5 - Regulating Neuronal Excitability

Question 1

*Basic layout of neurons in the motor cortex

Answer 1

MOTORCORTEX Motor neurons receive excitatory and inhibitory inputs Too little GABA = firing of neurons. Too much glutamate = firing of neurons.

Question 2

Basic underlying pathology in epilepsy

Answer 2

Too much firing of neurons in motor cortex

Question 3

Example of drugs that enhance GABA receptor activity

Answer 3

Benzodiazepines

Question 4

Type of drug that benzodiazepines are

Answer 4

Allosteric modulators of GABA receptors

Question 5

Examples of drugs that limits excitatory nerve activation in motor cortex 1 2

Answer 5

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

Question 6

Examples of anti-epileptic drugs

Answer 6

Benzodiazepine, phenytoin, ethosuxamide, felbemate

Question 7

Example of a drug that inhibits NMDA receptors on motor neurons

Answer 7

Felbemate

Question 8

Very basic outline of sensory pathway 1 2 3

Answer 8

1) Primary sensory afferent from site 2) Primary afferent enters dorsal horn of spinal cord, synapses with spinal interneuron 3) Signal sent to thalamus

Question 9

Basic effect of analgesics

Answer 9

Regulate sensitivity of neurons involved in pain pathways

Question 10

Where are local anaesthetics broadly active?

Answer 10

In the periphery (not centrally active). Regionalised action

Question 11

Broad effect of general anaesthetics

Answer 11

Depresses cortical processing of pain/sensory signal (not regionalised). Leads to loss of consciousness.

Question 12

Examples of classes of local anaesthetics 1 2 3

Answer 12

Aminoesterases Aminoamides Benzocaine

Question 13

Aminoesterases

Answer 13

EG: procaine. Short acting, hydrolysis by esterases

Question 14

Aminoamides

Answer 14

EG: lignocaine, bupivicaine, ropivicaine. Longer acting, hepatic metabolism

Question 15

Why are some local anaesthetics considered safe?

Answer 15

• selective binding to Na+ channel - reversible binding with no nerve damage - will affect all nerves / excitable tissue

Question 16

Uses of lignocaine

Answer 16

Anti-dysrrhythmic, local anaesthetic

Question 17

Effects of local anaesthetics at different sites 1 2 3

Answer 17

• Peripheral motor nerves - sensory loss but paralysis • Autonomic nerves - hypotension but CNS convulsions, coma • Heart – anti-dysrhythmic but cardiac arrest

Question 18

Difference in local anaesthitic-sensitivity of motor and sensory nerves

Answer 18

Motor neurons are less sensitive than sensory neurons

Question 19

Site of action of local anaesthetics

Answer 19

Interact with membrane Na+ channel. Bind transmembrane domain on cytoplasmic side of the channel.

Question 20

Difference between toxic and non-toxic local anaesthetics

Answer 20

Safe ones bind cytoplasmic side of Na+ channel. Toxic ones bind extracellular side of Na+ channel.

Question 21

Two mechanisms of local anaesthetic action

Answer 21

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

Question 22

Why can motor nerves and sensory nerves respond differently to local anaesthetics?

Answer 22

Motor nerves are myelinated, so drug needs to be hydrophobic to cross myelin sheath more effectively.

Question 23

*Hydrophobic mechanism for local anaesthetics

Answer 23

Fast-acting, but not so potent

Question 24

*Hydrophilic mechanism for local anaesthetics

Answer 24

Channel needs to be open for charged form of drug to be effective. Therefore is use-dependent.

Question 25

General properties of local anaesthetics 1 2 3 4 5 6 7 8 9

Answer 25

• 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)

Question 26

Effects of local anaesthetics that are proportional to blood levels 1 2

Answer 26

1) Cardiovascular - Direct myocardial depression - Depression of vasomotor centre - Hypotension (except for cocaine) 2) CNS - Excitation - Tremor - Convulsion - Respiratory arrest

Question 27

Effect of local anaesthetics that are not proportional to blood levels

Answer 27

Hypersensitivity

Question 28

Infiltration

Answer 28

Injection of local anaesthetic with a vasoconstrictor. This decreases absorption of anaesthetic into the bloodstream, and prolongs local action

Question 29

Nerve block

Answer 29

Injection of a local anaesthetic close to major nerves

Question 30

Four stages of anaesthesia

Answer 30

• 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

Question 31

Pharmaceutics

Answer 31

Formulation and method of administration of a drug

Question 32

Examples of inhalational general anaesthetics 1 2 3

Answer 32

Desflurane Sevoflurane Isoflurane

Question 33

Examples of intravenous general anaesthetics 1 2

Answer 33

Propofol Thiopentone

Question 34

Pharmacokinetic aspects of anaesthetics to consider 1 2 3 4 5 6

Answer 34

• Dose and duration of action • Absorption (inhalational) • Distribution (Vd, t1/2) • Biotransformation (metabolism) • Elimination (How – kidneys/liver/lungs) • Drug interactions

Question 35

Pharmacodynamics of general anaesthetics (side-effects) 1 2

Answer 35

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

Question 36

Lipid theory of general anaesthetic pharmacodynamics 1 2 3

Answer 36

• 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

Question 37

Receptor interaction theory of general anaesthetic pharmacodynamics 1 2

Answer 37

• Many anaesthetic agents inhibit excitatory receptors (glutamate, NMDA) • Many anaesthetic agents enhance effects on inhibitory receptors (GABA, glycine)