ANALGESICS. GENERAL AND LOCAL ANESTHETIC
AGENTS
Physiology
of pain
The
word "pain" comes from the Latin:
poena
meaning punishment, a fine, a penalty. Pain is an unpleasant sensation; nociception[1]
or nociperception[2]
is a measurable physiological event of a type
usually associated with pain and agony and suffering. A sensation of pain can
exist in the absence of nociception: it can occur in response to both external
perceived events (for example, seeing something) or internal cognitive events
(for example, the phantom limb
pain of an amputee). Pain is defined as “an unpleasant sensory and emotional
experience associated with actual or potential tissue damage, or described in
terms of such damage” - International
Association for the Study of Pain (IASP).
Scientifically, pain (a subjective experience) is separate and distinct
from nociception, the system which carries information, about inflammation,
damage or near-damage in tissue,
to the spinal cord and brain.
Nociception frequently occurs without pain being felt and is below the level of
consciousness. Despite it triggering pain and suffering,
nociception is a critical component of the body's
defense system. It is part of a rapid warning relay instructing the central nervous system
to initiate motor neurons in order to minimize
detected physical harm.
Pain too is part of the body's defense system; it triggers mental problem
solving strategies that seek to end the painful experience, and it promotes
learning, making repetition of the painful situation less likely.
Types of pain
Pain
can be classified as acute or chronic. The distinction between
acute and chronic pain is not based on its duration of sensation, but rather
the nature of the pain itself. In general, physicians are more comfortable
treating acute pain, which has as its source soft tissue damage, infection and/or
inflammation.
Many physicians
faced with patients who live with chronic pain have had no professional
training in pain management. It is not regularly taught in medical school, and
even recent legislation in some states to ensure that physicians receive
continuing education in pain medicine and end-of-life care do not guarantee
proper training in pain. In many states, there remains no legislation ensuring
that licensed physicians, even those who work in hospital emergency
rooms, have any pain
management training whatsoever.
Chronic pain has no time limit, often has no apparent cause and serves no
apparent biological purpose. Chronic pain can trigger multiple psychological
problems that confound both patient and health care provider, leading to
feelings of helplessness and hopelessness. The most common causes of chronic
pain include low-back pain, headache, recurrent facial pain, cancer pain, and
arthritic pain. Published information on pain perpetuate myths that do a
disservice to those who live with pain and many glossaries contradict one
another.
- Chronic pain
was originally defined as pain that has lasted 6 months or longer. It is
now defined as "the disease of pain." Its origin, duration,
intensity, and specific symptoms vary. The one consistent fact of chronic
pain is that, as a disease, it cannot be understood in the same terms as
acute pain, and the failure to make this distinction (particularly in
those who suffer chronic pain) has been and continues to be the cause of
multi-dimensional suffering, depression, social isolation, and
helplessness.
The experience of physiological pain can be grouped according to the
source and related nociceptors (pain detecting neurons).
- Cutaneous pain
is caused by injury to the skin
or superficial tissues. Cutaneous
nociceptors terminate just below the skin, and due to the high
concentration of nerve endings, produce a well-defined, localized pain of
short duration. Examples of injuries that produce cutaneous pain include
paper cuts, minor cuts, minor (first degree) burns
and lacerations.
- Somatic pain
originates from ligaments, tendons,
bones, blood vessels,
and even nerves
themselves. It is detected with somatic nociceptors. The scarcity of pain
receptors in these areas produces a dull, poorly-localized pain of longer
duration than cutaneous pain; examples include sprains
and broken bones. Myofascial pain usually is caused by trigger
points in muscles, tendons and fascia,
and may be local or referred.
- Visceral pain
originates from body's viscera, or organs.
Visceral nociceptors are located within body organs and internal cavities.
The even greater scarcity of nociceptors in these areas produces pain that
is usually more aching and of a longer duration than somatic pain.
Visceral pain is extremely difficult to localize, and several injuries to
visceral tissue exhibit "referred"
pain, where the sensation is localized to an area
completely unrelated to the site of injury. Myocardial ischaemia
(the loss of blood flow to a part of the heart
muscle tissue) is possibly the best known example of referred pain; the
sensation can occur in the upper chest as a restricted feeling, or as an
ache in the left shoulder, arm or even hand. "The brain freeze"
is another example of referred pain, in which the vagus nerve is cooled by
cold inside the throat. Referred pain can be explained by the findings
that pain receptors in the viscera also excite spinal
cord neurons that are excited by cutaneous tissue.
Since the brain normally associates firing of these spinal cord neurons
with stimulation of somatic tissues in skin or muscle, pain signals
arising from the viscera are interpreted by the brain as originating from
the skin. The theory that visceral and somatic pain receptors converge and
form synapses
on the same spinal cord pain-transmitting neurons is called "Ruch's
Hypothesis".
- Phantom limb pain,
a type of referred pain, is the sensation of pain from a limb that has
been lost or from which a person no longer receives physical signals. It
is an experience almost universally reported by amputees
and quadriplegics.
- Neuropathic pain,
can occur as a result of injury or disease to the nerve tissue itself.
This can disrupt the ability of the sensory nerves to transmit correct
information to the thalamus, and hence the
brain interprets painful stimuli even though there is no obvious or known
physiologic cause for the pain. Neuropathic pain is, as stated above, the
disease of pain. It is not the sole definition for chronic pain, but does
meet its criteria.
Figure
A: Antinociceptive pathways are activated when pain
signals in the spinothalamic tract reach the brain stem and thalamus. The
periaqueductal gray matter and nucleus raphe magnus release endorphins and
enkephalins. A series of physicochemical changes then produce inhibition of
pain transmission in the spinal cord.
Figure
B: 70% of endorphin
and enkephalin receptors are in the presynaptic membrane of nociceptors. Thus,
most of the pain signal is stopped before it reaches the dorsal horn. The
signal is then further weakened by dynorphin activity in the spinal cord. The
site of action of various analgesics is shown.
Figure C: Dynorphin activation of alpha receptors on inhibitory
interneurons causes the release of GABA. This causes hyperpolarisation of
dorsal horn cells and inhibits further transmission of the pain signal.
Major
Sources of Pain
|
Source |
Area Involved |
Characteristics |
Treatment |
|
Somatic |
body framework |
throbbing, stabbing |
narcotics, NSAIDS |
|
Visceral |
kidneys, intestines, liver |
aching, throbbing, sharp,
crampy |
narcotics, NSAIDS |
|
Neuropathic |
Nerves |
burning, numbing, tingling |
antidepressants,
anticonvulsants |
|
Sympathetically
Mediated |
overactive sympathetic
system |
no pain should be felt |
nerve blockers |
An analgesic (colloquially
known as a painkiller) is any member of the diverse group of drugs used to relieve pain (achieve analgesia). This
derives from Greek an-, "without", and -algia,
"pain". Analgesic drugs act in various ways on the peripheral and
central
nervous system; they
include paracetamol (acetaminophen), the nonsteroidal anti-inflammatory drugs (NSAIDs) such as the salicylates, narcotic drugs such as morphine, synthetic drugs with narcotic
properties such as tramadol, and various others. Some other
classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; these include tricyclic antidepressants and anticonvulsants.
Opioid
Analgesics—Morphine Type Source of opioids.
Papaver rhoeas L. Papaver somniferum L.
Morphine is an opium alkaloid. Besides
morphine, opium contains alkaloids devoid of
analgesic activity, e.g., the spasmolytic
papaverine, that are also classified as opium alkaloids. All semisynthetic derivatives (hydromorphone) and fully synthetic derivatives (pentazocine, pethidine = meperidine, l-methadone, and fentanyl) are collectively referred to
as opioids. The high analgesic effectiveness of xenobiotic opioids derives from their affinity for receptors normally acted upon by endogenous opioids (enkephalins, в-endorphin, dynorphins; A).
Opioid receptors occur in nerve cells. They are found in various brain regions and the spinal medulla, as well as in
intramural nerve plexuses that regulate the motility of the alimentary and
urogenital tracts. There are several types of
opioid receptors, designated µ, д, к, that mediate the various opioid effects; all belong to the superfamily of
G-proteincoupled receptors. Endogenous opioids are peptides that are cleaved from the precursors proenkephalin, pro-opiomelanocortin, and prodynorphin. All contain the amino acid sequence of the pentapeptides [Met]- or [Leu]-enkephalin (A). The
effects of the opioids can be abolished by antagonists (e.g., naloxone; A),
with the exception of buprenorphine.
Mode of action of opioids. Most neurons react to opioids with
hyperpolarization, reflecting
an increase in K+ conductance.
Ca2+ influx into nerve terminals during excitation is decreased, leading to a decreased release of
excitatory transmitters and decreased synaptic activity (A). Depending on the
cell population affected, this synaptic
inhibition translates into a depressant or excitant effect (B).
Effects of opioids (B). The analgesic effect results from actions at the level of the spinal cord (inhibition of
nociceptive impulse transmission) and the brain (attenuation of impulse spread, inhibition of pain perception).
Attention and ability to concentrate are impaired.
There is a mood change, the direction of which depends on the initial condition. Aside from the relief associated with the abatement of strong pain, there is a feeling of detachment (floating sensation) and sense of well-being (euphoria), particularly after intravenous injection and, hence, rapid buildup of drug levels in the brain. The desire to re-experience this state by renewed administration of drug may become overpowering: development of
psychological dependence. The atttempt to quit repeated use of the drug results in
withdrawal signs of both a physical (cardiovascular disturbances) and psychological (restlessness, anxiety, depression)
nature. Opioids meet the criteria of “addictive” agents, namely, psychological and physiological dependence as well as a compulsion to increase the dose. For these reasons, prescription of opioids
is subject to special rules (Controlled
Substances
Evidently, psychic effects (“kick,” “buzz,” “rush”) are especially intense with this route of administration. The user may also resort to other more unusual routes: opium can be smoked, and heroin can be taken as snuff (B).
Metabolism
(C). Like
other opioids bearing a hydroxyl group, morphine is conjugated to glucuronic acid and
eliminated renally. Glucuronidation of the OH-group at position 6, unlike that at position 3, does not affect affinity.
The extent to which the 6-glucuronide
contributes to the analgesic action remains uncertain at present. At any rate, the
activity of this polar metabolite needs to be taken into account in renal
insufficiency (lower dosage or longer dosing interval).
Tolerance. With repeated administration of opioids, their CNS effects can lose intensity (increased tolerance). In the course of therapy, progressively larger doses are needed to achieve the same degree of pain relief. Development of tolerance does not involve the
peripheral effects, so that persistent constipation during prolonged use may force a discontinuation of analgesic therapy however urgently needed. Therefore, dietetic and pharmacological measures should be taken
prophylactically to prevent constipation, whenever prolonged administration of opioid drugs is indicated.
Morphine antagonists and partial agonists. The effects of opioids can be
abolished by the antagonists naloxone or naltrexone (A), irrespective
of the receptor type
involved. Given by itself, neither has any effect in normal subjects; however, in opioid-dependent subjects, both precipitate acute
withdrawal signs.
Because of its rapid presystemic elimination, naloxone is only suitable for parenteral use. Naltrexone is metabolically more stable and is
given orally. Naloxone is effective as antidote in the treatment of opioid-induced respiratory paralysis. Since it is more rapidly eliminated than most opioids, repeated doses may be needed. Naltrexone may be used asan adjunct in withdrawal therapy. Buprenorphine behaves like a
partial agonist/antagonist at µ-receptors. Pentazocine is an antagonist at
µ-receptors and an agonist at к-receptors (A). Both are classified as “low-ceiling” opioids (B), because neither is capable of eliciting the maximal analgesic effect obtained with morphine or meperidine. The antagonist action of partial
agonists may result in an initial decrease in effect of a full agonist during changeover to the latter. Intoxication with
buprenorphine cannot be reversed with antagonists, because the drug dissociates only very slowly from the opioid receptors and competitive occupancy of the
receptors cannot be achieved as fast as the clinical situation demands.
Opioids in chronic pain: In the management of chronic pain, opioid plasma concentration must be kept
continuously in the effective range, because a fall below the critical level would cause the patient to experience pain. Fear of this situation would prompt
intake of higher doses than necessary. Strictly speaking, the aim is a
prophylactic analgesia.
Like
other opioids (hydromorphone, meperidine, pentazocine, codeine), morphine is rapidly eliminated, limiting its duration of action to
approx. 4 h. To maintain a steady analgesic
effect, these drugs need to be given every 4 h. Frequent dosing, including at
nighttime, is a major inconvenience for chronic pain patients. Raising the
individual dose would permit the dosing interval to be lengthened; however, it would also lead to transient peaks above the therapeutically required
plasma level with the attending risk of
unwanted toxic effects and tolerance development. Preferred alternatives include the use of controlled-release preparations of morphine, a fentanyl adhesive patch, or a longer-acting
opioid such as l-methadone. The kinetic properties of the latter, however,
necessitate adjustment of dosage in the course of treatment, because low dosage during the first days of treatment fails to provide pain relief, whereas
high dosage of the drug, if continued, will lead to accumulation into a toxic
concentration range (C). When the oral route is unavailable opioids may be administered by
continuous infusion (pump) and when appropriate under control by the patient –
advantage: constant therapeutic plasma level; disadvantage: indwelling
catheter. When constipation becomes intolerable morphin can be applied near the spinal
cord permitting strong analgesic effect at much lower total dosage.
Non-narcotic Analgetics
The exact mechanism of action of paracetamol is
uncertain, but it appears to be acting centrally. Aspirin and the NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and
also inflammation (in contrast to paracetamol and the
opioids). Paracetamol has few side effects, but dosing is limited by possible hepatotoxicity (potential for liver damage). NSAIDs may predispose to peptic ulcers, renal failure, allergic reactions, and hearing loss. They may also increase the risk of hemorrhage by affecting platelet function. The use of certain NSAIDs
in children under 16 suffering from viral illness may contribute to Reye's syndrome.
Paracetamol and NSAIDs
Paracetamol or acetaminophen, is a common analgesic and antipyretic drug that is used for the relief of fever, headaches, and other minor aches and pains.
Paracetamol is also useful in managing more severe pain, allowing lower dosages
of additional non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics to be used, thereby minimizing overall
side-effects. It is a major ingredient in numerous cold and flu medications, as well as many prescription analgesics.
It is considered safe for human use in recommended doses, but because of its
wide availability, deliberate or accidental overdoses are fairly common. In ancient and
medieval times, known antipyretic agents were compounds contained in
white willow bark (a family of chemicals known as
salicins, which led to the development of aspirin), and compounds contained in cinchona bark.
Cinchona bark was also used to create the anti-malaria drug quinine. Quinine itself also has antipyretic
effects. Efforts to refine and isolate salicin and salicylic acid took place throughout the middle-
and late-19th century, and was accomplished by Bayer chemist Felix Hoffmann (this was also done by French
chemist Charles Frédéric Gerhardt 40 years earlier, but he abandoned
the work after deciding it was too impractical).When the cinchona tree became
scarce in the 1880s, people began to look for alternatives. Two alternative
antipyretic agents were developed in the 1880s: acetanilide in 1886 and phenacetin in 1887. Harmon
Northrop Morse first
synthesized paracetamol via the reduction of p-nitrophenol with tin in glacial acetic acid in 1878, however, paracetamol was
not used medically for another 15 years. In 1893, paracetamol was discovered in
the urine of individuals who had taken phenacetin, and was concentrated into a white,
crystalline compound with a bitter taste. In 1899, paracetamol was found to be
a metabolite of acetanilide. This discovery was largely ignored at the time. Paracetamol has long been suspected
of having a similar mechanism of action to aspirin because of the similarity in
structure. That is, it has been assumed that paracetamol acts by reducing
production of prostaglandins, which are involved in the pain and
fever processes, by inhibiting the cyclooxygenase (COX) enzyme as aspirin does. However, there are important differences between the effects
of aspirin and those of paracetamol. Prostaglandins participate in the inflammatory response which is why aspirin has
been known to trigger symptoms in asthmatics, but paracetamol has no
appreciable anti-inflammatory action and hence does not have this side-effect.
Furthermore, the COX enzyme also produces thromboxanes, which aid in blood clotting — aspirin reduces blood clotting, but
paracetamol does not. Finally, aspirin and the other NSAIDs commonly have
detrimental effects on the stomach lining, where prostaglandins serve a
protective role, but, in recommended doses, paracetamol does not. Indeed, while aspirin acts as an irreversible inhibitor of COX and directly blocks
the enzyme's active site, paracetamol indirectly blocks COX,
and this blockade is ineffective in the presence of peroxides. This might explain why paracetamol
is effective in the central
nervous system and
in endothelial
cells but not in platelets and immune cells which have high levels of peroxides.
In 2002 it was reported that paracetamol
selectively blocks a variant of the COX enzyme that was different from the then
known variants COX-1 and COX-2. This isoenzyme, which is only expressed in the
brain and the spinal cord, is now referred to as COX-3. Its exact mechanism of
action is still poorly understood, but future research may provide further
insight into how it works. A single study has shown that administration of paracetamol increases the
bioavailability of serotonin (5-HT) in rats, but the mechanism is
unknown and untested in humans. In 2006, it was shown that paracetamol is converted to
N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous
cannabinoid. As
such, it activates the CB1 cannabinoid
receptor; a CB(1) receptor
antagonist
completely blocks the analgesic action of paracetamol. Paracetamol is metabolized primarily in the liver, where most of it (60–90% of a therapeutic dose) is
converted to inactive compounds by conjugation with sulfate and glucuronide, and then excreted by the kidneys.
Only a small portion (5–10% of a therapeutic dose) is metabolized via the
hepatic cytochrome
P450 enzyme system
(specifically CYP2E1); the toxic effects of paracetamol
are due to a minor alkylating metabolite (N-acetyl-p-benzo-quinone
imine, abbreviated as NAPQI) that is produced through this
enzyme, not paracetamol itself or any of the major metabolites. The metabolism
of paracetamol is an excellent example of toxication, because the metabolite NAPQI is
primarily responsible for toxicity rather than paracetamol itself. At usual doses, the toxic metabolite
NAPQI is quickly detoxified by combining irreversibly with the sulfhydryl groups of glutathione to produce a non-toxic conjugate
that is eventually excreted by the kidneys. Paracetamol is contained in many preparations (both over-the-counter and prescription-only medications). In some animals, for
example cats, small doses are toxic. Because of the wide availability of
paracetamol there is a large potential for overdose and toxicity.[9] Without timely treatment,
paracetamol overdose can lead to liver failure and death within days. It is
sometimes used in suicide attempts by those unaware of the
prolonged timecourse and high morbidity (likelihood of significant illness)
associated with paracetamol-induced toxicity in survivors. The toxic dose of
paracetamol is highly variable. In adults, single doses above
Aspirin, or acetylsalicylic acid is a drug in the family of salicylates, often used as an analgesic (to relieve minor aches and pains), antipyretic (to reduce fever), and as an anti-inflammatory. It also has an antiplatelet ("blood-thinning") effect
and is used in long-term, low doses to prevent heart
attacks and cancer.
Low-dose, long-term aspirin use irreversibly
blocks the formation
of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes
it useful for reducing the incidence of heart attacks. Aspirin produced for
this purpose often comes in 75 or 81 mg, dispersible tablets and is sometimes called "junior aspirin" or
"baby aspirin." New evidence suggests that baby aspirin may not be as
effective in preventing heart attacks and cerebrovascular accidents as
previously thought. High doses of aspirin are also given immediately after an
acute heart attack. These doses may also inhibit the synthesis of prothrombin and may, therefore, produce a second
and different anticoagulant effect, but this is not well understood.
Its primary, undesirable side-effects, especially in
higher doses, are gastrointestinal distress (including ulcers and stomach bleeding) and tinnitus. Another side-effect, due to its
anticoagulant properties, is increased bleeding in menstruating women. Because there appears to be a
connection between aspirin and Reye's syndrome, aspirin is no longer used to
control flu-like symptoms or the symptoms of
chickenpox in minors. Aspirin
was the first-discovered member of the class of drugs known as non-steroidal,
anti-inflammatory drugs (NSAIDs), not all of which are salicylates,
though they all have similar effects and a similar action mechanism.
Aspirin, as with many older drugs, has proven to be useful in many
conditions. Despite its well-known toxicity it is widely used, since physicians
are familiar with its properties. Indications for its use include:
·
Fever
·
Pain (especially useful for some forms of
arthritis, osteoid osteoma, and chronic pain)
·
Migraine
·
Rheumatic fever (drug of choice)
·
Kawasaki disease (along with IVIG)
·
Acute
myocardial
infarction
In addition, aspirin is recommended (low dose, 75-81 mg daily) for the
prevention of:
·
Myocardial
infarction — in patients with either documented coronary artery disease or at
elevated risk of cardiovascular
disease
·
Stroke — as secondary
prevention (i.e. to
prevent recurrence)
For adults doses of 300 to 1000 mg are generally taken four times a day
for fever or arthritis, with a maximum dose of 8000 mg a day. The correct dose
of aspirin depends on the disease process that is being treated. For instance,
for the treatment of rheumatic fever, doses near the maximal daily dose have been
used historically. For the prevention of myocardial infarction in someone with
documented or suspected coronary artery disease, doses as low as 75 mg daily
(or possibly even lower) are sufficient. For those under 12 years of age, the dose previously varied
with the age, but aspirin is no longer routinely used in children due to the
association with Reye's
syndrome; paracetamol or other NSAIDs, such as Ibuprofen, are now being used instead. Kawasaki disease remains one of the few indications
for aspirin use in children with aspirin initially started at 7.5-12.5 mg/kg
body weight taken four times a day for up to two weeks and then continued at 5
mg/kg once daily for a further six to eight weeks.
·
Aspirin
should be avoided by those known to be allergic to ibuprofen or naproxen.
·
Caution
should be exercised in those with asthma or NSAID-precipitated bronchospasm.
·
It
is generally recommended that one seek medical help if symptoms do not improve
after a few days of therapy.
·
Caution
should be taken in patients with kidney disease, peptic ulcers, mild diabetes, gout or gastritis; manufacturers recommend talking to
one's doctor before using this medicine.
·
Taking
aspirin with alcohol increases the chance of gastrointestinal hemorrhage (stomach bleeding).
·
Children,
including teenagers, are discouraged from using aspirin in cold or flu symptoms
as this has been linked with Reye's syndrome.
·
Patients
with hemophilia or other bleeding tendencies should
not take salicylates.
·
Some
sources recommend that patients with hyperthyroidism avoid aspirin because it elevates T4
levels.
Common side-effects
·
Gastrointestinal
complaints (stomach upset, dyspepsia, heartburn, small blood loss). To
help avoid these problems, it is recommended that aspirin be taken at or after
meals. Undetected blood loss may lead to hypochromic
anemia.
·
Severe
gastrointestinal complaints (gross bleeding and/or ulceration), requiring
discontinuation and immediate treatment. Patients receiving high doses and/or
long-term treatment should receive gastric protection with high-dosed antacids,
ranitidine or omeprazole.
·
Frequently,
central effects (dizziness, tinnitus, hearing loss, vertigo, centrally mediated vision
disturbances, and headaches). The higher the daily dose is, the more likely it
is that central nervous system side-effects will occur.
·
Sweating,
seen with high doses, independent from antipyretic action
·
Long-term
treatment with high doses (arthritis and rheumatic fever): often increased
liver enzymes without symptoms, rarely reversible liver damage. The potentially
fatal Reye's
syndrome may occur,
if given to pediatric patients with fever and other signs of infections. The
syndrome is due to fatty degeneration of liver cells. Up to 30 percent of those
afflicted will eventually die. Prompt hospital treatment may be life-saving.
·
Chronic
nephritis with long-term use, usually if used
in combination with certain other painkillers. This condition may lead to
chronic renal failure.
·
Prolonged
and more severe bleeding after operations and post-traumatic for up to 10 days
after the last aspirin dose. If one wishes to counteract the bleeding tendency,
fresh thrombocyte concentrate will usually work.
·
Skin
reactions, angioedema, and bronchospasm have all been seen infrequently.
·
Patients
that have the genetic disease known as Glucose-6-Phosphate Dehydrogenase
deficiency (G6PD) should avoid this drug as it is known to cause hemolytic
anemia in large doses depending on the severity of the disease.
The toxic dose of aspirin is generally
considered greater than 150 mg per kg of body mass. Moderate toxicity occurs at
doses up to 300 mg/kg, severe toxicity occurs between 300 to 500 mg/kg, and a
potentially lethal dose is greater than 500 mg/kg.[13] This is the equivalent of many
dozens of the common 325 mg tablets, depending on body weight. Note that
children cannot tolerate as much aspirin per unit body weight as adults can,
even when aspirin is indicated. Label-directions should be followed carefully. COX-2 selective inhibitor is a form of Non-steroidal anti-inflammatory drug (NSAID) that directly targets COX-2, an enzyme responsible for inflammation and pain.
Selectivity for COX-2 reduces the risk of peptic ulceration, and is the main feature of celecoxib, rofecoxib and other members of this drug
class. Cox-2-selectivity does not seem to affect other adverse-effects of NSAIDs (most notably an increased
risk of renal
failure), and some
results have aroused the suspicion that there might be an increase in the risk
for heart
attack, thrombosis and stroke by a relative increase in thromboxane. Rofecoxib was taken off the market in 2004
because of these concerns. In the course of the search for a specific inhibitor of the negative effects of prostaglandins which spared the positive effects,
it was discovered that prostaglandins could indeed be separated into two
general classes which could loosely be regarded as "good
prostaglandins" and "bad prostaglandins", according to the
structure of a particular enzyme involved in their synthesis, cyclooxygenase. Prostaglandins whose synthesis
involves the cyclooxygenase-I enzyme, or COX-1, are responsible
for maintenance and protection of the gastrointestinal
tract, while
prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2,
are responsible for inflammation and pain. The existing nonsteroidal
antiinflammatory drugs (NSAIDs) differ in their relative
specificities for COX-2 and COX-1; while aspirin is equipotent at inhibiting COX-2
and COX-1 enzymes in vitro and ibuprofen demonstrates a sevenfold greater
inhibition of COX-1, other NSAIDs appear to have partial COX-2 specificity,
particularly meloxicam (Mobic). Studies of meloxicam 7.5 mg per day for 23 days find a
level of gastric injury similar to that of a placebo, and for meloxicam 15 mg per day a
level of injury lower than that of other NSAIDs; however, in clinical practice
meloxicam can still cause some ulcer complications. A search for COX-2-specific inhibitors
resulted in promising candidates such as valdecoxib, celecoxib, and rofecoxib, marketed under the brand names Bextra, Celebrex, and Vioxx respectively.
Combinations
Analgesics are frequently used in combination, such as
the paracetamol and codeine preparations found in many
non-prescription pain relievers. They can also be found in combination with
vasoconstrictor drugs such as pseudoephedrine for sinus-related preparations, or with antihistamine drugs for allergy sufferers. The use
of paracetamol, as well as aspirin, ibuprofen, naproxen, and other NSAIDS concurrently with weak to mid-range opiates (up to about the
hydrocodone level) has been shown to have beneficial synergistic effects by
combating pain at multiple sites of action--NSAIDs reduce inflammation which,
in some cases, is the cause of the pain itself while opiates dull the
perception of pain--thus, in cases of mild to moderate pain caused in part by
inflammation, it is generally recommended that the two are prescribed together.
Topical or systemic
Topical analgesia is generally
recommended to avoid systemic side-effects. Painful joints, for example, may be
treated with an ibuprofen-
or diclofenac-containing
gel; capsaicin also is used
topically. Lidocaine
and steroids
may be injected into painful joints for longer-term pain relief. Lidocaine is also used
for painful mouth sores
and to numb areas for dental
work and minor medical procedures.
Local Anesthetics
Local
anesthetics reversibly inhibit impulse generation and propagation in nerves. In
sensory nerves, such an effect is desired when painful procedures must be
performed, e.g., surgical or dental operations.
Mechanism
of action. Nerve
impulse conduction occurs in the form of an action potential, a sudden reversal
in resting transmembrane potential lasting less than 1 ms. The change in
potential is triggered by an appropriate stimulus and involves a rapid influx
of Na+ into the interior of the nerve axon (A).
This
inward flow proceeds through a channel, a membrane pore protein, that, upon
being opened (activated), permits rapid movement of Na+ down a chemical
gradient ([Na+]ext ~
Mechanism-specific adverse
effects.
Since
local anesthetics block Na+ influx not only in sensory nerves but also in other
excitable tissues, they are applied locally and measures are taken to impede
their distribution into the body. Too rapid entry into the circulation would
lead to unwanted systemic reactions such as:
_
blockade of inhibitory CNS neurons,
manifested
by restlessness and seizures ; general paralysis with respiratory arrest after
higher
concentrations.
_
blockade of cardiac impulse conduction, as evidenced by impaired AV conduction
or cardiac arrest (countermeasure: injection of epinephrine).
Depression
of excitatory processes in the heart, while undesired during local anesthesia,
can be put to therapeutic use in cardiac arrhythmias.
Forms
of local anesthesia. Local
anesthetics are applied via different routes, including infiltration of the
tissue (infiltration anesthesia) or injection next to the nerve branch
carrying fibers from the region to be anesthetized (conduction anesthesia of
the nerve, spinal anesthesia of segmental dorsal roots), or by
application to the surface of the skin or mucosa (surface anesthesia). In
each case, the local anesthetic drug is required to diffuse to the nerves
concerned from a depot
placed
in the tissue or on the skin. High sensitivity of sensory nerves, low
sensitivity of motor nerves. Impulse conduction in sensory nerves is
inhibited at a concentration lower than that needed for motor fibers. This
difference may be due to the higher impulse frequency and longer action
potential duration in nociceptive, as opposed to motor, fibers. Alternatively,
it may be related to the thickness of sensory and motor nerves, as well as to
the distance between nodes of Ranvier. In saltatory impulse conduction, only
the nodal membrane is depolarized. Because depolarization can still occur after
blockade of three or four nodal rings, the area exposed to a drug concentration
sufficient to cause blockade must be larger for motor fiber. This relationship explains why sensory stimuli
that are conducted via myelinated Aд-fibers are affected later and to a lesser degree than
are stimuli conducted via unmyelinated C-fibers. Since autonomic postganglionic
fibers lack a myelin sheath, they are particularly susceptible to blockade by
local anesthetics. As a result, vasodilation ensues in the anesthetized region,
because sympathetically driven vasomotor tone decreases. This local
vasodilation is undesirable .
Diffusion
and Effect
During
diffusion from the injection site (i.e., the interstitial space of connective
tissue) to the axon of a sensory nerve, the local anesthetic must traverse the perineurium.
The multilayered perineurium is formed by connective tissue cells linked by zonulae occludentes and
therefore constitutes a closed lipophilic barrier. Local anesthetics in
clinical use are usually tertiary amines; at the pH of interstitial fluid,
these exist partly as the neutral lipophilic base (symbolized by particles
marked with two red dots) and partly as the protonated form, i.e., amphiphilic
cation (symbolized by particles marked with one blue and one red dot). The
uncharged form can penetrate the perineurium and enters the endoneural
space, where a fraction of the drug molecules regains a positive charge in
keeping with the local pH. The same process is repeated when the drug
penetrates the axonal membrane (axolemma) into the axoplasm, from which
it exerts its action on the sodium channel, and again when it diffuses out of
the endoneural space through the unfenestrated endothelium of capillaries into
the blood. The concentration of local anesthetic at the site of action is,
therefore, determined by the speed of penetration into the endoneurium and the
speed of diffusion into the capillary blood. In order to ensure a sufficiently
fast build-up of drug concentration at the site of action, there must be a
correspondingly large concentration gradient between drug depot in the
connective tissue and the endoneural space. Injection of solutions of low
concentration will fail to produce an effect; however, too high concentrations
must also be avoided because of the danger of intoxication resulting from too
rapid systemic absorption into the blood.To ensure a reasonably long-lasting
local effect with minimal systemic action, a vasoconstrictor (epinephrine,
less frequently norepinephrine or a
vasopressin derivative; is often co-administered in an attempt to confine the
drug to its site of action. As blood flow is diminished, diffusion from the
endoneural space into the capillary blood decreases because the critical
concentration gradient between endoneural space and blood quickly becomes small
when inflow of drug-free blood is reduced. Addition of a vasoconstrictor,
moreover, helps to create a relative ischemia in the surgical field. Potential
disadvantages of catecholamine-type vasoconstrictors include reactive hyperemia
following washout of the constrictor agent and cardiostimulation when
epinephrine enters the systemic circulation. In lieu of epinephrine, the
vasopressin analogue felypressin can be
used as an adjunctive vasoconstrictor (less pronounced reactive hyperemia, no
arrhythmogenic action, but danger of coronary constriction). Vasoconstrictors must not be applied in local
anesthesia involving the appendages (e.g., fingers, toes).
Characteristics
of chemical structure.
Local
anesthetics possess a uniform structure. Generally they are secondary or
tertiary amines. The nitrogen is linked through an intermediary chain to a
lipophilic moiety — most often an aromatic ring system. The amine function
means that local anesthetics exist either as the neutral amine or positively
charged ammonium cation, depending upon their dissociation constant (pKa value)
and the actual pH value. The pKa of typical local anesthetics lies between 7.5
and 9.0. The pka indicates the pH value at which 50% of molecules carry a
proton. In its protonated form, the molecule possesses both a polar hydrophilic
moiety (protonated nitrogen) and an apolar lipophilic moiety (ring system)—it
is amphiphilic. Graphic images of the procaine molecule reveal that the
positive charge does not have a punctate localization at the N atom; rather it
is distributed, as shown by the potential on the van der Waals’ surface.
The non-protonated
form (right) possesses a negative partial charge in the region of the ester
bond and at the amino group at the aromatic ring and is neutral to slightly
positively charged (blue) elsewhere. In the protonated form (left), the
positive charge is prominent and concentrated at the amino group of the side
chain (dark blue). Depending on the pKa, 50 to 5% of the drug may be present at
physiological pH in the uncharged lipophilic form. This fraction is important
because it represents the lipid membrane-permeable form of the local
anesthetic, which must take on its cationic amphiphilic form in order to exert
its action. Clinically used local anesthetics are either esters or amides.
This structural element is unimportant for efficacy;
even drugs containing a methylene bridge, such as chlorpromazine or imipramine,
would exert a local anesthetic effect with appropriate application. Ester-type
local anesthetics are subject to inactivation by tissue esterases. This is
advantageous because of the diminished danger of systemic intoxication. On the
other hand, the high rate of bioinactivation and, therefore, shortened duration
of action is a disadvantage. Procaine cannot be used as a surface
anesthetic because it is inactivated faster than it can penetrate the dermis or
mucosa. The amide type local anesthetic lidocaine is broken down
primarily in the liver by oxidative N-dealkylation. This step can occur only to
a restricted extent in prilocaine and articaine because both
carry a substituent on the Catom adjacent to the nitrogen group. Articaine
possesses a carboxymethyl group on its thiophen ring. At this position, ester
cleavage can occur, resulting in the formation of a polar -COO– group, loss of
the amphiphilic character, and conversion to an inactive metabolite. Benzocaine
(ethoform) is a member of the group of local anesthetics lacking a nitrogen
that can be protonated at physiological pH. It is used exclusively as a surface
anesthetic. Other agents employed for surface anesthesia include the uncharged polidocanol
and the catamphiphilic cocaine, tetracaine, and lidocaine.
Pharmacology and
Toxicology of Cocaine
Cocaine
(benzoylmethylecgonine, C17H21NO4) is an
alkaloid prepared from the leaves of the Erythroxylon coca plant,
which grows mainly in
Coca leaves were first used in medicine in
1596, but it was not until the mid 1800’s that cocaine was extracted. Freud
reported the effects of cocaine in 1884, and it was subsequently utilised in
ophthalmology and dentistry as a local anaesthetic.
Cocaine hydrochloride is prepared by
dissolving the alkaloid in hydrochloric acid, forming a water soluble salt. It
is sold illicitly as a white powder, or as crystals or granules.
Street names include ‘coke’,
‘charlie’, ‘nose-candy’, ‘snow’ and ‘wash’. This form of cocaine can be
‘freebased’, prior to smoking, in which it is dissolved in ether or ammonia.
The ‘freebase’ remains after the volatile substance has evaporated. Although
this form of cocaine was popular in the late 1970s, a further refinement of this
process became more prominent in the
Crack cocaine is produced when cocaine
hydrochloride is mixed with sodium bicarbonate (baking soda) and water, and
then heated. On cooling, ‘rocks’ are precipitated, and these are smoked in
crack pipes, or are heated on foil with the vapour inhaled. Crack is an
extremely ‘pure’ form of an already ‘pure’ substance (in comparison with other
drugs of abuse such as amphetamines). Cocaine can be administered as a drug of
abuse in the following ways,
|
|
Cocaine
hydrochloride – snorting (intranasal), smoking, intravenous
(including being mixed with heroin (‘speedball’ or ‘snowball’)), ingestion,
application to genitalia |
|
|
Crack
cocaine – inhalation of vapour from heated foil or pipe |
|
|
Coca leaves –
chewed/ ingested |
In the UK, cocaine is classified as a
Class A controlled drug, by virtue of Schedule 2 of the Misuse of Drugs
Act 1971 (as amended by the Misuse of Drugs Regulations 1985).
It is a criminal offence to ‘unlawfully possess’ (with or without intent to
supply), to import or export the drug, or produce it, and the police have
extensive ‘stop and search’ powers to enforce these offences.
Cocaine addicts are required to be notified
by doctors to the Chief Medical Officer under Regulation 3 of the Misuse
of Drugs (Notification of and supply to Addicts) Regulations 1973, and
Regulation 4 prevents doctors from prescribing cocaine unless they are licensed
to do so by the Home Secretary. However, this does not apply to those treating
organic disease or injury.
Epidemiology
Epidemiological data of drug misuse is not
freely available in the same way that it is in the
American data indicate that 23.7 million
people used cocaine between 1990-1, nearly 4 million of which were using crack.
(Cone 1993). Mortality from cocaine abuse has also risen, and cocaine accounts
for the most frequent substance related deaths.
Pharmacokinetics
Cocaine has a half life of 40-50 minutes, and it’s
effects on the body are felt rapidly, peaking after 15-20 minutes when
‘snorted’, and wearing off by 1.5 hours. When injected or ‘freebased’, or when
crack is smoked, the effects are almost instantaneous, and last for only 15
minutes or so.Cocaine is metabolised to nearly a dozen pharmacologically inactive
metabolites, the most important being benzoylecgonine and ecgonine
methyl ester, primarily in the liver by spontaneous hydrolysis. (Casale
et al 1994). Plasma cholinesterase also hydrolyses cocaine to ecgonine, and
approximately 20% of the drug is excreted untouched into the urine. Both
cocaine and its metabolites may be detected in urine up to 15 days after last
administration by a chronic user. Cocaethylene is the ethylbenzoylecgonine
form of cocaine produced in the presence of ethanol, resulting from
transesterification by hepatic enzymes. (da Matta Chasin et al 2000 p.2). It is
pharmacologically active, and it is formed at significantly lower
concentrations than either of its parent substances.
Mechanisms
of Action
Cocaine
is a central nervous system stimulant, which gives rise to feelings of
euphoria, excitement, increased motor activity and a feeling of being
energised. Its principal mode of action is the blockade of the transporter
protein that is responsible for the reuptake of monoamines (i.e. noradrenaline,
serotonin and most importantly dopamine) into presynaptic terminals of neurons
releasing these neurotransmitters. The result is that increased concentrations
of these monoamines are found in the synaptic space, and their effects are
potentiated. Blockage of the dopamine-reuptake transporter protein gives rise
to the characteristic ‘high’ of cocaine. Knockout mice that do not have the
gene encoding for this transporter protein are immune to the effects of
cocaine, and studies have attempted to identify the exact dopamine receptor
subtype on the post-synaptic neuron that is responsible for modulating the
effects of cocaine. It appears that the D2 subtype modulates cravings
associated with cocaine dependence and drug seeking behaviour, whilst the D1
subtype may modulate feelings of satiety, opening up possibilities for
therapeutic targeting of these receptors to treat cocaine dependence and abuse.
(Leshner 1996 pp.128-9). Dopamine hyperactivity as a result of cocaine
administration is particularly important in the nigrostriatal dopaminergic
system, which incorporates the limbic system of the brain – the ‘pleasure
centre’. The activation of the limbic system by the drug gives rise to the
intense euphoria, but in the chronic user, monoamine neurotransmitters are
depleted, triggering a reactive lowering of mood or depression (serotonin
depletion?), as well as disturbed sleep and eating cycles. Body temperature
control is adversely affected, and depletion of dopamine has been linked to the
onset of schizophrenia in susceptible individuals. In high doses, cocaine can
cause tremors and convulsions via its effects on the cortex and brainstem, and
can lead to respiratory and vasomotor depression. O’Dell et al (2000 p.677)
speculate that cocaine activation of serotonin (2) receptors may be responsible
for mediating convulsions. Chronic users can experience hallucinations,
delusions and paranoia. Peripherally, cocaine potentiates noradrenaline action,
and produces the typical ‘fight or flight’ sympathetic response of tachycardia,
hypertension, pupillary dilatation and peripheral vasoconstriction. Table 1 below lists the effects of cocaine.
Physical and Psychological
Effects of Cocaine (Sources: Stark et al
1996, Stark 1999, Wetli (1985))
|
Dose |
Physical
Effects |
Psychological
Effects |
Initial Low Doses
|
Tachycardia, tachypnoea, hypertension, Dilated
pupils (& flattened lenses), sweating, reduced appetite, reduced need for
sleep, reduced lung function, dry mouth, impaired motor control &
performance of delicate skills and driving |
Euphoria, sense of well being, impaired reaction
time and attention span, impaired learning of new skills |
|
Increased
doses |
Seizures, cardiac arrhythmias, myocardial
infarction, stroke, respiratory arrest |
Anxiety, irritability, insomnia, depression,
paranoia, aggressiveness, impulsivity, delusions, agitated/ excited delirium,
reduced psychomotor function |
|
Chronic
Use |
Erosions, necrosis and perforation of nasal septum,
anosmia, rhinorrhoea and nasal eczema (snorting), chest pains, muscle spasms,
sexual impotence, weight loss, malnutrition, vascular disease |
Dependence, disturbed eating and sleeping patterns |
Therapeutic
Uses of Cocaine
Cocaine is used as a surface local anaesthetic (it
blocks Na+-K+ activated ATPase across adrenergic neuron
cell membranes), particularly in Ear, Nose and Throat (ENT) surgery. It is also
sometimes used in palliative care of terminally ill patients.
Anesthesia means loss of sensation with or
without loss of consciousness. Anesthetic drugs are given to prevent pain and promote
relaxation during surgery, childbirth, some diagnostic tests, and some
treatments. They interrupt the conduction of painful nerve impulses from a site
of injury to the brain. The two basic types of anesthesia are general and
regional.
The state of “general anesthesia” usually includes
analgesia, amnesia, loss of consciousness, inhibition of sensory and autonomic
reflexes, and skeletal muscle relaxation. The extent to which any individual
anesthetic drug can exert these effects is variable to be able to induce
anesthesia smoothly and rapidly as well as to ensure rapid recovery from the
effects of the anesthetic. An ideal anesthetic drug would also possess a wide
margin of safety and be devoid of adverse effects. No single anesthetic agent
is capable of achieving all of these desirable effects without some
disadvantages when used alone. Thus, the modern practice of anesthesia involves
the use of combinations of drugs, taking advantage of their individual
desirable properties while attempting to minimize their potential for harmful
actions. Balanced anesthesia
includes the administration of medications preoperativelу for sedation and
analgesia, the use of neuromuscular blocking drugs intraoperatively, and the
use of both intravenous and inhaled anesthetic drugs.
General
anesthetics are usually given by inhalation or by intravenous injection.
Inhalation
Anesthetics: These are gases or volatile liquids (volatility is expressed
as vapor pressure that vary greatly in the rate at which they induce
anesthesia, potency, degree of circulatory or respiratory depression produced,
muscle relaxant action, and analgesic effects. Inhalation anesthetics have
advantages over intravenous agents in that the depth of anesthesia can be
changed rapidly by altering the inhaled concentration and, because of their
rapid elimination, they do not contribute to postoperative respiratory
depression.
Intravenous
Anesthetics: Cause rapid loss of
consciousness and induction is pleasant. However, they produce little muscle
relaxation and frequently do not obtund reflexes adequately. Repeated
administration results in accumulation and prolongs the recovery time. Since
these agents have little if any analgesic activity, they are seldom used alone
except in brief minor procedures.
Types of general anesthetics
Sites and mechanisms of action of drugs used for
anesthesia.
Ketamine (ketaject, ketalar), may be given intravenously or
intramuscularly. It induces a dissociative state in which the patient may appear to be awake but is
unconscious and does not respond to pain. Ketamine has been used in various
diagnostic procedures; in brief, minor surgical procedures that do not require
substantial skeletal muscle relaxation; and for changing dressings in burn
patients. It also may be used as an induction agent, especially when
cardiovascular or sympathetic depression is undesirable. When combined with
nitrous oxide, diazepam, and a muscle relaxant, ketamine may be employed for
major surgical procedures. Ketamine increases cerebral blood flow and
postoperative hallucinations occur occasionally.
Inhalational Agents: Diethyl ether, halothane nitrous oxide, enflurane,
methoxyflurane, cyclopropane, chloroform. Nitrous oxide, a gas at ambient
temperature and pressure, continues to be an important component of many
anesthesia regimens. Halothane, enflurane, and methoxyflurane are volatile liquids.
Other inhalational agents include ether, cyclopropane, and chloroform, which
have limited current use for reasons that include potential flammability
(ether, cyclopropane) and organ toxicity
(chloroform).
Intravenous Agents
Several drugs are used intravenuoisly to
achieve anesthesia:
(1) Thiobarbiturates (thiopental, methohexital).
(2) Narcotic
analgesics and neuroleptics.
(3) Arylcyclohexylamines (ketamine), which produce a state
called dissociative anesthesia.
(4) Miscellaneous drugs (etomidate, steroid anesthetics,
propanidid).
Signs
and stages of anesthesia
Since the introduction of general
anesthetics, attempts have been made to correlate their observable effects or
signs with the depth of anesthesia. Descriptions of the signs and stages of
anesthesia originate mainly from observations of the effects of diethyl enter,
which has a slow onset of central action due to its high solubility in blood.
These stages and signs may not occur so readily with the more rapidly acting
modern inhaled anesthetics and are unusual with intravenous agents. Many of the
signs refer to the effects anesthetic agents on respiration, reflex activity,
and muscle tone. Traditionally, anesthetic effects are divided into 4 stages of
increasing depth of CNS depression.
I.
Stage of analgesia: The patient initially experiences analgesia without
amnesia. However, later in stage I, both analgesia and amnesia ensue.
II.
Stage of excitement: During this stage, the patient often appears to be
delirious and excited but definitely is amnesic. Respiration is irregular both
in volume and rate, and retching and vomiting may occur. Incontinence and
struggling sometimes occur. For these reasons, efforts are made to limit the
duration and severity of this stage, which ends with the reestablishment of
regular breathing.
III.
Stage of surgical anesthesia: With the beginning of regular respiration, this stage
extends to complete cessation of spontaneous respiration. Four planes of stage
III have been described in terms of changes in ocular movements, eye reflexes,
and pupil size, which under specified conditions may represent sings of
increasing depth of anesthesia.
IV.
Stage of medullary depression: When spontaneous respiration ceases, stage IV is
present. This stage of anesthesia obviously includes severe depression of the
respiratory center in the medulla and the vasomotor center as well. Without
full circulatory and respiratory support, coma and death rapidly ensue.
In modern
anesthesia practice, the distinctive sings of each of the 4 stages described
above are often obscured. Reasons for this include the relatively rapid onset
of action of many inhaled anesthetics compared to that of diethyl ether and the
fact that pulmonary ventilation is often controlled with the aid of a
mechanical ventilator. In addition, the presence of other pharmacologic agents
given pre- or intraoperative can also influence the signs of anesthesia.
Atropine, used to decrease secretions, also dilates pupils; drugs such as
tubocurarine and succinylcholine affect muscle tone; and the narcotic
analgesics exert depressant effects on respiration. The most reliable
indications that stage III (surgical anesthesia) has been achieved are loss of
the eyelash reflex and establishment of a respiratory pattern that is regular
in rate and depth. The adequacy of ensuing depth of anesthesia for the
particular surgical situation is assessed mainly by changes in respiratory and
cardiovascular responses to stimulation.
Mechanisms
of action
A common neurophysiologic action of general anesthetics
is to increase the threshold of cells to
firing, resulting in decreased activity. Almost all anesthetics also reduce the
rate of rise of the action potential by interfering with sodium influx. One
interpretation of these effects is that the physical presence of anesthetic
molecules blocks or distorts neuronal membrane channels involved in sodium
conductance. Current theories of the
possible mechanisms by which anesthetics interfere with the sodium channel include
consideration of their molecular interactions with the lipid matrix of the
membrane and with hydrophobic regions of
specific membrane proteins. This interpretation is encouraged by several facts:
(1) There are few, if any, characteristics of chemical structure common to all
general anesthetic molecules. This
suggests that “receptor sites” for these drugs, if they exist, are quite
nonselective. (2) The potency of general anesthetics is well correlated with their lipid solubility
(Meyer-Overton principle). (3) The
interaction of anesthetics with artificial lipid membranes causes
changes in the physicochemical characteristics of these membranes suggestive of
a reduction of structural order in the lipid matrix. These changes in the lipid
matrix could alter the function of proteins in the membrane – eg, reducing
sodium conductance. Conversely, in experimental animals, general anesthesia can
be reversed quite rapidly by high pressure (eg, 50-100 atm), which increases
the ordering of lipids in the membrane bilayer. This has led to suggestions that
as the anesthetic molecule dissolves in the neuronal membrane, it causes a
small expansion that distorts the sodium channel. High pressure restores the
membrane to its former state to permit the normal influx of sodium that occurs
during generation of the action potential.
The neuropharmacologic basis for the effects
that characterize the stages of anesthesia appears to be a differential
sensitivity to the anesthetics of specific neurons or neuronal pathways. Cells
of the substantia gelatinosa in the dorsal horn of the spinal cord are very
sensitive to relatively low anesthetic concentration in the central nervous
system. A decrease in the activity of the dorsal horn interrupts sensory
transmission in the spinothalamic tract, including that concerning nociceptive
stimuli. These effects contribute to stage I, or analgesia. The disinhibitory
effects of general anesthetics (stage II), which occur at higher brain concentrations, result from complex neuronal
actions including blockade of many small inhibitiry neurons such as Golgi type
II cells, together with a paradoxic facilitation of excitatory
neurotransmitters. A progressive depression of ascending pathways in the
reticular activating system occurs during stage III, or surgical anesthesia,
together with suppression of spinal reflex activity that contributes to muscle
relaxation. Neurons in the respiratory and vasomotor centers of the medulla are
relatively unsensitive to the effects of the general anesthetics, but at high
concentrations their activity is depressed, leading to cardiorespiratory
collapse (stage IV).
Pharmacokinetics of inhaled anesthetics
Depth of anesthesia is determined by the
concentrations of anesthetics in the central nervous system. The rate at which
an effective brain concentration is reached (the rate of induction of
anesthesia) depends on multiple pharmacokinetic factors that influence the
uptake and distribution of the anesthetic. These factors determine the
different rates of transfer of the inhaled anesthetic from the lung to the
blood and from the blood to the brain and other tissues. These factors also
influence the rate of recovery anesthesia when inhalation of the anesthetic is
terminated.
GENERAL
ANESTHESIA
General anesthesia is a state of profound
central nervous system (CNS) depression, during which there is complete loss of
sensation, consciousness, pain perception, and memory. It has three components:
hypnosis, analgesia, and muscle relaxation. Several different drugs are usually
combined to produce desired levels of these components without excessive CNS
depression. This so-called balanced anesthesia also allows lower
dosages
of potent general anesthetics. General anesthesia is usually induced with a
fast-acting drug (eg, propofol or thiopental) given intravenously and is maintained
with a gas mixture of an anesthetic agent and oxygen given by inhalation. The intravenous
(IV) agent produces rapid loss of consciousness and provides a pleasant
induction and recovery. Its rapid onset of action is attributed to rapid circulation
to the brain and accumulation in the neuronal tissue of the cerebral cortex. The
drugs are short acting because they are quickly redistributed from the brain to
highly perfused organs (eg, heart, liver, kidneys) and muscles, and then to
fatty tissues. Because they are slowly released from fatty tissues back into
the bloodstream, anesthesia, drowsiness, and cardiopulmonary depression persist
into the postoperative period. Duration of action can be prolonged and
accumulation is more likely to occur with repeated doses or continuous IV
infusion. An anesthetic barbiturate or propofol may be used alone for
anesthesia during brief diagnostic tests or surgical procedures. Barbiturates
are contraindicated in patients with acute intermittent porphyria, a rare
hereditary disorder characterized by recurrent attacks of physical and mental disturbances.
Inhalation anesthetics vary in the degree of CNS depression produced and
thereby vary in the rate of induction, anesthetic potency, degree of muscle
relaxation, and analgesic potency. CNS depression is determined by the
concentration of the drug in the CNS. Drug concentration, in turn, depends on
the rate at which the drug is transported from the alveoli to the blood,
transported past the blood–brain barrier to reach the CNS, redistributed by the
blood to other body tissues, and eliminated by the lungs. Depth of anesthesia
can be regulated readily by varying the concentration of the inhaled anesthetic
gas.
General inhalation anesthetics should be given only by specially trained
people, such as anesthesiologists and nurse anesthetists, and only with
appropriate equipment.
REGIONAL
ANESTHESIA
Regional anesthesia involves loss of
sensation and motor activity in localized areas of the body. It is induced by
application or injection of local anesthetic drugs. The drugs act to decrease
the permeability of nerve cell membranes to ions, especially sodium. This
action stabilizes and reduces excitability of cell membranes. When excitability
falls low enough, nerve impulses cannot be initiated or conducted by the
anesthetized nerves. As a result, the drugs prevent the cells from responding to
pain impulses and other sensory stimuli.
Some local anesthetic is absorbed into the
bloodstream and circulated through the body, especially when injected or
applied to mucous membrane. The rate and amount of absorption depend mainly on
the drug dose and blood flow to the site of administration. The highest
concentrations are found in organs with a large blood supply (eg, brain, heart,
liver,
lungs). Systemic absorption accounts for most of the potentially serious
adverse effects (eg, CNS stimulation or depression, decreased myocardial
conduction and contractility, bradycardia, hypotension) of local anesthetics.
Epinephrine, a vasoconstrictor, is often
added to a local anesthetic toslow systemic absorption, prolong anesthetic
effects, and control bleeding. Anesthetic effects dwindle and end as drug molecules
diffuse out of neurons into the bloodstream. The drugs are then transported to
the liver for metabolism, mainly to inactive metabolites. The metabolites are
excreted in the urine, along with a small amount of unchanged drug.
Regional anesthesia is usually categorized
according to the site of application. The area anesthetized may be the site of
application, or it may be distal to the point of injection.
Specific types of anesthesia attained with
local anesthetic
drugs
include the following:
1.
Topical or surface anesthesia involves applying local anesthetics to skin or
mucous membrane. Such application makes sensory receptors unresponsive to pain,
itching, and other stimuli. Local anesthetics for topical use are usually
ingredients of various ointments, solutions, or lotions designed for use at
particular sites. For example, preparations are available for use on eyes,
ears, nose, oral mucosa, perineum, hemorrhoids, and skin.
2.
Infiltration involves injecting the local anesthetic solution directly into or
very close to the area to be anesthetized.
3.
Peripheral nerve block involves injecting the anesthetic solution into the area
of a larger nerve trunk or a nerve plexus at some access point along the course
of a nerve distant from the area to be anesthetized.
4.
Field block anesthesia involves injecting the anesthetic solution around the
area to be anesthetized.
5.
Spinal anesthesia involves injecting the anesthetic agent into the
cerebrospinal fluid, usually in the lumbar spine. The anesthetic blocks sensory
impulses at the root of peripheral nerves as they enter the spinal cord. Spinal
anesthesia is especially useful for surgery involving the lower abdomen and
legs. The body area anesthetized is determined by the level to which the drug
solution rises in the spinal canal. This, in turn, is determined by the site of
injection, the position of the client, and the specific gravity, amount, and concentration
of the injected solution.
Solutions of local anesthetics used for
spinal anesthesia are either hyperbaric or hypobaric.
Hyperbaric or heavy solutions are diluted with
dextrose, have a higher specific gravity than cerebrospinal fluid, and
gravitate toward the head when the client is tilted in a head-down position.
Hypobaric or light solutions are diluted with distilled
water, have a lower specific gravity than cerebrospinal fluid, and gravitate
toward the lower (caudal) end of the spinal canal when the client is tilted in
a headdown position.
6.
Epidural anesthesia, which involves injecting the anesthetic into the epidural
space, is used most often in obstetrics during labor and delivery. This route
is also used to provide analgesia (often with a combination of a local
anesthetic and an opioid) for clients with postoperative or other pain.
The extent and duration of anesthesia
produced by injection of local anesthetics depend on several factors. In
general, large amounts, high concentrations, or injections into highly vascular
areas (eg, head and neck, intercostal and paracervical sites) produce peak
plasma levels rapidly. Duration depends on the chemical characteristics of the
drug used and the rate at which it leaves nerve tissue. When a vasoconstrictor
drug, such as epinephrine, has been added, onset and duration of anesthesia are
prolonged because of slow absorption and elimination of the anesthetic agent.
Epinephrine also controls bleeding in the affected area.
ADJUNCTS TO
ANESTHESIA
Several nonanesthetic drugs are used as
adjuncts or supplements to anesthetic drugs. Most are discussed elsewhere and
are described here only in relation to anesthesia. Drug groups include
antianxiety agents and sedative-hypnotics, anticholinergics, and opioid analgesics.
The neuromuscular blocking agents are described in this chapter. Goals of
preanesthetic medication include decreased anxiety without excessive
drowsiness, client amnesia for the perioperative period, reduced requirement
for inhalation anesthetic, reduced adverse effects associated with some
inhalation anesthetics (eg, bradycardia, coughing, salivation, postanesthetic vomiting),
and reduced perioperative stress. Various regimens, usually of two or three
drugs, are used.
Antianxiety
Agents and Sedative-Hypnotics
Antianxiety agents and sedative-hypnotics are given to
decrease anxiety, promote rest, and increase client safety by allowing easier
induction of anesthesia and smaller doses of anesthetic agents. These drugs may
be given the night before to aid sleep and 1 or 2 hours before the scheduled
procedure. Hypnotic doses are usually given for greater sedative effects. A
benzodiazepine such as diazepam (Valium) or midazolam (Versed) is often used.
Midazolam has a rapid onset and short duration of action, causes amnesia,
produces minimal cardiovascular side effects, and reduces the dose of opioid analgesics
required during surgery. It is often used in ambulatory surgical or invasive
diagnostic procedures and regional anesthesia.
Anticholinergics
Anticholinergic
drugs are
given to prevent vagal effects associated with general
anesthesia and surgery (eg, bradycardia, hypotension).
Vagal stimulation occurs with some inhalation anesthetics; with
succinylcholine, a muscle relaxant; and with surgical procedures in which there
is manipulation of the pharynx, trachea, peritoneum, stomach, intestine, or other
viscera and procedures in which pressure is exerted on the eyeball. Useful
drugs are atropine and glycopyrrolate (Robinul).
Opioid
Analgesics
Opioid analgesics induce relaxation and
pain relief in the preanesthetic period. These drugs potentiate the CNS depression
produced by other drugs, and less anesthetic agent is required. Morphine and
fentanyl may be given in anesthetic doses in certain circumstances.
Neuromuscular
Blocking Agents
Neuromuscular blocking agents cause muscle relaxation, the third
component of general anesthesia, and allow the use of smaller amounts of
anesthetic agent. Artificial ventilation is necessary because these drugs
paralyze muscles of respiration as well as other skeletal muscles. The drugs do
not cause sedation; therefore, unless the recipients are unconscious, they can
see and hear environmental activities and conversations.
There are two types of neuromuscular
blocking agents: depolarizing and nondepolarizing. Succinylcholine is the only
commonly used depolarizing drug. Like acetylcholine, the drug combines with
cholinergic receptors at the motor endplate to produce depolarization and
muscle contraction initially. Repolarization and further muscle contraction are
then inhibited as long as an adequate concentration of drug remains at the
receptor site. Muscle paralysis is preceded by muscle spasms, which may damage
muscles. Injury to muscle cells may cause postoperative muscle pain and release
potassium into the circulation. If hyperkalemia develops, it is usually mild
and insignificant but may cause cardiac dysrhythmias or even cardiac arrest in
some situations. Succinylcholine is normally deactivated by plasma
pseudocholinesterase. There is no antidote except reconstituted fresh-frozen
plasma that contains pseudocholinesterase.
Nondepolarizing neuromuscular blocking
agents prevent acetylcholine from acting at neuromuscular junctions.
Consequently, the nerve cell membrane is not depolarized, the muscle fibers are
not stimulated, and skeletal muscle contraction does not occur. The prototype
drug is tubocurarine, the active ingredient of curare, a naturally occurring
plant alkaloid that causes skeletal muscle relaxation or paralysis. Anticholinesterase
drugs, such as neostigmine, are antidotes and can be used to reverse muscle paralysis.
Several newer, synthetic nondepolarizing agents are available and are preferred
over succinylcholine in most instances. The drugs vary in onset and duration of
action. Some have short elimination half-lives (eg, mivacurium, rocuronium)
that allow spontaneous recovery of neuromuscular function when an IV infusion
is discontinued. With these agents, administration of a reversal agent may be
unnecessary. The drugs also vary in routes of elimination, with most involving
both hepatic and renal mechanisms. In clients with renal or hepatic impairment,
the parent drug or its metabolites may accumulate and cause prolonged
paralysis. As a result, neuromuscular blocking agents should be used very
cautiously in clients with renal or hepatic impairment.
INDIVIDUAL
ANESTHETIC AGENTS. PRINCIPLES OF THERAPY
Preanesthetic
Medications
Principles for using preanesthetic drugs
(antianxiety agents, anticholinergics, opioid analgesics) are the same when
these drugs are given before surgery as at other times. They are ordered by an
anesthesiologist and the choice of a particular drug depends on several
factors. Some client-related factors include age; the specific procedure to be
performed and its anticipated duration; the client’s physical condition,
including severity of illness, presence of chronic diseases, and any other
drugs being given; and the client’s mental status. Severe anxiety, for example,
may be a contraindication to regional anesthesia, and the client may require
larger doses of preanesthetic sedative-type medication.
General
Anesthesia
General anesthesia can be used for almost
any surgical, diagnostic, or therapeutic procedure. If a medical disorder of a
vital organ system (cardiovascular, respiratory, renal) is present, it should
be corrected before anesthesia, when possible. General anesthesia and major
surgical procedures have profound effects on normal body functioning. When
alterations due to other disorders are also involved, the risks of anesthesia
and surgery are greatly increased. Because of the risks, general anesthetics
and neuromuscular blocking agents should be given only by people with
special training in correct usage and only in locations where staff, equipment,
and drugs are available for emergency use or cardiopulmonary resuscitation.
Regional and
Local Anesthesia
Regional or local anesthesia is usually
safer than general anesthesia because it produces fewer systemic effects. For example, spinal anesthesia is often the anesthesia of
choice for surgery involving the lower abdomen and lower extremities, especially
in people who are elderly or have chronic lung disease. A major advantage of
spinal anesthesia is that it causes less CNS and respiratory depression.
Guidelines for injections of local anesthetic agents include the following:
1. Local
anesthetics should be injected only by people with special training in
correct usage and only in locations where staff, equipment, and drugs
are available for emergency use or cardiopulmonary resuscitation.
2. Choice
of a local anesthetic depends mainly on the reason for use or the type of
regional anesthesia desired. Lidocaine, one of the most widely used, is
available in topical and injectable forms.
3. Except
with IV lidocaine for cardiac dysrhythmias, local anesthetic solutions must not
be injected into blood vessels because of the high risk of serious adverse reactions
involving the cardiovascular system and CNS
Nursing Process
Preoperative Assessment
• Assess
nutritional status.
• Assess
use of prescription and nonprescription drugs, especially those taken within
the past 3 days.
• Ask
about the use of herbal drugs during the previous week, especially those that
are likely to cause perioperative complications. For example, ephedra increases
risks of cardiac dysrhythmias, hypertension, myocardial infarction, and stroke;
feverfew, garlic, ginkgo, and ginseng can increase risks of bleeding; kava and
valerian can increase effects of sedatives.
• Ask
about drug allergies. If use of local or regional anesthesia is anticipated,
ask if the client has ever had an allergic reaction to a local anesthetic.
• Assess
for risk factors for complications of anesthesia and surgery (cigarette
smoking, obesity, limited exercise or activity, chronic cardiovascular,
respiratory, renal, or other disease processes).
• Assess
the client’s understanding of the intended procedure, attitude toward
anesthesia and surgery, and degree of anxiety and fear.
• Assess
ability and willingness to participate in postoperative activities to promote
recovery.
• Assess
vital signs, laboratory data, and other data as indicated to establish baseline
measurements for monitoring changes.
Postoperative Assessment
• During
the immediate postoperative period, assess vital signs and respiratory and
cardiovascular function every 5 to 15 minutes until reactive and stabilizing.
Effects of anesthetics and adjunctive medications persist into postanesthesia recovery.
• Continue
to assess vital signs, fluid balance, and laboratory and other data.
• Assess
for signs of complications (eg, fluid and electrolyte imbalance, respiratory
problems, thrombophlebitis, wound infection).
Nursing Diagnoses
• Risk
for Injury: Trauma related to impaired sensory perception and impaired physical
mobility from anesthetic or sedative drugs
• Risk
for Injury: CNS depression with premedications and general anesthetics
• Pain
related to operative procedure
• Decreased
Cardiac Output related to effects of anesthetics, other medications, and
surgery
• Risk
for Ineffective Breathing Patterns related to respiratory depression
• Anxiety
or Fear related to anticipated surgery and possible outcomes
Planning/Goals
The client will:
• Receive
sufficient emotional support and instruction to facilitate a smooth
preoperative and postoperative course
• Be
protected from injury and complications while selfcare ability is impaired
• Have
emergency supplies and personnel available if needed
• Have
postoperative discomfort managed appropriately
Interventions
Preoperatively,
assist the client to achieve optimal conditions for surgery. Some guidelines
include the following:
• Provide
foods and fluids to improve or maintain nutritional status (eg, those high in
protein, vitamin C and other vitamins, and electrolytes to promote healing).
• Help
the client maintain exercise and activity, when feasible. This helps promote
respiratory and cardiovascular function and decreases anxiety.
• Explain
the expected course of events of the perioperative period (eg, specific
preparations for surgery, close observation and monitoring during
postanesthesia recovery, approximate length of stay).
• Assist
clients with measures to facilitate recovery postoperatively (eg, coughing and
deep-breathing exercises, leg exercises and early ambulation, maintaining fluid
balance and urine output).
• Explain
how postoperative pain will be managed. This is often a major source of
anxiety. Postoperatively, the major focus is on maintaining a safe environment and
vital functions. Specific interventions include:
• Observe
and record vital signs, level of consciousness, respiratory and cardiovascular
status, wound status, and elimination frequently until sensory and motor
functions return, then periodically until discharge.
• Maintain
IV infusions. Monitor the site, amount, and type of fluids. If potential
problems are identified (eg, hypovolemia or hypervolemia), intervene to prevent
them from becoming actual problems.
• Give
pain medication appropriately as indicated by the client’s condition.
• Help
the client to turn, cough, deep breathe, exercise legs, ambulate, and perform
other self-care activities until he or she can perform them independently.
• Use
sterile technique in wound care.
• Initiate
discharge planning for a smooth transition to home care.
Evaluation
• Observe
for absence of injury and complications (eg, no fever or other signs of
infection).
• Observe
for improved ability in self-care activities.
• The client states that pain has been managed satisfactorily. If
blood is aspirated into the syringe, another injection site must be selected.
4. Local
anesthetics given during labor cross the placenta and may depress muscle
strength, muscle tone, and rooting behavior in the newborn. Apgar scores are usually
normal. If excessive amounts are used (eg, in paracervical block), local
anesthetics may cause fetal bradycardia, increased movement, and expulsion of
meconium before birth and marked depression after birth. Dosage used for spinal
anesthesia during labor is too small to depress the fetus or the newborn.
5. For
spinal or epidural anesthesia, use only local anesthetic solutions that have
been specifically prepared for spinal anesthesia and are in single-dose
containers. Multiple-dose containers are not used because of the risk of
injecting contaminated solutions.
6.
Epinephrine is often added to local anesthetic solutions to prolong anesthetic
effects. Such solutions require special safety precautions, such as the
following:
a. This
combination of drugs should not be used for nerve blocks in areas supplied by
end arteries (fin gers, ears, nose, toes, penis)
because it may produce ischemia and gangrene.
b.
This combination should not be given IV or in excessive dosage because the
local anesthetic and epinephrine can cause serious systemic toxicity, including
cardiac dysrhythmias.
c.
This combination should not be used with inhalation anesthetic agents that
increase myocardial sensitivity to catecholamines. Severe ventricular
dysrhythmias may result.
d.
These drugs should not be used in clients with severe cardiovascular disease or
hyperthyroidism.
e.
If used in obstetrics, the concentration of epinephrine should be no greater
than 1:200,000 because of the danger of producing vasoconstriction in uterine blood
vessels. Such vasoconstriction may cause decreased placental circulation,
decreased intensity of uterine contractions, and prolonged labor.
Topical Anesthesia of Mucous Membranes
When
used to anesthetize nasal, oral, pharyngeal, laryngeal, tracheal, bronchial, or
urethral mucosa, local anesthetics should be given in the lowest effective
dosage. The drugs are well absorbed through mucous membranes and may cause systemic
adverse reactions.
Use in
Children
Compared with adults, children are at
greater risk of complications (eg, laryngospasm, bronchospasm, aspiration) and death
from anesthesia. Thus, whoever administers anesthetics to children should be
knowledgeable about anesthetics and their effects in children. In addition, the
nurse who cares for a child before, during, and after surgical or other
procedures that require anesthesia or sedation must be skilled in using the nursing
process with children.
1.
Halothane has been commonly used. It causes bronchodilation and does not
irritate respiratory mucosa, features that make it especially useful for
children with asthma, cystic fibrosis, or other bronchospastic disorders. However,
the drug dilates blood vessels in the brain and increases intracranial
pressure, so it may not be indicated in clients who already have increased intracranial
pressure or mass lesions. Halothane may also sensitize the myocardium to
epinephrine, although children are less likely than adults to have ventricular dysrhythmias.
2.
Sevoflurane, a newer agent, may have some advantages over halothane in
pediatric anesthesia. It allows a faster induction and emergence, does not
stimulate the sympathetic nervous system or potentiate cardiac dysrhythmias,
and produces a minimal increase in intracranial pressure. However, it is much
more expensive than halothane.
3.
Propofol is approved for use in children 3 years of age and older. It has a
rapid onset; a rapid metabolism rate; and a smooth emergence with little mental
confusion, sedation, or nausea. It also decreases cerebral blood flow and
intracranial pressure, making it useful in neurosurgery. In addition, propofol
is widely used for sedation with diagnostic tests or special procedures that require
children to be sedated and immobile. Propofol may be given by injection for
induction and an IV infusion pump for maintenance of anesthesia or sedation.
Adverse effects include respiratory
depression, hypotension, and pain with injection. Slow titration of dosage, a
large-bore IV catheter, adding lidocaine, and slow drug injection into a rapidly
flowing IV can minimize these effects. In addition, the formulation now
contains an antimicrobial agent, which should reduce risks of infection.
4.
In general, infants and children have a higher anesthetic requirement, relative
to size and weight, than healthy adults.
5.
Some agencies allow parents to be present during induction of general
anesthesia. This seems to reduce anxiety for both parents and children.
6.
With muscle relaxants, the choice depends on the type of surgery and
anesthesia, contraindications to a particular agent, the presence of client
conditions that affect or preclude use of a particular drug, and the preference
of the anesthesiologist. For short surgical procedures, intermediate-acting
nondepolarizing agents (eg, atracurium, mivacurium) are commonly used.
Succinylcholine, formerly a commonly used agent, is now contraindicated for
routine, elective surgery in children and adolescents. This precaution stems
from reports of several deaths associated with the use of succinylcholine in children
with previously undiagnosed skeletal muscle myopathy. However, succinylcholine
is still indicated in children who require emergency intubation or rapid
securing of the airway (eg, laryngospasm, full stomach) and for intramuscular
administration when a suitable vein is unavailable.
7.
Children are more likely to have postoperative nausea and vomiting than adults.
8. Local anesthetics usually have the same
uses, precautions, and adverse effects in children as in adults. Safety and
efficacy of bupivacaine, dyclonine, and tetracaine have not been established in
children younger than 12 years of age. Benzocaine should not be used in infants
younger than 1 year of age. Dosages in children With spray preparations, do not
inhale vapors, spray near food, or store near any heat source. Use local
anesthetic preparations for only a short period. If the condition for which it
is being used persists, report the condition to the physician. Inform dentists
or other physicians if allergic to any local anesthetic drug. Allergic
reactions are rare, but if they have occurred, another type of local anesthetic
can usually be substituted safely. Use the drug preparation only on the part of
the body for which it was prescribed. Most preparations are specifically made
to apply on certain areas, and they cannot be used effectively and safely on
other body parts. Use the drug only for the condition for which it was
prescribed. For example, a local anesthetic prescribed to relieve itching may
aggravate an open wound. Apply local anesthetics to clean areas. For the drugs
to be effective, they must have direct contact with the affected area.
Do
not apply more often than directed. Local irritation, skin rash, and
hives can develop.
With
topical applications to intact skin, there is greater systemic absorption and
risk of toxicity in infants. A mixture of lidocaine and prilocaine (Eutectic
Mixture of Local Anesthetics [EMLA]) was formulated to penetrate intact skin,
provide local anesthesia, and decrease pain of vaccinations and venipuncture.
The cream is applied at the injection site with an occlusive dressing at least 60
minutes before vaccination or venipuncture. For topical application to mucous
membranes, low concentrations of local anesthetics should be used. EMLA cream
should not be used on mucous membranes (or abraded skin). These drugs are
readily absorbed through mucous membranes and may cause systemic toxicity.
Use in Older
Adults
Older adults often have physiologic
changes and pathologic conditions that make them more susceptible to adverse
effects of anesthetics, neuromuscular blocking agents, and adjunctive medications.
Thus, lower doses of these agents are usually needed. With propofol, delayed
excretion and a longer halflife lead to higher peak plasma levels. Higher
plasma levels can cause hypotension, apnea, airway obstruction, and oxygen desaturation
if dosage is not reduced. Long-term infusion may result in accumulation in body
fat and prolonged elimination.
With injections of a local anesthetic,
repeated doses may cause accumulation of the drug or its metabolites and
increased risks of adverse effects. Because cardiovascular homeostatic mechanisms
are often impaired, older adults may be at risk for decreased cardiac output,
hypotension, heart block, and cardiac arrest.
Use in Renal
Impairment
Most inhalation general anesthetic agents
can be used in clients with renal impairment because they are eliminated mainly
by exhalation from the lungs. However, they reduce renal blood flow, glomerular
filtration, and urine volume, as do IV general anesthetics.
Most neuromuscular blocking agents are
metabolized or excreted in urine to varying extents. Thus, renal effects vary among
the drugs, and several may accumulate in the presence of renal impairment
because of delayed elimination. With atracurium, which is mainly metabolized by
the liver with a small amount excreted unchanged in urine, short-term use of bolus
doses does not impair renal function. With long-term infusion, however,
metabolism of atracurium produces a metabolite (laudanosine) that accumulates
in renal failure and may cause neurotoxicity. With succinylcholine, liver
metabolism produces active metabolites, some of which are excreted through the
kidneys. These metabolites can accumulate and cause hyperkalemia in clients
with renal impairment. Thus, renal impairment may lead to accumulation of
neuromuscular blocking agents or their metabolites. The drugs should be used very
cautiously in clients with renal impairment.
Use in Hepatic
Impairment
Most inhalation general anesthetics are
minimally metabolized in the liver and therefore are unlikely to accumulate with
short-term usage. However, all general anesthetics reduce blood flow to the
liver, and the liver’s ability to metabolize other drugs may be impaired. Propofol
is metabolized mainly in the liver to inactive metabolites, which are then
excreted by the kidneys. Propofol clearance may be slower because of decreased
hepatic blood flow.
Neuromuscular blocking agents vary in the
extent to which they are metabolized in the liver. For example, atracurium, rocuronium,
and vecuronium are eliminated mainly by the liver. They may accumulate with
hepatic impairment because of delayed elimination. Succinylcholine is also
metabolized in the liver and should be used very cautiously in clients with
hepatic impairment.
With local anesthetics, injections of the
amide type (eg, lidocaine), which are metabolized primarily in the liver, are more
likely to reach high plasma levels and cause systemic toxicity in clients with
hepatic disease. The drugs should be used cautiously, in minimally effective
doses, in such clients. In addition, clients with severe hepatic impairment are
more likely to acquire toxic plasma concentrations of lidocaine and prilocaine
from topical use of EMLA because of impaired ability to metabolize the drug.
Use in
Critical Illness
Propofol, neuromuscular blocking agents,
and local anesthetics are commonly used in intensive care units. These drugs should
be administered and monitored only by health care personnel who are skilled in
the management of critically ill clients, including cardiopulmonary
resuscitation and airway management. Critical care nurses must often care for
clients receiving IV infusions of the drugs and titrate dosage and flow rate to
achieve desired effects and minimize adverse effects.
Propofol is an anesthetic used in subanesthetic
doses for short-term sedation of clients who are intubated and mechanically ventilated.
It has a rapid onset of action, and clients awaken within a few minutes of
stopping drug administration. It is given by continuous IV infusion in doses of
5 to 50 mcg/kg/min. Doses can be increased in small amounts every 5 to 10
minutes to achieve sedation and decreased in small amounts every 5 to 10
minutes to allow awakening. The rate of infusion should be individualized and
titrated to clinical response. As a general rule, the rate should be slower in older
adults, clients receiving other CNS depressant drugs (eg, opioids or
benzodiazepines), and critically ill clients. In addition, the level of
sedation may be adjusted to the client’s condition and needs, such as a lighter
level during visiting hours or a deeper level during painful procedures. Propofol
lacks analgesic effects, so
analgesia must be provided for patients in pain or those having painful
procedures. It also has antiemetic properties.
During propofol infusion, vital functions need to be
assessed and monitored at regular intervals. For neurologic assessment, dosage
is decreased every 12 or 24 hours to maintain light sedation. The drug should
not be stopped because rapid awakening may be accompanied by anxiety,
agitation, and resistance to mechanical ventilation. After assessment, the dose
is increased until the desired level of sedation occurs. For hemodynamic and
respiratory assessment, vital signs, electrocardiograms, pulmonary capillary
wedge pressures, arterial blood gas levels, oxygen saturation, and other
measurements are needed. Because propofol is expensive, some clinicians
recommend that its use be limited to 24 to 48 hours.
Neuromuscular blocking agents are used to facilitate mechanical ventilation, control
increased intracranial pressure, and treat status epilepticus. Clients
requiring prolonged use of neuromuscular blocking agents usually have
life-threatening illnesses such as adult respiratory distress syndrome,
systemic inflammatory response syndrome, or multiple organ dysfunction
syndrome. The most commonly used are the nondepolarizing agents (eg,
atracurium, vecuronium), which are given by intermittent bolus or continuous
infusion. When the drugs are used for extended periods, clients are at risk for
development of complications of immobility such as atelectasis, pneumonia, muscle
wasting, and malnutrition. In addition, the drugs may accumulate, prolong
muscle weakness, and make weaning from a ventilator more difficult.
Accumulation results mainly from delayed elimination.
Local anesthetics should be used with caution in critically ill clients,
especially those with impaired cardiovascular function such as dysrhythmias,
heart block, hypotension, or shock. Repeated doses may cause accumulation of
the drug or its metabolites or slow its metabolism. Reduced doses are indicated
to decrease adverse effects; if a local anesthetic (eg, bupivacaine) is infused
epidurally with an opioid analgesic (eg, fentanyl), dosage of both agents must be
reduced to decrease risks of respiratory arrest. In addition to usual uses of
local anesthetics, lidocaine is often given in coronary care units to decrease
myocardial irritability and prevent or treat ventricular tachydysrhythmias
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