Neuropharmacology Flashcards
What are the roles of the proteins found in the pre-synaptic and post-synaptic complexes?
- Neurotransmitter release
- Activation of receptor
- Action potential propagation
What are the receptors on the post-synaptic membrane at an excitatory synapse for glutamate?
AMPA
NMDA
What is a neurotransmitter?
A chemical substance that:
- Is synthesised, stored, and released from neurons
- Activates receptors to produce an effect on the post-synaptic cell
- Has its action terminated
Why are neurotransmitters important?
- Control behaviour
- Target for drug therapies
What are Inotropic Neurotransmitter Receptors?
- Ligand gated ion channels
- Fast neurotransmission
What does an inhibitory Inotropic Neurotransmitter Receptor do?
Neurotransmitter causes chloride influx and hyperpolarisation
What does an excitatory Inotropic Neurotransmitter Receptor do?
Neurotransmitter causes sodium influx and depolarisation
What are the types of neurotransmitter receptors at the post-synaptic membrane?
- Inotropic
- Metabotropic
What are Metabotropic Neurotransmitter Receptors?
- Induction of second messenger systems
- Slow neurotransmission neuromodulation
Describe second messenger systems
- Receptor coupled to G-protein
- Activates intracellular enzyme systems to produce an intracellular signal, the second messenger
- Affects often ion channels
What are the classes of neurotransmitters?
- Amino acids
- Biogenic Amines
- Peptides
- Others
What are the amino acid neurotransmitters?
- Glutamate
- GABA
What are the Biogenic Amines neurotransmitters?
- Acetylcholine
- Monoamines
What are the monoamines?
- Serotonin
- Catecholamines
What are the catcholamines?
- Dopamine
- Noradrenaline/ norepinephrine
- Adrenaline/ Epinephrine
What are the peptide neurotransmitters?
Substance P
What are the other neurotransmitters?
ATP
Nitric Oxide
(short acting)
What are agonists?
Drugs that occupy the receptors and activate them
What are antagonists?
Drugs that occupy the receptors but do not activate them. Block the receptor activation by agonists
What are the pathways that use glutamate?
- Cortical association
- Cortico-thalamic
- Cortico-spinal
- Basal ganglia
- Hippocampal
- Cerebellar
Describe glutamate
- Excitatory neurotransmitter
- Synthesised from glutamine in astrocytes in pre-synaptic neurone
- Removed from synapse by glutamate transporters
What are the subtypes of glutamate receptor?
- NMDA
- AMPA and Kainate
- Metabotropic
How can glutamate be an excitotoxin?
- High levels of glutamate, NMDA or AMPA kill neurons (sustained activation of receptors)
- Glutamate levels rise following stroke
- Glutamate receptor antagonists reduce brain damage following experimental stroke
Describe how glutamate is important in memory and learning
- High densities of NMDA and AMPA receptors in the hippocampus
- Role for glutamate receptors in long term potentiation
- Glutamate receptor antagonists inhibit long term potentiation and learning and memory;
- AMPA receptor potentiators enhance LTP and learning and memory
What does GABA stand for?
Gamma aminobutyric acid
What is GABA?
- GABA is the main inhibitory neurotransmitter of the CNS (although in some settings it can be excitatory).
- GABA acts via ionotropic (GABAA) and metabotropic (GABAB) receptors, and modulates flow of Cl- ions across the membrane.
- Some anti-epileptic drugs mimic the effects of GABA or increase bioavailability of GABA (eg gabapentin, vigabatrin)
What are Benzodiazepines?
- GABA inhibitory chloride channel
- Enhance effects of GABA= sedative, anxiolytic, anti-convulsant
What are the sites of the GABA inotropic channel?
- Barbiturate
- Benzodiazepine
- Neurosteroid
- GABA
What is another name for Serotonin?
5-HT (5-hydroxytryptamine)
How is serotonin synthesised?
- Tryptophan
- 5-Hydroxytryptophan
- 5-hydroxytryptamine (serotonin)
How is serotonin metabolised?
Serotonin + monoamine oxidase = 5- Hydroxy indoleacetic acid
What are the types of serotonin receptors?
- 5-HT1 (metabotropic)
- 5-HT2 (metabotropic)
- 5-HT3 (ionotropic
Describe the serotonin pathways/ projections
- Originate in the raphe nuclei in the brainstem
- Project throughout cerebral cortex, cerebellum and limbic system
- Sleep-wake cycles
- Mood and emotional behaviour
How is serotonin important in the management of depression?
- Tricyclic compounds= imipramine, block uptake of serotonin
- Selective Uptake Inhibitors = fluoxetine (Prozac)
- Monoamine Oxidase Inhibitors= phenelzine, reduce enzymatic degradation of serotonin
- serotonin remains in cleft for longer, bioavailability increases
How can the serotonin pathways be used clinically as drug targets?
- Anti-depressants
- Anti-emetics
- Migraine (triptans)
How is Acetylcholine synthesised and metabolised?
- Choline and acetyl CoA
- Broken down by acetylcholinesterase in synaptic cleft
- Choline transported back into axon terminal and used to make more ACh
Describe the ACh pathways in the brain
- Nucleus of maynert
- Amygdala
- Caudate nucleus
- Cerebral cortex
- Hippocampus
- Brainstem nucleus
- Thalamus
What disease is associated with loss of cholinergic pathways?
Alzheimer’s
Reductions particularly in frontal and temporal cortices
-Reduction in ACh transferase activity
What drugs are used in Alzheimer’s and what are the limitations of them?
ACE inhibitors= donepezil, rivastigmine, galantamine, tacrine (first)
- Gradual loss of efficacy
- Narrow therapeutic index
- Limited range of effects on cognition and behaviour
- Effective only in mild to moderate AD= slow symptoms but not curative
What are the classic pathological features of AD?
- Frontal and temporal atrophy
- Beta-amyloid plaques
- Neurofibrillary tangles
- Localised to hippocampus and cortex
What is the Amyloid pathway in AD?
-Amyloid is a component of amyloid precursor protein
=Integral transmembrane protein
=Axonally transported
=Synaptic transmission, neuroprotectant
How is amyloid precursor protein processed in pathways?
- Non amyloidogenic pathway= APP cleaved by a-secretase, products not pathogenic (amyloidogenic)
- Amyloidogenic pathway= cleaved by beta-secretase, gamma-secretase (mixture of enzymes) cleaves one of the APP fragments into amyloidogenic fragment= beta amyloid (accumulates in brain parenchyma in AD)
How do mutations in APP cause fAD?
Familial AD
Rare, account for less than 1%
Approx. 25 mutations
How can beta amyloid be a drug target?
Bapineuzumab
Antibody targeted against amyloid beta (passive immunotherapy)
Might bind to cortical amyloid beta and facilitate clearance
PET Scan
What are the clinical results of beta-amyloid immunisation?
- Reduces amyloid load and prevents cognitive decline in mice
- Reduces amyloid load but no improvement in CNA function in humans
- In the future, better immunisation earlier in disease, target subgroups
Describe dopamine synthesis
Tyrosine (tyrosine hydroxylase) DOPA (dopa decarboxylase) Dopamine
Describe dopamine metabolism
Dopamine (dopamine beta hydroxylase) Noradrenaline / (monoamine oxidase) DOPAC
What are the main pathways in dopaminergic neurotransmission?
Nigrostriatal Projections
Substantia nigra to basal ganglia
Involved in movement
How is dopamine associated with Parkinson’s disease?
- Degeneration of dopamine pathways in the basal ganglia/ substantia nigra
- Treatment by enhancing dopamine levels (L-DOPA)
- Adverse effects= psychosis
Describe the mesolimbic projections in dopaminergic neurotransmission
- Dopamine projections to the limbic system and cortex= reward, addiction
- Increased dopamine function in the frontal cortex associated with schizophrenia
What drugs are used in schizophrenia?
-Neuroleptics
=Chlorpromazine and related antipsychotics
=Dopamine receptor antagonists/ blocker
-Adverse effects= Parkinsonian syndrome
What is the blood brain barrier?
- Blood brain barrier - dynamic interface
- Separates the brain from the circulatory system (endothelium of capillaries and astrocyte foot processes)
- Protects the central nervous system from potentially harmful chemicals
- Regulates transport of essential molecules and maintains a stable environment
What is the role of the blood brain barrier?
Precise regulation of the local ionic microenvironment around axons and synapses is critical for reliable neuronal signalling
What are the cellular components of the BBB?
-Physical barrier – tight junctions on endothelial cells
=Seal aqueous paracellular diffusion between cells
-Pericytes
-Astrocyte end foot processes
What can cross the BBB?
- Lipid soluble agents, aqueous pathways water soluble agents
- Transcellular lipophilic pathways (cell membranes)
- Transport carriers= glucose, amino acids
- Receptor mediated endocytosis and transcytosis= insulin
How are drugs designed to cross the BBB?
- Almost all drugs for the brain presently in clinical practice are lipid soluble small molecules
- Criteria for crossing BBB:
(1) MW <400 Da threshold
(2) high lipid solubility, ie. low hydrogen bonding (≤7 hydrogen bonds)
What are the problems and solutions for how the BBB relates to pharmacological management of Parkinson’s?
-Dopamine too large to cross BBB
=L-Dopa (precursor) will cross via protein transport carrier (large neutral amino acid carrier)
*DOC and COMT inhibitors to prevent peripheral breakdown of levodopa
*MAO inhibitors to prevent breakdown of dopamine
*Dopamine agonists
What is Carbidopa-Levadopa combination therapy?
- L-dopa crosses BBB
- Carbidopa doesn’t cross BBB but helps prevent L-dopa breakdown in periphery
- Carbidopa inhibits DOPA-decarboxylase (DDC in brain and periphery)
What are the ways of drug administration that penetrate the BBB?
-Intrathecal drug administration:
=Baclofen for spasticity in multiple sclerosis
=Only a small proportion of oral baclofen penetrates brain/spinal cord
=Intrathecal pump in subarachnoid space in lower back administers drug directly into CSF
-Experimental BBB opening
=Opening of the BBB using intracarotid infusion of hyperosmolar solutions
=Effective delivery of chemotherapy drugs for brain tumours (metastatic carcinomas)
-Future approaches= Intranasal drug administration, Nanoparticles
