Week 10 Painkillers Flashcards
Define anaesthesia
a state characterised by loss of sensation; the result of pharmacological depression of nerve function or of neurological disease
Local anaeathesia
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
three structural requirements of LA’s
- 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
Procaine (Novocaine)
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
Lidocaine/lignocaine
- an amide and hypoallergenic
- anaesthetic effect occurs quickly
- causes vasodilation at injection site so is quickly absorbed away
How do we resolve vasodilation with non-cocaine LAs?
- 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)
Lidocaine toxicity issues
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
How and when are the drugs used?
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
Some LAs
Esters:
Long action: tetracaine
short action: procaine
surface action: cocaine, benzocaine
Amides:
long action: bupivacaine, repivacaine
medium action: lidocaine
the importance of pKa of a LA?
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
Why the worry about crossing membranes?
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
Na+ channel block of LAs
- 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)
How are LAs metabolised?
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.
Which nerve fibres are affected by LAs?
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.
Adverse effects of LAs
- 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.
Bupivicaine: binding affinity and cardiotoxicity
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
Choice of LAs in dentistry and medicine?
- 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.
When to choose a local or regional anaesthetic?
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.
and when would you NOT choose local anaesthesia?
- 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.
General anaesthesia
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.
Four stages of general anaesthesia
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.
Clinical induction and maintenance of GA
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.
The stages of general anaesthesia
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
GA Mechanism of action
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.