CNS Drugs 🧠 Flashcards
L: intro to CNS
what can input to CNS be described as (2 words)
afferent
sensory
what can output to CNS be described as (2 words)
efferent
motor
2 functions of the brain
sensory: reception vs perception
motor: decision based activity
What is reception?
stimulation of a receptor such as light, touch, or sound
What is perception?
process of organizing and interpreting sensory information, enabling us to recognize meaningful objects and events
What is memory?
- storage and retrieval of information
- info can be relied on and used to compare future experiences
What is the independent motor function?
- ability for motor function to occur without the use of sensory info
- useful in decision-based activity
How does information get in to (and out of) the brain?
- different tracts that carry axons and sensory info to the brain and feedback to the muscles
- sensory neurons send information from the eyes, ears, nose, tongue, and skin -> brain
- motor neurons carry messages away from the brain -> rest of body
What is Brodmann’s map?
The Brodmann areas are a way of mapping the cortex and its distinguished functions
.. where the info goes to
How may areas are found on the Brodmann map?
- 52 areas
2 cell types on brain and what are their funcitons?
neurones: info processing
glia: other functions
What is the consequence of damage to different areas of the Broadmann map
changes in an individual’s behaviour or personality
examples of areas of Brodmann mapping and function (vision, speech and language perception)?
- vison (area 17)
- speech (45)
- language reception (32)
What is a homonculus?
topographical-organized map of the proportional representation of the contralateral somatosensory or motor neurons on the cortex or passing through a part of the brain.
What are the primary sensory or motor cortices?
- areas of the cortex that are able to receive simple sensory/motor information
- the same info can be passed to other areas of the cortex that can deal with this info in a more complex way
What are the secondary sensory or motor cortices?
- info from the primary corticies are passed here
- The neurons in this secondary area are still able to process the information
unimodal association
Why are secondary cortices unimodal?
still processing 1 source of info (auditory) in a more complicated way
What are the tertiary sensory or motor cortices?
- multimodal areas
- bring info together from different sensory modalities and compare it to what is stored as info within the brain
- gives 3D representation, pain (combines detection of painful stimuli with memories of painful emotions in the past) and create a mental image
What is a connectome?
- a neural map of the connections within the brain
- shows the interactions between >1000 neurons to form circuits?
- circuits, synapses
- vast connectivity
- neuropharmacology
3 examples of drugs affecting neurotransmission
LDopa: mimics NT (Parkinsons)
SSRI: impact reuptake into synaptic terminal : depression
Opioid: act as NT receptor: pain
what drugs affect ion channels?
anti-epileptics- have unusual elect activity
brain= complex but to simplify, what 2 tyoes of signals?
electrical: APs
chemical: NT released @ synapses
L: drug abuse and addiction
What is drug misuse and an example?
- Using meds in ways other than intended use
- like taking 4 tablets when you were supposed to take 2
prescribed
what is drug abuse?
- Excessive use of a drug inconsistent with medical practice
- can lead to to psychoactive effects
- drug doesn’t have to be illegal
not prescribed
What is hedonism?
- pursuit of pleasure
- likely cause as to why people go back and repeat the same actions (taking drugs)
What is the mesolimbocortical system?
- comprised of 2 dopaminergic pathways: the mesolimbic and a mesocortical system
- also called the reward system
Where do the mesolimbic and a mesocortical pathways originate?
in the midbrain
How does the mesolimbic system cause pleasure?
- Neurones leave the ventral tegmental area (VTA) and run to other parts of the brain
- these neurons travel to the nucleus accumbens
- dopamine is the primary neurotransmitter
How does the mesocortical system cause pleasure?
- sends neurons from the VTA to the frontal lobe of the brain
– this area does all the high-level activity (abstract/rational thinking, problem solving)
What is the consequence of blocking the mesocortical system?
- issues with abstract/rational thinking, problem solving
What events can stimulate the dopaminergic pathways?
- natural rewards
- eating, drinking, sex, and extreme sports
How does heroin work?
- Binds to opiate receptors
- blocks inhibitory neurotransmitters (GABA) form binding to receptors
- there is an increased dopamine release at synapse and act on the nucleus accumbens
What factors are reached with chronic use of addictive substances?
o Tolerance
o Physical dependence
o Psychological dependence
What does increased tolerance to something mean?
with continued use there is a decrease in effect of the substance
How does drug tolerance affect behavioural adaptation?
Body gets used to drug in the system and may affect behaviour
How does drug tolerance effect metabolic processes?
increased exposure of liver cells to a drug may ⬆ production of metabolic enzymes and drug is metabolized quicker (person must take more drug)
How does drug tolerance effect neurobiological factors?
There are adaptive processes in the Mesolimbocortical pathway which decrease the level of dopamine transmission for exposure to any drug at a dose
- To get the same effect more drug must be taken
What would happen if someone taking drugs was to stop for a week and start again?
- body adjusts during the break
- on second exposure body may not be able to handle these amounts (overdose – may be fatal)
What is the physical dependence in drug addiction?
- refers to withdrawal symptoms
- body functions differently in absence of drug
What are the withdrawal symptoms in drug addiction?
o Caffeine-withdrawal headache
o Pain hypersensitivity with opioids
What are the neurological effects in drug addiction?
- Adaptive processes
- NS is used to presence of drug – in absence there is a degree of overcompensation -> symptoms
What is the psychological dependence in drug addiction?
- can be long term
- patient expresses a compulsion/urge to take the drug
- compulsion or need for the drug can override the person’s thinking and lead to impaired decision making (criminal behaviour)
What are the neurobiological effects in drug addiction?
o These can change the physical structure of the brain, new synapses and connections between neurons and different pathways
o When the drug is absent the physical changes can remain – leading to craving for long periods after stopping
What is the difference in the initial stage of drug taking compared to the addiction phase?
- initially taking this drug was used for pleasure
- in addiction the motivation for taking the drug is to avoid withdrawal symptoms or craving as opposed to for pleasure
What may affect ease of addiction for certain drugs?
- level/ speed of dopamine release
- severity/ length of withdrawal symptoms
why are some drugs more addictive than others?
Why is crack more addictive than cocaine which is more addictive than coca leaves?
- The extent of addiction depends on the PK of substance
- crack is inhaled which has a faster onset than snorting or chewing (cocaine/ coca leaves)
What can effect ability to become addicted to certain things?
o Genetics
o Quality of life
o Economical status
o What is available - If people don’t have the means to obtain these addictive substances there would be no way for them get addicted
How can addiction be treated (non-drug)?
- Motivational Interviewing
- Social Skills Training
- Combined behavioural and substance replacement
- Structured family and couple therapy
- Family training
- Detoxification
How can addiction be treated (drug)?
- reducing the dose gradually allows the body enough time to readjust to a lower dose and readapt to a non-drug state
- use substances with different PK properties (Heroin vs methadone) - Liquid has a slower onset than injection of heroin while still stimulation opioid receptors
- nicotine patches
BUT inc chance of relapse… timing of intervention critical
L: drugs affecting synaptic transmission in CNS
What is a must for centrally (brain) acting drugs?
must be able to cross the BBB – has to be lipophilic at blood pH
lipid soluble (unionised) at blood pH!
What are some centrally acting drugs?
· Drugs treating psychiatric and neurological disorders
· General anesthetics and analgesics must cross the BBB as well
What is synaptic transmission?
the process of information transfer at a synapse
transmitter through vesicle out of pre synatpic-> post synaptic thorugh cleft… to receptor
Where are neurotransmitters stored?
in vesicles within neuron endings
Where are neurotransmitters made?
- cell body of a neuron
- produced by enzymes
What is the process in order to fire an action potential?
- sodium influx @ axon hillock via voltage gated channels
- sodium depolarized the cell until the threshold is reached
– now an AP can be fired
What is the process in order to release an neurotransmitter?
- Depolarisation of the neuron stimulates calcium influx via the voltage gated Ca2+ channels
- calcium influx triggers exocytosis of NTs
What is the process neurotransmitter-receptor coupling and post synaptic effect?
- NT is released into the synaptic cleft
- NT diffuses to receptors on postsynaptic membrane
- NT-receptor binding allows for the firing of an AP from the post synaptic neuron
What are the 2 mechanisms of termination of synaptic transmission?
- Re-uptake of NTs
2. Enzymatic Breakdown of NT
What is the re-uptake termination mechanism?
- reuptake of the NT into the presynaptic terminal
- After reuptake, the NT can be metabolized
What is the enzymatic breakdown mechanism?
enzyme is present in synapse and can degrade the NT once it has been released from the Presynaptic terminal
process of synapse?
- biosynthesis: synthetic enzymes loaded into vesicles
- AP propagation: Na+ jumps
- NT release… Ca2+ triggers vesicles to release into cleft
- Receptor coupling: enz in vesicles then go to receptor of post synaptic neuron
- post synaptic effect
- signal termination: reuptake (presyn. takes enz back up)
OR
enzymatic breakdown by mitochondria in syn cleft
Which drugs can target neurotransmitter biosynthesis?
- L-DOPA - used in dopamine replacement therapy
- this used to treat parkinson’s disease
Which drugs can target Action potential propagation?
- Sodium channel blockers - used to treat epilepsy (phenytoin + carbamazepine)- anticonvulsant
- this decreases the high frequency firing of APs
- These drugs selectively block the inactivated state of the channel
- allow regular firing but only target high frequency firing channels
Which drugs can target Neurotransmitter release?
- calcium channel blockers
- reduce NT release due to inhibition for calcium influx
- Phenytoin = used in epileptic fit treatment
- Ethosuximide = used to treat absence epilepsy
Why are Post-synaptic receptor antagonists used?
o prevent the NT from binding to the postsynaptic receptors and generating a potential in the postsynaptic neuron
What are examples of Post-synaptic receptor antagonists?
- D2 receptor antagonist (neuroleptics - haloperidol)
- Ach muscarinic Antagonist (antiparkinsonian - benztropine)
- Serotonin antagonists (antiemetics - ondansetron)
Why are Post-synaptic receptor agonists used?
bind to receptors and stimulate a signal in the post synaptic neuron
What are examples of Post-synaptic receptor agonists?
- D1 receptor agonist (antiparkinsonian - Bromocriptine)
- µ-receptor agonists (analgesic - morphine)
- Serotonin (5-HT1A) agonists (Anxiolytic - buspirone)
What are allosteric modulators?
- group of substances that bind to a receptor to change that receptor’s response to stimulus.
What are some positive modulators of GABA-A receptors? and uses?
o Benzodiazepines (diazepam) or barbiturates (phenobarbitone)
o These enhance inhibitory transmission
o Can be used as a sedative/ hypnotic/anxiolytic
o Also used as a anticonvulsant or a general anesthetic
What drugs inhibit the uptake of Noradrenaline?
- Tricyclic antidepressants -Amitriptyline
- Unselective between noradrenaline and serotonin reuptake
What drugs inhibit the uptake of Serotonin?
- Selective serotonin re-uptake inhibitors/ SSRIs (fluoxetine/ Prozac)
- used as an antidepressant
What drugs inhibit the uptake of GABA?
- GABA uptake (GAT-1) blocker (tiagabine)
- Used as an anticonvulsant
What drugs inhibit the uptake of Dopamine?
- Dopamine uptake inhibitor (nomifensine)
- Used as an antiparkinsonian (antidepressant)
Which drugs can inhibit the enzymatic degradation of neurotransmitters?
- Monoamine oxidase inhibitors (MAOIs) - antidepressants (phenelzine)
- Selective MAO-B inhibitor - antiparkinsonian (selegiline)
- GABA transaminase inhibitor - anticonvulsant (vigabatrin)
Which drugs can inhibit the negative feedback on the release of neurotransmitters?
- Mianserin - α2 antagonist properties
- Also used as an antidepressant
DRUGS by clinical indication
What can be targeted to treat depression?
o The reuptake of inhibitory NTs
o The enzymatic degradation of inhibitory NTs
o The auto-receptors in negative feedback (antagonism)
What is the monoamine hypothesis?
- Depression is associated with low levels of serotonin and norepinephrine in the brain
- Low activity of monoaminergic receptors
How can Parkinson’s be treated?
o Replacement therapy via precursor (L-DOPA)
o Direct agonism
o Re-uptake inhibition
o Degradative enzyme inhibition
How can epilepsy be treated?
o Na+ channel blockers – decreases AP propagation (reduce over firing)
o Ca2+ channel blocker – decreases NT release (reduce over firing)
o GABAA receptor (positive) allosteric modulation
o GABA re-uptake inhibition
o GABA degradative enzyme inhibition
What is Alzheimer’s disease?
degenerative type of dementia that affects memory, thinking and behavior.
loss of acetylcholine ACh
What was attempted to treat Alzheimer’s?
- admin of ACh precursor and agonists of ACh receptor
- these had NO success
How is Alzheimer’s treated?
- inhibition of ACh metabolism via acetylcholinesterase inhibitors (donepezil, rivastigmine, galantamine)
L: general anaesthesia
What is the definition of anaesthesia?
the abolition of sensation
What needs compose the triad of general anaesthesia?
- need for unconsciousness
- need for analgesia
- need for muscle relaxation (primarily loss of reflexes)
What does general anaesthesia do to CNS activity?
it depresses it
What 2 theories attempt to explain the mechanism of action behind anaesthesia?
- the lipid theory
- the protein theory
What is the general chemical structure of inhalation anaesthetic compounds?
- simple
- unreactive
- short-chain
- different chemical classes
What did Meyer do in 1899 to test the ‘lipid theory’ of anaesthetics?
and conclusion made?
- added diff anaesthetics to water in a jar for tadpoles
- plotted a graph of MIC (for tadpoles to stop moving) against olive oil: partition coefficient to see relationship LogP
- concentration of agent = inversely proportional to lipid:water coefficient
- i.e. lipid solubility is important for anaesthetics to work - cell membrane, axon of myelin sheath?
According to the lipid theory, how do anaesthetics work?
anaes volume expansion or increasing the fluidity of the membrane
According to the lipid theory, what two parameters at what values are defined as anaesthesia?
- anaesthetic concentration in the cell membrane has reached 0.05mM
- the volume has expanded by 0.4%
According to the lipid theory, what can be done to reverse anaesthesia?
increasing the pressure
According to the protein theory, how do anaesthetics work?
- proteins = target
- lipid solubility required to bypass cell membrane and access proteins
- also required to bind to hydrophobic pockets in proteins
What are the two evidence points to support the protein theory?
- the ‘cut-off’ phenomenon
- stereoselectivity
Explain how the ‘cut-off’ phenomenon supports the protein theory.
⬆ C chain length of short-chain compounds ⬆ lipid solubility, ⬆ anaesthetic potency (lipid theory) but up to a certain point (protein theory)
- therefore if the molecule is too big, it can no longer ‘fit’ - indicates it needs to fit something, like a protein
Explain how stereoselectivity supports the protein theory.
- compounds can have isomers with identical lipid solubility but different potencies
- e.g. isoflurane’s +ve isomer > -ve isomer
- therefore due to affinity and binding of protein, not just lipid solubility
- stereo selectivity of anaesthetic potency is preserved w protein binding
What are the excitatory molecular targets of anaesthetics?
anaesthetics bind to and block the channels of:
- ACh
- NMDA glutamate receptor
- 5-HT
What are the inhibitory molecular targets of anaesthetics?
anaesthetics bind to and enhance the channels of:
- GABA-a
- glycine
- K*
What is the effect when anaesthetics bind to K+ channels?
inhibitory
will enhance the channel, allowing more K+ out-> hyperpolarisation of cell membrane …less excitable
CNS will be depressed
The majority of effects of anaesthesia are achieved through inhibition of s_ t_.
The majority of effects of anaesthesia are achieved through inhibition of s_ t_.
How does anaesthesia inhibit synaptic transmission?
- decreases NT release
- decreases post-synaptic responsiveness (axonal conduction has little importance here)
Of the general anaesthesia triad, action at where in the brain mediates unconsciousness?
depression at the reticular formation in the midbrain
Of the general anaesthesia triad, action at where in the brain mediates analgesia?
depression at the thalamus
After increasing the anaesthetic concentration to a certain level, what effects do you see on a %responders against [anaesthetic] graph? order of inc conc?
- loss of ability to form memory
- loss of consciousness
- loss of movement (+ motor reflexes)- surgical procedure anaesthesia
- CVS and resp system depression -fatal OD-> death
What are the 4 stages of classic anaesthesia?
- analgesia
- delirium (induction)
- surgical procedure
- medullary paralysis
Describe the first stage of anaesthesia
analgesia:
- reflexes still intact
- patient still conscious
- still feel pain
- drowsiness
Describe the second stage of anaesthesia
delirium (induction)… when most px die, v dangerous
- excitement
- delirium
- incoherent speech
- loss of consciousness !!
- unresponsive to non-painful stimuli
- muscle rigidity
- spasmodic movements
- vomiting
- choking
- cardiac arrhythmias
Describe the third stage of anaesthesia
surgical anaesthesia:
- regular breathing
- abolition of reflexes
- synchronised ElectroEncephaloGraph (brain activity)
- unresponsive to painful stimuli
- muscle relaxation
Describe the fourth stage of anaesthesia
medullary paralysis:
- medulla in charge in respiratory/cardiovascular centres
- respiration and circulation ceases
- death
- pupillary dilation
- EEG wanes
A good anaesthetic agent must be p_ and f_ _
potent and fast-acting
What parameter is used to measure anaesthetic potency?
minimum alveolar concentration (MAC)
- minimum conc required to produce immobility in 50% of patients in response to noxious stimuli
- i.e. there’s a 1 in 2 chance that at the patient will be anaesthetised at this concentration
Why does MAC vary between patients?
what are units?
Patients have different sexes, heights and weights
% in % of inspired air (v/v)
How does MAC relate to lipid solubility?
- MAC is inversely proportional to lipid solubility
- i.e. the more lipid soluble an agent is, the lower the conc required in patient’s inspired air ( %v/v) to produce anaesthesia
What assumption is made based on MAC at equilibrium about the anaesthetic concentrations?
inspired concentration = alveolar concentration = brain concentration
Based on the relationship between MAC and lipid solubility, what is the determinant of anaesthetic potency?
lipid solubility
potent =/=> fast acting
Why is it important to control the depth of anaesthesia?
- allows for prevention of OD
- allows for rapid induction and recovery of anaesthesia
What are the are the main factors determining the PK aspects of inhalation anaesthetics? 2
- properties of anaesthetic itself
- physiological factors
What are the different compartments in equilibrium that inhaled anaesthetics move between?
- gas
- blood
- brain
What partition coefficients exist and between what compartments for inhaled anaesthetics?
- between gas and blood: blood:gas partition coefficient
- between blood and brain: tissue:blood partition coefficient
What factors speed up the transfer of inhaled anaesthetic from gas to alveoli (lungs)?
- increasing the concentration of anaesthetic
- increasing the rate and depth of breathing
all -> increase in the speed of induction
What factor speeds up the transfer of inhaled anaesthetic from alveoli to blood?
- the gas’ solubility in blood
- the rate of pulmonary flow
- the partial pressure in mixed venous return
If the anaesthetic is in highly soluble gas, what is the nature of its transfer to the blood?
- blood has large capacity of anaesthetic to dissolve in
- therefore need higher conc to saturated blood before anaesthetic will want to leave blood and enter tissue
If the anaesthetic is in insoluble gas, what is the nature of its transfer to the blood?
- relatively (still need some solubility to enter blood) blood insoluble gas transfers to the brain faster
- this is due to the lower blood:gas coefficient (λ)
- leads to increased speed of induction
What is the relationship between the speed of induction the blood:gas coefficient?
- they’re inversely proportional
- lower the blood:gas coefficient (λ)= higher the speed of induction
= main factor driving the speed of induction
How does the rate of pulmonary blood flow impact the transfer of anaesthetic to the blood?
Inc CO to pulmonary circulation => faster transfer
- this is because more blood is supplying the lung
PP in mixed venous return:
- increases w time
- hence speed of transfer will slow down
What factors affect the rate of anaesthetic transfer from blood to tissue (and hence the speed of induction)?
- anaesthetic solubility in lean tissue
- anaesthetic solubility in adipose tissue
- tissue blood flow
- anaesthetic concentration in blood vs in tissue
What is lean tissue?
brain grey matter, muscle, essentially anything that’s not adipose tissue
How does anaesthetic solubility in lean tissue affect the rate of transfer from blood to tissue?
- tissue:blood partition coefficient for anaesthetics in lean tissue is 1
= will readily leave the blood and enter tissue - hence anaesthetic conc in the brain increases quickly
How does anaesthetic solubility in adipose tissue affect the rate of transfer from blood to tissue?
- tissue:blood partition coefficient is»_space;>1 in adipose tissue
- patient’s carrying a lot of fat will have a slower speed of induction
- slows down the rate of transfer and speed of induction - also potential for accumulation
How does tissue blood flow affect the rate of transfer from blood to tissue?
- high in lean tissue
- low in adipose tissue
- increases rate of transfer to lean tissue
p737!!
How does anaesthetic concentration in blood vs tissue affect the rate of transfer from blood to tissue?
as anaesthetic concentration in tissue increases, the rate of transfer decreases
How are inhalation anaesthetics metabolised?
- via lung
- excreted mainly unchanged
- e.g. only 0.2% of isoflurane and only 0.04% of N2O is changed
What inhalation anaesthetics have different metabolic profiles? How are they different?
- methoxyflurane (~50%)
- halothane (~30%) (toxicity possibility)
halothane
- ads
- disads
- potent, fairly fast
- possible liver tox
enflurane
- ads
- disads
- less liver damage
- possible seizures
isoflurane
- ads
- disads
- rapid acting, muscle relaxation
- bad smell
sevoflurane
- ads
- disads
- pleasant odour, rapid recovery
- metabolites could cause renal damage?
nitrous oxide 1:1 O2 (Entonox)
- ads
- disads
- rapid, good analgesic
- low potency: normally has to be combined with other agents
What is the definition of balanced anaesthesia?
using combinations of different drugs to increase the safety
Apart from inhalation anaesthetics, what other anaesthetics are used? when?
IV anaes
for short procedures and alone
How does the mechanism of intravenous anaesthetics differ to that of inhalation anaesthetics?
- interacts w specific single ligand-gated channels instead of multiple
- or NMDA receptor antagonist (ketamine)
How does ketamine work?
- NMDA receptor antagonist
- prevents glutamate (excitatory) action
rapid onset
What are the effects of ketamine?
- sensory loss
- analgesia
- no loss of consciousness
- paralysis
- surgical anaesthesia
What ligand-gated receptors do intravenous anaesthetics interact with? and what affect: enhance/depress
enhance GABA-A receptor action
What are 3 categories of adjuncts to general anaesthetics?
- pre-medication
- muscle relaxants
- anti-emetics
What are drug classes used in pre-medication?
- benzodiazepines (sedation, anxiolysis)
- diazepam
- lorazepam
- opioids (pain relief)
- anti-muscarinics (aid w intubation and dry up secretions in lungs allowing anaesthetic access)
What are examples of opioids used in pre-medication?
- fentanyl
- pethidine
- morphine
What are examples of anti-muscarinics used in pre-medication?
- atropine
- hyoscine
- glycopyronium
What is the purpose of pre-medication as an adjunct?
anxiolysis, sedation, amnesia
What is the purpose of muscle relaxants as an adjunct?
relax abdominal, tracheal, respiratory muscles
What is the purpose of anti-emetic as an adjunct?
reduce peri-operative nausea e.g. metoclopramide
What are examples of neuromuscular blockers as muscle relaxants?
atropine, hyoscine, glycopyronium
same as anti-muscarinics used in pre-medication
What drug classes are used as muscle relaxants?
- benzodiazepines
- neuromuscular blockers
L:Schizophrenia and anti pyschotic drugs
What are the clincial features of schizophrenia?
- onset: adolescence or early adulthood
- males, females equal
- after first diagnosis of pyschotic break symptoms can be controlled and go away woth meds but episodes can occur
- In chronic state you get a progressive decline in function
What does DSM stand for?
Diagnostic and Statistical Manual of Mental Disorders
Outline some of the positive type I symptoms?
delusions, hallucinations, disorganised speech, grossly disorganised or catatonic behaviour
Outline the negative type II symptoms?
reduced expression of emotion, social withdrawal, absence of normal responses and behaviours
schizophrenia is mainly
heridetary
describe what the Dopamine hypothesis is?
dopaminergic hyperactivity underlies schizophrenia and hyperactvity signalling is related to symptoms
Where does the evidence base come from to support the dopamine hypothesis?
the effects of dopaminergic agents
Outline how amphetamine abuse be used as evidence to support the dopamine hypothesis?
- dopamine releasing drug
- can -> toxic pyschosis (delirium)
- this manifests as paranoid delusions, visual or auditory delusions or compulsive behaviours
- If given to patient type I symptoms worsen so perhaps type I symptoms are due to dopamine
What other drugs behave in the same way as amphetamines i.e. symptoms manifest as type I symptoms thus provide evidence to support the dopamine theory?
Dopamine D2 recetpor agonists and L-DOPA
- too much LDOPA (dopamine precursor)–>?
Type I like symptoms
disappear when dose reduced
Which treatment drug was originally an antihistamine, does not cause excessive sedation, attentuates positive symptoms and became part of the first gen of neuroleptics?
Chlorpromazine
What are the 3 main classes of first gen neuroleptics?
Phenothiazines,
butyrophenones
thioxanthines
What are the 3 main classes of first gen neuroleptics?
Phenothiazines,
butyrophenones
thioxanthines
Which class of drug do chlorpromazine and fluphenazine belong to?
Phenothiazines
Which class of drug do haloperidol and doperidol belong to?
Butyrophenones
Which class do flupenthixol and clopenthixol belong to?
thioxanthines
First gen neuroleptics are receptor antagonists. Which receptors do they block to cause anti pyschotic activity?
dopamine receptors
Why are first gen neuroleptics esp phenothiazines termed as dirty drugs?
they lack specificity and bind to a number of different receptors including: dopamine: D1, D2, muscarinic, histamine, noradrenaline 5HT
Which gen of neurolepics are termed as atypical?
second gen
How do atypical neuroleptics differ from typical neuroleptics?
- different pharmacological profile e.g higher dopamine selectivity
- fewer motor extrapyrimadal side effects
- more effective against negative symptoms
- more effective in treatment of resistant schizophrenia
Which second gen neuroleptic is especially good at inducing fewer motor effects and are more effective negative symptoms?
clozapine
Why is clozapine not able to be licensed for first line use?
risk of serious side effects: agranulocytosis and myocarditis
What are the four classes of atypical neuroleptics?
selective dopamine receptor antagonists (D2/D3), multi acting receptor targeted agents (MARTAS), serotonin-dopamine antagonists
novel types
Sulpiride and amisulpride belong to which class of atypical neuroleptics?
selective dopamine receptor antagonists
clozapine and olanzapine belong to which class of atypical neuroleptics?
MARTAS
risperidone, zotepine and sertindole belong to which class of atypical neuroleptics?
serotonin-dopamine antagonists
quetiapine and aripiprazole belong to which class of atypical neuroleptics?
novel types
2 areas in the brain with dopaminergic cell bodies?
ventral tegmental area and substantia nigra
There are 3 major dopaminergic pathways. Where do these originate?
2 from VTA and 1 from substantia nigra
The mesocortical pathway is released in the frontal cortex. What is this area of the brain responsible for?
thinking, cognition and memory
The mesolimbic pathway ends in the nucleus accumbens, the part of the brain which is responsible for?
rewards and pleasure
What do neuroleptic drugs block in the limbic area and what is the effect of this?
- block dopamine receptors (D2) post synaptically
- decrease transmission of mesolimbic signalling
- stopping type I symptoms as that region may be responsible for dopamine hyperactivity
antipsychotic
What is the cause of motor side effects and how can these be avoided by ‘cleaner’ drugs?
receptors are blocked at the end of the nigrostriatal pathway which is crucial to normal movements
cleaner drugs are more selective therefore fewer side effects
List some of the dopaminergic side effects as a result of treatment?
- antiemesis
- increased prolactin release
- extra pyramidal symptoms
- acute motor disturbances such as dystonias
- chronic motor symptoms such as tardive dyskinesia
How might neuroleptic drugs cause antiemesis?
due to D2 receptor blocking in chemoreceptor trigger zone of the brain. When activating vomiting is stimulated
How might treatment lead to increased prolactin release?
released by pit gland. usually inhibited by dopamine but as dopamine is inhibited more is released
What side effects might men and women experience if they have increased prolactin release as a result of neuroleptic treatment?
breast swelling, pain and lactation
Dystonias go away if the drug dose is reduced. What is this and why does it occur in the first place?
- involuntary parkinsonian movements of face, tongue and neck
- due to blockade of D2 receptor in striatum
SE: motor disturbances of neuroleptic drugs
- acute
- chronic
- dystonias
- tardive dyskinesia
Tardive diskinesia is a chronic symptom involving involunatary movements of the face, tongue, limbs or trunk after taking the drug for a long time. Which drug has this never been seen in?
Clozapine
Non dopaminergic side effects are related to the blockage of other receptor sites. Outline these?
- antimuscarinic such as dry mouth and constipation
- postural hypotension due to adrenoceptor block
- sedation due to histamine h1 receptor block
Why do atypical neuroleptics have an increased liklihood of compliance?
better side effect profiles due to greater selectivity
lower incidence of motor disturbances
Which neuroleptics are the least likely to cause motor disturbances?
aripiprazole, MARTAs and quetiapine
non compliance can be reduced by changing the route of admin from oral to?
long acting depot injection
When are long acting depot injections used?
maintainence therapy when compliance is unrelated
long acting depot injections are deep IM injections of sustained release. How long are the intervals of treatment and how long do side effects last?
- intervals are 1-4 weeks
- side effects may persist for weeks despite the dose
