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Principles of Neuropharmacology / ME2361 > L9 - Local Anaesthetics > Flashcards

L9 - Local Anaesthetics Flashcards

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1
Q

What is the definition of a local anaesthetic?

A

A locally applied chemical that reversibly inhibits action potentials and therefore the perception of pain.

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2
Q

How do local anaesthetics differ from general anaesthetics?

A

Unlike general anaesthetics, local anaesthetics do not cause a loss of consciousness.

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3
Q

What are the routes of administration for local anaesthetics?

A

Topical application: Used for burns and small cuts.
Injections:
Sutures and dental work.
Peripheral nerve block:
For procedures like obstetric interventions or surgeries on the lower body.
Provides post-operative pain relief.
Epidural or spinal injections: Commonly used in obstetric procedures and lower body surgeries.

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4
Q

What are the two main types of local anaesthetics?

A

Amide-linked and ester-linked.

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5
Q

Name two amide-linked local anaesthetics and their key characteristics.

A

Lignocaine: Rapid onset of action.
Bupivacaine: Long duration of action.

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6
Q

Name an ester-linked local anaesthetic and its use.

A

Amethocaine:

Only licensed in the UK for topical application.
Widely used to prepare venepuncture sites in children and treat corneal abrasions.

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7
Q

Why can esters not be stored as long as amides?

A

The ester linkage is more easily broken, making them less stable.

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8
Q

What is a key difference in the metabolism of esters and its clinical relevance?

A

Metabolism of esters produces para-aminobenzoate (PABA), which is associated with allergic reactions.

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9
Q

How do amides differ from esters regarding allergic reactions?

A

Amides very rarely cause allergic reactions compared to esters

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10
Q

Why are amides more commonly used than esters?

A

Due to their longer shelf life, lower risk of allergic reactions, and greater stability

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11
Q

What is the sequence of events leading to pain perception in a nociceptor?

A

Activation of the nociceptor.
Depolarisation of the neuron, leading to action potential (AP) initiation.
Trains of APs are transmitted to the brain.
The brain interprets these signals as pain perception

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12
Q

How does an increase in AP frequency affect pain perception?

A

An increase in AP frequency leads to an increase in the perception of pain.

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13
Q

How do local anaesthetics affect voltage-gated sodium channels (VGNa+)?

A

Local anaesthetics inhibit VGNa+ channels, preventing depolarisation and the initiation of action potentials, thereby blocking the transmission of pain signals to the brain.

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14
Q

What is the primary effect of local anaesthetics on nociceptors?

A

They block nociceptor activity by inhibiting action potential propagation, leading to a reduction or elimination of pain perception.

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15
Q

What are the characteristics of Aδ fibres in pain perception?

A

Myelinated, allowing for fast conduction.
Conduction velocity: 5–25 m/s.
Responsible for first pain, which is quick and pin-prick-like.
Pain is highly localised.

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16
Q

What are the characteristics of C fibres in pain perception?

A

Non-myelinated, resulting in slower conduction.
Conduction velocity: 0.1–2.0 m/s.
Responsible for second pain, which is dull, throbbing, or burning.
Pain is diffuse.

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17
Q

Which pain fibres are more susceptible to local anaesthetics (LAs)?

A

Aδ fibres are more susceptible to LAs than C fibres.

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18
Q

Why might people still feel touch but not pain after local anaesthetic application?

A

The loss of nerve function proceeds in the following order:

Pain
Temperature
Touch

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19
Q

What is the structure of the α subunit in a voltage-gated sodium channel?

A

The α subunit is a single polypeptide chain with:

Four homologous domains (I-IV).
Each domain contains 6 transmembrane segments (S1-S6).

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20
Q

What is the role of the S4 segment in a voltage-gated sodium channel?

A

S4 acts as the voltage sensor for the channel.

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21
Q

Which segments form the pore of the voltage-gated sodium channel?

A

S5 and S6 segments form the pore.

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22
Q

What is the function of the cytoplasmic loop between the 3rd and 4th domains?

A

This loop acts as a ‘plug’ to close the channel pore.

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23
Q

What is the state of the voltage-gated sodium channel at rest?

A

The channel pore is closed in the resting conformation.

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24
Q

What triggers conformational changes in the voltage-gated sodium channel?

A

Membrane depolarization causes charged residues to move in response to the change in the electrical field.

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25
What happens after the conformational changes in the voltage-gated sodium channel?
The channel transitions to the open conformation allowing sodium ions to flow through.
26
What occurs approximately 1 millisecond after the channel opens?
The linker region plugs the open channel, leading to the inactivated conformation.
27
When does the inactivated conformation return to the resting state?
The channel returns to the resting state only after the membrane is repolarized during the refractory period.
28
What is the affinity of local anesthetics (LAs) for voltage-gated sodium channels in the resting state?
Low affinity; LAs prevent channel opening only at high concentrations.
29
What is the effect of LAs on sodium channels in the closed state?
High affinity; LAs prevent channel opening, which is the major effect in this state
30
How do LAs interact with sodium channels in the open state?
High affinity; LAs block the channel pore, but this is a minor effect.
31
What is the effect of LAs on sodium channels in the inactivated state?
High affinity; LAs extend the refractory period, which is the major effect in this state.
32
Where do local anesthetics bind on the voltage-gated sodium channel?
LAs bind to the internal side of the channel on domain IV, loop S6.
33
How does nerve depolarization frequency affect LA binding?
LA binding to sodium channels increases with the frequency of nerve depolarization, known as a use-dependent (phasic) block.
34
Why must local anesthetics (LAs) be positively charged to bind to voltage-gated sodium channels?
Because the binding site inside the channel requires LAs to be in their ionized form.
35
Why must LAs be unionized to cross the nerve membrane?
Unionized molecules are lipid-soluble, allowing them to diffuse across the lipid bilayer of the nerve membrane.
36
How can a molecule be both ionized and unionized for LA function?
LAs exist in an equilibrium between ionized and unionized forms. The unionized form crosses the nerve membrane. Inside the cell, the ionized form binds to the sodium channel.
37
What determines the proportion of ionized vs. unionized forms of LAs?
The pKa of the LA and the pH of the environment. At physiological pH (~7.4), most LAs exist in both forms, enabling their dual function.
38
What happens to the charge of the amine group in the base form of a local anesthetic (LA)?
In the base form, the amine group is neutral and can cross the membrane.
39
What happens to the charge of the amine group in the acid form of a local anesthetic (LAH+)?
In the acid form, the amine group is positively charged and can bind to the voltage-gated sodium channel (VGNa+).
40
Can a neutral LA cross the nerve membrane?
Yes, the neutral base form (LA) can cross the membrane due to its lipid solubility.
41
Can a positively charged LA (LAH+) bind to the VGNa+ channel?
Yes, the ionized acid form (LAH+) binds to the internal side of the VGNa+ channel.
42
What is the equilibrium reaction for a local anesthetic?
LA + H⁺ ⇌ LAH⁺ LA (neutral) crosses the membrane. LAH⁺ (ionized) binds to the VGNa+ channel.
43
Why is the ability to switch between neutral and charged forms critical for LA function?
The neutral form is necessary to cross the lipid membrane, while the charged form is required to block the sodium channel.
44
What is the pKa of a molecule?
The pKa is the pH at which the number of ionized molecules (LAH⁺) equals the number of neutral molecules (LA).
45
How does pH affect the ionization of a local anesthetic?
Low pH (acidic conditions) increases the proportion of ionized (LAH⁺) molecules. High pH (basic conditions) increases the proportion of neutral (LA) molecules.
46
How can pKa and pH be used to predict the ionization state of a local anesthetic (LA)?
If the pH is lower than the pKa, more of the local anesthetic will be in the ionized (LAH⁺) form. If the pH is higher than the pKa, more of the local anesthetic will be in the neutral (LA) form.
47
What is the effect of a low pH on the ionization state of local anesthetics?
Low pH leads to more ionized (LAH⁺) molecules, which are less able to cross the lipid membrane.
48
What is the effect of a high pH on the ionization state of local anesthetics?
High pH leads to more neutral (LA) molecules, which are more capable of crossing the lipid membrane.
49
How do local anesthetics (LA) and their protonated form (LAH⁺) interact with VGNa⁺ channels?
LA (neutral form) crosses the membrane and can enter the neuron. Once inside, LA may protonate to form LAH⁺, which binds to the VGNa⁺ channel and inhibits its function.
50
What happens when the pH is 7.4?
At pH 7.4 (physiological pH), there will be a mixture of neutral LA and ionized LAH⁺ molecules. However, a larger proportion will be in the neutral form (LA), allowing it to cross the membrane.
50
How does the pKa of a local anesthetic influence its ionization at different pH levels?
If the pH < pKa, more of the LA will be in the ionized (LAH⁺) form, reducing its ability to cross the membrane. If the pH > pKa, more of the LA will be in the neutral (LA) form, allowing it to more effectively cross the membrane and reach the site of action.
50
What happens when the pH is 7.0?
At pH 7.0 (lower pH, acidic conditions), more of the LA molecules will be in the ionized (LAH⁺) form, reducing the amount of LA available to cross the membrane and bind to VGNa⁺ channels.
51
How does the addition of H⁺ (lower pH) affect the ionization of LA?
The addition of H⁺ (lowering the pH) increases the proportion of ionized (LAH⁺) molecules, limiting the LA's ability to cross the lipid membrane. This can reduce the drug's effectiveness in blocking nerve conduction.
52
What is the pKa of Lignocaine?
The pKa of Lignocaine is 7.9.
53
What is the ionization state of Lignocaine at pH 7.4?
At pH 7.4, 24% of Lignocaine is in the unionized form (LA), and 76% is in the ionized form (LAH⁺).
54
How does the ionization state of Lignocaine change at pH 7.0?
At pH 7.0, a higher proportion of Lignocaine will be in the ionized (LAH⁺) form, reducing its ability to cross the membrane and bind to the voltage-gated sodium channels (VGNa⁺).
55
What happens to the Lignocaine molecules at pH 7.4?
At pH 7.4, the neutral form of Lignocaine (LA) is able to cross the membrane and enter the neuron, while the ionized form (LAH⁺) remains unable to cross the membrane but can bind to the voltage-gated sodium channels.
56
Why is the ionization of Lignocaine important for its action?
The unionized (LA) form can cross the neuronal membrane to reach the site of action, while the ionized (LAH⁺) form is primarily involved in binding to the voltage-gated sodium channels to block nerve conduction.
57
Check powerpoint slides for Calculations and Equations
Check powerpoint slides for Calculations and Equations
58
How does bicarbonate affect the onset of local anaesthesia?
Bicarbonate increases the pH of the local environment, which increases the proportion of unionized drug. This leads to faster onset of anaesthesia.
59
What is the role of adrenaline as an adjuvant in local anaesthesia?
Adrenaline is a vasoconstrictor that reduces the rate of systemic absorption of the local anaesthetic, thereby prolonging its effect at the site of action.
60
How does adrenaline affect blood loss during surgery?
: Adrenaline reduces traumatic blood loss from the site by vasoconstricting the blood vessels, limiting blood flow.
61
What is the mechanism of action of adrenaline in smooth muscle contraction?
Adrenaline binds to the α1-adrenoceptor, activating Gq, which increases levels of IP3. IP3 then releases Ca2+ from the sarcoplasmic reticulum (SR), and Ca2+ binds to calmodulin (CaM). This complex activates myosin light chain kinase (MLC-K), which phosphorylates Myosin-LC, resulting in smooth muscle contraction.
62
How does adrenaline affect blood flow and surgical outcomes?
Adrenaline causes vasoconstriction, which reduces blood flow to the site of administration, prolongs the effect of local anaesthetics, and reduces blood loss, improving the surgical field.
63
Where is the site of administration for local anaesthetics (LA)?
LA is administered to the site containing the nerves to be blocked, such as the skin, epidural space, etc. It can be applied topically or through injection.
64
How is a local anaesthetic absorbed into the body?
LA is absorbed into the systemic circulation, with absorption depending on the vascularity of the area. Some LAs have vasodilatory effects at low concentrations, increasing systemic absorption. Adrenaline is often co-administered to counteract this effect.
65
What factors influence the distribution of local anaesthetics?
LA is lipid-soluble and its distribution is influenced by plasma protein binding. The greater the protein binding, the longer the duration of action because less drug is available for metabolism.
66
What are the main routes of administration for local anaesthetics?
Topical application (for burns and small cuts) and injections (for sutures, dental work, peripheral nerve blocks, epidural/spinal injections, obstetric procedures, surgery on lower parts of the body, and post-operative pain relief).
67
How are amides and esters metabolized and excreted?
Amides are metabolized hepatically by amidases and excreted renally. Esters are broken down by plasma esterases and also excreted renally.
68
How is epidural anaesthesia administered?
Epidural anaesthesia is administered by injecting a local anaesthetic (LA), and sometimes an opioid (e.g., morphine), into the epidural space. The LA then diffuses across the dura mater into the cerebrospinal fluid (CSF).
69
Why is an epidural catheter used in epidural anaesthesia?
An epidural catheter is left in place to allow for continuous or incremental bolus of local anaesthetic to be administered as required.
70
What are the common uses of epidural anaesthesia?
Epidural anaesthesia is commonly used: During labour, including caesarean sections During some types of surgery For post-operative pain relief
71
What is the onset and duration of epidural anaesthesia?
Onset: Typically takes 30-40 minutes. Duration: Variable, depending on how long the catheter is left in place.
72
How is spinal analgesia administered?
Spinal analgesia is administered through a single injection of a local anaesthetic into the subarachnoid space.
73
What are the common uses of spinal analgesia?
Spinal analgesia can be used as an alternative to general anaesthesia (GA) for operations below the waist, such as: Caesarean sections (C-sections) Orthopaedic surgery on joints or bones of the leg
74
What happens when spinal analgesia is fully effective?
When spinal analgesia is fully effective: Patients are unable to lift their legs or feel pain in the lower part of the body. Patients retain sensation of movement or pressure.
75
What is the onset and duration of spinal analgesia?
Onset: Typically occurs within minutes. Duration: Typically lasts 1-2 hours.
76
What is the main concern with local anaesthetics if absorbed into the systemic circulation?
If local anaesthetics are absorbed into the systemic circulation, they may become toxic, leading to various adverse effects.
77
What is a common local effect of local anaesthetics?
Local irritation is a common adverse effect, particularly in skeletal muscles, which are most sensitive.
78
What are some central nervous system (CNS) effects of local anaesthetics?
CNS effects may include: Tingling of the lips Slurred speech Reduced level of consciousness Seizures
79
How can local anaesthetics affect the cardiovascular system?
Local anaesthetics can cause: Arrhythmias Reduced myocardial contractility However, lignocaine can be used as an antiarrhythmic for its cardiac effect
80
What are hypersensitivity reactions to local anaesthetics?
Hypersensitivity reactions are rare and typically occur with ester-linked local anaesthetics. These reactions usually manifest as: Allergic dermatitis Asthma

Principles of Neuropharmacology / ME2361 (8 decks)

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