Neuro 4 - psychopharmacology, epilepsy and memory Flashcards
Common features of monoamine pathways in cortical innervation
Serotonin, dopamine and noradrenaline are monoamine neurotransmitters
- few cell bodies, arise in upper brainstem
- radiate to most cortical areas
- modulatory function - released from varicosities on axon, not direct synapse-synapse transmission as with glutamate (so good drug target, less extreme)
Locus coeruleus - NA nucleus
Raphe nucleus - Serotonin
Substantia nigra - Dopamine
Monoamine neurotransmitter functions
NORADRENALINE
Attention
Arousal
SEROTONIN
Impulsivity
Flexibility
DOPAMINE
Reward
Learning
Have all -> cognition, emotion
NA + S -> anxiety, irritability
NA + D -> motivation
D + S -> appetite, aggression
Re-uptake inhibitors
Tricyclic antidepressants mainly!
Anxiety - SSRI’s, tricyclic antidepressants
Eating disorders - SSRI’s in anorexia/bulimia, amphetamine, sibutramine as anti-obesity
Behavioural disorders - cognitive enhancers. For ADHD - methylphenidate, amphetamine salts, atomoxetrine, modafinil
Addiction - buproprion to aid smoking cessation
(monoamine dysfunction may not be part of cause of disease, but drugs improve symptoms)
Attention deficit hyperactivity disorder
ADHD
Symptoms - inattention, hyperactivity, impulsivity
Type I - combined
Type II - predominantly inattentive
Type III - predominantly hyperactive-impulsive
Usually in children, some grow out of, sometimes persists into adulthood
Unsure of cause - probable neurodevelopment
> cortical / subcortical hypofunction - dysregulation of neurotransmission
Use ritalin, atomoxetine to increase cortical NA/DA - restore monoamine transmitter levels
Action of stimulant drugs
Noradrenaline enhances signals via α2A
Dopamine decreases noise via D1 stimulation
-> together, optimal attention
Unguided attention - too much noise - low D1/α2A
Misguided attention - high D1/α2A
Cognitive dysfunction in neurodegenerative disorders
Parksinson’s, Alzheimer’s
NA degeneration in both
- acetylcholinesterase inhibitors - learning and memory
- anti-muscarinics and dopaminergics - motor dysfunction
? noradrenergics and cognitive enhancers help? (maybe memory impaired as distracted)
Treating impulsive behaviours
ADHD, + addiction/obesity/aggression
ADHD in children - methylphenidate, amphetamine
Smoking cessation - DA and NA re-uptake inhibitor
ADHD - non-stimulant NAT inhibitor
Non-stimulants, so options for treating addiction
Is drug abuse voluntary?
Initially, yes
Only 10-15% who try get addicted, some people more vulnerable
Drug addicts - reduced self control, altered judgement and decision making, changes in learning and memory - impaired dopamine system
-> drugs stimulate pleasure and reward, brain designed to learn to repeat these, reduced control
Drugs to treat obesity
Consider obesity as impulse control disorder - not just less food more exercise
Amphetamine - very effective!
Atomoxetine
Symptoms of schizophrenia
POSITIVE
- delusions
- hallucinations
- disorganised thought
- abnormal behaviour
- –> can be treated well with antipsychotics, but need to consider other elements
NEGATIVE
- blunted emotions
- anhedonia - can’t feel pleasure/reward
- speech poverty
- attention impairment
- loss of motivation
COGNITION IMPAIRMENT
- new learning
- memory
- executive function
MOOD
- depression
- anxiety
- impulse control
Antipsychotic drugs (= neuroleptics)
Two classes:
TYPICAL - D2 antagonists, but also bind to many others
- phenothiazines - chlorpromazine
- butyrophenones - haloperidol
ATYPICAL - 5-HT2 (serotonin) and D2 antagonists, less extrapyramidal side effects
- clozapine
- risperidone
- aripriprazole
Aetiology of schizophrenia
Poorly understood
- Environmental and genetic factors
- pregnancy complications - flue, pre-eclampsia, delivery, gestational diabetes
- socioeconomic group
- stress
- cannabis
Hypoglutamergic/hyperdopaminergic function alters impact to cortex
Neurochemistry behind schizophrenia
Hyperdopaminergic - treat with D2 receptor blockade
Serotonergic dysfunction - treat to block 5-HT2 also
Glutamate hypofunction - treat with NMDA agonists
(serotonin, dopamine, noradrenaline and GABA all work together)
D2 receptor blockade effects
(typical antipsychotics)
In mesolimbic pathway - reduces positive symptoms
In mesocortical pathway - increases negative symptoms, cognitive deficits
In nigrostriatal pathway - induces motor side-effects (parksinsonism)
In tuberoinfundibular pathway - some increased hormone secretion
-> good effect on positive symptoms, but major side effects
Old treatments for schizophrenia
Insulin-induced coma
Prefrontal lobotomy
Electroconvulsive shock therapy (ECT)
D2 and 5-HT2 blockade effects
(atypical antipsychotics)
Improved efficacy, fewer side effects
- Faster on/off kinetics - easily displaced by endogenous agonist (eg in motor pathway)
- 5-HT2 antagonism
- Other targets
Aripriprazole
D2 receptor partial agonist (atypical antispychotics) AND 5-HT2 antagonist
Where excessive dopamine, antagonist effect (eg mesolimbic pathway)
Where low dopamine, agonist effect (eg mesocortical pathway)
-> prevents total blockage of D2 receptors, conserves some normal function - agonises where necessary
Receptor blockade in schizophrenia treatment and associated side effects
D2 - extrapyramidal (involuntary motor), prolactin elevation
M1 - cognitive deficits, dry mouth, constipation, increased HR, urinary retention, blurred vision
H1 - sedation, weight gain, dizziness
alpha1 - hypotension
5HT2c - satiety (appetite) blocked -> weight gain
Mental state examination
Appearance and behaviour Speech Mood Anxiety Hallucinations? Thought content Features of thought disorder? Cognition Insight
Drugs of abuse
- most stimulate nucleus accumbens, centre for reward and learning
- best drugs have fast on/off pharmacokinetics, to best mimic endogenous neurotransmitters
- 15% of those abusing drugs -> addicted
Opioids (drugs of abuse)
Target μ opioid receptor (MOP)
- > reduce GABA inhibition of dopamine neurones - disinhibition
- > induces feelings of euphoria
HEROIN
- diamorphine
- more rapid, as more methyl groups, more lipophilic
- > constipation, respiratory depression (most common cause of overdose death)
- – treat with naloxone in overdose
Stimulants (drugs of abuse)
COCAINE
- blocks dopamine re-uptake to presynaptic membrane
-> continued stimulation of nucleus accumbens
Mixed with bicarbonate -> crack cocaine - as is more unionised so enters cells faster
Fastest effects when smoked
AMPHETAMINE/METHAMPHETAMINE = speed, crystal meth
- cause dopamine release, and inhibits reuptake
- meth more popular - extra methyl group so more lipid soluble, faster uptake and effect
MDMA (drugs of abuse)
= ecstasy
- 5HT (serotonin) release, inhibits 5HT reuptake
(this directly stimulates nucleus accumbens)
Cannabis (drugs of abuse)
THC is active ingredient - tetrahydrocannibinol
- highly lipophilic, so rapid onset, but persists for long time
CB1 receptors in brain
-> feeling of wellbeing, appetite stimulant, effects on cerebellum (movement), reduced memory (hippocampus)
Long term -> reduced motivation, cognitive deficiciency, potentially induces schizophrenic episodes
Calls to legalise for medicinal use - pain, muscle spasms (parksinson’s)
Ketamine (drugs of abuse)
NMDA antagonists
- reduced glutamate activity to interneurones, so can’t have inhibitory effect on nucleus accumbens
Long term -> ketamine induced ulcerative cystitis needing bladder removal - Bristol bladder! and psychosis possible
Nicotine (legal high - drugs of abuse)
Stimulates dopamine release to nucleus accumbens
+ in combination with tobacco -> highly addictive - psychological, physical dependence, tolerance
90% lung cancer deaths
80% emphysema deaths (COPD)
Lowers birth weight in pregnancy
Ethanol (legal high - drugs of abuse)
Increased inhibition of GABA inhibition to dopamine neurones
- so increased dopamine release to nucleus accumbens
also -> aggression, poor coordination, amnesia, liver damage
(when taken with cocaine, converts cocaine to toxic metabolite)
Treatment of addiction
Reduce withdrawal syndrome
- ‘easy’ part, manage symptoms with replacement therapy or directly targeting symptoms
Reduce cravings
- most will relapse 3 months later (well past withdrawal), so need to use eg CBT
Reduce relapse
- treat underlying reason for drug use - CBT/partial agonist/psychological management/support groups
Definition of anxiety
Fear response - series of defensive responses, autonomic reflexes, and states of arousal/alertness to (potentially) negative stimuli - NORMAL
Anxiety - anticipation of fear in the absence of external stimuli, general feeling or according to certain situations - ABNORMAL
- brain regions for fear response (eg amygdala) should be shut down usually, here they are not inhibited
- disruption of serotonergic (5-HT) system
Types of anxiety
General anxiety disorder - general increase in anxiousness, no clear stimulus causing
Social anxiety disorder (clear stimulus)
Phobias - is stimulus, but wouldn’t usually trigger fear response in others
Panic disorder - sudden attacks of overwhelming fear, particularly physical symptoms
Post traumatic stress disorder - recall of traumatic event
Obsessive compulsive disorder - compulsive, ritualistic behaviour driven by irrational anxiety
Body dismorphic disorder - distorted view of appearance causing anxiety
Psychological interventions to anxiety
FIRST LINE - not drugs!
Counselling
Psychotherapy
Cognitive behavioural therapy
Pharmacological interventions to anxiety
SECOND LINE to psychotherapy
Antidepressants - but slow onset action (3-4w), sometimes increases anxiety initially
Benzodiazepines - faster onset, but induce dependence and have side effects
5-HT₁ₐ receptor agonists - slow onset action (3-4w), sometimes increases anxiety initially
Antiepileptic drugs - gabapentin, pregabalin, tiagabine, valproate - can be effective in general anxiety disorder
β adrenoreceptor antagonists - treat symptoms not cause
Anti-psychotics - helpful in some types (rare)
Anxiolytic, sedative and hypnotic definitions
ANXIOLYTICS
Help to bring down over-aroused nervous system
SEDATIVES
Depress level of nervous system to below normal - helpful in acute anxiety, or before stressful experience eg surgery
HYPNOTIC
Further depress nervous system, cause sleep - eg in insomnia
Anxiolytic drugs
Antidepressants
Buspirone (5HT1a agonist)
β adrenoreceptor antagonists
Relieve anxiety only
Hypnotic drugs
Antihistamines
(chloral hydrate, sodium oxybate)
NOT anxiolytic, just sleepy
Anxiolytic, sedative and hypnotic drugs
Benzodiazepines
Z drugs - Zopiclone (similar), used mainly as hypnotics
Barbituates - phenobarbitone
Antidepressants use for anxiety
Usually first drug class to try
SSRIs common
- selective serotonin re-uptake inhibitors, inhibit 5-HT transporter so serotonin remains for longer
- sertraline, citralopram, fluoxetine
(something else going on, or would have rapid response)
SNRIs maybe
- venlafaxine
MAOIs/TCAs not as common - side effects severe, less effective generally. Used after others not effective maybe.
Also treats depression that may be associated with anxiety - good
Benzodiazepines
- eg NITRAZEPAM, LOPRAZOLAM, ZOLPIDEM, DIAZEPAM
Anxiolytic, sedative and hypnotic drug
Clinical use - anti-anxiety - sedative - hypnotic - anticonvulsant - muscle relaxant (used pre surgery, to aid sleep, anti-epileptic)
Side effects
- drowsiness (bad in treating general anxiety), confusion, amnesia, impaired motor coordination, lack of depth perception, reduced REM sleep
SHOULD NOT BE USED ROUTINELY TO TREAT ANXIETY - may be useful in acute, severe situation for up to 4 weeks
- Different lengths of action contribute to function (eg short half life useful for insomnia, not anxiety)
- Become tolerant long term
- Physical dependence, withdrawal symptoms, need to withdraw slowly
Benzodiazepines mechanism of action
Bind to GABAₐ receptor (2 alpha, 2 beta, 1 gamma subunit - pentameric structure. Also variations in subunits, many many combinations possible, some variations more/less sensitive to drugs than others)
Enhance affinity of GABA binding
Increase frequency of Cl- ion channel opening
(-> hyperpolarise, more negative, inhibits neurone firing)
- though channel open more frequently, still open for same amount of time
Flumazenil
Benzodiazepine antagonist
- reverses actions, but not recommended for overdose treatment as side effects eg seizures
-> anxiety in those who don’t take benzodiazepines
Barbituates
eg PHENOBARBITONE
Anxiolytic, sedative and hypnotic
Agonise GABAₐ receptors - but non selective
- channel opens same number of times, but open for longer
Common use before benzodiazepines, now not
- tolerance
- dependence
- anaesthesia and death in overdose
Still used as anaesthetics, rarely anxiety
5-HT₁ₐ receptor agonists
eg BUSPIRONE
Anxiolytics
PARTIAL agonists - less sedation and motor side effects - safer
Some side effects - nausea, dizziness, headache, restlessness, but fewer than others
- no tolerance
- no dependence
Ineffective against panic attacks or severe anxiety
- takes weeks to have therapeutic action
- may initially increase anxiety
(yet only licensed for short term use, few months)
5-HT₁ₐ receptors are somatodendritic autoreceptors (expressed on cell body/dendrites of serotonergic neurones) in raphe nucleus
- receptors desensitise on repeated exposure
- so enhanced 5-HT release all over brain
(so repeated treatment -> anxiolytic effect, good to desensitise receptors)
HENCE why takes weeks to have effect
β adrenoreceptor antagonists
eg PROPANOLOL
Anxiolytic
Remove peripheral symptoms only, doesn’t treat anxiety
(palpitations, sweating, tremor)
- so useful for eg panic attack
No CNS effect
Hypnotic drugs
Antihistamines
- diphenhydramine, promethazine
- uses drowsiness (side effect) as main effect, though do get hangover
Melatonin receptor agonists
- pineal gland hormone - increased secretion at night to synchronise circadian rhythm -> sleep
- effective esp in elderly, autistic children
