OPIOIDS/BELUM SELESAI

TRI WIDHIYONO PAMUNGKAS

Mechanisms of Action
Opioids bind to specific receptors located throughout the central nervous system and
other tissues. Four major types of opioid receptor have been identified (Table 84): mu (, with
subtypes -1 and -2), kappa (), delta ( ), and sigma ( ).
Although opioids provide some degree of sedation, they are most effective at producing
analgesia.
The pharmacodynamic properties of specific opioids depend on which
1. receptor is bound,
2. the binding affinity,
3. and whether the receptor is activated.
Although both opioid agonists and antagonists bind to opioid receptors, only agonists are
capable of receptor activation.
Agonistsantagonists (eg, nalbuphine, nalorphine, butorphanol, and pentazocine) are drugs
that have opposite actions at different receptor types.
The pure opioid antagonist naloxone is discussed in Chapter 15.
Endorphins, enkephalins, and dynorphins are endogenous peptides that bind to opioid
receptors.
These three families of opioid peptides differ in their protein precursors, anatomic
distributions, and receptor affinities.
Opiatereceptor activation inhibits the presynaptic release and postsynaptic response
to excitatory neurotransmitters (eg, acetylcholine, substance P) from nociceptive neurons.
The cellular mechanism for this neuromodulation may involve alterations in potassium and
calcium ion conductance.
Transmission of pain impulses can be interrupted at the level of the dorsal horn of the spinal
cord with intrathecal or epidural administration of opioids. Modulation of a descending
inhibitory pathway from the periaqueductal gray through the nucleus raphe magnus to the
dorsal horn of the spinal cord may also play a role in opioid analgesia. Although opioids exert
their greatest effect within the central nervous system, opiate receptors have also been
isolated from somatic and sympathetic peripheral nerves.

StructureActivity Relationships
Opiatereceptor interaction is shared by a chemically diverse group of compounds.
Nonetheless, there are common structural characteristics, which are shown in Figure 86. Small
molecular changes can convert an agonist into an antagonist. Note that the levorotatory
isomers are generally more potent than the dextrorotatory isomers.
Pharmacokinetics
ABSORPTION
Rapid and complete absorption follows the intramuscular injection of morphine and
meperidine, with peak plasma levels usually reached after 2060 min.
Oral transmucosal fentanyl citrate absorption (fentanyl "lollipop") is an effective method of
producing analgesia and sedation and provides rapid onset (10 min) of analgesia and sedation
in children (1520 g/kg) and adults (200800 g).
The low molecular weight and high lipid solubility of fentanyl also allow transdermal
absorption (the fentanyl patch).
The amount of fentanyl released depends primarily on the surface area of the patch but can
vary with local skin conditions (eg, blood flow).
Establishing a reservoir of drug in the upper dermis delays systemic absorption for the first few
hours.
Serum concentrations of fentanyl reach a plateau within 1424 h of application (peak levels
occur later in elderly patients than in young adult patients) and remain constant for up to 72 h.
Continued absorption from the dermal reservoir accounts for a prolonged fall in serum levels
after patch removal. A high incidence of nausea and variable blood levels have limited the
acceptance of fentanyl patches for postoperative relief of pain.
Experimental studies have explored the possibility of an inhalation delivery of liposome-
encapsulated fentanyl.
DISTRIBUTION
Table 85 summarizes the physical characteristics that determine distribution and
uptake of opioid analgesics. The distribution half-lives of all of the opioids are fairly rapid (520
min). The low fat solubility of morphine slows passage across the bloodbrain barrier, however,
so that its onset of action is slow and its duration of action is prolonged. This contrasts with the
high lipid solubility of fentanyl and sufentanil, which allows a rapid onset and short duration of
action. Interestingly, alfentanil has a more rapid onset of action and shorter duration of action
than fentanyl following a bolus injection, even though it is less lipid soluble than fentanyl. The
high nonionized fraction of alfentanil at physiological pH and its small V
d
increase the amount of
drug available for binding in the brain. Significant amounts of lipid-soluble opioids can be
retained by the lungs (first-pass uptake) and later diffuse back into the systemic circulation. The
amount of pulmonary uptake depends on prior accumulation of another drug (decreases), a
history of tobacco use (increases), and coincident inhalation anesthetic administration
(decreases). Redistribution terminates the action of small doses of all of these drugs, whereas
larger doses must depend on biotransformation to adequately lower plasma levels.
BIOTRANSFORMATION
Most opioids depend primarily on the liver for biotransformation. Because of their high
hepatic extraction ratio, their clearance depends on liver blood flow. The small V
d
of alfentanil
is responsible for a short elimination half-life (1.5 h). Morphine undergoes conjugation with
glucuronic acid to form morphine 3-glucuronide and morphine 6-glucuronide. Meperidine is N-
demethylated to normeperidine, an active metabolite associated with seizure activity. The end
products of fentanyl, sufentanil, and alfentanil are inactive.
The unique ester structure of remifentanil, an ultrashort-acting opioid with a terminal
elimination half-life of less than 10 min, makes it susceptible to rapid ester hydrolysis by
nonspecific esterases in blood (red cells) and tissue (see Figure 86) in a manner similar to
esmolol (see Chapter 12). Biotransformation is so rapid and so complete that the duration of a
remifentanil infusion has little effect on wake-up time (Figure 87). Its context/sensitive half-
time (the time required for the plasma drug concentration to decline by 50% after termination
of an infusion) is approximately 3 min regardless of the duration of infusion. This lack of drug
accumulation following repeated boluses or prolonged infusions differs from other currently
available opioids. Extrahepatic hydrolysis also implies the absence of metabolite toxicity in
patients with hepatic dysfunction. Patients with pseudocholinesterase deficiency have a normal
response to remifentanil.
EXCRETION
The end products of morphine and meperidine biotransformation are eliminated by the
kidneys, with less than 10% undergoing biliary excretion. Because 510% of morphine is
excreted unchanged in the urine, renal failure prolongs its duration of action. The accumulation
of morphine metabolites (morphine 3-glucuronide and morphine 6-glucuronide) in patients
with renal failure has been associated with narcosis and ventilatory depression lasting several
days. In fact, morphine 6-glucuronide is a more potent and longer-lasting opioid agonist than
morphine. Similarly, renal dysfunction increases the chance of toxic effects from
normeperidine accumulation. Normeperidine has an excitatory effect on the central nervous
system, leading to myoclonic activity and seizures that are not reversed by naloxone. A late
secondary peak in fentanyl plasma levels occurs up to 4 h after the last intravenous dose and
may be explained by enterohepatic recirculation or mobilization of sequestered drug.
Metabolites of sufentanil are excreted in urine and bile. The main metabolite of remifentanil is
eliminated renally but is several thousand times less potent than its parent compound, and thus
is unlikely to produce any noticeable opioid effects. Even severe liver disease does not affect
the pharmacokinetics or pharmacodynamics of remifentanil.

Effects on Organ Systems
CARDIOVASCULAR
In general, opioids do not seriously impair cardiovascular function.
Meperidine tends to increase heart rate (it is structurally similar to atropine), whereas high
doses of morphine, fentanyl, sufentanil, remifentanil, and alfentanil are associated with a
vagus-mediated bradycardia.
With the exception of meperidine, the opioids do not depress cardiac contractility.
Nonetheless/namun, arterial blood pressure often falls as a result of bradycardia, venodilation,
and decreased sympathetic reflexes, sometimes requiring vasopressor (eg, ephedrine) support.
Furthermore, meperidine and morphine evoke histamine release in some individuals that can
lead to profound drops in systemic vascular resistance and arterial blood pressure.
The effects of histamine release can be minimized in susceptible patients by slow opioid
infusion, adequate intravascular volume, or pretreatment with H
1
and H
2
histamine antagonists.
Intraoperative hypertension during opioid anesthesia, particularly morphine and
meperidine, is not uncommon.
It is often attributable to inadequate anesthetic depth and can be controlled with the addition
of vasodilators or volatile anesthetic agents.
The combination of opioids with other anesthetic drugs (eg, nitrous oxide, benzodiazepines,
barbiturates, volatile agents) can result in significant myocardial depression.
RESPIRATORY
Opioids depress ventilation, particularly respiratory rate.
Resting PaCO
2
increases and the response to a CO
2
challenge is blunted, resulting in a shift of
the CO
2
response curve downward and to the right (Figure 88).
These effects are mediated through the respiratory centers in the brain stem.
The apneic thresholdthe highest PaCO
2
at which a patient remains apneicis elevated, and
hypoxic drive is decreased.
Gender differences may exist in these effects, with women demonstrating more respiratory
depression.
Morphine and meperidine can cause histamine-induced bronchospasm in susceptible patients.
Opioids (particularly fentanyl, sufentanil, and alfentanil) can induce chest wall rigidity severe
enough to prevent adequate ventilation.
This centrally mediated muscle contraction is most frequent after large drug boluses and is
effectively treated with neuromuscular blocking agents.
Opioids can effectively blunt the bronchoconstrictive response to airway stimulation such as
occurs during intubation.
CEREBRAL
The effects of opioids on cerebral perfusion and intracranial pressure appear to be
variable. In general, opioids reduce cerebral oxygen consumption, cerebral blood flow, and
intracranial pressure, but to a much lesser extent than barbiturates or benzodiazepines. These
effects presume a maintenance of normocarbia by artificial ventilation; however, there are
some reports of mildand usually transientincreases in cerebral artery blood flow velocity
and intracranial pressure following opioid boluses in patients with brain tumors or head
trauma. Because opioids also tend to produce a mild decrease in mean arterial pressure, the
resulting fall in CPP may be significant in some patients with abnormal intracranial elastance.
Any small rise in intracranial pressure that opioids may cause must be compared with the
potentially large increases in intracranial pressure during intubation in an inadequately
anesthetized patient. The effect of most opioids on the EEG is minimal, although high doses are
associated with slow -wave activity. High doses of fentanyl may rarely cause seizure activity;
however, some cases may actually be severe opioid-induced muscle rigidity. EEG activation has
been attributed to meperidine.
Stimulation of the medullary chemoreceptor trigger zone is responsible for a high
incidence of nausea and vomiting. Physical dependence is a significant problem associated with
repeated opioid administration. Unlike the barbiturates or benzodiazepines, relatively large
doses of opioids are required to render patients unconscious (Table 86). Regardless of the
dose, however, opioids do not reliably produce amnesia. Intravenous opioids have been the
mainstay of pain control for more than a century. The relatively recent use of opioids in
epidural and subdural spaces has revolutionized pain management (see Chapter 18).
Unique among opioids, meperidine and structurally similar sameridine have local
anesthetic qualities when administered into the subarachnoid space. Meperidine's clinical use
has been limited by classic opioid side effects (nausea, sedation, and pruritus), which may not
be as pronounced with sameridine. Intravenous meperidine (25 mg) has been found to be the
most effective opioid for decreasing shivering.
GASTROINTESTINAL
Opioids slow gastric emptying time by reducing peristalsis.
Biliary colic may result from opioid-induced contraction of the sphincter of Oddi.
Biliary spasm, which can mimic a common bile duct stone on cholangiography, is effectively
reversed with the pure opioid antagonist naloxone.
Patients receiving long-term opioid therapy (for cancer pain, for example) usually become
tolerant to most of the side effects, except constipation because of the decreased
gastrointestinal motility.

ENDOCRINE
The stress response to surgical stimulation is measured in terms of the secretion of specific
hormones, including
1. catecholamines,
2. antidiuretic hormone,
3. and cortisol.
Opioids block the release of these hormones more completely than volatile anesthetics.
This is particularly true of the more potent opioids such as fentanyl, sufentanil, alfentanil, and
remifentanil.
In particular, patients with ischemic heart disease may benefit from attenuation of the stress
response.
Drug Interactions
The combination of opioidsparticularly meperidineand monoamine oxidase inhibitors may
result in respiratory arrest, hypertension or hypotension, coma, and hyperpyrexia. The cause of
this dramatic interaction is not understood.
Barbiturates, benzodiazepines, and other central nervous system depressants can have
synergistic cardiovascular, respiratory, and sedative effects with opioids.
The biotransformation of alfentanil, but not sufentanil, may be impaired following a 7-day
course of erythromycin, leading to prolonged sedation and respiratory depression.