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pharm opiods analgesics

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Oxycodone (oxycontin)
syemisythetic of morphine for pain. orally effective. ABUSE OF THE SUSTAINED RELEASE PREP IS #1 KILLER OF ABUSERS therefore sustained release oxycontin used only in opoid tolerant patients
Time ot peak effect/duration of axn for Morphine, Meperidine, Fentanyl
Morphine = 20miutes to peak/4hrs DOA, Demerol 15min to peak and 2-4 hrs DOA, Fentanyl 5 min to peak 12-30min DOA
Psychological dependence
develops in some pts as the result of euphoric effects
oral pharmacokinetics of morphine
slow and erratic oral absorption; undergoes large first pass effect in liver therefore IM, IV or SC is perfered,
Moderate Agonists
Codeine, xoycodone, prophoxyphen
other Generalized effects of opioids
nausea, vomiting by direct stimulation of chemoreceptor trigger zone (CZT) in area postrema. VESTIBULAR gait weakness in ambualtory pts, PUPILS constrict (MIOSIS) by excitment of oculomotor neurons increasing parasymp stim to eye (no tolerance)...this is blocked by atropine or naloxone. GI tract relieves diarrhea and dysentery by decreasing motility and increasing tone in gut (constipation mediated centrally and locally (no tolerance),BILLARY TRACT spasms with epigastric distress or biliary colic due to contraction of gallbaldder and constriciton of biliry sphincter even at theraputic doses (dont give to cholitis)
Levomethadyl
longer acting cogner of methadone adminsterd orally q 2-3 days
Methadone
a PhenylheptylaMine-the l-isomer is th active form for analgesia, potent analgesic like morphine but acts longer (25-52 hrs), highly effective orally, BLOCKS REINFORCEMENT AND DECREASES CRIMINAL ACTIVITY FOR H ABUSERS ( 50-100mg/day) Individual Docs cannont provide therapy.
17-N atom
produce antagoonist by substituting this group with larger bulky group
give the respective AA sequences of met-enkephalin an dleu-enkephalin
Tyr-Gly-Gly-Phe-Met, tyr-Gly-Gly-Phe-Leu (notice only a chage in the last AA Met for Met-enkephalin and Leu for Leu-enkephalin
Rx used for pre Anestheisa/general anesthesia
morphine, fentanyl
C3 AND C6 OH GROUP SUBSTITUION AND/OR ACETYLATION
substitution at these sites decreases first pass liver metabolism by glucoronide conjugation (codein increased bioavailablity), acetylation of both OH-Groups increases lipid solubility (HERIOIN)
Rx used for cough
Codein greater antitussive axn effect than morphine, also hydrocodone and dextromethorphan
narcotic
greek word for stupor
opioid
all drugs natural an dsynthetic with morphine like activity (opioid agonists (analgesics), opioid antagonisists, endorphins)
Generalized effects on respiration/cough
MSO4 is potnet respiratory depressant, dose dependent-death may occur especially in asthma, COPD. Decreasesd sensitivity of brain stem respiratory center neruons to CO2 tension; carotid and aortic bodies are less affected. Cough reflex depresssed (morphine and codeine used as antitussics
Opioid antagonists and mixed agonists-antagonists
pure antagonist = naxloxone, naltrexone. Mixed agonist-antagonsits pentazocine, Nalbuphine, Butorphanol. Partial agonists = Buprenorphine
Opioid antagonists
Naloxone (narcan), Naltrexone (ReVia)
Metabolism and excretion of morphine/ which are demethylated and which are hydrolyzed prior to conjugation and which are directly conjugated
conjugated in lver to morphine-6-glucuronide an active metabolite. duration 4-6hrs. other opiods are demethylated (ex codein) and ester groups are hydrolyzed DEMEROL AND HEROIN) FOLLOWED BY GLUCURONIDE FORMATION. polar metabolites of excreted are primarily in urine and some in bile
Fentanyl (sublimaze) (Duragesic patch) (LOZENZE = oral stick)
potent analgesic with RAPID onsed and Short Duration (30min-1hr). Used with droperidol (Innovcar) in anesthesia. Widely ABUSED by medical personal. Metabolized by CPY3A4, EXCRETED IN URINE.
Endorphins
endogenous opioid peptides: met-enkephalin and leu-enkephalin
Tricyclic antidepressants/antipsychotics
increased sedation and variable effects on resp depression
Prophyxophene (darvon)
derivative of methadone (d-isomer) weak analgesic 1/2 potentcy as codeine (l-isomer has antitussci axn).
neuroendocrine effects of opioids
decrease release of LH, FSH, ACTH, and endorphines. decrease testosterone and cortisol. increase release of prolactin, GH and antidiuretic hormone b diminishing dopaminergic inhibition. Increase ADH (urinary retention)
RX well absorbed orally
codeine and oxycodone
MOA inhibitors with opioids
absolutely contraindicted in demerol, relative contraindicatined in narcotic analgesics because of high incidence of hyperpyrexic coma
Withdrawal risks per drug
Strong agonists are associted with more severe withdrawal sx. Narcotic antagonists induce withdrawal rapidly. Morphine, Meperidine, Methadone and Fentanyl all have severe withdrawal sx (in concordance with their greater efficacy and addiction liability) and codeine and propoxyphene have less efficacy, less addiciton liablity and less severe withdrawal sx
Opiate
durgs derived from opium (morphine, codeine, and semisynthetic derivatives)
Synthetic opioid analgesics
PhenylPIPERIDINES and PhenylHEPTYLAMINES
Diphenoxylate
(lomotil with atropine)/(loperamide=imodium) Meperidine cogners with more selective constipating activity
4. drugs used for tx of withdrawal
1. METHADONE-cross dependence and tolerance (levomethadyl=long acting), 2.Clonidine (catapress): alpha-2 adrenergic agonist decreases symp symptoms. 3. Buprenophine -mixed agonist/antagonists long acting 4. Maltrexone (ReVia) - antagonist for maintenance
Meperidine (and derivatives)
similar to morphine except: weaker on mg basis (75-100mg of demerol =10mg morphine), SHORTER DURATION 2-4 hrs, well absorbed orally and DEMETHYLATED TO NORMEPERIDINE IN LIVER. same degree of resp depression as Morpine but no CV effects when given orally/IV dosing increases PVR thus INCREASES BP. Significant antimuscarinic effects: DILATES PUPIL (verses pinpoint), dry mouth, blurry vision, GREATER CNS EXCITATION with toxic doses=anexeity, tremors, convulsions.
Cellular mechnisms
binds to opiod receptors: G-protein coupled receptor decreases Adenylyl Cylcase and ion gateing PRESYNAPTIC EFFECTS: decreased Ca++ current and decreased Neuro Tx release (glutamate). POSTSYNAPTIC hyperpolarization of the neuronal membrane by increasing K+ current and decreasing neuronal firing (decreasing resonse of pst synaptic neuron to excitatory neuro txs.
Rx for antidiarrhea
diphenoxylate with atropine (lomotil), loperamide (imodium) or codein)
PhenylpiperiDines synthetic opoids analgesics
D=Demerol, diphenoxylate (atropie in lomotil), fentanyl
Physical dependence and withdrawal
dependes on dose, frequency and duration of use
nalbuphine (naubain and Betorphanol (stadol)
newer agonists-antagonists opioids that are for IV/nasal spray. analgesia equals morpine. (stong K-agonists and Mu antagonists) CEILING effect for resp depression that my become important with O.D..30MG. No further depression. Minimal abuse
Binding affinity
determined by the alpha analgesic potency of the drug
Overactivty withdrawal or abstinence syndrome
autonomic hyperactivity: lacrimation, rhinoorhea, sweating, piloerection (goosbumbs), dilate pupils, increased BP and HR, hyperpyrexia, emesis, diarrhea, abdominal pain. Behavioral hyperexcitablilty: anxiety, restlessness, ywaning, tremor, insomnia. Muscle and Joint pain. Rarely life threatending
Generalized clinical uses of opoids
relive pain of almost any type especially for sever constant pain. (fixed interval dosing works best)
Adverse reactions of morphine:pathognomonic triad
coma, pinpoint pupils, resp depression: also bp flass and shock may result with prolonged hypoxia
Generalized MOA of Opioid Analgesics
anagesia at mu receptor (spinal and supraspinal) delta and kapa receptors (spinal) directly decrease transmission of neurons decreasing pain perception may involve inhibiotn of relase of neuro transmiters including SUBSTANCE-P, GLUTAMINE, ACh, NE, AND 5-HT. Opoids also activate deending pain inhibitory neurons by INHIBITING GABAergic INTERneurons!!!!!! also act in modulating pain through inflammed tissue
PREFERRED OVER MORPHINE FOR ANALGESIA DURING LABOR
Meperidine (Demerol)...also Fentanyl is used
Tolerance
pharmacodynamic, developes to many by not all of the effects of morphine and other opioids (analgesia, euphoria, lethal effects) minimal or NO TOLERANCE TO CONSTIPATION AND MIOSIS. mechanism of tolerance= changes in second messanger systems related to Ca++ flux, adenylyl cyclase inhibitoin of G protein synthesis (up regulate cAMP, Dwon regulate mu receptor and receptor uncoupling. Glutamate or titric oxide prod may ply role in porphine tolerance dependence
list the 3 main Opoid receptors and describe their activity
MU=morpine like analgesia, resp depression, eupohria, physical dependendce, typical agonist effects (SUPRASPINAL), 2. DELTA RECEPTOR spinal analgesia enkephalins (interact selectively) 3. KAPPA receptors-spinal analgesia, miosis, sedation (petazocin-like) (note multiple sub times mu1, mu2, delta 1 and 2 etc
Generalized Cardio effects of opioids
no direct effects on BP or HR except large doses cause ortho hypotension and brady cardia resulting from peripheral arteriolar and venous dilation from release of HISTAMINE and central depression of ADRENERGIC TONE (except demerol casues tachycardia!!!) Smooth mm general increase in tone therefore URINE RETENTION
Codeine
less poetned analgesic than morpine but highly effective orally. good antitussic activity. lower abuse potential due to less euphoria and less dependence
Pharmacological effects of Antagonists
COMPETITIVE ANTAGONISTS AT mu RECEPTORS (AND SOME OTHER RECEPTORS). free of agonist activity in absence of opioids.
Buprenophine
25-50 times more potend than morphine on wt basis. partial mu-receptor agonist wiht long DOA. (precipitates withdrawal in morphine useers). approved for OFFICE BASED POIOID DETOX AND MAINTENCES. RESISTANT TO NARCAN
RX acute pulmonary edema and dyspnea
given IV morphine dramaticlaly relieves dyspnea due to pul edema and acute left ventricular failure: unknown MOA +vasodilating effect and DECREASE VENOUS RETURN, DECREASE PRELOAD
Generalized behavioral effects of Opioid Analgesics
mixed CNS depressant/Stimulant - higher doses can lead to sedation, drowsiness, mental clouding (in painfree pt is dysphoric producing malase and sleep) with pain (psychic or physical) prduces euphoria (decrease anexiety, increasse sleep) in toxic doses morphine can casue excitment, this may predominate in pts to convulsions or coma (meperidine or phopoxyphene)
Contraindications and cautions with opoid agonists
pul dz with decreased reserve (COPD), Bronchial asthma, increased ICP, Neonates, preg, elderly, severe liver or kidney dz, reduced BV (hypotension)
PhenylheptylaMines
Methadone
Pentazocine (Talwin)
a kappa-agonist with weak mu-antagonst/partial agonist properties; actiovates kappa-receptor in spinal cord. MOA-RELEASES NE FROM SYMP FIBERS=intermediate potencey analgesic if IV. SAME EFFECTS AS MORPHINE EXCEPT: INCREASE BP, HR HALLUCINATIONS. ceiling effect for resp depression. (weak opoid antagonistic effect therefore may cause withdrawal in pts addicted to morphine) oral prep with narcan to prevent dissolution and IV injection
uses of Antagonists
DOC for opioid overdose= NALOXONE. tx for opioid abuse = naltrexone with clonidine or buprenorphine. Tx of ETOH=naltrexone
S/E of opioids
behaviorial restless ness, nausea, vomiting, incrased ICP, constipation, urinatery retention, orthostatic hypotn, itching, urticaria
Release of Histamine by opioids
releases form mast cells causeing uticaria sweating vasodilaiton and bronchoconstriction (avoid in asthmatics)
Pharmacokinetics of Antagonists
naloxone not effective orally. undergoes rapid 1st pass to glucuronide, with short DOA (1-4 hrs), Naltrexone undergoes 1st pas metabolism but is effecte when given larger doses orally, LONG DOA (24-48HRS QOD)
Distribution of morpine which have better bbb solubility
varying degrees of plasma protein binding. enteral all body tissues including fetus (dont use in labor) only small percent crosses BBB. HEROIN, METHADONE AND FENTANYL MORE LIPID SOLUBLE
Classes of opioid agonists
opium alkaloids and derivatives, synthetic opiod analgesics, moderate agonists, mixed agonists, other analgesics, pure opiod antagonists
General use of Opioid Analgesics
reslatively selective relif of pain without loss of consciousness by increasing pain threshold at spinal cord (alteration in bain preception of pain) most effective fordull continous pain and pathologic pain. MOA
Tramadol (ultram)
a synthetic analgesic. binds to mu-opoid receptors; inhibits reuptake of NE and Serotonin (increases NE and 5HT). partly antagonized by narcan. Dependence possible. given orally...OD resp depresion and seizure
Ketamine
A NMDA antagonist can block tolerance!!!
TX or overdose
Naloxone (narcan) IV 0.4-0.8mg iv repeated
preferentail binding sites of opioid agoinsts and atagonists
binding to sterospecific an dsaturable receptor bindings sites i locus ceruleus, hypothalamus, thalamus, periaqueductal gray and other regions of pain perception such as the dorsal horn of spinal cord

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