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Year 3 Sem 1 COPY COPY > PA30324 1. Pharmacology > Flashcards

PA30324 1. Pharmacology Flashcards

1
Q

Why is Neurology important? (consider statistics)

A
  1. sixth of England population aged 16-64 have a mental health problem
  2. Problems increasing especially for young people
  3. Women are more likely to be diagnosed
  4. Men are more likely to commit suicide
  5. Mental health problems start early
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2
Q

What are the possible anti-psychotic medication affects?

A
  1. Weight gain
  2. Appetite control
  3. metabolic syndrome
  4. Energy (somnolence and apathy therefore decreased activity)
  5. Heart rhythm
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3
Q

Which conditions can be targeted via Brain?

A
  1. Analgesia
  2. Parkinson’s Disease
  3. Alzheimer’s Disease
  4. AIDS
  5. Tumours
  6. Anxiety
  7. Depression
  8. Sleep disorder
  9. Appetite
  10. Convulsions
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4
Q

> 98% of small-molecule drugs and virtually all large-molecule cannot enter the brain from the systemic circulation.

Why is that ?

A
  • Brain requires significant amounts of small, hydrophillic molecules such as glucose and amino acids
  • Ion concentrations need to be tightly controlled

-

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5
Q

What are nerve cells?

A
  • Also known as a neuron or neurone
  • Excitable cells
  • Amiotic meaning they don’t divide
  • Have high metabolic rate
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6
Q

What is an excitable cell?

A
  • Neurones are an example
  • Neurones have a resting membrane potential i.e an electrical potential difference between inside and outside
  • The membrane potential can change in response to simulation
  • Excitability depends on ion channels in the membrane
  • Channels may be voltage-gated or transmitter (ligand)-gated
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7
Q

What are the K+, Na+, Cl- ion concentrations intracellularly and extracellularly?

A

Intracellular
K+: 140mM
Na+: 10-15mM
Cl-: 4-30mM

Extracellular
K+: 4-5mM
Na+: 145mM
Cl-: 110mM

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8
Q

Describe membrane potential Depolarisation and Hyperpolarisation regarding sodium channels and potassium channels

A
  • If sodium channel opens and allows movement of sodium ion into the cell, Depolarisation occurs making inside of the cell more postively charged
  • If potassium channel opens and allows movement of potassium ions from inside to outside the cell, the cell becomes negatively charged and hence Hyperpolarisation
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9
Q

What is an action potential and what do they do?

A
  • Large transient change in membrane potential and is an ‘all or none’ response
  • Action potentials are very rapid (as brief as 1-4ms) and may repeat at frequencies of several hundred types per second
  • To cause an action potential, a cell must utilise several types of ion channels
  • Actions potentials flow down axons. When they reach axon terminals they cause release of neurotransmitters
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10
Q

How does cell communicate with action potentials?

A
  • Actions potentials are generated in presynaptic neurone by graded potentials
  • They invade synaptic terminals
  • Release chemical synaptic transmitter
  • Generate graded potential in postsynaptic neurone
  • Postsynaptic potential can be inhibitory or excitatory
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11
Q

Describe how neurotransmitter is released by exocytosis

A
  1. Transmitter synthesised and stored in vesicles
  2. Action potential invades presynaptic terminal
  3. Action potential depolarises terminal and opens VGCC letting Ca2+ enter
  4. Ca2+ triggers vesicle fusion
  5. Transmitter released by exocytosis
  6. Transmitter binds to receptors
  7. Ion flow causes postsynaptic response
  8. Transmitter removed by enzyme breakdown or reuptake
  9. Vesicle retrieved from terminal membrane
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12
Q

What is ligand gated ion-channel and what effect does it have?

A
  • ionotropic receptor
  • like voltage gated ion channels
  • They are pores in the membrane that open in response to ligand binding
  • Ions come in so effect is either a hyper/depolarisation
  • Fast millisecond time scale
  • eg) nicotinic acetylcholine receptor
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13
Q

What is G-protein coupled receptor (GPCR) and what effect does it have?

A
  • protein complex that dissociates from the receptor when the ligand binds and signals to both ion channels
  • This produces changes in hyper/depolarisation and at the same time can activate an enzyme called Adenylyl Cyclase to activate second messenger pathways
  • relatively slow form of transmission (seconds)
  • eg) muscarinic acetylcholine receptors
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14
Q

What are the characteristics of graded (local) potentials?

A
  • Can be depolarization or hyperpolarisation
  • Graded: size/duration
  • Decay rapidly
  • Travel small distances
  • Show summation
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15
Q

Describe excitatory synapse

A
  • involves transmitter-gated ion channel (Na+)

- EPSP (excitatory postsynaptic potential)

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16
Q

Describe inhibitory synapses

A
  • involves transmitter-gated ion channel (Cl-)

- IPSP (inhibitory postsynaptic potential)

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17
Q

Describe role of Glutamate and GABA as a neurotransmitter

A
  • GABA and Glutamate regulate action potential traffic

GABA

  • inhibitory neurotransmitter
  • stops action potentials

Glutamate

  • excitatory neurotransmitter
  • starts action potential/ keeps them going
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18
Q

What effects do neurotransmitter receptors have?

A
  • Slower, more diffuse and modulatory effect
  • Affect multiple intracellular messengers e,g) ion channels, cAMP, IP3, Ca2+

Gs and Gq
- generally excitatory

Gi
- generally inhibitory

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19
Q

Name…

  • 4 neurones with different complex structures
  • 3 types of synapses
A

Neurones

  • retinal ganglion
  • motor neurone
  • pyramidal neurone
  • purkinje neurone

Synapses

  • axo-axonic
  • axo-somatic
  • axo-dendritic
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20
Q

What are CNS disorders so hard to treat?

A
  • Neurones are highly complex structures interconnected in complex network
  • Numerous synapses on each neurone
  • Numerous neurotransmitters and receptors
  • Multiple possible sites for dysfunction
  • Multiple sites of possible intervention
  • Numerous possible drug targets possible for a single neurotransmitter but drugs rarely selective
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21
Q

What are the 12 sites of action of CNS drugs?

A
  1. Substrate transporter
  2. Synthesis pathway
  3. Vesicular transporter
  4. Vesicular movement
  5. Release process
  6. Postsynaptic ionotropic receptors
  7. Postsynaptic GPCR
  8. Second messenger systems
  9. Uptake transporter
  10. Enzymatic degradation
  11. Presynaptic receptors
  12. Membrane ion channels
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22
Q

What is CSF?

A
  • Cerebrospinal Fluid
  • Produced by choroid plexus
  • Aqueous solution of NaCl + glucose
  • Buoyancy & cushioning
  • Compensation of changes in brain volume
  • Drug delivery
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23
Q

Define Rewarding and Reinforcing

A

Rewarding

  • subjective
  • often linked to euphoria
  • feeling of great happiness or well-being
  • can lead to addiction

Reinforcing

  • objective
  • when an animal will perform a behaviour in order to obtain that stimulus
  • e.g) it is rewarding
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24
Q

Define the following terms
- Psychological dependence

  • Physical independence
  • Tolerance
A

Psychological dependence
- Craving, compulsive drug use, loss of control, addiction

Physical independence
- When stopping a drug causes a withdrawal symptom

Tolerance
- When continued use of a drug results in the need for increasing doses for equivalent effect

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25
Q

What is ICSS (intra-cranial self-stimulation)?

A
  • Implanted electrodes into different tparts of rat brains

- When the rat pressed a lever, received electrical stimuli directly into that brain region

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26
Q

What is mesolimbic pathway?

A
  • sometimes referred as reward pathway
  • dopaminergic pathway in the brain
  • sets of projection neurones in the brain that synthesise and release neurotransmitter dopamine
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27
Q

How do the following drugs with different pharmacologies all cause increase DA levels in NAcc?

  • Cocaine & Amphetamine
  • Opiates
  • Ethanol
  • Nicotine
  • THC
A

Cocaine & Amphetamine
- Increase DA release or inhibit re-uptake

Opiates

  • act on μ-opioid receptors on GABAergic neurones.
  • Cause disinhibition of DA neurones in VTA

Ethanol

  • acts directly on DA neurones in VTA
  • decreases AHP, increases firing rate

Nicotine

  • acts on nicotinic acetylcholine receptors on DA neurones in VTA
  • increases firing rate

THC
- acts on cannabioid receptors on GABAergic neurones

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28
Q

What else does Ethanol do other than acting directly on DA neurones in VTA, decreasing AHP, increasing firing rate?

A
  • GABAa allosteric modulator
  • NMDA receptor antagonist
  • Calcium channel antagonist
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29
Q

Define the following terms

  • Pain
  • Nociception
  • Nociceptors
  • Algesia
  • Analgesia
A

Pain
- the subjective conscious appreciation of a stimulus that is causing, or threatening to cause, tissue damage

Nociception
- physical process of detection and transmission of damaging or potentially damaging (noxious) stimuli

Nociceptors
- Structures which detect noxious stimuli

Algesia
- Induction of a condition leading to nociception and pain

Analgesia
- Reduction or prevention of either nociception or pain without loss of consciousness

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30
Q

Describe the process of Nociception

A
  1. Noxious stimuli
  2. Primary transduction, Channel opening
  3. Secondary transduction. Change in membrane voltage
  4. Depolarisation and action potential generation
  5. Transmitter release
  6. Second order neurone reseonse
1 = Skin/viscera
2,3 = Sensory receptor
4,5 = Primary afferent axon
6 = Spinal cord
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31
Q

What signals are detected in nociceptors?

A

ASIC

  • Acid sensing ion Channel
  • H+

P2x3

  • Purinergic receptor
  • ATP
  • Mechanical stimulation

VGNa

  • Voltage gated sodium channel
  • Mechanical stimulation

VR-1/TRPV-1

  • Vanilloid 1
  • Capsaicin
  • H+
  • heat

All induce Na+ into depolarisation/excitation and action potential firing

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32
Q

Define the following altered detection of pain and 2 possible sites of action

  • Hyperalgesia

- Allodynia

A

Hyperalgesia
- Increased response to a noxious stimulus

Allodynia
- Painful responses to a non-noxious stimulus

Possible sites

  1. Peripheral sensitisation
    - Increased sensitivity of peripheral nociceptors
  2. Central sensitisation
    - Increased transmission in spinal cord
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33
Q

How does prostaglandin induce pain?

A
  • Act as signals to control several different processes
  • Sensitize bradykinins
  • 5-HT, histamine, ATP, K+ are released by tissue damage
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34
Q

Which difference does AMPA and NMDA receptors show regarding excitatory neurotransmission?

A

AMPA
- fast postsynaptic EPSP

NMDA
- slow postsynaptic EPSP

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35
Q

How is itch induced?

A
  • Afferent input via Aδ and C fibres from free never endings
  • Inflammation, particularly histamine, can cause it
  • Analgesics dont inhibit itch
  • Strong central component
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36
Q

How do analgesic drugs reduce pain?

A
  • Increases inhibition of nociception
  • Inhibits peripheral sensitisation
  • Inhibits central sensitisation
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37
Q

How do opiates drugs act?

A
  • Acts on opioid receptors

- Mimic endogenous opioids

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38
Q

Describe Worth Health Organisation Pain Ladder

A

Mild pain
- NSAIDS e.g aspirin, ibuprofen

Moderate pain
- codeine, buprenorphine

Severe pain
- morphine, fentanyl

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39
Q

What are the desirable/undesirable behavioural responses of μ-opioid receptor activation?

A

Desirable

  • analgesia
  • euphoria
  • constipation
  • sedation
  • cough suppression

Undesirable effects

  • respiratory depression
  • euphoria
  • constipation
  • sedation
  • nausea & vomitting
  • tolerance
  • itching
  • dependence
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40
Q

What are NSAIDS?

A
  • Non-steroidal anti-inflammatory drugs
  • Most widely used therapeutic agents
  • Cox inhibitors
  • inhibits Arachidonic acid → Prostaglandin H2
  • Anti-inflammatory
  • Anti-pyretic
  • Analgesic
  • All effects related to decreased prostaglandin synthesis
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41
Q

What are the disadvantages of NSAIDS?

A

Prostaglandin involved in many processes

  • multiple side-effects
  • severe gastric irritation
  • kidney disorders
  • paracetamol overdose
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42
Q

What is neuropathic pain?

A
  • pain related to peripheral nociception
  • sometimes called pathological pain: serves no purpose

Could be due to

  • peripheral nerve damage
  • peripheral nerve terminal damage or infection
  • spinal damage
  • thalamic stroke
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43
Q

What are the alternative analgesic approaches?

A
  • Tricyclic antidepressants, antiepileptic drugs
  • Capsaicin cream
  • Cannabinoid receptor agonists
  • Glutamate receptor blockers
  • Neurokinin receptor blockers
  • Vanilloid receptor blockers
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44
Q

Describe Glutamate and GABA

A

Glutamate

  • main excitatory transmitter in the CNS (aspartate)
  • activates a large family of ionotropic and metabotropic receptors
  • synthesised from glutamine

GABA

  • main inhibitory transmitter in the CNS
  • activates a large family of ionotropic and metabotropic receptors
  • synthesised from glutamate
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45
Q

Describe distribution of amino acid transmitter

A
  • Not localised to discrete brain regions, uniquitous
  • Glutamate mostly found in pyramidal neurones
  • GABA mostly found in short local interneurones
  • GABA also found in longer projection neurones
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46
Q

Describe briefly metabolism of transmitter amino acids in the brain

A
  • Glutamate in the CNS comes either from glucose (via Krebs cycle) or glutamine
    : synthesised by glial cells and taken up by neurones
  • Glutamate can be converted to GABA by the enzyme glutamic acid decarboxylase (GAD)
  • GABA cn be inactivated by GABA-transaminase
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47
Q

Describe metabolism of Glutamate in the brain

A
  • Glutamate (Glu) is stored in synaptic vesicles and released by calcium-dependent exocytosis
  • Released Glu is taken up into nerve cells and glial cells (astrocytes) by excitatrory amino acid transporter (EAAT) proteins
  • In astrocytes, Glu is converted to Glutamine (Gln) and recycled via transporters (GlnT) back to neurones
  • Glu is taken up into synaptic vesicles by vesicular glutamate transporters (VGluT)
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48
Q

Describe ionotropic receptors and metabotropic receptors

A

Ionotropic receptors

  • ligand-gated ion channels
  • multisubunit receptors
  • heterogenous receptors
  • affects physiological function and pharmacology
  • rapid cellular effects
  • mediate fast hyperpolarisation and therefore inhibition

Metabotropic receptors

  • G protein-coupled receptors
  • hetero- and homodimers
  • activate second messenger systems
  • slower effects on synaptic transmission
  • may be autoreceptors located presynaptically on nerve terminals
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49
Q

Describe the main sties of drug action on GABAa receptors?

A
  • GABAa receptors have multiple modulatory or allosteric sites
  • Highly permeable to Cl- ions
  • Drug actions at allosteric sites ‘turn up’ or ‘turn down’ gating of Cl- ions in the presence of GABA bound to the orthosteric sites
  • Many therapeutic agents target the GABAa receptors
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50
Q

Describe GABAa receptor pharmacology

A

Anaesthetics
- e.g) etomidate & propofol are volatile anaesthetics that act on GABAa receptors

Barbiturates
- e.g) pentobarbital has sedative/anticonvulsant effects

Benzodiazepines
- multiple actions eg) anxiety relieving, anticonvulsant, hypnotic

Neurosteroids
- metabolites of progesterone & deoxycorticosterone

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51
Q

Describe the GABAb receptors

A
  • GABAb receptors are heterodimers
  • R1 has ‘venus fly trap’ GABA binding site
  • R2 traffics the receptor to the cell surface
  • Close calcium channels presynaptically to reduce transmitter release (Autoreceptor)
  • Open potassium channels postsynaptically eliciting a slow hyperpolarisation
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52
Q

Describe excitatory synapses

A
  • Glutamatergic ionotropic receptors are cation channels
  • Generates Excitatory PostSynaptic Potential (EPSP)
  • Fast excitatory neurotransmission
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53
Q

Describe the main sites of drug action on NMDA receptors?

A
  • Highly permeable to Ca2+ (excitotoxicity)
  • Readily blocked by Mg2+ but is voltage sensitive and disappears when cell is depolarised
  • Activation requires glycine as well as glutamate
  • Ketamine and phencyclidine are selective antagonists of NMDA receptors
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54
Q

Describe metabotropic glutamate receptors (mGluRs)

A
  • 8 different G protein coupled receptors
  • Function as homo and heterodimers
  • Slow, neuromodulatory role
  • Many types, connected to different second messenger systems
  • No drugs on the market: clinical potential in pain, Parkinson’s disease, epilepsy and drug abuse
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55
Q

How does pre-synaptic receptors control neurotransmitter release?

A

presynaptic NMDA receptor
- increase glutamate release by increasing Ca2+ influx

presynaptic mGlu receptors
- decrease glutamate release by decreasing Ca2+ influx

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56
Q

How does glutamate bind so many receptors?

A
  • It is not a rigid molecule
  • Different constituents can rotate along two different axes
  • Can adopt different conformations
  • Rotates about alphabeta and betagamma bonds
  • Nine rotamers are possible
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57
Q

Give examples of amine neurotransmitter and what they do

A

Amine neurotransmitter systems in the CNS are

  • Noradrenaline (NA)
  • Dopamine (DA)
  • 5-hydroxytryptamine (5HT)
  • Acetylcholine (Ach)
  • Histamine

DIFFUSE, MODULATORY SYSTEMS
- Cell bodies are restricte to a small number of brainstem nuclei

  • Axons project widely throughout the nervous system
  • Modulate (+/-) fast excitation or inhibition via multiple receptors
  • Lack specialised synaptic contacts
  • Key roles in arousal, attention, sleep and survival
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58
Q

Describe Noradrenaline pathways in the CNS

A
  • Origin in Locus Coeruleus
  • C1 group may use adrenaline
  • Diffuse innervation of forebrain, particularly cerebral cortex and hippocampus
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59
Q

Describe Noradrenaline functions in the CNS

A
  • Acts at a1, a2, b1 and b2 receptors (GPCRs)
  • Brainstem
    : blood pressure control
    : baroreceptor reflex
  • Descending
    : movement and pain
  • Ascending
    : arousal and mood
    : cognitive processes, learning and memory, movement, attention
  • Depletion in forebrain (cortex, hippocampus)
    : involved in depression
  • Overactivity in mania
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60
Q

Describe Noradrenaline synthesis

A
  • Identical to autonomic nervous system
    1. Substrate is tyrosine
    2. Hydroxylation to DOPA -rate limiting
    3. Decarboxylation to dopamine
    4. b-hydroxylation within vesicles
    5. End product inhibition
  • Only NA neurones express dopamine-b-hydroxylase
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61
Q

Noradrenaline synthesis

- important therapeutic points regarding TH (tyrosine hydroxylase)

A
  • TH and DbOH synthesis increased on demand
    : increased gene expression
  • TH blockade depletes NA
    : Depression
  • TH saturated
    : NA unaltered by increased substrate
  • Synthesis increased by L-DOPA
  • Blockade of vesicular uptake (reserpine)
    : depression
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62
Q

How is Noradrenaline activated and inactivated?

A
  • Reuptake by NET (Norepinephrine transporter)

- Degradation by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)

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63
Q

Describe Dopamine pathways in the CNS

A
  • midbrain origin
    : SN (substantia nigra) and VTA (ventral tegmental area)
  • Nigro-striatal most important pathway
  • VTA to cortex and hippocampus
    : mesolimbic/mseocortical pathways
  • TI systems from hypothalamus to pituitary
  • Reward Chemical
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64
Q

What does Dopamine do in the CNS?

A
  • Act as D1-5 dopamine receptors
    : all GPCRs
  • Control of movement
    : Nigro-striatal - Parkinson’s disease
  • Control of attention, emotion and reward
    : VTA to cortex/limbic system - mesocorticolimbic system
    : Schizophrenia
    : Involved in a
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65
Q

What does Dopamine do in the CNS?

A
  • Act as D1-5 dopamine receptors
    : all GPCRs
  • Control of movement
    : Nigro-striatal - Parkinson’s disease
  • Control of attention, emotion and reward
    : VTA to cortex/limbic system - mesocorticolimbic system
    : Schizophrenia
    : Involved in actions of drugs of abuse
  • Control of endocrine function
    : TI system controls pituitary hormone output
  • Brainstem
    : vomitting
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66
Q

Describe Dopamine synthesis and inactivation

A
  • As noradrenaline
  • No dopamine-b-hydroxylase in vesicles
  • Only release dopamine (DA)
  • Inactivation via uptake, MAO and COMT
  • Uptake transporter specific for DA
    : dopamine transporter (DAT)
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67
Q

Describe TI pathway

A

Tuberoinfundibular Pathway

  • Projects from hypothalamus to anterior pituitary
  • inhibits prolactin release
  • Blockade of D2 receptors in this pathway can lead to hyperprolactinemia which clinically manifests as amenorrhoea, galactorrhoea and sexual dysfunction
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68
Q

Describe 5-hydroxytryptamine (5HT, serotonin) pathways in the CNS

A
  • Arise from raphe nuclei
  • Forebrain and cerebellum from dorsal and median raphe
  • Caudal raphe to spinal cord and cerebellum
  • Appetites chemical
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69
Q

What does 5HT do in the CNS?

A
  • Receptors: 5HT 1-7 mostly GPCR
  • Control of mood
    : cortical/limbic system projections
    : dysfunction in depression
  • Control of sleep (thalamus)
    : Activation - wakefulness/insomnia
    : Decreased activity - sleep and sedation
  • Control of feeding (hypothalamus/limbic system)
    : Increase - loss of appetite and weight
    : Decrease - feeding/weight gain
  • Control of sensory transmission
    : Gating of spinal transmission (pain)
    : Cortical inputs dampen sensory overload
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70
Q

How is 5HT synthesised?

A
  1. Substrate is dietary tryptophan
  2. Uptake and hydroxylation
  3. Decarboxylation by AADC
  4. Concentration into vesicles
  5. Inactivation by re-uptake and MAO
  6. Uptake transporters specific for 5HT (not DA/NA)
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71
Q

Read
5HT Synthesis and inactivation
- important therapeutic points

A
  • Tryptophan hydroxylase not saturated
    : tryptophan availability is rate limiting
    : tryptophan or 5HTP - increase 5HT synthesis
  • Vesicular uptake blocked by reserpine
    : 5HT depletion - depression
  • Inactivation by re-uptake
    : blocked by antidepressants - SSRIs
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72
Q

Describe Acetylcholine (ACh) pathways in the CNS

A
  • Projection to cortex/limbic system from magnocellular neurones
  • Projection to hippocampus
  • Projections from brainstem to thalamus and other sites
  • Local interneurones in basal ganglia
  • Memory/Motivation chemical
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73
Q

What does ACh do in the CNS?

A
  • Both nicotinic (ionotropic) and muscarinic (GPCR) receptors
  • Arousal, sleep, waking
    : Reticular activating systems from brainstem
    : Increased ACh- arousal
  • Basal forebrain nuclei involved in cognition
    : Degeneration in Alzheimer’s disease
  • Learning and memory
    : Septo-hippocampal pathway
    : Alzheimer’s disease
  • Motor control (basal ganglia)
    : Parkinson’s disease and Hauntington’s chorea
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74
Q

Describe ACh synthesis

A
  • Same as NMJ (Neuromuscular junction)
    1. Substrate is dietary choline
    2. Active uptake
    3. Acetyl CoA from mitochondria
    4. Acetylation of choline (ChAT)
    5. Active transport into vesicles
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75
Q

Read

ACh - important therapeutic points

A
  • ChAT not saturated - choline rate limiting
    : choline increases ACh synthesis
  • Inactivation by acetylcholinesterase in synaptic cleft
    : Free choline + acetic acid
    : Active uptake of choline
  • Increasing ACh
    : Alzheimer’s therapy
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76
Q

What is histamine and its role?

A
  • Produced from the amino acid histidine
  • Synthesised and localised to the tuberomammillary nucleus within the hypothalamus
  • Storage, release and reuptake mechanisms not well defined
  • Histamine H1, H2, H3 and H4 receptors are GPCRs
  • Histamine neurones project to monoamine and cholinergic neurones involved in arousal, attention, learning and memory
  • Plays a role in sleep
  • Plays a role in feeding and energy balance
  • Newer allergy antihistamines dont cross BBB
  • Histamine H2 antagonists dont cross BBB
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77
Q

Just READ

Summary of Amines

A
  • Amines primarily modulate fast excitatory and inhibitory transmission
  • Synthesis, reuptake and degradation are all important drug targets
  • Noradrenaline and 5HT important target in depression
  • Dopamine important target for schizophrenia, Parkinson’s and reward/addiction
  • Acetylcholine important target for Alzheimer’s treatments
  • histamine future target in Alzheimer? Anti-obesity?
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78
Q

What are Primary headache and Secondary headache?

A

Primary headache

  • no detectable underlying cause
  • tension-type headache
  • migraine
  • cluster headache

Secondary headache

  • caused by underlying condition
  • extracranial: e.g sinusitis, otitis
  • intracranial e.g vasculitis, meningitis, abcess, tumour
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79
Q

Describe the following types of headache

- Tension type

A

Tension type

  • Pain comes and goes
  • Feeling of pressure of tightness
  • Not associated with other symptoms
  • Bilateral localisation
  • Variable duration, episodic
  • Patient remains active or prefers to rest
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80
Q

Describe the following types of headache

- Migraine

A

Migraine

  • Pain moderate to severe
  • Throbbing
  • Worse with exertion
  • Associated with photo/phonophobia
  • Associated with aura
  • 60-70% unilateral localisation
  • Duration 4-72hrs
  • Typically patient rests in quiet dark room
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81
Q

Describe the following types of headache

- Cluster

A

Cluster

  • Abrupt onset
  • Continuous excruciating pain
  • Associated with tearing, congestion, rhinorrhea, pallor, sweating
  • Unilateral localisation
  • Duration 0.5-3hrs, many per day
  • Patient remains active
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82
Q

What is the background of of Tension-type heache (TTH)?

A
  • Lifetime risk of experiencing tension type headache is 70-80%
  • About 50% of adults aged 40 yrs experience episodic tension-type headachee
  • Prevalence is higher in women than men
  • Most patients treated with OTC medicines and do not seek medical attention
  • Episodic
    : infrequent episodic TTH, frequent episodic TTH, chronic TTH
  • Pathophysiology unclear
  • Theory of increased muscle tension unproven: often posterior neck muscles
  • Episodes of headache are not associated with nausea or vomitting
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83
Q

What is the treatment options for Tension-type headache?

A

First line treatment
- OTC analgesics paracetamol, NSAIDS

Second line treatment
- Aspirin + paracetamol + caffeine

Medication overuse headche

  • Limit treatment to 2-3 days per week
  • High risk of rebound headaches
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84
Q

What is ‘medication overuse headache’?

A
  • Continued use of painkillers causes headache (mechanism unknown’
    : worldwide prevalence 1-2% of population
    : headache present >15days/month
  • Drugs causing overuse headaches
    : Paracetamol, Aspirin and NSAIDS >15days/month
    : Triptans, opioids, ergots >10days/month
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85
Q

Describe prevalence of migraine and sex difference

A

Prevalence

  • approx 10-15% of adult population
  • pre-puberty 6% in both males/females
  • post-puberty, rises to 18% in menstruating women
  • menstrual migraine attacks triggered by falling oestrogen levels
  • post-menopause, migraine frequency falls in many women

Genetic factors
- ~50% of migraineurs have 1st degree relative with the condition

Environmental factors
- many triggers such as chocolate, cheese, cured meat, red wine, stress, lack of sleep, too much sleep, flashing lights, weather changes

86
Q

Describe phases of migraine headache

A

Prodromal/Premonitory phase

  • visual disturbances
  • paraesthesias
  • emotional changes

Headache phase

Resolution phase

  • pulsating
  • throbbing
  • continuous pain
  • head or pain in entire head particularly behind the eyes
87
Q

What is aura?

A
  • classic migraine (without aura is common migraine)
  • Focal neurological disturbances
  • Preceding or accompanying headache
  • may include
    : motor features
    : sensory disturbances, typically visual
  • occurs regularly in 15% of migraine patients
  • Linked to CSD (cortical spreading depression)
    : slowly prepagating wave of depolarisation (triggered by K+ disturbance?)
    : decrease in regional cerebral blood flow
88
Q

What are the causes of migraine pain?

P.S
- Central nervous system (CNS) is devoid of sensory pain receptors

  • Intracranial blood vessels in the dura mater and the large arteries of the circle of Willis, are supplied with sensory nerves and receptors that can respond to thermal, mechanical or distension stimuli
  • Nerves innervating intracranial blood vessels have their cell bodies in ganglia belonging to the sympathetic, parasympathetic and sensory nervous system
A

Vascular theory
- implicated intracerebral vasoconstriction, followed by extracerebral vasodilation, as cause of headache

Neuronal theory

  • Cortical spreading depression (CSD)
  • an advancing wave of neural inhibition progresses slowly over the cortical surface at 2mm/min
  • leads to ionic balance disturbance and local blood flow reduction

Inflammation theory

  • Activation of trigeminal nerve terminals in the meninges and extracranial vessels is primary event in a migraine attack- triggers pain directly
  • Induces inflammatory changes through the release of neuropeptides and other inflammatory mediators from senseory nerve termianls
89
Q

What are the treatment options of migraine?

A

Acute episode

  • Analgesics (NSAIDs)
  • Triptans (5HT 1B/D Receptor agonists)
  • Combination
  • Anti-emetic

Prophylaxis

  • B-blockers
  • Antiepileptic drugs
  • Antidepressants
  • Ca channel block
90
Q

What is Triptans?

A
  • selective 5HT receptor agonists with high affinity for the 5HT.1B and 5HT.1D receptors
  • Neuronal 5HT receptors are implicated in mood, feeding, cognition, reward, impulsivity, sleep, circadian, rhythms, vomitting reflex
  • 5HT.1B receptors are on smooth muscle cells of blood vessels and cause vasoconstriction when stimulated
  • 5HT.1D receptors lie on trigeminal nerve terminals and their stimulation blocks the release of vasoactive peptides from trigeminal neurones
91
Q

What are the treatment options for cluster headache?

A

Acute treatment

  • subcutaneous sumatriptan (rapid and effective)
  • nasal triptan for people who do not want sc preparation
  • do not offer paracetamol, NSAIDs, oral triptans

Prophylactic treatment
- Verapamil, CCB can be considered (off-label)

92
Q

What is stroke and its prevalence

A
  • Transient or permanent interruption in cerebral blood supply - ischaemia - lack of O2/glucose
  • ~100,000 strokes in UK each year
  • ~1 in 8 strokes are fatal within the first 30 days (4th biggest cause of death in UK)
  • 1.2 million stroke survivors in UK
93
Q

Describe 2 types of stroke

A
  1. ischaemic (thrombic) stroke
    - incidence 85%
    - lower mortality
    - thrombic - internal large or small vessels
    - embolic - external: air, fat
  2. Haemorrhagic stroke
    - incidence 15%
    - higher mortality
    - intracerebral
    - subarachnoid
94
Q

What are the symptoms of stroke?

A
  • difficulty talking or understanding words
  • loss of feeling or strange feelings on one side
  • weakness of the face, arm or leg on one side
  • severe unexplainable headache
  • sudden decreased, blurred vision
  • unexplained diziness or loss of balance
95
Q

What is the primary cause of cell death in stroke?

A

Excitotoxicity
- excessive release of glutamate

  • neurones excited to death
  • Ca2+ overload
  • Also Alzheimer’s, Parkinson’s, Huntington’s, amyotrophic lateral sclerosis
96
Q

How does excitotoxicity happen?

A
  • failure of glucose/O2
  • Na-K pump fails
  • increased [K+]o, [Na+]i
  • depolarisation
  • increased Ca2+ influx
  • increased glutamate release
    : failed glutamate uptake, increased depolarisation
  • more Ca2+/Na+ influx
  • enzyme activation, free radical production
  • damage and death

Other factors

  • Na+ drags water in: cell swelling
  • oedema in penumbra: vascular compression, more ischaemia
  • repolarised neurones hyperactive: reperfusion injury when blood/O2 restored
97
Q

Describe peri-infarct depolarisation

A
  • Neurones in core never repolarise
    : death by necrosis
  • Neurones in penumbra repolarise
  • Repolarisation uses energy (ATP)
    : energy depletion - depolarisation
  • Repeated cycle lasting 6-8 hours
  • More excitotoxic death
98
Q

What are the treatment options for stroke?

A

Treatment A
- Tissue plasminogen activator (tPA) only licensed treatment
: restores blood flow, disperses thrombus
: within 3 hours
: only for ischaemic (thrombotic) stroke

Treatment B
- Reduce risk of future strokes
: antihypertensives (e.g ACEi) - ischaemic and haemorrhagic
: statins - cholesterol reduction - ischaemic
: antiplatelet drugs - ischaemic only
: anticoagulants - ischaemic only

99
Q

Describe other examples of excitotoxicity than stroke-related

A
  • Other diseases states such as Alzheimer’s, Parkinson’s, motor neurone disease
  • Food-induced excitotoxicity

: Amnesic shellfish poisoning
: Neurolathyrism
: Guam disease

100
Q

Define mood and mood disorders.

Describe backgrounds of mood disorders

A

Mood
- conscious state of mind or predominant emotion

Mood disorders
- abnormal elevation or lowering of mood

  • Complex and heterogeneous
    : includes depression and mania
  • Leading cause of illness worldwide
    : globally, more than 300 mil people of all ages suffer from depression (WHO)
    : suicide is the second leading cause of death in 15-29y/o (WHO)
  • can occur with anxiety, psychosis and other psychiatric symptoms
  • commonly involves somatic symptoms and disorders
  • difficult to categorise, diagnose and treat
101
Q

JUST READ

Facts and Figures about depression

A

Depression is common
- lifetime prevalence of unipolar depression 5%
: ~1 in 38 adults in UK at any one time
: globally > 300 mil patients with depression (WHO)

Co-morbidity is common
- 2/3 of those with MDDwill also meet criteria for anxiety disorder at some point

MDD twice as common in women than men

  • similar discrepancy occurs in many countries
  • difference emerge in adolescence

Symptoms variation

  • across cultures
  • across life span

Episodic, recurrent can lead to suicide

102
Q

Describe DSM-5 criteria (diagnosing major depression)

A

EITHER
- depressed mood most of the day, nearly every day

OR
- diminished interest/pleasure in everyday activities, nearly all day

PLUS 4 or more of the following

  • significant weight loss/gain or change in appetite
  • insomnia/hypersomnia
  • slowing down of thought and reduction of physical movement
  • fatigue or loss of energy nearly every day
  • feelings of worthlessness or excessive or inappropriate guilt
  • diminished concentration, or indecisiveness
  • recurrent thoughts of death or suicide
103
Q

Describe severity of a depressive episode

A

subthreshhold - mild - moderate - severe

= number of symptoms/functional impairment

104
Q

How is depression assessed and why?

A

Clinician administered assessment scales

  • Hamilton Depression Rating Scale (HAM-D or HDRS)
  • Montgomery-Asberg Depression Rating Scale (MADRS)

Self-rating assessment scales
- Beck Depression Inventory (BDI)

Why?

  • Assess severity of symptoms
  • Evaluate response to treatment
  • Promote self-management strategies
105
Q

What are different types of Major Depressive Disorder (MDD)

A

Episodic
- symptoms tend to disappear over time

Recurrent
- once depression occurs, future episodes likely

Subclinical depression

  • sadness plus 3 other symptoms for 10 days
  • significant impairments in functioning even though full diagnostic criteria are not met
106
Q

What is Dysthymic Disorder (Dysthymia)?

A

Chronic depression
- depressed mood for at least 2 years (not severe enough for Major Depression episode

Plus 2 other symptoms

  • poor appetite or overeating
  • sleeping too much or too little
  • psychomotor agitation or retardation
  • loss of energy
  • feelings of worthlessness
  • difficulty concentrating or indecisiveness
  • recurrent thoughts of death or suicide
107
Q

Describe Bipolar disorders

A
  • usually involve episodes of depression alternating with mania ( difficult to recognise)

Mania
- states of intense elation or irritability

Mixed episode
- symptoms of both mania and depression in the same week

Hypomania

  • symptoms of mania but less intense
  • four or more days of elevated mood
  • doesnt interfere with functioning
  • hypomania alone is not a DSM diagnostic category
108
Q

Describe criteria for Manic and Hypomanic episodes

A

Elevated expansive or irritable mood

Plus 3 of the followings

  • psychomotor agitation or increase in goal-directed behaviour
  • excessive talking or pressured speech
  • flights of ideas; racing thoughts
  • reduced need for leep
  • grandiosity or inflated self esteem
  • easily distractible
  • excessive involvement in pleasurable activities with negative consequences

For manic episode

  • symptoms last for 1 week OR require hospitalisation
  • symptoms cause significant distress or functional impairment

For hypomanic episode

  • symptoms last at least 4 days
  • clear changes in functioning but impairment is not marked
109
Q

What are the 3 forms of Bipolar Disorders?

A 
Bipolar I (More towards Mania)
- at least one episode or mania or mixed episode

Bipolar II
- at least one major depressive episode with at least one episode of hypomania

Cyclothymic disorder (Cyclothymia) (More towards Severe Depression)
- Milder, chronic form of bipolar disorder
: lasts at least 2 years
- Numerous periods with hypomanic and depressive symptoms

110
Q

READ

some facts and figures about Bipolar disorders

A
  • Prevalence rates for Bipolar Disorder lower than MDD
  • Average age of onset in 20s
  • No gender differences
  • Tends to be recurrent
  • Severe mental illness
111
Q

What are further subtypes of Depressive Disorders?

A

Seasonal (SAD)
- episodes happen regularly at a particular time of year

Rapid cycling (Bipolar I and II)
- at least 4 episodes within past year

Postpartum onset
- within 4 weeks of giving birth

Catatonic features
- extreme physical immobility or excessive peculiar physical movement

Psychotic features
- Delusions or hallucinations

Melancholic
- inability to experience pleasure

112
Q

What are the common medical conditions associated with Mood Disorders?

A
  • Pulmonary disease (COPD, asthma)
  • Endocrine disorders
  • Cancer
  • Cardiovascular disease
  • CNS
  • Neurological disorders
  • Folate dificiency
  • Chronic pain
  • Sleep apnea
113
Q

What causes mood disorders?

A
  1. Genetic factors (heritability estimates)
    - 93% Bipolar Disorders
    - 37% Major Depression
  2. Neurotransmitter dysfunction
    - monoamines
    - neuroendocrine
    - neurogenesis
    - glutamate
  3. Psychosocial/environmental factors
    - stressful life events
    - co-morbidity such as chronic pain
    - medication
114
Q

What is monoamine hypothesis?

A
  • depression is a functional deficit of 5HT and/or noradrenaline in the brain
115
Q

Describe the 4 stepped care model (NICE) of depression

A

Step 1
All known and suspected presentations of depression
- assessment, support, psychoeducation, active monitoring and referral

Step 2
Persistent subthreshold depressive symptoms
- mild to moderate depression
- low-intensity psychosocial intevention, psychological interventions, medication and referral

Step 3
Persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions
- moderate to severe depression
- medication, high-intensity psychological intervention, combined treatment, collaborative care

Step 4
Severe and complex dperession
- risk to life
- severe self-neglect
- medication, high-intensity psychological intervention, electroconvulsive therapy, crisis service, combined treatments
116
Q

Give 3 examples of psychological treatment of mood disorders?

A

Interpersonal psychotherapy (IPT)

  • short term psychodynamic therapy
  • focus on current relationships

Cognitive therapy

  • monitor and identify automatic thoughts
  • replace negative thoughts with more neutral or positive thoughts
  • behavioural activation

Mindfullness based cognitive therapy (MBCT)
- strategies, including medication, to prevent relapse

117
Q

What is elctroconvulsive therapy in mood disorders?

A

Electroconvulsive therapy (ECT)

Reserved for

  • severe depression with high risk of suicide
  • depression with psychotic features
  • treatment non-responderse

Induce brain seizure and momentary unconsciousness

  • unilateral ECT
  • side effects: memory loss
118
Q

What is Monoamine oxidase inhibitors (MAOIs)?

A

e.g phenelzine, tranylcypromine, iproniazid

irreversible inhibitors of monoamine oxidase

MAO is widely expressed

  • within nerve terminals regulates intraneuronal concentration of NA/5HT
  • in the gut wall inactivates endogenous/ingested amines

Enzyme excists in two forms MAOA and MAOB

  • MAOA = substrate preference = 5HT
  • MAOB = substrate preference = DA
119
Q

What is cheese reaction regarding irreversible MAOIs?

A
  • Tyramine (diet) normally metabolised by MAO in the gut/liver

During non-selective MAOI

  • Tyramine not metabolised but absorbed
  • Tyramine has sympathomimetic effects
  • Can result in acute hypertension, headache, angina, cardiac arrest, pulmonary oedema, intracranial haemorrhage
120
Q

Describe clinical utility of MAOIs

A

Major side effects of MAOIs

  • hypotension (sympathetic block)
  • atropine-like effects
  • hepatocellular jaundice

Decline in use with concern over safety

  • Hypertensive crisis (tyramine, symapthomimetic amines)
  • Potentiation of drug action (TCA, alcohol)

Renewed interest with development of selective and reversible inhibitors of MAO

121
Q

Descrobe Reversible inhibitors of MAOA (RIMA)

A
  • monoclobemide
  • reversible action allows MAOA inihibition to be partially overcome by high concentration of substrates e.g tyramine
  • unlikely to result in ‘cheese reaction’ if tyramine or sympathetic amines ingested
122
Q

What is TCAs

A
  • Tricyclic antidepressants
  • e.g imipramine, amitriptyline, clomipramine
  • block the uptake of amines by nerve terminals
    : 5HT=NA&raquo_space; DA
    : competitive with endogenous substrate
    : relatively non-selective
  • receptor blockade e.g mAChRs, HA, 5HT
    : contributes to side effect profile
  • major metabolised also active
123
Q

What is SSRIs?

A
  • selective serotonin reuptake inhibitors
  • e.g fluoxetine, paroxetine, citalopram
  • MOST commonly prescribed class of antidepressants = 1st line
  • also used to treat anxiety disorders
124
Q

Name some monoamine receptor blockers

A
  1. Mirtazapine
    - blocks a2 adrenoceptors/5HT2c receptors
    - enhanced NA/5HT release
  2. Trazodone
    - blocks 5HT2a/2c and 5HT reuptake
  3. Mianserin
    - blocks multiple 5HT receptors a1/2 adrenoceptors
  4. Agomelatine
    - blocks melatonin receptors
    - useful for depression with sleep disturbance
125
Q

What are the limitations of antidepressants?

A

Efficacy of antidepressants

  • <40% achieve remission from symptoms
  • Robust effect in preventing relapse in recurrent MDD

Tolerability

  • side effect profile deters use
  • e.g emotional blunting/detachment with SSRI

Time to onset/discontinuation effects
- typically 4-6 weeks to onset of therapeutic benefit

Safety of antidepressants

  • risk of suicide
  • older drugs are cardiotoxic
126
Q

What are the medications for bipolar disorder?

A
  • a.k.a mood stabilising drugs
  • Lithium
    : upto 80% receive at least some relief with this mood stabiliser
    : potentially serious side effect = Lithium toxicity
  • Anticonvulsants
    : e.g valproate, lamotrigine
    : prevent relapse to depression
  • Antipsychotics
    : e.g olanzapine, risperidone, quetiapine
127
Q

Describe clinical utility of Lithium

A

Mainly used prophylactically

  • only reduce mania in acute episodes
  • reduce both depressive and manic phases
  • long term treatment to prevent relapse
  • effects seen after 3-4 weeks of treatment

Narrow therapeutic window

  • therapeutic range 0.4mmol/L - 1.0mmol/L
  • potentially fatal > 1.5mmol/L
  • plasma conc monitoring required
128
Q

Describe the classification of overweight and obesity (adults) regarding BMI and waist circumference

A 
Healthy weight
- BMI 18.5-24.9
Overweight
- BMI 25-29.9
Obesity I
- BMI 30-34.9
Obesity II
- BMI 35-39.9
Obesity III
- BMI 40 or more

Waist circumference

  • Men 94-102cm high risk
  • Men >102cm very high risk
  • Women 80-88cm high risk
  • Women >88cm very high risk
129
Q

What intervention is appropriate for each classification of obesity?

A 
1 = General advice on healthy weight and lifestyle
2 = Diet and physical activity
3 = Diet and physical activity; consider drugs
4 = Diet and physical activity; consider drugs; consider surgery

co-morbidities = T2DM, hypertension, CV disease, osteroarthritis, dyslipidaemia, sleep apnoea

Overweight

  • with low waist circumference = 1
  • with high waist circumference = 2
  • with very high waist circumference = 2
  • with comorbidities present = 3

Obesity I

  • with low waist circumference = 2
  • with high waist circumference = 2
  • with very high waist circumference = 2
  • with comorbidities present = 3

Obesity II

  • with low waist circumference = 3
  • with high waist circumference = 3
  • with very high waist circumference = 3
  • with comorbidities present = 4
130
Q

Define obesity

A
  • a disorder of homeostatic control of energy balance
  • High calorie, energy and dense food
  • Decline in physical activity
  • Body weight and body fat content are typically stable over time
    = energy homeostasis or balance
  • The brain regulates food intake & feeding behaviour in response to input from circulating signals
    = adiposity negative feedback
131
Q

Describe CNS regulation of energy homeostasis

A

Meal initiation
- multiple external factors

Meal size
- multiple external factors

Reward

  • involves the dopaminergic VTA/Nacc
  • can trigger eating in resonse to fasted states especially for alatable food

Leptin
- secreted by adipose circulates in proportion to body fat content, to reduce food intake

Interaction
- Leptin acts at LepRs in the brain and enhances brain response to satiety signals

Gut distension
- input from vagal nerve also satiety signals

Nutrients
- also inhibit food intake glucose, FFAs

Gut peptides
- secreted in response to food intake involved in perception of satiety include GLP1, CCK = termination of meal

132
Q

Describe how brain circuits control feeding behaviour

A

1a) Agouti-related protein (AGRP) & Neuropeptide (NPY)
- stimulates feeding behaviour
- orexigenic

1b) Proopiomelanocortin (POMC) & a-melanocyte stimulating hormone (aMSH)
- inhibits feeding behaviour
- anorexigenic

2) Hypotahalamic paraventricular nucleus (PVN)
3) Nucelus of the solitary tract (NTS)
4) food intake decreases

Leptin (insulin) decreases orexigenic and increases anorexigenic

133
Q

How does 5HT plays an important role in feeding behaviour?

A
  • Lesion of the dorsal raphe nuclei induces hyperphagia
  • Increased synaptic availability of 5HT decreases food intake
  • Administration of 5HT precursor tryptophan reduces food intake
  • Administration of 5HT, the intermediary in 5HT synthesis, also reduces food intake
  • Multiple 5HT receptors mediate satiety effects of 5HT in the brain
  • 5HT in the periphery is stored in enterochromaffin cells in the GI mucosa
134
Q

Describe genetic factors and obesity

A
  • Twin studies indicate genetic influence on obesity

Leptin in humans

  • many obese patients develop ‘leptin-resistance’
  • leptin therapy in humans only effective in those with a congenital leptin deficiency
135
Q

What are the anti-obesity agents in the market that are licensed in UK, FDA approved and withdrawn?

A

Licensed in UK

  1. Orlistat (Xenical)
    - Triacylglycerol lipase inhibitor

FDA approved

  1. Liraglutide
    - GLP-1 receptor agonist
  2. Phentermine
    - noradrenergic sympathomimetic amine
  3. Lorcaserin
    - selective 5HT2C receptor agonist
  4. Naltrexone/Bupropion
    - opioid R antagonist/NA and DA reuptake inhibitor

Withdrawn

  1. Sibutramine
    - NA and 5HT reuptake inhibitor
    - withdrawn due to cardiovascular risks
  2. Rimonabant
    - Cannabinoid receptor antagonist
    - withdrawn due to psychiatric side effects
136
Q

What is Orlistat?

A
  • only UK licensed anti-obesity agent
  • Lipase inhibitor
  • prevents the breakdown of dietary fats to fatty acids and glycerol
  • decreases absorption of 30% of dietary fat
  • oily stools, abdominal cramps, flatus with discharge
  • produced 2.9% greater reduction in body weight than placebo-controls
137
Q

Define ‘anxiety’ in terms of physiological and pathological

A
  • a normal, physiological response to threatening situations that serves a protective function
  • pathological when there is a bias to interpret non-threatening situations as threatening
  • the concern about the stressor is out of proportion to the realistic to threat and can occur without exposure to an external stressor
    = pathological anxiety
138
Q

Give examples of different anxiety disorders

A
  • Simple/Specific phobias
  • Social phobia/ social anxiety disorder (SAD)
  • Panic disorder
  • Post-traumatic stress disorder (PTSD)
  • Generalised anxiety disorder (GAD)
  • Obsessive compulsive disorder (OCD)
  • Premenstrual dysphoric disorder (PMDD)
139
Q

Describe how Generalised Anxiety Disorder (GAD) is diagnosed

A

DSM criteria for GAD includes
- excessive anxiety and worry about several events or activities most days of the week for at least 6 months

  • Difficulty controlling feelings of worry
  • At least three of the following symptoms
    : restslessness, fatigue, trouble concentrating, irritability, muscle tension or sleep problems
  • Anxiety or worry that causes significant distress or interferes with daily life

Some disorders that commonly occur with GAD

  • phobias
  • panic disorder
  • depression
  • substance abuse
  • PTSD
140
Q

What are the core features of the following disorders?
- Panic disorder

  • Social anxiety disorder
  • Generalised anxiety disorder
  • Posttraumatic stress disorder
A

Panic disorder
- Experience panic attacks ‘might die’

Social anxiety disorder
- Blushing, speech embarassment

Generalised anxiety disorder
- Worry, tension, future threat

Posttraumatic stress disorder
- flashbacks to known trigger ‘will die’

141
Q

What does a person with anxiety experience?

A

Negative cognition

  • bias to interpret unthreatening situations as threatening
  • context/memory/reinforcement

Physiological symptoms: autonomic activation

  • Racing heart
  • Palpitations
  • Restlessness
  • Sweating
  • Increased blood presure

Defence/ Avoidance behaviours
- Activation of aminergic pathways

142
Q

Describe normal response to threat

A
  1. Threatening stimulus
  2. Stress/Fear response innate or learned

Leads to..

  • defence/avoidance behaviours
  • autonomic activation ‘fight or flight’
  • arousal/alertness increased vigilance
  • negative emotions (aggression anger)
  • HPA corticosteroid secretion (metabolic effects)
143
Q

What are the treatments for anxiety disorders?

A

Pharmacotherapy

  • b-blockers: target autonomic symptoms
  • Benzodiazepines
  • Antidepressants (SSRI)
  • Buspirone (Partial agonist at 5HR1A receptor)
144
Q

How does B-adrenoreceptor blockers e.g propranolol reduce anxiety?

A

Treat the physiological symptoms of anxiety
- reduce the sympathetic manifestations of stress/fear response

No effect on affective components

Useful in treating phobias
- evidence for use in curing phobias

Useful in treating PTSD
- effects on memory consolidation

145
Q

Describe how Benzodiazepines bind to allosteric site on the GABAa receptor

A
  • Functional GABAa receptors are pentameric combinations of different subunits arranged to form integral chloride ion channel
  • Most prevalent receptor in mammalian brain consists of two a, two β and one γ- subunit
  • GABA binds between a and β-subunits
    : so 2 molecules to activate receptor
  • Benzodiazeepines bind at the interface between a/γ-subunits and affect chloride ion conductance to regulate GABAergic inhibition
146
Q

Describe structure of benzodiazepines and the influence of R side groups

A
  • The core of all BZ ligands is a benzene ring joined to a 7-membered 1,4-diazepine ring

R side groups influence the

  • affinity of the BZ to bind the receptor
  • intrinsic efficacy of BZ to produce a functional test
  • BZ agonists have 100% intrinsic efficacy
  • BZ inverse agonists bind to the site but produce the opposite effect and are said to have negative intrinsic efficacy
  • BZ antagonists bind to the BZ site but are unable to activate the receptor
  • other properties such as lipophilicity, water solubility
147
Q

What are the undesired effects of Benzodiazepines?

A

Memory loss
- useful pre-meds for anaesthesia

Sedation
- Flunitrazepam is a BZ agonist

Abuse potential
- Temazepam use in opioid addicts

Addictive
- some people develop tolerance/physical dependence with long-term BZ use

Withdrawal symptom
- characterised by irritability, cognitive impairment, insomnia, dysphoria, hypersensitive to light/sound

148
Q

What are the symptoms of Psychosis?

A

Hallucinations
- Sight, sound, smell, touch, taste

Delusions
- e.g persecutory, grandoise

Confused and disturbed thoughts
- e.g rapid constant speech, disturbed speech, loss of train of thought

Lack of insight and self-awareness
- unaware that the delusions or hallucinations aren’t real

149
Q

What are the causes of psychosis?

A
  • Alzheimer’s, Parkinson’s, Huntingtong’s diseases
  • Depression, bipolar disorder
  • Some types of epilepsy
  • Stress, trauma
  • Lack of sleep
  • Drugs
  • Schizophrenia

Can be treated with antipsychotics

150
Q

What is Schizophrenia?

A
  • Divided mind, or fragmented thinking
  • NOT multiple/split personalities
  • division between internal thought and external reality
  • Chronic mental illness

POSITIVE
- Increased in abnormal active behaviours
: hallucinations, delusions, disordered thoughts, disturbed speech

NEGATIVE
- absence of normal active behaviours
: affective blunting, avolition, anhedonia, poverty of speech, social withdrawal, neglect of hygeine

COGNITIVE
- disturbance of normal though process
: poor executive function, poor decision making, poor cognitive flexibility, recognition deficits, memory problems, attention deficits

151
Q

Describe aetiology of Schizophrenia

A

Largely unknown, likely to be multifactorial

  1. Genetic
    - strongly inherited: 50% in monozygotic twins
    - no specific gene identified: >100 genes implicated (susceptibility genes)
  2. Environmental
    - no specific factors implicated
    - pregnancy and delivery complications
    - prenatal and childhood virus infection
    - urban birth and residence
    - psychosocial factors (dysfunctional family environment)
152
Q

Describe relation between Dopamine and Schizophrenia

A
  • Cocaine and amphetamine enhance dopamine and cause psychosis
  • D2 receptor gene polymorphism is risk factor in Schizophrenia
  • Antipsychotics are all D2 receptor antagonists

Mesolimbic pathway

  • Increase in D2 receptors effect
  • Postive symptoms

Mesocortical pathway

  • Decrease in D1 receptors effect
  • Negative and Cognitive symptoms
153
Q

Describe ‘Typical’ (first generation) antipsychotics

A
  • ~80% D2 receptor block required for antipsychotic effect
  • High affinity D2 receptor antagonists
    : e.g chlorpromazine, haloperidol
  • Effective ONLY against positive symptoms

Serious DA related side effects:
extrapyramidal
- acute dystonias (Parkinson’s like)
- tardive dyskinesia (Huntington’s like)

  • Increased prolactin release (galactorrhea) because D2 block causes increased prolactin levels
  • reduced pleasure

Non-DA related side effect

  • most antipsychotics are also antagonists at other GPCR
  • sedation, hypotension, peripheral autonomic, sexual dysfunction
154
Q

Describe ‘Atypical’ (second generation) antipsychotics

A
  • D2 antagonists but relatively low affinity
    : e.g Clozapine, Olanzapine, Risperidone, Aripiprazole
  • Effective against both postive and negative symptoms
  • Less side effects than ‘typical’ antipsychotics, especiaslly motor effects
  • High affinity 5HT2 receptor antagonists
  • But other side effects
    : weight gain
    : diabetes
    : Agranulocytosis (leukopenia)
155
Q

Describe relation between 5HT2 receptors and Schizophrenia

A

Problems with selective D2 receptor antagonists

  • serious dopaminergic-related side effects
  • only control positive symptoms

5HT2 receptor antagonists can cause psychotic episodes (LSD)

5HT2 receptor antagonists (particularly 5HT2A antagonists) could be beneficial

156
Q

Define the following terms

  • Ictal
  • Interictal
  • Epileptogenesis
A

Ictal
- the actual seizure or convulsion

Interictal

  • quiescent state between seizures
  • some abnormal spike activity can be recoroded

Epileptogensis
- the underlying process leading to development of epilepsy

157
Q

Define Epilepsy

A
  • Sudden excessive high frequency neuronal discharge
  • Not random but highly synchronous
  • A disorder of the cerebral cortex
  • May be loss of consciousness
  • Behavioural changes related to site of discharge (focus)
158
Q

Just read

- some facts and figures about Epilpsy

A
  • 0.5 - 1% of population
  • children and elderly susceptible
  • 2% : one seizure
  • 30,000 new cases p.a
  • 30% drug-refractory
  • 20-30% refractory to surgery
  • 1000 deaths per year 50% SUDEP
  • 60-90% undiagnosed or untreated in developing countries
159
Q

What are the causes of Epilepsy?

A
  • 70% idiopathic/cryptogenic
  • genetic: rare familial disorders
  • congenital: structural abnormalities (dysplasia)
  • birth trauma: ischaemia
  • neurological/neurodegenetrative (elderly)
  • head trauma: penetrating or non-penetrating
  • metabolic: glucose/electrolyte imbalance
  • disease: meningitis, tumour, abcess
160
Q

What can epilepsy be recorded?

A

Electro-EncephaloGraphy (EEG)
- electrophysiological monitoring method to record electrical activity of the brain

Magneto-EncephaloGraphy (MEG)
- functional neuroimaging technique for mapping brain activity by recording magnetic fields produced by electrical currents occuring naturally in the brain

161
Q

How can epilepsy be imaged?

A

PET (positron emission tomography)
- monitors local metabolism

MRI (Magnetic resonance imaging)
- structure and volume

fMRI (functional Magnetic resonance imaging)
- relates activity to structure

162
Q

Where do the seizures arise in Epilepsy?

A
  • Anywhere
  • Subcortical rare
  • mostly cortical
    : frontal, parietal, occipital, temporal
  • Temporal most prevalent (30-40%)
    : hippocampus, entorhinal cortex, amygdala
    : drug refractory
    : surgical resection
  • Cortical activity
    : dynamic balance between inhibition and excitation

2 Levels

  • Intrinsic: ion channels
  • Network: synaptic transmission

Disturbed balance: excessive synchrony and epilepsy

  • ↑ excitation, normal inhibition
  • ↓ inhibition, normal excitation
  • ↓ inhibition, ↑ excitation
163
Q

Describe intrinsic balance - membrane ion channels

A

Destabilising/Depolarising
- Na+, Ca2+ ions influx

Stabilising/Hyperpolarising
- Cl- influx, K+ outflow

164
Q

Describe Synaptic balance (regarding epilepsy)

A

Excitation

  • glutatmate
  • EPSP

Inhibition

  • GABA
  • IPSP

So.. Across the network

  • excitatory neurones recurrently excite each other
  • excitatory recurrently excite inhibitory neurones
  • inhibitory neurones recurrently control excitation
  • loss of inhibition can lead to epilepsy
165
Q

How do we treat epilepsy?

A
  • Block destabilising currents
  • Increase stabilising currents
  • Reduce synaptic excitation
    : block glutamate release
    : block glutamate receptors
  • Increase synaptic inhibition
    : increase GABA release
    : potentiate GABA receptors
  1. Blocking voltage gated Na-channels
    - e.g phenytoin, carbamazepine, iamotrigine, sodium valproate
  2. Blocking voltage gated Ca-channels
    - e.g ethosuximide, gabapentin, phenytoin(?)
  3. Blocking glutatmate release
    - Na-channel blocker, Ca-channel blocker
  4. Drugs acting at GABA synapses
    - increase GABA levels
    - e.g vigabatrin, sodium valproate
166
Q

Define sleep and what its for

A
  • a readily reversible state of reduced responsiveness to, and interaction with, the environment
  • Cortical recovery
  • Organising/storing memories
  • Metabolism/weight homeostasis
  • Sleep deprivation may provide clues
167
Q

Describe Sleep Cycle

A

Rapid Eye Movement (REM)

  • ~20 min
  • dreaming

Non Rapid Eye Movement

  • Stages 1~4
  • 60-90 min
  • repeat cycle 4-6 x
  • As a night of sleep progresses the non-REM to REM cycle is repeated several times
  • Each cycle has shorter and shallower non-REM periods and longer REM periods
168
Q

What does electroencephalogram record?

A
  • Records the activity of populations of neurones
169
Q

Describe changes in REM sleep

A

EEG like that of an active waking brain (paradoxial sleep)

  • Oxygen consumption of brain is high
  • Vivid dreaming
  • Loss of skeletal muscle tone (atonia)
  • Bursts of rapid eye movements
  • Sympathetic activity predominates
170
Q

Which activity is dominated in REM sleep, Sympathetic or Parasympathetic?

A
  • Sympathetic

- REM sleep is accompanied by changes in HR, respiration, local blood flow

171
Q

Describe changes in NREM sleep

A

Non-REM sleep is a rest period

  • Muscle tension reduced
  • Body temperature is lowered
  • Energy consumption lowered
  • Increase in parasympathetic activity
  • Brain rhythms slow (slow wave sleep)
172
Q

Describe brain mechanisms of sleep

A

Ascending Reticular Activating Sysmtem (RAS)

  • Locus coeruleus: noradrenaline
  • Raphe nuclei: serotonin
  • Brainstem/forebrain: acetylcholine
  • Midbrain: Histamine

↑ Firing of these neurones = AWAKENING
↓ Firing of these neurones = FALLING ASLEEP

RAS&raquo_space;> THALAMUS&raquo_space;> CORTEX

173
Q

Which neurones of the brain stem control the onset/offset of REM periods?

A

REM-on cells are cholinergic neurones in the brainstem

REM-off cells are serotoninergic and noradrenergic neurones in the brainstem

174
Q

Give examples of sleep regulating substances

A

Interleukins
- immune mediators

Melatonin

  • derived from 5HT in endocrine pineal gland
  • cure for jet leg?

Hypocretin-orexin
- hypothalamic neuropeptide regulates appetite, metabolism

Stimulatns
- e.g caffeine, cocaine, amphetamine

175
Q

What is insomnia and what types present?

A

Sleep disorder

  1. Transeint insomnia
    - e.g noise, shift work jet lag
  2. Short-term insomnia (primary insomnia)
    - e.g emotonal problems, stress, anxiety
  3. Chronic insomnia (secondary insomnia)
    - e.g pain, depression, anxiety, alcohol abuse, dyspnoea

(Fatal familial insomnia - very rare)

176
Q

What are Hypnotics?

A
  • A drug used to induce and maintain sleep
  • Good sleep hygiene: behavioural, environmental & temporal factors

Use should be

  • intermittent
  • short term (<2 weeks) if daytime impairment is severe
  • tolerance may develop
  • withdrawal syndromes can occur

Treatment aims to shorten time to sleep, increase total duration of sleep, without suppressing sleep cycle and REM sleep

177
Q

Name some benzodiazepine and non-benzodiazepine hypnotics and

A

1) Benzodiazepine Hypnotics
Long acting
- flurazepam/ Dalmane (2-keto)
- may give rise to hangover effect

Short acting

  • temazepam/ Restoril (3-OH), triazolam/ Halcion
  • little or no hangover effect

2) Non-Benzodiazepine Hypnotic
- Zaleplon, Zolpidem, Zopiclone (Z drugs)
- Non-benzodiazepines that bind to GABAa receptor
- Short duration of action
- less likely to cause rebound insomnia than BZs
- Dependence maybe a problem

178
Q

Name some OTC and herbal sleep medicines

A

1) OTC
Antihistamines
- Promethazine (Phenergan)
- Diphenhydramine (Nytol)

Natural remedies

  • melatonin
  • tea
  • lavender
  • Valerian (active ingredients bind to GABA , 5HT, Adenosine receptors)
179
Q

Describe Motor control hierarchy in terms of Level, Structures and Function

A 
1)
Level 
- High
Structures 
- Sensory and association neocortex basal ganglia
Function 
- Planning and strategy
2)
Level
- Middle
Structtures
- Motor cortex cerebellum
Function
- Tactics and preparation and direction
3) 
Level
- Low
Structures
- Brain stem spinal cord
Function
- Execution
180
Q

In Motor pathways, what are the following pathways in charge of?

  • Lateral pathways
  • Ventromedial pathways
A

Lateral pathways

  • large muscle control of upper body
  • voluntary control of skilled movement

Ventromedial pathways

  • visual
  • auditory and balance
  • directional control, orientation and balance
  • postural control reflex movements
181
Q

Describe the Basal Ganglia

A
  • a group of structures found deep within the cerebral hemispheres
  • the structures generally included are caudate, putamen and globus pallidus in the cerebrum, substantia nigra in the midbrain, and subthalamic nucleus in the diencephalon
  • the basal ganglia receive information from the cortex, much of which is sent first to the caudate and putamen. After the information is processed by the basal galgnlia, it is sent back to cortex by way of thalamus.
182
Q

Describe direct and indirect pathways through the basal ganglia

A

Direct

  • Cortex excites CP (caudate/putamen)
  • CP inhibits GPi
  • inhibition of thalamus is reduced
  • excitatory input to cortex increased

Indirect

  • Cortex excites CP
  • CP inhibits GPe
  • GPe inhibition of STN is reduced
  • STN excitation of Gpi increases
  • GPi inhibition of thalamus is increased
  • excitatory input to cortex decreased

Modulation by SNc

  • Nigro-striatal dopamine pathway
  • Activates direct pathway via D1
  • Inhibits indirect via D2
  • balances the pathways
183
Q

Where in the cortex does basal ganglia fit in?

A

Prefrontal

  • decision making
  • volition
  • planning and exceution
184
Q

Where in the cortex does crebellum fit in?

A

Sensory

  • positional control
  • directional control
  • error correction
  • learning
185
Q

What are the motor disorders involving the basal ganglia?

A

Parkinson’s disease
- Hypokinetic: impaired movement, tremor

Huntington’s disease
- Hyperkinetic: chorea

Associated disorders

Obsessive-compulsive disorder

  • Lesions in caudate/putamen: repetitive motor responses
  • Treated with SSRIs

Tourette’s syndrome
- Rapid stereotyped movements or sounds
: increased activity in nigro-striatal pathway
: treated with dopamine D2 receptor antagonists

186
Q

Describe Parkinson’s disease symptoms

A

Akinesia
- absence or reduction of movement

Bradykinesia
- slowness of movement

Rigidity
- resistance to passive movement

Tremor
- pill rolling

Poor balance

Speech problems

Progressively
- depression, anxiety, sleep disturbance, cognitive dysfunction

187
Q

Describe pathology of Parkinson’s disease

A

Primary
- loss of DA cells from SNc

Degeneration of nigro-striatal patwhay

Genetic mutations

  • mutant synaptic proteins: aggregation
  • mutant Parkin (ligase): prevents proteolysis
  • Oxidative stress: mitochondrial dysfunction
  • Cell death

Parkinsonis

  • drug induced
  • neuroleptics
  • MPTP

So….

  • Loss of DA neurones
  • Imblanace in direct and indirect pathways
  • Increases activation of Gpi via indirect
  • Decreases inhibition via direct
  • Increase inhibition of thalamus
  • Switches off thalamo-cortical pathways
  • Loss of cortico-spinal output
  • Decreased movement, rigidity etc
188
Q

How do we treat Parkinson’s diseases?

A

Dopamine synthesis and inactivation

  • inactivation via uptake, MAO and COMT
  • Uptake transporter specific for DA
  • Increase DA sythesis
  • First line = Oral L-DOPA
  • Converted to DA by DOPA-decarboxylase
  • Combined with peripheral decarboxylase inhibitors
  • 80% improvement, 20% full recovery

However,

  • time limited: progressive degeneration
  • dyskinesias
  • On-off syndrome (swinging)
  • nausea
  • hypotension
  • anorexia
  • psychosis
189
Q

What are the symptoms of Huntington’s disease?

A
  • Chorea: involuntary jerking
  • Grimacing
  • Balance and gait problems
  • Cognitive decline, memory loss, depression
  • swallowing and speech
  • Death 10-20yrs following diagnosis
190
Q

Describe the pathology of Huntington’s disease

A
  • Primary: cell death in caudate/putemen
  • Impared striatal-nigral and striato-pallidal transmission
  • Nigro-striatal preserved
  • progressive: degeneration of GP
  • Huntington protein: normal function unclear
  • Mutant Huntingtin: genetic defect
    : expanded repeats of codon for glutamine
    : dense protein aggreegates migrate to nucleus
    : apoptosis = cell death

So…

  • Loss of caudate neurornes
  • Decreased inhibition of GPe
  • Increased inhibition of STN
  • Decreased excitation of GPi/SNC
  • Decreased inhibition of thalamus
  • Increased thalamo-cortical activity
  • Increase in cortico-spinal output
  • Hyperkinesia, facial tics etc
191
Q

How do we treat Huntington’s disease?

A
  • No cure
  • Baclofen (antispasticity)
  • D2 antagonists
  • Treat symptoms e.g depression
  • Neuroprotection
192
Q

What is Cerebellar dysfunction?

A
  • Ataxia
  • Fine motor control, gait and co-ordination
  • Multiple types and causes
    : genetic, trauma, stroke, alcohol and drugs
  • Degeneration of
    : cerebellar cortex
    : spino-cerebellar pathways
    : ponto-cerebellar pathways
    : deep cerebellar nuclei
    : cerebellar-cortico pathways
  • No cure: treat symptoms
  • Symptoms progressive
193
Q

Define the following terms

  • Learning
  • Memory
  • Engram
A

Learning
- Acquisition of new information or knowledge

Memory
- Storage or retention of acquired knowledge

Engram
- Physical representation or location of memory

194
Q

Describe 3 different classification of memory

A

1) declarative
- daily episodes
- words and meanings
- history

2) emotional
- preferences
- aversions

3) procedural
- motor skills
- associations
- priming cues
- puzzle solving

195
Q

Which brain areas are involved in the 3 different types of memory?

A

1) declarative
- entorhinal/parahippocampal cortex
- hippocampus

2) emotional
- amygdala
- hypothalamus, autonomic and hormonal output

3) procedural
- cerebellum
- striatum
- brainstem and spinal motor output

196
Q

What is Hebb’s law?

A
  • theory claiming that an increase in synaptic efficacy arises from a presynaptic cell’s repeated and persistent stimulation of a postsynaptic cell.
  • Synapses strengthened by intense activity
  • Memory depends on populations of interacting neurones
  • Pattern of strengthened synapses defines memory
197
Q

How is memory stored?

A

1) external stimulus presented
2) reverberating activity (short-term memory)
3) strengthened synapses (long-term memory)
4) circle

198
Q

How does a synapse get stronger?

A
  • Increase in the strength after repeated stimulation is called Long Term Potentiation (LTP)
  • LTP indudction has a voltage threshhold
  • Low rate of stimulation does not depolarise membrane sufficiency (High = repolarised in the graph)
199
Q

What is NMDA receptor?

A
  • dual gating
  • Glutamate alone: no current flows
  • Channel blocked by Mg2+
  • Depolarisation to repetitive activation of AMPAr relieves Mg2+ block
  • Both Ca and Na flow through NMDAr channel
  • Ca-entry = cellular changes lead to increased AMPAr response (LTP)
200
Q

Describe relation between NMDA receptors and LTP (Long term Potentiation)

A

1) High frequency
- EPSP potentiated
- High frequency tetanus induces LTP at glutamate synapse

2) High frequency plus 2-AP5
- EPSP not potentiated
- Pharmacological blockade of NMDAr prevents LTP

3) High frequency plus low Ca2+
- EPSP not potentiated
- Reducing extracellular ca2+ from 2 to 0.2 mM prevents LTP

201
Q

How is LTP (Long term Potentiation) manifested?

A

Postsynaptic

  • More AMPAr
  • More sensitive AMPAr
  • More synapses

Presynaptic

  • Increased release
  • More release sites
  • More vesicles
202
Q

Describe 3 LTP (Long Term Potentiation) induction mechanisms

A
  1. Phosphorylation of AMPAr by PKC
  2. Insertion of new receptors by CaMKII. Also synthesis of new receptors
  3. Retrograde messenger - Nitric Oxide - presynaptic changes
203
Q

What is Pavlovian (classical) conditioning?

A
  • learning through association and was discovered by Pavlov

- In simple terms two stimuli are linked together to produce a new learned response in a person or animal.

204
Q

What is Pavlovian (classical) conditioning?

A
  • learning through association and was discovered by Pavlov

- In simple terms two stimuli are linked together to produce a new learned response in a person or animal.

205
Q

What are the cognition enhancers a.k.a smart drugs?

A

Cholingergic modulation

  • anticholinesterases: donepezil
  • agonists: nicotine, arecoline

Stimulants

  • amphetamine
  • methylphenidate

5HT drugs

GABAa receptor blockers

AMPAkines

mGluR drugs

206
Q

Name 2 disorders of memory

A
  1. Amnesia
    - drug induced: alcohol
    - head trauma: temporary or permanent
    - retrograde or anterograde
  2. Dementias
    - syndrome characterised by a decline in cognitive functions sufficient to cause impairment in social and occupational performance
    - Loss of multiple memory categories
    - Inability to form new memories
    - associated with general cognitive decline
    - memory impairment first presenting symptom
207
Q

What is Alzheimer’s disease?

A
  • Most common dementia at >65 yrs
  • 2:1 female:male
  • memory deficits: presenting symptoms
  • initiation deficits
  • visuo-spatial deficits
  • language deficits: word finding, comprehension
  • impaired judgement and executive functions
  • psychotic episodes
208
Q

Describe the cellular pathology of Alzheimer’s

A

Diagnostic hallmarks

  • Neuritic plaques (NP)
  • Neurofribrillary tangles (NFT)
  • Primarily affect glutamate and acetylcholine neurones and terminals
  • Aberrant function: synapse loss, neuronal death, brain shrinkage
209
Q

What is Amyloid Precursor Protein (APP)?

A
  • integral membrane protein expressed in many tissues and concentrated in the synapses of neurones
  • Primary function not known but has been implicated as a regulator of synapse formation, synaptic plasticity and iron export
210
Q

How do we treat Alzheimer’s ?

A 
A) Symptomatic
Cholinersterase inhibitors
- donepezil, rivastigmine, galantamine
- enhance ACh at nicotinic and muscarinic receptors
- small improvements in cognition

Memantine

  • non-competitive NMDA receptor blocker
  • Neuroprotective
  • slight improvements in cognition
B) Disease progression
Secretase inhibitors (In trial)
Anti-amyloid-beta vaccine (In trial)
Anti-tau vaccine (In trial)
Statins (some epidemiological evidence)

Year 3 Sem 1 COPY COPY (7 decks)

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