Theme 4: The Nervous System (L8-13) Flashcards
1
Q
What types of receptors stimulate serotonin?
A
G-protein coupled receptors
Ligand gated ion channels
2
Q
What NT is an ester?
A
Acetylcholine
3
Q
What type of NT are monoamines?
A
Serotonin
Norepinephrine
Dopamine
4
Q
What NTs are amino acids?
A
Glutamate
GABA
5
Q
What NTs are peptides?
A
Substance P
Enkephalins
B-endorphins
6
Q
What are the different ionotropic glutamate receptors?
A
AMPA/kainate
NMDA
7
Q
What re the ionotropic GABA receptors?
A
GABA-A
8
Q
What areas does acetylcholine work in?
A
CNS
Autonomic nervous system
Neuromuscular junction
9
Q
What are the properties of norepinephrine?
A
CNS-neuromodulator - increase arousal and alertness
ANS - postganglionic transmitter SNS
10
Q
What is the function of histamine?
A
Promotes wakefulness
Neuromodulator
11
Q
What are the properties of dopamine?
A
CNA - reward pathways, DA projections on striatum in PD
Increase Na+ excretion in kidney, reduces motility in GI, reduces activity of lymphocytes
12
Q
What are the different functions of serotonin?
A
Gut - created in GI (enterochromaffin cells), transmitter in enteric nervous system
Blood - in vessels, vasoconstriction - positive inotropic action on heart, platelets store 5HT and release to promote vasoconstriction and clotting
CNS - reward and mood
13
Q
What are the different categories of near-drugs?
A
Sedative - calming
Hypnotic - sleep
Anti-convulsant - inhibit seizures
Anxiolytics and antidepressants - reduce anxiety and/or depression
Antipsychotics - tranquillisers
Mood stabiliser - anti-manic
14
Q
What drugs can be used as antidepressants?
A
Barbituates and SSRIs
15
Q
What drugs can be used as anxiolytics?
A
Barbituates, benzodiazepines and SSRIs
16
Q
What drugs can be used as sedative hypnotics?
A
Quetiapine and benzodiazepines
17
Q
What drugs can be used as antipsychotics?
A
Quetiapine
18
Q
What drugs can be used as anticonvulsants?
A
Barbituates, benzodiazepines and gabapentin
19
Q
What drugs can be used as mood stabilisers?
A
Quetiapine and gabapentin
20
Q
What was the early GABA antagonist used?
A
Hemlock - caused facial muscular contraction causing a sinister smile
21
Q
What is the function of GABA neurons?
A
They are inhibitory neurons
A: directly hyperpolerising
B: indirectly hyperpolarising
22
Q
What are the targets of the GABA A and B channels?
A
A: sedative/hypnotics
B: Baclofen - muscle relaxant
23
Q
What are the properties of the GABA A receptors?
A
Chloride permeable ion channels
Many different subunits:
19 homologous subunit gene products
6α, 4β, 3γ, 2ρ, δ, ε, θ and π
Mammalian: α1, β2 and γ2
Receptors containing α,β,X are 2:2:1 stoichiometry
Receptors containing α,β only are 2:3 stoichiometry
All must contain an α subunit
24
Q
What was the effect of benzodiazepines and barbiturates on GABA A receptors?
A
Benzodiazepines - more frequent channel opening so increased opening probability
Barbiturates - Increased channel open duration
25
What are barbiturates?
Sedative/hypnotic/anaesthesia inducing agent/anticonvulsant
Positive allosteric modulators of GABA A receptors
26
What are the most common examples of barbiturates?
Pentobarbital
Butobarbital
Phenobarbital
Sodium thiopental
27
What are barbiturates used for?
Pento/sodium thiopental - induction of general anaesthesia
Pheno and pentobarbital - in some cases of epilepsy
Sedation and hypnosis to calm and induce sleep
28
What are the different classes of barbiturates?
Ultrashort-acting
Short/intermediate acting
Long-acting
29
What are ultrashort acting barbiturates used for?
Anaesthesia - for greater control, allows doctors to allow patients to come in and out easily
30
What are short/intermediate acting barbiturates used for?
Anaesthetic, insomnia (hypnotics) and anxiolytics
31
What are long acting barbiturates used for?
Anticonvulsants ONLY or rarely daytime sedatives
32
Why are there differences in time acting for barbiturates?
Thiopental - highest lipid solubility, rapid action
Phenobarbital - lowest lipid solubility, low plasma binding, longest duration of action
33
What is phenobarbital approx half-life?
53-118h
34
How is phenobarbital excreted?
Metabolised by the liver and products excreted in the urine
35
How are barbiturates lethal?
Overdose is lethal as it leads to respiratory depression
Acts as a direct agonist at higher concentrations
10x full hypnotic dose leads to severe poisoning
36
How can barbiturates be made lethal?
If taken with alcohol and other CNS antidepressants
37
What drugs can be used for low barbiturate overdose?
bicuculline
38
What drugs can be used for high barbiturate overdose?
Picrotoxin
39
What are benzodiazepines?
Sedatives/hypnotics/anticonvulsants/muscle relaxants
Positive allosteric modulators of GABA A receptors (probability of opening)
40
What are the most common examples of benzodiazepines?
Diazepam (valium) - sedation and anxiety
Alprazolam (xanax) - sedation and anxiety
Temazepam (restoril) - sleep aid
Midazolam (versed) - pretreatment for procedures - sedation, anxiolysis and amnesia and status epileptics
41
How are BZs useful?
Strong muscle-relaxants and useful in treatment of muscle spasms though tolerance is built
42
Are benzodiazepines or barbiturates safer?
Benzodiazepines
43
How do BZDs effect other GABA receptor subunits?
Has other effects that act on the α2,3 and 5 subunits which cause anxiolytic, motor impair and ethanol potentiation
44
Where is the BZ site?
Interface of α and γ subunit - pharmacology is determined by the isoforms whether it is the α4 or 6
45
What are the differences type I and II BZD receptors?
Type I - α1 isoform concentrated in cortex, thalamus and cerebellum
Sedation and anterograde amnesia and some anticonvulsant effects
Type II - α2,3,5 isoforms concentrated in limbic system, motor neurones and spinal cord
Anxiolytics and myorelaxant effects
46
What are the drawbacks of BZDs?
Cause pharmacodynamic tolerance (down regulation of receptors)
Tolerance develops to hypnotic and myorelexant effects days to weeks and anticonvulsant and anxiolytic effects weeks to months
Withdrawal can lead to rebound symptoms and physical withdrawal symptoms
47
What is the interfacial gap in the binding sites?
It is the difference in occupancy of the different drugs and GABA alone
Diazepam allows stabilisation compared to the other drugs
48
What is flumazenil?
It is a BZ antagonist which can be used in BZ overdose
Multiple doses may be required due to the long half lives of BZs
49
What are Z drugs?
Hypnotic agents with a similar MOA to BZDs
Positive allosteric modulators of GABA A receptors
Z drugs show preference for the α1 subunits which preserves deep sleep
50
What are examples of hypnotic agents?
Zolpidem
Eszopiclone - α2 and 3 activity
Zaleplon - shorter half-life fewer hangover efects
51
What is Zolpidem?
It is an hypnotic agent using α1 subunit in GABA A some effect in α2 and 3 and little in 5 so a potent sedative
52
What is Zopiclone?
Hypnotic agent using α1 subunit of GABA A and longest duration
Eszopiclone - S-enantiomer greater efficacy in α2 and 3
53
What is Zaleplon?
Hypnotic agent using selective binding at BZ1 receptors and low affinity and potency in α2 and 3, ultrashort-acting
54
What can be targeted to suppress seizures?
The GABA neurones controlling excitatory signalling
Which work by suppressing neuronal firing through allowing Cl- to enter
55
What are the different types of inhibition?
Feedforward - feeds onto inhibitory neurones
Feedback - goes backwards onto inhibitory neurones
Lateral
56
How are seizures monitored?
Using an EEG
57
What are focal seizures?
They originate at one specific area over the brain causing a wide range of symptoms
58
What can happen in the development of focal seizures?
They can lead to generalised seizures
59
How are seizures initiated?
They are high frequency bursts of action potentials "paroxysmal depolarising shift"
Hypersynchronisation of neuronal population (overwhelm other neurones)
Distal seizure propagation
60
What is the paroxysmal depolarising shift?
It is a characteristic of the seizure by strengthening the synaptic connections through synaptic plasticity and overcoming network inhibition
61
What are the functions of inhibitory circuits in seizures?
They act to constrain the spread of seizures (feedforward and back)
62
What is a common class of anticonvulsant?
Pro-GABAergic agents
63
What is the significance of voltage-gated Na+, K+ and Ca2+ channels in epilepsy?
Na+ - repetitive firing
K+ - abnormal repolarisation
Ca2+ - excess transmitter release; pathophysiologic intracellular processes
64
What is the significance of non-NMDA, NMDA and GABA receptors in epilepsy?
Non-NMDA - maintain paroxysmal depolarising shift
NMDA - initiates PDS, activates pathophysiologic processes
GABA - limits excitation
65
When was the first anti-convulsant founded and what was it?
Bromide in 1857
66
What are the treatments for focal seizures?
Lamotrigine and levetiracetam (1st line)
Carbamazepine, Sodium valproate and zonisamide
67
What are the treatments for tonic-clonic seizures?
Sodium valproate (1st line newly diagnosed)
Lamotrigine may exacerbate myoclonic seizures
68
What are the treatments for absence seizures?
Ethosuxamide or sodium valproate
69
What are the treatments for myoclonic seizures?
Sodium valproate (newly diagnosed)
Levetiracetam (second line or females child-bearing age)
70
What are the treatments for atonic and tonic seizures?
Sodium valproate with lamotrigine as adjunct (if necessary)
71
What effect can some anticonvulsants have?
They can cause contraindications like exacerbating absence seizures and myoclonus (carbamazepine, oxcarbaepine and phenytoin)
Gabapentin, pregabalin, tiagibine and vigabatrin contraindicate myoclonic epilepsies and worsen seizures
72
Which drugs can cause status epilepticus?
Tiagabind and vigabatrin induce absence
73
What are the pharmacokinetics of anticonvulsants?
Half life is important (suppression for long duration)
Dosage once or twice a day
As doses increase so do adverse effects
Drug-drug interactions through CYPs and plasma binding
74
What is an example of an anticonvulsant used to block Na+ channels?
Phenytoin - not as safe
75
What is the mechanism of phenytoin?
Prolongs the activation state by blocking fast sodium current - prevents repetitive firing
76
Which drugs have a use dependent blockade?
Phenytoin
Carvamzepine
Volproic acid
Lacosamide
Zonisamide
Topiramate
77
What are the adverse effects of phenytoin?
Neurologic effects, hirsutism (hair growth), gingival hyperplasia (enlarged gums), impaired insulin secretion, mild neuropathy and rash
78
What are the pharmacokinetics of phenytoin?
Narrow TI
Small dosage increases can increase plasma concentration with acute toxic side effects
79
What seizure types is phenytoin used for?
Tonic clonic and focal (exacerbate absence or myoclonic seizures)
80
Why is phenytoin known as a teratrogen?
Syndrome consists of craniofocal anomalies and mental retardation
81
What was the first anticonvulsant drug developed?
Phenytoin
82
What is carbamazepine?
It is a primary drug used for generalised and focal seizures and for treatment of trigeminal neuralgia
83
What is the mechanism of action of carbamazepine?
It limits the repetitive firing of action potentials by sustained depolarisation
83
Which other drug is carbamazepine chemically related to?
Tricyclic antidepressants
84
What can happen during acute intoxication with carbamazepine?
Stupor(reduced consciousness) or coma, hyper irritability, convulsions and respiratory depression
85
What are the adverse effects over prolonged therapy with carbamazepine?
Drowsiness, vertigo, ataxia (lack of muscle coordination), diplopia (double vision) and blurred vision
Frequency of seizures may increase especially in cases of overdose
86
What are the pharmacokinetics of carbamazepine?
Generally safe and well tolerated
Short half-life so dosing 3 times a day
87
What is the mechanism of action of lamotrigine?
Acts on voltage gated sodium and calcium channels
Suppresses rapid firing of neurones via inactivated state (efficacy in focal epilepsy)
VGCCs inhibition efficacy in generalised seizures (childhood and absence)
Decrease in synaptic release of glutamate
88
What are the common adverse reactions of lamotrigine?
Rash, Stenevens-Johnson stndrome, toxic epidermal necrolysis and/or rash-related death
89
What disorder is lamotrigine also used in?
Bipolar disorder
90
What is the mechanism of action of valproate (valproic acid)?
Prolongs inactivated state - sodium channels
Inhibits low threshold T-type calcium channels
Increase in GABA - inhibits GABA transaminase and upreulates glutamate decarboxylase
Inhibits HDAC (anti seizure through gene expression)
Used in bipolar disorder
91
What are the adverse effects of volproic acid?
CNS: sedation, ataxia(lack of muscle coordination), tremor
GI effects
Hepatotoxicity and pancreatitis
Plasma binding so increase free concentration of other drugs
Prolongs duration of action of barbiturates, BZDs and narcotics
Risk of congenital malformations
92
What is lacosamide?
Adjunctive therapy for partial onset seizures in adults
93
What is the mechanism of action of lacosamide?
Selectively enhances sodium channel slow inactivates
From hundreds of milliseconds to seconds of sustained depolarisation
Stabilises hyperexcitable neuronal membranes, inhibits firing and reduces long-term availability
94
What are non-VGSC agents?
They enhance the inhibitory neurotransmission
95
What are the drugs used for direct action on inhibitory transmission?
Barbiturates and BZDs - positive allosteric modulators - increase open probability or channel open time
Z-drugs - similar to BZDs and MOAs are ineffective in seizures
96
What are the differences between barbiturates and Z-drugs?
Additional actions of barbiturates on excitability and glutamate release or subunit effects
97
What is the first choice for status epilepticus?
BZDs (diazepam) often with phenytoin
98
Which drugs have an indirect effect on inhibitory neurones?
Gabapentin and pregabalin
99
What is the mechanism of action of gabapentin?
Developed as GABA mimicking drug but elevates GABA synthesis instead via glutamate decarboxylase and branched chain aminotransferase
Inhibit release binding α2δ subunit of N-type VGCCs - decrease in glutamate
Use-dependent on sodium channels
100
What is pregabalin?
Adjunctive treatment of particle seizures (with/without secondary generalisation)
Neuropathic pain including diabetic peripheral neuropathy (α2δ subunit N-type VGCCs binding)
101
Which drugs decrease excitation?
Perampanel - AMPA-receptors
Felbamate - GABA and NMDA-receptors
Topiramate - VGSCs, GABA and AMPA-receptors
102
What is levetiracetam?
It binds SVA2 which was found to be a potential target for anti epileptic therapy
Was found using blind trials and KO mice
103
What is the mechanism of action of levetiracetam/brivaracetam?
Binds SV2
Reduced short term plasticity at glutamatergic synapses - alter protein-protein interaction at synapse
104
What are the adverse symptoms?
Neuropsychiatric symptoms: agitation hostility, apathy, anxiety, emotional lability and depression (13% patients)
Hallucinations, suicidal thoughts or psychosis (1% patients)
105
What is the mechanism of action of ethosuximide?
T-type VGCCs - works to reduce currents underlying bursts of action potentials (thalamic oscillatory activity)
Reduction without modifying voltage dependence of steady-state inactivation or recovery from inactivation
Does not inhibit sustained repetitive firing or enhance GABA responses at relevant concentrations
106
What are the different forms of depression?
Major depression
Persistent depression disorder
Bipolar disorder
Seasonal affective disorder (SAD)
Psychotic depression
Peripartum depression
Premenstrual dysphoric disorder
Situational depression
Iatrogenic depression
107
What are the risk factors of depression?
Familial - 30-40% genetic
Common factors - adverse childhood events, ongoing/recent stress (SA), lifetime trauma, low social support and marital problems/divorce
108
What are the links between depression and chronic pain?
Chronic pain worsen depression symptoms (suicide)
Bodily aches and pains common symptom - incidence of more intense pain
Higher levels of cytokines so more responsive therefore cause more pain by triggering inflammation
109
How can depression be treated?
CBT- the way they think
Interpersonal therapy - patients relationships and the effects
Problem-solving therapy - problems needing solutions
110
What is the pathophysiology of generalised anxiety disorder?
Hypofunction of serotonergic neurones (5HT) and GABAergic neurones with overactivity of noradrenergic neurones (locus coeruleus) excessive excitation
Hippocampus-amygdala circuit amplifies aversive events - changes in dopaminergic and 5HT
111
Which neurones impact GAD?
Serotonergic neurones
GABAergic neurones
Noradrenergic neurones
112
What is the pathophysiology of depression?
Effect of reserpine
Tryptophan depletion
113
What are the functions of antidepressants?
First (iproniazid) promote monoamine signalling
Pro-aminergic drugs increase CNA levels one or more monoamines
114
How can tryptophan help treat depression?
Increase uptake in the diet can improve signalling in the brain by helping low mood with talk therapy
115
What are the different monoamines in depression?
Dopamine, noradrenaline and serotonin (5HT)
116
What are the NICE guidelines for depression?
Step system from 1-4
117
What do the different antidepressants either work on?
TCAs - monoamine reuptake
SNRIs - block 5HT and NE uptake
SSRIs - block 5HT uptake
MAOIs - block monoamine metabolism
118
What is the function of monoamine oxidase A?
Degrades amine neurotransmitters (dopamine/NE/5HT) oxidative deamination and acts on tyramine
119
What is the function of monoamine oxidase B?
Principally metabolises dopamine (no consequence for tyramine)
120
Why are certain antidepressants not used?
Because of tyramine toxicity due to non-selective MAOI
121
What were the first treatments for anxiety?
Barbiturates (phenobarbital)
122
What is the timeline of anxiolytic prescription?
1960s-1980s: BZDs
1960: Librium approved, BZD tranquilliser
1963: Valium approved, most prescribed
Valium short term therapy
Dependence and premature discontinuation results in relapse
Withdrawl BZDs after chronic treatment
123
What are SSRIs?
Selective serotonin reuptake inhibitors
1st line
Significant evidence in major depressive disorder
Fluoxetine 1970s (prozac)
124
What are the current main choices of antidepressants?
Citalopram, escitalopram, fluoxetine, paroxetine and sertraline
125
Why do SSRIs take so long to take effect?
Stops the reuptake of serotonin so serotonin levels have to adjust to regulate other NTs
126
What is the mechanism of 5HT in the brain with the use of SSRIs?
5HT1A receptors act as inhibitory somato-dendritic auto receptors
Blockade 5HT, elevated 5HT within raphe nuclei
Elevated 5HT reduces expression of inhibitory 5HT1A receptors
5HT neuron is now dis-inhibited
5HT output now enhanced
127
What are the differences between the different SSRIs?
Citalopram - 2nd most serotonin selective (minor metabolites cardiotoxic, pro-convulsant)
Escitalopram - S-enantiomer citalopram, more potent, more selective and reduced side effects
Fluoxetine - 1st SSRI, long half-life, potent CYP2D6
Paroxetine - possibly more effective, most sedating, highest weight gain risk, potent CYP2D6 inhibitor
Sertraline - widely proscribed, mildest ADRs, moderate CYP2D6 inhibitor
128
What are some of the ADRs of SSRIs?
Nausea, sexual dysfunction, agitation, weight gain, insomnia, worsen anxiety, BZDs counteract ADRs, suicidal ideation, serotonin syndrome, can change seizure threshold in anti epileptics, fewer ADRs escitalopram
129
What is the acronym used for SSRI discontinuation syndrome?
FINISH
130
What does FINISH stand for?
Flu-like symptoms
Insomnia
Nausea
Imbalance
Sensory disturbances
Hyperarousal
131
What happens when SSRI course finished?
They have to be tapered off due to withdrawal like symptoms (FINISH)
132
What are tricyclic antidepressants?
Treatment of depression (imipramine, dibenzazepine analogue of chlorpromazine)
Not originally for depression but induced mania in psychiatric patients
133
How do TCAs act?
Serotonin-norepinephrine reuptake inhibitors (SNRIs) block serotonin transporter and NE transporter - enhance neurotransmission
Highly effective - related by different drugs with higher safety and less side effect (SSRIs)
134
What are the common ADRs of TCAs?
Blurred vision, dry mouth, constipation, orthostatic hypotension, urinary retention, rash and hives, tachycardia, increased risk of seizures
135
Which receptors do TCAs target?
SERT, NET, α1 adrenoreceptor, H1, M1 and 3
136
Which receptors cause side effects of TCAs?
α1 adrenoreceptor, H1, M1 and 3
137
What happens in TCA overdose?
24-76 hour half-life (inc. OD)
Inhibit α receptors - hypotension TCA OD
Inhibit VGSCs - slow cardiac conduction, prolong QRS and AV block
life-threatening toxicity - cardiotoxicity
Therapies improve conduction (hypertonic sodium bicarbonate
138
What are the most common SNRIs?
Venlafaxine and duloxetine (more effective than SSRIs - fewer side effects than normal TCAs)
139
What are the differences between SNRIs and TCAs?
SNRIs: higher affinity for SERT than NET
TCAs: higher affinity for NET than SERT
(NOT CLOMIPRAMINE)
140
What is the mechanism of venlafaxine?
Inhibit neuronal serotonin and NE reuptake and weak inhibitors of dopamine reuptake
No pharmacological action at adrenergic, histamine, muscarinic, dopamine or postsynaptic serotonin receptors
Low doses, dual mechanisms (5HT and NE)
No evidence of SNRIs more effective Han SSRIs
141
How is resistance depression treated?
Response rate for single antidepressant poor (non-responsive)
6-7wks to achieve remission of depressive symptoms
Compliance is critical (decrease likelihood of relapse)
~40% remained non-responsive
142
What are rapid acting antidepressants?
Psylocybin - 5HT2a psychedelic action
Ketamine - NMDA blocker
Electro convulsive therapy
143
What is psychosis?
It is a thought disorder characterised by disturbances of reality and perception, impaired cognitive functioning, and inappropriate/diminished mood
144
What are the different disorders psychosis denotes?
Dementia, depression, drug use etc.
145
What is schizophrenia?
It is a type of psychosis characterised by a clear sensorium but marked thinking disturbance
146
What are factors of schizophrenia?
Effects ~1% of the population
Onset in adolescence (prodromal symptoms - early signs)
Umbrella term for multiple diseases
Developmental disorder
Two-hit hypothesis model
147
What are the schizophrenia treatments?
Neuroleptics (long-term)
Episodic (short-term treatment)
148
What are recent schizophrenia studies?
They focus on the genetics and new hypotheses on aetiology (e.g. neuroinflammation)
149
What are the different types of symptoms in schizophrenia?
Positive (e.g. hallucinations, disorganised thoughts/speech)
Negative (e.g. alogia- less words, avolition- give up easily)
Cognitive (e.g. poor memory, poor judgement & insight)
150
What are the different drugs that can induce psychosis?
Levodopa
CNS stimulants (cocaine, amphetamines, khat)
Apomorphine
Phencyclidine (PCP) - indirect dopamine
151
What do antipsychotics act as?
D2 receptor antagonists
152
What are the different pathways targeted in the brain during schizophrenia?
Mesolimbic pathway
Mesocortical pathway
Negrostratal pathway
Tuberoinfundibular pathway
153
What is schizophrenia caused by?
An overactive dopamine system in the brain in the mesocortiyal and mesolimbic pathway
154
What are positive schizophrenia symptoms caused by?
Dopamine, acetylcholine and inflammation
155
What are negative schizophrenia symptoms caused by?
Serotonin, glutamate, GABA
156
What are cognitive schizophrenia symptoms caused by?
Acetylcholine, serotonin and glutamate
157
What are properties of DA receptors?
5 different subtypes
D1 'like' (D1&5):
G protein coupled (Gαs)
Stimulate adenylyl cyclase
Postsynaptic
D2 'like' (D2,3&4):
G protein coupled (Gαi/o)
Inhibit adenylyl cyclase
Pre and postsynaptic
158
Where are D1 receptors expressed?
Substantia nigra
Nucleus accumbens
Olfactory bulb
159
Where are D5 receptors expressed?
Substantia nigra
Hypothalamus
Kidney
Hear
Sympathetic ganglia
160
Where are D2 receptors expressed?
Substantia nigra
Nucleus accumbens
Ventral tenemental area
161
Where are D3 receptors expressed?
Olfactory bulb
Nucleus accumbens
162
Where are D4 receptors expressed?
Hart
Blood vessels
Substantia nigra
Hippocampus
Amygdala
Gastrointestinal tracts
163
What was the first anti-psychotic?
Chlorpromazine
164
What are properties of first generation anti-psychotics?
D2 receptor antagonist (high-affinity) - some antimuscarinic effects
Managing schizophrenia, psychoses, mania, severe anxiety and nausea
Side effects: muscle spasms, restlessness and agitation
165
What are other typical first generation antipsychotics?
benperidol, flupentixol and haloperidol
166
What are the different modes of action of antipsychotics?
They block the D2 receptors in the limbic/cortical areas (affinity correlates to therapeutic efficacy)
167
What are properties of second generation anti-psychotics?
Dopamine-serotonin receptors antagonists (5HT1A agonist, high dissociation form D2)
Atypical antipsychotics may be more effective (greater side effects)
Higher propensity for metabolic adverse effects
168
What are examples of second generation anti-psychotics?
Amisulpride, olanzapine, risperidon and clozapine
169
How is response of antipsychotics produced?
By D2 occupancy (>65% occupancy correlated to response in drug)
170
Which anti-psychotics have a higher affinity for D3?
Cariprazine, blonanserin, bexxpiprazole and asenapine
171
Which anti-psychotics have a high affinity for D2 receptors?
Risperidone and Ziprasidone
172
Which anti-psychotics have a low affinity for D3 receptors?
Clozapine and quetiapine
173
What are other effects of first generation antipsychotics?
Antagonism M1, H1 and alpha 1 receptors
174
What are other effects of second generation antipsychotics?
Antagonism of M1, H1, 5HT2C and alpha 1 receptors
175
What are the SDA-type antipsychotics?
Risperidone, perospirone and lurasidone
176
What are the MARTA-type antipsychotics?
Clozapine, olanzapine and quetiapine
177
What is the D2 partial agonist antipsychotic?
Aripiprazole
178
What happens to the levels of dopamine and GABA in the mesolimbic dopamine pathway?
Glutamate acts on NMDA receptor to release GABA which releases dopamine which acts on the D2 receptor
179
What happens to the levels of dopamine and GABA in psychotic state?
There is less glutamate so less GABA which provides more dopamine to act on D2
This also occurs in phencyclidine ketamine use
180
What does disruption of dopamine nigrostriatal pathway cause?
Dystonia (movement disorder)
Akinesia (absence of voluntary movement)
Rigidity
Tremor
Dyskinesia (uncontrolled movements)
181
What does disruption of dopamine mesolimbic pathway cause?
Agitation, psychosis, mania, disorganisation, thrill/drug seeking
182
What does disruption of dopamine hypothalamic pathway cause?
Prolactin elevation
Amenorrhea (absence of menstrual periods)
Galactrorrhea (unintended production of breast milk)
Sexual dysfunction
183
What does disruption of dopamine mesocortical pathway cause?
Negative symptoms
Cognitive impairment
Depression
184
What is antipsychotic classification?
Side effect profile based
Group I: sedation (H1)
Group II: anti-cholinergic (cognition)
Group III: Extrapyramidal side effects (outside primary motor area)
185
What are the different phenothiazines?
Chlorpromazine (I)
Thioridazine (II)
Fluphenazine (III)
186
What are extrapyramidal side effects?
Extrapyramidal system in brains cerebral cortex
Parkinsonism & dystonia
Tardibe dyskinesia
Akathisia
Neuroleptic malignant syndrome
187
When does EPS brain in antipsychotic administration?
As dosage increases so does D2 receptor occupancy
188
Which antipsychotic has a narrower therapeutic window?
The typical has a narrower therapeutic window
189
What is the extent of antipsychotics helping an individual with a particular illness?
It is the efficacy + tolerability + compliance
190
What is the effectiveness is there are no side effects?
There is no actual effect on the patient
191
What are the safety concerned side effects of antipsychotics?
Life threatening
Acute/chronic
CVD, metabolic syndrome, diabetes
NMS and laryngospasm
192
What are the barriers to medication adherence with antipsychotics?
Stigma
ADRs
Homlessness/substance abise
Forgetfulness
Lack social support
193
When do patients have distress of antipsychotics?
Akinesia
Wight gain
Anticholinergic
Sexual problems
Muscle rigidity
Akathisia
194
What are the side effects of D2?
- Extrapyramidial
Parkinson's syndrome, tar dive dyskinesia (D2 mediated)
- galactorrhea
195
What are the side effects of H1?
Sedation
196
What are the side effects of M1?
Dry mouth, blurred vision and constipation
197
What are the side effects of α1?
Postural hypotension
198
What is Parkinson's disease?
Chronic and progressive movement disorder (tremor, stiffness or slowing of movement)
Problems with movement, anosmia (smell), mental health, sleep, pain, etc.
Progressive loss of DA neurones in substantiated nigra
Idiopathic (spontaneously arises, unknown cause)
199
What are the motor symptoms?
Resting tremor
Muscle rigidity
Suppression of voluntary movements
200
What happens to the substantial nigra in PD?
Neuromelanin forms which signifys loss of neurones
201
What is the therapeutic aim to treat PD?
Increase DA neurotransmission in the striatum
202
What type of drugs decrease dopamine transmission?
Antipsychotics/ antiemetics
203
What are the dopamine precursors?
Tyrosine and L-DOPA
204
What does dopamine also produce?
Noradrenaline
205
What are the broader system level effects of losing dopamine?
Reduced NA levels
Altered release and re-uptake
Compensatory hyperactivity
Worsened cognitive deficits
Exacerbation of motor symptoms
Increased risk of mood disorders
206
What are the features of the basal ganglia circuitry in PD?
Motor cortex stimulates movement via glutamate
Loss of dopamine from SN leads to overactivity of ACh neurones in striatum
Inhibition of thalamus via indirect pathway = reduced movement (bradykinesia)
207
What are the PD-symptomatic medical treatments?
Levodopa
Dopamine receptor agonists (apomorphine)
Selegeline
Entacaptone
208
What is cross talk in PD?
It is the different NT receptors in the same synapse as dopamine
209
What is the function of Amantadine?
It is a weak antagonist of the NMDA receptor which increases DA release and blocks DA reuptake
210
What are the properties of co-administration in PD?
Carbidopa (enzyme inhibitor) - doesn't cross BB so reduced peripheral conversion of levodopa to dopamine (decrees dosage of levodopa + side effects)
211
What is the problem of co-administering carbidopa and levodopa?
More toxicity in the peripheral tissues and less metabolism in GI
212
What are the side effects of levodopa?
Non-Motor: nausea, anorexia, orthostasis, sleepiness, hallucinations
Motor: dyskinesias
213
What are the side effects of dopamine agonists?
Frequent: nausea, sleep attacks, hypotension, compulsive behaviours, LE edema
214
What are the different therapies for PD?
Levodopa, dopamine agonists, MAO-B inhibitors
COMT-inhibitors and others
Deep brain stimulation
215
What are the disease modifying therapies being developed for PD?
α-synuclein targeting therapies
LRRK2 inhibitors
Mitochondrial & antioxidant therpies
GBA modulators
Growth facto & gene therapies
Anti-inflammatory therapies
216
What is Alzheimers disease?
A chronic neurodegenerative disease of the brain resulting in progressive loss of cognitive function
Neurones are lost in the outer layer of the cortex
217
What happens in Alzheimers?
There is a build up of β amyloid into amyloid plaques
218
How are the symptoms modulated in Alzheimers diseases?
Via the cholinergic system (cognitive symptoms)
Drugs target the breakdown of ACh
This doesn't stop the progression of the disease
219
What are the molecular mechanisms that link to Alzheimers disease?
Genetic risk factors
Astrocyte and microglia
neuron
Mitochondrial dysfunction
Oxidative stress
BBB alteration
Aβ
Tau tangles
Immune system
Metal ions imbalance
220
How is dementia related to Alzheimers?
Alzheimers causes dementia (most common form)
221
How were most Alzheimers drugs discovered?
Using genetics - the backup of genetics provides more support for approval of drugs
222
What are the 2 different forms of Alzheimer disease?
Familial and sporadic
223
What is familial Alzheimers disease?
It is early-onset
Unimodal progeroid disease
Autosomal dominant
Genetic linkage
PSEN1&2 and APP
224
What is sporadic Alzheimers disease?
Late onset
General population
SNPs with small effect sizes
GWAS- genome wide associated study
225
What is the largest risk factor for late onset Alzheimers?
ApoE4 genotype
226
What are the genes that cause Alzheimers in familial AD?
Presenilin (PSEN1&2) and Amyloid precursor protein (APP)
227
What is amyloid-β precursor protein (APP)?
Aβ is a small fragment of APP (transmembrane protein)
Function not completely known - implicated in neuronal stem cell development, signalling systems promoting growth of axonal and dendritic process, synaptic maintenance, synaptic plasticity, lipid homeostasis
228
How is APP processed?
Non-amyloidogenic pathway:
APP + α-secretase = sAPPα + c83
sAPPα + C83 + γ-secretase = p3 and AICD
Amyloidogenic pathway:
APP + β-secretase = C99 + sAPPβ
C99 + sAPPβ + γ-secretase = Aβ(TOXIC) + AICD(regulates gene expression)
229
What is gamma secretase?
A complex of 4 proteins
PSEN1(presenilin-1)
Nicastrin
APH-1(anterior pharynx-defective 1)
PEN-2(presenilin enhancer 2)
Cleavage of substrates in the membrane (APP, e.g. notch)
230
How is γ-secretase production linked to Aβ?
The cleavage generates slightly different sizes Aβ peptide
Variable protein cleavages and then nibbling of the cut ends
EO-FAD mutations in PSEN or APP: increase in the Aβ
231
What happens when γ-secretase increases the production of Aβ?
EO-FAD mutations in PSEN or APP: increase in the Aβ 40:42 ratio
More toxic forms of Aβ produced (42)
Aggregation/oligomerisation increase
Cell death increase
Dementia
232
What does it mean if there are many mutations in the APP protein?
They could increase the amyloidogenic processing of APP
Increase Aβ1-42 production
Increase neurotoxicity
Alzheimers disease
They don't always increase Aβ
Reduce amyloidogenic processing of APP
Less Aβ1-42 production
Neuroprotection
AD protection
233
Where is the APP gene located?
On chromosome 21
Meaning there is an increased predisposition of AD in people with Down's syndrome (most often by the age of 40)
>50% downs syndrome develop dementia (from AD)
234
What are the 2 pathological hallmarks of AD?
Extracellular amyloid plaques
Intracellular neurofibrillary tangles
235
What are the disadvantages of mutations in tau gene (MAPT)?
It is linked to other forms of dementia (fronototemproal demential)
236
What is MAPT?
Microtubule associated protein tau
237
What are the features of MAPT?
Nucleus in soma
Long axons
Proteins, Organelle transported from cell body to synapse
Essential role in active transport of axonal proteins, vesicles and organelles throughout the axon
Essential for synaptogenesis and activity induced synaptic plasticity
238
What is the role of tau in AD?
In AD microtubules collapse meaning tau is free so it aggregates in neurofibrillary tangles
239
What is the amyloid cascade hypothesis?
It is APP combining with mutations in chromosome 21 and PSEN1/2 FAD mutations
Aβ42 aggregation forming soluble forms of oligomeric Aβ and deposited amyloid-β peptide which creates aggregate stress
Forms paired helical filaments
Meaning neuronal dysfunction and death
Leading to dementia
240
What are the new therapeutic strategies for AD?
BACE1 inhibitors
γ-secretase inihibtors
Aβ antibodies
Tau-based drugs
241
How are monoclonal antibodies used in AD?
They have specific sequences to opsonise the amyloid plaques as they are recognised by the Fc region of the antibody and microglia
242
How would monoclonal antibodies targeting amyloid β work?
They promote phagocytosis and stop the amyloid sticking which allows the plaques to unravel
243
What are the different monoclonal antibodies used in AD?
Aducanumab (targets plaque)
Donanemab (targets plaque)
Gantenerumab (targets plaque)
Lecanemab (targets protofibril)
244
What are the features of aducanumab?
It does increase the clearance of Aβ
More data required
Increasing dose over a year (cannot be used for a prolonged period e.g. lifetime)
245
What is an opioid?
A compound with morphine-like activity
246
What is an opiate?
Substance extracted from opium
Exudate of unripe seed capsule of Papaver somniferum
Contains 2 types of alkaloids
247
What are the different phenanthrene derivatives?
Morphine
Codeine
248
What is the pathophysiology of pain?
It is ill-defined, unpleasant sensation, evoked by external or internal noxious stimulus
Analgesics can be used to relieve the pain without altering consciousness
249
What are the 2 components of pain perception?
Nociceptive (process and sense) and affective (psychological)
250
What is nociception?
It is the sensory nervous system's processes of encoding potentially harmful stimuli
Nociceptors to CNS (sensory detect through nociceptors)
251
What are the steps of nociception?
Transduction
Transmission
Modulation
Perception
252
Name the drugs used to modulate pain perception
Acetaminophen, A2 agonists, COX-2 inhibitors, NMDA antagonists, opioids
253
Name the drugs used to modulate pain
Acetaminophen, anticonvulsants, neuraxial opioids, NMDA antagonists
254
Name the drugs used to modulate pain transmission in the dorsal horn
A2 agonists, COX-2 inhibitors, local anaesthetics and opioids
255
Name the drugs used to modulate pain transmission peripheral nerve
Anticonvulsants and local anaesthetics
256
Name the drugs used to modulate pain transduction
COX-2 inhibitors, local anaesthetics and NSAIDs
257
What do anaesthetics target?
Voltage-gated Na+ channels
258
What are the different types of opioid receptors?
μ (mu) (MOP), δ (delta) (DOP), κ (kappa) (KOP) and NOP
259
Which opioid receptors are naloxone sensitive?
MOP, DOP and KOP
260
Which receptor releases the endogenous protein endomorphin?
MOP
261
Which receptor releases the endogenous protein enkephalin?
DOP
262
Which receptor releases the endogenous protein dynorphin?
KOP
263
Which receptor releases the endogenous protein Nociceptin/Orphanin FQ (N/OFQ)?
NOP
264
What pathway do opioid receptors stimulate?
Gi of GPCR which produces:
Inhibition of VG Ca2+ channels
Allows K+ transport
Adenylate cyclase reduced cAMP
MAPK activation
265
Which NTs are impacted when VG Ca2+ channels close on the presynaptic neurone?
Glutamate, ACh, NA, serotonin and substance P
266
Where are mu receptors located which produce analgesia when activated?
Suraspinal (thalamus, insular cortex, amygdala, hypothalamus and more)
Spinal cord (dorsal horn)
Periphery
267
Which receptor are opioids most likely to act on?
Opioid analgesics primarily act on the mu receptor (analgesia, euphoria, respiratory depression and physical dependence)
268
What are the features of butorphanol and nalbuphine?
MOR & KOR antagonists (KOR preference)
Visceral and inflammatory pain
Greater in females
KOR upregulation potentiates reward-related effects of drug abuse in males only
269
What is the function of MOR?
Pain perception and sensorimotor integration
270
What is the function of KOR?
Pain perception and neuroendocrine function
271
What is the function of DOR?
Motor, olfactory and cognitive functions
272
What are the different classes of opioids?
Natural
Semi-synthetic
Fully synthetic
Endogenous
273
What are natural opiates?
Alkaloids contained in resin of opium poppy (codeine, morphine and thebaine)
274
What are semi-synthetic opiates?
Created from natural opioids (hydromorphone, oxycodone and diacetylmorphine (heroin))
275
What are fully synthetic opiates?
Fentanyl, methadone and tramadol
276
What are endogenous opioid peptides?
Produced naturally in the body (endorphins, enkephalins, dynorphins and endomorphins)
277
What is the chemical link between opioids?
There is no clear link between structure and activity
But are described based on chemistry
Phenanthrene (morphine and codeine)
Phenylheptylamines (methadone)
Phenylpiperidines (fentanyl)
Morphinans (butorphanol)
278
What are the different modes of action of opioids?
Full or partial mu-opioid receptor agonist (partial has less respiratory depression)
279
What is an example of an opioid that is a full agonist?
Methadone (mu receptor)
280
What are examples of opioids that are partial agonists?
Buprenorphine (MOR, KOR and DOR)
Naltrexone (KOR)
Nalmefene (KOR)
281
What are examples of opioids that are partial agonists?
Naltrexone (MOR)
Nalmefene (MOR)
282
What are the least and most potent drugs in comparison to morphine?
Codeine dihydrocodein (least 1/10)
Fentanyl (most 100x)
283
What is used to compare the therapeutic ranges of drugs?
LD50/IC50 (relative potency of analgesic)
284
What are the effects of agonists at the mu receptor?
Analgesia
Anaesthetic/sedation
Depress respiration
Euphoria
285
What are the other side effects of agonists at opioid receptors?
Anti-tussive (cough suppressant)
Reduction in GI motility
Contraction of pupils
286
What does morphine get metabolised too?
Morphine-3-glucuronide (neuroexcitatory)
Morphine-6-glucuronide (4-6x potent)
Accumulation gives unexpected results
287
Which semi-synthetic opioid has similar metabolism to morphine?
Hydromorphone
288
Which chemical class of opioids are rapidly hydrolysed?
Esters
289
How are phenylpiperidine opioids metabolised?
Hepatic - oxidative metabolism
Meperidine, fentanyl, alfentanil and sufentanil
Normeperidine causes seizures in renal failure
290
Why are the precise mechanism of opioids unknown?
Because it is difficult to monitor the level of response and levels of different drugs
291
What is biotin used for in opioids?
It labels the drug which clearly shows the areas of the brain effected by that drug
292
How many MOP are there?
3
293
How many DOP are there?
2
294
How many KOP are there?
K1: a,b
K2: a,b
K3
295
What happens when an opioid acts on a receptor?
Causes analgesia which decreases neuronal transmitter release and decreases nociceptive impulse propagation (pain threshold increased)
296
How do opioids activate reward pathways?
They inhibit the activity of the nucleus accumbens output neurones which releases dopamine
297
What is tolerance?
A state in which response to given concentrations of a drug is reduced
More drug has to be given to achieve the same response
298
How does tolerance take place in the μ receptors?
Receptor adaptation
299
What happens in opioid overdose?
It leads to respiratory depression thereby causing death
300
What are opioids good for?
Treating dull, constant pain rather than sharp, periodic pain
301
What are the different side effects of opioids?
Depression of respiratory centre
Constipation
Excitation
Euphoria
Addiction
Nausea
Pupil constriction
Tolerance and dependence
Bradycardia
302
What are the future ideas of opioid development?
Using different balanced ligands which stimulate different pathways (cAMP or arrestin MAPK)
303
Which drugs have been shown to have biased agonism?
Morphine at μ promotes more of the arrestin pathway and inhibits the cAMP (analgesia) pathway leading to respiratory depression, etc.
Where as oliceridine only stimulates G-protein which produces analgesia
304
What effect does MOR have on mood and reward?
Mood: decreased anxiety and depressive-like behaviours
Reward: essential for reinforcing effects of opioids
305
What effect does DOR have on mood and reward?
Mood: Increased anxiety and depressive-like behaviours
Reward: modulates ethanol self-administration
306
What effect does KOR have on mood and reward?
Mood: no change in baseline anxiety
Reward: Involved in stress and anti-reward systems
307
What are the different effectors from opioid receptors?
Channels
β-arrestins
GRKs
Protein kinases
PKC and PKA
CaMK
MAPKs
308
What are the different ligands that bind to opioid receptors?
Endogenous and exogenous (orthosteric and allosteric)
