Opioid Analgesics:

Opioid receptors : G protein coupled: Mu (), Kappa (k) CNS excitation/seizures, Delta () Activation of Opioids receptors cause --- Inhibition of adenylyl cyclase, Activation of K current (outward, Supression of Ca current Acute Opioid Toxicity: Respiratory depression. Pin point pupils. Stupor and coma.Urinary retention. Hypothermia. Therapeutic uses of Opioids: Analgesic, Dyspnea due to acute left ventricular failure, Diarrhea Loperamide, Cough Dextromethorphan / Codeine MK! Most opioids are associated w/ biliary colicky pain.so if a Q asks to use one of these for a pt w/ this painthen give meperidine b/c of its anti-cholinergic actions so it may not exaggerate the biliary colicky pain!!!! Type Drug Clinical Uses MOA Adverse Effects Other Agonists Morphine Analgesia inhibit ascending pain CTZ stimulated vomiting. C/I: transmission from the biliary colic b/c Sphincter of MK!!Cough reflex is periphery. Eye : Stimulation of oddi constricts. depressed activate descending inhibitory EdingerWestphall nucleus Neonates have low conjugation dextromethorphan / codeine. pain pathway from the Miosis PIN POINT PUPIL capacity and immature BBB brainstem. (pathognomonic of opioid which can cause unexpectedly poisoning) profound respiratory Respiration is depressed. depression. C/I neonates and Temperature regulating center Truncal muscle rigidity elderly b/c of resp. depression. depressed. especially with high dose Bronchial asthma. Head injury. Vasomotor centre depressed. fentanyl. Undiagnosed abdominal pain (b/c cant use in biliary colicky Morphine is converted to MK!!!GIT : Constipation pain). Pregnancy. morphine-6- glucuronide, Decrease gastric emptying. active metabolite. Spasm of anal and ileocecal sphincters. TQ!!!!Physical dependence : - ALVIMOPAM is used to evident by withdrawal ameliorate the GIT effects of syndrome which includes chronic opioid use. rhinorrhea, sweating, yawning METHYLNALTREXONE and diarrhea. can reverse opioid induced Psychological dependence : constipation (Alvimopam and persists for months despite loss methylnal trexone dont of physical dependence. antagonize analgesic actions TOLERANCE TO MOST but just reverse GIT actions) ACTIONS OF OPIOIDS EXCEPT IN EYE AND GIT. CVS : Vasodilatation: increase release of histamine, Withdrawal: TQ!: Pain and depression of vasomotor irritability,Hyperventilation, center. Diarrhea, Pupillary dilation, Lacrimation, runny nose, TQ!!Morphine in angina. Chilliness and gooseflesh -- decrease preload. (generally opposite of acute -- negative chronotropic effects) effect. Morphine is used in dyspnea due to LVF. Urinary retention and prolongation of labor

Morphine Congeners: Codeine

Less potent and efficacious than morphine as analgesic

Morphone Congener: Tramadol Meperidine & Congeners Analgesic efficacy similar to morphine.

MK!!!Analgesic effect of codeine is due to its conversion to morphine by CYP2D6. 10% of caucasian population have genetic polymorphism leading to inability to convert codeine to morphine. Other polymorphism can lead to ultra-rapid metabolism. More selective cough suppressant low dose may involve other type of receptors (not opioid receptor.) Used with acetaminophen/aspirin. It also inhibits reuptake of NorAdrenaline and 5-HT. Converts to nor-meperidine that increases action of NE and 5HT in brain so cant use w/ MAO inhibitors b/c can lead to serotonin syndrome and death.

Good oral bioavailability and low abuse liability

Oxycodone: Used with acetaminophen (percocet). Abuse liability present.

Seizures are the most common side effect. Does not cause much constipation as does morphine. Does not prolong labor. It has the potential to cause dependence.

It should not be used within 14 days of MAOI because of risk of serotonin syndrome. TQ!!!! Should not be used with MAO inhibitors convulsions and coma.

Meperidine Congners: Diphenoxylate Loperamide Fentanyl & congeners

Used for symptomatic treatment of diarrhea

Used mainly in anesthesia

Methadone & congeners

It is used in the treatment of opioid dependence, chronic pain and also neuropathic pain.

Diphenoxylate available only in combination with atropine. MK!! Loperamide do not cross BBB. It is 100 times more potent than morphine as analgesic. Rapid onset and short duration. Transdermal patches, lozenges available. It is an NMDA antagonist and monoamine reuptake inhibitor. High oral bioavailability and half life of ~ 24 hrs

Muscle rigidity is an adverse effect

Analgesic and respiratory depression similar to morphine

Propoxyphene

Dextro-propoxyphene is an analgesic by acting as a weak u agonist Used with acetaminophen (Darvocet N).

Cardio-toxic in high dose

Sufentanil, Remifentanil (short acting) Epidural fentanyl and sufentanil for postoperative pain and labor analgesia are popular. Tolerance and dependence develops very slow. Unlike other opioids, methadone is associated with QT interval prolongation and arrhythmia. On November 19, 2010 the U.S. Food and Drug Administration asked manufacturers of products containing dextropropoxyphene to withdraw them from sale

MK!!! Dextromethorphan: Antitussive

Free of analgesic action and addictive potential Less constipation Moderate to severe pain including angina pectoris The effects depends on previous exposure to opioids. TQ!!!In nave individuals, they relieve pain. In opioid dependence, they can precipitate withdrawal syndrome. They cause less respiratory depression than morphine. Less dependence and abuse liability Good analgesic

Partial Agonists/Mixed Agonist-Antagonists

Nalbuphine

Pentazocine

Moderate to severe pain

Hallucinations and sympathetic stimulation. Increase load on heart

Orally used in combination with naloxone Nasal formulation, more effective in women Sublingual pill, transdermal patches, Long acting

Butorphanol

Migraine, balanced anesthesia

Buprenorphine

As analgesic and in combination with naloxone orally to treat opioid dependence Used in the treatment of opioid overdose. Competitive antagonist of all opioid receptors Inactive orally high first pass metabolism. It blocks endogenous opioid peptides also.

Antagonists

Naloxone (IV only for overdose)

Half life 1-3 hrs: i.v only (short half life is clinically relevant) Actions of buprenorphine and tramadol are not fully reversed by naloxone. (b/c buprenorphine has really tight binding to the receptor and has a really long half life and tramadol has non-opioid receptor based actions) More potent than naloxone. Long duration of action (1-2 days).

Naltrexone (opiod dependence tx long term)

Used to treat alcohol and chronic tx of opioid dependence (not usually for overdose!) used primarily in alcohol dependence methadone patients who have not been able to successfully taper off the drug.

Orally active, Pure antagonist

Nalmefene Rapid detox treatment beneficial for: opioid dependent individuals who are looking for an alternative to methadone treatment.

universal opioid antagonis patients who have attempted detoxification either on their own or in a clinical setting but unsuccessful. Trying to wash drug from body under anesthesia and cant always prevent withdrawal symptoms which can sometimes be fatal

Opioids Morphine Fentanyl

Comments MS Contin, a long acting morphine. Morphine + Naltrexone combination for round the clock analgesia. IV, intrathecal, epidural, transdermal and oral transmucosal route. Transdermal fentanyl cause fatal respiratory depression. Pts warned that fever, exposure of patch to heat can cause increased release of the drug. Concomitant use of CYP 3A4 inhibitors like clarithromycin can cause dangerous increases in serum concentrations of fentanyl. Not for opioid-nave patients It may be also effective for neuropathic pain along with nociceptive pain. Dose related QT interval prolongation and death have been reported; a pretreatment EKG and follow-up at 30 days and then annually recommended. Oxy Contin, long acting preparation 1.5 times more potent than morphine

Methadone Oxycodone Oxymorphone is metabolite of oxycodone Meperidine

Should be used for short term (upto 48hrs). IM injection can cause muscle fibrosis. Repeated doses lead to accumulation of normeperidine which can cause tremors and seizures. In patients taking MAOI, it can cause encephalopathy and death. Has some anti-cholinergic like actions. Analgesic effect by hydrocodone is highly dependent on metabolism to O-demethylated morphine, hydromorphone, by the cytochrome 450 CYP2D6 . In the population, there are a group of patients that are less responsive to hydrocodone opioid (~10% of the Caucasian population). On the other hand, ultra-rapid metabolizers (up to 7% of Caucasians and up to 30% of Asian and African populations) may have increased toxicity due to rapid conversion.

Hydrocodone (Vicodin) typically with acetaminophen