5 - Regulating Neuronal Excitability Flashcards
*Basic layout of neurons in the motor cortex
MOTORCORTEX Motor neurons receive excitatory and inhibitory inputs Too little GABA = firing of neurons. Too much glutamate = firing of neurons.
Basic underlying pathology in epilepsy
Too much firing of neurons in motor cortex
Example of drugs that enhance GABA receptor activity
Benzodiazepines
Type of drug that benzodiazepines are
Allosteric modulators of GABA receptors
Examples of drugs that limits excitatory nerve activation in motor cortex 1 2
1) Phenytoin (doesn’t cause sedation as a side-effect). Might selectively target action potential generation in nerves that are firing excessively 2) Ethosuxamide inhibit T-type Ca2+ channels on excitatory neurons
Examples of anti-epileptic drugs
Benzodiazepine, phenytoin, ethosuxamide, felbemate
Example of a drug that inhibits NMDA receptors on motor neurons
Felbemate
Very basic outline of sensory pathway 1 2 3
1) Primary sensory afferent from site 2) Primary afferent enters dorsal horn of spinal cord, synapses with spinal interneuron 3) Signal sent to thalamus
Basic effect of analgesics
Regulate sensitivity of neurons involved in pain pathways
Where are local anaesthetics broadly active?
In the periphery (not centrally active). Regionalised action
Broad effect of general anaesthetics
Depresses cortical processing of pain/sensory signal (not regionalised). Leads to loss of consciousness.
Examples of classes of local anaesthetics 1 2 3
Aminoesterases Aminoamides Benzocaine
Aminoesterases
EG: procaine. Short acting, hydrolysis by esterases
Aminoamides
EG: lignocaine, bupivicaine, ropivicaine. Longer acting, hepatic metabolism
Why are some local anaesthetics considered safe?
- selective binding to Na+ channel - reversible binding with no nerve damage - will affect all nerves / excitable tissue
Uses of lignocaine
Anti-dysrrhythmic, local anaesthetic
Effects of local anaesthetics at different sites 1 2 3
• Peripheral motor nerves - sensory loss but paralysis • Autonomic nerves - hypotension but CNS convulsions, coma • Heart – anti-dysrhythmic but cardiac arrest
Difference in local anaesthitic-sensitivity of motor and sensory nerves
Motor neurons are less sensitive than sensory neurons
Site of action of local anaesthetics
Interact with membrane Na+ channel. Bind transmembrane domain on cytoplasmic side of the channel.
Difference between toxic and non-toxic local anaesthetics
Safe ones bind cytoplasmic side of Na+ channel. Toxic ones bind extracellular side of Na+ channel.
Two mechanisms of local anaesthetic action
Interact with membrane – Na+ channel 1) Hydrophobic - fast, non use dependent - eg benzocaine - 2) Hydrophillic – slow, use dependent - eg aminoesters & aminoamides Rate of onset/offset limited by diffusion across membranes Lignocaine is 65% protonated at pH 7.4
Why can motor nerves and sensory nerves respond differently to local anaesthetics?
Motor nerves are myelinated, so drug needs to be hydrophobic to cross myelin sheath more effectively.
*Hydrophobic mechanism for local anaesthetics
Fast-acting, but not so potent
*Hydrophilic mechanism for local anaesthetics
Channel needs to be open for charged form of drug to be effective. Therefore is use-dependent.
General properties of local anaesthetics 1 2 3 4 5 6 7 8 9
- Prevent propagation of nerve action potential - Small fibres more sensitive - (sensory > ANS > motor) - Stabilize axon membrane - No change in resting membrane potential - Effect more pronounced in basic medium - Uncharged species more active? - At pH 7.4 more ionised form. - Charged & uncharged both essential - Greater effect at high frequency (hydrophilic form can access binding site more easily)
Effects of local anaesthetics that are proportional to blood levels 1 2
1) Cardiovascular - Direct myocardial depression - Depression of vasomotor centre - Hypotension (except for cocaine) 2) CNS - Excitation - Tremor - Convulsion - Respiratory arrest
Effect of local anaesthetics that are not proportional to blood levels
Hypersensitivity
Infiltration
Injection of local anaesthetic with a vasoconstrictor. This decreases absorption of anaesthetic into the bloodstream, and prolongs local action
Nerve block
Injection of a local anaesthetic close to major nerves
Four stages of anaesthesia
• Stage 1 Amnesia Euphoria • Stage II “Excitement” Excitement Delirium Resistance to handling •Stage III “Surgical anaesthesia” Unconsciousness Regular respiration Decreasing eye movement •Stage IV “Medullary depression” Respiratory arrest Cardiac depression and arrest
Pharmaceutics
Formulation and method of administration of a drug
Examples of inhalational general anaesthetics 1 2 3
Desflurane Sevoflurane Isoflurane
Examples of intravenous general anaesthetics 1 2
Propofol Thiopentone
Pharmacokinetic aspects of anaesthetics to consider 1 2 3 4 5 6
• Dose and duration of action • Absorption (inhalational) • Distribution (Vd, t1/2) • Biotransformation (metabolism) • Elimination (How – kidneys/liver/lungs) • Drug interactions
Pharmacodynamics of general anaesthetics (side-effects) 1 2
Respiratory All anaesthetics increase likelihood of: • Impaired ventilation • Depression of respiratory centre • Obstruction of airways • Retention of secretions Cardiovascular All anaesthetics increase likelihood of: •Decreased vasomotor centre function •Depress contractility •Peripheral vasodilation •Cardiac arrythmias •Inadequate response to fall in BP or CO
Lipid theory of general anaesthetic pharmacodynamics 1 2 3
• Close correlation between anaesthetic potency and lipid solubility • Meyer- Overton: anaesthesia is caused by volume expansion of membrane lipids. • Effect can be reversed by pressure
Receptor interaction theory of general anaesthetic pharmacodynamics 1 2
• Many anaesthetic agents inhibit excitatory receptors (glutamate, NMDA) • Many anaesthetic agents enhance effects on inhibitory receptors (GABA, glycine)
