Week 10 Painkillers

Question 1

Define anaesthesia

Answer 1

a state characterised by loss of sensation; the result of pharmacological depression of nerve function or of neurological disease

Question 2

Local anaeathesia

Answer 2

ability to have anaesthesia (loss of sensation) in a defined region of the body. Produced by direct application of drug into operative site.

goal is reversible block of sensory perception of pain, with patient’s consciousness maintained

Question 3

three structural requirements of LA’s

Answer 3

• lipophilic groups (aromatic ring)
• intermediate bond (ester or amide linkage)
• hydrophilic group (basic amine side chain; either tertiary of quaternary amino group)

rule: if it has 2 i’s in its name its an amide. one i is an ester
most common: procaine, lidocaine, bupivicaine, tetracaine

Question 4

Procaine (Novocaine)

Answer 4

one of the very first synthetic LAs.

• less toxic and not as addictive as cocaine
• very long time of onset of action
• wore off too quickly
• not nearly as potent as cocaine
• causes vasodilation, so is quickly absorbed away from injection site (needs to stay local so this is an issue)
• is an ester and has a very high potential to cause allergic reactions

Question 5

Lidocaine/lignocaine

Answer 5

• an amide and hypoallergenic
• anaesthetic effect occurs quickly
• causes vasodilation at injection site so is quickly absorbed away

Question 6

How do we resolve vasodilation with non-cocaine LAs?

Answer 6

• cocaine blocks NA reuptake transporters as well, which increases NA = vasocontriction
• synthetic LAs lack this NA effect to varying degrees, with net vasodilation of the local blood vessels increasing the blood flow in the area and absorption into circulation before the LA has a complete effect, increasing adverse effects
• synthetic LAs are always mixed with low concs of adrenaline which causes vasoconstriction and slows blood flow through the area, keeping LA in position long enough to produce long-lasting numbness (1-2hrs)

Question 7

Lidocaine toxicity issues

Answer 7

side effects of lidocaine include drowsiness, tinnitus, dysguesia, dizziness, and twitching

as the dose increases: seizures, coma, respiratory depression and arrest may occur

S - slurred or difficult speech
A - altered cardio system
M - muscle twitching
S - seizures

Question 8

How and when are the drugs used?

Answer 8

Based on duration of action:

ultra short: 2% lignocaine (wo vasoconstrictor)

short: procaine, lignocaine (1:100.000 epinephrine)

intermediate: articaine, meprivacaine, prilocaine, 2$ lignocaine (1: 200,000 epinephrine)

long: bupivacaine, etidocaine, 2% lignocaine (1:200,000) epinephrine

Question 9

Some LAs

Answer 9

Esters:
Long action: tetracaine
short action: procaine
surface action: cocaine, benzocaine

Amides:
long action: bupivacaine, repivacaine
medium action: lidocaine

Question 10

the importance of pKa of a LA?

Answer 10

all LAs are weak bases that can exist as either:
unionised (B) or
ionised (BH+)

In an acid proton-rich environment, equilibrium shifts to the left, increasing (BH+).
Alkaline conditions will shift to the right

all LAs are more ionised and un-ionised as all pka values are greater than 7.4.

if a LA has a lower pH - mostly uncharged at pH 7.4, it can better cross membranes + have a “rapid” onset of action

if LA has a higher pKa value, mostly charged at pH 7.4, it will not be as able to cross membranes and have a slower onset of action

Question 11

Why the worry about crossing membranes?

Answer 11

the binding site of LAs in on the inner surface of voltage-dependent Na+ channels.

Sodium ion channels can exist in three different states: closed, open and inactivated

LAs have a binding site on the inactivation gate of the channels, preventing them from transitioning back to closed and open states

Question 12

Na+ channel block of LAs

Answer 12

• is concentration-dependent, with charged form being effective
• is reversible
• is voltage sensitive (greater impact with depolarisation)
• is use-dependent (greater access to inactivated state of the channel)

Question 13

How are LAs metabolised?

Answer 13

Amide LAs are degraded by
cytochrome P450 enzymes in the
liver and then excreted in urine or
stool. Hepatic disease requires
caution in use.

Ester LAs are inactivated by plasma
esterase enzymes.

Question 14

Which nerve fibres are affected by LAs?

Answer 14

LAs have greatest effect on small diameter afferent neurons of the peripheral nerves, making them useful in reducing pain transmission.
– Myelinated (Ad) fibres with rapid conduction velocities due to saltatory
conduction (less surface area to be affected)
– Non-myelinated C fibres with low conduction velocities (but more surface area)

Motor neurons, which have a relatively large diameter, are not generally affected by LAs due to their increased surface area.

Question 15

Adverse effects of LAs

Answer 15

• temporary weakness or paralysis of the affected area. This is often useful after surgery, and wears off with time.
• CNS, high concentrations have a biphasic effect. Inhibitory interneurons are blocked first, leading to initial excitatory effects, such as tingling, visual disturbances, tremors, dizziness, followed by convulsions. Next, all central neurons
  may experience depression, leading to coma.
• Cardiovascular system, a reduction in myocardial contractility and force of contraction can occur due to block of cardiac Na+ channels reducing phase 0 of the cardiac action potential. Decreased Na+ movement reduces Ca2+ mobility as well.
• Adrenaline included in injections can also have CV effects.

Question 16

Bupivicaine: binding affinity and cardiotoxicity

Answer 16

Bupivicaine can be used for prolonged anesthesia with its long duration of action plus its tendency to provide more sensory than motor block make it popular for providing prolonged analgesia during labor or the postoperative period.

Bupivacaine is more cardiotoxic (severe ventricular arrhythmias and reduced heart function) than equal doses of lidocaine if it reaches sufficient systemic concentrations.

Although both lidocaine and bupivacaine rapidly block cardiac Na+ channels, bupivacaine dissociates much more slowly than does lidocaine during diastole, so a
significant fraction of Na+ channels at physiological heart rates remains blocked with bupivacaine, giving rise to adverse effects.

Concentration and pharmacodynamic interactions are the key

Question 17

Choice of LAs in dentistry and medicine?

Answer 17

• The choice of LA should be individualized for each patient, considering the duration of procedure and vasoconstrictor being used to prolong its action, CV health, presence of infection, etc.
• If the duration of numbness is too long, the possibility of “self-mutilation” must be considered in certain patients (for example,
  children).
• In patients for whom postoperative pain is expected, a long-acting LA such as bupivacaine may help with postoperative pain. The total dose of local anesthetic and vasoconstrictor must be determined for each patient based upon body weight. Small children or frail individuals will require below average dosages.

Question 18

When to choose a local or regional anaesthetic?

Answer 18

Anaesthetists report that they would
choose local anaesthesia for themselves as:
* local anaesthesia avoids some of the risks and unpleasantness, such as nausea and vomiting, which sometimes occurs with general anaesthesia;
*local anaesthesia often lasts longer than the surgery, providing pain relief for several hours after the operation;
*local anaesthesia may reduce blood loss.

Question 19

and when would you NOT choose local anaesthesia?

Answer 19

• The type of surgery may not be suitable, e.g., abdominal surgery, which requires general anaesthesia.
• Some surgeons are not used to operating on awake patients and may be too rough or impatient for successful regional anaesthesia.
• Some patients cannot cope with the idea of being awake during surgery..
• Although most types of local and regional anaesthesia have a very high success rate, patients may still feel touch and pressure. This worries some patients.

Question 20

General anaesthesia

Answer 20

the loss of ability to perceive pain associated with loss of consciousness, amnesia etc

produced by either intravenous or inhalation anaesthetic agents

Usually thought to consist of:
* Unconsciousness
* Analgesia (loss of pain)
* Amnesia (loss of recall)
* Immobility and muscle relaxation
* Hemodynamic control in cases of blood loss, tissue ischaemia, reperfusion of tissue, impaired
coagulation issues, etc.

General anaesthetics have relatively low therapeutic indices, which necessitates the monitoring of patients when they are used. For
some drugs, we do not have “antagonists” to reverse effects.

Question 21

Four stages of general anaesthesia

Answer 21

Stage 1. Initial analgesia (loss of pain).

Stage 2. Excitement/delirium, with loss of consciousness (hypnosis), but with heightened reflexes. QUICK!

Stage 3. Surgical anaesthesia, with all reflexes disappearing as stage deepens. Respirator may be used with endotracheal tube.

Stage 4. Medullary paralysis, with respiratory failure and death. This is why patient monitoring is crucial.
Currently, induction of general anaesthesia involves the use of drug combinations to produce unconsciousness, analgesia, neuromuscular blockade, amnesia, and reduction of motor and ANS reflexes.

Question 22

Clinical induction and maintenance of GA

Answer 22

GA usually involves the induction of unconsciousness (hypnosis) with an
i.v. GA drug and then maintenance with an inhaled GA drug, with or
without opioids and neuromuscular blockers.

Question 23

The stages of general anaesthesia

Answer 23

Analgesia
- preliminary introduction
- sedate patient with opioids or start inhaled GA
- preoxygenate

Excitement (transition)
- induction of GA
- administer IV GA or continue inhaled GA
- secure airways and treat hiccoughs, myoclonus,

General Anaesthesia
- maintenance of GA
- adjust IV or inhaled GA
- avoid underdosing (stage II) or overdosing (stage IV)

Excitement (transition)
- emergence from GA
- stop inhalation or IV and reverse NMBs
- treat breath-holding, vomiting, and shivering PRN

Question 24

GA Mechanism of action

Answer 24

Around 1900, it was reported a
strong correlation of inhalation
anaesthetic potency with solubility in oil.

This led to the “lipid theory” that GAs
work by a common and nonspecific
mechanism in which they “dissolve” into the nerve membrane, causing changes to its structure.

Data did not support this as isomers
differed in potency, and altering cell
membranes with temperature changes is not effective.

Question 25

modern anaesthetic drugs

Answer 25

Intravenous (PET)
- Propofol
- Etomidate
- thiopental

Volatile (SIN)
- Sevoflurane
- Isoflurane
- Nitrous Oxide

The inhaled GAs include halogenated hydrocarbons that are volatile at room temperature; these can hyperpolarise neurons or affect synaptic transmission.

The intravenous GAs include aromatic ringed structures, such as thiopental, propofol, and etomidate; tend to exert substantial effects on synaptic transmission.

Question 26

MOA: GABAA receptors as targets

Answer 26

Most GABAA receptors have 2a, 2b and one y(gamma) or d(theta) subunit.

Those with a y(gamma) are mostly at synapses, but can occur peripherally, whereas those with a d(theta) are typically peripheral of the
synapse.

Almost all GAs are positive allosteric modulators of GABAA receptors, except for cyclopropane, ketamine and xenon.

b) GAs prolong channel opening and increase postsynaptic inhibition.

Question 27

Effects on GABAA receptor subunits

Answer 27

Almost all anaesthetics work as positive allosteric modulators on GABAA receptors, with varying affinities for the a- and b-subunits as well as their interfaces.

Question 28

MOA: Glycine receptors as targets

Answer 28

• Glycine may modulate reactions to noxious stimuli as well, as some inhalation anaesthetics are positive allosteric modulators of glycine receptors which plays a role in inhibitory transmission in the spinal cord and brainstem.
• This is not true for all compounds, as etomidate and ketamine do not have such effects, while propofol and barbiturates do.

Question 29

MOA: NMDA glutamate receptors as targets

Answer 29

Xenon, nitrous oxide, and ketamine do not exert their main effects on the GABAA or glycine receptors.

Xenon reduces NMDA receptor function by competing with glycine for its positive allosteric binding site; ketamine blocks the NMDA pore.
Others GAs may impact GABAA primarily, but also have secondary effects by reducing glutamate receptor function.

Inhibiting excitatory receptors is net inhibition…

Question 30

MOA: Two-pore domain K+ channels as targets

Answer 30

TREK and TASK are potassium ion channels with two pores.

These ion channels are directly activated by low concentrations of some inhaled anaesthetics, such as xenon, nitrous oxide and cyclopropane, reducing excitability. They are located pre and post-synaptically and are usually open at rest. Blocking them post-synaptically is thought to lead to hyperpolarization. IV anaesthetics do not seem to have effects via this
mechanism.

Question 31

What is happening within the brain
and where?

Answer 31

In theory, we would expect effects to be somewhat uniform across the CNS.
* In practice, there are areas that seem to be particularly crucial for effective anaesthesia.
– a reduction in cerebral metabolic rate (CMR) and cerebral blood flow (CBF), particularly in the thalamus, which is a major centre for sensory input from the periphery.
– Such suppression may cause transition from awake to anaesthetized states, as well as affecting natural sleep pathways within the brain.
– Hippocampal activity is also reduced by GAs, which is thought to be the cause of the desired amnesia

Question 32

ADME: Inhalation General Anaesthetics

Answer 32

Partial pressure gradients determine
movement of the inhalation gas within the body.
* The more soluble the drug is, the slower its rate of transfer across the blood-brain barrier; the less soluble, the faster its transfer.

The brain is one of several organs which are rich in blood vessels, collectively receiving 75% of cardiac output (CO).
* Once these tissues have achieved equilibrium, levelling off occurs.
* In most surgical procedures, the poorly perfused areas of the body are a non-factor in the diffusion volumes of GAs.

Question 33

Inhalation Anaesthesia and the Minimum Alveolar Concentration (MAC) unit

Answer 33

• One MAC represents the drug vapour concentration (partial pressure) at which 50% of patients exposed to surgical incision do not show a motor response.
• The lower the MAC value, the more potent the inhaled anaesthetic.
• Duration of anaesthesia, gender, height and weight seem to have little
  effect on MAC. MAC values for infants are higher and for elderly are lower than those of young adults.
• Opioid analgesics and benzodiazepines appear to decrease MAC.
• MAC values are additive; addition of nitrous oxide will decrease the MAC of another volatile anaesthetic.

Question 34

Isoflurane

Answer 34

• Clear liquid at room temp, is run through a vaporising apparatus for
  use.
• Is a positive allosteric modulator for the GABAA, inhibits glutamate and potentiates glycine receptors, as well as inhibiting potassium channels.
• Isoflurane also reduces gap junction
  channel activity in the CNS.
• Neuronal acetylcholine receptor
  subtypes may be antagonised as well.

Question 35

Desflurane

Answer 35

• Desflurane is thought be positive
  allosteric modulator of GABAA channels, antagonize glutamate receptors, agonist of glycine receptors and inducer of K+ channels.
• Used in outpatient surgery due to its rapid onset and recovery.
• It can irritate the trachea and bronchi, causing coughing and bronchospasm. Pungent odour.
• Induction occurs via IV agent, and then desflurane used to maintain anaesthesia. 1 MAC = 6-8%

Question 36

Nitrous oxide (N2O)

Answer 36

• Commonly used, “laughing gas” at moderate doses. Colourless and odourless gas at room temp. Not
  flammable or explosive.
• Weak anaesthetic, but good analgesic.
• Positive allosteric modulator of GABAA receptors (less potent), potentiates glycine receptors and inhibits glutamate receptor function.
• Works by activating opioid receptors in the periaqueductal grey matter (PAG).
• Very insoluble in blood, leading to rapid induction and emergence for GA after surgery and is excreted
  unchanged.
• It reduces the MAC of other drugs, such as halothane, when given simultaneously, allowing for less halothane to be used with fewer side-effects.
• Oxygen (100%) is used to reverse anaesthetic effects.

Question 37

Halothane

Answer 37

• Pleasant smelling, non-explosive;
  moderately rapid in induction
• Potent anaesthetic, but unsatisfactory analgesic, so usually combine with N2O or an opioid.
• Concentration-dependent respiratory and cardiovascular depression.
• Lowest mortality associated with a GA, but post-operative complication of hepatitis in 1:35,000 cases.
• Genetically susceptible patients may
  have a hyperthermic crisis.
• Not commonly used any more due to the issues as above.

Question 38

Clearance of inhaled GAs

Answer 38

• Inhaled GAs don’t need to be metabolised in order to be eliminated, the percentage of GA is
  reduced and supplemental O2 is
  used to displace.
• The loss of drug in expired air allows for rapid removal of the drug
  from the body, and reversal of
  anaesthesia.

Question 39

Intravenous anaesthetics

Answer 39

• Most commonly used for induction of anaesthesia; lipophilicity (ring structures) and rapid distribution to the brain and vessel rich organs results in rapid onset and short duration with a single bolus dose. Drug ultimately accumulates in fatty tissues.
• Not generally suitable for maintaining anaesthesia as their elimination from the body is
  relatively slow compared to inhalation agents.
• PK factors affect individual variability in sensitivity, e.g. patient with cardiomyopathy may require a lower dose; elderly patients also require smaller dose due to smaller VD.
• Duration of effect depends upon rate of redistribution or metabolism.

Question 40

Propofol

Answer 40

• is a positive allosteric modulator
  of the GABAA receptors, slight antagonism of glutamate
  receptors.
• may have abuse potential as it
  creates a sense of well being
• may cause apnoea, with concentration-dependent decrease in respiration.
• may cause hypotension and bradycardia (20%) as it depresses cardiac function;
• narrow therapeutic window, and
  no reversal medication; overdose can be lethal.
• Metabolised in liver, clearance process may be reduced in elderly and neonates.

Question 41

Propofol’s concentration-response curve

Answer 41

Correlation between propofol plasma
concentration and anaesthetic depth.

Propofol can be used to induce and
maintain anaesthetic on its own, with
rapid recovery and better patient
experience.

Note that this is NOT a sigmoid curve
– and patient monitoring is a MUST.

There have been reports of patients
experiencing severe metabolic acidosis, renal failure, cardiovascular
distress, and arrhythmia. This may
occur in particularly ill patients,
especially in children.

Question 42

Thiopental sodium

Answer 42

• Belongs to barbiturate class, positive allosteric modulator of
  GABAA receptors.
• Thiopental is used for its rapid
  and smooth onset and short duration of action thus not ideal for short procedures.
• Metabolised slowly in the liver and excreted in the urine.

Question 43

Etomidate

Answer 43

• Etomidate is a non-barbiturate hypnotic that affects the reticular-activating system to produce anaesthesia via positive allosteric modulation of GABAA receptors, enhancing open time.
• Like barbiturates and propofol, etomidate is does not induce analgesia.
• Etomidate induces unconsciousness within one circulation time.
• Respiratory depression is less than thiopental; nausea and vomitingare
  common.
• Recovery is rapid as a result of extensive redistribution and rapid
  metabolism.

Question 44

STEEP curves and patient factors

Answer 44

The concentration–response curves
for anaesthetic-induced loss of
consciousness are extremely steep
(approx 0.2 log units!).

Many factors, including genetic
variability, pharmacokinetics and
age, tend to broaden population
concentration–response curves;
with age, the switch between conscious and unconscious states
can be seen to occur over a very narrow range of concentrations for a
given anaesthetic.

Question 45

What about being conscious and paralysed during surgery?

Answer 45

• This is exceedingly rare
• Typically, patient’s blood pressure and heart rate would go up before they would regain awareness. These are monitored to guide the amount of anaesthetic used.
• If someone is extremely ill or in a serious accident, vital signs may be less reliable.
• Those who abuse drugs and alcohol may sometimes be less affected by anaesthesia than others due to cross-tolerance.
• Regardless, anaesthetists can also monitor brain waves to ensure that the patient stays asleep, adjusting anaesthesia until the procedure is over

Question 46

The symphony of pharmacology in general anaesthesia

Answer 46

• a sedative or anxiolytic premedication (e.g. a benzodiazepine),
• an intravenous anaesthetic for rapid induction (e.g. propofol),
• a perioperative opioid analgesic (e.g. alfentanil or remifentanil)
• an inhalation anaesthetic to maintain anaesthesia during surgery (e.g. nitrous oxide and isoflurane),
• a neuromuscular-blocking agent to produce adequate muscle relaxation
  (e.g. vecuronium) for access to the abdominal cavity for example,
• an antiemetic agent (e.g. ondansetron) and
• a muscarinic antagonist to prevent or treat bradycardia or to reduce
  bronchial and salivary secretions (e.g. atropine or glycopyrrolate).

Towards the end of the procedure:
* an anticholinesterase agent (e.g. neostigmine) to reverse the
neuromuscular blockade) and
* an analgesic for postoperative pain relief (e.g. an opioid such as morphine and/or a non-steroidal anti-inflammatory drug).