Neuropharmacology Flashcards
1
Q
What is the NS divided into?
A
Central NS + Peripheral NS
2
Q
What is the CNS divided into?
A
Spinal cord - nerves between the brain + periphery NS
Brain stem - connects brain to spinal cord
Brain - divided into hindbrain, midbrain + forebrain
3
Q
What is the PNS divided into?
A
Autonomic NS - sympathetic NS (fight + flight) + parasympathetic NS (fest + digest)
Somatic NS (voluntary)
4
Q
Where does the PNS + SNS have OPPOSING factors?
A
Heart, GI + bladder
5
Q
Where does the PNS + SNS have the SAME factors?
A
Salivary glands
6
Q
In what tissues does only 1 system represent?
A
Sweat glands + blood vessels (mainly sympathetic)
Ciliary muscle (mainly parasympathetic)
7
Q
Adrenoceptors are what type of receptors?
A
G-protein coupled receptors
8
Q
What are the key + ancillary symptoms of depression?
A
Key features
- low mood
- Anhedonia (lack of pleasure)
- lack of energy
Ancillary symptoms (may be there)
- sleep (hypersomnia (too much) or asomnia (too little)
- weight
- appetite change
- low self esteem
- guilt
- suicidal thoughts
- difficulty in concentration
9
Q
What are the 2 types of depression?
A
- unipolar (mood always low with thoughts of suicide)
- bipolar (mood swings: low (depression), high (mania)
10
Q
What is necessary for a diagnosis of depression?
A
Min 2 weeks, min 2 key symptoms + 3 ancillary
11
Q
What are the 3 main NT involved in depression?
A
There is a functional deficiency in CNS monoamine transmission
NA -attention -motivation -pleasure -reward (When stressed, you release more NA = pay more attention
Dopamine (DA)
- pleasure/reward
- energy
- alertness
Serotonin
- mood
- development of obsessions + compulsions
12
Q
What are the main causes of depression?
A
- family history
- stress
- +/- events
- certain medication
- chronic alcohol use
- imbalance of chemicals in brain
13
Q
How can we modify transmission?
A
- block re-uptake (antagonist) = increase NT in synapse
- activate receptor (agonist)
- increase released NT
- block calcium channels = NT can’t be released
- act on synthesis + storage of NT
- use drugs which act on enzymes which breakdown NT
14
Q
What is synaptic plasticity?
A
Long term adaption (e.g. gene regulation)
15
Q
What is neurogenesis?
A
Generation of new neurones, mostly responsible for synaptic plasticity
16
Q
What is neuromodulator?
A
Mediator that cats by modulating e.g. facilitating action of NT
17
Q
What is neurotrophic factor?
A
Regulate the growth + development of neurones
18
Q
What do tricyclic antidepressants do?
A
- NA + serotonin reuptake inhibitors e.g. imipramine + amitriptyline
- block alpha 1 = alpha 1 expressed in blood vessels = postural hypotension
- predominantly NA reuptake inhibitors e.g. desipramine
- block receptors for ACh
- block peristalsis = constipation
- block salivary production = dry mouth
- block H1 = sleepiness
- give active metabolites (breakdown molecules but keep them active)
19
Q
What are the 3 types of TCAs?
A
NA-selective e.g. desipramine
Non-selective (close to 1) e.g. amitriptyline (blocks serotonin + NA equally)
Serotonin-selective (SSRIs) e.g. citalopram
20
Q
What phase 1 enzyme is responsible for metabolising 1/4 of all clinical drugs? What does this mean?
A
CYP2D6
Higher risk of drug interactions, as lots of different drugs uterlise same enzyme
21
Q
What does polymorphic mean?
A
You can have lots of variants of the gene
22
Q
What is pharmacogemomics?
A
Area of pharmacology that studies the genetic variance of enzymes involved in drug metabolism
23
Q
What are the 4 types of genertic variance?
A
Non-functional
- e.g. CYP2D6*4
- will express an enzyme that is either slow/non functioning
- the phenotype, the pt would be called POOR METABOLISER
- there is a high concentration of drug in blood = more side effects + toxicity
Reduced function
- e.g. CYP2D6*10
- phenotype would be an INTERMEDIATE METABOLISER
- rate of functioning slower
Fully functional
- e.g. CYP2D6*1
- phenotype would be an extensive metaboliser
Multiplied gene
- e.g. CYP2D6*2xN (gene multipled)
- phenotype would be an ultra-rapid metaboliser
- rapidly broken down into metabolites = little therapeutic effect
24
Q
What is the effect of SSRIs being active metabolites?
A
The effect stays for longer because the metabolism of the antidepressant leads to another antidepressant
25
Where is serotonin produced?
1% produced in brain, rest in periphery = has an important role in platelet aggregation
26
What are the effects of serotonin syndrome?
- diaphoresis (pallor)
- agitation
- tachycardia
- clonus movement (mixture of contracting + relaxing of libs esp lower limbs
- tremor
- hyperthermia
- hyperreflexia
- increased bowel sounds (may have diarrhoea)
27
What drugs or combo of drugs cause serotonin syndrome?
- Opioids e.g. tramadol taken alongside MAOi
- MAOi + SSRIs
- Ecstacy overdose
28
What are SNRIs? And what is there side effects?
Serotonin/NA re-uptake inhibitors e.g. duloxetine
- lower doses inhibit serotonin re-uptake
- larger doses inhibit serotonin + NA
SE
- N
- anxiety
- insomnia
- sexual dysfunction
- gastric upset
29
What is tyramine and what is it’s effect on cardiovascular system?
Tyramine is produced in GI tract
It can combine with NA re-uptake molecule and be transported inside presynpatic termination of norageneric neurone to be metabolised = increased release NA
The more tyramine accumulated the more NA released = tachycardia, increased HR
30
What do MAOi do? And what are the side effects?
Inhibit enzyme MAO (breaks down main monoamines + tyramine) = more monoamines + tyramine (restriction on food that contains tyramine e.g. cheese) = hypertension
SE
- N
- headache
- stiff neck
- dry mouth
- drug/food interaction
31
What is the 1st choice for antidepressants?
SSRIs e.g. fluoxetine = less side effects
32
What are the side effects of SSRIs?
- N
- anxiety
- insomnia
- sexual dysfunction
- gastric upset
33
What is lithium used for?
Treatment of mania, bipolar or unipolar recurrent disorder.
Has narrow therapeutic range =dangerous drug
SE
- N+V
- diarrhoea
- polyuria
- hair loss
- weight gain
- enlarged thyroid
34
What other drugs are used to treat bipolar depression?
Antiepileptics
- e.g. carbamazepine
- blocks Na+ channels
- better tolerance than lithium
- SE; diarrhoea, N, hair loss, weight gain
Antipsychotics
- e.g. risperidone
- SE; agitation, blurred vision, Parkinsonian symptoms, drowsiness, dizziness, hypertension, GI disturbances, hyperglycaemia + hypercholesterolemia
35
What is anxiety?
An unpleasant state on tension, apprehension or uneasiness that seems to arise from an unknown source
36
What is an anxiety disorder?
An abnormal response that it umpires daily activity
37
What are the different classifications of anxiety?
- generalised anxiety disorder
- panic disorder
- social phobia
- OCD
- PTSD
- phobias - specific to particular que e.g. acrophobia (fear of open spaces)
38
What NTs are involved in anxiety?
NA, serotonin + GABA
39
What happens when GABA binds to a GABA receptor on chloride ion?
- causes shape modification = opens chloride channel
- chloride enters cell = makes potential inside more negative (more hyperpolarised state makes it harder to induce an AP).
40
Why are benzodiazepines used to treat anxiety?
They are neuromodulators, that don’t act directly, but modify GABA transmission. Only facilitate action of GABA.
Positive allosteric modulation of GABA A receptor.
Only alpha 1,2,3,5 are BZ sensitive. If GABA A has alpha 4 or 6 BZs won’t bind (means BZs won’t act on certain tissues).
BZs bind to GABA on another site (allosteric modulation). = Makes GABA more effective as it binds to receptors for longer
Causes;
- Reduction of anxiety, aggression
- induction of sleep (hypnotic)
- reduction of muscle tone (acting on spinal cord)
- anticonvulsant effect
Overdose - only certain amount of GABA, so cause side effects e.g. sleepiness, resp depression
41
Barbiturates are also prescribed for anxiety, depression. Why is overdose of barbiturates much worse then BZs?
High doses of barbiturates can open chloride channels, when BZs can’t
42
BZs are classified on duration of effect, what are the 3 classifications?
```
Short acting (3-5h)
-e.g. triazolam
```
Intermediate (6-24h)
-e.g. lorazepam
```
Long acting (24-72h)
-e.g. diazepam
```
43
What are the side effects of BZs?
- drowsiness, confusion, amnesia
- minimal CV/resp depression
- tolerance + dependence
- withdrawal symptoms (rebound insomnia)
- prolonged sleep (overdose - flumazenil antidote)
44
What are the interactions of BZs?
- CNS depressants e.g. alcohol, barbiturates, antihistamines (increase effect of BZs)
- cytochrome P450 inhibitors e.g. cimetidine (increase side effects)
- CYT P450 inducers e.g. rifampicin (reduce therapeutic effect)
45
When are BZs contraindicated?
- acute pulmonary insufficiency
- sleep apnea
- neuromuscular respiratory weakness
- unstable myasthenia gravis
46
What other drugs are used to treat anxiety?
SSRIs e.g. fluoxetine
- uses; depression, anxiety disorders, OCD, phobia
- they are selective serotonin reuptake inhibitors
TCAs
- uses; depression, anxiety with depression, panic attacks
- they are serotonin + NA reuptake inhibitors
Buspirone
- uses; mild anxiety, NOT for panic attacks
- 5-HT1A partial agonist (increase action of serotonin in brain)
beta blockers e.g. propranolol
- uses; phobias
- work by blocking beta receptors of sympathetic system
Zolpidem + zaleplon
- uses; sleep disorders
- action similar to BZs
47
What is psychosis, and what are the important types?
It’s an abnormal condition of the mind, causing chronic disordered thinking + disturbed behaviour.
Most important types;
- Schizophrenia
- affective disorders (mania)
- organic psychosis e.g. alcoholism
48
What are the positive + negative symptoms of schizophrenia?
Positive symptoms (caused by hyperaction of doperminergic receptors e.g. in some neurones of mesolimbic pathyway)
- delusions
- hallucinations
- combativeness
- insomnia
Negative symptoms (caused by deficiency of dopamine in the mesocortical pathway)
- poor speech
- Social withdrawal
49
What are the 4 main types of DA pathway?
Mesolimbic
-regulates emotions, behaviour, role in pleasure
Mesocortical
-regulation of behaviour
Nigrostriatal
-regulation of movements
Tubero-infundibular
-regulation of certain hormones
50
Antipsychotics are used to treat SCZ, how do they work?
Act on CNS by;
- block D2 receptors on;
- mesolimbic system = sedation + antipsychotic impaired performance
- nigrostriatal System = gives extra-pyramidal side effects (EPSs) =
effects motor coordination in extra-pyramidal system). Gives effects
similar to Parkinson’s (Parkinsonism)
- tubers-infundibular System = effects pituitary gland; causes
endocrine effects e.g. impotence, weight gain + gynaescomastia
-blocks musclarinic receptors = dry mouth, constipation
-blocks alpha receptors = hypotension
-blocks histamine + serotonin = sedation
51
What are antipsychotics classified into?
Typical (1st gen e.g. haloperidol)
- has extra-pyramidal effects
- less effective on negative symptoms
Atypical e.g. clozapine, risperidone
- has LESS extra-pyramidal effects
- more effect on negative symptoms
52
What are psychostimulants classified into?
-respiratory stimulants e.g. doxapram (used for post anaesthetic
resp depression
-convulsants
-psychomotor stimulants e.g. amphetamine, modafinil (increase DA + NA release)
-hallucinogens or psychotomimetic drugs
53
What are the clinical uses of psychostimulants?
- ADHD e.g. detamphetamine
- apnoea of premature
- narcolepsy e.g. modafinil
Side effects;
- euphoria, insomnia, anorexia + psychosis
- tolerance + dependence
- hypertension, inhibition of GI motility
54
What are methylxanthines?
They are a psychomotor stimulant. Antagonism of A2 receptors
E.g. caffeine, theophylline
Uses;
- caffeine + aspirin for pain
- caffeine + ergotamine for migraine
- caffeine + apnoea for prematurity
- theophylline as bronchodilator
55
How do cognition enhancers work and what are there uses?
E.g. piracetam
Increases motivation, concentration, memory + cognitive. Reduces fatigue.
MOA
- increases blood flow
- supports neural metabolism
- enhancement of neurotransmission
Uses;
- AD
- dementia
- mild cognitive impairment
- brain surgery
56
What are chronic neurodegenerative diseases caused by?
Protein misfolding + consequent aggregation. This is because misfolding causes hydrophobic residues that are normally buried in the core of the protein to be exposed on its surface = gives strong tendency of molecule to stick to cell membrane + aggregate.
In NS aggregates often form structures known as amyloid deposits.
If the result is a large insoluble aggregate the neurones die. Dead neurones in the CNS are NOT replaced, nor can there terminals regenerate when there axons are disturbed.
E.g. AD (beta-amyloid misfolding), Huntington’s Disease (Huntingtin misfolding)
57
What protective mechanisms does the brain have that limits the accumulation of protein aggregates?
- chaperone proteins - bind to newly synthesised or misfolded proteins + encourage them to fold correctly.
- uniquitination reaction - prepares the protein for destruction within cell
Accumulation of protein deposits occurs when the protective mechanisms are unable to cope.
58
How are misfolded proteins usually removed?
Intracellular degradation pathways
59
What are the 2 main systems in CNS involved in motor coordination + postural tone?
- pyramidal
| - extraparamadal. Causes; rigidity, tremor, hypokinesia, postural instability
60
What are some features of PD?
- onset usually >50
- slowly progressive
- stooped posture
- bradykinesia
- reduced blinking + inability to show emotions
- tremors
- mental deterioration
- muscle rigidity
- depression
- shuffling gait
- rarely occurs in black population
61
What’s the pathophysiology of PD?
-Progressive degeneration of DA neurones in nigrostriatal
pathway = means you lose doperminergic inhibition + also get
excess stimulation of cholinergic neurones = causes imbalance of DA/
ACh = loss of muscle tone + coordination of movements
If pt loses >80% of neurones in this pathway = Parkinsonism symptoms
-2 NT involved in regulation of motion;
- DA = inhibits cholinergic neurones , regulate voluntary + involuntary
movement, inhibits ACh neurones
-ACh = excitatory
62
What are the 2 types of PD?
Primary
-maybe genetic
Secondary
- infection
- trauma
- drugs
63
What is PD treatment aimed at?
- increasing DA
- decreasing ACh
To restore balance to DA/ACh
64
What drugs are used in neurodegenerative diseases?
- dopaminergic drugs e.g. levodopa
- anti musclarinic drugs = reduces ACh effect
- MAOb e.g. selegiline
65
How can you increase doperminergic transmission?
- Give levodopa in doperminergic neurones = transformed to dopamine
- block enzymes that break down dopamine
- activate dopamine receptors
66
How is levodopa broken down?
- 70% metabolised in GI tract
- 30% absorbed
- 27-29% metabolised in peripheral tissue
- only 1-3% crosses BBB + reached brain
67
What are the adverse effects of levodopa?
Initial
- postural hypotension
- N+V
- cardiac arrhythmias - dopamine is precursor of NA = more dopamine = more NA
- exacerbation of asthma
Prolonged
- abnormal movements
- cognitive effects
- anxiety, psychosis, confusion
- inappropriate sexual behaviour
68
Why do you give levodopa nor dopamine?
Dopamine can’t cross BBB but levodopa can, so if you gave dopamine, you would only get peripheral effects
69
What are the drug interactions with levodopa?
- antipsychotics esp 1st gen, block action of levodopa by blocking D2 receptors
- anticholinergics -reduce absorbed of levodopa from stomach
- non-specific MAOi - prevents degradation of peripherally synthesised DA = hypertension
70
Why is levodopa effective at start of PD but not near the end?
Levodopa needs neurones to convert to dopamine. However, as PD progresses, fewer neurones survive.
71
What are the 2 proteins involved in AD?
Beta amyloid and neurofibrillary tangles
72
What changes occur in brain of someone with AD?
- shrinking of hippocampus
- shrinking of cerebral cortex (impaired cortex)
- enlarged vesicles
73
What are the treatments of AD?
- NMDA antagonist e.g. memantine. It mimics the action of glutamate which normally works on that receptor. It excites cells
- cholinersterase inhibitors e.g. donepezil. acetylcholinesterase breaks down ACh = increase ACh (important for memory + cognitive processes)
74
Epilepsy is categorised into what 2 categories?
- convulsive (violent, involuntary muscle contraction)
| - non-convulsive
75
When are seizures classified as epilepsy?
When seizures are chronic + recurrent
76
How to seizures come about?
When a set of neurones depolarise at high rates with sincronised acitivity. If it starts at particular part of brain = foci. It can spread + propagate to rest of body.
- focal onset
- motor
- non-motor (absence)
- focal to bilateral tonic clonic
- generalised onset (start everywhere and at same time)
- motor = tonic clonic or other motor
- unknown onset
- motor
If it starts on a particular part + spreads to rest of brain = called secondary generalised (secondary to focal onset).
77
How are seizures diagnosed?
Using electroencephalography, it detects electrical activity of cortex
78
What are the 2 classifications of epilepsy?
Generalised - both hemispheres, convulsive or not
- tonic-clonic (grand mal)
- tonic phase = sustained powerful muscle contraction
- clonic phase = alternating contraction + relaxation of muscles
- absence (petit mal)
Partial (localised)
- only one side of brain
- if there’s motor disturbance, generally affects opposite side of body
- simple
- complex
79
What are the 4 glutamate receptors?
- NMDA - slow excitatory
- AMPA - fast excitatory
- kainate - fast excitatory
- mGlu - regulate synaptic transmission
80
What are the antiepileptic drugs?
Na+ channel blocker e.g. carbamazepine, phenytoin
- uses; partial, generalised seizures
- 🙁 affects immune system cells, N + visual disturbances
- Ca2+ channel blocker e.g. valproic acid
- increase GABA neurotransmission e.g. BZs
- NMDA blockade e.g. felbamate
- glutamate blockade e.g. lamotrigine
81
What are the 2 main types of drug abuse?
- hard - lead to physical addiction, more dangerous e.g. alcohol, nicotine
- soft - no physical addition, still at risk of psychological dependence e.g. cannabis, LSD
82
What causes the rewarding effect of drugs?
Increase in DA in the mesolimbic system
83
What is the replacement from for opioids?
Methadone
84
What is the drug interaction between Amiodarone + amitriptyline?
Both prolong QT
85
What enzyme breaks down GABA?
GABA transaminase.
This is inhibited by vigabatrin (used in epilepsy)
86
What does binding of GABA to GABAA do?
Increases Cl- permeability = hyperpolarises the cell =reduces its excitability
87
What does binding of GABA to GABAB do?
Inhibits calcium channels + opens potassium channels = reducing excitability
Baclofen is a selective inhibitor at GABAB receptor + is muscle relactant
88
What does Gabapentin do?
Can increase GABA release or decrease removal
89
To reduce unwanted conversion of levodopa, what can it be combined with?
Carbidopa
90
What are the side effects of levodopa?
- conversion to dopamine in peripheries causes N+V due to stimulation of the CTZ
- postural hypotension due to peripheral vasodilation
- dyskinesia
- GI bleeding
- SCZ like syndrome
91
What do catechol-O-methyltransferase inhibitors do in treatment of SCZ?
Inhibit enzyme that breaks down about 30% of levodopa
