IC4 Neuropharmacology Flashcards
Pharmacology is concerned with the changes in ___, ___, and ____ of the body, brought about by chemical substances
Pharmacology is concerned with the changes in function (physiology), structure (anatomy), and chemical properties (biochemical properties) of the body, brought about by chemical substances
[Neurochemistry]
Taking a cholinergic synapse,
What enzyme is involved in acetylcholine synthesis?
ChAT (Choline acetyltransferase)
- catalyzes synthesis of acetylcholine from choline + acetyl-CoA
[Neurochemistry]
Taking a cholinergic synapse,
What are the transporters involved?
VAChT (vesicular acetylcholine transporter)
- transport acetylcholine into synaptic vesicles
SDHACU (sodium dependent high affinity choline utake)
- reuptake transporter; choline uptake from synaptic cleft back into presynaptic cholinergic neurons
[Neurochemistry]
Taking a cholinergic synapse,
What are the receptors involved?
Presynaptic autoreceptors (e.g., m2 muscarinic receptors)
- feedback regulation, to prevent excessive amount of acetylcholine, inhibit further neurotransmitter release
Postsynaptic receptors
- activate signaling pathways on dedrite/soma
GPCR and ion channels (types of pre/postsynaptic receptors)
- GPCR (mAChR = muscarinic) => second messenger activity
- Ion channels (nAChR = nicotinic) => depolarization; propagation of action potential
[Neurochemistry]
Taking a cholinergic synapse,
How is acetylcholine broken down?
AChE (acetylcholinesterase)
- breaks down acetylcholine, choline can be reuptake by SDHACU transporter
[Neurotransmitters]
Glutamate
- Main transmitter in excitatory synapses
- Implicated in learning and memory
[Neurotransmitters]
GABA
- Major transmitter in inhibitory synapses
- Receptors are important drug targets for sedatives (e.g., benzodiazepines)
[Neurotransmitters]
Acetylcholine
- Involved in learning, arousal, reward
- NMJ
- Implicated in Alzheimer’s disease (deficit in acetylcholine)
[Neurotransmitters]
Dopamine
- Involved in motor system, reward
- Implicated in Parkinson’s (deficit in dopamine)
- Major source: substantial nigra in basal ganglia
[Potential drug targets in synaptic transmission]
What are some ways to improve agonistic drug effects (excitatory)? 6
- Increase the synthesis of neurotransmitter molecules (e.g., by increasing the amount of precursor)
- Destroy degrading enzymes to increase the number of neurotransmitter molecules
- Increase release of neurotransmitter molecules (e.g., increase calcium influx?)
- Bind to autoreceptors to block their inhibitory feedback regulation effect
- Bind to postsynaptic receptors to activate and increase the effect of neurotransmitters
- Block deactivation of neurotransmitter molecules (e.g., block degradation, block reuptake)
[Potential drug targets in synaptic transmission]
What are some ways to enhance antagonistic drug effects (inhibitory)? 5
- Block synthesis of neurotransmitter molecules (e.g., destroy synthesizing enzyme, choline acetyltransferase)
- Cause neurotransmitter molecules to leak from the vesicles, and be destroyed by degrading enzymes
- Block release of neurotransmitter
- Activate autoreceptors to inhibit further neurotransmitter release
- Bind to postsynaptic receptor to block the effects of neurotransmitter
[BBB considerations]
Functions of the BBB
- Modulation of the entry of metabolic substance (e.g., glucose - fundamental source of energy for neurons)
- Control of ion movements (Na+K+ATPase), pumps sodium into CSF, pumps K+ out of CSF into blood
- Prevention of access to the CNS by toxins and by peripheral neurotransmitters
[BBB considerations]
Non-saturable transport across BBB
Non-saturable: transmembrane diffusion
- Most drugs with low MW and high lipid solubility and diffuse across the membrane
Considerations
- MW <500Da (Lipinski’s)
- Lipid solubility (too high => sequestered in capillary bed, uptake by peripheral tissues)
- Charge
- Tertiary structure
- Protein binding
- PGP expression - PGP blocks the brain uptake of PGP substrates
[BBB considerations]
Saturable transport across BBB
Saturable: transporter system (rate of uptake is dependent on number of transporters)
- Rate of uptake across BBB around >10x transmembrane diffusion
- Rate of uptake across BBB regulated by cerebral bloodflow, co-factors, hormones, peptide modulators
- Specific regions of brain express transporters for regulatory molecules (e.g., L-dopa, Vit B12)
- Efflux transpoters decrease uptake of drugs (e.g., PGP)
[BBB considerations]
How might disease state affect penetration across BBB into CNS?
Neuroinflammation (e.g., meningitis) causes BBB to become leaky, thereby facilitating drug penetration across BBB
=> Uncoupling between BBB functions and CNS needs
