Anaesthesiology: Pharmacology of Anaesthesiology Flashcards
(38 cards)
1
Q
Induction agent
A
- A drug which induces **loss of consciousness in **one arm-brain circulation time when given at an appropriate dose
- BDZ, Opioids are sometimes used to induce anaesthesia
—> but do NOT produce rapid LOC
—> therefore not considered to be an induction agent
Exception: Ketamine
2
Q
***Drugs for inducing GA
A
- Barbiturates
- Etomidate
- Propofol
- Ketamine
(Inhalation induction:
- more difficult to perform on adults
- slower than IV induction
- patient will go through the “excitement” phase of anaesthesia induction with risk of coughing, breath holding and laryngospasm
- for children / people with difficulty cannulation (e.g. IVDU))
3
Q
- Barbiturates (e.g. Thiopentone)
A
MOA:
- Potentiate effect of GABA at inhibitory GABAA receptor
Pharmacokinetics:
- Rapid brain uptake, rapid redistribution, hepatic elimination
- ***Slow metabolism & prolonged elimination
Effects:
- CVS: ↓ MAP, ↑ HR, Myocardial depression
- Respiratory: Depression ventilator centre, retain some airway reflexes
- CNS: ↓ CMRO2 (cerebral metabolic rate of oxygen), ↓ CBF (cerebral blood flow), ↓ ICP, anti-convulsant
Uses:
- ***Obstetrics
- ***Epilepsy / seizures
- ***RSI (rapid sequence induction)
- ***Neurosurgical emergency
4
Q
- Etomidate
A
MOA:
- Potentiate effect of GABA at GABAA receptor
Pharmacokinetics:
- Rapid onset & redistribution
- Hydrolysed by plasma esterases & liver
Effects:
- CVS: CVS stability, ***NO effect on contractility, SVR, HR
- Respiratory: ***Minimal effect on respiration
- CNS: ↓ CMRO2, ↓ CBF, ↓ ICP
- Others: Inhibits 11-β hydroxylase —> ***Adrenocortical suppression
Uses:
- ***Cardiac patients
- ***Haemodynamically unstable patients
5
Q
- Propofol
A
MOA:
- Potentiate effect of GABA at inhibitory GABAA receptor
Pharmacokinetics:
- ***Rapid onset & redistribution
- Metabolised in liver, ***high clearance
Effects:
- CVS: ***↓ SVR, ↓ cardiac contractility, ↓ preload
- Respiratory: Respiratory depression, obtunds laryngeal reflexes
- CNS: ↓ CMRO2, ↓ CBF, ↓ ICP, burst suppression
- Others: **fast clear headed wake-up, **anti-emetic, ***propofol infusion syndrome
Uses:
- Most suitable for ***infusion of induction agents
6
Q
- Ketamine
A
MOA:
- Inhibits excitatory NT glutamate at ***NMDA receptors
- ***Dissociative anaesthesia rather than hypnosis
Pharmacokinetics:
- Rapid onset, Slower redistribution
- Hepatic metabolism to norketamine
Effects:
- CVS: ↑ HR, ↑ SVR, ↑ CO by ***SNS activation
- Respiratory: Little effect on RR, bronchodilator, salivation, reflexes preserved
- CNS: ↑ CBF, ↑ ICP, ↑ CMRO2, ***hallucinations, amnesic
- Others: ***analgesic
Uses:
- ***Shocked patients
- As ***analgesic
7
Q
Length of action of an IV bolus
A
- An IV bolus of an appropriately dosed induction agent (other than ketamine) will keep the patient asleep for **3-5 mins
—> ∵ fall in **effector site (brain) concentration + **plasma concentration as drug **redistributes to other parts of body (fat, muscle, skin)
Actual elimination t1/2 of most induction agents: Several hours
Ketamine:
- onset time of 30s (slower than thiopentone)
- effects last for 5-10 minutes
8
Q
***GA maintenance
A
- Volatile anaesthetic agents (Inhalation)
- Nitrous oxide (Inhalation)
- Induction agent (IV)
9
Q
- Volatile anaesthetic agents (Inhalation)
A
Mainstay of anaesthetic maintenance
- Sevoflurane
- Desflurane
- Isoflurane
- Halogenated ether compounds (comes in liquid form)
- Vaporiser: adds a known concentration of volatile agent to a ***gas mixture (usually N2O, O2 or air/O2) which patient inhales via a breathing circuit
- Concentration can be adjusted to keep appropriate concentration of volatile in the lungs
- When volatile is stopped, as the patient ***exhales it is eliminated
—> when the alveolar concentration drops to a critical level
—> patient wakes up
Sevoflurane:
- ***Sweet + pleasant smelling
- ***Non-irritant
- Low blood/gas solubility —> quicker induction than other volatile agents
Desflurane:
- ***Irritant
- Lowest blood/gas solubility
Halothane
- Pleasant smelling
- Historical use (∵ risk of Inhalational hepatitis + long induction time)
10
Q
- Nitrous oxide (Inhalation)
A
- Given with O2 or air in a gas mixture to inhale
-
**Weak anaesthetic
—> not suitable as a sole anaesthetic for maintenance
—> used in **combination with a volatile anaesthetic gas
—> need to breathe 104% to achieve anaesthesia
Advantages:
- Good ***analgesia
- Reduces MAC (Minimum alveolar concentration: Alveolar concentration of inhaled agent which prevents movement in response to a standard painful stimulation in 50% of subjects)
Disadvantages:
- ***PONV
- Diffusion into gas filled spaces
- Effects on bone marrow
- Environmental issues
11
Q
- Induction agent (IV)
A
In theory:
- ALL induction agents are suitable to maintain anaesthesia if given as **infusion or **regular boluses
Problems with maintenance with induction agent:
1. ***Accumulation
- All drugs accumulate on continuous or repeat dosing
—> Very prolonged duration of action
—> Thiopentone a good example: accumulates with repeated dosing
- Dose timing
- Difficult to judge when to give another dose if using bolus technique
- Could be a problem if patient is paralysed - SE
- Etomidate: **Adrenocortical suppression
- High doses of Propofol: **Propofol infusion syndrome
- Ketamine: ***hallucinations
12
Q
Queen Mary Hospital
A
Total Intravenous Anaesthesia:
- Use of ***Propofol as both induction & maintenance agent
- Special pharmacokinetic syringe pumps with computer programs “models” incorporated calculate the concentration of propofol in plasma and the brain for that particular patient’s weight/ (sometimes age, sex, height too)
—> adjusts over time for redistribution & elimination - All anaesthesiologist needs to do is determine what concentration of propofol is appropriate
- Used with ultra-short-acting opioid ***Remifentanil: synergistic effect
13
Q
SE of GA agents
A
Occur during recovery period:
- Hypoxia
- Hypotension
- Sedation
- Confusion and agitation
- N+V
- Headache
- Shivering
14
Q
Hypoxia
A
- Hypoventilation
- Airway obstruction: tongue, edema, laryngospasm
- Respiratory depression
- Residual NMJ blockade
- Poor analgesia - V/Q mismatch
- ↓ CO & FRC - Shunt
- Small airways closure —> lung perfused but not ventilated - Diffusion hypoxia
- N2O more soluble than O2
—> when N2O stopped, diffuses into alveoli from blood faster than N2 can diffuse in opposite direction
—> concentrates N2O compared to other gases in alveoli
—> ↓ FiO2
15
Q
Hypotension
A
Multiple causes for hypotension:
- Vasodilator & cardiac depressant effects of anaesthetic drugs
- Hypovolaemia
16
Q
Sedation
A
Multiple causes for sedation: 1. Residual effect of anaesthetic/analgesic drugs 2. Hypoxia 3. Hypotension 4. Hypoglycaemia 5. Hypothermia 6. Electrolyte disturbance 7. Intracranial pathology etc.
17
Q
Confusion and agitation
A
Multiple causes for confusion and agitation:
- Residual effect of anaesthetic/analgesic drugs
- Hypoxis
- Hypotension
- Hypoglycaemia
- Hypothermia
- Electrolyte disturbance
- Intracranial pathology
- Pain + disorientation
- Urinary retention
- Post-anaesthetic cognitive dysfunction
18
Q
Shivering
A
Multiple causes for confusion and agitation:
- ↑ Muscle activity
- ↑ O2 consumption —> bad for those with impaired myocardial O2 supply
19
Q
Local anaesthesia
A
Na channel blocker:
- LA enter the nerve in unionised lipid-soluble free base form
—> inside the nerve, it ionises
—> ionised form enters + blocks Na channels
—> once enough Na channels are blocked
—> drops below threshold of critical level
—> ***depolarisation is prevented
—> action potentials cannot be generated (∵ all or nothing)
—> nerve blockade
20
Q
Calculating safe dose for LA
A
Depends on:
- Drug
- Weight of patient
- Vasoconstrictor additive
Bupivacaine:
- Max recommended dose: 2 mg/kg
- Max recommended dose with vasoconstrictor: 2 mg/kg
- **long-acting LA —> very suitable for **post-operative pain relief
- can become very dangerous if toxic levels develop from overdose or inadvertent IV injection
Levobupivacaine:
- Max recommended dose: 2 mg/kg
- Max recommended dose with vasoconstrictor: 2 mg/kg
- ***less cardiotoxicity in overdose situation than Bupivacaine
- takes longer to take effect than Lignocaine, this will not be an issue if the block is used in combination with GA
Lignocaine:
- Max recommended dose: 3 mg/kg
- Max recommended dose with vasoconstrictor: 7 mg/kg
- ***short-acting
Ropivacaine:
- Max recommended dose: 3 mg/kg
- Max recommended dose with vasoconstrictor: 3 mg/kg
- ***less potent than Bupivacaine and potentially less toxic when overdose
- ***less motor blockade than Bupivacaine
21
Q
LA toxicity
A
Neurological S/S:
- ***Lightheadness, Dizziness, Drowsiness
- ***Tingling around lips, fingers / generalised
- ***Metallic taste
- ***Tinnitus
- BOV
- Confusion
- Restlessness
- Incoherent speech
- Tremors / Twitching
- ***Full-blown convulsions with LOC / Coma
CVS S/S:
- ***Bradycardia (can Tachycardia)
- ***Hypotension
- CVS collapse
- Respiratory arrest
- ***QRS + PR prolongation
- ***AV block
- Change in T wave amplitude
22
Q
LA toxicity vs LA allergy
A
LA toxicity:
Causes:
1. Inadvertent IV injection (failure to aspirate before + during injection)
2. Overdosage of LA
3. High plasma levels (∵ IV injection / high dose given continuously over a prolonged period, rapid injection / absorption over a highly vascular site e.g. intercostal)
4. High risk injection sites
- Lumbar plexus
- Intercostal block
5. Narrow therapeutic window agents (e.g. Bupivacaine)
Effect:
- Initially CNS effect —> CVS effect
Management:
- ***Stop injecting drug
- Assess ABC + give ***high flow O2 simultaneously
- Hyperventilation may help increase pH (if metabolic acidosis) - Treat convulsions with ***BDZ (IV Midazolam / Diazepam / Lorazepam / Thiopental (barbiturate))
- Treat hypotension with ***Vasopressors (Ephedrine / Phenylephrine / NE / E)
- Call for senior help, declare medical emergency, get nurses to bring resuscitation trolley
- Immediate CPR if cardiac arrest
- Advanced airway
- IV access
- Prompt defibrillation - 20% ***Intralipid
- Prepare for protracted resuscitation
LA allergy:
- True allergy to amide local anaesthetics is rare
- Ester local anaesthetics are more likely to be associated with allergic reactions
23
Q
Anxiolytics
A
BDZ
MOA:
- Works by enhancing GABAA inhibitory neurotransmission
Effect:
- Sedative
- Hypnotic
- Anti-convulsant
- Amnesic
- Muscle relaxation
Uses in anaesthesia:
- For sedation, premedication / anxiolysis, occasionally GA induction at high doses, anti-convulsant
SE:
- CNS
- dose related depression
- amnesia - CVS
- mild / minimal effects on CVS —> effects more marked in elderly - Respiratory
- loss of sensitivity to CO2 —> effect varies from no effect to apnoea, ↓ tidal volume
Midazolam:
- Most commonly used BDZ in anaesthesia
- Water-soluble due to imiazole ring structure —> becomes lipid-soluble inside body
- More potent than Diazepam
- Onset time: 30s
- Peak action: in 3-5 minutes
- t1/2: 2-4 hours
- High affinity for BZ receptor
- Action terminated by redistribution from brain to other sites
BDZ reversal agent: Flumazenil
24
Q
Antiemetics
A
N+V:
- mediated by
1. Afferents from gut / vagus
2. Vestibular system
3. Chemoreceptor trigger zone (CTZ) - in area postrema at floor of 4th ventricle outside of BBB
These mediate with ***ill-defined area of brainstem traditionally known as “vomiting centre” & nucleus tractus solitarius (NTS)
- Implicated receptors:
1. 5HT3
2. D2
3. H1
4. ACh
5. NK1
Drugs:
- Anticholinergics
- Antihistamines
- Antidopaminergics
- ***Antiserotonin (1st line)
- ***Steroids (1st line)
25
PONV risk factors
Multifactorial
1. Patient factors
- ***Female
- ***Young
- ***Non-smoker
- History of PONV
- Travel sickness
2. Surgical factors
- Surgery type: ***ENT, eye, abdominal, gynaecological
- Surgical technique: ***Laparoscopic
- Surgical complication: Swallowed blood
3. Anaesthetic factors
- Pharmacological: ***Opioid, ***N2O, Volatile agent
- Others: dehydration, poorly controlled pain, anxiety
- Failure to give prophylaxis in high-risk patient
26
1. Anticholinergics
- Antagonism of muscarinic ACh receptor
- 2nd-line anti-emetic
- Useful for ***motion sickness, opioid-induced vomiting
- Use is limited by SE (e.g. sedation, dry mouth, confusion)
Example:
- Hyoscine
27
2. Antihistamines
- Antagonism of H1 receptor
- 2nd-line anti-emetic
Example:
- Cyclizine
28
3. Antidopaminergics
- Antagonism of D2 receptor
- 2nd-line anti-emetic
Examples:
- Prochlorperazine
- Metoclopramide
29
4. Antiserotonin
- Antagonism of 5-HT3
- ***1st-line anti-emetic
- ***Prolong QTc, risk of ***torsades de pointes
Example:
- Ondansetron
30
5. Steroids
- Unknown mechanism of action for anti-emetic effect
- ***1st-line anti-emetic
Example:
- Dexamethasone
31
Analgesics
1. Paracetamol
2. Opioid
3. NSAID
32
1. Paracetamol
MOA:
- Unknown
- Traditionally thought to work via inhibition of central prostaglandn synthesis, possibly multi-receptor action
—> COX (but not COX1 or COX2)
—> Serotonergic
—> Endocannabinoid
- Now known to not have anti-inflammatory properties
PK:
- Hepatic clearance
Uses:
1. Anti-pyretic
2. Analgesic
- Consistenly shown in studies to ↓ pain scores
- Enhance analgesia when used in conjunction with other classes of analgesics —> ***Opioid-sparing + ***Anti-hyperalgesic
- No effect on platelet adhesiveness
- No gastric irritation, N+V
33
2. Opioid
SE:
1. Respiratory depression
2. Sedation
3. N+V
4. Bradycardia + Hypotension
5. Constipation
6. Histamine release
7. Hormonal effects
- suppression of ACTH, prolactin
8. Tolerance + Dependence
Caution: Renal failure
- Morphine is metabolised by the liver to active metabolite morphine-6-glucuronide and inactive metabolite morphine-3-glucuronide. These are ultimately excreted by the kidney
—> patient will be more susceptible to SE of morphine, and it is important to monitor this patient carefully, particularly HR, BP, SPO2, RR, sedation score
PCA:
Advantages compared to PRN administration:
1. Intravenous administration
- no bioavailability issues
2. Small drug doses given at intervals
- less chance of sudden “high” plasma level, more likely to maintain a constant plasma level
3. Patient titrates drug to their own desired effect
4. Safety
- too much drug —> sedated patient —> unable to press PCA button
5. Psychological wellbeing
- patient in control
6. No waiting to obtain drug
- opioids are controlled drugs, administering is onerous on nurses
7. Research shows overall amount of opioid used generally less than with other methods of administration
34
3. NSAID
Cyclo-oxygenase (COX) blockers
SE (more common in the elderly):
1. Renal disease
- NSAIDs block prostaglandin (PG) synthesis
—> ↓ Renal blood flow, Na retention
—> Renal failure
- Also risk of interstitial nephritis + ↑ K
2. Heart failure
- Na + H2O retention worsen cardiac failure
3. Gastric ulceration, GI bleed
- PGs inhibit gastric acid secretion which have cytoprotective effects on mucosa
4. Low platelets / bleeding
- NSAIDs block ***Thromboxane A2 synthesis —> needed for aggregation, adhesion + vasoconstriction
5. Asthmatics
- blockade of COX pathway
—> shunts arachidonic acid to be converted to ***leukotrienes via lipo-oxygenase pathway
6. IHD
- COX 2 associated with ***thrombosis risk
—> Inhibition of COX2 mediated ***PGI2 production in coronary wall
—> Loss of ***vasodilating + ***anti-thrombotic properties
—> combined unopposed COX1 production of Thromboxane A2 (vasoconstricting + prothrombotic)
35
NMJ blockers
Types:
1. Depolarising
2. Non-depolarising
Use:
- Relax laryngeal / vocal cord muscles
36
1. Depolarising NMJ blockers
MOA:
***Agonist of ACh receptor
—> causes prolonged receptor activation / depolarization
—> receptor becomes ***refractory + deactivated
—> until membrane potential is reset
Example: ***Succinylcholine (aka Suxamethonium)
Succinylcholine:
- Only depolarizing NMJ blocker in clinical use
- Structurally: 2 ACh molecules joined together
- Recovery by ***diffusion of succinylcholine away from receptor
—> ultimately broken down by ***plasma cholinesterase
- Profound block within 60s
- Recovery begins in 3 mins
- Full recovery 12-15 mins
- ***Rapid onset (45s)
—> particularly suitable for rapid sequence induction (RIS) is important
—> minimise duration in which the patient has an unsecured airway
—> time from ***induction of anaesthesia to ***intubation is short
- ***Rapid offset (5 mins)
—> if wear off
—> patient can spontaneously breathe
—> otherwise patient in apnea (∴ still have to ***preoxygenate patient in case cannot secure airway / ventilate patient —> able to tolerate 5 mins of apnea)
SE of Succinylcholine:
1. ***Parasympathetic effects
- Cardiac: activation of muscarinic receptors at SA node —> Severe bradycardia / AV nodal rhythm after repeated dosing (children esp. vulnerable)
- ↑ Bronchial + Salivary secretions
- ↑ Intra-gastric pressure
2. ***HyperK
- rise in serum K: 0.5-1 mmol/l
- ***MUST check K before administration
- may cause dangerous hyperkalaemia in renal patients, muscular dystrophy, burns & paraplegic patients
3. Muscle pain
4. ***Malignant hyperthermia / hyperpyrexia
5. Allergy
- type 1 hypersensitivity + anaphylaxis
6. ↑ IOP
7. Prolonged paralysis
- in those with abnormal variants of plasma cholinesterases
8. Tachyphylaxis
- ↓ response after repeated dosing, may precede development of NMJ blockade ~ to non-depolarisers + prolonged paralysis
37
2. Non-depolarising NMJ blockers
```
Example:
- Benzylisoquinolinium
—> ***Atracurium
- Aminosteroid
—> Pancuronium
—> Vecuronium
—> ***Rocuronium
```
MOA:
Competitive inhibition of ACh receptor at post-synaptic membrane
—> act as ***antagonists at the ACh receptor (vs depolarizing neuromuscular blockers which act as agonists)
—> Depolarisation by ACh is progressively diminished ∵ ↓ number of available receptors
—> eventually failure to generate an AP
—> action terminated by drug being broken down / diffusing away from receptor / displacement of drug away from receptor (by increasing availability of ACh)
Rocuronium:
- Fast onset time (when used in high doses)
- Longer offset time but Sugammadex enable it to be quickly reversed
Reversal:
1. Neostigmine (AChE inhibitor)
—> ↑ concentration of ACh at synaptic cleft
—> displace non-depolarizing neuromuscular blocker from ACh receptors
2. Sugammadex
- chelating agent for NMJ blocker
38
Maintain Neuromuscular blockade
1. Atracurium
- ~45% of atracurium broken down by a process called ***Hofmann degradation at standard body temperature & pH, the drug will spontaneously break down and degradation is not dependent on any intact liver or kidney function
2. Pancuronium
- long acting amino-steroid non-depolarizing NMJ blocker
- broken down by kidney —> prolonged elimination time + duration of action in renal failure
3. Vecuronium
- non-depolarizing amino-steroid NMJ blocker
- broken down in liver, but some undergoes renal excretion, leading to increased duration of action in renal failure
4. Rocuronium
- mainly liver excreted but elimination t1/2 is increased 37% in renal failure
