Pharm_GA_LA Flashcards
LA(1-17), GA(18-30)
What are the 2 major types (class) of Local Anaesthetics (LA)s?
- Ester LAs
- Amide LAs
MOA for Local Anaesthetics (LA)s
Stop axonal conduction by blocking sodium channels in the axonal membrane when applied locally in appropriate concentration
- Prevent Na ion entry
- Slow down or bring conduction to a halt
Many LA bind most strongly to which of the following states?
(1) Closed
(2) Activated
(3) Inactivated
(4) Deactivated
Many LA bind most strongly to the inactivated and activated states.
LA works better when there’s more pain.
The passage of train of action potentials causes the Na channel to cycle through open and inactivated states.
Mechanism behind the Onset of LA
Think Size & pH
Anaesthetics that penetrate the axon most rapidly have the fastest onset.
Small size -> High Lipid Soluility
Low Ionization (@Tissue pH) –> Faster Onset
pH dependency
LA molecules are weak bases (pKa 8-9),
mainly (but not completely) ionized at physiological pH
LA potency is strongly pH-dependent:
-Alkaline pH -> increased LA activity (proportion of ionized molecules is low)
-Acidic pH -> decreased LA activity (proportion of ionized molecules is high)
When skin is burnt, alkaline pH increases.
When skin is inflamed, LA does not work well
Different types/class of LA,
and how each of the class metabolize in the body system
Ester type - metabolize by blood esterases, higher chance of allergic reactions
(E.g. Procaine)
Amide type - metabolize by liver enzymes, low allergic reactions
(E.g. Lidocaine)
Pharmacokinetics of LAs
- Absorption
Absorption mainly by local action
- minimal amount will get into the bloodstream
Systemic Distribution by 2-compartment model
- Alpha phase: Steep exponential decline in LA, rapid distribution in blood & highly perfused organs (brains, liver, heart & kidney)
followed by
- Beta phase: Slower decline in LA, may assume a nearly linear rate of decline
Distribution to less perfused tissue (e.g. muscle, gut)
What is the S/E, A/E, or Caution in the use of LA?
Potential risk of Toxicity.
(LA blocks all types of voltage-gated sodium channels)
Unintended large doses of LA if accidentally injected by IV/ intra-arterial can give rise to systemic toxicity.
Over-dose of LA injected locally & subsequently leads to high & toxic blood level following absorption - hence the onset of toxic S/S may appear late as compared to the direct IV scenario (immediate)
How do we mitigate over the risk of toxicity in the use of LA?
LA can be combined with Epinephrine. (administer together, not before or after LA)
Epinephrine is a vasoconstrictor,
Hence reduced blood flow, rate of absorption into the system is slower.
List of LAs with high toxicity
Bupivacaine
Cocaine
O-tuluidine
List of LAs with high toxicity
- Bupivacaine
Bupivacaine is more cardiotoxic than most other LAs
(Double check if its suitable for cardiac patients)
List of LAs with high toxicity
- Cocaine
Cocaine blocks NA(Norepinephrine) reuptake,
Increased NA causes vasoconstriction & hypertension
List of LAs with high toxicity
- O-tuluidine
O-toluidine (metabolite of prilocaine)
- Causes methaemoglobin
Blood will start to turn blueish,
Ability to have oxygen exchange is compromised, treat by giving:
- IV methyleneblue/ ascorbic acid methaemoglobin to haemoglobin
Patient is allergic to PABA,
Which type of LA is suitable ?
(Amide / ester?)
Patient allergic to PABA, it will trigger an allergic reaction when given Ester type LAs.
Ester type LAs can be hydrolysed to PABA.
- Triggering an allergic reaction (mild to severe)
(skin rash, anaphylactic shock)
Amide type of LA is more suitable for patients allergic to PABA
Methods of Administration for LAs
Commonly used LAs for Ear, Nose, Throat procedures
Cocaine gives good penetration and vasoconstriction, thus most often used for ear, nose and throat procedures
Clinical applications for Epidural anaesthetics (Injected)
Epidural anaesthetics
Regional nerve block (analgesia)
Lidocaine, bupivacaine (may combine with opioid fentanyl to reduce LA dose)
Clinical applications for Dental anaesthesia (injected)
Dental anaesthesia
- Lidocaine (short time)
- Bupivacaine (long time)
(may combine with epinephrine -> vasoconstrictor -> control bleeding)
Different types/class of General Anaesthetics (GA)s
- Inhalation Anaesthetics
- Intravenous (IV) Anaesthetics
Classification of Inhalant GAs
(mode of administration)
Volatile Liquids:
- Halothane
- Enflurane
- Desflurane
- Isoflurane
- Sevoflurane
Gases:
- Nitrous Oxide
MAC
Minimum alveolar concentration (MAC)
- is an index of inhalation anaesthetic potency ie.
low MAC = high anaesthetic potency - is defined as the minimum concentration of drug in the alveolar air that will produce immobility in 50% of patients exposed to a painful stimulus.
Pharmacokinetics (PK) of GAs
- Absorption
- concentration of anaesthetic in inspired air
- solubility of GA
- blood flow through lungs
Any incr. in the factors above will incr. GA uptake into blood.
Pharmacokinetics (PK) of GAs
- Distribution
determined by regional blood flow -> which tissue(s) receive GA
Anaesthestic levels in these tissues equilibrate with those in blood quickly after of administration
Pharmacokinetics (PK) of Volatile Liquids GAs
- Elimination
Export in Expired breath
inhalation anaesthetics are eliminated almost entirely via the lungs
minimal hepatic metabolism
factors that determine uptake also determine elimination
eg. since blood flow to brain is the highest, anaethetic levels drop rapidly when administration is stopped
Metabolism
note: some metabolites can be toxic
eg. inorganic fluorides of isoflurane and enflurane are nephrotoxic; halothane is hepatotoxic
Volatile Liquids GA
- Halothane
- First modern inhaled anaesthetic, standard for comparison
- Volatile liquid, non-flammable and non-irritating
- Potent (MAC 0.75%)
- Medium rate of onset and recovery
- Little or no analgesia until unconsciousness supervenes
- Causes respiratory depression dose-dependently
- Decreases B.P. due to depression of cardiac output Bradycardia & arrhythmia may also occur leading to hypotension and dysrhythmia
- Relaxes skeletal muscle and potentiates skeletal muscle relaxants
- May lead to halothane-associated hepatitis
Volatile Liquids GA
- Isoflurane
Pungent smell
Potent (MAC 1.4%)
Medium rate of onset and recovery
Similar to halothane with less hypotension and arrhythmia
Decreases B.P. due mainly to decrease in systemic vascular resistance
Volatile Liquids GA
- Sevoflurane
Potent (MAC 2%)
More rapid rate of onset and recovery
Metabolized in the liver to release inorganic fluoride, also nephrotoxic
Unstable when exposed to carbon dioxide absorbents in anaesthetic machines, degrading to a compound that is potentially nephrotoxic
Gaseous GA -
Nitrous Oxide
Odourless gas
Non-flammable
Rapid onset and recovery but lack potency (MAC 105%)
Nitrous oxide alone gives analgesia and amnesia but not complete unconsciousness or surgical anaesthesia
Patients undergoing GA receive nitrous oxide to supplement the analgesic effects of primary anaesthetic
When used alone: as analgesic agent (eg. dentistry, during delivery*)
Major concern: postoperative N&V
- N2O use in obstetric is known as Entonox – a premixed N2O & O2, 50% each
Intravenous Anaesthetics
- an induction agent is a substance that induces unconsciousness
- it does not necessarily keep you asleep for very long!
most agents depress respiration – you will need to take over ventilation of patients
may be used alone or to supplement the effects of inhalation agents
What are the advantages of using both inhaled and intravenous GAs
Inhaled + Intravenous anaesthetics (2 Advantages):
1.Permit dosage of the inhalation agent to be reduced, and
2.Produce effects that cannot be achieved with an inhalation alone
Intravenous GAs
- 3 types
- Thiopentone
- Propofol
- Ketamine
Intravenous GAs
- Thiopentone
- A barbiturate with extremely high lipid solubility
- Enters the brain easily and rapidly - rapid onset of
- action (unconsciousness occurs 10-20sec after IV)
- Single Dose: Re-distributes to less vascularized tissues – ultra-short duration of action
(Injected alone & w/o inhale agents, patients wake up ~10min) - Multiple doses/infusions: duration of action depends on clearance
- Slow elimination, large Vd, active metabolite (pentobarbital), liver cirrhosis –> can result in prolongation of clinical action.
- Extensively bound to plasma protein -
small amount of free drug can be excreted by glomerular filtration + reabsorption in tubules. - Less than 1% excreted unchanged
Intravenous GAs
- MOA
Cause CNS depression by potentiating the action of the neurotransmitter GABA on the GABA-A receptor-gated chloride ion channels
Intravenous GAs
- Propofol
the most common IV anaesthetic used in Singapore –
(ready made in injectable form, no need to re-constitute (unlike thiopentone)
Induction rate is similar to thiopentone, and recovery is more rapid (patients move sooner and feel better)
Used both for induction & maintenance
Rapid onset (unconsciousness develops within ~60sec)
Short duration of action (~3-5min following single injection) because rapid redistribution from brain to other tissues
Extensively used in “day surgery”
- needs continuous, low-dose infusion for extended effects
Reduced post-operative vomiting (may be related to an anti-emetic action)
Significant cardiovascular effect during induction (decrease b.p. and negative inotropic) – hypotension
To be used with caution in elderly patients, patients with compromised cardiac function, hypovolemic patients
Benefits of using Propofol over Thiopentone
- does not req. constitution (ready made IV)
- less post-op side effects
- rapid onset, rapid recovery
- short duration of action
Concerns of using Propofol
Significant cardiovascular effect during induction (decrease b.p. and negative inotropic) – hypotension
To be used with caution in elderly patients, patients with compromised cardiac function, hypovolemic patients
Intravenous GAs
- Ketamine
- racemic (potency: S- > R+); I/M, oral, rectal routes
- Produces a state known as dissociative anaesthesia
ie. patient feels dissociated from environment - Can cause sedation, immobility, analgesia, and amnesia
- Rapid induction; Responsiveness to pain is lost
- **Metabolized in liver **to less active metabolite, excreted in urine & bile
* Large Vd, rapid clearance -> suitable for continuous infusion without the lengthening in duration of action
- Unpleasant psychologic reactions (hallucination, disturbing dreams, delirium) may occur during recovery from ketamine
Risks of psychologic adverse reactions may be reduced with premedication of diazepam or midazolam
- It is the** only IV anaesthetic that possess analgesic property **
-> hence very popular in 3rd world country as the only anaesthetic, due to the lack of other anaesthetic agents.
Adjuncts Anaesthetic
? what are these for?
- Sedation
- Amnesia
- Analgesia
- Lower GA doses used
- Reduce GA side effects
List of adjuncts anaesthetics / post-op care
1) Benzodiazepines
Anxiolytics, amnesia, sedation prior to induction of anaesthesia
2) α2 Adrenergic Agonists
Sedation prior to and/or during procedures in non-intubated patients
3) Analgesics
Typically administered with GA to reduce anaesthetic requirement
4) Neuromuscular Blocking Agents
Induction of anaesthesia to relax muscles (jaw, neck, airway) to facilitate
laryngoscopy and endotracheal intubation
List of adjuncts anaesthetics / post-op care
- BZD
1) Benzodiazepines
Anxiolytics, amnesia, sedation prior to induction of anaesthesia
Used for anxiolysis, amnesia and sedation prior to induction of anaesthesia (perioperative period) or
Used for sedation during procedures not requiring GA
Rapid onset when used for induction
(unconsciousness develops in 80sec; peak ~2min);
sedates ~30min when used by itself.
Metabolized in liver (elderly tend to be more sensitive, slower recovery)
Midazolam (BZD group of drugs) usually has a high therapeutic index
-> it has relatively lesser cardiovascular & respiratory depressing effect compare to other IV anaesthetics.
**Side effects are compounded **by concurrent usage of other agents (e.g. in
Michael Jackson’s case - where multiples drugs had been administered)
Adverse effects can be minimized by injecting midazolam slowly
(over 2 or more minutes) and by waiting another 2 or more minutes for full effects to develop before dosing again
List of adjuncts anaesthetics / post-op care
- α2 Adrenergic Agonists
Dexmedetomidine (I/V)
- Highly selective α2 adrenergic receptor agonist
- Short term sedation (<24hrs)
- Sedation and analgesic effects
(doesn’t produce reliable GA even at maximal doses) - Little respiratory depression
Tolerable decrease in blood pressure and heart rate
Undesirable side effects: nausea, dry mouth, hypotension, bradycardia
List of adjuncts anaesthetics / post-op care
- Analgesics (NSAIDs)
- Minor surgical procedures -> COX-2 inhibitors and paracetamol
- Opioids (Fentanyl, morphine) – perioperative period
- Agonist activity at µ-opioid receptors
- Relative potency to morphine [duration of action]:
- Choice – based primarily on duration of action
- Metabolized in liver
(except remifentanil is hydrolyzed by tissue & plasma esterases) - Excretion: urine, bile
List of adjuncts anaesthetics / post-op care
- Neuromuscular blockers
- Depolarizing: Succinylcholine
- Non-depolarizing (eg. vecuronium)
- Administered during induction of anaesthesia to relax muscles of jaw, neck, airway
–> facilitate laryngoscopy and endotracheal intubation - Aids many surgical procedures and provide additional insurance of immobility
Note: barbiturates will precipitate when mixed with muscle relaxants
–> should be allowed to clear from the IV line prior to injection of muscle relaxant
Nitrous oxide differs from other Gas in __
?
Nitrous oxide differs from other Gas in :
(1) very high MAC, cannot be used alone to produce GA &
(2) high analgesic potency, frequently combined with other Gas to supplement their analgesic effects
Principle adverse effects of GA
Principal adverse effects of GA:
- depression of respiratory
- cardiac performance
Differences between GA and LA
GA produce unconsciousness
and insensitivity to painful stimuli
(____) Mac = (___ ) Potency
(Low) MAC = (High) potency
Mechanism of action by inhalation anaesthetics
