4. Nervous System Flashcards
1
Q
What are the divisions of the Nervous System?
A
-Central Nervous System
-Peripheral Nervous System
-Enteric Nervous System
2
Q
What are the divisions of the Peripheral Nervous System?
A
-Sensory Nervous System
-Motor Nervous System
3
Q
What are the divisions of the Motor Nervous System?
A
-Autonomic Nervous System
-Voluntary Nervous System
4
Q
What neurotransmitter aids in general neuronal excitation (and give the type of receptor)
A
-Glutamate
-LGIC and GPCR
5
Q
What neurotransmitter aids in general neuronal inhibition (and give the type of receptor)
A
-GABA
-LGIC and GPCR
6
Q
What neurotransmitter aids in reward signalling (and give the type of receptor)
A
-Dopamine
-GPCR
7
Q
What neurotransmitter aids in mood regulation (and give the type of receptor)
A
-Serotonin
-LGIC and GPCR
8
Q
What neurotransmitter aids in the alerting network (and give the type of receptor)
A
-Noradrenaline
-GPCR
9
Q
Give classes of neurodrugs
A
-Sedatives
-Hypnotics
-Anticonvulsants
-Anxiolytics and Antidepressants
-Antipsychotics
-Mood stabilisers
10
Q
What is the purpose of sedatives?
A
-Calming effect
-Used for acute anxiety or agitation, muscle relaxation, preoperative sedation, mild insomnia
11
Q
What is the purpose of hypnotics?
A
-Sleep inducing
-Short term treatment of insomnia , and inducing sleep before surgeries
12
Q
What is the purpose of anticonvulsants?
A
-Seizure inhibition
-Treating epilepsy and various causes of seizures, treating neuropathic pain
13
Q
What is the purpose of anxiolytics and antidepressants?
A
-Reduce anxiety/depression
-Treating acute anxiety, panic disorders, major depressive disorder, OCD, PTSD
14
Q
What is the purpose of antipsychotics?
A
-Neuroleptics, reducing psychosis
-Used for schizophrenia, bipolar disorder, severe depression, delirium and agitation
15
Q
What is the purpose of mood stabilisers?
A
-Antimanic and antidepressant effects
-Used for bipolar disorder, preventing mood swings between mania and depression, also used for borderline personality disorder
16
Q
Describe the key distinctions between GABA-A and GABA-B receptors
A
-GABA-A is ionotropic (directly controls ion channels), while GABA-B is metabotropic (involves G-protein signaling).
-GABA-A receptors involve Cl⁻, leading to rapid hyperpolarization.
GABA-B receptors influence K⁺ channels and sometimes Ca²⁺ channels, leading to a more gradual inhibitory effect.
17
Q
Describe the structure of the GABA-A receptors
A
-Pentameric
-Made up of five subunits (chosen from 19)
-Which determine the pharmacological and functional characteristics of the receptor
18
Q
Describe what barbiturates target, and their mechanism of targeting
A
-Target GABAa
-Binding ot an allosteric site on the receptor (positive allosteric modulators)
-Increases the duration of chloride ion channel opening
-Not as subtype specific as others
19
Q
Give examples of commonly used barbiturates
A
-Pentobarbital
-Butobarbital
-Phenobarbital
-Sodium barbital
20
Q
Describe the uses of barbiturates
A
-Sedative: Barbiturates produce calming effects by suppressing excessive neural activity, making them useful for treating anxiety and inducing sleep.
-Hypnotic: At higher doses, barbiturates can induce sleep, and they have been used in the treatment of insomnia.
-Anticonvulsant: Barbiturates are effective in seizure control (e.g., phenobarbital is used as an anticonvulsant) due to their global suppression of neuronal excitability.
-Muscle Relaxation: Their sedative effects also help in muscle relaxation.
21
Q
Describe the different uses of barbiturates based on duration of action, and give examples
A
-Short-acting barbiturates (e.g., thiopental) are used for induction of anesthesia. It has a high lipid solubility, allowing it to cross the blood-brain barrier quickly and produce rapid effects.
-Long-acting barbiturates (e.g., phenobarbital) are used for seizure control and as a sedative in some chronic conditions. They enhance inhibition, resulting in neuroinhibition and suppression of neural activity.
22
Q
How can barbiturate overdose be lethal?
A
-Due to severe CNS depression
-Leading to respiratory failure, cardiovascular collapse, and organ failure
23
Q
Name the antidotes to barbiturates based on dosage.
A
-Low doses of barbiturates: Bicucuclline (competitive antagonist)
-High doses of barbiturates: Picrotoxin (non-competitive antagonist)
24
Q
Describe what benzodiazepines target, and their mechanism of targeting
A
-GABAa
-Bind to the benzodiazepine site
-Increasing the frequency with which the channel opens
25
Give examples of commonly used benzodiazepines
-Diazepam (Valium for sedation and anxiety)
-Alprazolam (Xanax for sedation and anxiety)
-Temazepam (Restoril for sleep aid)
-Midazolam (versed sedation, anxiolysis and amnesia)
26
Describe the uses of benzodiazepines
-Anxiolytic (Anti-anxiety): Benzodiazepines are primarily used for anxiety disorders, where they help reduce the overactivity of the brain regions involved in anxiety responses.
-Sedative/Hypnotic: Many benzodiazepines are used to treat insomnia due to their ability to induce sleep by enhancing the GABAergic inhibition in the brain.
-Muscle Relaxant: Benzodiazepines also have a muscle-relaxing effect, which is helpful in treating conditions like muscle spasms and spasticity.
-Anticonvulsant: Some benzodiazepines, such as diazepam and lorazepam, are used to control seizures due to their ability to suppress abnormal electrical activity in the brain.
-Amnesic Effects: High doses of benzodiazepines can lead to anterograde amnesia (difficulty forming new memories), which is sometimes used intentionally in medical procedures (e.g., in conscious sedation).
27
Give the drawbacks to Benzodiazepines
-Although BZDs do not induce pharmacokinetic tolerance, they do still cause pharmacodynamic tolerance (downregulation of receptors over time)
-Tolerance develops to hypnotic and myorelaxant effects within days to weeks and to anticonvulsant and anxiolytic effects within weeks to months
-Withdrawal of dose can lead to rebound symptoms (return of original symptoms, but often more severe) and physical withdrawal symptoms such as depression, suicidal behaviour, psychosis, seizures, and delirium tremens
28
Describe the issue surrounding benzodiazepine metabolism
-Some benzodiazepines are metabolized in the liver into active compounds that continue to have a pharmacological effect.
-These metabolites can prolong the drug’s action, sometimes leading to prolonged sedation or CNS depression, which can be problematic
29
Describe flumazenil
-Benzodiazepine competitive antagonist used as a reversal agent for BZD overdose or toxicity
-Short half life, meaning it may need to be administered multiple times
-Flumazenil can precipitate withdrawal symptoms, including anxiety, agitation, seizures, and tachycardia.
29
Describe Z drug hypnotic agents
-Similar MOA to BZDs, but structurally unrelated
-Positive allosteric modulators of GABA A receptors (probability of opening)
-In contrast to BZDs, which non selectively bind to and activate all BZ receptor subtypes, Z drugs show preference for the a1 containing receptors, which may explain the relative absence of myorelaxant and anticonvulsant effects, as well as the relative preservation of deep sleep
30
Give types of neuronal inhibition
-Feedforward
-Feedback
-Lateral
31
What can be used to monitor seizures?
Electroencephalogram
32
What is the main cause of seizures
-Imbalance between excitation and inhibition
-ie Excessive glutamate activity via overactivation of NMDA and AMPA
-Reduced GABA activity, meaning less inhibition by GABAa and GABAb
33
Describe the initiation of seizures
-Neurones experience sudden, prolonged bursts of depolarisation leading to repetitive action potentials
-Causing paroxysmal depolarising shift
-Hyperexcitable neurones recruit nearby neurones, amplifying seizure activity, leading to hypersynchronisation with distal seizure propagation
33
What is paroxysmal depolarising shift
-Sudden, prolonged depolarisation of neurones due to excessive glutamate-mediated excitation
-And failing surround GABA inhibition, preventing seizure spread
-DEFINING FEATURE OF EPILEPTIC NEURONES
34
Describe focal seizures
-Begin in a specific area
-Symptoms depend on affected region
-May stay localised or spread to generalised seizures
35
Describe generalised seizures
-Originate from widespread, synchronised cortical activity
-Involving both hemispheres from the start
36
Describe the link between focal and generalised seizures, and how they may spread
-Focal seizures can spread via key pathways to become generalised (focal to bilateral tonic-clonic)
-Spread may occur through corpus callosum or thalamocortical circuits
37
Describe the role of pathological voltage gated Na+, K+ and Ca2+ channels in epilepsy
-Na+: Repetitive action potential firing
-K+: Abnormal action potential repolarisation
-Ca2+: Excess transmitter release, activates pathophysiologic intracellular process
38
Describe the role of pathological non-NMDA, NMDA and GABA receptors in epilepsy
-Non-NMDA: Maintains PDS
-NMDA: Initiates PDS; Ca2+ activates pathophysiologic intracellular processes
-GABA: Limits excitation (fails to)
39
Describe the treatment guidelines for focal seizures
-Lamotrigine and levetiracetam for first line treatment
-Then carbamazepine, sodium valproate and zonisamide
40
Describe the treatment guidelines for tonic-clonic seizures
-Sodium valproate for first line treatment
-Lamotrigine is alternate but may exacerbate myoclonic seizures
41
Describe the treatment guidelines for absence seizures
Ethosuximide or sodium valproate
42
Describe the treatment guidelines for myoclonic seizures
-Sodium valproate as first line
-Levetiracetam is second line or for females of child bearing age
43
Describe the treatment guidelines for atonic and tonic seizures
Sodium valproate with lamotrigine as adjunct if necessary
44
Describe examples of anticonvulsants exacerbating seizures
-Carbamazepine, oxcarbazepine, and phenytoin can exacerbate absence and myoclonus seizures
-Gabapentin, pregabalin, tiagabine and vigabatrin can exacerbate myoclonic seizures
45
Describe how pharmacokinetics of anticonvulsants impacts treatment
-Most drugs approved as anticonvulsants have longer half life, so can be taken once or twice a day
-Higher doses are given by increasing number of times per day the drug is taken, in order to minimise bolus dose, in order to reduce adverse effect risk
46
Give the targets for anticonvulsant drugs
-Voltage gated Na+ channel
-Voltage gated K+ channel
-Voltage gated Ca2+ channel
-Non NMDA receptor (Maintains PDS)
-NMDA receptor (initiates PDS)
-GABA receptors
46
Are seizures dangerous?
-Seizure itself does not cause any distinct damage to the brain
-Apart from injuries from falling and seizing
47
Describe the action of classical anticonvulsants target VGSCs
-Bind inactivated Na+ channels (which are more frequent in rapidly firing neurones during seizures)
-Preventing repetitive firing without significantly affecting normal neuronal activity
-This slows Na+ channel recovery, reducing the likelihood of repeated uncontrolled firing
-By limiting Na influx, excessive depolarisation is prevented, stopping the paroxysmal depolarising shift
48
Give examples of drugs utilising a use dependent blockade against VGSCs to target seizures
-Phenytoin
-Carbamazepine
-Valproic acid
-Lacosamide
-Lamotrigine
49
Describe phenytoin as anticonvulsants
-Voltage dependent blockade of fast sodium current
-Known teratogen, causing craniofacial anomalies and a mild form of mental retardation
-Licensed for tonic clonic and focal seizures but may exacerbate absence or myoclonic seizures
-Narrow therapeutic index and non linear pharmacokinetics, small dosage increases in some patients may produce large increases in plasma concentration with acute toxic side effects
-Complex drug drug interactions
49
Give some common adverse reactions with phenytoin
-Neurologic effects
-Hirsutism
-Gingival hyperplasia
-Impaired insulin secretion
-Mild neuropathy
-Rash
50
Describe carbamazepine as anticonvulsants
-Carbamazepine is a primary drug for the treatment of generalized and focal
seizures.
-It is also used for the treatment of trigeminal neuralgia.
-Related chemically to the tricyclic antidepressants.
-Like phenytoin, carbamazepine limits the repetitive firing of action potentials
evoked by a sustained depolarization
-ie Use dependent blockade
51
Describe the adverse reactions associated with carbamazepine
-Acute intoxication with carbamazepine can result in stupor or coma,
hyperirritability, convulsions, and respiratory depression.
-During long-term therapy, the more frequent AEs include drowsiness, vertigo,
ataxia, diplopia, and blurred vision. The frequency of seizures may increase,
especially with overdose.
-Generally safe and well tolerated, but short half life requires TID dosage
52
Describe lamotrigine as anticonvulsants
-Acts on both VGSCs and VGCCs
-Like phenytoin, suppresses sustained rapid firing of neurons via inactivated
state; probably explains lamotrigine’s efficacy in focal epilepsy.
-Also inhibits voltage-gated Ca2+ channels, (N- & P/Q-type) which may account
for efficacy in primary generalized seizures in childhood, including absence
attacks. This leads to a decrease in the synaptic release of glutamate
-Also used in bipolar disorder
53
Describe the adverse reactions surrounding lamotrigine
-Generally safe and well tolerated
-Most common ADR is rash; can be serious including Stevens-Johnson
syndrome, toxic epidermal necrolysis, and/or rash-related death
53
Describe valproate/valproic acid as anticonvulsants
-At least 4 significant anticonvulsant MOAs
-VGSCs – prolongs inactivated state like phenytoin & Carbamazepine
-Inhibits low threshold T-type VGCCs
-Increases GABA through inhibition of GABA transaminase and up
regulating glutamate decarboxylase
-Inhibitor of histone deacetylase (HDAC). Thus, some of its antiseizure
activity may be due to its ability to modulate gene expression through
this mechanism
54
Describe the adverse reactions surrounding valproate/valproic acid
-Generally safe and well tolerated within therapeutic window.
-CNS effects: sedation, ataxia, tremor
-GI effects
-Risk of Hepatotoxicity and pancreatitis
-Has high levels of plasma binding, so can increase free
concentration of other drugs.
-Prolongs duration of action of many drugs including barbiturates,
BZDs, and narcotics.
-Major risk of congenital malformations
55
Describe lacosamide as anticonvulsants
-Anticonvulsant
-Enhancing Slow Inactivation of Voltage-Gated Na⁺ Channels
-Unlike classical Na⁺ channel blockers (e.g., phenytoin, carbamazepine), which target fast inactivation, lacosamide selectively enhances slow inactivation.
-This reduces excessive neuronal excitability while preserving normal physiological firing.
56
Describe direct anticonvulsant agents that act on inhibitory transmission via GABA
-Barbiturates and BZDs, positive allosteric modulators of GABAa
-Increase either Probability of opening or mean channel open time.
-BZDs (especially diazepam) is first choice for status epilepticus
56
Give indirect anticonvulsant agents that act on inhibitory transmission via calcium channels
-Gabapentin (elevates GABA synthesis)
-Pregabalin
57
Give different anticonvulsant drugs and their targets in decreasing excitation (excluding VGSCs)
-Perampanel: AMPA receptors
-Felbamate: GABA and NMDA receptors
-Topiramate: VGSCs, GABA, plus AMPA receptors
58
Describe the mechanism of action of levetiracetam and brivaracetam as anticonvulsants
-MOA mediated by binding to synaptic vesicle protein 2 (has a role in seizures)
-Reduces short term plasticity at glutamatergic synapses, may alter protein-protein interactions at the synapse
-Generally safe and well tolerated, but should be avoided in psychiatric patients
59
Describe ethosuximide as anticonvulsants
-Mainly used for absence seizures
-Targets T type VGCCs, reducing the current
60
Give types of depression
-Major depression
-Persistent depressive disorder
-Bipolar disorder
-Seasonal affective disorder
-Psychotic depression
-Postpartum depression
-Premenstrual dysphoric disorder
61
What is likelihood of depression correlated with?
More so with previous depression than recent life stress
62
Give the risk factors for depression
30 to 40% is genetically mediated
Other 60 to 70% if environmental, eg
-Adverse events in childhood
-Ongoing or recent stress due to interpersonal adversities (including childhood sexual abuse)
-Other lifetime trauma
-Low social support
-Mairital problems and divorce
63
Give the link between depression and chronic pain, and reasons for this
-Chronic pain can worsen depression symptoms and is a risk factor for suicide
-Bodily aches and pains are a common symptom, and those with more severe depression feel more intense pain
-Depressed have higher levels of cytokines, which trigger pain by promoting inflammation
64
Describe types of therapies used to treat depression
Cognitive behavioural therapy helps the patient see how behaviours and the way they think about things plays a role in their depression.
-Interpersonal therapy focuses on the patient’s relationships with other people and how they affect them.
-Problem-solving therapy focuses on the specific problems faced by the patient and helps them find solutions.
65
Describe the neurotransmitter pathophysiology of General anxiety disorder
-Decreased GABAergic inhibition
-Increased Glutamatergic activity
-Serotonin dysfunction
-Noradernaline hyperactivity from locus coeruleus
66
Describe the neural circuit pathophysiology of general anxiety disorder
-Amygdala overactivity (leading to constant fight or flight)
-Prefrontal cortex hypofunction (reduced regulation of amygdala)
-Hippocampal dysfunction (inability to distinguish between real and perceived threats, leading to exaggerated responses to minor stresses)
67
Describe the neurotransmitter pathophysiology of Depression
-Monoamine hypothesis suggests imbalances:
-Decreased serotonin (mood dysregulation and increased anxiety)
-Decreased noradrenaline (impaired arousal, energy and motivation)
-Decreased dopamine (contributes to anhedonia/loss of pleasure)
68
Describe the neural circuit pathophysiology of Depression
-Prefrontal cortex hyperactivity (poor emotional control and persistent negative thoughts)
-Amygdala hyperactivity (heightened stress sensitivity and excessive negative emotions)
-Loss of hippocampus volume (worsened mood regulation)
69
Describe the mechanism of action of most antidepressants, and give examples
Most antidepressants either modulate monoamine uptake or synthesis
-TCAs reduce monoamine reuptake
-SNRIs block 5HT and NE uptake
-SSRIs block 5HT uptake
-MAOIs block monoamine metabolism
70
Give some drug classes used for anxiety
-SNRIs
-SSRIs
-TCAs
-MAOIs
-Atypical antidepressants
-Pregabalin
-Melatonergic antidepressants
-BZDs
71
Give some drug classes used for depression
-TCAs
-SSRIs
-SARIs
-SNRIs
-NRIs
-NaSSAs/Tetracyclines
-MAOIs including RIMAs
-Atypical antidepressants
-Melatonergic antidepressants
72
What is the action of Monoamine oxidase, including A and B
-MAOA degrades amine neurotransmitters (DA, NE, 5HT) via oxidative deamination. Also acts on tyramine
-MAOB principally metabolises DA and so has no consequences for tyramine intake
73
Give examples of SSRIs
-Citalopram
-Escitalopram
-Fluoxetine
-Paroxetine
-Sertraline
73
Describe how benzodiazepines are used adjunctively alongside SSRIs, SNRIs or other antidepressants
-Antidepressants take 2-6 weeks to show full efficacy
-BZDs provide immediate symptom relief
-Meaning they can be used as a temporary stopgap
74
Describe the mechanism of action of SSRIs, and why they have a delayed onset of effect
-SSRIs inhibit SERT, preventing serotonin re-uptake into presynaptic neurones, increasing serotonin levels in the synapse
-Over time, 5HT1A auto receptors (on presynaptic neurones) down regulate due to prolonged serotonin exposure
-Removing inhibition of serotonin release, leading to greater synaptic serotonin availability
75
Describe Citalopram as a SSRI
-Selective SERT inhibition (very high specificity)
-Few drug interactions
-QT prolongation risk at high doses
-Risk of suicide in adolescents
76
Describe Escitalopram as a SSRI
-More selective and potent than citalopram
-Fewer side effects Tham citalopram
-QT prolongation risk at high doses
-Risk of suicide in adolescents
77
Describe Fluoxetine as a SSRI
-Longest half life (4-6 days)
-Less withdrawal risk
-Potent CYP2D6 inhibitor
-Can cause initial agitation/insomnia
-Risk of suicide in adolescents
78
Describe Paroxetine as a SSRI
-Strong anxiolytic properties (good for GAD, PTSD)
-Anticholinergic effects (sedating)
-Shortest half life, with high withdrawal risk
-Potent CYP2D6 inhibitor
-Risk of suicide in adolescents
79
Describe Sertraline as a SSRI
-Mild dopamine re-uptake inhibition
-Good for both depression and anxiety
-Most widely prescribed with mildest ADRs (nausea, diarrhoea)
-Can cause initial agitation/insomnia
-Risk of suicide in adolescents
80
Give common adverse reactions associated with SSRIs and SNRIs
-Nausea
-Sexual dysfunction
-Agitation
-Weight gain
-Insomnia
-Mild anxiety (leading to non adherence)
-Serotonin syndrome
-Suicidal ideation
81
Describe the common characteristics found in SSRI discontinuation syndrome
FINISH
-Flu like symptoms
-Insomnia
-Nausea
-Imbalance
-Sensory disturbances
-Hyperarousal
82
Describe the mechanism of action of tricyclic antidepressants in depression
-Inhibit serotonin transporter (SERT) increasing 5HT
-Inhibit noradrenalin transporter, increasing NA
-However aren't very selective, acting on histamine, muscarinic, adrenergic receptors
83
Give common side effects associated with Tricyclic antidepressants
-Blurred vision,
-Dry mouth,
-Constipation,
-Orthostatic hypotension
-Urinary retention
-Rash, hives
-Tachycardia
-Increased risk of seizures
84
Describe what occurs during Tricyclic antidepressant overdose
-TCAs have a 24-76-hour half-life which extends in OD.
-Inhibition of α‐adrenergic receptors ‐> hypotension related to tricyclic antidepressant overdose.
-Tricyclic antidepressants also inhibit cardiac VGSCs, -> slowed cardiac conduction, prolonged QRS complex and atrioventricular block.
85
Describe venlafaxine as an antidepressant
-Potent inhibitor of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake.
-Unlike TCAs, SNRIs have minimal or no pharmacological action at adrenergic (α1, α2, and β), histamine (H1), muscarinic, dopamine, or postsynaptic serotonin receptors
-Venlafaxine functions like an SSRI in low doses (37.5 mg/day) and as a dual mechanism agent affecting serotonin and norepinephrine at doses above 225 mg/day
86
Name some "rapid acting antidepressants"
-Psylocibin
-Ketamine
-Electroconvulsive therapy
87
Describe treatment-resistant depression
-Treatment-resistant depression (TRD) refers to major depressive disorder (MDD) that fails to respond to at least two adequate trials of different antidepressants from different classes.
-It is a significant clinical challenge, affecting 20–30% of depressed patients.
88
What is psychosis?
-Psychosis is a broad symptom characterised by a disconnection from reality, affecting thoughts, perceptions and behaviours
-Core features include hallucinations, delusions, disorganised thinking, and impaired reality testing
89
What is schizophrenia?
-Severe chronic psychiatric disorder characterised by persistent psychotic symptoms, including cognitive and emotional dysfunction
90
What are the types of symptoms of schizophrenia
-Positive symptoms (excess of normal function)
-Negative symptoms (loss of normal function)
-Cognitive symptoms
91
Give examples of positive symptoms of schizophrenia
-Hallucinations
-Delusions
-Disorganised speech and behaviour
-Catatonia or abnormality in movements
92
Give examples of negative symptoms of schizophrenia
-Social withdrawal
-Flat effect (reduced emotional expression)
-Lack of pleasure
-Lack of motivation
93
Give examples of cognitive symptoms of schizophrenia
-Poor memory
-Difficulty in decision making
-Poor judgement and insight
-Poor concentration and attention
-Impaired sensory perception
94
What drug types may induce schizophrenia?
-Dopaminergic drugs (main contributor) eg amphetamines, cocaine, levodopa
-NMDA antagonists eg ketamine, PCP
95
What areas of the brain are indicated to be involved in the dopamine hypothesis for schizophrenia?
-Mesolimbic pathway: positive symptoms
-Mesocorticol pathway: negative symptoms
-Nigrostriatal pathway: side effects
-Tuberoinfundibular pathway: side effects
96
Since the dopamine hypothesis is an oversimplification, which neurotransmitters are involved in causing negative symptoms?
-Serotonin
-Glutamate
-GABA
97
Since the dopamine hypothesis is an oversimplification, which neurotransmitters are involved in causing cognitive symptoms?
-Acetylcholine
-Glutamate
-Serotonin
98
Describe the D1-like subfamily of dopamine receptors
-D1 and D5 receptors
-Activation leads to increased intracellular cAMP via Gas signalling
-EXCITATORY
99
Describe the D2-like subfamily of dopamine receptors
-D2, D3, D4 receptors
-Activation leads to decreased intracellular cAMP via Gai signalling
-INHIBITORY
100
Describe the mechanism of action of typical/first generation antipsychotics
-Dopamine D2 receptor antagonists
-Blocking in the mesolimbic pathway, however side effects come from blocking in the nigrostriatal pathway and tuberoinfundibular pathway
101
Describe chlorpromazine as an antipsychotic
-Mechanism: D2 receptor antagonist but also blocks alpha-1, histamine (H1), and muscarinic receptors, leading to sedative and anticholinergic effects.
-Indications: Schizophrenia, mania, and nausea/vomiting (e.g., as a pre-anesthetic).
-Side Effects: Sedation, orthostatic hypotension, anticholinergic effects (dry mouth, constipation, blurred vision), EPS, and weight gain.
102
Give examples of typical/first generation antipsychotics
-Chlorpromazine
-Benperidol
-Flupentixol
-Haloperidol
103
Give some typical side effects associated with typical antipsychotics
-Extrapyramidal symptoms (movement related)
-Neuroleptic malignant syndrome (life threatening)
-Prolactin elevation
-Anticholinergic effects
-Sedation and othrostatic hypotension
104
Describe the symptoms of Parkinson's disease
-Motor symptoms (bradykinesia, resting tremor, rigidity)
-Autonomic dysfunction (Orthostatic hypotension, constipation, urinary issues)
-Neuropsychiatric (depression, anxiety)
-Sleep disorders (insomnia)
-Sensory changes (loss of smell, pain)
105
Describe the neurophysiology of Parkinson's disease
Caused by:
-Dopaminergic neuron degeneration in substantia nigra
-Lewy bodies composed of a-synuclein accumulate in surviving neurones, corresponding to oxidative stress, mitochondrial dysfunction and inflammation
-Basal ganglia circuit dysfunction, with overactive indirect pathway
106
Describe where in the brain dopamine producing neurones are lost in Parkinson's disease
-Substantia nigra pars compacta
-Reducing DA levels in the striatum (caudate { putamen)
-This disrupts the basal ganglia circuits
107
Describe how disruption of the basal ganglia circuit causes Parkinson symptoms
-Direct (movement facilitation) and indirect (movement inhibition) pathways are unbalanced
-Less activation of D1 receptors on STN→ weaker direct pathway → reduced movement.
-Less inhibition of D2 receptors in thalamus → stronger indirect pathway → excessive movement suppression.
-Resulting in bradykinesia, rigidity and tremors
108
Is Dopamine the only neurotransmitter involved in Parkinson's?
NO
-Ach excess contributes to tremor
-5HT and NA deficits contribute to mood disorders, depression and autonomic dysfunction
-Glutamate overactivity contributes to excitotoxicity ie neurodegeneration
109
Describe the formation of Lewy bodies in Parkinson's disease
-α-Synuclein normally helps regulate synaptic vesicle function and neurotransmitter release.
-In PD, α-synuclein misfolds, forming toxic oligomers and insoluble fibrils.
-These aggregates accumulate into Lewy bodies, disrupting cellular function.
109
Describe how Lewy bodies contribute to Parkinson symptoms
-Mitochondrial Dysfunction: Lewy bodies interfere with mitochondrial energy production, leading to oxidative stress and cell damage.
-ER Stress and Protein Misfolding: Lewy bodies overwhelm the endoplasmic reticulum (ER) and ubiquitin-proteasome system (UPS), impairing the cell’s ability to clear damaged proteins.
-Synaptic Dysfunction: Accumulated α-synuclein disrupts neurotransmitter release, contributing to motor and non-motor symptoms.
110
What is the role of antipsychotics in Parkinson's?
Can reduce dopamine transmission, causing drug-induced Parkinsonism
110
Describe how decreasing dopamine has broader effects at the system level (outside of Parkinson's)
-Reducing precursor for NA, altering NA release and reuptake
-As a result compensatory NA hyperactivity occurs, leading to worsened cognitive deficits, exacerbation of motor symptoms and mood disorders
111
Give the types of symptomatic treatments for Parkinson's disease
-Levodopa and carbidopa
-Dopamine agonists
-MAOb inhibitors
-Amantadine
-Anticholinergics
112
Describe the use of Levodopa and Carbidopa in symptomatic treatment of Parkinson's
-Levodopa crosses the BBB and is converted into dopamine in the brain
-Carbidopa inhibits DOPA decarboxylase in the peripheral, preventing side effects
-Reduces bradykinesia, rigidity, and other Parkinsonism symptoms
113
Describe the use of dopamine agonists in symptomatic treatment of Parkinson's
-Directly stimulate D1 and D2 receptors in the striatum, bypassing the need for dopamine production
-Reduces motor fluctuations, tremors, bradykinesia and rigidity
114
Describe the use of MAOb inhibitors in symptomatic treatment of Parkinson's
-Inhibits monoamine oxidase-B, which breaks down dopamine, prolonging its action
-Mildly improves symptoms, but can be added to Levodopa to reduce "wearing off"
115
Describe the use of anticholinergics in symptomatic treatment of Parkinson's
-Blocks muscarinic cholinergic receptors in the striatum, counteracting dopamine deficiency
-Best for tremors in younger patients, but has anticholinergic side effects
116
Describe the use of Amantadine in symptomatic treatment of Parkinson's
-Increases dopamine release, blocks NMDA glutamate receptors, and has mild anticholinergic effects
-Helps to reduce cross talk
-Reduces dyskinesia's in late PD, providing mild symptoms relief in early PD
117
Give some side effects associated with Levodopa and carbidopa
-Wearing-off effect (symptoms return before the next dose).
-Dyskinesias (involuntary movements, e.g., chorea, dystonia) after prolonged use.
-Hallucinations, confusion, impulse control disorders.
118
Give some side effects associated with dopamine agonists
-Nausea, dizziness, hypotension.
-Hallucinations, impulse control disorders (e.g., gambling, hypersexuality).
-Daytime sleepiness ("sleep attacks").
119
Describe the evolution of Parkinson symptoms
-Early stage: Loss of smell, depression, anxiety
-Early symptomatic: Tremor, bradykinesia, rigidity
-Moderate Parkinsons: Tremor, rigidity, and bradykinesia worsen, more pronounced postural instability, more severe cognitive changes
-Advanced Parkinsons: Severe postural instability, freezing episodes worsen, loss of facial expression, dementia, autonomic dysfunction, hallucinations
119
Give a drug antagonist the effect of levodopa
Phenothiazines
120
Give some treatments for Parkinson's that aim to modify/reduce the disease
-α-Synuclein-Targeting Therapies
-LRRK2 Inhibitors
-Mitochondrial & Antioxidant Therapies
-GBA Modulators (Lysosome Boosters)
-Growth Factor & Gene Therapies
-Anti-Inflammatory Therapies
121
Describe the cholinergic hypothesis for Alzheimer's disease
-AD is caused primarily by the decline in ACh levels due to cholinergic neurone degeneration in the basal forebrain
-Correlating to cognitive decline and memory impairment
122
What treatments for Alzheimer's disease have been created utilising the cholinergic hypothesis
-Acetylcholinesterase inhibitors, preventing ACh breakdown
-Key drugs involved Donepezil, Rivastigmine, Galantamine
-Modest improvement in cognition, daily functioning and behaviour
-Delays disease progression but does not stop neurodegeneration
123
Give some possible molecular mechanisms associated with the development of Alzheimers disease
-Genetic risk factors
-Amyloid beta
-Tau protein
-Astrocyte, microglia
-Neurones
-Mitochondrial dysfunction
-Oxidative stress
-BBB alteration
124
Describe the two types of Alzheimer's disease based on genetics
-Familial Alzheimer's Disease (FAD), occurring before 65 years old
-Sporadic Alzheimer's Disease (SD), occurring after 65 years old
125
Give some key genes involved in Familial Alzheimer's Disease, and how these impact Alzheimer's evolution
-Amyloid Precursor protein gene (Mutations lead to abnormal processing producing toxic amyloid beta peptides)
-PSEN1 gene (involved in the γ-secretase complex, cleaving APP to produce Aβ. Mutations lead to overproduction of Aβ42)
-PSEN 2 gene (Similar to PSEN1)
126
Give some key genes involved in Sporadic Alzheimer's Disease, and how these impact Alzheimer's evolution
-APOE gene, with the 𝛆4 genotype carrying the strongest genetic risk
127
Describe the inheritance pattern of Familial Alzheimer's Disease
These mutations follow an autosomal dominant pattern, meaning that a single copy of the mutated gene is sufficient to cause the disease
128
Where is the amyloid precursor protein gene located, and what is this implication?
-Found on chromosome 21
-Meaning three copies are found in trisomy 21
-Meaning more Aβ is produced, meaning by age 40 almost all people with Down's have amyloid plaque deposits in the brain and tau tangles
129
What is the function of Amyloid precursor protein?
-APP plays a role in neuron development and the formation of synapses, which are critical for learning and memory.
-APP is involved in cell-to-cell interaction and communication, particularly in the brain.
-APP and its cleaved fragments can participate in intracellular signaling pathways that influence neuronal survival and function.
130
Describe the non-amyloidogenic (normal) pathway of processing amyloid precursor protein
-α-secretase cleaves APP within the Aβ region of the protein.
-This results in the production of a soluble sAPPα fragment and a membrane-bound fragment, C83.
-C83 is further cleaved by γ-secretase, producing a smaller intracellular fragment (AICD) and a non-toxic fragment.
-No amyloid beta is produced
130
Describe the amyloidogenic (abnormal) pathway of processing amyloid precursor protein
-β-secretase (BACE1) cleaves APP at a different site, releasing sAPPβ and creating a larger membrane-bound fragment, C99.
-C99 is then cleaved by γ-secretase, generating amyloid-beta (Aβ) peptides.
-Aβ peptides can vary in length, with Aβ40 and Aβ42 being the most common.
-Aβ42 is particularly prone to aggregation and forms amyloid plaques
131
Describe γ-secretase in the amyloidogenic pathway
-Multisubunit complex consisting of PSEN1, Aph1, Pen2, and Nicastrin
-PSEN1 mutations are linked to FAD and increased production of Aβ42
132
Describe the effect of mutation in Amyloid Precursor proteins, and give examples
-V717l, increases amyloidogenic processing of APP, increasing Aβ-42 production, increasing neurotoxicity, leading to AD
-A673T, reducing Aβ-42 production, leading to neuroprotection and AD protection
133
What are the major pathological hallmarks of Alzheimer's Disease
-Extracellular amyloid plaques (Aβ)
-Intracellular Neurofibrillary tangles (Tau)
134
What is Tau?
-A microtubule associated protein
-Involved in stabilisation of microtubules in neurones, and supporting axonal transport
-This is vital for cell survival and communication
135
Describe the hyperphosphorylation of Tau in Alzheimer's disease
-Gain of an excessive number of phosphate groups on serine and threonine residues
-Reducing tau's affinity for microtubules, causing tau to detach from the microtubules, forming insoluble aggregates
136
Describe the consequence of Tau hyperphosphorylation in Alzheimer's disease
-Tau's hyperphosphorylation causes it to aggregate into paired helical filaments (PHFs) and eventually form neurofibrillary tangles (NFTs) inside the neurons.
-These NFTs accumulate within the cell body and axons of neurons, leading to synaptic dysfunction, cellular stress, and neuronal death.
137
Describe the link between Amyloid-beta and Tau hyperphosphorylation in the Amyloid cascade hypothesis for Alzheimer's disease
-Aβ oligomers induce Tau phosphorylation by activating kinases
-Aβ plaques promote the spread of tau pathology via interneuron transmission of tau aggregates
-Tau mediates the neurotoxic effects of Aβ
138
What are the current disease modifying treatments for Alzheimer's disease focus?
-Monoclonal antibodies (eg Aducanumab, Lecanamab) that target amyloid beta
-This promotes its removal from the brain
139
What is opium?
-Natural substance extracted from the dried latex of the opium poppy plant
-Containing a mixture of active alkaloids, including morphine, codeine and thebaine
140
What are opiates?
-Subcategory of opioids that are naturally occurring compounds derived directly from opium
-Including Morphine, Codeine and Thebaine
141
What are opioids?
-A broad class of drugs that bind to opioid receptors in the brain, producing analgesic and euphoric effects
-Including Natural opiates, semisynthetic opioids, and fully synthetic opioids
142
Describe the key components of pain perception/nociception
-Transduction (stimulus detection)
-Transmission (signal conduction to CNS)
-Modulation (pain amplification or suppression)
-Perception (conscious experience of pain)
143
Describe transduction in nociception
-Nociceptors (pain receptors) convert a painful stimulus (mechanical, thermal, or chemical) into electrical signals.
-Key molecules include bradykinin, Prostaglandins, histamine, TRPV1 receptors and ASIC receptors
144
Describe transmission in nociception
-Nerve fibers transmit pain signals from the site of injury to the spinal cord and brain via two main pathways:
-Aδ fibers (fast, sharp pain)
-C fibers (slow, dull, burning pain)
145
Describe modulation in nociception
-Pain signals can be enhanced or inhibited by neural pathways.
-Descending inhibitory pathways from the periaqueductal gray (PAG) and raphe nuclei in the brainstem release endorphins, serotonin, and norepinephrine to suppress pain.
146
Describe perception in nociception
-The brain processes pain in multiple areas, including:
-Somatosensory cortex (localization and intensity of pain)
-Limbic system (emotional response)
-Prefrontal cortex (cognitive evaluation of pain)
147
Name drugs that induce analgesia in the transduction component of nociception
-NSAIDs inhibit COX, reducing prostaglandins that sensitise nociceptors
-Local anaesthetics block voltage-gated Na+ channels in nociceptive neurones
148
Name drugs that induce analgesia in the modulation component of nociception
-Opioids activate descending inhibitory pathways via μ-opioid receptors
-NMDA receptor antagonists prevent sensitisation by blocking glutamate signalling
148
Name drugs that induce analgesia in the transmission component of nociception
-Local anaesthetics block voltage-gated Na+ channels in nociceptive neurones
-Opioids bind to μ-opioid receptors in spinal cord and brain to reduce neurotransmitter release
-Alpha-2 agonists inhibit norepinephrine release in the spinal cord, reducing pain signalling
149
Name drugs that induce analgesia in the perception component of nociception
-Opioids reduce pain perception in the cortex and limbic system.
-Anticonvulsants used for neuropathic pain by stabilizing nerve activity.
150
Describe the cellular action of opioid receptor binding
-Inhibition of adenylyl cyclase, reducing cyclic AMP (cAMP) levels. This reduces the activity of PKA, decreasing neurotransmitter release (eg glutamate, substance P
-Opens G-protein-gated inwardly rectifying potassium (GIRK) channels. This leads to K⁺ efflux, causing neuronal hyperpolarization
-Closing of Voltage-Gated Ca²⁺ Channels (↓ Neurotransmitter Release) reducing Ca²⁺ influx, decreasing the release of excitatory neurotransmitters (eg glutamate and substance P)
151
Give types of opioid receptors
-Mu (MOP)
-Delta (DOP)
-Kappa (KOP)
-NOP
152
What are the primary function and affects for the Mu Opioid Receptor?
-Primary receptor responsible for opioid analgesia
-Euphoria (linked to addiction)
-Respiratory depression (primary cause of opioid overdose death)
-Sedation
-Physical dependence
-Reduced gastrointestinal motility (constipation)
-Pupil constriction (miosis)
153
Name some endogenous ligands for the Mu opioid receptor
Endorphins
154
Describe the location of Mu Opioid receptors, and the associated functions
-Brainstem: respiratory depression, analgesia
-Spinal cord: Inhibition of pain transmission
-Mesolimbic system: Euphoria and reward
-GI tract: Constipation
155
Name some agonists targeting Mu Opioid receptors
-Morphine
-Fentanyl
-Heroin
156
Describe the primary function and effects for the Kappa Opioid receptor
-Spinal analgesia (less potent than MOR-mediated analgesia)
-Dysphoria (unpleasant feeling, opposite of euphoria)
-Sedation
-Diuresis (increased urination due to inhibition of vasopressin release)
-Hallucinations (some KOR agonists like Salvinorin A cause dissociative effects)
-Less respiratory depression compared to MOR
157
Name some endogenous ligands for the Kappa opioid receptor
Dynorphins
158
Describe the location of Kappa Opioid receptors, and the associated functions
-Spinal cord: Pain modulation
-Hypothalamus and pituitary: inhibition of ADH
-Limbic system: Dysphoria, stress response
159
Describe the primary function and effects for the Delta Opioid receptor
-Mild analgesia (less than MOR)
-Antidepressant & mood-enhancing effects
-Potential neuroprotective effects
-No significant respiratory depression
-Seizure risk (high DOR activation can cause convulsions)
160
Name some endogenous ligands for the Delta opioid receptor
Enkephalins
161
Describe the location of Delta Opioid receptors, and the associated functions
-Cerebral cortex: Modulation of cognition and mood
-Spinal cord: Pain inhibition
-Hippocampus: Neuroprotection, seizure regulation
162
Name locations of Mu Opioid Receptors in the CNS
-Neocortex
-Caudate putamen
-Nucleus Accumbens
-Thalamus
-Hippocampus
-Amygdala
-Nucleus tractus soliarius
163
Name locations of Kappa Opioid Receptors in the CNS
-Caudate Putamen
-Nucleus accumbens
-Hypothalamus
-Amygdala
-Pituitary
164
Name locations of Delta Opioid Receptors in the CNS
-Olfactory areas
-Neocortex
-Caudate putamen
-Nucleus accumbent
-Amygdala
165
Describe subtypes of opioids
-Phenanthrenes (morphine, codeine)
-Phenylheptylamines (methadone)
-Phenylpiperidines (fentanyl)
-Morphinans (butorphanol)
166
What are the benefits of partial Mu Opioid Receptor agonist
-Less likely to reach respiratory depression
-Allowing for efficient analgesia with less toxicity
167
Give examples of different analgesic opioids relative potency compared to morphine
-Codeine: 1/10 with 3-6 hours of action
-Methadone: 5-10 with 8-12 hours of action
-Fentanyl: 100 with 72 hours of action
168
How are opioids metabolised and eliminated?
-Phase I: Primarily by CYP3A4 and CYP2D6
-Phase II: Primarily by glucuronidation by UGT
-Excreted primarily by renal elimination, some by biliary
169
Give the clinical relevance of CYP isoforms in opioid metabolism
-CYP2D6 ultrarapid metabolizers convert codeine → morphine more efficiently, increasing overdose risk.
-CYP2D6 poor metabolizers may not experience full analgesic effects from prodrugs like codeine.
-CYP3A4 inducers (e.g., rifampin) can increase fentanyl metabolism, reducing efficacy.
170
Describe opioid activation of the reward pathway?
-Opioids bind to MORs on Gabaergic neurones in the Ventral Tegmental Area
-Inhibition of GABA release occurs increasing dopamine release into the nucleus accumbens
-Creating feelings of euphoria and reward
-This reinforces drug seeking behaviour
-Enkephalins may directly activate the nucleus accumbens
171
Describe tolerance development following chronic opioid use
-Continuous opioid binding leads to receptor internalization and downregulation, requiring higher doses for the same effect.
-Over time, opioid-induced dopamine surges weaken, making users less sensitive to the drug’s euphoria.
-Tolerance to one opioid (e.g., heroin) can lead to tolerance to others (e.g., fentanyl).
172
Describe dependence following chronic opioid use
-The brain compensates for constant opioid-induced inhibition by increasing excitatory neurotransmitter activity (glutamate, norepinephrine).
-The reward system relies on opioids to maintain dopamine release, meaning natural rewards (food, social interaction) become less pleasurable.
173
Describe withdrawal following chronic opioid use
Without opioids, the brain overcompensates, causing:
-Severe dopamine depletion, causing anhedonia, depression and cravings
-Overactive noradrenaline, causing anxiety, agitation, sweating and tremors
-Increased pain sensitivity due to low endogenous opioid levels
174
What may be given to prevent opioid overdose?
Naloxone - MOR antagonist
174
Describe what causes death in opioid overdose?
-μ-opioid receptor (MOR) activation in the medulla and pons reduces the brain’s ability to detect high CO₂ levels.
-Decreased respiratory drive → Less oxygen intake (hypoxia) → Increased CO₂ levels (hypercapnia).
-Apnea (complete cessation of breathing) can occur, leading to brain damage and death within minutes.
175
Describe biased agonism in opioid tremens
-Biased agonism (or ligand bias) is the ability of a drug to preferentially activate one signaling pathway over another when binding to the same receptor
-A biased opioid agonist preferentially activates G-protein signaling while avoiding β-arrestin recruitment. This approach can:
-Enhance analgesia without increasing tolerance.
-Reduce respiratory depression, lowering overdose risk.
-Decrease constipation and other side effects.
