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Drugs and the Brain > Drugs all the drug things in all the drugs universe > Flashcards

Drugs all the drug things in all the drugs universe Flashcards

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1
Q

Constitutive receptor activation

A

Receptor that is active even in the absence of a ligand - can exist physiologically or be induced

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2
Q

Inverse agonist

A

Binds to the receptor and reduces its effect - e.g. with constitutive receptor activation

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3
Q

Spare receptors

A

More receptors are available than required to elicit a full response from an agonist

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4
Q

Choroid plexus

A

Where CSF is produced

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5
Q

Arachnoid villae

A

Where CSF is returned to the circulation

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6
Q

Tricarboxylic acid (TCA) cycle or the Krebs cycle

A

Glutamate, Aspartate, GABA and Glycine all involved in this stage of respiration - a problem for drugs that target amino acid production without knock-on effects

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7
Q

VGluT

A

Packages Glutamate into vesicles

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8
Q

EEAT

A

“Mops up” Glutamate from synaptic cleft in both neurons and glia

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9
Q

Glutamate “minor pathway”

A

Glutamate is taken back into the presynaptic neuron after release by EEAT or reconstituted from Glutamine before repackaged into vesicles

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10
Q

Glutamate “major pathway”

A

Glutamate is taken up into glia (an astrocyte) and metabolised to Glutamine and transported out of glia and into the neuron by GlnT

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11
Q

Glutamate ionotropic receptors…

A

AMPA, Kainate and NMDA (homo/heteromeric assembly of 4 subunits forming a pore-loop structure)

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12
Q

AMPA receptor properties…

A

Fast EPSP, wide CNS distribution, permeable to Na and K (+Ca) depends on subunit structure, 4 subunits each with a receptor for Glu but needs only 2 to bind to be active

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13
Q

Kainate receptor properties…

A

Act similarly to AMPA Rs but are less widespread and can be found on pre-synaptic terminals and less permeable to Ca than some AMPA Rs

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14
Q

NMDA receptor properties…

A

Highly permeable to Ca (+other ions), easily blocked by Mg (voltage sensitive, must be depolarised to ~-40mV) so has a non-linear current/voltage relationship. Activation also requires Glycine (which is normally an inhibitory NT)

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15
Q

Group 1 (mGluR1, mGluR5), Group 2 (mGluR2, mGluR3), and Group 3 (mGluR4, nGluR6, mGluR7, mGluR8) metabotropic receptor locations…

A

Group 1 - somatodendritic (input modification - antagonist to treat pain, PD, epilepsy), Group 2 - somatodendritic and nerve terminal (output modification - agonist decreases Glu release and antagonist as a cognitive enhancer), and Group 3 - nerve terminal (affects postsynaptic cell functioning - agonist to decrease Glu release)

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16
Q

Glutamic acid decarboxylase (GAD)

A

Forms GABA from glutamate - good histological marker for GABA neurons

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17
Q

GABAa receptor properties….

A

Ionotropic. Pentameric structure. Usually 2alpha 2beta and 1gamma (most common alpha2beta3gamma2). 2 GABA molecules bind at alpha beta interface. Cl influx is inhibitory (fast IPSP). Benzodiazepines bind at alpha gamma interface to increase channel opening frequency. Extra-synaptic GABAa Rs produce longer “tonic” inhibition which may be useful for treatment of epilepsy.

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18
Q

GABAb receptor properties….

A

Metabotropic. Dimers. Gprotein coupled Rs that act by: inhibiting vgated Ca channels (to inhibit NT release presynaptically), opening K (TREK-2) channels (reducing post synaptic excitability) and by inhibiting adenylate cyclase (decreasing cAMP which is usually excitatory) which can reduce the opening time of NMDA Rs (as adenylate cyclase often potentiates these)

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19
Q

GABAc receptor properties….

A

New. Ionotropic. Variant of GABAa Rs?

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20
Q

Glycine reuptake transporter proteins…

A

GlyT1 (astrocytes) and GlyT2 (spinal cord)

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21
Q

Glycine properties…

A

Synthesised from serine (also available through diet) and acts on pentameric receptors

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22
Q

Strychnine (a glycine antagonist) acts by…

A

Stopping the effects of glycine released by Renshaw cells (that regulate aMNs) in the spinal cord leading to convulsions (due to over-activity in contracting muscle and over-relaxation in antagonist muscle) - glycine uptake inhibtion may be useful for treatment of pain, PD and epilepsy

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23
Q

Catecholamine defining chemical structure…

A

1,2 dihydroxybenzene (5HT has only one OH group)

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24
Q

End point inhibition of dopamine…

A

DA binds to Tyrosine Hydroxylase and inhibits its own synthesis - control mechanism

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25
Q

Catecholamine synthesis pathway…

A

Tyrosine > (Tyrosine hydroxylase) > DOPA > (DOPA decarboxylase) > Dopamine > (Dopamine beta-hydroxylase) > Noradrenaline > (Phenylethanolamine N-methyltransferase) > Adrenaline

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26
Q

Enzyme used to convert Tyrosine > DOPA

A

Tyrosine hydroxylase

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27
Q

Enzyme used to convert DOPA > Dopamine

A

DOPA decarboxylase

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28
Q

Enzyme used to convert Dopamine > Noradrenaline

A

Dopamine beta-hydroxylase

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29
Q

Enzyme used to convert Noradrenaline > Adrenaline

A

Phenylethanolamine N-methyltransferase

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30
Q

Features of diffuse modulatory transmission (such as with DA)…

A

Projections from remote sparse nuclei (input) and massive axonal divergence (output)

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31
Q

4 main DA pathways…

A

Nigrostriatal (calls in SN and axons in striatum), Meso-limbic (cells in VTA and axons in limbic structures), Meso-cortical (cells in VTA project to frontal cortex) and Tuberohypophyseal (from ventral hypothalamus to median eminence/pituatory gland)

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32
Q

Link between DA and NorAdr in rodents…

A

VTA feeds back to Locus Ceruleus (NorAdr region) and parabrachium so modifying DA actions has known-on effects for NorAdr

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33
Q

Dopamine receptors…

A

Metabotropic, linked to adenylate cyclase. D1 type (D1 and D5 receptors) and D2 type (D2, D3 and D4 receptors). D1 type increase cAMP to result in post-synaptic inhibition. D2 type decrease cAMP and/or increase IP3 to result in pre- and post-synaptic inhibition and stimulation/inhibition of hormone release.
Therefore depending on the DA receptor activated cAMP may lead to increased action of PKA to produce phospho DARPP-32 (by phosphorylation) which in turn inhibits protein phosphatase-1 (which dephosporylates/inactivates proteins). However D2 receptor activation leads to decreased cAMP levels and therefore reduced action of PKA leading to relatively more dephosphorylation of proteins.
The presence of calcium (possibly through NMDA Rs) can also act on this cycle by increasing conversion of phospho DARPP-31 to DARPP-32.

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34
Q

Enzymes involved in DA breakdown…

A

MAO, COMT and Aldehyde dehydrogenase

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35
Q

NorAdr cells mainly located in…

A

pons and medulla (biggest conc in Locus Ceruleus/A6) - very widespread connections throughout cortex, hippocampus etc

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36
Q

Areas in descending pathways involved in pain…

A

PAG (periaqueductal grey matter), LC (locus ceruleus) and NRM (nucleus raphe magnus) - linked to NorAdr

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37
Q

Noradrenaline receptor types…

A

Metabotropic. Alpha 1 is coupled positively to IP3. Alpha 2 is negatively coupled to cAMP. Beta 1 and beta 2 are positively coupled to cAMP. All widely distributed on pre and post synaptic cells on neurons and glia. Beta 3 (in periphery) is also positively coupled to cAMP.

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38
Q

Serotonin is derived from the amino acid…

A

Tryptophan

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39
Q

Catecholamines (eg DA and NorAdr) are derived from the amino acid…

A

Tyrosine

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40
Q

5HT similarities to catecholamines in synthesis and breakdown…

A

Both formed from amino acids from the diet. Both involve decarboxylation (by dopa decarboxylase) in their synthesis and MAO in their breakdown.

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41
Q

5HT distribution and projection…

A

Distribution of 5HT cells is similar to NorAdr (in pons and upper medulla), mostly in raphne nuclei. Project forward through same fibre bundle as NorAdr to cerebral cortex, hippocampus, BG, limbic region and hypothalamus. Project backwards to cerebellum, medulla and spinal cord.

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42
Q

Serotonin receptor types…

A

5HT 1-7 with variants so 14 types (+ subtypes). All expressed in CNS and metabotropic except 5HT3 which is an ionotropic cation channel. Pre and post synaptic locations.

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43
Q

Acetylcholine is synthesised by…

A

Choline + acetyl co-enzyme A > (choline acetyltransferase/ChAT) > ACh. (ChAT is a good histological marker for ACh cells)

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44
Q

Ach is broken down by…

A

(Acetylcholinesterase) > Acetic acid + choline

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45
Q

Two main cell groups of ACh in brain…

A
  1. Pedunculopontine (PPT)/ laterodorsal tegmentum (LD)

2. Magnocellular forebrain (NbM and septohippocampal) (+ scattered small groups of interneurons) with wide projections.

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46
Q

ACh has roles in pontine nuclei, ventral forebrain (NbM), septohippocampal area and striatal interneurons for…

A

Pontine nuclei - arousal, sleep/wake, ventral forebrain (NbM) - arousal, septohippocampal area - learning (short term) and striatal interneurons - motor control

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47
Q

ACh receptor types…

A
  1. Nicotinic - ionotropic, increase cations, excitatory, FAST (very useful in PNS eg NMJ). nAChR. Pentameric structure. Mostly presynaptic (CNS), facilitating Glutamate release, though some post-synaptic sites (+NMJ).
  2. Muscarinic - metabotropic, influences K permeability, mixed effects, SLOW (useful for CNS and learning). 5 subtypes mAChR 1-5. M1, M3 and M5 are excitatory through non-linear action of M-current. M2 and M4 are inhibitory through actions on K (hyperpolarisation) and Ca (reducing NT release) channels.
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48
Q

Fast and slow excitation in post-synaptic cell by ACh is due to…

A

Fast EPSP is due to ionotropic R and slow is due to metabotropic R e.g. by closing a K channel. In the slow EPSP phase the cell is more excitable.

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49
Q

Structure of ACh receptor…

A

Five subunits (alpha, beta, gamma, delta or epsilon). Each subunit has a transmembrane alpha helix (M” helix) which combine to form the pore. Each alpha subunit contains an ACh binding site. Binding of 2 ACh molecules induces a conformational change where large hydrophic regions in the pore are replaced by negatively charged small polar molecules.

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50
Q

Selection of an ion by a channel pore depends on…

A

Its charge (e.g. ACh Rs have three rings of -vely charged glutamate and aspartate residues that attract cations and repel anions) and its size (varies by ion and hydration shell)

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51
Q

When the -vely charged Glutamte and Aspartate residues of the ACh receptor are replaced by Arginine and Lysine (+vely charged)…

A

The receptor still opens in response to ACh but now attracts anions (e.g. Cl) rather than cations

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52
Q

Histamine is found in…

A

mast cells in the brain and magnocellular neurons in the posterior hypothalamus. It influences sleep and arousal.

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53
Q

Histamine is synthesised and metabolised by…

A

It is synthesised by histidine decarboxylase from Histidine. It is metabolised by histamine methyltransferase to form methylhistamine which is broken down by MAO.

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54
Q

Histamine receptor types and there pharmacological uses…

A

H1, H2 and H3. All gprotein coupled with 7 transmembrane domains. H1 is coupled to IP3 and increases neuronal excitability. H2 is positively coupled to cAMP and is also excitatory. H3 is possibly an autoreceptor or heteroreceptor on other NTs.
H1 antagonists lead to decreased cAMP levels and are used for allergies and stings, some cross BBB to produce sedation (e.g. chlorfenamine, triprolidine).
H2 receptors are targeted for ulcer treatment.

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55
Q

Chlorfenamine and triprolidine

A

H1 antagonists that cross BBB to produce sedation

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56
Q

Neuropeptides are produced in…

A

the soma of the cell. But can be produced as pro-transmitters and altered at the site. They are packaged in dense-core vesicles for release and have post-synaptoc action on gprotein coupled receptors. e.g. substance P, oxytocin, vasopressin, VIP.

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57
Q

Adenosine is a purine (e.g. ATP, ADP, AMP) and acts on…

A

gprotein coupled Rs A1, A2A A2B and A3. May be more “proactive” than transmissive. Involved in termination of tadpole swim response.

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58
Q

Melatonin is made in…

A

the pineal gland from 5HT.

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59
Q

Melatonin receptor types…

A

MT1 and MT2 coupled to gproteins - found in brain and retina. Secretion rather than transmission, driven by circadian light cycle from retinal input. Possible target for ADs and jet lag.

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60
Q

NO is produced by…

A

Nitric Oxide synthase (NOS) which is controlled by intracellular calcium levels. NO has excitatory and inhibitory effects possibly through control of levels of levels of cGMP. NO is not synaptic/packaged in vesicles. Has volume action (over seconds to minutes and far reach). Sometimes found as a co-transmitter (eg with ACh). Has a role in LTD/LTP and neurotoxicity (in large amounts due to free radicals)

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61
Q

Lipid NTs are formed from…

A

Arachidonic acid. e.g. prostaglandins, leukotrienes, eicosanoids, including the endogenous endocannabanoids: anandamide and 2AG.

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62
Q

Anandamide and 2AG

A

Endocannabanoids. CB1 and CB2 receptors used as retrograde signallers, but can alter both Glu and GABA release (metabotropic). Links to LTP etc by acting in a retrograde manner on surrounding cells.

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63
Q

Psychomotor stimulants

A

e.g. ampetamine, cocaine, MDMA. Effect on mental function and behaviour. Induce euphoria, reduced sense of fatigue. Increase motor output. Act on central catecholamine pathways and similar paths. Repeated use leads to tolerance and sometimes dependance. Withdrawal on cessation of use.

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64
Q

Amphetamine and related compounds chemical structure…

A

A benzene ring with proximal amine group (like catecholamines). Compounds don’t mimic catecholamine activity but disrupt packaging and reuptake which disturbs signalling.

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65
Q

Psychomotor stimulants act by…

A

Increasing availability of NorAdr and DA at synapse. Amphetamine etc are substrates for the catecholamine uptake systems (e.g. NET/DAT) slowing uptake of catecholamines and increasing their concentration at the synapse. They also prevent catecholamine vesicular packaging by actions on transporters, increasing catecholamine concentration in the terminal. Amphetamine is also a MAO inhibitor further increasing catecholamine concentration in the cytosol. This increased cytosolic concentration reverses the remaining action of NET/DAT pushing transmitters out non-vesicularly.

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66
Q

Behavioural effects of psychomotor stimulants…

A

Locomotor stimulation (due to DA), euphoria and excitement, insomnia (due to inc NorAdr), increased stamina, anorexia, and peripheral effects of raised BP and inhibition of gastric mobility + adverse effects of anxiety, irritability and restlessness. High doses induce paranoia/panic.

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67
Q

Clinical uses of amphetamines…

A

Treatment of narcolepsy (possible form of epilepsy). Modafinil (another amine uptake inhibitor) offer better control without dependence. Also used to treat ADHD e.g. methylphenidate (Ritalin)

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68
Q

Methylphenidate

A

Used to treat ADHD, aka Ritalin

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69
Q

Atomoxetine

A

Used to treat ADHD. A selective NorAdr reuptake inhibitor (can be used with methylphenidate).

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70
Q

Modafinil

A

Used to treat ADHD in adults, also a cognitive enhancer. A general amine reuptake inhibitor.

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71
Q

Chronic use of amphetamines leads to…

A

Can induce “amphetamine psychosis” , like acute schizophrenia - hallucinations, paranoia and hallucinations. Repetitive stereotypical behaviours may also develop e.g. self biting, scratching.

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72
Q

Cocaine acts by…

A

Similar mechanisms to amphetamine, but equally on uptake of DA, NorAdr and 5HT. Taken nasally it destroys local tissue by vasoconstriction. Metabolised rapidly by the liver and one metabolite is measurable in human hair.

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73
Q

Chronic use of cocaine leads to…

A

Toxic effects, mainly CV, can be acute or chronic. Can produce strong psychological dependence (substance dependence). Can produce foetal malformation in pregnancy.

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74
Q

Caffeine acts by…

A

Inhibiting central adenosine receptors (A1 and A2). Adenosine and ATP are modulatory generally resulting in decreased CNS activity. It also inhibits phosphodiesterase enzyme, which increases local cAMP and therefore protein phosphorylation. Also has peripheral diuretic actions on kidneys.

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75
Q

Psychomimetic properties…

A

Psychedelic/Hallucinogenic. Affect thought, perception and mood. No psychomotor effects. Minimal intellectual impairment. Autonomic side effects are low. Little or no dependence liability. e.g. LSD, psilocybin, mescaline, ecstasy, ketamine, phencyclidine and cannabis.

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76
Q

LSD etc act by…

A

Partial agonist activity at 5HT2A receptors (possibly within the cingulate cortex) which may indirectly block glutamate activation of NMDA receptors (ketamine also does this). LSD also activates 5HT1A autoreceptors on 5HT cells in the raphne nucleus, slowing their firing rate. Mescaline may also act on 5HT2A Rs or possibly amine transporters. Psylocibin is metabolised to a compound active at several 5HT receptors.

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77
Q

Ketamine

A

Dissociative anaesthetic agent used by vets. Produces euphoria and hallucinations at higher doses, along with detachment and disorientation. Block NMDA receptor. Long term use can result in paradoxical bladder defects. Dangerous in overdose especially with alcohol, barbiturates or heroin.

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78
Q

Phencyclidine (PCP)

A

Analogue of ketamine. Produces euphoria and hallucinations at higher doses, along with detachment and disorientation. Can cause psychotic episodes. Block NMDA receptor. Long term use can result in paradoxical bladder defects. Dangerous in overdose especially with alcohol, barbiturates or heroin.

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79
Q

Nicotine acts by…

A

Stimulating central nAChRs - heavily expressed in cerebral cortex, hippocampus and ventral tegmentum when stimulating inc DA). Enhances transmitter release and increases neuronal excitability. Nicotine can lead to desensitisation of receptors as it is not removed as quickly as ACh and can eventually lead to “synaptic block”. Chronic administration leads to increased numbers of nAChRs. Overall effect may be a balance between excitation and synaptic block. Nicotine inhibits spinal reflexes leading to muscle relaxation (possibly by stimulating glycinergic renshaw cells). Low nicotine doses cause central arousal, large doses cause sedation. Reaction times improve with small doses. Nicotine causes excitation in the meso-limbic DA reward system, rats choose to drink nicotine solutions over water.

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80
Q

Nicotine chronic use and dependence…

A

Produces psychological dependence, physical dependence and tolerance. Smoking cessation leads to withdrawal which can be alleviated by nicotine therapy. Harmful effects of cough, cancer, coronary heart disease etc.

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81
Q

Cannabis ingestion leads to…

A

Euphoria, relaxation, reduced pain, increased laughter and talkativeness, hunger and light-headedness. Also decreased problem solving ability, reduced STM, and decreased psychomotor performance. High doses can produce personality changes and hallucinations. Some evidence of tolerance and physical dependence.

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82
Q

Delta-tetrahydrocannabinol (THC)

A

Active ingredient in cannabis

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83
Q

Cannabidol (CBD)

A

Precursor to THC. Lack psycho-activity but can be used as anticonvulsant.

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84
Q

Cannabinol

A

Breakdown product of THC. Lack psycho-activity but can be used as anticonvulsant.

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85
Q

Pharmacological effects of cannabis (in CNS)…

A

Sense of relaxation, feeling of sharpened awareness, subjective slowing down of time, analgesia, anti-emetic activity (uses for chemotherapy?)

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86
Q

Pharmacological effects of cannabis (in PNS)…

A

Tachycardia, vasodilation, reduction in intraocular pressure, bronchodilation, anti-emetic activity

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87
Q

Adverse effects of cannabis…

A

Overdose leads to mild respiratory depression with confusion and dizziness. In rodents THC is teratogenic. Tolerance and physical dependence sometimes seen. Abstinence leads to similar symptoms as alcohol withdrawal. Psychological dependence. Increased likelihood of schizophrenia? Ladder of drug use?

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88
Q

Cannabis acts by…

A

High lipid solubility first suggested general anaesthetic like action on membranes. Acts on Gprotein receptors CB1 (primarily central) and CB2 (primarily peripheral) that usually use endocannabinoids such as Anandamide and 2AG. Receptors are more in high CNS as opposed to eg brain stem but are very common.

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89
Q

Actions of endocannabinoids…

A

2AG is made using PLC and Anandamide is made using PLD enzyme from membrane lipids in the post-synaptic neuron. The enzymes are Ca dependant (rely on post synaptic Ca conc). They then are pumped out by EMT and act in a retrograde manner on the pre-synaptic cell and are most often inhibitory (by reducing NT release by decreasing Ca influx). They are not packaged in vesicles as they are too lipid soluble and are instead activated on demand. They are taken up by a transporter and degraded locally.

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90
Q

Alzheimers Disease leads to…

A

Loss of declarative memory and cognitive functions, then psychosis.

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91
Q

Brain characteristics of AD…

A

Atrophy (narrowed gyri and widened sulci), reduced brain weight and enlarged ventricles. Presence of extracellular plaques of a peptide amyloid, surrounded by swollen axons and dendrites. Affected but survivign neurons contain neurofibrillatory tangles (hyperphosphorylated Tau protein - makes them sticky)

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92
Q

Neurofibrillatory tangles

A

Seen in AD. Hyperphosphorylated Tau protein inside of cells.

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93
Q

Amyloid plaques

A

Seen in AD. Extracellular polymers of Amyloid Beta peptide.

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94
Q

NT changes in AD…

A

Loss of cholinergic neurons from the basal forebrain occurs early. Cholinesterase inhibitors increase ACh availability to improve symptoms.

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95
Q

Cholinesterase inhibitors

A

Used to treat AD. Loss of cholinergic neurons in basal forebrain.

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96
Q

Basal forebrain

A

Affected in AD. includes the Nucleus basalis of Meynert (NbM) part of the substantia innominata, the diagonal band (of Broca) and the medial septal nuclei. Loss of cholinergic neurons. Connections to hippocampus and neighbouring regions.

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97
Q

Tacrine

A

Used to treat AD. Affects both AChE and BuChE (not CNS selective). Acts for 6h taken 2-3 times daily. Oral. Cholinergic side effects (abdominal pain, nausea, diarrhoea) and hepatoxicity.

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98
Q

Donepezil

A

Used to treat AD. CNS, AChE selective. Acts for 24h taken once daily. Oral. Slight cholinergic side effects (abdominal pain, nausea, diarrhoea).

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99
Q

Rivastigmine

A

Used to treat AD. CNS selective. Acts for 8h, taken twice daily. Oral. Cholinergic side effects (abdominal pain, nausea, diarrhoea) ten to subside eventually. Gradual dose escalation to minimise side effects.

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100
Q

Galantamine

A

Used to treat AD. Acts for 8h, taken twice daily. Oral. Slight cholinergic side effects (abdominal pain, nausea, diarrhoea).

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101
Q

Memantine

A

Used to treat AD. NMDA antagonist. Acts for 24h, taken once daily. Oral. Side effects of constipation, hypertension, dyspnoea, headache, dizziness, drowsiness.

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102
Q

Immediate causes of death in AD…

A

Pneumonia and dehydration.

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103
Q

AD is a result of…

A

Disordered protein folding. Abnormal configuration, hydrophobic regions exposed, can aggregate and be “sticky”, may be insoluble and so cannot be removed. Happens at a low rate normally but is increased in disease. Leads to cell death. Beta-Amyloid and Tau are misfolded leading to plaques and neurofibrillatory tangles respectively.

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104
Q

Messy long explanation about AD…

A

Beta-Amyloid comes from APP (Amyloid precursor protein) which is cleaved in normal function by secretases (enzymes). Alpha-secretase in normal physiology produces sAPP (growth factor function). Beta/Gamma-secretases form Abeta42 (+40) which is insoluble so aggregate (although some can be cleared as they are produced in small amount normally perhaps to stabilise synapses) but a genetic APoE4 mutation (meaning you are more at risk of developing AD) means they are cleared less. The aggregation is made up of oligomers (which may cause cell death) these then form polymers of amyloid plaques. There is also a relationship between oligomers and the Tau pathway (phosphorylation) which leads to increased amounts of paired helical filaments > tangles > cell death.

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105
Q

Amyloid cleaving in AD…

A

3 enzymes cleave the amyloid precursor protein (APP) to give rise to amyloid beta. N terminus may also be neurotoxic and de-stable synapses.

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106
Q

Predicting AD early can be done by…

A

Brain imaging (e.g. MRI) to visualise cell loss/ventricular enlargement. Also by cognitive tests for cognitive impairment in early years and brain imaging at this stage.

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107
Q

You can visualise plaques (amyloid beta) by…

A

Using PET (when tagged)

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108
Q

Mice with an experimental APP transgene mutation that are immunised with antibodies to remove amyloid plaques…

A

Preserves cognitive performance and they perform similarly to controls.

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109
Q

PD is characterised by…

A

Akinesia, bradykinesia, muscular rigidity and tremor. Also shuffling gait, flexed posture, reduced facial expression, decreased blinking and micrographia.

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110
Q

The basal ganglia includes…

A

Striatum (caudate nucleus and putamen), Globus Palidus (internal and external segments), Sustantia nigra (pars compacta and pars reticulata) and the sub thalamic nucleus.

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111
Q

Pathway for DA in BG…

A

Nigrostriatal pathway (from SNc to striatum)

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112
Q

Synaptic input to a medium spiny neuron in the striatum includes…

A

Extrinsic - SNc (modulates cortical input to neuron with DA), cortex and thalamus (both using glutamate). Intrinsic - large INs using ACh and Other INs using GABA (modulatory and inhibition).

113
Q

Direct and Indirect pathways…

A

2 populations of spiny cells with D1 and D2 Rs.
Direct pathway
Activation of D1 receptors excites GABAergic cells in putamen.
Enhanced inhibitory output from putamen inhibits GPi GABAergic cells.
Decreased inhibitory output from Gpi reduces inhibition of thalamic cells.
Thalamocortical excitatory drive is increased.

Indirect pathway
Activation of D2 receptors inhibits GABAergic cells in putamen.
Decreased inhibitory output from putamen excites Gpe GABAergic cells.
Enhanced inhibitory output from GPe inhibits GPi GABAergic cells.
Enhanced inhibitory output from GPe inhibits SubThalamic Nucleus excitatory cells.
Decreased excitatory drive from STN reduces excitastion of Gpi GABAergic cells
Decreased inhibitory output from Gpi reduces inhibition of thalamic cells.
Thalamocortical excitatory drive is increased.

114
Q

PD is characterised by brain changes…

A

Degenertion of SNc cells > loss of DA input to striatum > loss of D1 excitation of direct pathway and D2 inhibition of indirect pathway (often indirect pathway is more resistant) > increases inhibition to thalamus > impaired movement. Activity of STN also increases as indirect pathway is more active (so further increases Gpi activity).

115
Q

MPTP

A

Heroin substitute. Toxic components are broken down by MAOb to MPP+ which is neurotoxic and selectively taken up by SN DA cells. Can be used in animal models of PD as well as 6-hydroxydopamine.

116
Q

MPP+

A

Can be used in animal models of PD.

117
Q

6-hydroxydopamine

A

Can be used in animal models of PD.

118
Q

4 BG loops to cortex…

A

Motor, Occulomotor, Executive/Associative, Emotion/Motivaiton … all use SN and DA to modulate so are affected in PD.

119
Q

In the absence of DA modulatory control on the BG…

A

BG begins to fire in bursts (patterns) at set frequencies which is sent to the cortex which fires at a different frequency and so cortical activity is disrupted

120
Q

L-Dopa

A

Used to treat PD. A substrate for dopa decarboxylase, leads to increased DA levels in CNS. Can cause peripheral effects so is given with carbidopa or benserazide to block peripheral dopa decarboxylase (doesn’t cross BBB). Can also be combined with entacarpone or tolcapone, COMT inhibitors, working peripherally to prevent L-Dopa metabolism and centrally to prevent DA metabolism.

121
Q

Carbidopa

A

Given with L-Dopa in treatment of PD to block peripheral dopa decarboxylase and reduce peripheral effects (doesn’t cross BBB).

122
Q

Benserazide

A

Given with L-Dopa in treatment of PD to block peripheral dopa decarboxylase and reduce peripheral effects (doesn’t cross BBB).

123
Q

Entacapone

A

Given with L-Dopa in PD. COMT inhibitors, working peripherally to prevent L-Dopa metabolism and centrally to prevent DA metabolism.

124
Q

Tolcapone

A

Given with L-Dopa in PD. COMT inhibitors, working peripherally to prevent L-Dopa metabolism and centrally to prevent DA metabolism.

125
Q

L-Dopa side effects…

A

Involuntary writhing movements/dyskinesia - reduces after 2 years. Also there are rapid changes in clinical status - the “on/off effect” - symptoms like hypokinesia suddenly reappear for short periods - possibly due to short plama half life of dopa or the loss of DA stores. Also neusea (can be treated with domperidone – itself a dopamine antagonist, but works via chemo-trigger zone at the blood-brain interface and does not (normally) cross into the CNS). Also postural hypotension and psychological effects - schizophrenia like symptoms (delusions and hallucinations) - more commonly confusion, insomnia, nightmares.

126
Q

Domperidone

A

Used to treat nausea in PD domperidone – itself a dopamine antagonist, but works via chemo-trigger zone at the blood-brain interface and does not (normally) cross into the CNS

127
Q

Bromocriptine

A

DA agonistused in PD. Orally active ergot derivative. Use limited by side effects (mainly nausea/vomiting).

128
Q

Pergolide

A

DA agonist used in PD. Orally active ergot derivative. Use limited by side effects (mainly nausea/vomiting).

129
Q

Pramipexole

A

DA agonist used in PD. More active at D2 and D3 Rs, don’t have the L-Dopa “on/off effect”. Use limited by side effects such as compulsive behaviour like gambling and hyper-sexuality through actions on DA mediated reward circuits.

130
Q

Ropinirole

A

DA agonist used in PD. More active at D2 and D3 Rs, don’t have the L-Dopa “on/off effect”. Use limited by side effects such as compulsive behaviour like gambling and hyper-sexuality through actions on DA mediated reward circuits.

131
Q

Selegeline

A

MAOb inhibitor used in treatment of PD. Often combined with L-Dopa. Is metabolised to amphetamine so has unwanted effects.

132
Q

Rasagiline

A

MAOb inhibitor used in treatment of PD. Often combined with L-Dopa. Is not metabolised to amphetamine like selegeline.

133
Q

Amantadine

A

Used in treatment of PD. Possibly causes enhanced DA release

134
Q

Benztropine

A

Anti-muscarinic used to treat PD. ACh receptors on dopaminergic nerve terminal reduce release – so blockade enhances release – but with many antimuscarinic side-effects e.g dry mouth, loss of accommodation (blurred vision)

135
Q

Non-drug treatments of PD…

A

Deep brain stimulation or neural transplantation

136
Q

6-OHDA

A

Catecholaminergic neurotoxin taken up by transporters for animal models of PD. Pretreated with deimipramine, a NorAdr transporter blocker for DA selectivity. Causes bradykinesia. In mice expressing channelrodopsin in direct pathway neurons these effects are counteracted with illumination.

137
Q

Huntingtons disease symptoms…

A

Dementia and chorea. Death in 15-20 years.
Probably due to reduced local inhibition, resulting in increased dopaminergic activity
Results in early neural degeneration in the striatum, affecting cells in the indirect pathway
Removes an inhibitory influence on GPe and subthalamic nucleus.
In turn enhances GPe’s inhibition of Gpi and Sub-thalamic nucleus (reducing its excitatory drive to Gpi)
Result is reduced inhibitory drive to the thalamus.
So, thalamo-cortical drive to motor areas increases (opposite of Parkinsons disease)

138
Q

Tetrabenazine

A

Used in treatment of Huntingtons disease. Inhibitor of vesicular monoamine uptake (vMAT), decreases DA levels.

139
Q

Chlorpromazine

A

Used in treatment of Huntingtons disease. DA antagonist, usually used as an anti psychotic.

140
Q

Haliperidol

A

Used in treatment of Huntingtons disease. Suppresses chorea.

141
Q

Olanzapine

A

Used in treatment of Huntingtons disease. Suppresses chorea.

142
Q

Risperidone

A

Used in treatment of Huntingtons disease. Suppresses chorea.

143
Q

Quetiapine

A

Used in treatment of Huntingtons disease. Suppresses chorea.

144
Q

Aspirin

A

Non-steroidal anti inflammatory drug (NSAID) targets cyclooxygenase enzymes that catalyse prostaglandin biosynthesis.

145
Q

Paracetemol

A

Non-steroidal anti inflammatory drug (NSAID) targets cyclooxygenase enzymes that catalyse prostaglandin biosynthesis. But not anti inflammatory.

146
Q

Ibuprofen

A

Non-steroidal anti inflammatory drug (NSAID) targets cyclooxygenase enzymes that catalyse prostaglandin biosynthesis.

147
Q

Inflammatory response…

A

Chamicals such as Prostaglandins (esp PGE2), Bradykinin, 5HT etc are released following tissue damage. This leads to sensitisation/activation of nociceptive neurons, vasodilation (inflammation - white blood cells arrive), degranulation of mast cells. Mast cells then release histamine and PGD2 (prostaglandin) which activate the inflammatory response more.

148
Q

Bradykinin acts by…

A

Actions on B2 receptor and therefore PKC to potentiate eg TRPV1 channel and allow Na influx > depolarisation

149
Q

Prostaglandins act by…

A

Actions on prostanoid receptors through PKA to open vgated Na channel in nociceptor membrane to increase sensitivity. Bradykinins that act as a stimulus on nociceptors produce prostaglandin that sensitise the nociceptor this is called a “self sensitisation loop”. Prostaglandins will not produce a reponse alone (as they do not act as a stimulus)

150
Q

Opiods act by…

A

Actions on gprotein coupled receptors through PKA to open K channels

151
Q

Prostaglandins are synthesised by…

A

From the precursor Arachidonic acid (derived from membrane phospholipids) using the enzyme PLA2. It is then converted to prostaglandins by COX1/COX2. Inducable enzyme - process only begins with tissue damage. Every prostaglandin contains 20 carbon atoms including a 5 carbon ring, but they vary depending on location (as another enzyme forms the final product). Prostaglandin E2 is in skin and involved in nociception

152
Q

Cyclooxygenase types…

A

COX1 - constitutively expressed (COX inhibitors produce side effects here eg used in stomach to protect it from acid), COX2 - induced in damaged/infected cells (involved in inflammatory response - drug target), COX3 - splice variant of COX1?

153
Q

Inhibitors of COX…

A

Aspirin - irreversible, Paracetamol - reversible (competitive), Ibuprofen - reversible (non-competitive). Used for mild/moderate pain. Aspirin/paracetemol can be combined with low potency opioid analgesics to increase effect: codeine (“co-codamol” w/paracetemol), dihydrocodeine (“co-dydramol” w/paracetemol). Side effects GI upsets (dyspepsia, nausea, ulcers - by action on COX1), skin reactions, renal damage, liver damage (esp paracetemol - breakdown product overloads enzyme - toxic), bronchospasm in ‘aspirin-sensitive asthmatics’ (as arachidonic acid not broken down so produces leukotrienes)

154
Q

Arachidonic acid

A

Precursor for prostaglandins

155
Q

Other actions of prostaglandins…

A

Bronchoconstriction (but recall aspirin induced asthma), Inhibition of platelet aggregation (but thromboxanes, part of prostanoid family increase aggregation), vasodilation/control of body temperature. So COX inhibitors will reduce these actions.

156
Q

Core temp can be increased by…

A

Piloerection (inc heat conservation) and inc heat production with shivering or exercise

157
Q

Core temp can be decreased by…

A

Increasing heat loss by vasodilation or sweating and decreasing heat production by limiting movement

158
Q

Difference between pyresis (fever) and hyperthermia…

A

Pyresis - ‘body thermostat’ is raised so you increase heat gain/conservation but feel cold (because PGE2 have increased the thermostat - released from preoptic area of hypothalamus - acts on EP1 receptors). Thermoreceptors = Transient Receptor Potential channels. Body temp has a phase lag behind thermostat changes over time, aspirin may reduce thermostat to normal (antipyretic). Hyperthermia - thermostat has not increased but conditions are wrong, heat production > loss, feel hot. Aspirin is ineffective in reducing temperature in this case.

159
Q

Sensory (afferent) inputs for nociception…

A

Adelta fibres are myelinated and produce sharp initial pain. C fibres are unmyelinated and produce chronic, dull pain.

160
Q

Ascending pathways involved in pain…

A

Spinothalamic (relays at thalamus - identifies location of pain on somatotopic map), Spinoreticular (relays at reticular formation - medulla and pons level - makes you “jump”), Spinomesencephalic (to periaqueductal grey matter - to do with control of pain)

161
Q

Descending pathways involved in pain…

A

Periaqueductal grey matter (PAG), Locus coeruleus (LC, arousal centre) and Nucleus raphne magnus (NRM, 5HT area). 2 pathways project to spinal cord using 5HT and NorAdr to control incoming nociceptive input

162
Q

Naloxone

A

Opioid antagonist. Competitive at all 3 opioid receptors but mostly Mu. Given alone has little effect. After agonist reverses all effects of full agonists and agonist actions od mixed action compounds (but larger doses required). Used to treat respiratory depression (in overdose or newborns when analgesics used during delivery). Short action, metabolised in liver. In dependant patients produces precipitate withdrawal syndrome, used to treat overdose (titrated carefully to reverse respiratory depression but not precipitate withdrawal), used in “treatment” of dependance (mixed in tablets for IV misuse)

163
Q

Endorphins, enkephalins, dynorphins

A

Endogenous opioids - similar Tyr, Gly, Gly, Phe, Leu initial structure

164
Q

Opioid receptors…

A

Three subtypes. Negatively linked to adenylyl cyclase (decreases cAMP > opens K channels > hyperpolarisation + decreased Ca levels > reduced NT release).
Mu (MOPr). Subtypes 1, 2 and 3. Gprotein coupled. Open K channels, reduce post synaptic excitability, inhibit NT release (esp ACh, glutamate). Reponsible for most analgesic effects. Side effects: respiratory depression, constipation, euphoria, sedation, dependence.
Delta (DOPr). Subtypes 1 and 2. Act similarly to Mu receptors. Produces analgesia. Can be “proconvulsant”.
Kappa (KOPr). Subtypes 1, 2 and 3. Reduce Ca activity so inhibit NT release. Analgesia at spinal level. May elicit sedation, dysphoria/hallucinations. KOPr activity in analgesics may be coupled to MuR antagonsm.
Others ie ORL1 (NOPr).

165
Q

Enkaphalinergic interneurons act by…

A

Decreasing nociceptive information send to ascending pathways. Opioids may mimic their actions.

166
Q

Opiods act by…

A

Blocking release of NTs (e.g. glutamate/substance P), mimicking action of Enk INs, enhancing descending pathway activity (by opioid receptors in PAG/LC/NRM

167
Q

Morphine, codeine

A

Opioid agonists. Action at spinal level - Mu2, Delta2, Kappa1. Action at supraspinal level - Mu1, Delta 1+2, Kappa3. Vary in analgesic efficacy, absorption, duration of effect, side effects e.g. codeine produces more nausea. Also produce sedation, cough suppression, euphoria, respiratory depression, nausea, itch. Also have peripheral actions of reduction of inflammation (inhibits adenylyl cyclase, increased cAMP, prevents inflammatory mediators?) and increased threshold for pain and pain tolerance. Better against dull, chronic pain.

168
Q

Naloxone, Naltrexone

A

Opioid antagonists. Done by substitution of large groups on the N atom at positron 17 in morphine.

169
Q

Buprenorphine, Pentazocine

A

Mixed actions at opioid Rs. Buprenorphine - partial Mu agonist - analgesia, other opioid effects. Very sedative, nausea and vomiting. Respiratory depression not fully reversed by naloxone. Reduced abuse potential. Withdrawal less intense than morphine - used to treat opioid dependence (suppresses euphoria of other drugs)

170
Q

Diamorphine

A

Diacetyl morphine (prodrug) - more lipid soluble so faster onset of action as goes quickly through BBB + deacylated to produce morphine

171
Q

Opioid-induced nausea…

A

Nausea triggered at chemoreceptor trigger zone (CTZ) through opioid receptors, this activates the vomit centre in the CNS (modified by descending inputs) > vomit reflex

172
Q

loperamide

A

Mu opioid R agonist, cannot cross BBB, immodium (action on GI tract)

173
Q

Cough suppression of opioids…

A

Action at cough centre in CNS. Via Mu, delta Rs? Can produce antitussive action without analgesia. Done by adding large subsituent at position 3 on morphine molecule. e.g. codeine, pholcodine (modified codeine).

174
Q

Dextromethorphan

A

Cough suppressant without analgesia

175
Q

Nalorphine

A

Mixed action opioid. Mu antagonist, delta and kappa partial agonist. Some analgesia with lower abuse potential and also dysphoria.

176
Q

Pentazocine

A

Mu antagonism (reduced euphoria, reduced abuse potential, limited respiratory depression), Kappa agonist (analgesia). Rarely used now, frequent prolonged use leads to dependence.

177
Q

Tramadol

A

Mu weak agonist (analgesic), weak inhibitor of monoamine reuptake (eg NorAdr and 5HT) so similar effects as SSRIs (changes mood, inc analgesic potential). Used therapeutically as analgesic for moderate to severe pain but can lead to dependence.

178
Q

Tolerance in analgesics…

A

Increasing time between first and second dose reduces effect of second dose

179
Q

Dependence in analgesics…

A

Morphine inhibits cAMP production, system responds by increasing adenylate cyclase expression (tolerance). Once morphine is removed there is a spike in cAMP production (dependence) and withdrawal symptoms

180
Q

Stages of general anaesthesia…

A

Movement between stages depends on dose.
Stage 1 (induction) - Ether=fast. Reduced responses to pain, conscious but drowsy.
Stage 2 - Excitement (can hold breath, talk, vomit, move), loss of response to non-painful stimuli, gag reflex - coughing increased.
Stage 3 - Surgical anaesthesia. Regular respiration. Possibly some reflexes, muscle tone preserved, progressive shallowing of breathing.
Stage 4 - Anaesthetic overdose, medullary paralysis - respiration and vasomotor control ceases (eg heart rate and blood pressure).
Desire fast 1 and 2, stable 3 and no stage 4. Often combine anaesthetics and with analgesics, muscle relaxants or anxiolytics.
eg Propofol (IV) for fast induction, inhaled N2O or halothane for stage 3, supplementary analgesic such as morphine, and neuromuscular blocker such as atracurium.

181
Q

Volatile anaesthetics…

A

Ether, N2O, Chloroform, Halothane, Xenon, Enflurane, Isoflurane

182
Q

IV anaesthetics…

A

Propofol, Etomidate, Ketamine, Midazolam(induction agent)

183
Q

Lipid theory for general anaesthetics…

A

From Meyer-Overton correlation, more lipid soluble > more potent. Acts by lipid pertubation: Fluidisation or Volume expansion - effects function of neuron. Problems: adding long carbon chains increases lipid solubility but reduces potency - so binding site involved? Physical chemistry shows membranes don’t change much. Enantiomeric pairs differ in actions but have same effect on bilayer. Some anaesthetics specifically target proteins.

184
Q

Minimum Alveolar Concentration (MAC)

A

Measure of potency for anaesthetics. Concentration required to produce anaesthesia in 50% of patients. Lower MAC = more potent

185
Q

Protein theory for general anaesthetics…

A 
If binding site is in hydrophobic region fits into lipid theory. Proteins targeted:
GABAa Rs (many volatile, IV. Not Xe, ketamine) - function POTENTIATED - IVs act on beta subunit and volatiles at beta and alpha interfaces
NMDA Rs ( ketamine, Xe, volatiles) - function INHIBITED
Two-pore K channels - function POTENTIATED
186
Q

Blood-gas partition coefficient

A

A measure of how well the drug dissolves in blood. Determines rate of induction and recovery. Want a drug that dissolves well in gas and poorly in blood (low coefficient) as it will leave the blood more quickly.

187
Q

Oil-gas partition coefficient

A

High coefficient means high potency but lots of the drug will dissolve in fat which is poorly vascularised so will take a long time to leave and lead to a slowly resolving hangover - worse the fatter the patient and more lipid soluble the drug.

188
Q

Types of anaesthetic…

A

Inhalational, Intravenous, Dissociative and Neurolept (only veterinary use)

189
Q

Inhalation anaesthetics pros and cons…

A

Pros: easy to maintain degree of anaesthesia bc of fast air:blood equilibrium and rapid emergence from anaesthesia.
Cons: cumbersome and expensive apparatus, administered via a mask, atmospheric pollution (use scavengers) - high greenhouse gas effect, some deplete ozone. Can use closed circuit anaesthesia or Xenon is unreactive but expensive.
Metabolism unimportant for elimination but produces toxic metabolites. Fluranes generate fluoride, causes renal toxicity. Halothane is converted to bromide and TFA, hepatoxic. Problems for staff: liver disease, leukaemia, abortion, birth defects

190
Q

Halothane

A

Inhaled anaesthetic. Isoflurane more common, less hepatoxic but more expensive. Fast induction/recovery, few post op effects, vasodilator and cardiac depressant - monitor depth of anaesthesia.
Adverse effects: cardiac dysrhythmias, respiratory depressant, sensitises heart to NorAdr (SNS effects), can cause ventricular extra-systoles. Not in use for phaeochromocytoma (tumour secreting Adr). Hepatoxic with repeated exposure.

191
Q

Nitrous oxide

A

N2O. Low blood:gas partition coefficient. Analgesic at concentrations lower than those which cause unconsciousness. Used in trauma and obstetrics, chloroform alters uterine contractivity. Low potency so often used as adjunct with other drugs. Rapidly leaves tissues and dilutes lungs of oxygen - transient hypoxia - extra oxygen needed at end of anaesthesia.
Contraindictions: early pregnancy, pernicious anaemia, scuba diving. Greenhouse gas (300x CO2).

192
Q

Enflurane

A

Similar to halothane (potency/induction speed). Less fluoride production than other fluranes. EEG changes and seizures during induction/recovery. Avoid with epileptic patients (lowers seizure threshold)

193
Q

Isoflurane

A

Widely used. No metabolism, little toxicity, not proconvulsive. Expensive. Hypotension (-ve ionotrope - alters muscle contraction, decreases sytemic vascular resistance). Coronary vasodilator - myocardial ischaemia recently disputed. Possible worries regarding neurodegeneration.

194
Q

Sevoflurane

A

Rapid induction (very low blood:gas coefficient). Very little metabolism. Very high cost! Concerns regarding neurodegeneration. Recovery so rapid that post op pain relief is needed.

195
Q

IV anaesthetics pros and cons…

A

Pros: rapid induction so no stage 2, simple apparatus, pleasant induction, no atmospheric pollution.
Cons: hard to control level, recovery can be slow due to redistribution and metabolism, finite duration (but can infuse) so only used for short surgeries or induction agent, vein damage eg thrombophlebitis.

196
Q

Thiopental

A

(IV). Barbituate. Very lipid soluble, crosses BBB fast. Induction depends on blood flow. Rapidly redistributed into tissues: liver, kidneys, brain, muscles. Slowly distributes into fat (slow blood flow).
Rapid decline in blood levels (redistribution) then drops slowly (long time to be cleared). Metabolism and fat distribution. Rapid awakening, long hangover. No repeated doses to maintain effect as it worsens hangover. Blood plateau becomes elevated - accumulation.
Problems: increases HR and cardiac O2 demand (cardiac depressant). Pooling of blood in periphery, respiratory depression (used in euthenasia/lethal injections), tissue necrosis or arterial spasm: gangrene.
Contraindictions: low circulating blood volume, cardiac disease, severe asthma

197
Q

Etomidate

A

(IV). Acts on BDZ site of GABAa Rs. Hypnotic (no analgesia). Favoured - large margin between anaesthesia and resp/CVS depression. Useful if patient has CV issues. Fast metabolism (liver), less hangover. Involuntary movements (give short-acting BDZ). Post operation nausea/vomiting. Possible problems with adrenal insufficiency (drug suppresses production of corticosteroids from adrenal gland)

198
Q

Propofol

A

(IV). Acts on BDZ site on GABAa R. Rapid metabolism - rapid recovery, no hangover. Can be continuously infused to maintain anaesthesia without inhaled agent. None of the effects of etomidate (involuntary movements, adrenal suppression). Day surgery.
Also used for euphoria or sleep induction.
Steep dose-response curve, difficult to monitor dose.

199
Q

Ketamine

A

“Dissociative anaesthetic” - trance like. Analgesia, Amnesia, but patient still partly conscious. Little effect on respiration, blood pressure. Heart rate increased. Very safe for emergency situations (as CV system is not depressed). High abuse potential. Olneys lesions - brain damage.

200
Q

Neurolept amnesia

A

Combination of neuroleptic (major tranquilizer ie anti psychotic) and opioid. Effects similar to ketamine. Not used frequently on humans - common in vetenary medicine. Used in tranquilizer guns eg large animal immobilon. Anti pscyh eg Acepromazine.

201
Q

Psychosis symptoms…

A

Delusions, thought disorder, catatonia, hallucinations

202
Q

Causes of psychosis…

A

Schizophrenia, Bipolar, Illegal drugs, Prescription drugs, PTSD, Sleep deprivaiton, Caffeine intoxication, AD

203
Q

Schizophrenia symptoms…

A

+ve: delusions, hallucinations, catatonia, disordered thoughts, stereotyped movements.
-ve: loss of social contact, loss of emotional response, anhedonia, lack of motivation, cognitive problems

204
Q

Historical therapies for schizophrenia…

A

Insulin shock, fever therapy, ECT, lobotomies

205
Q

Genetic factors of schizophrenia…

A

1% usually, 8-10% if near relative, 50% in twins. Probably many “tendency genes” eg DISC1. Requires environmental impact too.

206
Q

Environmental factors of schizophrenia…

A

Winter birth (maternal exposure to viruses?), substance abuse (amphetamine > psychosis, cannabis?) but schizophrenics also have high risk for substance abuse (cause/effect?)

207
Q

Social factors of schizophrenia…

A

Difficult childhood conditions: discrimination, dysfunctional families, abuse/trauma.

208
Q

Schizophrenia: neurodevelopmental or neurodegeneratie?

A

Neurodevelopmental: age of onset (teen/early adult), structural differences in brian.
Neurodegenerative: progression of disease in many cases, reductions in brain volume, excitotoxicity?

209
Q

Schizophrenia DA hypothesis

A

Reserpine depletes DA - improvement in positive symptoms.
Amphetamine increases DA - causes psychosis.
L-DOPA and DA agonists - cause psychosis
1:1 relationship of D2 occupancy (antagonism) and plasma level of drugs.
Tuberhypophyseal DA pathway: hormone release from pituatory
Mesolimbic DA pathway: increased DA (+ve symptoms) - synapses on ventral striatum.
Mesocortical DA pathway: emotion. Decreased DA (-ve symptoms).
Nigrostriatal DA pathway: synapses on doral striatum (motor) and associative (excessive DA release - role in schizophrenia?)

210
Q

Other receptors involved in schizophrenia…

A

NMDA R dysfunction - NMDA antagonists cause psychosis. AMPAkines may be new therapeutic approach.
Serotonin receptors - LSD causes psychosis. Probably not directly involved but 5HT activity gives better therapeutic profile.
Muscarinic receptors - Not directly involved but mAChR antagonist activity gives better therapeutic profile.
Antipsychotics aren’t very selective - side effects.

211
Q

Common antipsychotic side effects

A

Movement disorders (‘Extrapyramidal’): Dystonias and tardive dyskinesia (Striatal D2 receptors) - uncontrollable writhing/twisting
Galactorrhea: tuberohypophyseal D2 receptors inhibit prolactin release - leads to lactation
Sedation: ? H1 antagonism (like sedating anti-histamines)
Weight gain: ? H1 and 5HTR antagonism. Can lead to diabetes, heart disease etc
Anti-muscarinic effects: dry mouth, blurred vision, memory problems, cardiac problems. (effect on PSNS).

212
Q

Chlorpromazine

A

First effective antipsychotic. Group 1 Phenothiazine. CPZE: “standardization” of doses
Not used very frequently now.
Side effects: very sedating, moderate extrapyramidal, moderate muscarinic , moderate galactorrhea, neuroleptic malignant syndrome.
Derivatives have similar efficacy, differ in side effect profile

213
Q

Haloperidol

A

Most commonly used typical antipsychotic. Higher potency than chlorpromazine. Also used as an antiemetic. Variety of formulations (how “packaged”). Side effects: lower sedation, lower muscarinic, high risk of EPS, restlessness, neuroleptic malignant syndrome

214
Q

Risperidone

A

Atypical antipsychotic. Improves +ve and -ve symptoms. Available orally, as IM and depot. Side effects: moderate sedation, moderate weight gain, galactorrhea, EPS at higher doses. Licensed for short term use (6wks) on the elderly for AD - risk of stroke and sudden death when longer

215
Q

Quetiapine

A

Atypical antipsychotic. Side effects: very sedating (causes drowsiness/tiredness), moderate muscarinic effects, moderate weight gain, moderate hypotension, no EPS, no galactorrhea. Available in sustained release formulation (slow release from GI tract)

216
Q

Olanzapine

A

Atypical antipsychotic. Oral and IM. Side effects: weight gain, dizziness, tiredness, GI tract problems.
Diabetes risk as after a high glucose meal fat (rather than glucose) is metabolised as an energy source, leads to insulin resistant diabetes

217
Q

Asenapine

A

Atypical antipsychotic. Oral only. Minimal weight gain side effects, Moderate sedation, low muscarinic effects. Expensive.

218
Q

Clozapine

A

Atypical antipsychotic. Caused blood disorder when first released (Agranulocytosis), now must test blood. Very effective for drug resistant schizophrenia. Prescribed as drug of last resort - failure of at least two drugs, one atypical.
Side effects: Agranulocytosis, muscarinic effects (as agonist M4) hypersalivation, cardiac effects (tachycardia), highly sedating, constipation, weight gain/diabetes.
Induced agranulocytosis: Loss of white blood cells > infection (treat with antibiotics) > death.
Monitored: often initiated as in-patient. White blood cell count. daily, weekly, biweekly, monthly after. 3 days missed and start over.

219
Q

Antipsychotic formulations…

A

Orally - voluntary
IM injection - psychiatric emergency situations, involuntary, could be for first dose for insight into illness.
IM depot injection - involuntary, disorganised patient. Every 2/4 weeks. Eliminates cohort non-compliance. Sometimes effect delayed. eg risperidone (Risperdal consta), pipotiazine (depot only), haloperidol, aripiprazole

220
Q

Adjuvant therapy for antipsychotics…

A

Sometimes used in combination with SSRI, mood stabilizer to treat schizophrenia and with mood stabilizers to treat bipolar. Mood stabilizers eg lithium, sodium valporate, lamotrigine.

221
Q

Features of epilepsy…

A

Muscle rigidity, convulsions, psychic (changes in perception) and loss of consciousness

222
Q

Driving restrictions in epilepsy…

A

Free of day time seizures for one year (with medication)
Night time seizures only for three years
Doctors must inform DVLA

223
Q

Diagnosis of epilepsy

A 
EEG (can localise focus of epilepsy and type)
Video EEG (correlates EEG with seizure activity) - when sleep deprived produces abnormal EEG patterns without full seizure
CT/MRI to look for underlying causes eg tumour
PET scans to look at abnormal functioning in regions
224
Q

Types of seizures

A

Generalised seizures (whole brain involved)
Myoclonic (myoclonus) - twitching of muscle or muscle group - brief jerks
Clonic (clonus) - rapidly repeating myoclonus - quivering muscle
Tonic: a phase in which there is muscle contraction (initial rigidity) - can get Tonic-Clonic
Atonic: loss of muscle tone, “drop seizure” collapse
Absence seizures - petit mal, more common in children. Brief lapses in consciousness with rapid recovery. Can happen frequently during day. Motor components in some cases.
Ictal: pertaining to a seizure or stroke

225
Q

Tonic-clonic seizures

A

‘Classic’ epileptic seizure. Three phases:
Aura (not always present) - psychic symptoms eg sensory perception, hallucinations (focal seizure with maintained consciousness/simple partial seizure)
Tonic - muscle rigidity, vocalisations
Clonic - convulsions, incontinences, lasts several minutes
Post-ictal sleep is often seen
Patient confused and feels ill when consciousness regained

226
Q

Status Epilepticus

A

Variant of tonic-clonic seizure. Repeated/continuous seizures lasting >5 minutes. Life threatening condition (20% morbidity). Can result in permanant brain damage due to high frequency in brain and oxygen starvation as muscles are rigid and breathing stops. Treated with BDZs etc.

227
Q

Classification of epilepsy…

A

Symptomology: Tonic-clonic, absence etc
Age of onset: neonatal, infancy, childhood, adolescent/adult, not age related
Aetiology: Genetic (eg change in gene expression, inherited tendency genes or predisposition - due to channelopathies - GABAa Rs, neuronal nAChR and VS channels), structural/metabolic (eg tumour) and unknown origin
Triggers: must occur spontaneously, stress can increase frequency, some have particular triggers eg photosensitive, reading, music, hot water
Brain area: EEG can identify. Often included in name eg ADNFLE (Autosomal dominant nocturnal frontal lobe epilepsy)

228
Q

Juvenile Myoclonic Epilepsy

A

Commonly inherited. Frequently get absence/tonic-clonic seizures too. Associated with exams due to sleep deprivation and caffeine consumption.
Mutations in four genes lead to JME:
GABAaR alpha subunit
GABAaR delta subunit
CLCN2 chloride channel
CACNB4 calcium channel beta subunit (accessory subunit)

229
Q

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

A

Frequently misdiagnosed as nightmares. Linked to mutations in nAChR alpha and beta subunits. nAChR regulates release of other NTs and receptors change sensitivity to ACh and desensitisation altered (if exposed to agonist for too long)

230
Q

Hyperekplexia

A

Startle syndrome. Not an epilepsy. EEG generally normal. Channelopathy. Mutations in proteins associated with glycinergic transmission in spinal cord. Glycine receptor subunits, glycine transporters, cytoskeletal proteins. Animal homologues exist.

231
Q

Mechanisms of anticonvulsants…

A
  • Na channel inhibition
  • Ca channel inhibition
  • GABAergic potentiation (receptor potentiation, uptake inhibition, metabolism inhibition)
  • Other
232
Q

Carbemazepine

A

Blocks vgated Na channels (secondary action on GABAa Rs). First line treatment for tonic-clonic seizures.
Also used as a mood stabilizer, neuropathic pain treatment
Oxycarbazepine, eslicarbazepine: related
Pharmacokinetics: auto-induces CYP3A4 9metabolises drug)
takes a while to reach steady plateau
interaction with grapefruit juice!
because of induction of CYP, many interactions
Side effects: teratogenic, risk of lupus, worsens JME, cognitive problems

233
Q

Lamotrigine

A

Sodium channel blocker
(some secondary mechanisms?)
First line treatment for tonic-clonic seizures
Second line for absence
Can exacerbate myoclonic seizures at higher doses (careful in JME)
Also used to treat bipolar disorder
Side effects:
sedation, sleep disturbances, rash
binds to eye pigment (consequences unknown!)

234
Q

Phenytoin

A

Structurally related to barbiturates
Stabilises voltage-gated sodium channels in inactivated state
Effective against most types of epilepsy EXCEPT absence seizures
No-longer a first line treatment in the UK
Side effects:
Teratogenic
Risk of lupus
Cerebellar atrophy
Acne, hirsuitism
Gingival overgrowth
Pharmacokinetics: steep dose-response curve - hard to manage dose

235
Q

Gabapentin/Pregabalin

A

Structures similar to GABA. But….
Believed to act on alpha2delta subunit of calcium channel (effects trafficking of R)
Pregabalin also increases GAD levels… increased synthesis of GABA
Also used for neuropathic pain, anxiety (Lyrica)
Side effects:
Sedation/dizziness
Suicidal thoughts
Seizures upon withdrawal

236
Q

Ethosuximide

A 
First choice drug for absence seizures
can exacerbate other types of epilepsy
Blocks T type calcium channels
Lacks the liver toxicity seen with valproate
Side effects:
sedation, nausea
237
Q

Benzodiazepines

A 
Used in treatment of epilepsy. Potentiate actions of GABAA receptors (at allosteric site)
Diazepam:
only really used for status epilepticus (tolerance limits use long term)
Clobazam:
also used to treat anxiety
Clonazepam:
also acts on Ca2+ channels
Side effects:
sedation, dependence
seizures on withdrawal
238
Q

Tiagabine

A 
Epilepsy treatment.
GAT1 inhibitor (transports GABA into cell)
Adjuvant medication for partial seizures
? other uses
panic attacks
neuropathic pain
Side effects:
Sedation, dizziness
Paraesthesias (pins and needles)
Provokes seizures in non-epileptic patients
Overdose
- Very sedating, seizures, amnesia, confusion
239
Q

Vigabatrin

A 
Treatment for epilepsy.
Irreversible GABAT inhibitor (which usually breaks down GABA in nerve terminals)
Adjuvant medication
? other uses
- addictions
- panic attacks
Short plasma T1/2
 - Irreversible so
once daily ok
Side effects:
Visual disturbances
Depression, psychosis, sedation
? teratogenic actions
240
Q

Valproate

A 
First line treatment for range of epilepsies
BUT!! Mechanism unclear
?GABAT inhibitor (breaks down GABA)
enhances post-synaptic GABA function
?inhibits sodium channels
?inhibits calcium channels
‘Epilim’ ‘Depakote’
Also used in bipolar disorder, migraine
Side effects:
Liver toxicity (can be sudden onset)
Teratogenic – folic acid antagonist
(anencephaly, spina bifida)
?Cognitive changes/brain structure changes with long term use.
241
Q

Topiramate

A 
Epilepsy treatment.
Complex mechanism of action
enhanced GABA transmission
block of sodium channels
block of AMPA receptors
(inhibition of carbonic anhydrase)
Second-line treatment for tonic-clonic
? Bipolar disorder, alcoholism
Side effects: 
sedation, paraesthesias, cognitive problems, birth defects
242
Q

Psychological symptoms of anxiety…

A

Irritability, fearful anticipation (dread), cognitive disturbance, minor depressive symptoms

243
Q

Physical symptoms of anxiety…

A

Hyperventilation, sympathetic arousal, sleep disturbance, increased muscle tension

244
Q

Characteristics of a panic attack…

A

Physiological symptoms, parasthesiae, fear of loosing control, detachment from reality

245
Q

Barbituates…

A

High addiction liability, high risk of suicide (resp depression). Rarely used for anxiety - for severe insomnia. Thiopental and phenobarbitone used in surgery and epilepsy (respectively).
Enhance actions of GABA on GABAa Rs - distinct from BDZs

246
Q

Benzodiazepines…

A

For epilepsy. Prescriptions usually low dose for short time (2 wks). - tolerance. Not due to enzyme induction (receptor changes?) Tolerance not as bad as barbituates.
Relatively safe (prolong sleep), interaction with alcohol/other drugs: resp depression. Flumazenil = antidote but ?convulsant.
Dependance. Increased anxiety on withdrawal. Shakes, dizziness. Short acting drugs produce withdrawal very quickly eg triazolam.
No major addicion, only psych dependence.
Act at GABAa Rs increase channel opening frequency. Increase affinity of GABA.
Oral, IV diazepam for status epileptiticus. IV midazolam pre-surgical.
Anxiolytics, hypnotics, anticonvulsants - diazepam (valium), chlordiazepoxide (librium), nitrazepam (mogadon), flunitrazepam (rohypnol).
Reduce anxiety and aggression, sedate, reduce muscle tone, anticonvulsant, cause anterograde amnesia.
Uses: anxiety, insomnia, muscle relaxant, anticonvulsant.
Well absorbed orally, accumulate in fat, plasma peak in 1hr, diazepam analogues half long half life.
BDZs metabolised to active metabolites, cleared from body slowly, long hangover effect.

247
Q

Antidepressants (SSRIs) used to treat anxiety…

A

Citalopram, Paroxetine (paxil), Sertaline, Fluoxetine (Prozac)

248
Q

Buspirone

A

Used in general anxiety, non-sedating, non-drowsy, ineffective vs panic attacks, not anticonvulsant.
5HT1A partial agonist. Inhibitory autoreceptor - so inc 5HT (fast action but clinical delay)
Side effects: nausea, dizziness, headache.
Contraindications/interactions: carbemazepine, haloperidol, greapefruit juice, liver/kidney dysfunction, asthma etc.

249
Q

Function of GABA receptors…

A

GABAA: ligand-gated chloride channels (nicotinoid)
GABAB: G-protein coupled receptors - dimer
GABAC: ligand-gated chloride channels (nicotinoid)

250
Q

Flumazenil

A

BDZ antagonist. Parmacologically inactive, applied alone has no effect on GABAa function. Blocks potentiation by flunitrazepam. Used to reverse BDZ sedation (overdose)

251
Q

β-carbolines DMCM…

A

BDZ inverse agonist. Negative allosteric modulator. Proconvulsant, anxiogenic. Act at same site as flunitrazepam (compete in binding assay). Actions can be blocked by flumazenil (antagonist). Decrease GABAa channel opening frequency.

252
Q

Type I/Type II BDZ receptors…

A

CL218-872:
High affinity Type I Benzodiazepine binding sites
Low affinity Type II
Differ in regional distribution in brain.

253
Q

GABA and BDZ binding on GABAa R..

A

GABA - alpha and beta interface

BDZ - gamma2 subunit required for high affinity binding (at interface of alpha and gamma)

254
Q

BDZ knock in study…

A

On alpha1, 2 or 3 subunit converted His to Arg in BDZ site. No change in GABA sensitivity or receptor assembly, complete loss of BDZ binding.

alpha1: sedative, amnesic actions - selective drugs: sleeping tablets
alpha2: anxiolytic actions - selective drugs: anti-anxiety without sedation

255
Q

Elevated Plus Maze

A

Animal test for anxiety. Time length spent in light space.

256
Q

Rotorod Test

A

Animal test for sedation. If drowsy will fall of rotating rod.

257
Q

Water Maze Test

A

Animal test for amnesia. Must navigate to platform using remembered cues.

258
Q

Monopolar depression symptoms…

A

Melencholic depression:
insomnia, diurnal mood variations, anorexia, loss of joy, loss of interest
Atypical depression:
weight gain, increased sleep, anxiety
Dysthymia: mild depressive symptoms that persist a number of years

259
Q

Depression diagnosis…

A

Sub-threshold depressive symptoms: Fewer than 5 symptoms
Mild depression: few, if any, symptoms in excess of the 5 required to make the diagnosis, and symptoms result in only minor functional impairment
Moderate depression: symptoms or functional impairment are between ‘mild’ and ‘severe’
Severe depression: most symptoms, and the symptoms markedly interfere with functioning. Can occur with or without psychotic symptoms.

Key symptoms:
persistent sadness or low mood; and/or
marked loss of interests or pleasure
at least one of these, most days, most of the time for at least 2 weeks

if any of above present, are there associated symptoms?
disturbed sleep (decreased or increased compared to usual)
decreased or increased appetite and/or weight
fatigue or loss of energy
agitation or slowing of movements
poor concentration or indecisiveness
feelings of worthlessness or excessive or inappropriate guilt
suicidal thoughts or acts

260
Q

Bipolar subtypes…

A

BP1: Classic mania depression. Depression and mania and high mood and psychotic symptoms.
BP2: Depressive episodes and hypomania. Mania not as pronounced.
Cyclothymia: Mild depression and hypomania.

261
Q

Manic episode characteristics…

A 
Severely elevated mood
Racing thoughts
Hyperactivity
Psychotic symptoms
-delusions (grandeur, persecution)
-hallucinations
Impulsiveness
Risk taking
-Hypersexuality, gambling, excessive spending
Lack of insight into illness
Highly debilitating
262
Q

Mania subtypes…

A

Mixed episode:
patient has elevated energy levels, psychosis etc but is simultaneously depressed
high risk of suicide
Hypomania:
mildly elevated mood and energy level
often seen as a “personality trait”
individuals can be highly productive whilst hypomanic

263
Q

Heritability of depression…

A

Twin studies: MDD about 50% heritability
First degree relative: 3-4 x risk
BD also highly heritable (40-70%)
Many genes involved (no “depression gene” or “bipolar gene”)
-serotonergic transmission
-BDNF (brain derived neurotrophic factor)
Genes involved in BD increase risk of MDD but not vice versa

264
Q

Dysfunction of PFC and Hc (HPA axis) in depression…

A

Hypothalamus secretes CRF > Pituatory gland (anterior) secretes ACTH > Adrenal cortex produces cortisol which then results in negative feedback to hypoT and pituatory gland (by glutocorticoid Rs).
50% of depressed patients have hyperactivity of HPA
80% of severely depressed patients have HPA hyperactivity
Reflected in increased cortisol levels
Dexamethasone (synthetic glutacorticoid) reduces cortisol less in depressed patients than controls showing that their negative feedback is reduced. (PFC exerts inhibitory control on hypothalamus. If activity of PFC goes down, that of hypothalamus increases and cortisol increases. Hc also modultes hypoT)

265
Q

Dexamethasone

A

Synthetic glutacorticoid used to suppress cortisol levels but has reduced effects in depressed individuals

266
Q

Parts of the brain affected in depression…

A

Show atrophy. PFC, Hc, Amygdala, Anterior cingulate cortex.
Activity is decreased in PFC during depressive phase and increased during manic episodes.
Activity of hypothalamus is increased in many depressives. (PFC exerts inhibitory control on hypothalamus. If activity of PFC goes down, that of hypothalamus increases and cortisol increases. Hc also modultes hypoT)
Apoptosis in PFC and Hc lead to depression, also seen increased depression with Cushings syndrome (inc cortisol levels/long term treatment with GC).

267
Q

Monamine hypothesis in depression…

A

Iproniazid (1952) developed to treat tuberculosis
Patients seemed “inappropriately happy”
Approved as AD in 1958
Irreversible MAO inhibitor

Reserpine (early antihypertensive, antipsychotic)
Blocks VMAT, depletes MA
Suggested to cause depression

Serotonin levels lowered in depressed patients

Tryptophan (5HT precursor) depletion lowers mood, induces relapse

Almost all AD drugs act by altering serotonin or NA transmission. Effects on transmission are very quick but AD effects delayed by 2-4 weeks
MA hypothesis explains this by changes in receptor expression

268
Q

5HT receptor intracellular signalling…

A 
Decrease cAMP (Gi)
5-HT1A	
5-HT1B
5-HT1D
5-HT1E
5-HT1F
5-HT5A
5-HT5B (??)

Increase cAMP (Gs)
5-HT4
5-HT6
5-HT7

Increase inositol phosphates and Ca (Gq)
5-HT2A
5-HT2B
5-HT2C

Ligand gated cation channel
5-HT3

269
Q

MA hypothesis and HPA axis combined roles in depression…

A

Delay in effect of the antidepressant drugs is caused by the time taken for neurogenesis and for restoration of the HPA axis control.
Drugs act on MA sites but this influences HPA axis to regenerate depleted brain regions and restore HPA axis control (and GCR changes)

270
Q

Types of MAO inhibitors…

A

Two types: A and B
A: 5HT, NA, dopamine. Also dietary monoamines
B: primarily dopamine (used in PD)
Located on outer mitochondrial membrane
Inhibiting MAO (by MAOI) increases presynaptic MA
Effect on MA immediate, but two weeks+ to clinical AD effect
Non selective (A vs B) irreversible inhibitors
Examples: phenelzine, tranylcypromine, isocarboxazid
Very effective in MDD, bipolar (+ mood stabilizer), anxiety disorders
Doctors very reluctant to prescribe due to large number of interactions, esp. dietary: Tyramine (related to Tyrosine - DA precursor) normally broken down in liver by MAO
When MAO-A inhibited, tyramine from diet can cause big problems! Tyramine is recognised by the vesicular transporter and displaces NorAdr which is then released non-vesicularly and has effects on SNS.

271
Q

Moclobemide

A 
Selective for MAO-A
Reversible inhibitor
Very fewer adverse effects
Relatively fast onset
Useful in MDD, bipolar (plus mood stabilizer), anxiety disorder
272
Q

Warrior Gene

A

30 base repeated sequence in promoter
2R, 3R, 3.5R, 4R, 5R
Some give higher MAO-A activity than others
2R -> low expression, associated with violence
- lots of controversy due to racial distribution of allele
Tg8 – transgenic mice lacking MAO-A
more aggressive to intruder mice

273
Q

Tricyclic antidepressants

A

Developed in 1950s, first line treatments for MDD
Very “dirty drugs”
Pronounced effects at mAChR, H receptors, 5HT receptors, a1 adrenergic
Many side effects plus high suicide morbidity in overdose
Now largely replaced by SSRIs and SNRIs
Sometimes used in treatment resistant MDD
Pain, migraine
Examples: Amitriptyline, nortriptyline, imipramine.
Block reuptake mechanisms (by transporters) to increase MA NT levels at synapse - delay before clinical effects

274
Q

SSRIs/SNRIs

A

Selective serotonin (/noradrenaline) reuptake inhibitors
Now the most widely used AD drugs
“2nd Generation AD drugs”
Example SSRIs: citalopram, paroxetine, sertraline, fluoxetine (Prozac)
Example SNRI: venlafaxine, duloxetine
Useful in MDD, anxiety disorders, premature ejaculation
Much lower overdose suicide risk than TCA, older MAOI
Unwanted effects:
Nausea, anorexia
Insomnia
Sexual side effects (anorgasmia)
Increased aggression, suicide ideation, self-harm possible in early stages of treatment
- FDA suggests that this may particularly be a problem with young people

275
Q

Mirtazapine

A

Noradrenaline specific serotonin antidepressant (NaSSA)
Antagonist of 𝛂2 adrenoceptors and 5HT2C receptors
Highly sedating (H1 antagonist)
Generally very effective and well tolerated
Faster onset of action than other AD drugs
Antagonist of 5HT/NorAdr auto/heteroreceptors that usually inhibit release of NTs

276
Q

Other drugs and treatments for depression…

A

NRIs (Noradrenaline reuptake inhibitors) e.g. bupropion, reboxetine)
Ketamine
Opioids
Drugs acting via GC mechanisms (stimulate neurogenesis?)
Non drug therapies:
30-40% of patients don’t benefit from drugs(? genetic factors)
Cognitive behavioral therapy (CBT) can be effective (can be combined with drugs)
Electroconvulsive therapy (ECT)
Indications for ECT:
May be suicidal
Failed to respond to drugs
In a debilitating stupor
Suffer other pyschotic illness (chance
of adverse drug actions)

277
Q

Antidepressant Discontinuation Syndrome

A

‘Flu-like symptoms, motor and cognitive disturbances when drug is stopped
Usually lasts 1-4 weeks
Particular problem with paroxetine and venlafaxine
Need to taper dose gradually
“Oppositional tolerance model” -CNS compensates by altered receptor expression etc

278
Q

Treatment of bipolar disorder…

A

“Mood stabilizing” drugs
Lithium (acts by: inhibition of IP3 pathway? Modulation of cAMP signalling? Inhibition of glycogen synthase kinase-3? neurotrophic factors?) - narrow therapeutic window and many adverse effects
Anticonvulsants: e.g. lamotrigine, valproate, carbamazepine
Sometimes give antipsychotics as adjuvant medication e.g. risperidone
Occasionally give AD drugs alongside mood stabilizers (may precipitate mania- as mood is increased)

279
Q

Animal models of depression

A 
Chronic stress (pain) -> learned helplessness (due to inc cortisol)
animal does not try to escape from pain
eg forced swim test or suspend from tail - if gives up trying early then drug is ineffective

Drugs and the Brain (1 decks)

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