Transmitters and Receptors Flashcards
What is essential for drugs to do to act in the CNS?
Cross BBB
Where do drugs interfere with chemical neurotransmission?
Synthesis Storage Release Reuptake Metabolism Receptor
Why isn’t the second line of cocaine as good as the first line?
NA depleted from first line
What happens to motor nerves in epilepsy?
Excessive discharge
What is the function of phenytoin?
Limits excitatory nerve action in epilepsy
On what receptor does phenytoin have an action
Na channels on post-synaptic terminals
What conformation must Na channels be in for phenytoin to work?
Only blocks Na channels when they’re open
What is the challenge of administering phenytoin?
Firing that gives epileptic seizure one day is different to firing on another day
Means that phenytoin concentrations have to be in window
What is the function of benzodiazepines?
Enhance GABA receptor activity > enhance inhibitory input in epilepsy
What are the therapeutic outcomes of benzodiazepines in epilepsy?
Increased tonic inhibition
Decreased excessive discharge
Describe GABA
Main inhibitory transmitter in CNS
- GABA A - ligand-gated receptor
- GABA B - GCPRs
What does activating the neuropeptide Y (NPY) 1 receptor do?
Reduce anxiety
What is the effect of antagonising the H1 receptor in the CNS?
Sedative
20% of the population has a point mutation in the H1 receptor. How do these people respond to antihistamines?
Antihistamines make them hyperexcitable
What are benzodiazepines used in?
Epilepsy Anxiety Sleep disorders Premedication - sedation for medical procedures Acute alcohol withdrawal
What is insomnia?
Not being able to sleep when, or as well as one should
Is insomnia a disease or a symptom?
Symptom - important to ID and treat underlying cause
What is anxiety?
Manifestation of fear response in anticipatory manner, independent of external events
What do beta-adrenoceptor antagonists do in anxiety?
Block physical signs - Sweating - Tremor - Tachycardia Little effect on CNS
What are clinically recognised anxiety disorders?
Generalised anxiety states
Panic disorder
Phobias
Post-traumatic stress disorder
What are generalised anxiety states?
Excessive anxiety lacking clear reason or focus
What is panic disorder?
Overwhelming fear in association with somatic signs
What are phobias?
Strong fears of specific things/situations
What are the side effects of anxiolytics?
Degree of sedation
Drowsiness
What are three classes of sedative, hypnotic and anxiolytic agents?
Benzodiazepines
Non-benzodiazepines
Barbiturates
What are some non-benzodiazepines?
Beta-adrenoceptor antagonists
Buspiron
Zopiclone
Zolpidem
Describe barbiturates
General depressants - produce all levels of CNS depression
Effective but
- Very toxic
- Low therapeutic index
- Induction of liver enzymes
- Abrupt withdrawal could cause death
Obsolete as anxiolytics/hypnotics - used now in controlled situations
- Anaesthetics for people who have prior history of being allergic to other anaesthetics
- Anticonvulsant
Why are benzodiazepines safer to administer than barbiturates?
Wider therapeutic index
- Less depression of respiratory and cardiovascular centres
- Less dependence
- Safe in overdose
When aren’t benzodiazepines safe in overdose?
Additive effect when taking multiple benzodiazepines
What responses do benzodiazepines elicit?
Sedation and induction of sleep - Reduce time to fall asleep - Increase duration of sleeep Reduction of anxiety and aggression Reduction of muscle tonee - Anticonvulsant but reduces coordination Obliterate memory - Use as premedicant
What effect do benzodiazepines have on neurons?
Interfere with GABAergic transmission
Which receptor do benzodiazepines interact with?
GABA A only
What do allosteric molecules modulate?
Orthosteric ligand affinity
Orthosteric ligand efficacy
Receptor activating level
What drug class does diazepam belong to?
Benzodiazepines
How does diazepam work?
Has specific binding sit on GABA A > increase in receptor affinity for GANA
Increases frequency of GABA receptor Cl channel opening
What is the mechanism of action of benzodiazepines?
Bind regulatory site
- Increase GABA affinity for receptor
- Allosteric modulators
Enhance response to GABA
- Facilitate opening of Cl channels
- Increase frequency - no change in conductance/mean opening time
- Increase sensitivity of receptor with no change in maximum response
What is the mechanism of action of barbiturates?
Bind GABA receptor > prolongs opening of channel
Increases sensitivity and maximum responses
What are the advantages of allosteric modulators?
Ceiling of effect of inhibitors
- Increased therapeutic window
Positive modulation of endogenous agonist effect rather than continuous effect of exogenous agonist
- Physiological regulation continues
Great receptor subtype selectivity possible
What is the pharmacodynamic profile of benzodiazepines?
Similar
What are the unwanted effects of benzodiazepines?
Drowsiness
Confusion
Impaired coordination
What are the disadvantages of benzodiazepines?
Interaction with - Alcohol - acts on GABA receptors dysregulating them > synergistic - Antihistamines - Barbiturates Long lasting hangover effects Withdrawal symptoms Dependence
Can you develop tolerance to benzodiazepines?
Yes
What are the signs of physical and psychological withdrawal from benzodiazepines?
Nausea Tremor Anxiety Depression Insomnia
What determines the use of benzodiazepines?
Pharmacokinetic profile
- Active orally but differ in duration of action
- Generation of active and inactive metabolites
What is potency?
Relative position of dose-effect curve along dose axis
Does potency have clinical significance?
Not really
More potent drug not clinically superior
When is low potency a disadvantage?
If dose so large that it’s awkward to administer
Why are barbiturates more potent than benzodiazepines?
Increase frequency of Cl ion channel opening at GABA A receptor
Why are barbiturates more efficacious than benzodiazepines?
Increase duration Cl channel is open
Why are barbiturates more toxic than benzodiazepines in overdose?
Direct opening of Cl ion channel
Describe zolpidem
Short-term treatment for insomnia
Non-benzodiazepine but binds to benzodiazepine site
Very little anticonvulsant activity
Short duration of action
Describe zopiclone
Short-term treatment of insomnia
Non-benzodiazepine
Describe buspirone
Antiolytic Non-benzodiazepine Partial agonist at 5HT 1A receptor - Inhibitory autoreceptors regulating transmitter release Slow onset - Up to 2 weeks Little dependence Side effects - Nausea - Dizziness - Headache
