Neuropharmacology Flashcards
Why is neuronal death an important event?
There is limited capacity for neurons to divide and re-establish synaptic contacts
Death produces largely irreversible changes in brain function
Common neurodegenerative conditions
Alzheimer’s
Parkinson’s
Huntington’s
Motor neuron diseases
Creutzfeld-Jakob disease
Acute brain ischaemia and stroke
Mechanisms underlying neurodegeneration
Excitotoxicity
Oxidative stress
Apoptosis
What is the main mechanism of excitotoxicity?
Glutamate-induced excitotoxicity
What is the main ion causing the damage seen in glutamate-induced excitotoxicity?
Calcium
Describe what happens following the excitation of glutamatergic neurons
- Glutamate activates AMP receptors, depolarising the plasma
- This leads to the opening of voltage-dependent calcium channels and unblocks NMDA channels
- Stimulation of NMDA receptors allows Ca2+ influx
- Stimulation of metabotropic receptors activates PLC which releases Ca2+ from the ER
- Cell membrane Na+/Ca2+ exchange further increases Ca2+ concentration
How does calcium lead to excitotoxicity?
The increase in Ca2+ concentration leads to activation of Ca2+-dependent enzymes
These cause degradation of proteins and membrane damage
Overloading of the mitochondria with Ca2+ interferes with their function
Leading to ROS production
What is another consequence of mitochondrial damage in glutamatergic neurons?
The malfunction of mitochondria following Ca2+ overloading means that the production of ATP decreases
There isn’t enough energy available for the pumps to work, so the mechanisms for increasing [Ca2+] become unopposed
Which molecules prevent elevations in ROS?
Anti-oxidants
These defense mechanisms are overwhelmed in neurodegenerative conditions
What are most potential drug targets aimed at in neurodegenerative disorders?
Calcium entry
Intracellular protease activation
Free radical damage
Inflammatory response
Membrane repair
Pathological mechanisms behind stroke
Brain ischaemia leads to rapid cell death in the hypoxic area
Followed by neurodegeneration in the adjacent areas
This leads to depolarisation in neurons, causing a release of glutamate
What drugs can help the prognosis of stroke?
Fibrinolytic drugs given at the correct time
Can improve blood flow and reduce further damage
Dependent on the stroke being thrombic, not haemorrhagic
Characteristics of Parkinson’s disease
Tremor at rest
Muscle rigidity
Difficult performing voluntary movements
An imbalance in which neurons is an important factor in PD?
Dopaminergic and cholinergic fibres of the striatum
Loss of dopamingergic fibres in the nigrostriatal pathway is coupled with an excessive activity of cholinergic fibres of the striatum
What causes the damage to nigrostriatal dopaminergic neurons in PD?
Excitotoxicity
Oxidative stress
Apoptosis
Common treatments of Parkinson’s
Levodopa
Dopamine receptor agonists
Amatidine
Muscarinic antagonists
What is main treatment for Parkinson’s?
Levodopa
Mechanism of action of Levodopa
Increases the concentration of dopamine in the basal ganglia
Given with carbidopa to prevent the systemic effects of dopamine
When does Levodopa work best?
When coupled with MAO-B or COMT inhibitors
Example of a MAO-B inhibitor
Selegiline
Example of a COMT inhibitor
Entacapone
Unwanted effects of Levodopa
Acute schizophrenia-like syndrome linked to increased dopamine concentration
Disorientation
Insomnia
Nightmares
What is carbidopa?
A DOPA decarboxylase inhibitor
When are dopamine agonists used?
In adjuncts to Levodopa
Peripheral side effects of Levodopa
Postural hypotension
Nausea
Mechanism of action of Amitidine
Antiviral agent
Increases neural release of dopamine
Mechanism of action of muscarinic antagonists
Decreases the characteristic tremor in PD patients
Side effects of Muscarinic antagonists
Sedation
Confusion
What is Alzheimer’s?
Age-related dementia
What is Alzheimer’s associated with?
Loss of neurons
Shrinkage of the brain tissue
Underlying pathological mechanism behind Alzheimer’s
Amyloid plaques
Tau tangles
The loss of which neurons are thought to be a key factor in Alzheimer’s?
Cholinergic receptors
Drugs used in Alzheimer’s
Anticholinesterases
NMDA antagonists
What is epilepsy?
Condition where intermittent high-frequency firing of a localised group of cerebral neurons cause seizures
Discharge can remain localised or spread to other regions of the brain
What are the two types of seizures?
Partial seizures - abnormal discharge is localised to a relevant area
General seizures
Example of partial seizures
Jerking of a limb
Complex behavioural change
Is there loss of consciousness in partial seizures?
No
What are the two major forms of general seizures?
Tonic-clonic or grand mal epilepsy
Petit mal epilepsy
Describe grand mal epilepsy
Initial tonic convulsion followed by jerking of the whole body
Accompanied by sudden loss of consciousness
Describe petit mal epilepsy
Episodic loss of consciousness
Otherwise known as absence seizures
What is status epilepticus?
When generalised convulsions follow each other without consciousness being regained
Medical emergency
How many patients respond well to antiepileptic drugs?
75%
Why do antiepileptic drugs need to have as few side-effects as possible?
The drugs need to be taken lifelong
The fewer the side-effects, the better
What are the three main mechanisms by which anti-epileptics work?
Inhibition of action potential generation through Na+ channels or T-type Ca2+ channel block
Enhancement of GABAergic transmission
Reduction of glutamatergic transmission
Why is blocking Na+ and T-type Ca2+ channels an effective therapy for epilepsy?
Reduces the influx of positive ions into the cell, reducing the depolarisation of the neurons
Reduces the release of neurotransmitters from the presynaptic membrane
Reduces the propagation of the action potential in the post-synaptic membrane
Targets on the neurons that reduce depolarisation
Na+ channels
Ca2+ channels
NMDA receptors
AMPA receptors
GABA receptors
Targets on the neurons that reduce neurotransmitter release
Ca2+ channels
Na+ channels
Mechanism of action of Carbamezapine
Binds to inactivated Na+ channels (hyperpolarisation)
Preventing them from returning to a normal state to allow for further action potential generation
Unwanted effects of Carbamezapine
Narrow therapeutic index
- Vertigo
- Confusion
- Sedation
Mechanism of action of Ethosuximide
Inhibits T-type Ca2+ channels
For which type of epilepsy is Ethosuximide prescribed for?
Used only for absence seizures
Mechanism of action of Valproate
Increases GABA concentration in the brain through blocking the enzyme that degrades it pre-synaptically
Mechanism of action of Benzodiazepine
Increases opening of GABA channels
Allows more Cl- to enter the cell
Hyperpolarising the cell
Characteristic of newer antiepileptics
Can affect all types of epilepsy
