PHARM; Lecture 25, 26, 27 - Anxiolytics, sedatives and hypnotics; Alzheimer's disease; Anti-Parkinsonian drugs and neuroleptics Flashcards
(55 cards)
Pharm
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.
Pharm
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
Pharm
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
Pharm
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
Pharm
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
Pharm
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
Pharm
What is the nigrostriatal pathway?
Cell bodies originate in the substantia nigra zona compacta and project to the striatum - Control of Movement.
Pharm
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
Pharm
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
Pharm
What are the 2 families of receptors?
x
Pharm
What is the epidemiology of Parkinson’s?
Parkinson’s is the least prevalent neurological disorder (parkinson’s, alzheimers, epilepsy, stroke)
Pharm
What are the cardinal signs of Parkinson’s disease?
x
Pharm
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.
Pharm
What are the non-motor symptoms of Parkinson’s?
x
Pharm
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
Pharm
How do you stage Parkinson’s?
x
Pharm
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
Pharm
How does Dopamine pass into the brain from the blood?
x
Pharm
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)
Pharm
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!
Pharm
What are the acute and chronic side effects of L-DOPA?
Off periods can be very troublesome
Pharm
What are DA agonists and what are their side effects?
x
Pharm
What are the 2 types of MAO inhibitors?
Useful but even better when given with L-DOPA
Pharm
What are the COMT inhibitors?
Could precipitate a heart attack in heart compromised patients
