Page 582 - Basic _ Clinical Pharmacology ( PDFDrive )

568 SECTION V Drugs That Act in the Central Nervous System

compound, fentanyl. An extremely potent analog, carfentanil, Since each controlled-release tablet of oxycodone contains a large
is used in veterinary medicine for sedating large mammals, eg, quantity of oxycodone to allow for prolonged action, those intent
elephants. Adulteration of street heroin with carfentanil has been on abusing the old formulation have extracted crushed tablets and
responsible for many deaths in humans. injected high doses, resulting in misuse and possible fatal overdose.
In 2010, the FDA approved a new formulation of the controlled-
O release form of oxycodone that reportedly prevents the tablets from
C CH 2 CH 3 being cut, broken, chewed, crushed, or dissolved to release more oxy-
N
codone. It is hoped that this new formulation will lead to less misuse
by snorting or injection. The FDA is now requiring a Risk Evalua-
N tion and Mitigation Strategy (REMS) that will include the issuance
of a medication guide to patients and a requirement for prescriber
CH 2 CH 2 C 6 H 5
Fentanyl education regarding the appropriate use of opioid analgesics in the
treatment of pain. (See Box: Educating Opioid Prescribers.)
These opioids differ mainly in their potency and biodisposi-
tion. Sufentanil is five to seven times more potent than fentanyl. N CH 3
Alfentanil is considerably less potent than fentanyl, but acts more CH 2
rapidly and has a markedly shorter duration of action. Remifen-
CH 2
tanil is metabolized very rapidly by blood and nonspecific tissue
esterases, making its pharmacokinetic and pharmacodynamic H 3 C O O OH
half-lives extremely short. Such properties are useful when these Codeine
compounds are used in anesthesia practice. Although fentanyl
is now the predominant analgesic in the phenylpiperidine class, Phenylheptylamines
meperidine continues to be used. This older opioid has signifi- Propoxyphene is chemically related to methadone but has
cant antimuscarinic effects, which may be a contraindication if extremely low analgesic activity. Its low efficacy makes it unsuit-
tachycardia would be a problem. Meperidine is also reported to able, even in combination with aspirin, for severe pain. The
have a negative inotropic action on the heart. In addition, it has increasing incidence of deaths associated with its use and misuse
the potential for producing seizures secondary to accumulation caused it to be withdrawn in the United States.
of its metabolite, normeperidine, in patients receiving high doses
or with concurrent renal failure. Given this undesirable profile, Phenylpiperidines
use of meperidine as a first-line analgesic is becoming increas-
ingly rare. Diphenoxylate and its metabolite, difenoxin, are not used for
analgesia but for the treatment of diarrhea. They are scheduled
Morphinans for minimal control (difenoxin is Schedule IV, diphenoxylate
Schedule V; see inside front cover) because the likelihood of their
Levorphanol is a synthetic opioid analgesic closely resembling misuse is remote. The poor solubility of the compounds limits
morphine that has μ-, δ-, and κ-opioid agonist actions, serotonin- their use for parenteral injection. As antidiarrheal drugs, they are
norepinephrine reuptake inhibition, and NMDA receptor antago- used in combination with atropine. The atropine is added in a
nist properties. concentration too low to have a significant antidiarrheal effect but
is presumed to further reduce the likelihood of misuse.
MILD TO MODERATE AGONISTS Loperamide is a phenylpiperidine derivative used to control
diarrhea. Due to action on peripheral μ-opioid receptors and
Phenanthrenes lack of effect on CNS receptors, investigations are ongoing as to
whether it could be an effective analgesic. Its potential for misuse
Codeine, dihydrocodeine, and hydrocodone have lower is considered very low because of its limited access to the brain. It
binding affinity to μ-opioid receptors than morphine and often is therefore available without a prescription.
have adverse effects that limit the maximum tolerated dose The usual dose with all of these antidiarrheal agents is two
when one attempts to achieve analgesia comparable to that of tablets to start and then one tablet after each diarrheal stool.
morphine.
Oxycodone is more potent and is prescribed alone in higher
doses as immediate-release or controlled-release forms for the OPIOIDS WITH MIXED RECEPTOR
treatment of moderate to severe pain. Combinations of hydro- ACTIONS
codone or oxycodone with acetaminophen are the predominant
formulations of orally administered analgesics in the United States Care should be taken not to administer any partial agonist or drug
for the treatment of mild to moderate pain. However, there has with mixed opioid receptor actions to patients receiving pure ago-
been a large increase in the use of controlled-release oxycodone at nist drugs because of the unpredictability of both drugs’ effects;
the highest dose range. An intravenous formulation of oxycodone reduction of analgesia or precipitation of an explosive abstinence
is available outside the United States. syndrome may result.