Pharmacology and Therapeutics - C Bailey Flashcards
At rest, which part of the cell is the most positively charged….
The inside or outside?
The outside!
As the K+ channel is open allowing the high K+ concentration inside to move to the outside
Also due to the high sodium content outside
What is an ionotropic receptor?
What is a metabotropic receptor?
Ionotropic –> A ligand gated ion-receptor
Metabotropic –> A GPCR
Explain Glutamate and GABA synapses and how they work
Glutamate –> Activate Na+ channels which cause an excitatory response (EPSP)
GABA –> Activate Cl- channels which make an inhibitory response (IPSP)
If a synapse causes a Gi response or Gs response, what will occur?
Gi –> Make action potentials less likely
Gs –> Make action potentials more likely
Will Myelin Shieth speed up or slow down transmission?
Speed up
What is CSF?
Cerebrospinal Fluid
Produced in the choroid plexus
A solution of NaCl and glucose (with low levels of K+ and Ca2+) that gives protection to the brain
Define Noiciception
The physical process of detection and transmission of damaging or potentially damaging (noxious) stimuli
What is the main cause of depolarisation in free nerve endings?
An influx of Na+ ions via various transporters that are activated due to different reasons
Why does referred pain occur?
When 2nd order neurones are shared. So signals are sent to more than just the one place
What’s the different between hyperalgesia and allodynia?
Hyperalgesia –> Increased response to a noxious stimulus
Allodynia –> Painful responses to a non-noxious stimulus
How does Noiciceptor Sensitization occur?
After an injury or autoimmune response, H+/ATP/K+ will directly depolarise the noiciceptors
Substance P (from the noiciceptor) makes the blood vessels contract/leaky and causing more mast cell degranulation
These make noicieptors more sensitive due to tissue damage, causing action potentials to occur more often.
What are the 2 types of receptor that glutamate will bind to?
AMPA –> Rapid depolarisation
NMDA –> Slow but sustained depolarisation
What is ‘Wind-Up’ in terms of nociception?
Stimulation of the same magnitude will cause more action potentials as the number of stimulations increase
Why will holding injuries in sport actually decrease the pain that is felt? (Gate Control)
As touch receptors (mechanoreceptors) in the skin stimulate the inhibition of the the dorsal horn projection pathway, which tells us of pain.
Why do Enkephalins help reduce our pain levels?
The 4 enkephelins we have will bind to all opiate receptors via Gi coupled GPCRs, increased K+ efflux and minimising Ca2+ influx. This has an inhibitory effect on action potentials, meaning that they are less likely
How do opioids work in the Periaqueductal Grey (PAG)?
GABA is inhibited by opioids, which means the neurone towards the raphe magnus is stimulated. This is good as 5-HT is produced in the raphe magnus, which reduces pain
What is the main opioid receptor?
And why?
Mu
This is because it is the most widespread in the body and gives the most analgesic effect
What is the main effect/outcome of opioids and NSAIDs?
Opioids –> Boost the decending inhibiton of noiciception
NSAIDs –> Inhibit peripheral sensitisation
How do NSAIDs work?
Block the COX1/2 enzymes, hence preventing the conversion of Arachiadonic Acid to Prostaglandin H2
How is neuropathic pain treated?
Due to it being unrelated to noiciception, it cant be treated with NSAIDs or opioids.
Treated with TCAs and antiepileptic drugs mainly
Also: Capsacin cream/CGRP receptor blockers/Na+ receptor blockers/Cannabinoid receptor agonists
What’s the difference between psychological and physcial dependence?
Psychological - ‘Addicition’ such as craving and loss of control
Physcial - When stopping a drug will cause withdrawal effects
What is known as the ‘Reward Pathway’?
The Mesolimbic Pathway
From the Ventral Tegmental Area (VTA) to the Nucelus Accumbens
What are 2 ways of preventing the reward pathway being successfully stimulated?
Use 6-OHDA –> Destroys the dopaminergic neurone that completes the pathway
D1/2 Antagonists –> Act on the nucleus accumbens
How do opioids increase dopamine levels in the body?
They inhibit GABA neurones, increasing the stimulation of dopaminergic neurones (and so dopamine)
How does Ethanol increase dopamine levels?
They stimulate dopamine neurones directly, by keeping K+ channels open for longer…which speeds up repolarisation (decrease after-hyperpolarisation) and so more action potentials fire (quicker)
Why does ethanol cause the characteristic memory and movement problems?
An NMDA Antagonist –> causes memory loss
A Calcium Channel Antagonist –> Causes movement problems
How does Cannabis and Nicotine affect the mesolimbic pathway?
THC (Cannabis) –> Same as opioids…inhibit GABA which in term stimulates dopamine production
Nicotine –> Acts on ACh receptors on dopaminergic neurones in the VTA
What are the 2 types of Stroke?
And which is the most common?
Ischaemic –> Occurs from blocked arteries
This is the most common
Haemorrhagic –> Blood vessels leak out/rupture
What is the main mechanism of action of strokes?
Excitotoxicity
Glutamate is excessively released, which stimulates Ca2+ influx…causing a positive membrane potential (due to lack of O2/glucose meaning the Na+/K+ pump to not function!!)
How can increased calcium levels cause more calcium to enter the cell during a stroke
The elevated calcium activates proteases and lipases which causes structual damage. This damage allows more calcium to enter the neurones
What is Peri-Infarct Depolarisation?
Where neurones are damaged in the penumbra when blood returns. This causes the ATP/O2 to run out and cause the depolarisation cycle to occur again.
This cannot occur for neurones in the core
What is the only licenced treatment for ischaemic stoke?
Tissue Plasminogen Activator (tPA)
Must be used within 3 hours of the stroke occuring for it to be effective
What type of drugs can cause food-induced excitotoxicity?
Glutamate receptor agonists
What are the 4 main types of drugs used for secondary prevention of strokes?
Antihypertensives
Antiplatelets (ischaemic only)
Statins (ischaemic only)
Anticoagulants (ischaemic only)
What are the 4 key components of psychosis?
Hallucinations
Delusions
Confused and disturbed thoughts
Lack of insight and self-awarness (not aware that the hallucinations aren’t real)
What is Schizophrenia?
And what are the 3 components that the effects are categorized into?
A divided mind…..A division between interal thought and external reality
Positive –> Increase in abnormal active behaviours
Negative –> Absense of normal active behaviours
Cognitive –> Disturbances of normal thought processes
Who are most likely to develop schizophrenia?
Those with strong genetic connections
Young men and post-menopausal women
What pathways cause schizophrenic effects?
And why?
Mesocortical –> Decreased levels of D1 receptors cause negative and cognitive symptoms
Mesolimbic –> Increased levels of D2 receptors which cause positive symptoms
What are the differences between typical and atypical antipsychotics?
Typical - High affinity D2 antagonists that have lots of extrapyrimidal side effects like parkinsonism (due to their work in the nigrostriatal pathway) and increased pro-lactin level (due to work in the tuberoinfundibular pathway)
Effective only against positive symptoms
Atypical - D2 and 5HT3 antagonists, so effective against the positive and negative effects (negative as 5HT3 activates D1 receptors). Also less motor side effects
Side effects include weight gain and diabetes
Define Engram
And what is Hebb’s Law?
A physical representation or location of memory
Hebb’s Law states that if a neurone is releasing a neurotransmitter at the same time as another (connected neurone) is firing APs then the synapse becomes stronger
This over time produces a long term memory that can be activated with only part of the memory being shown (as the brain can fill in the gaps)
What are the 3 subdivisions of memory?
Declarative –> The consious part of memory
Emotional
Procedual
Why is the amygdala useful?
It allows us to remember fearful experiences….so we’re less likely to get into that same situation again!
What does removing the temporal lobe do?
Lose the ability to make new short term memories, but long term was okay
What is Long Term Potentiation (LTP)?
Consistant stimulation of glutamate-mediated EPSPs through AMPA receptors will cause an increased signal strength once the threshold has been reached
High levels of Ca2+ (to act on NMDA receptors) is vital for LTP…along with the NMDA receptors
Why is Magnesium so important in the brain?
As it blocks NMDA receptors at the resting membrane potential (-70mV) and will only be removed at -40mV, which occurs when AMPA receptors are consitatnly activated
Glutamate is also required to activate this receptor…hence the name ‘dual gating’
How can we make LTPs more likely?
What are the 3 mechanisms of LTP generation?
PKC can cause phosphorylation of AMPA receptors, stimulating more AMPA receptors being made. This is stimulated by calcium (1)
CaMKII can cause the insertion and synthesis of new AMPA receptors (2)
Nitric Oxide can move rapidly across the synapse (due to being a gas) which stimulates glutamate release from the pre-synaptic membrane (3)
What is consolidation and re-consilidation in terms of memory?
Consolidation - Going over already known knowledge
Re-consolidation - Using the memory over and over again
Where is the most damage done in Alzheimers disease?
The entorhinal cortex
Hence the memory and speech problems
How are Plaques and Tangles formed in Alzheimer’s?
Plaques –> B-secretase cleaves APP and then so does Y-secretase, forming AB40/42
Enzyme ApoE4 then causes these to aggregate into a plaque
Tangles –> The plaque aggregate then active kinases, causing hyperphosphorylation of Tau…which forms the tangles that can cause neuronal death
What are the 2 main treatments for the symptoms of Alzheimer’s?
Cholinesterase inhibitors –> Due to cholinegic neurones being damaged early on
Memantine –> Can improve congnition via its non-competitive NMDA receptor blocking
What are 2 diagnostic hallmarks of Alzheimer’s disease?
Neuritic Plaques (NP) –> Extracellular, non-soluble amyloid B protein
Neurofribrillary Tangles (NFT) –> Intracellular, abnormal cytoskeletal protein tau
What are the main negatives of stimulating each of the opioid receptors?
Mu –> Respiratory depression
Kappa –> Dysphoria
Gamma –> Pro-convulsant
