharmacological profile
- correlation between receptor binding and biological activity
Receptor sensitivity
- High binding affinity (often pico molar). if micro molar it’s not to a receptor
- signal amplification is needed
Slope of a curve with higher affinity will be?
Steeper
To get affinity you use?
Km which is half the Kmax
Lower Km means?
Higher affinity (need less of it to bind)
What are the two parameters you can measure from dose response curve?
Potency - sensitivity of organ or tissue to drug - dose dependent
Efficacy - maximal effect induced by a certain drug - dose independent
2 kinds of dose-effect response curves
Gradual - usual curve - one person - correlates dose to effect intensity
Cumulative - population . group - correlates to effect frequency
How do we assess potency on a dose response curve
Look at ED50 - dose that gives 50% of the effect
3 features that makes log scale dose response curve more convenient
1 - much wider dose interval
- ED50 and potency is at inflection point so immediately you realise potency value
- central portion is a straight line - easier to understand
Agonist define
drug that act on binding a receptor induces a cellular / biological response effect
Antagonist define
drug that on interacting with receptor does not induce any response, but reduces the response induced by co-existing agonist. Indirect effect by interfering with agonist.
Law of mass action
the rate of a reaction is directly proportional to the concentration of the substance
The higher the equilibrium constant K is, the …. the affinity?
Lower
Occupational therapy
Effect is proportional to the concentration of agonist-receptor complexes
Full agonist - define
Every drug that when binding to the receptor produces a maximal effect - intrinsic activity is equal to 1
Partial agonist
every drug that when binding to the same receptor produce less effect than a full agonist, intrinsic activity is between 0 and 1
Why do we need partial agonists clinically
Full agonist may go over the max limit of therapeutic window
Partial agonists differ from FULL agonists in terms of?
EFFICACY (thus in terms of potency they can be opposite - partial agonist can be more potent than full agonist!)
ON a graph, if you don’t see any response, what does this mean?
It is an antagonist!
3 Types of antagonists
- Pharmacological: same receptor! competitive / non competitive (mostly used in Pharma)
- Chemical - no receptor, blocks the ion
- Physiological antagonist (work on different receptors but antagonise each other eg Act vs Adrenaline)
Discuss efficacy and potency of a agonist in the presence of a competitive antagonist. What does it do the the curve?
Less potent but efficacy is the same - meaning you can still achieve the max response but you will need a higher dose.
Shifts the curve to the right
If you use a agonist with a NON competitive antagonist - what happens to curve, efficacy and potency
The curve will lower indicating reduced efficacy - potency we would need to calculate
Competitive inhibition:
Where does the antagonist bind on receptor?
Discuss affinity and concentration here
Ortosteric - meaning same site as agonist
The drug with the highest affinity for the site will win, also the concentration is important. You can displace antagonist with higher concentration of agonist
Non competitive inhibition:
Where does it bind, can you overcome it?
allo = different site
Changes the active site, so agonist binds less
Here to get a full response you have to wait until antagonist goes way.
Reversible (surmountable) antagonist - what does it do to the dose response curve?
To the right (decreasing agonist potency) - but does not normally affect maximal effect
Irreversible antagonist - what does it do to the dose response curve?
Shift the curve to the right in non parallel manner (potency is not modified), but DECREASES EFFICACY /maximal effect
Partial agonist in presence of a full agonist can act like a?
Competitive antagonist
What is an inverse agonist
For example with GABA A - binding causes inhibition - so we use Benzodiazepines (agonist which binds allosterically to receptor increasing effect of GABA). But some substances binding to the same site can cause the OPPOSITE EFFECTS = Beta-carbolines = convulsions
Flumazenil = binds to the same site = competitive antagonist (its an antidote to benzodiazepines intoxication). Inverse agonists are found only for CONSTITUTIVE activity.
What is constitutive receptor activity and what helped us discover it?
it means the receptor signals in the absence of an agonist (spontaneous activity). Thus the binding to receptor can either increase or decrease the spontaneous activity. (because remember if activity is zero it can only go up). Efficacy is vectorial, it can go up and down.
How can a receptor signal by itself
Protein structure is dynamic, eventually it can find an active confirmation in the absence of agonist. Mutations also occur
Spare receptors:
the receptor ocupancy curve is to the right of the response curve - the organ is more sensitive (common in hormones)
Post receptor elements
Shifts the curve to the LEFT
Therapeutic index of a drug
DT50 (toxic) / DE50 (therapeutic)
A good index is necessary for a general drug. Say penicillin is 100, you can increase dose 100 fold before toxic effect is seen.
2 locations of receptor
Cytosol
Nucleus
4 types of receptors
inotropic metabotropic enzymatic - tyrosine kinase all above are membrane bound intracellular - function is always to control gene transcription
All intracellular receptors are mediated by
gene transcription
Muscular nicotinic -channel components
2 alpha, beta gamma
Neuronal nicotinic - channel components
2 x Alpha 3 x beta
nicotine acts by stimulating mostly
NEURONAL NICOTINIC receptors (so NOT nicotinic muscular!)
The stimulus to poop after smoking is due to:
nicotinic receptors in periphery response, does not act on the muscle, acts on the neurons - stimulates peristalsis.
GABA A receptor - describe
ionotropic - pentamer of 5 proteins, 5 subunits,
2 alpha, 2 beta, 1 gamma - but many different forms of each of these subunits.
controls the flux of CHLORIDE ions, negative charge = hyperpolarisation = inhibition.
(ethanol, anaesthetic, benzo)
Benzodiazepine and Phenobarbitals effect on GABA receptor
Benzo: channels open more frequently
Pheno (barbituate): increases the time not frequency that the channel is open
Explains why barbiturates are so dangerous, response depends on concentration. BUT benzodiazepines have an upper limit, when GABA is at max, benzo won’t do more.
2 kinds of metabotropic receptors
1 regulating activity of enzyme
2. ion channel - regulate the opening and closing
G protein coupled receptors -discuss similarity between all of them and difference
ALL OF THEM: ALWAYS a single protein = always 7TMD Carboxy inside, N outside.
Difference between them:
is in the loops and terminal domains.
What are the functions of 7TM receptors?
Mediate sense perceptions :
sight, smell taste
Discuss G proteins structure
G protein is not a single protein - it is a trimer consisting of 3 subunits:
Alpha, Beta, Gamma. Activated by binding of GDP / GTP. The G-protein is much bigger than its receptor.
Which subunits changes GTP to GDP?
Alpha subunit. Beta gamma unit stays together. cos their loops are intertwined.
Beta is very small - has a propeller structure = stability
Most metabotropic receptors are?
dimeric - 2 receptors on one G protein.
Discuss dual regulation of adenyl cyclase?
enzyme can be stimulated by receptors coupled to both Gi and Gs - amount of cAMP is dictated by the amount of inhibition / stimulation
Discuss the conformation of Protein Kinase PKA
cAMP dependent kinase, 4 proteins, 2 regulatory, 2 catalytic. Camp binding causes catalytic sites to dissociate and they can then phosphorylate proteins.
What breaks down camp
phosphodiesterase
3 families of protein kinases stimulated by
cAMP
Ca++ and DAG
Ca=Calmodulin complex
base vasodilation and contraction on 2nd messengers
vasodilation (camp)
Contraction - Phospholipase c
2 ways you can regulate a response
- Increase function of receptor - sensitisation / upregulation
- decrease response - desensitisation / down regulation
Discuss difference between desensitisation and downregulation.
desensitisation - repeated stimulation causes decreased response - seconds to minutes
downregulation - over hours
Ways to downregulate:
Inducer of metabolic enzymes - reduce effect of drug quicker. Pharmacokinetic tolerance
What is pharmacological / receptor mediated tolerance
Downregulation caused by giving drug multiple times
Name 2 kinds of receptor desensitisation (ologous)
- Homologous - only the receptor stimulated is desensitised (phosphorylated) - once phosphorylated ARRESTINS can bind - endocytosis.
- Heterologous - when other receptors are phosphorylated and desensitised too
Discuss the Arrestin pathway in desensitisation
Once receptor is desensitised via phosphorylation, arrestins bind, endocytosed
- receptor can dephophorylate and go to membrane and be restored = RECEPTOR RECYCLING
- alternative pathway - lysosome fusion and degradation
What is pleuridimensional efficacy?
different responses due to different elements. We can have biased ligands.
What is a biased ligand -
ligands that selectively activate or block only certain signalling pathways coupled by GPCR
2 responses can happen when agonist binds a receptor
- cascade and cell response
2. beta arrestin - desensitisation
3 things that the beta arrestin does once bound
- desensitisation (steric hindrance due to binding)
- scaffold formed for many different proteins and cascades.
- internalising
Describe the beta arrestin protein
cytosolic protein that binds to phosphorylated receptors. When not bound normally has a buried C terminus, but when bound exposes C terminus so other proteins can bind
Biased ligand binds in which manner
Allosterically
Acute heart failure is characterised by
low cardiac output
normal or elevated BP
elevated RAAS system
Vicious cycle.
Which of the opiod receptors are responsible for respiratory depression
mu
Discuss GPCR oligomerisation
can form dimers or oligomers:
- homooligomers - all the same
- heterooligomers - all different
Gaba B receptor - discuss the type and 2 forms, and how it functions
GABA B receptor 1 is METABOTROPIC (GABA A is ionotrophic):
GBR1 - stays in ER
GBR2 - reaches membrane but doesn’t respond
2 brings 1 to membrane, can function only as a dimer.
Heteroreceptor as it has 2 different receptors.
How do GABA B1/2 form dimers? 3 ways
- disulphide bond formation
- coiled coil interaction
- transmembrane interaction
What is the point of GPCR dimerisation
- essential to bring to surface of cell (receptor maturation
- response
- pharmacological diversity - different drugs can act on both receptors or a drug can activate both
What is a Janus molecule
Bivalent ligand:
- peptide - long enough to bind both at same time
- 2 headed drug with a chain - spacer needs to be precise.
Discuss a enzymatic receptor - name, what they work on and mechanism
Tyrosine-kinase receptors - for growth factors and insulin, dimers that only form once ligands bind = activated.
tyrosine kinase autophosphorylate (opposite tails) serving then as a scaffold for a host of other signalling proteins - final response is GENE TRANSCRIPTION.
