Applied Neuropharmacology Flashcards
Describe a synaptic transmission - Ca2+ dependant exocytosis
Synthesis and packing of neurotransmitter in presynaptic terminals
Na action potential reaches terminal
Activates voltage gated Ca channels which triggers the exocytosis of pre-packaged vesicles of transmitter
Describe synapse transmission after Ca dependant exocytosis
Transmitter diffuses across cleft and binds to ionotropic and/or metabotropic receptors to evoke postsynaptic response
Presynaptic auto receptors inhibit further transmitter release
Transmitter inactivated by uptake into glia or neurons
Transmitter metabolised within cells
What are some ways which there can be pharmacological manipulation to reduce synaptic transmission?
Block voltage gated Na channels
Inhibit synthesis an packaging of neurotransmitter
Activate presynaptic inhibitory receptors
Block postsynaptic responses
Block voltage gated Ca channels
Increase breakdown of neurotransmitter
Block release machinery
Increase uptake of transmitter
What is an example of a pharmacological agent which blocks voltage gated Na channels?
Local anaesthetic
What is an example of a pharmacological agent which blocks release machinery?
Botulinum
What are some pharmacological manipulations to potentiate synaptic transmission?
Block uptake of transmission - SSRI
Block breakdown of transmitter - anti-cholinesterase
Potentiate effects of transmitter on receptor
Activate postsynaptic receptors with an agonist
Increase synthesis and packaging of neurotransmitter
What are some neurotransmitters?
Acetylcholine
Monoamines - NA, dopamine, serotonin
Amino acids - glutamate, GABA, Glycine
Purine - ATP and adenosine
Neuropeptides - endorphins, CCK, Substance P
NO
Does neurotransmitters have one or multiple functions?
Multiple as minimal range of neurotransmitters
Often have function in brain and PNS separated by BBB
What does each neurotransmitter have?
Own anatomical distribution, own range of receptors it acts on, and own range of function in different regions
Where is the anatomical distribution of dopamine in the brain?
Brainstem
Basal ganglia
Limbic region and frontal cortex
What are the physiological effects of dopamine?
Voluntary movement
Emotions and reward
Vomiting
Acts on tubero-infundibular pathway
What is Parkinson’s disease?
Degeneration of DA cells in the SN
Dopamine deficiency in basal ganglia
How is dopamine synthesised?
From glycine - tyrosine - DOPA to dopamine
How can DA synthesis be modulated in vivo?
Can give injection of DOPA to increase DA but has side effects in periphery
This increases DA in BBB
Need to pharmacologically block AAAD so dopamine isn’t increased in periphery and stops unwanted side effects
Describe dopamine receptors
No ionotropic receptors
5 subtypes of metabotropic receptors D1-5
Depending on which receptors - different effects and regions of brain effected
What are the key enzymes in dopamine metabolic breakdown?
Monoamine oxidase B - MAO-B
catechol-O-methyltransferase - COMT
What is dopamine metabolised into?
Homovanillic acid
What are the symptoms of Parkinson’s disease?
Stiffness, slow movements, change in posture and tremor
What is a DA precursor drug?
Levodopa
What are some DA agonist drugs?
Ergots - no loner used, bromocriptine
Non-ergots - ropinirole, pramipexole, rotigotine
Apomorphine
What are some enzyme inhibitors used for PD?
Peripheral AAAD inhibitors - carbidopa, benserazide
MOAB inhibitors - selegiline, rasagiline, safinamide
COMT inhibitors - entacapone, opicapone
What is the function of peripheral AAAD inhibitors?
Decrease peripheral side effects of levodopa and slows greater proportion of oral dose to reach the CNS
What is the function of MOAB and COMT inhibitors?
Decreases metabolism of dopamine and increases effectiveness of levodopa
What is given with levadopa?
Carbidopa or Benserazide to decrease peripheral side effects
COMT inhibitor to decrease DA metabolism
What can worsen or be caused by dopaminergic drugs?
Nausea, vomiting, psychosis, impulsivity/ abnormal behaviours
What does dopaminergic drugs help improve?
Some motor features of PD
Limb rigidity, bradykinesia and tremor
What does dopaminergic drugs fail to help in PD?
Midline features
Dysarthria, balance and cognition
What does dopamine antagonists improve and worsen?
Improves nausea, vomiting, and psychosis
Worsens parkinsonism
Describe DA antagonists antiemetics and vomiting
Worsens PD and should not be given
The vomiting centre in medulla is outside the BBB - need a DA antagonist that dosen’t cross the BBB - domperidone
What is domperidone?
DA antagonist, anti-emetic, does not cross BBB, no antipsychotic properties and relatively safe in PD
Has permitted therapeutic use of apomorphine
Risk is QT prolongation
What is dyskinesia?
Abnormal involuntary movements
Dopaminergic drugs may cause this but DA antagonists may cause PD
What are some long term effects of DA antagonist use?
Antipsychotics/ anti-dizziness
Often cause PD as receptor blockage at basal ganglia
Dyskinesia
