LA & GA Drugs Flashcards
MOA of LA
Stop axonal conduction by BLOCKING SODIUM CHANNELS in the axonal membrane when applied LOCALLY in APPROPRIATE
CONCENTRATION –> prevent sodium ion entry –> slow down or bring conduction to a halt
NON-SELECTIVE modifiers of neuronal function, ie. they will BLOCK ACTION POTENTIALS in all neurons to which they have access
Use-Dependency concept of LA (MOA)
Depth of LA nerve block increases with action potential frequency because LA
molecules:
- gain access to the channel more readily when channel is open (LA works better when you are in more pain)
- have higher affinity for the inactivated than for the resting (closed) channels
How to achieve selectivity for LAs?
By delivering LA to a limited area (topical application, injection into a limited area)
Factors affecting LA action
- More lipid soluble drugs are more potent and act longer
- more hydrophobic: more potent, acts longer - Act on all nerves
Size: Smaller nerve > bigger nerve
Frequency of firing: high (sensory) > low (motor)
Position: circumferential > deep (large nerve trunk)
e.g. More superficial neurons (easier for LA to get to) >deeper neurons
Myelination: myelinated > nonmyelinated
- pH dependency
What kinds of axons do LAs have the greatest effect on?
Small myelinated axons
Small myelinated axons > small non-myelinated axons >
large myelinated axons
Note:
1. Size if axons most important factor
2. Myelination (2nd most impt factor)
Type A neuronal fibers
Function: Proprioception, motor
Size: Large
Least sensitive to block –> least sensitive to LA
Type C neuronal fibers
Anatomically located at dorsal root
Function: Pain
Size: very small
Most sensitive to block –> most sensitive to LA
Which fiber type will LA be more potent on? Type A fiber or Type C?
Type C Pain fibers
Factors affecting LA action - pH dependency
LA molecules are weak bases
Potency is strongly pH-dependent:
- Alkaline pH –> increase LA activity
- Acidic pH –> decrease LA activity
LA will not be very effective if tissues are already inflamed (acidic pH) –> best to receive LA before inflammation
Plays critical role in LA penetrate nerve sheath and axon membrane to reach the inner end of the sodium channel (LA binding site)
Main drug classes of LAs
Esters (-COO)
- Cocaine (medium duration)
- Tetracaine (long duration)
- Procaine
Amides (-CONH)
- Lidocaine (medium duration)
- Mepivacaine (medium duration)
- Bupivacaine (long duration)
Method of metabolism (how is it broken down?) of ester-type LAs
Plasma/tissue non-specific esterases
Method of metabolism (how is it broken down?) of amide-type LAs
Hepatic enzymes
What type of LA should a patient with chronic liver disease be prescribed with?
Ester-type LA
NOT AMIDE-TYPE (to prevent stressing hepatic enzymes when the liver is already diseased)
What determines the onset of LA
Anaesthetics that penetrate the axon most rapidly have the fastest onset
small size, high lipid solubility,
low ionization (@ tissue pH) –> faster onset
What leads to LA toxicity?
- Unintended large dose of LA if accidentally injected IV / intra-arterial –> systemic toxicity
- excessive (overdose) LA injected locally & subsequently leads to high (& toxic) blood level following absorption –> systemic toxicity (however onset of toxic S&S appear late)
Why is LA used in combination with epinephrine?
Epinephrine: reduces vessel diameter, causes vasocontriction
Prevent LA systemic distribution from site of action –> lowers rate of absorption into systemic circulation
Which organs will be most affected by LA toxicity?
- Brain (CNS)
- Heart (CVS)
How will the brain (CNS) be affected by LA toxicity?
sleepiness – visual and auditory – restlessness – nystagmus – shivering – convulsion – stoppage of vital functions – death
How will the heart (CVS) be affected by LA toxicity?
cardiac contraction – arteriolar dilation – hypotension – cardiovascular collapse
A patient has a heart disease. Which LA should NOT be prescribed to him?
Bupivacaine.
Bupivacaine is more cardiotoxic than most other LAs.
Which LA blocks NA (noadrenaline/ norepinephrine) reuptake? (causing vasoconstriction and hypertension)
cocaine
Which LA (ester/amide type) can be hydrolysed to PABA derivatives and what are the consequences?
Ester LAs
Ester LAs are hydrolysed to p-aminobenzoic acid (PABA) derivatives, which cause allergic reactions in a small percentage of the population (skin rash/anaphylactic shock)
A patient has a known allergy to PABA. Which type of LA should be prescribed?
Amide type LA
NO ESTER LA as ester LAs will be hydrolysed to PABA derivatives
Ester type vs Amide type LAs
Ester type:
- good for people with liver disease
Amide type:
- good for people with PABA allergies
Dangers of prilocaine
Prilocaine can be metabolised to O-toluidine which causes methaemoglobin (dysfunctional haemoglobin –> blood loses red colour, turns bluish)
How to treat methaemoglobin:
- iv methyleneblue/ascorbic acid
(which converts methaemoglobin to haemoglobin)
Clinical applications of LA – Topical (surface)
- Skin (minor burn/wound)
- Eye (remove foreign objects)
- Dental (applied on gum)
- Otorhinolaryngology (insertion of endoscope for GU scope)
- Gynaecology (episiotomy cuts, lidocaine)
Clinical applications of LA – Injected
- Epidural anaesthetics
(lidocaine, bupivacaine) - Dental anaesthesia
Lidocaine (short term)
Bupivacaine (long term, note cardiotoxicity!)
combine with epinephrine –> for vasocontriction –> reduces rate of absorption into systemic circulation
What affects the choice of LA drug use?
Based on duration of action
Surface anaesthesia requires rapid penetration of the skin (mucosa) and limited tendency to diffuse away.
Note: Cocaine gives good penetration and vasoconstriction, thus most often used for ENT procedures, but clinical use in SG is very limited
What is GA used for?
To produce unconsciousness and a lack of responsiveness to all painful stimuli (inhibition of sensory and autonomic reflexes)
ie. triad of hypnosis, amnesia, analgesia
provide conditions for interventions - surgery, skeletal muscle relaxation
What should be the endpoint of GAs?
Keep patients safe and alive upon GA reversal
What is the additional consideration for GA?
Control of physiology
What are the stages for GA?
Pre-assessment
Induction of anaesthesia
Airway management
Maintenance of anaesthesia
Reversal/Emergency
Post-operative Care
What constitute an ideal GA? (What properties should an ideal anesthetic drug have?
Unconciousness
Analgesia
Muscle relaxation
Amnesia
Brief and pleasant
Depth of anaesthesia can be raised or lowered with ease
Minimal adverse effects
Margin of safety - large
NO SINGLE AGENT HAS ALL OF THESE PROPERTIES
What are the 3 properties of balanced anaesthesia?
Pain relief
Unconsciousness
Inhibition of reflex
What is the purpose of balanced anesthesia?
To ensure that induction is smooth and rapid, and that analgesia and muscle relaxation are adequate
What are the drugs used in combination in GA?
Inhalation anaesthetics + IV anaesthetics
What is the most commonly used drug for induction of anaesthesia?
Short-acting barbiturates
What is the most commonly used drug for muscle relaxation?
Neuromuscular blocking agents
What are the most commonly used drugs for analgesia?
Opioids and nitrous oxide
Inhalant GAs - How does the blood solubility affect the onset?
The higher the blood solubility, the slower the onset
As blood solubility increases, the longer the anaesthetic stays in the blood instead of going to the brain.
Does nitrous oxide have a faster or slower onset than halothane?
Nitrous oxide has a faster onset because its blood solubility is lower.
Classify the following inhalation aneasthetics into volatile liquids and gases:
Halothane
Enflurane
Desflurane
Isoflurane
Sevoflurane
Nitrous oxide
Volatile liquids: -ane
Halothane
Enflurane
Desflurane
Isoflurane
Sevoflurane
These are adminstered using an agent specific-vaporizer
Gas:
Nitrous oxide
What is the proposed MOA of inhalation anesthetics?
- Enhance neurotransmission at inhibitory synapses via allosterically increasing GABA receptor sensitivity to action by GABA itself (positive allosteric modulator)
- Depressing neurotransmission at excitatory synapses via blocking glutamate neurotransmitter acting on NMDA receptor thus preventing NMDA receptor activation (negative allosteric modulator)
oh god idk what this all means
What is minimum alveolar concentration (MAC)?
An index of inhalation anasthetic potency (low MAC = high anasthetic potency)
Defined as the minimum concentration of drug in the alveolar air that will produce immobility n 50% of patients exposed to a painful stimulus.
MAC values alter with age, condition, concomitant administration of other drugs etc.
What are the MACs of nitrous oxide, isoflurane, sevoflurane, & desflurane?
Nitrous oxide: 105% (not even 100% of NO will make 50% of patients immobilised)
Isoflurane: 1.2%
Sevoflurane: 2.2%
Desflurane: 6.3%
What the factors that affect the absorption of inhalation GAs into the blood?
- Concentration of anasthetic in inspired air
- Solubility of GA
- Blood flow through lungs
Increase in any of these factors -> increase rate of GA uptake into blood
What affects the distribution of GAs?
Determined by regional blood flow - which tissues receive GA
Anaesthetic levels in highly perfused organs (brain, liver, lungs, heart) equilibrate with those in blood quickly after administration
How are GAs eliminated?
- Expired breath
- inhalation anaesthetics are eliminated almost entirely via the lungs
- minimal hepatic metabolism
- factors that determine uptake also determine elimination - Metabolism
(some metabolites can be toxic)
What are the important properties of halothane?
- Volatile liquid, non-flammable and non-irritating
- LITTLE OR NO ANALGESIA until unconsciousness supervenes
- Decreases BP due to depression of cardiac output, bradycardia & arrythmia may also occur leading to hypotension and dysrythmia
- May lead to halothane-associated hepatitis
What are the important properties of isoflurane?
- POTENT (MAC 1.4%)
- Medium rate of onset and recovery
- Decreases BP due mainly to decrease in systemic vascular resistance
What are the important properties of sevoflurane?
- Metabolized in the liver to release inorganic fluoride (nephrotoxic)
Which metabolites of which inhalant GAs are toxic?
Inorganic fluorides of isoflurane and enflurane are nephrotoxic; halothane is hepatotoxic
What are the important properties of nitrous oxide?
- Non-flammable
- Rapid onset but lacks potency (MAC 105%)
- Nitrous oxide alone gives analgesia and amnesia but not complete unconsciousness or surgical anaesthesia
- No effect on BP and respiration
- When used alone - analgesic agent (dentistry, during delivery)
What is the main concern with nitrous oxide?
Postoperative nausea & vomiting
Which inhalant GAs are compatible with epinephrine?
Isoflurane, Enflurane, Sevoflurane, Nitrous oxide
NOT Halothane
What are the common IV GAs and what are their dosages?
Thiopentone 4-7 mg/kg
Etomidate 0.2-0.3 mg/kg
Propofol 2-4 mg/kg
Ketamine 1.5mg/kg
Midazolam 0.02 mg/kg
What are the properties of IV GAs?
- Induction agent (induces unconsciousness)
- Does not keep patient asleep for very long
- May be used alone or to supplement the effects of inhalation GAs
- Depress respiration - need to take over ventilation of patients
What the 2 advantages of using inhalation + IV GAs?
IMPORTANT
- Permit dosage of the inhalation agent to be reduced
- Produce effects that cannot be achieved with inhalation alone
What are the important properties of thiopentone (sodium thiopental)?
- Enters the brain easily and rapidly - rapid onset of action (unconsciousness occurs 10-20s after IV)
- Ultra-short duration of action -> If used alone, patient will wake up in ~10 min
- Multiple doses/infusions: duration of action depends on CLEARANCE
- Extensively bound to plasma protein - small amount of free drug can be excreted by glomerular filtration + reabsorption in tubules
What is the MOA of thiopentone?
Causes CNS depression by potentiating the action of the neurotransmitter GABA on the GABAa (alpha) receptor-gated chloride ion channels
What are the important properties of propofol?
- Induction rate is similar to thiopentone, recovery is more rapid (patients move sooner and feel better)
- Rapid onset (unconsciousness develops within 60s)
- Extensively used in “day surgery” - needs continuous, low-dose infusion for extended effects
- SIGNIFICANT CVS EFFECT during induction (decrease BP and negative inotropic) -> hypotension -> to be used with caution in elderly pts, pts with compromised cardiac function, hypovolemic pts
What are the important properties of ketamine?
- Produces a state known as dissociative anaesthesia (pt feels dissociated from environment)
- Rapid induction
- Large Vd rapid clearance -> suitable for continuous infusion without the lengthening in duration of action
- Psychologic adverse reactions (hallucination, disturbing dreams, delirium) during recovery -> risks may be reduced with premedication of diazepam or midazolam
What types of drugs can augment GAs?
Sedation
Amnesia
Analgesia
Why do we augment GAs?
Lower GA doses used -> reduce GA side effects
What are the classes of drugs that are used as anaesthetic adjuncts?
Benzodiazepines (anxiolytics, amnesia, sedation prior to induction of anaesthesia)
a2 (alpha-2) Adrenergic Agonists (sedation prior to and/or during procedures in non-intubated pts)
Analgesics
Neuromuscular Blocking Agents (induction of anaesthesia to relax muscles (jaw, neck, airway) to facilitate laryngoscopy and endotracheal intubation)
What are the important properties of IV Midazolam (benzodiazepine)?
- Used for sedation during procedures not requiring GA
- Metabolized in liver (elderly tend to be more sensitive, slower recovery)
- Side-effects are compounded by concurrent usage of other agents
What are the important properties of α2 (alpha-2) adrenergics - IV dexmedetomidine?
- Short term sedation (<24hrs)
- Little respiratory depression
What are the important properties of analgesics (NSAIDs)?
- Opioids (fentanyl, morphine) - perioperative period
- Relative potency to morphine [duration of action]
Sufentanil (1000x) (intermediate ~15min)
Remidentanil (300x) (ultra short ~10min)
Fentanyl (80x) (intermediate ~30min)
Alfentanil (15x) (intermediate ~20min) - Metabolized in liver (except remidentanil is hydrolyzed by tissue & plasma esterases)
What are the important properties of neuromuscular blockers?
- Non-depolarizing (eg. vecuronium)
- Aids many surgical procedures and provide additional insurance of immobility
(Key Points) GA produces _________
unconsciousness and insensivity to painful stimuli
(Key Points) What is balance anaesthesia?
3 properties:
Pain relief
Unconsciousness
Inhibition of reflex
To ensure that induction is smooth and rapid, and that analgesia and muscle relaxation are adequate
(Key Points) How is MAC related to potency?
The lower the MAC, the higher the potency
(Key Points) How are inhalation GAs eliminated?
Mostly through expired air
(Key Points) What are the principal adverse effects of GA?
Depression of respiratory and cardiac performance
(Key Points) How does nitrous oxide differ from other inhalation GAs?
- Very high MAC (cannot be used alone to produce GA
- High analgesic potency -> frequently combines with other inhalation GAs to supplement their analgesic effects
(Key Points) How is induction of anaesthesia accomplished?
With a short-acting barbiturate (thiopentone)
(Key Points) IV Ketamine causes what type of state?
Dissociative anaesthesia
