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Neuropharmacology

From Mediwikis
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Hypnotics, Sedatives, Anxiolytics and Opioids

Definitions

  • Anxiolytics- allay anxiety (n.b. NOT used clinically for treating anxiety disorders! acute only)
  • Sedatives- promote drowsiness
  • Hypnotics- promote sleep
  • Tranquilizers- hypnotics, sedatives, anxiolytics
  • Allosteric modulator- enhances effect of agonist by binding to receptor and enhancing neurotransmitter, no direct effect

Barbituates

  • Narrow Therapeutic Index
  • Greater effects at lower doses
  • Pentobarbital, sodium thiopental (lethal)

Benzodiazepine

  • Safer in overdose
  • Using in acute situations
  • Tolerance and withdrawal so not for chronic conditions, increases GABA binding affinity- can lead to rebound convulsions if they are stopped rapidly
  • ɣ2- selective- most GABA A
  • long acting – chlordiazepoxide, Diazepam

Hypnotics

  • Increase GABA, melatonin
  • Decrease histamine, noradrenaline and 5HT
  • Z hypnotics GABAa positive allosteric, selective for α1, fast onset, short duration
  • Antihistamines- antagonists of H1, promethazine
  • Melatonin agonists- MT1 and MT2, circadian

Opioids

When opioid receptors are activated they:

  • Inhibit neuronal firing increasing K+ conductance
  • Inhibit transmitter release lowering calcium entry
  • Disinhibition of VTA increasing dopamine release from nucleus acumens

Drugs

Morphine

  • Mu and delta receptor agonist
  • Causes analgesia, euphoria, respiratory depression, antitussive, decrease in GI motility
  • Completely absorbed through GI
  • T1/2 3 hours
  • At risk involve those with impaired metabolism, (young/old, kidney or renal failure) and those with chronic *lung disease due to the respiratory suppression side effects

Diamorphine

  • Heroin
  • Half Life longer than morphine
  • Parenteral administration

Methadone:

  • Half Life 24 hours
  • Oral
  • First line treatment for addicts

Pethidine:

  • Less potent and less euphoric
  • Orally absorbed
  • Half Life 6-8 hours
  • Extensive metabolism
  • Used in child birth

Codeine:

  • Weak opioid
  • Half Life 2-4 hours
  • Extensively metabolised
  • Mild pain, diarrhoea and anti-tussive treatment

Naloxone:

  • Non-selective opioid antagonist
  • Half Life 20-30 mins
  • Used in an opioid overdose
  • Unpleasant for addicts, like going cold turkey
  • In high doses heroine is no longer rewarding

Mechanism of drug action:

  • Mu inhibits GABA release
  • Enhanced VTA neurone activity
  • Enhanced dopamine release in nucleus acumens

Treatment for dependence:

  • Methadone – 24 hours
  • Buprenorphine- reduces cravings/ no high
  • LAAM- longer acting the methadone
  • Lofexidine alpha 2 agonist
  • Naltrexone- post withdrawal decreases cravings and if relapse no high (also treats alcohol)

Anaesthesia

Local

Bind to voltage dependent Na+ channels on neurones at an intracellular site after diffusing across the cell membrane.

Chemical Structures

Aromatic ring:

  • Need a moderately hydrophobic molecule to diffuse through lipid bilayer
  • More hydrophobic drugs are generally more potent, but can’t be too hydrophobic as they will become trapped in the lipid bilayer

Amine group:

  • Weak bases can be ionised (protonated) or unionised
  • PKA is the pH when 50% is ionised and 50% isn’t. Physiological pH is around 7.4 and most LAs have pKa around 8-9. Hence, at physiological pH most LA molecules are going to be ionised
  • Only the unionised form can cross the bilayer, but once it crosses the base is re-ionized before binding to the target

Ester group:

  • Procaine
  • Rapidly metabolised by tissues and plasma cholinesterase
  • Half Life less than 3 minutes
  • Not that stable so used less

Amide group:

  • Lidocaine
  • Metabolised slowly in liver by cytochrome p450
  • Half Life - 1-3 hours
  • More common

Adrenaline can localize and extend duration of a local anaesthetic, it decreases absorption into systemic circulation meaning less toxicity. Inflammation stops local anaesthetics working as a low pH increases the ionised proportion and therefore decreases the portion which can cross the membrane. Low pH decreases efficacy. Myelinated nerves are not blocked as readily, the nerves with small diameter with no myelination are most readily blocked.

Administration

Topical

  • High conc in oil
  • Short term- lidocaine

Infiltration

  • Intradermal/subcutaneous
  • Fast- dentists- lidocaine

Peripheral Block

  • Injection around nerve trunk
  • Eg. Brachial plexus

Central Block

  • Injection near spine
  • Above and below numbness- eg: epidural

Regional IV

  • Limb after tourniquet put on
  • Manipulate fractures

General Anaesthetics

Adjunct Medicines

  • Benzodiazapines: Anxiolysis and amnesia given 15-60 minutes before surgery
  • H2 blockers: Prevent gastric acid secretion which may cause lung inflammation- Ranitadine
  • Antimuscarinic: Prevents bradycardis and secretion of fluid into respiratory tracts- Atropine
  • Nmj blockers: Facilitates incubation and suppresses tone- Succinylcholine
  • Analgestic: Relieve pain- Fentanyl
  • Antimetic: Prevents post operation nausea and vomiting

Inhalation

Partition co-efficient = Anaesthetic dissolved in blood: same volume in contact with blood High Solubility in blood

  • Slow induction and recovery
  • Slow adjustment
  • Doesn’t leave or enter brain until the blood reservoir is filled

Low Solubility in blood

  • Fast induction and recovery

Lipid Solubility

  • More potent in high oil/gas partition
  • Lower potency in low oil/gas partition

Drugs

  • Nitrous oxide: good anaesthetic with low potency but must be used in conjunction with other drugs
  • Sevoflurane: used in day cases and children due to fast onset/recovery
  • Isoflurane: pungent odour, not used for induction
  • Halothane: not used now due to potential toxic accumulation

IV

  • Non-volatile IV cannot be removed by ventilation
  • Recovery is rapid as drug is redistributed throughout the body

Drugs:

Thiopentone:

  • High lipid solubility so rapid transfer across BBB
  • Accumulates in body hangover
  • Short duration due to redistribution

Propofol:

  • Rapid metabolism and recovery, no hangover
  • Alone for induction and maintenance

Ketamine:

  • Dissociative anaesthesia so may appear awake
  • Slower onset
  • Longer duration

Anticonvulsants

Definitions

  • Seizure: synchronous discharge of neurones
  • Convulsion: muscular contractions
  • Epilepsy: disorder of repeated seizure
  • Anticonvulsant- drug against epilepsy/seizure of other origins
  • GABA- inhibitiory
  • GLUTAMATE- excitory
  • Na+, Ca2+ voltage gated channels- excitability
  • Therefore anticonvulsants ain to increase GABA and stop voltage gated channels

GABA

  • Newer anticonvulsants target GABAergic transmission – vigabatrin and tigabide
  • GABAa- ligand gated Cl- channel with complex modulation
  • GABAb- G protein linked

Barbiturates and benzodiazepines:

  • Modulate GABAa
  • Enhance GABAergic transmission
  • Act on  part of complex to increase chlorine entry
  • Barbituates need a higher conc to activate channel

Tiagabine:

  • Blocks GABA re-uptake
  • Succinic seialdehyde on presynaptic membrane

Vigabatrin

  • Blocks GABA metabolism
  • GABA transaminase

Valproate

  • Increase synthesis
  • Decrease metabolism

Sodium Channels

  • Open at -55mV
  • Depolarisation increases intracellular potential
  • Paroxysmal depolarising shift- rapid depolarisation of membrane, electrical phenomena in epileptic focus
  • Provokes repetitive firing
  • Use and voltage dependent

Carbamzepine

  • Complex partial, general seizures and trigeminal neuralgia
  • Narrow TI
  • Short half life
  • Phenytoin and valproate
  • Block voltage gated Na+ channels
  • Block repetitive firing

Calcium Channels

  • T type involved in 3Hz activity in thalamus

Ethosuximide

  • Against petit mal/absence
  • Ineffective against tonic/clonic as no increase in GABA or repetitive firing block

Antidepressants

Monoamine (5HT, NA) dysfunction is thought to contribute towards depression. Avoid simplistic models like "low 5HT causes depression" since, as with most areas in medicine, the truth is more complicated!

Tricyclic Antidepressants

  • Amitriptyline, Imipramine, Lofepramine
  • Block re-uptake of Serotonin & Noradrenaline via SERT & NET transporters
  • Also act as Sodium & Calcium channel blockers
  • Delayed onset of 2-3 weeks before action
  • Side effects are caused by affinity for the post synaptic membrane- M1, H1 alpha 1
    • Arrythmias/ Heart block (especially amitriptyline)
    • CNS- Anxiety, dizziness, confusion, sleep disturbance
    • Antimuscarinic- dry mouth, blurred vision, constipation
    • Tolerance to side effects develops in time

Selective Serotonin Reuptake Inhibitors

  • Fluoxetine, Sertraline, Citalopram
  • Inhibit reuptake of serotonin by post-synaptic nerve cells
  • Autoreceptors detect increase in serotonin and therefore reduce serotonin secretion

Side effects:

  • GI- Nausea & Vomiting, dyspepsia, abdo pain, constipation
    • Often temporary for first 4 weeks
  • Sexual Dysfunction
  • Withdrawal syndrome- similar to recurrence of original illness
  • Suicide risk in children and young adults

Serotonin/ noradrenaline reuptake inhibitor

  • Venlafaxine


Noradrenaline Reuptake Inhibitor

  • Reboxetine

Monoamine Oxidase Inhibitors

  • Metabolise transmitter outside of VMAT2 vesicle
  • Decreases intraneuronal breakdown
    • MAOa- breaks down 5HT/NA
    • MAOb- breaks down DA
  • Selective for MAOa; less of a stimulant
  • Tyramine rich diet (Wine, cheese) can lead to hypertensive crisis
  • SSRI interaction- 2 week gap ebtween taking MAOIs and SSRIs

Mirtazepine

  • Noradrenergic, specific serotinergic
  • Tetracyclic
  • Used in major depressive disorder

Side effects (due to muscarinic effects)

  • Appetite, weight gain, dry mouth, constipation
  • Postural hypotension