Module 1: Principle Of Pharmacology Flashcards
What is. Pharmacology?
The study of drugs and poisons
What is a drug?
Any substance used to exert a biological effect
What impacts the ease & rate of uptake of drug into the body?
The route of administration (ie oral, IV, etc)
The absorption
What are the 2 main tissue reservoirs?
Body fat
Blood proteins
What are the 2 main divisions of pharmacology?
Pharmacokinetics (movement around the body)
Pharmacodynamics (examination of drug interactions)
What is specificity and selectivity?
Specificity - drug having a single action at a tissue or organism level
Selectivity - ability of drug to affect one type of cell above others
What is an agonist?
Activator, Causes a shape change in the receptor.
Can be true agonist, partial agonist OR inverse agonist (causes a shape change AWAY from the active conformation)
In they key/lock metaphor - the agonist is the key that opens the lock
What is affinity?
Ability of drug to bind receptor.
Occupation is governed by affinity
What is efficacy?
Ability to activate receptor to elicit effect. (Only agonists have efficacy)
Activation is governed by efficacy
What is potency?
Range of concentrations required to have an impact
What is biased agonism?
Where different agonists can bind to the same receptor but cause different responses.
In other words, the shape change induced by the agonist can favour one signalling cascade over another
What are the 2 possible mechanisms for action of partial agonists?
- That the partial agonist only elicits a partial conformational change
- That the partial agonist elicits a full conformational change, but not all of the time
What is an inverse agonist?
Drug that interacts with a receptor to create a non-active conformational change. So it IS still a shape change, but in the opposite direction to the active form.
What is an antagonist?
An anti-agonist - it prevents the action of an agonist. It can bind to a receptor but not change it’s conformation.
It has affinity, potency but does not have efficacy
What are the 3 main categories of antagonist?
- Competitive antagonist (competes against agonist for same site on receptor)
- non-competitive antagonist (ie straight jacket when trying to raise your arm - binds to a different site on the receptor that stops the agonist)
- irreversible antagonist (binds to same site on receptor, but can’t be removed)
What is the difference between Antagonist and antagonism?
Antagonist is the compound
Antagonism is the process
What is chemical antagonism?
An agonist itself becomes chemically bound to a chemical antagonist (ie bind to the agonist rather than receptor)
What is pharmacokinetic antagonism?
Changing the agonist half-life in the body by promoting elimination or altering its distribution/uptake
What is physiological antagonism?
Competition between 2 opposing systems in the body, ie when 2 drugs administered that affect opposing systems and effects cancel out.
What is the purpose of a receptor?
To translate an incoming signal into a cellular response
What are the primary groupings of receptors?
Ionotropic (ion channels)
Metabotropic (rely on metabolic event)
Kinase linked receptors
Nuclear receptors
What response scales can you expect with ionotropic and metabotropic receptors?
ionotropic - milliseconds
Metabotropic - seconds
How do ligand-gated Ion Channels avoid accidental activation?
It will often require 2 simultaneous events to activate the channel (ie binding of 2 ligand molecules)
Where are ligand-gated ion channels located?
In electrically excitable cells (ie heart, brain, nerves, skeletal muscles)
What effects can ligand-gated ion channels cause in a cell?
A change in membrane potential of the cell - can have a flow on effect on voltage-gated ion channels.
Either stimulators (influx of + ions) = depolarisation
Or Inhibitory (influx of - ions) = hyperpolarisation
What are GPCRs?
G Protein coupled receptors
what category of receptor does GPCR fall into?
Metabotropic
What is the basic structure of GPCRs?
- 7 transmembrane domains (can form a circle for binding pocket to nestle into)
- Extracellular N terminus
- Intracellular C terminus
The 3rd intracellular loop and the C terminal tail shift their position and act like “chopsticks” to “pick up” the G protein
What is a PAR and what type of receptor is it? And what is it’s role?
Protease-activated receptor. It is a type of GPCR. This is the “smoke alarm” warning system of the cell.
How are PARs different from other types of GPCRs?
Same basic structure, but it has a tethered ligand that is cleaved to activate the receptor. This means they are “1 use only”
What are 3 new GPCR types?
Proton-sensing and lysolipid-sensitive G protein coupled receptors
- activated by protons or lipids
- associated with cancer
Calcium-sensing receptors
- important role in suppressing parathyroid hormone secretion
What are G proteins?
Heterotrimeric compounds composed of α, β and γ proteins in combination. They interact with GPCRs.
How does the G protein α subunit activity differ from the β and γ subunits?
the α subunit is a GTPase. At rest it is bound with GDP, then when activated (binds with GTP instead), the GPCR receptor is activated and can interact with G protein.
The enzyme part of α subunit can then cleave a phosphate to become GDP again (inactive form).
Different types of α subunits have different effects on adenylate cyclise activity (activate or inhibit)
What is the action of β-γ subunits of G proteins?
- acts as signalling molecules once liberated from α subunit
- appears to always function together
What are the steps of G protein signalling?
- GPCR inactive. G protein subunits together, α subunit bound to GDP.
- GPCT receptor activated by ligand, conformational change in positioning of 3rd intracellular loop & C terminus tail allowing interaction with G protein. α subunit exchanges GDP for GTP and dissociates from βγ.
- Both α and βγ active at specific target effectors.
- α subunit cleaves phosphate to reform GDP, collapses in and rejoin βγ to form G protein again.
What are RGSs and what is their job?
Regulators of G-protein signalling.
Their job is to regulate α subunit activity
What are the 3 types of RGS?
- GAPs (GTPase-Activating Proteins)
- promotes enzyme of activity to turn GTP to GDP which reduces action time of α. - GEFs (Guanine Nucleotide Exchange Factors)
- encourages α subunit to drop GDP and uptake GTP, increases signalling of α. - GDIs (Guanine Nucleotide Dissociation Inhibitors)
- prevents activation of G proteins
What is the impact of RGSs?
- some neurodegenerative disorders associated with alterations to these
- represent targets for drugs
- activity of some poisons require inactivation of these
- cancers proposed to include mutations of these
Why is cAMP important?
It regulates many proteins either directly or through activation of PKA
What is cAMP
Cyclic AMP - made by adenylate cyclase from ATP
What is the activity of a protein kinase?
Moving phosphate molecules. As a result, critical to kinase cascades
What are RTKs
Receptor tyrosine kinase
What is the key summary of RTK activity?
Monomers form dimer Dimer self phosphorylation That attracts other proteins They get phosphorylated They trigger cascades Really important for gene transcription
What is special about nuclear and cytoplasmic receptor transcription factors?
They are a receptor and also a transcription factor (rather than being a receptor that then activates a separate transcription factor)
What are the classes of nuclear receptors?
Class I - move from cytoplasm into the nucleus, homodimer
hybrid class - nucleus only, heterodimer with retinoid receptor
Class II - nucleus only, heterodimer for all except retinoid receptor
What are the 2 phases of gene transcription from nuclear receptors?
Primary response - direct regulation of small number of genes, within 30min
Secondary response - gene transcribed in primary response are transcription factors that transcribe additional genes
What are 2 primary types of signalling?
Neuronal - punctual & rapid
Hormonal - can have a short-lived signal with long-lived response
What is desensitisation?
Loss of sensitivity of a receptor to continuing stimulation by agonist.
Loss of response due to ongoing treatment with a drug.
What is arrestin and what does it do?
A compound that can recognise receptors that have gone through repeated cycles of phosphorylation/dephosphorylation. It binds and removes the receptor from the membrane.
This is in the process of homologous desensitisation.
What is homologous and heterozygous desensitisation?
Homologous: only the receptor that is in a constantly-activated state is regulated
Heterologous: All receptors of a certain type are regulated (whether activated or not)
What is remodelling?
Process by which cells adapt to continued presence of a drug to change the response of the entire network or organ
