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BMSc - Neuropharmacology and Behaviour > Clinical Anaesthesia > Flashcards

Clinical Anaesthesia Flashcards

1
Q

What are GAs?

A

A reversible, drug induced state of unconsciousness (including muscle relaxation and analgesia)

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2
Q

What are the different stages of anaesthesia?

A

Stage 1 = state of analgesia or disorientation
Stage 2 = stage of excitement or delirium
Stage 3 = state of surgical anaesthesia
Stag 4 = medullary paralysis - ultimately cardio/resp arrest

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3
Q

Describe the triad of GA

A

Narcosis
Muscle Relaxation
Analgesia
== balanced GA

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4
Q

Describe the different narcosis agents

A

Inhalational (induction and maintenance) - isoflurane, sevoflurane (sweet smelling, smooth induction, good for children), desflurane (low blood/gas solubility co-efficient, rapid onset and offset, highly irritant to airways, useful for maintenance and rapid wakeup)

IV anaesthetics (smooth and rapid induction):

  • Propofol (often with midazolam to produce synergistic action, allowing for a reduced dose of each agent, reducing SE)
  • Thiopentone
  • Etomidate
  • Ketamine (dissociative)

Frequent bolus for maintenance - total intravenous general anaesthesia

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5
Q

How are inhalational anaesthetics produced?

A

Must be vaporised

Pass anaesthetic gases such as oxygen, NO or air over the liquid anaesthetic, transferred to patient

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6
Q

Describe the drawbacks of IV anaesthetic induction

A

Although a smooth induction, there are significant SE

Propofol; hypotension, resp depression

Thiopentone; hypotension (less so than Propofol), resp depression

Etomidate; cardiovascular smooth induction but can produce pain on injection

Ketamine; unusual form of anaesthesia, dissociative

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7
Q

How is muscle relaxation achieved in GA?

A

NMJ agents that target NAChARs on post synaptic membrane on skeletal muscle

These are different from general muscle relaxants (BZD, baclofen)

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8
Q

What are the 2 groups of NMJs in GA?

A

Depolarizing - suxamethonium

Non-depolarizing - atracurium, vecuronium, rocuronium

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9
Q

Within the dorsal horn, where do the nociceptor fibres terminate in the laminae of rexed

A

Layer 1 and 2 (C fibres)

Layers 1 and 5 (A-delta)

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10
Q

Where is the substantia gelatinosa located?

A

Layer 2 of laminae of rexed

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11
Q

How is pain controlled in the peri-op period?

A

Pain assessment is used to guide analgesia (visual analogue scale)
WHO pain ladder
Other techniques; LA (local infiltration or regional block), centrally acting (non-opioid); amitriptyline, gabapentinoids
Non-pharma; TENS, acupuncture (release of endogenous opioids)
Psychological

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12
Q

Describe the ideal analgesic drug

A

Suppressive of all pain types (MSK, visceral, dull, shooting)

Inexpensive

Does not inhibit other sensations e.g. motor block

Good oral bioavailability/ easily metabolised and excreted

Non-toxic

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13
Q

Describe opioids

A

Mixture of alkaloids from opium poppy

Phenanthrene derivative
2 planar rings and 2 aliphatic rings
Morphine derivatives; based on substitution at C3 and C6 to OH and N17

Semi-synthetic opioids:

  • Methadone (long half life)
  • Piperidines (pethidine, fentanyl; short half life with high potency)
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14
Q

Describe the central effects of opioids

A 
Analgesia 
Sedation 
Euphoria (dependence) 
Respiratory depression (careful titration) 
Anti-tussive 
N+V (use antiemetics) 
Pupillary constriction
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15
Q

Describe the peripheral effects of opioids

A

Hypotension (direct CVS depression, vasodilation, alongside central effect)

Increases sphincter tone and reduces gastric motility = constipation, nausea

Urinary retention

Histamine release = itch (pseudoallergic effect)

Immunosuppressant effect - poorer outcomes after surgery

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16
Q

Describe the opioid receptors

A

Mu (OP3/ MOR)
Kappa (OP2/ KOR)
Delta (OP1/ DOR)
Sigma (not true opioid receptor)

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17
Q

Where can the mu receptors exert analgesic effects?

A

Supra-spinal
Spinal
Peripheral

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18
Q

Describe the different endogenous ligands?

A

Mu; beta endorphin, endomorphin
Delta; enkephalin (met and leu enkephalin)
Kappa; dynorphin

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19
Q

Describe the MOA of opioids

A

Act via Gi/o
Inhibit calcium entry via N and P/Q channels (also R)
Facilitate potassium efflux via IR channels (GIRK)
Inhibits cAMP
Inhibit nT release

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20
Q

What are the advantages and disadvantages of PCA?

A

Up to 12 mg of morphine per hour

Ad:

  • Dose matches need
  • Reduced nursing workload coordination
  • Patient autonomy

Disad:

  • Expensive
  • Cooperation and breakthrough pain
21
Q

What are other routes of opioid administration (not IV, IM)

A

Oral; not immediately after major abdo surgery, not suitable for NBM or PONV (peri-op nausea and vomiting)

Sublingual; limited to buprenorphine (partial agonist)

Transdermal (fentanyl); highly lipophilic therefore well absorbed, useful for chronic pain

22
Q

What are the benefits to a spinal and epidural opioid injection?

A

Excellent analgesia
Spinal - directly into CSF into substantia gelatinosa

SE:

  • Resp depression
  • Urinary retention (men)
  • Itching +++
  • N+V
23
Q

What is the bioavailability of opioids?

A

Ratio of a drug that reaches the systemic circulation in comparison with IV injection

Oral morphine = extensive first pass metabolism (only 30% reaches systemic)

Synthetic morphine 6 glucuronide achieves bioavailability of up to 50%

Topical/ sublingual - increased bioavailability

IV/ spinal/ epidural analgesia

24
Q

Describe the metabolism and excretion of opioids

A

Converted to polar metabolites (liver) and excreted via kidney

Hydroxyl groups are conjugated with glucuronide (e.g. morphine)

Esters are hydrolysed by esterase’s (pethidine)

N-demethylation also occurs (methadone) - this is why methadone has a long half life

25
Q

When are NMJ drugs needed?

A

Tracheal intubation
Mechanical ventilation
Surgery where muscle relaxation is required

26
Q

Describe the basic physiology of the neuromuscular junction

A

Motor nerves extend form brainstem (cranial nerves) or spinal cord to the skeletal muscle

Insulated with myelin, speeding conduction to 50-100 m/s (saltatory conduction)

Axon terminates in motor end plate

27
Q

Describe the most common subtype of nicotinic ACh receptors

A

2 alpha 1
Beta 1
Epsilon
Delta

Forms a pentameric structure around a central pore

ACh binds to alpha 1; conformational change, allowing Na+ influx into the post synaptic endplate = endplate potential

28
Q

What is the action of botulinum toxin?

A

Reduces the release of ACh

Flaccid paralysis

29
Q

What do NMJ blockers target?

A

Nicotinic ACh receptors on post synaptic membrane

30
Q

What is the only depolarising NMB?

A

Suxamethonium - quaternary ammonium compound (2 ACh molecules)
Each ACh moiety binds to an alpha subunit - opening the channel

Clinically:

  • Fasciculation then relaxation (refractory period)
  • Rapid onset (60-90 secs)
  • Rapid offset (3-5 mins) due to plasma cholinesterase’s
31
Q

Describe the different phases of suxamethonium NMJ blockade

A

Despite initial activation of nicotinic ACh receptors, the ongoing activation leads to inactivation = paralysis

Phase 1 block:

  • Persistent activation of endplate nicotinic receptors
  • Prolonged depolarisation of endplate
  • Inactivation of voltage-gated sodium channels

Phase 2 blocks:

  • Desensitization of endplate nicotinic receptors
  • Repolarization of endplate
  • Receptor desensitization maintains blockade
32
Q

How is sux metabolised?

A

Plasma pseudocholinesterase’s

Gene encoding plasma cholinesterase’s is E1u

3 abnormal genes: E1a (atypical), E1s (silent), E1f (fluoride-resistant) associated with decreased enzymatic activity

94% of population are heterozygous for usual gene (normal response to sux); E1a homozygotes in 0.03% of population, E1s in 0.001% and E1f in 0.0003% = all remain apnoeic for 1-2 hours - suxamethonium apnoea

33
Q

What are the SE of suamethonium?

A

Muscle pains

Increased intraocular/ intragastric (regurgitation = aspiration pneumonia) / intrathoracic pressure

Increased ICP

Hyperkalaemia (issue in elderly, or renal issues)

Increased vagal tone (incr parasymp activation) - brady

Anaphylaxis (quaternary ammonium compound)

Prolonged apnoea (plasma cholinesterase deficiency)

Trigger for malignant hyperpyrexia (inherited condition due to mutation within ryanodine (sarcoplasmic reticulum) resulting in intense muscle spasms and hyperthermia

34
Q

Describe non-depolarizing NMJ agents

A

Competitive nicotinic receptor antagonists at NMJ

Highly ionised/ water soluble

2 main classes:

  • Benzylisoquinolinium; tubocurarine/ atracurium/ mivacurium
  • Aminosteroids; vecuronium, rocuronium
35
Q

What is the half life of tubocurarine?

A

100 mins

Causes twitch-tension

36
Q

What is a feature of all non-depolarizing muscle agents?

A

Post-tetanic fade

Twitch height after sustained tetanus is reduced following administration

Fade due to blockade of pre-synaptic ACh receptors

37
Q

Describe atracurium

A

Quaternary ammonium compound broken down by Hoffman Degradation (temp and pH dependent) and plasma esterase’s
Undergoes spontaneous hydrolysis; not reliant on normal hepatic and/or renal metabolism

38
Q

What is the benefit of Hoffman Degradation of Atracurium?

A

Provides a safety net for patients (especially those with hepato-renal failure)

Duration; 20-30 mins

No direct cardiac effects (c.f. suxamethonium)

Histamine release (local - itch, wheals. Systemic; hypotension, bronchospasm)

39
Q

Describe vecuronium

A

Aminosteroids

Possess a quaternary ammonium ion attached to the steroid nucleus (androstane) and an acetate ester

Minimal histamine release, mild bradycardia and moderately rapid onset

Active metabolites (50-70% of parent drug activity)

Reversal; largely through redistribution, elimination t1/2 is about 60 mins

Prepared as a powder with mannitol

40
Q

Describe rocuronium

A

Rapid onset curonium, desacetoxy analogue of vec

Similar onset time as sux; 60-90 secs

Metabolised in liver; t1/2 = 40-60 mins

Novel reversal agent; sugammadex

41
Q

How can the reversal of NMJB be achieved?

A

For non-depolarizing agents; increase ACh within the synaptic cleft to act as competition. This is achieved by blocking activity of acetylcholinesterase

42
Q

Describe the action of anticholinesterases in the reversal of non-depolarizing NMJB

A

Inhibit acetylcholinesterases to prolong half life of ACh
Short acting = edrophonium
Medium acting = neostigmine/ pyridostigmine
Irreversible = dyflos

43
Q

Describe ACh

A

nT at NMJ (nicotinic AChRs) and also parasympathetic nervous system/ ganglia (muscarinic AChRs), and therefore when using anticholinesterases co-administration with atropine of glycopyrrolate (anti-muscarinic) is required to prevent unwanted muscarinic effects (parasympathetic NS):

  • Brady
  • Hypotension
  • Bronchoconstriction
  • Incr peristaltic activity
  • Hypersalivation
  • Incr lacrimation
44
Q

Describe irreversible anticholinesterases

A

Pentavalent organo-phosphorous compound
Used as insecticides and chemical weapons; dyflos or parathion

Relies on synthesis of new enzyme s(days/ weeks)

Chronic exposure = neurological symptoms

Prophylactic (medium acting) carbamates and atropine (anti muscarinic) may prevent poisoning

Centrally acting agents have potential use in Alzheimer’s disease

45
Q

Describe sugammadex

A

Modified gamma-cyclodextran

Eight neg charged carboxy thio-ethers binds to the quaternary nitrogen of rocuronium (and vecuronium)

Rapid reversal of mod or deep paralysis (1-2 mins)

Minima risk of residual paralysis

Avoids autonomic SE assoc with neostigmine and muscarinic antagonists

Cost prohibits widespread use

46
Q

Compare non depolarizing drugs from depolarizing drugs

A

Non-depolarizing = competitive muscle relaxants compete with ACh for receptor sites at NMJ, with action reversal with anticholinesterases such as neostigmine

Non-depolarizing have a slower onset of action than sux

Non-depolarizing; classified by duration of action (short = 15-30 mins, intermediate (30-40 mins) and long (60-120 mins), although duration of action is dose-dependent

Short/ intermediate = atracurium, vecuronium
Long duration of action = pancuronium

Non-depolarizing agents have no sedative or analgesic effects, and furthermore do not trigger malignant hyperthermia

Patients in intensive care or tracheal intubation/mechanical ventilation = non-depolarizing agent is chosen according to onset of action

  • Rocuronium due to rapid onset can facilitate intubation
  • Atracurium or cisatacurium are suitable for long term NMJ blockade because duration of action is not dependent on elimination by liver or kidneys
47
Q

Describe atracurium

A

Benzylisoquinolinium NMJB with intermediate duration of action

Undergoes non-enzymatic metabolism which is independent of liver or kidney function, thus allowing use in patients with hepatic or renal impairment

CV effects are assoc with significant histamine release; which can be minimised by slow administration or divided doses over 1 min

48
Q

Describe rocuronium

A

Effect within 2 mins, most rapid onset of non-depolarizing NMJ drugs
Aminosteroids with intermediate duration of action
Minimal CV effects; high doses produce mild vagolytic activity

49
Q

Describe sux

A

Most rapid onset of action of all NMJBs
Ideal if fast onset and brief duration of action are required e.g. tracheal incubation (RSI)

Action cannot be reversed and recovery is spontaneous; anticholinesterases such as neostigmine potentiate the NMJ block

Should not be given after anaesthetic induction because paralysis is usually preceded by painful muscle fasciculation’s

Tachycardia occurs with single use, bradycardia occurs with repeated doses

Premed with atropine reduced bradycardia as well as excessive salivation assoc with sux

Prolonged paralysis may occur in dual block, which occurs with repeated or high doses of sux
Development of non-depolarising block following initial depolarising block.

Myasthenia gravis = resistant to sux but may develop dual block = delayed recovery

BMSc - Neuropharmacology and Behaviour (27 decks)

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