Opioids

Describe the molecular mechanism of action of opioid analgesics

Opioid drugs, typified by morphine, produce their pharmacological actions, including analgesia, by acting on receptors located on neuronal cell membranes. The three types of opioid receptor, m, d and k are all coupled to inhibitor G proteins. The presynaptic action of opioids is to inhibit neurotransmitter release. This is done via a decrease in Ca influx. Postsynaptically, opioids increase K+ efflux, leading to hyperpolarization and decreased neuronal activity *open K+ channels, close Ca 2+ channels => decreased synaptic transmission

A patient known to be a heroin abuser comes to ER with a painful stab wound . The ER physician administers Nalbuphine for the pain. Why is this not a good idea? a. The patient is probably tolerant to Nalbuphine. b. The drug may precipitate a withdrawal state. c. Nalbuphine is a weaker analgesic than codeine . d. Vasodilating effects of nalbuphine increase blood loss . e. Nalbuphine is a strong miu receptor agonist

b. The drug may precipitate a withdrawal state. Mixed agonists-antagonists (nalbuphine) can displace mu receptor agonists (heroin) from receptors, resulting in the rapid development of symptoms of withdrawal in patients who are physically dependant on these drugs...a phenomenon called precipitated withdrawal.

A 33-year-old woman is being treated with phenelzine for a major depressive disorder. She is brought to the emergency department after sustaining extensive injuries in an automobile accident. She is given several drugs for the treatment of her injuries. Somewhat later, she has a severe reaction consisting of excitation, sweating, rigidity, hypertension, severe respiratory depression, and coma. Which of the following drugs is absolutely contraindicated to give with phenelzine and is most likely responsible for the reaction observed in this patient? a) Amiodarone b) Cefazolin c) Fenoldopam d) Lorazepam e) Meperidine

e) Meperidine This patient was being treated with phenelzine, a drug that inhibits monoamine oxidase and increases serotonin levels in the brain. Meperidine, an opioid agonist, should not be used concurrently with monoamine oxidase inhibitors because its metabolite, normeperidine, blocks the neuronal reuptake of serotonin. This can cause the accumulation of serotonin and lead to life-threatening reactions, including excitation, sweating, rigidity, hypertension, severe respiratory depression, coma, and vascular collapse. Likewise, the concurrent use of fluoxetine or another selective serotonin reuptake inhibitor could also cause a serious drug reaction, called the serotonin syndrome, and may include confusion, seizures, and severe hypertension as well as less severe symptoms.

we haveto do signs of opiod withdrawal and signs of toxicity. and drugs used for dependance

histamine and vasodilation

which opioid shold you evaluate the risk of qt prolongation? Methadone may cause a QT prolongation what role can methadone play in treating opioid dpeendance Methadone is a long acting opioid that reduces the patients pain to a tolerable level so that he or she can function relatively normally. However, methadone does not cause the euphoric symptoms that drew the patients to opioids in the first place. The patient is then weaned off methadone slowly. Because the withdrawal symptoms of methadone are not as severe and take longer to develop compared with other opioids, the process is more tolerable prototypical strong opioid - morphine ake a slie about the type of opioid recpetors beieng g inhibitory

wach the kaplan video histamine ? add the part about vasodilation and inrease risk of herniation in head injury??

The triad of signs and symptoms that is most often present in a patient shortly after taking an overdose of heroin includes which of the following? A) Coma, miosis, cyanosis B) Coma, miosis, urticaria C) Coma, mydriasis, flushing D) Coma, mydriasis, gooseflesh E) Legcramps, mydriasis, cyonosis

A) Coma, miosis, cyanosis Explain better

A 42-year-old man who has been your patient for the last 20 years comes to your office seeking help for drug addiction. For the last 5 years he has been in Narcotics Anonymous (NA) and in a local methadone maintenance program for treatment of heroin addiction. He receives a full range of social and psychological services, arranged through NA. He had one relapse early in his treatment, but has been stable since then. Because you see him for short visits on a near-monthly basis, you know that he is highly motivated and rarely misses a meeting. However, he is concerned because the methadone program from which he receives his medications is closing due to state budget constraints. The nearest methadone clinic will be over 100 miles away. While they will give him a 5- to 7-day supply of medications, he will still have to travel at least once a week, and he does not drive. He wants to know if you can help him once the clinic closes. Which of the following is a medication that might benefit this patient and that can be prescribed through a private physician's office? A. Buprenorphine B. Clonidine C. Levo-alpha-acetylmethadole D. Methadone E. Naltrexone

A. Buprenorphine Buprenorphine, a mixed agonist/antagonist, is proven to reduce illicit opioid use with long-term therapy. It is the first medication that is approved to treat addiction to opioids and can be prescribed by physicians in their own offices. To prescribe this agent, physicians need to be able to refer patients to full-spectrum care for any social and psychological needs, as well as obtain a waiver from the federal Controlled Substances act; the waiver can be obtained after 8 hours of CME training in opioid addiction and the use of buprenorphine. This is in stark contradistinction to the agent most commonly used to treat heroin abuse, methadone (choice D). Unless they are working in a licensed methadone clinic, physicians have limited ability to prescribe methadone for opioid addiction. It can be prescribed by a private physician for temporary maintenance or detoxification for a maximum of 3 days while the patient awaits admission into a licensed methadone program. In recent years, the number of deaths from overdose of methadone, previously considered a relatively safe medication, has climbed dramatically, bringing into question the drug's central role in the long-term treatment of opioid addiction. Clonidine (choice B) is often used as a supplemental treatment to control withdrawal effects. It is not effective as a lone agent. Levo-alpha-acetylmethadol (choice C) is a long-acting version of methadone that has shown promise in the treatment of opioid addiction. However, there have been a number of deaths from arrhythmia, because the drug may prolong QT intervals. It is recommended only in patients who fail other treatments. Further, it has the same stringent limitations as methadone. Naltrexone (choice E) is an opioid antagonist that will reverse the effects of heroin. It causes immediate withdrawal and is understandably not popular with patients suffering from opioid addiction.

Which of the following opioid drugs has low intrinsic activity at mu receptor and has antagonist activity at the kappa receptors ? A nalbuphine B buprenorphine C nalorphine D butorphanol

B buprenorphine

Where is morphine primarily metabolized? What are the major metabolites

Morphine is metabolised primarily in the liver Morphine is metabolized primarily into morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G)[60] via glucuronidation

55yo M with constipation since starting OTC medication 2 weeks ago for a chronic, persistent cough and sinus congestion. Which ingredients is causing new symptom? - Dextromethorphan

NBME 16 q????

Inhibition of what receptors can decrease morphine tolerance?

NMDA

Does Morphine cross the BBB?

No Morphine is the *Least lipophilic of the common opioids The more lipids soluble opioids such as fentanyl and methadone readily penetrate into the CNS

A 17 year old boy is brought to the emergency department 20 minutes after becoming unresponsive while using heroine at a party. His friends say that he inhaled a large amount of heroine. He is obtunded. His temperature is 35.9 C (96.6 F), pulse is 75/min, respirations are 6/min, and blood pressure is 100/60 mm hg. Administration of which of the following is the most appropriate initial step in management? A)Fluids B)Flumazenil C)Methadone D)Naloxone E)Naltrexone

D)Naloxone

How do the effects of mixed agonist/antagonist opioids differ based on the previous exposure of the patient to opioids?

In naive patient (no opioid exposure): Mixed agonist-antagonists show agonist activity In patient with opioid dependence: Mixed agonist-antagonists show blocking effects (produce withdrawal symptoms)

Opioids and acute pulmonary edema

Intravenous morphine dramatically relieves dyspnea caused by pulmonary edema associated with left ventricular failure, possibly via the vasodilatory effect. This, in effect, decreases cardiac preload and afterload, as well as anxiety experienced by the patient

Which two opioids are likely to cause Serotonin Syndrome when used in conjunction with SSRIs or MAOIs?

Meperedine and Tramadol

Why is parenteral administration of opioid agonists often necessary?

Opioid agonists are metabolized in the liver by CYP450 enzymes. They often exhibit a strong first pass effect that tends to make parenteral administration necessary.

A 75-year-old patient with advanced metastatic prostate cancer and a long history of renal failure has severe bone pain. He is given meperidine. Two days later he develops a generalized seizure. What is the likely mechanism of this complication? (A) Buildup of meperidine (B) Buildup of meperidine metabolite levels (C) Brain metastases (D) Hypercalcemia (E) Worsening renal failure

Meperidine (Demerol) is metabolized into a neurotoxic metabolite called normeperidine which increases the risk of seizures. Active metabolite normeperidine accumulates with renal dysfunction, leading to toxicity

A 17-year-old male presents with altered mental status. He was recently admitted to the hospital due to a tibial fracture suffered while playing soccer. His nurse states that he is difficult to arouse. His temperature is 98.6 deg F (37 deg C), blood pressure of 130/80 mm Hg, pulse of 60/min, and respirations of 6. Exam is notable for pinpoint pupils and significant lethargy. Which of the following describes the mechanism of action of the drug likely causing this patient's altered mental status? 1. Neuronal hyperpolarization due to potassium efflux 2. Neuronal depolarization due to potassium influx 3. Neuronal hyperpolarization due to sodium influx 4. Neuronal depolarization due to sodium efflux 5. Neuronal hyperpolarization due to chloride influx

1. Neuronal hyperpolarization due to potassium efflux

Match the feature with the correct Opioid * * * * * * * *Least lipophilic of the common opioids

* * * * * * * *Least lipophilic of the common opioids: Morphine

Morphine

* * *conjugated w/ glucorinic acid in the liver to two main metabolites: Morphine-6-glucoronide and morhphine-3-glucoronide * (M-6-glucoronide is the main analgesic) * *elderly pts more sensitive due to decrease in metabolism, lean body mass, or renal fxn * * * *

Morphine

* *Not lipophilic and does not readily cross the BBB * *minimal effects on the heart * * *

Buprenorphine

*Mixed agonist/antagonist *Partial agonist at the mu opioid receptor and an antagonist at the kappa receptor *Long duration of action due to high affinity and tight binding to mu receptor *Less severe withdrawal symptoms compared to methadone *Approved for private office based detoxification (methadone is only available at specialized clinics)

Meperedine

*Short duration of action and low potency *Only used short term (<48 hrs) *Has anticholinergic effects *Causes Mydriasis; all other opioids cause miosis (due to anticholinergic effects) *Active metabolite: Normeperidine has significant neurotoxic actions (can lead to delirium, hyperreflexia, myoclonus, and possibly seizures) **Seizures caused by Meperedine can't be treated with opioid antagonists such as naloxone (use benzos)* *Serotonin Syndrome associated with SSRIs or MAOI use

Tramadol

*Very weak opioid agonist *Also inhibits 5-HT and norepinephrine reuptake *Typically prescribed to treat chronic pain. *Adverse Effects: Similar to opioids. Decreases seizure threshold. Serotonin syndrome

You are a physician in an urban health clinic in which approximately 20% of your patients use intravenous heroin regularly. You would like to incorporate drug rehabilitation into your practice. Which of the following options is the most effective therapy for use in the primary care setting? A. Buprenorphine intramuscularly three times weekly B. Buprenorphine orally or sublingually three to seven times weekly C. Heroin maintenance D. Methadone maintenance E. Naltrexone orally daily

B. Buprenorphine orally or sublingually three to seven times weekly Oral or sublingual buprenorphine maintenance therapy has recently been proposed as a new office-based therapy for opiate dependence. Buprenorphine is a drug with mixed properties, acting as an agonist at the receptor and an antagonist at the receptor. It is usually administered at a dose of 8 to 32 mg daily for 3 to 7 days a week. The advantages of buprenorphine over other maintenance options include a low potential for overdose, easier detoxification, and a ceiling threshold that limits its ability to cause a feeling of euphoria. In a recent placebo-controlled trial, buprenorphine with or without naloxone was shown to lead to a significant decrease in the proportion of urine samples positive for opiates and a decrease in opiate cravings. In contrast to methadone, buprenorphine is the first drug approved for the office-based treatment of opiate addiction. Primary care physicians in the community can prescribe buprenorphine if they are designated as addiction specialists by completing training programs through the American Society for Addiction Medicine, the American Psychiatric Association, and the American Osteopathic Association, among others (http://www.fda.gov). Â Methadone has long been the standard for drug treatment for heroin addiction. However, methadone can be given only within the structure of a drug treatment program and is not available for primary care physicians in the office. Methadone is a long-acting opioid that blocks the euphoria of heroin and decreases craving. In Great Britain, heroin maintenance has been used in a similar fashion, although heroin has a higher street value and a greater potential for misuse. Naltrexone is an opioid antagonist that is used in conjunction with psychological support because it too blocks the euphoria from heroin. However, patients must be free from narcotics for 5 days before the initiation of therapy because it will precipitate acute narcotic withdrawal.

A 23 year old female comes to the physician because of a 3 week history of persistent cough that is worsened by the cold air in her drafty apt. She does not smoke, drink or use no medications, and has no history of asthma or chronic pulmonary disease. P/E shows no abnormalities. Short term cough suppressant tx is initiated with a drug that does not cause constipation and has a low potential for substance abuse. This drug is most likely which of the following A. Codeine B. Dextromethorphan c. Hydromorphone d. Oxycodone e. Tramadol

B. Dextromethorphan Dextromethorphan **********

Which of the following characteristics of buprenorphine best account for its effectiveness in the treatment of opioid dependence and detoxification? A. Sublingual formulation with naloxone B. High opioid mu-1 receptor affinity and slow receptor dissociation C. Partial kappa receptor agonist activity D. Low oral bioavailability necessitating parenteral administration E. High intrinsic activity at the opioid mu receptor

B. High opioid mu-1 receptor affinity and slow receptor dissociation

Why is Morphine contraindicated in head injury?

Because morphine can make level of consciousness hard to assess. Morphine produces effects which may obscure neurological signs of increase in intercranial pressure in patients with head injuries he reason that Morphine has a relative contra-indication in the un-intubated brain injured patient is that the degree of sedation it produces can confound assessment of the Glasgow Coma Score (GCS). The respiratory depression it produces and is augmented by other factors/drugs may also lead to hypercarbia and consequent secondary rise in intracranial pressure.

Name four opioids that have mixed agonist/antagonist effects?

Buprenorphine Pentazocine Butorphanol Nalbuphine

Patients usually develop tolerance to all opioid effects EXCEPT: A. Sedation. B. Pruritus. C. Constipation. D. Pain relief. E. Respiratory depression

C. Constipation. Tolerance does not develop to miosis and constipation

A 42-year-old man involved in an automobile accident sustains multiple fractures of the right leg and arm and is suffering from severe pain. In the emergency department, his wife reports that her husband is a recovering heroin addict who has been enrolled in a methadone program for 3 months and is also taking phenelzine for depression. The most appropriate drug to alleviate the patient's severe pain is A. Butorphanol. B. Meperidine. C. Morphine. D. Nalbuphine. E. Pentazocine.

C. Morphine. Buprenorphine, Pentazocine, Butorphanol, Nalbuphine are all mixed agonist/antagonists at the opioid receptors and can produce withdrawal symptoms in a patient dependent on opioids Meperedine is contraindicated in this situation because it is associated with Serotonin syndrome when used with MAOIs or SSRIs

A 31-year-old woman, gravida 4, para 3, at 36 weeks' gestation comes the labor and delivery ward with painful contractions. Her prenatal course was unremarkable. Examination shows that her cervix is 5 cm dilated, 100% effaced and the fetal heart rate is in the 130s and reactive. She is given meperidine for pain control. She progresses rapidly and less than 2 hours later she delivers a 7-pound, 6-ounce (3,345g) handsome male fetus. The one-minute APGAR score is 1 and the infant is making little respiratory effort. Which of the following is the most appropriate next step in management? A. Blood transfusion B. Glucose C. Naloxone D. Penicillin E. Sodium bicarbonate

C. Naloxone Meperidine can be used as a systemic analgesic during labor. It is an opioid and readily crosses the placenta; therefore, the fetus is exposed to the medication. As an opioid, it causes respiratory depression. Neonates are at greatest risk for respiratory depression when delivery occurs approximately 2 to 3 hours after meperidine is administered to the mother. This neonate was born approximately 2 hours after maternal administration of meperidine, which makes neonatal respiratory depression likely. Naloxone is a pure opioid antagonist that displaces the opioid from its receptor sites and can help to reverse the opioid-induced respiratory depression. It has a short duration of action so repeat doses may be necessary

A 31-year-old male visits your office for drug detoxification. He gives a long history of heroin abuse and several addiction treatment failures. He is started on a methadone detoxification program that turns out to be effective. Which of the following methadone properties justifies its substitution for heroin in this patient? A. Partial agonist activity B. Low potency C. No respiratory suppression D. Long half-life E. Short withdrawal F. Low bioavailability

D. Long half-life Methadone is the drug of choice for treating heroine addiction and abuse. Heroine is an opiate and it produces similar physiologic effects as other opiates and thus treating heroine addiction and abuse involves the use of other opiates. Methadone is a mu receptor agonist. It is a potent, long acting opiate with good oral bio availability. Its long half-life and sustained effects after chronic dosing allows for continuous suppression of withdrawal symptoms in heroine dependent patients. It causes similar pharmacologic and physiologic effects as other opioids and its effects on miosis and respiratory depression can be seen up to 24 hours after one dose. (Choice A) Methadone is a mu receptor agonist. Using agents with partial agonist activity can precipitate withdrawal. (Choice B) Methadone is a strong mu receptor agonist with potent analgesic effects. (Choice C) Methadone can cause respiratory depression like most opioids. (Choice E) Methadone binds to protein in many tissues. After chronic dosing, it accumulates significantly in tissues. When methadone is discontinued, methadone is slowly released from tissues to maintain low levels in the blood. This allows for a very mild but extended withdrawal syndrome

Which of the following drug may precipitate opioid withdrawal symptoms if used in a patient who suffers from prostate cancer and is treated with oral morphine for choronic back pain? A.Methadone B.Codeine C.Meperidine D.Pentazocine E.Fentanyl

D. Pentazocine Pentazocine works through partial agonist and weak antagonist activity at mu receptos.because of weak antagonist it can cause withdrawal symptoms in patients who are dependent or tolerant to morphine or other opioids

What are the four major subtypes of opioid receptors?

Delta Kappa Mu nociceptin

An 85-year-old woman is diagnosed with a fracture of the right femur and begins treatment with morphine by patient-controlled analgesic pump. Three days later, her respirations are 6/min. Physical examination shows pinpoint pupils. Her serum creatinine concentration is 1.8 mg/dL. Which of the following best explains this patient's clinical deterioration after the initiation of morphine therapy? A) Chronic dosing of morphine decreases its bioavailability B) Morphine bioavailability increases with chronic dosing C) Morphine downregulates mu-opioid receptors with chronic dosing D) Morphine inhibits its own metabolism E) Morphine is metabolized to active metabolites that accumulate

E) Morphine is metabolized to active metabolites that accumulate