Transmitters Flashcards
Drugs acting on the CNS increase receptor signalling by:
(3)
- Increasing availability of NT
E.g, PD - more pre-cursor supplied (L-DOPA)
E.g., Depression - metabolism / uptake blocked (SSRIs) - Direct receptor activation
E.g., Benzodiazepines for anxiety & epilepsy - Act as antagonists
E.g., Anti-schizophrenic drugs
Why is it hard to target the CNS?
CNS has high connectivity - NTs can have actions at many brain sites
Harder to quantify symptoms
Multiple receptors - drugs need to have functional specificity - (e.g., 5-HT has multiple receptors, some excitatory, some inhibitory, therefore inc receptor signalling by increasing [transmitter] may cause multiple effects)
Receptors up- and down-regulate in response to drugs
Crossing BBB - difficult for drugs based on peptides
What are CNS disorders caused by EXCESS activity?
Chronic pain, epilepsy, anxiety, SCZ
What are CNS disorders caused by reduced activity?
PD, AD, Depression
What is the cause & treatment of EPILEPSY?
Motor disorder caused by uncontrolled neuronal activity due to overactive glutamatergic transmission / reduced GABA function
Treatments:
1. Drugs that block Na+ channels - reducing repetitive neuronal firing
2. Drugs that enhance GABA function (benzodiazepines)
3. Barbiturates (for severe cases) - open Cl- channels causing major inhibition
What is the cause & treatment of SCZ?
Cause: Increased DA function (different to pathways that fail in PD)
Treatment: DA2 receptor antagonist (but too much DA2 antagonism will cause patients to get motor problems like in PD)
What type of disorder is anxiety and how do you treat it?
Mood disorder triggered by external events
Treatment: benzodiazepines / drugs that increase 5-HT receptor function
What are the 2 major types of pain?
Neuropathic & inflammatory
What is the hall mark sign of PD?
Dopaminergic neuronal death of the substantia nigra (nigrostriatal projections) - causing low levels of DA in the basal ganglia
Accumulation of “Lewy Bodies” (alpha synuclein) & tau protein
What are the symptoms of PD?
Symptoms: muscle rigidity, akinesia, resting tremor
Early PD = resting tremor & bradykinesia
Late PD = executive function & memory deficits (correlated with appearance of Lewy bodies) as degeneration spreads
What is the mainstream treatment of PD?
L-DOPA (DA precursor) - can cross the BBB - given with drugs that reduce metabolism of DA & L-DOPA
What are examples of late-stage PD treatments?
Bromocriptine / Pergolide / Ropinirole - D2 agonists
Apomorphine - D1 & D2 agonist
Amantadine - D1 & D2 & others agonist
Domperidone - peripheral D2 antagonist, given as adjunct
The efficacy of L-DOPA in PD treatment depends on what?
Surviving neurones
What are the issues with increasing DA (e.g., in treatment of PD)?
DA can be metabolised into NA - causes undesirable effects (e.g., inc HR)
DA acts at several locations - several effects (not specific)
Where does DA act in the brain?
Nigrostriatal pathway - inc movement (+ve)
Mesolimbic pathway - liking / wanting / addictive behaviour (-ve)
Mesocortical pathway - psychotic effects - SCZ-like symptoms (-ve)
Pituitary - hormonal effects (prolactin) (-ve)
Chemoreceptor trigger zone - causes vomiting
Periphery - DA responsible for urine regulation - inc DA = dec BP
What are adjunct therapies given with L-DOPA to regulate DA metabolism in PD treatment?
Carbidopa / Benzerazide - blocks DOPA decarboxylase - doesn’t cross BBB - reduces peripheral side effects
Selegiline - blocks MAO - prevents DA metabolism - inc [DA] in brain
Entacapone - blocks COMT - prevents DA metabolism - inc [DA] in brain
What are adjunct therapies given with L-DOPA to reduce nausea in PD treatment?
(DA acting at CTZ causes nausea)
Carbidopa / Benzerazide - blocks DOPA decarboxylase - dec peripheral DA
Domperidone - blocks signalling in CTZ - doesn’t cross BBB - stops vomiting
AD is characterised by what?
Extracellular (A-beta) amyloid plaques + intracellular neurofibrillary tangles (tau protein) proceeded by extensive cells death / brain shrinkage
What is the cause of AD?
Neuronal degeneration - particularly ACh pathways
Why can you not use the same treatment strategy as PD in AD (i.e., increasing precursor)?
Due to major role of ACh in autonomic & motor systems
What are the pre-dementia, early & advanced symptoms of AD?
Pre-dementia - short term memory loss & decline in exec function
Early - further decline in short term memory & exec function, some motor deficits (diagnosable here)
Advanced - long-term memory impairment, procedural memories also affected (hallucinations / lose ability to perform basic tasks)
What are the treatment strategies for AD?
AChE inhibitors (e.g., Donepezil, Rivastigmine, Galantimine)
Memantine
Aducanumab
What are the side effects of AChE inhibitors in the treatment of AD?
*Symptomatic treatment - very limited therapeutic efficacy + several side effects:
Fatigue, insomnia, hallucinations, muscle cramps
What is the mechanism of action of Memantine in AD treatment?
NMDA receptor inhibitor
*Mechanisms unclear, limited efficacy + several side effects
What is the mechanism of Aducanumab (AD treatment)?
Anti-amyloid antibody recently approved
Limited efficacy & side effects (inc. brain swelling & bleeding)
What is the treatment strategy for depression?
Block of re-uptake / metabolism of NA & 5-HT (MA NTs critical for mood regulation) - to inc synaptic levels
Draw the basal ganglia circuitry
Effect of dopaminergic neuronal death in SN in PD
• Neurones from the substantia nigra pars compacta travel to the striatum via the nigrostriatal pathway and can modulate the activity of the indirect pathway through DA release in the striatum. This is thought to inhibit the indirect pathway facilitating movement. This is thought to be one reason by DA depletion in PD can lead to difficulties initiating movement.
• DA increases motor activity by inhibiting the indirect pathway and exciting the direct pathway. In PD many DA neurones lost – less activation of direct pathway + more activation of indirect pathway – tremor may result from reduced D2-mediated inhibition of striatal cholinergic neurones
Pain
• Acute pain involves activation of nociceptors on peripheral C-fibres – but once tissue damage & inflammation occurs, peripheral actions of prostanoids, bradykinin, 5-HT etc play a major role in sensitisation and activation of C-fibres.
o NSAIDs (aspirin & ibuprofen) act to block actions of prostanoids at injury site
o Local anaesthetics block Na+ channels – reduce firing of pain fibres
• Very brief acute pain is transmitted via AMPA receptors
o If peripheral stimulus continues, peptides released from C-fibres that enable spinal NMDA receptor activation – giving rise to central states of hyperexcitability which are of major importance to many pain states.
• Morphine action the mu opioid receptor (receptor for endogenous opioid peptides), as do most clinically used opioid drugs.
What are the Glutamate receptors ?
Postsynaptic ionotrophic AMPA & NMDA
Presynaptic ionotrophic Kainate & metabotrophic mGlu(1-8)
What is the uptake transporter and elimination mechanism for each of the monoamines?
DA - taken up by DAT
NA - taken up by NAT
5-HT - taken up by SERT
All broken down by MAO + COMT
How is glutamate synthesised?
General metabolism
How is GABA synthesised?
From glutamate via glutamate decarboxylase
How is ACh synthesised?
From acetyl coA + choline
How is DA synthesised?
From tyrosine via tyrosine hydroxylase & dopa decarboxylase
How is NA synthesised?
From DA by DA-beta-hydroxylase
How is 5-HT synthesised?
From tryptophan
Where is ACh produced?
Medial septal nuclei
Basal nucleus of Meynert
Pontemesencephalotegmental complex
Where is DA produced?
Substantia nigra
Ventral tegmental area
Where is NA produced?
Locus coeruleus
Where is 5-HT produced?
Raphe nuclei (in brainstem)
