Week 1 - Understanding drug action in the CNS Flashcards
Drugs affecting neurotransmission (CNS Disorders)
How are neurotransmitters released
- Influx of Na+ ions into pre-synaptic neurone trigger depolarisation = action potential (AP) fired
- AP travels along cell body / neourne reaching pre-synaptic terminal
- Arrival of AP at terminal causes voltage gated Ca2+ channels to open
- Influx of Ca2+ ions at terminal causes vesicles to fuse with pre-synaptic membrane (exocytosis)
- N.transmitter is released from vesicles into synapse / synaptic cleft
- N.transmitters bind to receptors on post-synaptic membrane
- causing excitatory or inhibitory signal
NOTE: influx of Cl- prevents depolarisation = no AP fired
How is CNS diseases diagnosed, treated, risk factors and symptoms
Diagnosis: with a DSM-5
Treatment: pharmacological (mainly used) and/or non-pharmacological interventions
Risk factors: genetic (suceptibility genes), environmental, threshold
Symptoms: positive, negative and cognitive (may affect QoL)
What CAUSES schizophrenia and what drugs affect schizophrenia
Antipsychotics - D2 antagonists
CAUSED BY:
- ↑ dopamine at associative striatum (brain)
- ↑ causes psychotic symptoms
- more dopamine at synapses = over-activation of D2 receptors
How does antipsychotics work
Schizophrenia treatment
They are D2 antagonists (at dopamine receptor)
- Bind to D2 receptor, blocking it + prevent dopamine from binding
- Antipsychotics get into brain + compete with dopamine for D2 receptor
NOTE:
- ↑ levels of dopamie are still in brain BUT are blocked from binding preventing over-actiavtion of receptor
- stop taking antipshcyotics dopamine continues binding = over-activation = relapse = psychotic symptoms
- need to take ANTI-PSYCHOTICS for LIFE as it doesnt treat ↑ levels of doapmine just prevents bindining
Whats the difference between oral Rispeidone and Risperidone ISM
EBL QUESTION
Oral Risperidone:
- 1st pass metabolism (extensive hepatic metabolism via CYP2D6)
- eliminated via renal excretion
Risperidone ISM:
(a montly IM injection)
- Is a microparticle = has higher surface area to volume ratio
= ↑ dissolution + solubility, stable bioavailability
- Microparticle is activated upon adminstration or when in contact with physiological fluid
- After single adinstration reach therapeutic levels within 2hr without loading dose or oral additions
- Controlled release of drug over extended period of time = maintains therapeutic level = improved efficacy
- ↓ dosing frequency
- ↓ drug level variability
- steady state conc. NO peaks or troughs
- Has high specificity to brain targets = ↓ SE / ADRs
- prevents fluctuations and blockage going above required amount (need 60% BUT above 70% = SE)
- Improved BBB pentration
- Improved patient adhernace
- Bypass 1st pass metabolism + avoids renal clearance
What are the side effects of antipsychotics
Schizophrenia treatment
Motor symptoms
- Antipsychotics can block D2 receptors in other places inhibiting normal dopamine transmission
- e.g. induce parkinson’s disease if D2 receptors in motor system are blocked
What CAUSES parkinson’s disease and what drugs affect it
Dopaminergic drugs
CAUSED BY:
- loss of dopamine neurones in nigrostriatal pathway
- i.e. motor pathway
- loss of neurone = ↓ dopamine released
What treatment is used for parkinson’s disease
Dopaminergic drugs
- Dopamine agonist
- acts on post-synaptic membrane
- stimulates dopamine receptor in motor pathway PLUS other D2 receptors = psychosis side effect
- L-dopa
- pre-cursor of doapmine = ↑ dopamine synthesis
What CAUSES epilepsy (seizures) and what drugs affect it
Anticonvulsants
Seizures CAUSED BY:
- loss of balance between excitation (glutamate) and inhibition (GABA or Na+ channel inactivation)
- glutamate + GABA are major n.transmitters in CNS
What are the 4 categories of anticonvulsants drug mechanism
Epilepsy treatment
- Drug that inhibits Na+ channels
- ↓ influx of Na+ = ↓ depolrisation = ↓ AP firing
- ↓ excitatory tone - Drugs that inhibit Ca2+ channels
- ↓ influx of Ca2+ at pre-synaptice terminal = ↓ release of n.transmitter
- ↓ excocytosis - Drugs that enhance GABA-mediated inhibition
- ↑ GABA synthesis = ↑ inhibition
- GABA is synthesised by enzyme GAD
- GABA is released from vesicles in presynpatic neurone
- use of GABA agonist = ↑ inhibition
- prevnting re-uptake of GABA = ↑ inhibiton
- inihibit GATs (GABA transporter ~ GAT-1 to GAT-4)
- inhibit GABA-T (enzyme that breaksdown GABA) - Drugs that inhibit glutamate receptors
- antagonist prevents glutamate from binding = ↓ over-excitation = ↓ seizures
- when glutamate binds to ionotropic AMPA receptor = opening = ↑ influx of Na+ and small Ca2+ = depolirasiation
- when ionotropic NMDA receptor opens = ↑ influx of Ca2+ and small Na+
- NOTE: difficult to block due to glutamate receptors being present all over body
Explain the balance in preventing seizures
Balance between excitatory postsynaptic potential (EPSP) and inhibitory postsynaptic potential (IPSP) manages epilepsy
- more towards EPSP = seizures
- more towards IPSP = control
What CAUSES Alzhemier’s disease and what drugs affect it
Cholinesterase inhibitors
- drug doesnt prevent disease from progressing
- it helps people function at a higher level than they would without the drug
- treatment becomes ineffective as more neurones die as AcH wont be released
CAUSED BY:
- amyloid beta (toxic species) isnt removed properly = clumps together forming oligmers
- these are toxic to brain tissue
- amlyoid becomes deposited in brain as plaques (diagnostic factor)
How is Cholinesterase inhibtiors used for Alzhemier’s disease
Inhibitors ↑ amount of acetylcholine (AcH) in body
- AcH helps messgaes travel around brain
- AcH is a n.transmitter
How it works
1. AcH is released from vesicles into synaptic cleft
2. AcH activates receptors on post-synaptic membrane
3. Cholinesterase Inhibitor inhibits enzyme = prevents the breakdown of AcH in synapse = ↑ levels of AcH remains present
- AcH usually broken down by enzyme into choline acetate which is removed via choline transporter
- inhibiting breakdown = NOT removed by transporter
What are the novel aproaches for Alzheimer’s disease
Novel treatment tries to treat disease / stop progression by preventing amlyoid plaque formation
DONE BY:
- ↓ amyloid production via modulators
- ↓ aggregation via anti-aggregants
- immunotherapy which clears out oligmers in brain
How do CNS stimulants affect the CNS
e.g. cocaine, amphetmine, nicotine
Change neurotransmission in the Mesolimbic pathway (a.k.a. reward pathway)
- becomes addictive if this pathway is affected
Cause user to get a high / euphoria (good feeling)
