Pharmacodynamics Flashcards
Define pharmacodynamics.
Drug action at the molecular level.
There are 4 classes of endogenous protein that drugs act on to mimic or influence NTs. What are they?
- Enzymes
- Receptors
- Transporters
- Ion channels
What is Kd?
The disassociation constant.
What does Kd tell us?
The concentration of drug required to fill 50% of the receptor sites at equilibrium.
Thus if a drug has a low Kd value, what does it tell us?
The drug has a high affinity for its receptor, as a low concentration is needed to fill 50% of the receptor sites.
What are dose-response curves used to show?
Drug potency.
Define potency.
The ‘strength’ of a drug, essentially how efficiently it acts on its target
What is potency measured by?
ED50.
Define ED50.
The concentration of a drug required to produce 50% of the maximal response.
If a drug is a partial agonist, but has a low Kd and low ED50 value, can it produce a maximal response?
No: even with high affinity and high potency a partial agonist can never produce a maximal response.
With ligand-gated ion channels, the NT is the ligand. Describe the binding between the ligand and receptor.
It is weak, non-covalent association. Thus it is reversible, with rapid association and disassociation.
Why do ligand-gated ion channels produce such fast responses?
Because the receptor IS the effector.
Ligand-gated ion channels are monomeric and extrinsic. True or false?
False: they are multimeric and intrinsic.
There are 3 classes of ligand-gated receptors. What are they?
- Nicotinic
- Glutamate receptors
- GABA receptors
a) which NT binds nicotinic receptors?
b) Describe what happens when this NT binds the receptor.
a) ACh
b) Causes a conformational change that allows Na+ to flood into the cell, producing an excitatory response.
Describe what happens when glutamate binds its ligand-gated receptor.
Makes the cell permeable to Na+. This is the fastest mode of excitation (does not involve shape change).
a) Which GABA receptor is the ligand-gated ion channel?
b) Describe what happens when glutamate binds this receptor.
a) GABA-A
b) Causes a conformational change that causes Cl- to flood in, causing an inhibitory response
Which drugs target GABA-A receptors in the treatment of anxiety?
Benzodiazepines: they cause hypnotic, sedative, relaxant effects
Nicotinic and GABA-A receptors are from the same receptor superfamily. Which superfamily is this?
The Cys-loop ligand-gated channel family
Why are metabotropic receptors so slow?
They involve second messengers that activate ligand-gated ion channels.
What is another name for metabotropic receptors and why?
GPCRs or G-protein coupled receptors: G-proteins are the second messengers.
What happens to GPCRs when a ligand (NT) binds?
G-proteins are activated that act on a wide range of receptors.
Describe what happens in G-protein activation.
GDP is bound to the alpha-subunit. This is phosphorylated to form GTP. Energy from phosphorylation activates the G-proteins. GTP is then hydrolysed back to GDP.
Why can a single ligand binding a GPCR cause a huge response?
G-protein activation is a continuous cycle, so the effect of ligand binding is self-perpetuating.
There are 7 transmembrane domains in a GPCR. These can act as independent monomers. True or false?
True.
What is the a) extracellular and b) intracellular terminus of a GPCR?
a) Amino group
b) Carboxyl group
There are 4 types of metabotropic receptor. What are they and what do they do?
- Gs = stimulatory, these increase NT release.
- Gi = inhibitory, these decrease NT release
- Gq = activates phospholipase C
- G12/13 = involved in cellular function
How are Gs GPCRs stimulatory?
They activate adenylate cyclase.
Adenylate cyclase increases ATP hydrolysis.
This increases the levels of cAMP.
cAMP activates PKA.
Why can the effects of Gs stimulation be long-lasting?
The catalytic subunit of PKA (5L) translocates to the nucleus and initiates gene transcription. This is involved in long-term memory.
PKA has numerous effects. List some.
Involved in lipid, glycogen and glucose metabolism.
Involved in reward in the nucleus accumbens.
Gs receptors are in a constant state of equilibrium. Even without the presence of NTs some are synthesising cAMP. Where does the equilibrium lie under normal conditions?
In favour of the receptors not producing cAMP.
There are 3 ways in which drugs can affect Gs receptors. What are they?
- Agonists: bind the receptors producing cAMP and shift the equilibrium in their favour.
- Inverse agonists: binds the receptors not producing cAMP and shifts the equilibrium in their favour.
- Antagonists: binds the receptors but cause no change to cAMP levels as antagonists do not cause a biological change.
Gq is a lithium target. This is used to treat which disorders?
Bipolar and mania.
G12/13 is involved in cellular processes. Which ones?
Proliferation, migration, embryogenesis and apoptosis.
