OPIODS Listen to Audio -meperidine -morphine -fentanyl -sufentanil -alfentanil -remifentanil mechanism of action structure-activity relationship pharmacokinetics effects on organ systems drug interaction MECHANISM OF ACTION 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 PHARMACOKINETICS 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 Drug Interactions 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