Regulating Neuronal Excitability Flashcards
What is an example of a neurotransmitter not stored in a vesicle?
NO
What kind of inputs do motor nerves receive?
Excitatory
Inhibitory
What happens in epilepsy?
Excessive discharge
Too little inhibition - get spasms
Too much excitation - excessive motor stimulatio
What are the two neurotransmitters relevant to epilepsy?
GABA
Glutamate
What is the best target for modulating inhibitory activity in epilepsy?
Enhance GABA receptor activity
How do benzodiazepines work?
Used to treat epilepsy
Enhance GABA receptor activity
Allosteric modulators
Increase GABA binding
How do you reduce excitatory input in epilepsy?
Limit excitatory nerve activation Inhibit T-type Ca channels - Specific to some neurons - More readily expressed on excitatory nerves Inhibit NMDA receptor
Describe phenytoin
Used in treating epilepsy
Stops nerve action by inhibiting Na channels
Describe ethosuximide
Inhibits T-type Ca channels
Stops vesicle release
Describe felbemate
Inhibits NMDA receptor
Enhances GABA receptor
What else do many epileptic drugs cause?
Sedation; eg:
- Benzodiazepines
- Some others
Analgesia
What are some examples of analgesics?
NSAIDs
Anti-pyuretics
Opioids
What is an analgesic?
Targets pain/sensory pathways
Sets threshold to determine what degree of excitation is sent to brain
Increases pain threshold
What is a local anaesthetic?
Targets pain/sensory nerves as well as others in the region
No loss of consciousness
What is a general anaesthetic?
Depresses cortical processing of pain/sensory signal
Causes loss of consciousness
Not regionalised
Which drug category has the highest degree of selectivity?
a) Analgesics
b) Local anaesthetics
c) General anaesthetics
b) Local anaesthetics
What was the first local anaesthetic?
Cocaine
Describe local anaesthetic agents
Drugs that reversibly block conduction of nerve impulses at axonal membrane - influence action potential
What are the weak base local anaesthetics?
Aminoesters - Eg: procaine - Shorter acting - Hydrolysis by choliesterases Aminoamides - Eg: lignocaine, bupivicaine, ropivicaine - Longer acting = 1-1.5 hrs - Hepatic metabolism Benzocaine
What are examples of lethal toxins that share a target with local anaesthetics?
Tetrodotoxin in puffer fish
Saxitoxin in dinoflagellates
Describe the clinical use of local anaesthetics
Safe
- Very specific binding to Na channel
- Reversible binding with no nerve damage
- Will affect all nerves/excitable tissues because Na channel fundamental to all excitable tissues
Local application to limit systemic distribution - makes them safe
What are the effects if local anaesthetics act on non-sensory nerves?
Peripheral motor nerves - Paralysis Autonomic nerves - Hypotension - CNS convulsions - Coma Heart - Anti-dysrhythmic - Cardiac arrest
What happens to the nerves with increasing concentrations of local anaesthetic?
More sensory block
More motor block because drug reaches these fibres
More autonomic block
What is the relative sensitivity of nerve types to local anaesthetics?
Sensory > autonomic > motor
What is the site of interaction of local anaesthetics?
Intracellular transmembrane domain on Na channel
What is the difference in binding between local anaesthetics and toxins that share the same receptor target?
Local anaesthetics bind intracellularly and toxins bind extracellularly
What are the two mechanisms of action of local anaesthetics?
Hydrophobic - Faster - Non-use dependent - Eg: benzocaine Hydrophilic - Slower - Use dependent Eg: aminoesters, aminoamides - Mainly ionised at physiological pH
What determines the rate of onset/offset of local anaesthetics?
Rate of diffusion across membrane
Describe how hydrophobic local anaesthetics block the Na channel
Enter cell by diffusing across lipid membrane
Block gate like plug
Describe how hydrophilic local anaesthetics block the Na channel
Non-ionised form diffuses across membrane into cell
Re-ionises
Blocks channel in ionised form
What are the general properties of local anaesthetics?
Prevemt propagation of nerve action potential
Small fibres more sensitive
Stabilise axon membrane
- No change in resting membrane potential
Effect more pronounced in basic medium
- Allows more drug to cross membrane
Greater effect at high frequency
What happens when local anaesthetics are used during an infection?
Infection creates more acidic environment
Decreases effect of drug, therefore need higher concentration to get same effect as normal
What is the toxicity of local anaesthetics?
Generally safe
Toxicity proportional to blood level - if they enter bloodstream
Cardiovascular effects
- Direct myocardial depression
- Depression of vasomotor centre
- Hypotension - except cocaine > causes hypertension instead
Can cross BBB > CNS effects
- Inhibitory fibres more sensitive > excitation
- Tremor
- Convulsion
- Respiratory arrest
Are hypersensitivity reactions proportional to blood level?
No
Who can get hypersensitivity reactions to local anaesthetics?
Both patient and practitioner, as even handling drugs can cause development
Describe the topical application of local anaesthetics
Over the counter
- Lozenge: throat drops containing benzocaine
- Gels: generally poorly absorbed across skin and over inflamed areas because even though fibres exposed, at low pH
- Contain very low concentrations of lignocaine
- Menthol doing most of the work
Professional use only
- Eye drops: ocular procedures, often including a dye
- Injection: specific procedural use; eg: IV lignocaine for dysrhythmia
What are the types of ways local anaesthetics are used when injected?
Infiltration: combination with vasoconstrictor prolongs action
Nerve block: injection close to major nerves
Epidural and intrathecal
What are the stages of anaesthesia?
Stage 1 - Amnesia - Euphoria Stage 2 - Excitement - Delirium - Resistance to handling Stage 3 - Unconsciousness - Regular respiration - Decreasing eye movement Stage 4 - Medullary depression - Respiratory arrest - Cardiac depression and arrest
How can general anesthetics be formulated?
Inhalation
IV
What does formulation of general anaesthetics influence?
Slight differences in pharmacokinetics
What are some inhaled general anaesthetics?
Desflurane
Sevoflurane
Isoflurane
What are some IV general anaesthetics?
Propofol
Thiopentone
What are the relevant pharmacokinetics for general anaesthetics?
Dose and duration of action Absorption - when inhaled Distribution - Vd - t1/2 - Get into compartments other than brain Metabolism Elimination - Kidneys - Liver - Lungs Drug interactions
What are the side effects of general anaesthetics?
Happen at final endpoint depression = stage 4 Respiratory - Impaired ventilation - Depression of respiratory centre - Obstruction of airways - Retention of secretions Cardiovascular - Decreased vasomotor centre function - Depress contractility - Peripheral vasodilation - Cardia arrythmias - Inadequate response to fall in BP or CO
What is given to counteract the retention of secretions that happens when a patient is given general anaesthetics?
Anti-muscarinics administered
What are the two theories on mechanism of action of general anaesthetics?
Lipid theory
Receptor interaction
What is the lipid theory in relation to mechanism of action of general anaesthetics?
Close correlation between anaesthetic potency and lipid solubility
Anaesthesia caused by volume expansion of membrane lipids
Effect can be reversed by pressure - pushed out of membranes
What is the receptor interaction in relation to mechanism of action of general anaesthetics?
Many anaesthetic agents inhibit excitatory receptors
- Glutamate
- NMDA
Many anaesthetic agents enhance effects on inhibitory receptors
- GABA
- Glycine
What is an NMDA receptor agonist?
Ketamine
