Neuropharmacology (Conditions) Flashcards
What are the different types of strokes?
- Occlusion: Caused by blockage of cerebral vasculature due to embolus or atherosclerosis.
- Haemorrhage: Haemorrhaging of cerebral vessel increases local pressure, occluding vessels nearby.
What are transient ischaemic attacks (TIAs)?
Brief interruption to cerebral blood supply that resolves within 24 hours, followed by full recovery.
What is the anatomy of area of brain affected by stroke?
- Ischaemic core: Neurones immediately adjacent to occluded vessel die very quickly following occlusion and cannot be saved.
- Penumbra: Neurones in region further out from point of occlusion are compromised, but are able to recover after restoration of blood flow
How can strokes be treated?
- Clot-busting drugs
- Hypothermia
How can ischaemia cause raised [Ca2+]i?
Direct:
- Reduced ATP results in reduced activity of PMCA and SERCA.
- Reduced ATP results in reduced activity of Na+/K+-ATPase causing increased [Na+]i and reducing activity of NCX.
Indirect (excitotoxicity):
- Release of Glu from pre-synaptic cells causes opening of NMDA channels resulting in Ca2+ influx.
- mGluRs activate IP3 that cause release of intracellular Ca2+.
How can toxicity be caused by raised [Ca2+]i?
- Activation of intracellular enzymes that cause direct cell damage, including:
- Proteases: Cytoskeleton breakdown
- Lipases: PLA breaks down membrane phospholipids
- NOS - Activation of caspases that drive apoptosis
- Production of free radicals that cause protein/DNA damage that drive apoptosis/necrosis
Aside from Ca2+, what are the other mechanism that can cause damage during stroke?
- Zn2+ neurotoxicity: Zn2+ in NT vesicles is released during ischaemia and causes toxicity
- Inflammation
- Ischaemic reperfusion injury
What are the ways in which nerve death due to ischaemia can be reduced?
- NMDA receptor antagonists
- Glycine receptor antagonists
- Free radical scavengers
- Anti-inflammatory compounds
What are the types of anxiety disorders?
- Phobias
- Panic disorders
- Post traumatic stress disorders (PTSDs)
- General anxiety disorders
- Obsessive compulsive disorders
What are the risk factors for insomnia?
- Stress
- Ageing
- Shift work
- Drug/alcohol abuse
What is the likely cause of narcolepsy?
Destruction of hypothalamic neurones producing orexin, which promotes wakefulness.
What are the types of epileptic seizures?
- Generalised seizures: Involvement of both hemispheres. There are 2 variants:
- Non-convulsive
- Convulsive - Simple seizures: No effect on consciousness or memory
- Complex seizures: Loss of consciousness or memory
- Status epilepticus: Seizure lasting more than 5 minutes
What are the types of convulsive seizures?
- Tonic: Rigidity of extremities
- Clonic: Jerking of extremities
- Tonic-clonic (grand mal): Tonic followed by clonic
- Myoclonic: Bilateral jerking of specific muscle group bilaterally
What are the types of non-convulsive seizures?
Absence seizure (petite mal)
What is the pathophysiology of absence seizures?
- Activation of T-type Cavs in thalamocortical neurones causes activation of neurones.
- Thalamocortical neurones stimulate cortex and reticular thalamic nucleus.
- After period of time, T-type Cavs in thalamocortial neurones inactivate.
- GABA neurones from reticular thalamic nucleus inhibit thalamocortical neurones and causes re-activation of Cavs.
- Cycle continues
What are the negative effects of taking anti-epileptics in women specifically?
- Some anti-epileptics induce Cyp3A4 and so enhance metabolism of oral contraceptives
- Some anti-epileptics are teratogenic
- Some anti-epileptics may cause vitamin K deficiency in newborn
Why should MAOIs and SSRIs not be used in combination?
Causes dangerous rise in levels of 5-HT to cause:
- Confusion
- Dizziness
- Hyperthermia
What evidence is there to support involvement of dopamine in Schizophrenia?
- There is strong correlation between affinity of antipsychotic drugs for D2 receptor and effective dose
- D2 antagonists relieve positive symptoms
- Increased levels of dopamine by amphetamines/L-DOPA causes Schizophrenia-like symptoms
What evidence is there against involvement of dopamine in Schizophrenia?
- D2 antagonism by antipsychotics is fast but their effects are slow to manifest
- D2 antagonists are less effective against negative symptoms
- Antipsychotic drugs don’t work on all schizophrenics
What evidence is there to support involvement of Glu in Schizophrenia?
- NMDA receptor antagonists produce psychosis.
- Patients with schizophrenia have lower levels of Glu receptors in brain
What evidence is there to support involvement of 5-HT in schizophrenia?
Agonists of 5-HT receptors cause psychosis (e.g. LSD is agonist for 5-HT2A)
What are examples of typical (1st generation) anti-psychotics?
- Chlorpromazine
- Haloperidol
What is the main side effect of typical anti-psychotics?
Extrapyramidal motor (Parkinson-like) side effects
What are examples of atypical (2nd generation) anti-psychotics?
- Clozapine
- Risperidone
- Olanzapine
What is the main side effect of atypical anti-psychotics?
Metabolic side effects (e.g. weight gain, type II diabetes)
What causes Alzheimer’ disease?
Formation of amyloid plaques extracellularly and neurofibrillary tangles (NFT) intracellularly disrupts function of neurones
How does plaque formation in Alzheimer’s disease occur?
- Amyloid precursor protein (APP) is cleaved by β-secretase (instead of usual α-secretase to give soluble APP)
- Intermediate then cleaved by γ-secretase to give β-amyloid 40/42 that aggregate to form plaques
What is the general strategy for treatment of Alzheimer’s?
Cholinergic neurones in the basal forebrain are vulnerable to degeneration in Alzheimer’s and mediate memory. Improving cholinergic transmission may improve symptoms of Alzheimer’s.
