(10-13)CNS Pharmacology

What is anxiety?

Anticipatory fear response, which is often independant of external events

What are symtoms of the fear response(Anxiety)?

• Defensive behaviours

• Autonomic reflexes

• Alertness

• Corticosteroid secretion

• Negative emotions

What are the different forms of Anxiety?

• Panic disorder, Overwhelming fear with marked somatic symptoms

• Autonomic reflexes

• Alertness

• Corticosteroid Secretion

• Negative Emotions

What are the Animal models used to study ‘fear’ for Anxiety?

• Light/Dark box

• Elevated Cross test

What is measured in Animal Anxiety model tests?

• Time spent in different environments

• More time spent in ‘safe’ environment (e.g. Dark box), more anxious/ more fear

• Anxiolytic drugs increase time spent in more exposed environment

What is the target of Anxiolytics and Hypnotic drugs?

GABA A Receptor

What is the structure of GABA A receptors, how does GABA bind?

• 5 subunits

  • wide variety of subunit compositions

• GABA binds to the orthosteric site

What are the two types of binding on GABA A receptors?

• Orthosteric - Primmary binding site

• Allosteric - Seccondary binding site (influence binding of orthosteric ligands)

How do Benzodiazepines interact with GABA A receptors and GABA?

• Benzo’s bind to allosteric site

  • On their own do nothing

• Positive allosteric regulator

  • Increase the signalling of the receptor

  • Cause GABA to bind more easily / increase affnity

What did studies in Transgenic Mice reveal about GABA A receptors in Anxiety?

The importance of the alpha2 subunit,

• In alpha2 (H101R), anxiolytic efects of diazemap are largely reduced

What are the physiological effects of Benzodiazepines?

Sedation/Anxiolytic

• Decreased responsivenes to constant level of stimulation

Hypnosis

• Latency of sleep onset is decreased, Rem sleep decreased

Anteriograde Amnesion

• Prevents memory of expirienses while under their influence

Anti-convulsant

• Inhibit development and spread of epileptiform activity

What is the difference between Benzodiazepines anf Barbituates on GABA A receptors?

• Benzo’s increase probability of opening - increasing GABA affinity

• Barbituates increase duration of opening - changes in gating behavours

What is PAM and NAM?

Positive Allosteric Modulation - Stabilises receptor with increased affinity

Negative Allosteric Modualtion - Stabilises the receptor in way with reduced affinity

What are the adverse effects of Benzodiazepines?

• Tollerance

  • May be overcome by increasing does

  • Metabolic tolerance common with missuse

• Missuse

• Physical dependance (Characterized by withdrawal)

  • Increase anxiety, insomnia, CNS exitability, convinsions

  • More problematic with drugs with short halflives

  • Withdrawal may be aliviated by using slower acting drug

What are the effects of increasing concentrations of Benzodiazepines vs Barbituates?

• Increasing Barbituates becomes fatal, (sedation → hypnosis → aneshesia → coma → death)

• Increasing Benzodiazepines on own = fine (Sedation → hypnosis)

  • With other CNS depesant (e.g. alchohol) however becomes fatal

What drugs are used to treat Anxiety?

• Benzodiazepines - use is now limited

  • Acute Anxiety

  • Co-adminitered with anti-depressantsduring stabilisation period)

• Propranol (betablockers)

• Anti-depressants - SSRIs, used for phobias, generalised anxiety, ptsd, ocd

• Atypical antiphycotics (generalised anxiety, ptsd)

• Antiepileptic drugs (generalised anxiety)

What drugs are used to treat Insomnia?

• Depends on underlying cause and wether short term or chronic

• Melatonin receptor agonists

• Oexin receptro antagonsists

• Over the counter sleep aids: H1 receptor antagonists i.e. Anti-histamines (Promethazie)

What are the symptoms of epilepsy?

• Unprovoked seziures

• High frequency discharge by a group of neurones

• Can be partial or genralized

• Diagnosed with EEG

• Symptoms depend on area of brain effected

What happens in a Partial Seziure?

• Dischage begins localy and often remains localy

• Symptoms include: Involatary muscle contractions, abnormal sensory expirience,autonomic dischage, effects on mood/behaviour (phycomotor epilepsy)

• Usually confined to one hemisphere

What happens in a generalized seziure?

• Whole brain involved

• Immideate loss of consciosnes common

• Calcium channels appear to be involved

• Can be simple (Conscoisness not lost) or complex (Conscousnes is lost)

What is Status Epilipticus?

When a seziure does not stop, medical emergency

What is the cause of Epilepsy and the aim of drugs treating it?

• Caused by an imbalance of exitatory and inhibitory neurotransmission

• Strategy is to either decrease exitatory neurotransmission, or increase inhibitory neurotransmission

• Inhibit abnormal neuronal discharge

What are Chemical Animal Models of Epilepsy?

Mammals or Zebrafish

• Penecillin (inhibits GABA A receptor)

• Pentylene-Tetrazol (PtZ)

• Used to trigger accute seziures

What is the Kindling Model?

An Animal Model for Epilepsy, involves:

• Repeated low level electrical stimulationof brain regions

• Causes localised hyper sensitivity and adaptive changes in networks

• Leads to an Animal that shows spontaneous seziures

Why is GABA mediated transmission a target of Anti-Epileptic drugs?

Aims to counterballance hyper exitatability of the CNS, done by increasing inhibitory Neurotranmission, e.g. GABA

What are the different ways GABA neurotrasmission can be increased?

• GABA A receptor iteslf, increasing its activity

• GABA Untake inhibitors

• Inhibitors of GABA Metabolism

The last 2 affect all GABA transmission rather than specific GABA receptors, Less selective

What are some Anti-Eplieptic drugs than increase GABA receptor activity and their usage and problems?

• Benzodiazepines e.g. Clonazepam, Clobazam, Dazepam

  • Used for I/V status epilepticus

  • Problems: sedation, tolerance, withdrawal

• Barbituates e.g. Phenobarbitone, primidone

  • Problems: low therapeutic index, sedation,complex pharmacokinetics

What is tiagabine?

A GABA uptake inhibitor, Anti-epileptic

What are some Metabolic Inhibitors of GABA and what are their problems?

• Vigabatrin, problems: depression

• Valproate, problems: high protein binding, rarely hepatotoxic, tetraogenic

What is Sodium-Valproate used for?

• Antiepileptic

  • Broad spectrum, generalised and partial seziures

• Acts as a mood stabiliser in bi-polar disorder

• Migrane treatment

What is the mechanism of action of Sodium-Valproate, why is it controversial?

Loads of mechanism of action, idk which one

• Was though to prevent GABA metabolism by increased expression of glutamate decarboxylase

• Similar in structure so might act as competitive inhibitor the GABAlysis enzymes (whatever theyre called)

• May act else where, sodium channels, NMDA receptors? idk

Why are voltage gated Na channels targets for Antiepileptic dugs?

• Aim is to stop high frequency discharge from occuring in the first place by limiitng the action potential propogation in neurons firing abnormally

• Imprtant that only neurons behaving abnormally are acted on

How do Use-dependant Sodium channels work as Antiepileptics?

• Prolongs the refactory period by stabiliszing the inactive state

• Reduces the maximum frequencyh that action potentials can be generated

• Use-dependant, only affects the neurones firing abnormally

What are some Na+ channel inhibitors used in the treatment of epilepsy and what are their problems?

• Phenytoin, problems: complex phamracokinetics, vertigo, ataxia, headaches, rashes

• Carbamazepine, most widely used antiepileptic, Problems: microsomal enzyme induction, shoulnt be combined with other drugs

• Lamotisirie, problems: nausea diziness, ataxia, rashes

What is a Antiepileptic drug that works on Ca2+ channels?

Ethosuximide

• T-type Ca channel inhibitor, used for absense seziures

What are the Amine Transmitters in the CNS, what are they associated with?

• Noradrenaline

• Dopamine

• 5-Hydroxytryptamine

• Acetly Choline

Associated with high level brain behavours, e.g. emotion, cognition and awareness

What are the Noradrenaline receptors and pathways in the CNS?

• Alpah1 receptors - widely distributed, involved in motor control, cognition, fear

• Alpha2 receptors - involved in regulation of blood pressure, sedation and analgesion

• Beta1 in cortex, stiatum and hippocampus, contribute to long term effects of antidepressants

• LC neuronal activity is increased with behavoural arousal, controls wakefulness and alertness, control of mood (defficientcy linked to depression)

What are the Dopamine pathways in the CNS?

• Nogrostriatal - Fine motor control

• Mesocortical and Mesolimbic - Behavioural effects, perserveranse, pleasure-euphoria-reward (motivatio), compulsion

• Tuberhypoayseal pathway; pituitary hormaone secretion e.g. prolactin

Involved in many dissorders, Parkinsons, ADD, Schizophrenia, Depression

What enzymes are responsible for termianting DA, why are they usefull?

• COMT & MAO

• Found extracellularly and intracellulaly

• Measurement of DA metabolic products can be used to monitor DA release in patients and Animals

What are the two fammilies of Dopamine receptors?

• D1 like - D1,D5, stimulate adenly cyclase

• D2 like - D2,D3,D4, inhibit adelnly cyclase

What is the difference between D1 like and D2 like DA receptors?

• D1 like are Gs coupled receptos, stumulates adenyl cyclase

  • Increase cAMP, PKA and protein phosphorlyation

• D2 like are Gi coupled receptors, inhibits adenyl cyclase

  • Activate potasium channels, inhibit VGCC,

• D2 oppose the effects of D1

What do Amphetamines and Cocaine do to DA and NA Transmission?

Increase them

• Stimulate secretion, displacing DA and NA vesicles

• Cause re-uptake transporters to work in reverse

• Cocain inhibits DA transporters

• Feelings of euphoria

What are the positive symptoms of schizophrenia?

• Hallucinations (voices)

• Delusions (paranoid)

• Thought dissorders (Irrational/wild, delusions of grandeur, garbeled scentences)

• defects in attention

• Bizare behaviour

• Aggresion

What are the Negative symptoms of Schizophrenia?

• Blunting of emotions

• Withdrawal from social contacts

• Flatening of emotional response, anhedonia, reluctance to preform everyday tasks

What are the Environamental and Genetic causes of Schizophrenia?

• Strong hereditary element

• Result of abnormalities which arise early in life and disrupt to the normal development of the brain

• No single responsible gene resonsible

• Bunning loud in adolecense is an environmental factor

What is the Neuroanatoical and neurochemical basis of Schiozophrenia?

• Overactivity of the mesolimbic pathway associated with positive symptoms, increased D2 activity

• Decreased activity in mesocortical pathway associated with -ve symptoms, D1 receptors implicated

What pathway and receptors are implicated with positive symptoms of Shizophrenia?

• Mesolimbic

• Increased D2 activity (inhibitory DA receptors)

What pathway and receptors are implicated with negative symptoms of Shizophrenia?

• Decreased activity in the mesocortical pathway

• D1 receptors (stimulating)

What is Reserpine?

• DA antagonist, blocks DA storage

• Controls the positive symptoms of schizophrenia

What type of drugs are used against Schizophrenia?

• DA D2 antagonists

• ~80% occupancy needed to decrease positive symptoms

What are some examples of 1st generation Anti-phycotics and their side effects?

Typical/clasical/conventional

• Chlorpromazine, Haloperidol

• Side effects - Motor disturbances (extraprymidal effects) anf prolactin secretion

What are some examples of 2nd generation Anti-phycotics and their side effects?

Atypical

• Clozapine, risperidone

• Side effects - Extraprymidal, less than 1st generation

What are some unwanted Side Effects of Anti-phycotic drugs?

• Parkinsons like symptoms

• Acute reverisble dystonias (Spasms)

• Slowly developing irreversible tardine dyskenisia (invuluntary movements)

• Increased prolactin

• Sedation

• Hypotension

• Weigh gain

• Dry mouth

• Blurred vision