PHARM; Lecture 25, 26, 27 - Anxiolytics, sedatives and hypnotics; Alzheimer's disease; Anti-Parkinsonian drugs and neuroleptics Flashcards
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How does GABA transmission work?
- Synthesised from glutamate; which is converted to GABA by GAD (!!).
- GABA taken up into vesicles waiting for action potential, which reaches terminal, depolarises and releases GABA.
- GABA travels across cleft, reaching the receptors which stimulates GABAa (ion channel = Cl- channel).
- Cl enters the postsynaptic cell, which causes hyperpolarisation; reducing firing of postsynaptic cells.
- GABA deactivated by reuptake in Glial cells and into presynaptic terminal (via GABA channel). GABA transaminase breaks down GABA into SSA, which then enters the TCA cycle.
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How is GABA metabolised?
GABA needs to be reuptaken first; 2 metabolising enzymes are mitochondrial enzymes, which if you block the metabolism, you can enhance GABA mediated transmission
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What is the GABAa receptor and how does it work?
- 4 proteins:
- GABAa receptor protein,
- barbiturate receptor protein,
- Benzodiazepine receptor protein,
- Chloride channel protein
- There is a peptide called GABA modulin that links together the GABA receptor protein and benzodiazepine receptor protein
- GABA receptor protein is the binding site for GABA
- Once GABA is bound to the GABA receptor protein, it allows GABA modulin to link together the GABA receptor protein and the benzodiazepine receptor protein
- Pathway 1 in the diagram shows the normal physiological action of GABA - those two protein link and results in opening of the chloride channel protein
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How does Bicuculline work on the GABAa receptor?
- Competitive antagonist for the GABA-A receptor
- Benzodiazepine binds to a site on the benzodiazepine receptor protein
- Benzodiazepines bind to that binding site and it has TWO main effects that facilitate GABA-mediated inhibition:
- Facilitate GABA-mediated opening of the chloride channel (number 2 in the diagram)
- Facilitate binding of GABA to its own binding site - they increase the affinity of binding of GABA to the GABA binding site (number 3)
- This effect is reciprocated - in the presence of GABA binding we get a facilitation of benzodiazepine binding
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How does Flumezanil work on the GABAa receptor?
- Competitive benzodiazepine antagonist
- Barbiturates binds to the barbiturate receptor protein and has three main effects on GABA neurotransmission:
- Facilitate GABA mediated opening of the Cl- channel (number 4)
- Facilitate GABA binding to its receptor (number 5) but this is NOT reciprocated
- At higher concentrations, barbiturates can have a direct action on the chloride channel
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What is the effect of barbiturates vs benzodiazepenes on the GABAa?
Both enhance Cl influx but in different ways -> Barb less as BDZ work by enhancing GABAa, but Barb also induce inhibitory action in brain and direct action on Cl channel.
That’s why we can induce surgical anaesthesia with barb but not BDZ
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What is the nigrostriatal pathway?
Cell bodies originate in the substantia nigra zona compacta and project to the striatum - Control of Movement.
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What is the mesolimbic pathway?
Cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule - Involved in emotion
Can affect the other pathways
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What is the tuberoinfundibular system pathway?
Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminence and pituitory gland - Regulate hormone secretion
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What are the 2 families of receptors?
x
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What is the epidemiology of Parkinson’s?
Parkinson’s is the least prevalent neurological disorder (parkinson’s, alzheimers, epilepsy, stroke)
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What are the cardinal signs of Parkinson’s disease?
x
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What are the presenting symptoms of Parkinson’s disease?
Symptoms appear on one side of the body first (unilateral onset).
Symptoms spread to both sides of the body.
Generally symptoms worsen with some patients becoming severely disabled.
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What are the non-motor symptoms of Parkinson’s?
x
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What is the neuropathology of Parkinson’s disease?
Main reason for motor deficit is due to the substantia nigra to putamen pathway being damaged, but it is quite an important pathway
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How do you stage Parkinson’s?
x
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What are the biochemical changes that can occur in the brain?
Marked reduction in caudate nucleus/putamen dopamine content Necessary to loose 80-85% of the dopaminergic neurons and deplete 70% of the striatal dopamine before symptoms appear! Compensatory mechanism prevent the appearance of clinical symptoms -> drugs can’t be used to prevent as it will already be too late when symptoms present
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How does Dopamine pass into the brain from the blood?
x
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How does L-DOPA form part of the DA replacement therapy?
DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme DOPA decarboxylase (DD). However, DD also present in peripheral tissues. If administered alone 95% of L-DOPA is metabolised to dopamine in the periphery - major side effects of nausea & vomiting. Drug: Peripheral DOPA decarboxylase inhibitor + L-DOPA. Preparations:- Sinamet (Carbidopa + L-DOPA) Madopar (Benserazide + L-DOPA)
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What does L-DOPA treat and how would you administer L-DOPA?
Hypokinesia, rigidity & tremor Still the Gold Standard drug in head-to-head trials vs dopamine agonists. Question the diagnosis of PD if the response to L-DOPA is poor! Start with low dose of the drug and increase dose until maximum benefit without side effects. Effectiveness of L-DOPA declines with time!
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What are the acute and chronic side effects of L-DOPA?
Off periods can be very troublesome
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What are DA agonists and what are their side effects?
x
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What are the 2 types of MAO inhibitors?
Useful but even better when given with L-DOPA
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What are the COMT inhibitors?
Could precipitate a heart attack in heart compromised patients
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What are the positive, negative symptoms and cognitive deficits associated with schizophrenia?
Hallucinations can change perceptions of normal life, may cause frightening and crazy images
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What is the genetic risk of schizophrenia?
x
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What are the 4 outcomes of schizophrenia diagnosis?
x
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What is the role of DA in schizophrenia?
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What is the glutamate theory in schizophrenia?
x
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What is the aetiology and pathogenesis of schizophrenia?
x
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What is the MoA of antipsychotics?
x
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What are the side effects of specific medications for schizophrenia?
x
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What causes the anti-emetic effect of neuroleptics?
x
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What causes the acute dystonia and tardive dyskinesia of antipsychotics?
x
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What are the endocrine effects and blockade of certain receptors of antipsychotics?
x
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What are the different clinical uses of BZD and BARBs?
Anaesthetics Barbiturates only: THIOPENTONE Anti-convulsants DIAZEPAM (BZD) CLONAZEPam (BZD) PHENOBARBITAL (BARB) Anti-spastics: DIAZEPAM - because it has an action in the spinal cord and reduces the propagation of action potentials in the alpha motor neurones Anxiolytics Sedative/hypnotic
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What are anxiolytics?
remove anxiety without impairing mental or physical activity (used to be referred to as minor tranquilisers)
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What are sedatives?
reduce mental and physical activity without producing loss of consciousness
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What are hypnotics?
Induce sleep
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What are the characteristics of ideal anxiolytics, sedatives and hypnotics?
Have a wide margin of safety Not depress respiration Produce natural sleep (hypnotics) Not interact with other drugs Not produce hangovers Not produce dependence/tolerance
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What are the pharmacokinetics of barbiturates and unwanted effects?
x
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What are the pharmacokinetics, metaboliosm, excretion, DOA of benzodiazepines?
Diazepam, Oxazepam and Temazepam
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How are benzodiazepines metabolised?
Oxazepam is directly metabolised in the liver to inactive glucuronide;
temazepam metabolised initially into oxazepam, then converted into glucuronide.
Nordiazepam is an active metabolite
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Which drugs are used as anxiolytics and which as sedatives and hypnotics?
For anxiolytics you need a long acting BDZ so it can last during the day
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What are the advantages of benzodiazepines?
Wide margin of safety: overdose -> prolonged sleep (rousable, with rare respiratory depression), flumenazil can be given IV if patient has OD’d on BDZ which reverses the action as it is a competitive antagonist; mild effect on REM sleep; DOESN’T induce liver enzymes
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What are the unwanted effects of BDZ?
x
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What is Zopiclone?
Sedative/hypnotics; short acting t1/2=5h; acts at BZD receptor (cyclopyrrolone); similar efficacy to BZD; minimal hangover effects but dependency still a problem
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What are some other anxiolytics - antidepressants, antiepileptics and antipsychotics?
Antidepressant = SSRIs: effective, delayed response, popular. Antiepileptic = Valproate, tiagabine. Antipsychotic = olanzapine, quetiapine, both with marked side effects. Propanolol = improves physical symptoms, like tachycardia and tremor. Buspirone = 5HT1A agonist, fewer side effects (
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What is the epidemiology of Alzheimer’s?
Main risk factor – Age Huge economic cost in the UK BUT low research investment Nov 2016 – ONS announces AD & dementia are leading cause of death in UK Genetics - APP, PSEN, ApoE (hereditary ~ 8%)
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What are the symptoms of Alzheimer’s?
Memory loss – especially recently acquired information Disorientation/ confusion – forgetting where they are Language problems – stopping in the middle of a conversation Personality changes – becoming confused, fearful, anxious Poor judgement – such as when dealing with money
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What is the amyloid hypothesis?
x
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What is the Tau hypothesis?
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What is the inflammation hypothesis?
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What re the 3 anticholinesterases and the NMDA receptor blocker used in Alzhemier’s?
x
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What are the treatment failures in Alzheimer’s?
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