opiods
OPIODS
-meperidine
-morphine
-fentanyl
-sufentanil
-alfentanil
-remifentanil
mechanism of action
structure-activity relationship
pharmacokinetics
effects on organ systems
drug interaction
Four major types of opiod receptors:
-mu receptors ( mu-1, mu-2)
-kappa receptors
-delta receptors
-sigma receptors
Endogenous peptides which bind opiod receptors:
-endorphins
-enkephalins
-dynorphins
Opiod- receptor activation:
-produces analgesia
-inhibits presynaptic release of acetylcholine and substance P in nociceptive neurons
-inhibits postsynaptic response to acetylcholine and substance P in nociceptive neurons
-may involve changes in potassium and calcium ion conductance
-intrathecal and epidural administration of opiods can interrupt pain impulses at the dorsal horn of spinal cord
-periaqueductal gray and nucleus raphe may also be involved in the analgesic effects of opiods
STRUCTURE-ACTIVITY RELATIONSHIPS
-chemically diverse group of compounds which share a common opiod-receptor interaction
Absorption
-oral transmuscosal fentanyl citrate absorption is effective in producing analgesia and sedation with onset approx 10 minutes
-transdermal patch of fentanyl is possible due fentanyl's low molecular weight and high lipid solubility
-intramuscular injection of meperidine and morphine has peak effects after 20 - 60 minutes
-intravascular route of analgesics allows for more closer titration from a clinically trained experienced practioner
Distribution
-distribution half live is generally rapid (5 - 20 minutes) for all analgesics except for morphine
-morphine has a lower lipid solubility and crosses the BBB more slowly therefore the onset and duration of action are prolonged
-fentanyl and sufentanil have high lipid solubility therefore have a rapid onset of action and have a short duration of action
-alfentanil has less solubility compared to fentanyl but has a more rapid onset due its high nonioned fraction at nl pH and small Vd
Biotransformation
-mainly involves the liver
-high hepatic extraction fraction ratio therefore the clearance of opiods is generally dependant on hepatic blood flow
-meperidine is N-demethylated to normeperidine which is an active metabolite which may be associated with seizure activity
-morphine is conjugated with glucuronic acid forming active metabolites of morphine 3-glucuronide and morphine 6-glucuronide
-metabolites of fentanyl, sufentanil, and remifentanil are inactive
Remifentanil
-ultra short acting opiod
-has a unique ester structure allowing hydrolysis by nonspecific esterases in blood and tissue
-terminal elimination half-life less than 10 minutes
-context-sensitive half-time is approximately 3 minutes regarless on duration of infusion time
-lack of drug accumulation following repeated dosing or prolonged infusion
-presumed extrahepatic hydrolysis due to lack of toxic metabolites in hepatic dysfunctional patients
-normal response to remifentanil in patients with pseudocholinesterase deficiency
Excretion
-primarily excreted by the kidneys in the urine
-metabolites of morphine and meperidine are eliminated by the kidneys with less than 10% excreted within the bile
-accumulation of morphine metabolites in renal failure patients may be associated with narcosis and ventilatory depression
-accumulation of merperidine metabolites in renal failure patients may be associated with narcosis and ventilatory depression
-late secondary peak fentanyl plasma levels may occur upto 4 hours after the last intrvenous dose
-late secondary peak fentanyl plasma levels may be due to exterohepatic recirculation or sequestered drug mobilization
-sufentanil metabolites are excreted in the urine and bile
-remifentanil metabolites are excreted in the urine
PHARMACODYNAMICS
Effects on organ systems
Central nervous system
-reduce CMR02
-reduce CBF
-reduce ICP
-variable effects on cerebral perfusion pressure (CePP) and ICP
-pts with decreased intracranial compliance may have significantly decreased CePP with an associated decreased MAP w.opiods
-stimulation of the medullary chemotrigger zone (CTZ) may be associated with a high incidence of nausea and vomiting
-potential for physical dependance with repeated doses of opiods
-not a reliable amnestic agent
-use of opiods in spinal and epidural anesthesia has helped to provide better pain management
-meperidine has local anesthetic properties when administered intrathecally
Cardiovascular system
-generally cardiovascular function is not impaired
-high doses of opiods generally are associated with vagal mediated bradycardia (exception meperidine)
-meperidine in high doses is associated with an increase in heart rate due to its structural similarities to atropine
-opiods generally do not depress myocardial contractility (exception meperidine)
-mean arterial pressure may decline with opiods due to bradycardia, venodilation or decreased sympathetic tone
-meperidine and morphine are more associated with histamine release which causes vasodilation and profound decreased in BP
-opiods in combination with volatile anesthetics may be involved with significanty myocardial depression
Respiratory system
-depress ventilatory function primarily respiratory rate
-decreased respiratory ventilatory response to a rising PaC02 level
-increased apneic threshold
-decreased hypoxic drive
-morphine and meperidine may be associated with histamine-induced bronchoconstriction
-may be involved with chest wall rigidity severe enough to prevent adequate ventilation more common after large boluses
-chest wall rigidity can usually be corrected with either reversal or use of muscle relaxants
Gastrointestinal
-delay gastric emptying be decreasing peristalic contractions
-opiod induced contraction of the sphincter of Oddi may cause biliary colic
Endocrine
-block the release of stress hormones elevated during surgery (catecholamines, ADH, and cortisol) more than volatile anesthetics
-blocking the release of stress hormones is especially beneficial for ischemic heart diseased patients going in for surgery
Opiods with MAO inhibitors may result in:
-respiratory arrest
-hypertension
-hypotension
-coma
-hyperpyrexia
-opiods with benzodiazepines, barbiturates, and other CNS depressants can cause synergistic cvs, resp, and sedative effects
Search
Bookmark Us
