Pharmacology and Therapeutics - S Bailey Flashcards
Where is Glutamate mostly found?
And where is GABA normally found?
Glutamate –> Pyrimidal neurones
GABA –> Interneurones and long projection neurones
How is Glutamate synthesised and metabolised?
Made from glucose (krebs cycle) or via glutamine (glial cells)
Glutamate is stored in vesicles (via VGluT) and and released by calcium dependent exocytosis.
This Glu is taken up by nerve cells and glial cells (astrocytes) by AA transporters (EAATs). Here it is broken down to glutamine, which moves back to the neurones via transporters (GlnT)
How is GABA synthesised and metabolised?
Made from glutamate via Glutamic Acid Decarboxylase
Broken down via GABA transaminase to succinic semi-aldehyde and then to succinate via Succinic dehydrogenase
Succinate then enters the TCA cycle
Which GABA receptor is metabotropic?
What is the main drug agonist at this receptor?
GABA(B)
As a heterodimer GPCR, with GABA binding to R1 of the “venus fly trap” binding site
Baclofen to treat spaciticity
What are ionotropic GABA receptors made up of?
2 Alpha
2 Beta
1 Gamma
What is the make up of ionotropic glutamate receptors?
And what are the 3 version of the receptor?
They are tetrameric (4 subunits)
AMPA
NMDA
KAINATE
How many metabotropic glutamate receptors are there?
Eight (8)
How many rotamers does glutamate have?
Nine (9)
What are the 2 types of mood disorder?
Bipolar Disorders
Unipolar Disorders (depression)
What is the DSM-5 criteria?
A diagnostic tool for depression
Either low mood for most days, or deminished interest in things most day….including 4 of the following
Significant weight gain/loss
Insomnia/hypersomnia
Slowing of thoughts
Fatigue
Feelings of worthness of guilt
Diminished concentration most days
Recurrent thoughts of death or suicide
Split the HAM-D (HDRS), MADRS and BDI assessements for depression into 2 categories of how they are done
Done by clinician –> HAM-D and MADRS
Self-Assessment –> BDI
What’s the main difference between MDD and Dysthymic Disorder?
MDD –> Episodic and recurrent
Dysthymic –> Low mood for at least 2 years (chronic depression) with 2 other major symptoms
This mood isn’t serious enough to be an MDD episode
What are the 3 forms of bipolar disorder?
Bipolar I –> At least episode of mania or mixed episode
Bipolar 2 –> At least on major depressive episode with at least one episode of hypomania
Cyclothymic Episode (Cyclothymia) –> A mild form of bipolar that lasts at least 2 years that contains various events of hypomania and depressive symptoms
What are the key symptoms of mania?
Psychomotor agitation
Excessive talking or slurred speech
Racing thoughts
Reduced need for sleep
Inflated self-esteem
Easily distractable
Excessive involvment in pleasurable activites with negative consequences
What are the causes of mania and depression? In terms of neurotransmitters
MDD –> Low 5-HT and/or NA and Dopamine
Mania –> High levels of NA and Dopamine, whilst low levels of 5-HT
Name 4 types of non-pharmacological treatments of mood disorders?
Interpersonal Psychotherapy (IPT) –> Focus on current relationships
Cognitive Therapy –> Replace negative thoughts with postive ones
Mindfulness Based Cognitive Therapy (MBCT) –> Strategies such as meditation to prevent replase
Electroconvulsive Therapy (ECT) –> Induces a brain seizure
Reserved for those with the greatest risk of suicide
How do MAOIs work?
And what is the mechanism of their side effect?
Irreversibly inhibit monoamine oxidase, which prevents the break down of 5-HT (MAOA) and DA (MAOB)
Tyramine is also metabolised by MAO normally, so these drugs prevent this, meaning it’s absorbed…which allows its sypathomimetic effects to occur (such as hyertension and cardiac arrest) due to it being like NA
Known as the ‘cheese reaction’
How do TCAs work?
Block the uptake of amines by nerve terminals
Whilst they can block DA, they are much more selective to NA and 5-HT
They are long acting due to having active metabolites
Why are SSRIs better than TCAs?
They are safer in overdose (which is useful in depressed people)
Better side effect profile
What are the 3 main types of drug that are used to treat bipolar disorder?
Mood stabilisers
Lithium –> Used prophylactically and has a narrow therapuetic range
Anticonvulsants –> Used to prevent relapses (valproate/lamotrigine)
Antipsychotics –> Used mainly to prevent mania (olanzapine/risperidone)
Explain the classification of obesity
What role can Leptin play in anti-obesity?
Secreted by adipose tissue, with its levels being proportional to the level of body fat
It binds to leptin receptors which sends satiety signals to the brain, making you stop eating
However people can build up leptin resistance….
What are the 2 parts of the Hypothalamic Arcuate Nucleas (ARC)?
AGRP –> Stimulates feeding behaviour (orexigenic), which inhibits the PVN and NTS
POMC –> Inhibits feeding behaviour (anorexigenic), stimulating the PVN and NTS
What role can 5HT have in obesity?
5HT acts as a satiety signal, so having more means you will eat less. So eating its precuroser (tryptophan) means you will eat less food overall
5HT is stored in enterochromaffin cells in the GI mucoss (periphery) to act as said satiety signal
What is the only UK licensed medication for anti-obesity?
Orlistat
Works by inhibiting lipase, so prevents the breakdown of dietary fats (so they can be passed out without being absorbed)
What are the 3 core elements of anxiety disorders?
Negative Cognition –> Bias to interpret unthreatening situations as threatening
Physiology –> Racing heart etc
Avoidance
What is the Amygdala?
The “fear centre”
Takes information from our emotions, memories and senses to figure out if the situation is something to be feared
It then sends this information to the hypothalamus (fight or flight) and periaquaductal grey (avoidance behaviour)
The amygdala also stimulates the release of amine neurontransmitters to increase alertness and attention
At what stage of the stepped care approach for GAD are drugs added in?
Stage 3 to 4
Where do benzodiazepines specifcally bind?
Between the gamma and alpha sub units of the GABA(A) receptor
What are the 3 subtypes of benzodiazepines?
And how does this effect their metabolism?
2-Keto –> Oxidised in the liver
Long acting
3-OH –> Conjugated to glucuronide radicals
Short acting
Triazolo –> Oxidised with fewer active metabolites (than 2-keto)
What is sleep?
And why is it useful?
A reversible state of reduced responsiveness to, and interaction with, the environment
Useful for cortical (the cortex) recovery, organising and storing memories and weight homeostasis
What are the 2 stages of the sleep cycle?
REM –> 20 min….the dreaming stage
Sympathetic activity occurs (increased HR) and there is a high O2 demand
NREM –> 4 stages that consist of 60-90mins total
Increased parasympathetic activity
Usual sleep will contain around 4-6 cycles of these, with them becoming quicker as the night progresses
What is the RAS (in reference to sleep)?
And what are REM On/Off cells?
The Ascending Reticular Activating System
Contains several neurones that cause sleep when firing is reduced, and awakeness when firing is increased
Locus Coeruleus –> NA
Raphe Nuclei –> Serotonin
Brainstem/Forebrain –> ACh
Midbrain –> Histamine
REM On Cells –> Cholinergic neurones in the brainstem
REM Off Cells –> Serotonergic and noradrenergic neurones in the brainstem
Name 3 sleep regulating substances
Interleukins –> Part of the immune response, which explains sleepiness during infection
Melatonin –> Synchronises our circadium rhythm, with levels increasing at night. Derived from 5HT
Hypocretin orexin –> Regulates 5HT/NA neurones and metabolism
People with narcolepsy have low levels of hypocretin orexin
What are the 4 types of insomnia?
Transient –> Caused by noise (usually)
Short-Term –> Caused by emotional problems or stress
Chronic –> Caused by mental problems, pain or alcohol abuse
Fatal Familial –> Genetic condition that causes death within a year
Name a scale that is used to assess if somebody has insomnia
Epworth sleepiness scale
Presynaptically, what is the result of NMDA and mGluR receptors?
NMDA –> Increase glutamate release by increasing calcium influx
mGluR –> Decrease glutamate release by decreasing calcium influx
What converts dopamine to noradrenaline?
Dopamine B-Hydroxylase in vesicles
What are the type of neurones that are present in the following….
Ventral Tegmental Area
Locus Coeroleus
Dorsal Raphe Nuclei
VTA –> Dopmainergic
LC –> Noradrenergic
DRN –> Serotoniergic
Listing from highest to lowest, what are the frequency of the 4 different brain rhythms that we see during sleep?
Beta –> Over 14Hz
Alpha –> 8-13Hz
Theta –> 4-7Hz
Delta –> 4Hz
The greater the frequancy, then smaller the visual representation!!
What is the pharmacophore of benzodiazapines?
A benzene ring bound to a 7 membered 1,4 diazepine ring
Does Noradrenaline bind to ionotropic or metabotropic receptors in the CNS?
Metabotropic
What’s the difference between a primary and secondary headache?
Primary –> No underlying cause (eg, tension/migraine/cluster)
Secondary –> Caused by an underlying condition (eg, extra/intracranial)
What are the 3 types of primary headaches?
Tension –> Feelings of pressure that comes and goes
Bilateral
Patient prefers to be active or to rest
Migraine –> Throbbing feelings that are worse on exhaustion
Associated with photophobia and an aura
Unilateral
Typically rest in dark rooms
4-72 hours
Cluster –> Abrupt onset with continuous pain
Associated to with tearing, congestion, rhinorrea, pallor and sweating
Unilateral
0.5-3 hours with many per day
What are the OTC treatments for tension type headaches?
First line –> Paracetamol or NSAIDs
Secondary –> Aspirin + Paracetamol and Caffeine
Should only be used for 2-3 days per week to prevent a medication induced headache
What’s the difference between a common and classic headache?
Common –> Without
Classic –> With aura
What are the 3 phases of migraines?
Prodromal/Premonitory –> Aura, nausea, mood changes and fatigue
Headache
Resolution –> Pulsating or continuous pain and lack of concentration
How can pain be sensed in headaches?
Sensory nerves are present in the dura matter and circle of Willis
What are the 3 theories of migraine pain?
Vascular –> Intracerebral vasoconstriction and extracerebral vasodilation
Neuornal –> Corticol Spreading Depression (CSD) occurs which causes a disregulation of ions and local blood flow
Inflammation –> Release of inflammatory mediators from sensory nerve terminals
What is the neurovascular theory of migraine pain?
Neurones from the TG release Calcitonin Gene Releated Peptide (CGRP) causing vasodilation in the meninges. Also causes local inflammation
TG and TNC are activated, stimulating rostral brain areas
This is central sensitisation
How do Triptans work?
5HT agonists, with high affinity for 5HT-1B/1D receptors
1B –> On smooth muscle causing vasoconstriction
1D –> On nerve terminals, blocking vasoactive peptides
What is the one 5HT receptor that is ionotropic?
5-HT3
What are the treatments for cluster headaches?
Acute –> SC sumpitriptan (or nasal if preffered)
NOT paracetamol/NSAIDs/aspirin/caffiene
Prophylaxis –> Veramapril (CV side effects however)
What does Reserpine do?
Inhibits 5HT and NA storage….which lowers mood
