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Opioid Toxicity.pptx
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- 2. Overview Opioids -all natural, synthetic, and semisynthetic agents with morphine-like actions. Opiates – naturally occurring opioids. Opium (Gk) juice in reference to poppy juice from opium poppy (Papaver sp) Morphine (prototype) – isolated by Sertürner in 1803 and named it after Morpheus Profound analgesia, sedation and euphoria Endorphin - endogenous opioid peptides -endomorphins, dynorphins, enkephalin Narcotic - refers to any agent that induces sleep(nonspecific)
- 3. Classifications Source Naturalopioids - codeine, morphine Semi-synthetic – hydrocodone, heroin Synthetic - fentanyl, tramadol, and pethidine (meperidine). Potency Strong agonist - Morphine, Oxymorphone, Heroine, Methadone, Fentanyl, Pethidine(Meperidine). Mild to Moderate agonist – Oxycodone, Codeine, dihydrocodeine, tramadol
- 4. Pharmacokinetics Absorption Wellabsorbed enterally or parenterally. Transdermal patches, Rectal suppositories, buccal transmucosal (lozenges) Oral route – 1st pass effect Serum therapeutic doses reached 1 to 2hrs after oral ingestion Heroine –IV (1 min) inhalation (3 -5 min) or SC (10 min) Distribution High volume of distribution – can cross BBB Predilection for highly perfused tissues (brain, lungs, liver, kidneys, and spleen) Adipose tissues – poorly perfused but serve as reservoirs
- 5. Pharmacokinetics Metabolism andExcretion All opioids undergo hepatic metabolism and renal elimination The more polar the less the CNS effects and the more excretable Renal impairments increases the risk of toxicity 1. Morphine undergo glucuronidation morphine-3-glucuronide (M3G) - neuroexcitatory properties morphine-6-glucuronide (M6G) – 4-6 times more potent analgesia 2. Heroin (diacetylmorphine) is hydrolyzed to morphine. 3. Pethidine, fentanyl – hepatic oxidation
- 6. Pharmacokinetics Cytochrome P45Oenzyme Codeine and Tramadol (met by CYP2D6) → Morphine & O-desmethyltramadol resp oxycodone (met by CYP2D6) – less active metabolites Fentanyl (CYP3A5) – inert metabolites Polymorphism of receptor genes and Cytochrome P450 enzyme Interindividual variability and drug interactions.
- 7. Pharmacodynamics 3 typesof opioid receptors – mu-(µ), kappa-(κ) and delta –(δ) CNS - Dorsal horn of spinal cord, areas of nociception, resp centre and euphoria. Systemic – Sensory nerves, GIT, Endothelial of CVS, Immune cells. Cellular effects on neurons 1. close voltage-gated Ca2+ channels on presynaptic nerve to reduce transmitter release. Nociceptive nerve – glutamate, acetylcholine, norepinephrine, serotonin, and substance P. 2. Hyperpolarize postsynaptic neurons by opening K+ channels Activation of descending inhibitory pathways that inhibit pain transmission neurons.
- 8. Clinical Application Analgesia– MI, renal colic, cancer patient, obstetrics Antidiarrheal effects – loperamide, lomotil Antitussives – codeine in cough mixtures Anti-Shivering – pethidine Anaesthesia – pre-medicant due the sedative, anxiolytic, and analgesic effects. Main anaesthetic medication Adjunct with other agents intra-operatively Regional anaesthesia – epidural or subarachnoid space
- 9. Epidemiology United NationsOffice on Drug and Crime (UNODC) The global prevalence of opiate (heroin, morphine, and opium) - 0.4% of the population aged 15-64 years. The global number of opiate users increased from 17.7 million in 2015 to 19.4 million in 2016 70,000-100,000 people die from opioid overdose each year 40 million pills of counterfeit tramadol were seized at the port of Cotonou, Benin in 2016 – INCB. Benin, Nigeria, Ghana, Togo, Niger, Sierra Leone, Cameroon and Cote d’Ivoire – Tramadol CDC in the US in 2010 enough opioid analgesics were sold to medicate every American adult with a typical dose of 5 mg of hydrocodone every 4 hours for 1 month
- 10. Street Names Morphine– M, Miss Emma, Monkey, China Girl, Murder-8 etc Heroine - The Dragon, Snowball, Tar, White, White Nurse. Tramadol – Chill pill, Tramal Lite, Trammies, Super Tramadol-X 200 brand are known in Cameroon as ‘tomatoes’
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- 13. Diagnostic Strategies -History People at risk of opioid overdose 1. People with opioid dependence Reduced tolerance ( after incarceration or rehab) 2. People on prescribed opioids 3. Combined with other sedatives 4. Other co-morbidities --- lung disease, liver or renal impairment 5. Household members of people in possession of strong opioids (children)
- 14. Diagnostic Strategies -History People likely to witness an overdose (Source of history) 1. People at risk of an opioid overdose, their friends and families 2. people whose work brings them into contact with people who overdose health care workers and the police, Emergency service workers, People providing accommodation to people who use drugs, Peer education and outreach workers 3. Time of ingestion, quantity, and co-ingestants. 4. Pill bottles, drug paraphernalia, or eyewitness accounts may assist in the diagnosis
- 15. Clinical Features OpioidToxidrome --- CNS depression, Resp depression, and Pupillary miosis Needle track are sometimes evident Skin-popping (SC) and Mainlining (IV) Powdery substances may be seen on around the nose. Pruritus, flushed skin, and urticaria Febrile – (co-infections OR co-ingestants – cocaine OR adulterants – scopolamine) Physical injuries
- 16. Skin Popping andMainlining
- 17. Clinical Features Respiratorysystem Bradypnoea – (4 to 6 cycles/min) Hypopnoea – reduced tidal volumes Pink frothy sputum, hypoxia, dyspnoea, bronchospasm & muscular rigidity- Acute Lung Injury Cardiovascular Hypotension (Orthostatic hypotension) Bradycardia and arrhythmias Pethidine, cocaine, cerebral hypoxia – tachycardia and hypertension
- 18. Clinical Features Gastrointestinal Nausea & Vomiting Constipation and in severe cases paralytic ileus (absent bowel sounds) Kidneys and urinary tract urinary retention from urethral sphincter spasm and decreased detrusor tone Heroine nephropathy
- 19. Clinical Features Nervoussystem Reduced GCS, Euphoria, analgesia and reduced mentation (drowsiness) Seizures – pethidine, propoxyphene, tramadol Acute psychosis anxiety, agitation and dysphoria – less frequent Miosis in overdose (sometimes a red eye) Mydriasis -Morphine, pethidne, diphenoxylate/atropine (Lomotil), propoxyphene and CNS hypoxia Hearing loss Hypertonicity, myoclonus, and seizures – pethidine and propoxyphene
- 20. Special CNS Features Parkinsonian symptoms – Bradykinesia, rest tremors, rigidity, and postural instability Pethidine produced in street labs - MPTP metabolites Focal lesions in Substantia nigra. Heroine Associated Spongiform leukoencephalopathy (HASL) psychomotor retardation, dysarthria, ataxia, tremor etc Chasing the dragon Serotonin Syndrome Caused by ingesting 2 or more serotonergic drugs (MAOI, SSRI, TCA etc) Pethidine, Tramadol, fentanyl, oxycodone, hydrocodone.
- 22. Diagnostic Strategies -Investigations Biochemistries: RBS, BUE and Cr SPO2 monitoring Arterial blood gases A 12-lead ECG – propoxyphene or methadone QRS widening, QT prolongation or torsades de pointes. Chest X-ray - hypoxemia and coarse crackles (rales) Abdominal X-rays – Body packers/mule. Urine toxicology screen - positive for days after last use Serum acetaminophen and salicylate concentrations
- 23. Differential Diagnosis Benzodiazepinesand Barbiturates toxicity Hypoglycaemia Gamma-hydroxybutyrate – liquid ecstasy, liquid x etc Clonidine toxicity Alcohol toxicity Cannabinoid poisoning Meningitis
- 24. Supportive Treatment SupplementalOxygen – Bag and mask, Endotracheal tube Correction of dehydration and/or electrolyte imbalance – IV RL or NS Correction of Hypoglycaemia Abortion of any seizures - Diazepam GIT Decontamination Body packer, multi-drug ingestion or opioid combination products whole-bowel irrigation and activated charcoal Continuous cardio-resp monitoring Dialysis cannot clear opioids
- 25. Treatment: Antidote Antidote– Naloxone*, Nalmefene Indicated in case of significant cns and resp depression Naloxone Onset (1 – 2)min; Maximal effect (5-10)min; Duration of action (1 to 2hrs) IV Naloxone (0.4 to 2 mg ) for adults IV Naloxone ( 0.1 mg/kg in the children < 5yrs ) OR (0.1-2mg/dose in children >5yrs) 0.1-0.4 mg of IV aliquots every 1-2 minute until ventilation is adequate Chronic users - 0.04 to 0.2 mg and then slowly titrated up gradually (avoids acute withdrawal) IM Naloxone – 2mg stat Intranasal spray (Narcan Nasal Spray) – 0.4mg/spray. Reconsider the diagnosis if the patient fails to respond after 10 mg.
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- 27. Admission and DischargeCriteria Asymptomatic adults – observed for at least 4hrs Asymptomatic children – at least 24hrs Adults with resp depression – admitted for 12-24hrs Length of detention – dependent on opioid half life. Diphenoxylate-atropine (Lomotil) – has long T1/2 Asymptomatic Body packers – discharged after passing out all packets Psychiatric evaluation or drug abuse counseling Discharge to a stable social setting
- 28. Complications Acute LungInjury Cellulitis Osteomyelitis Horner syndrome Endocarditis Heroine Associated Spongiform leukoencephalopathy Heroine Nephropathy Parkinsonian disorder Withdrawal symptoms
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- 30. Withdrawal CNS excitation,(Restlessness, agitation, anxiety and mydriasis). Cognition and mental status are unaffected. Dysphoria and drug craving may be severe and prolonged Nausea, vomiting, diarrhea, and abdominal cramps High BP and pulse, tachypnea Onset depends on drug meperidine (8-12 hrs) and methadone (2-4 days) Symptoms peak between 36 and 48 hours and subside after 72 hours Treatment is symptomatic Clonidine Avoid using opioid routinely
- 31. New YorkTime – Opiophobia has left Africa in Agony Despite that risk, under no circumstances should adequate pain relief ever be withheld simply because an opioid exhibits potential for abuse or because legislative controls complicate the process of prescribing narcotics . (Katzung Basic Pharmacology)
- 32. References Rosen EmergencyMedicine 8th Edition, Opioids Medscape, Opioid toxicity Nelson Textbook of Paediatrics 20th Edition, 2015 Katzung Basic Clinical Pharmacology 12 Edition WHO Critical Review Report : Tramadol 2018 WHO Community management of opioid overdose 2014
Editor's Notes
- #3 Opioid is more precise and is the correct medical term for the agents that act on opiate receptors in the body
- #4 Methadone - Tolerance and physical dependence develop more slowly and withdrawal effects are milder Opioids - Available alone or in combination with other agents (e.g., acetaminophen and salicylates).
- #5 However, because of the first-pass effect, the oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect. Very important, particularly after frequent high-dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl
- #6 The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys. Some of the opioid are rendered inerts by the liver and excreted by the kidneys. Others like tramadol, codeine and small amounts of morphine are converted to more potent analgesics
- #7 30% of individuals of European descent and 50% of Asian descent,8 which is associated with increased dosage requirements for pain control
- #8 This spinal action has been exploited clinically by direct application of opioid agonists to the spinal cord, which provides a regional analgesic effect while reducing the unwanted respiratory depression, nausea and vomiting, and sedation that may occur from the supraspinal actions of systemically administered opioids.
- #9 Diminished largely because a number of effective synthetic compounds have been developed that are neither analgesic nor addictive. Non-infective diarrhoea
- #16 Direct toxic effects are extensions of their acute pharmacologic actions.
- #18 Acute lung injury - Acute lung injury is a disorder of acute inflammation that causes disruption of the lung endothelial and epithelial barriers. The alveolar–capillary membrane is comprised of the microvascular endothelium, interstitium, and alveolar epithelium. Condition in which fluid collects in the air sacs of the lungs, depriving organs of oxygen
- #19 Mechanisms include opioid-induced delayed gastric emptying, direct stimulation of the chemoreceptor trigger zone, and vestibular stimulation
- #20 Dysphoria is a state of generalized unhappiness, restlessness, dissatisfaction, or frustration
- #21 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-dine) - a side product during synthesis of a meperidine analogue Psychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individua Heroine Associated Spongiform leukoencephalopathy (HASL) rare condition that is characterized by progressive damage (-pathy) to white matter (-leuko-) in the brain (-encephalo-), particularly myelin
- #23 twisting of peaks"), is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia that exhibits distinct characteristics on the electrocardiogram
- #24 The differential diagnosis encompasses all causes of depressed mental status coexistence of miosis and respiratory depression greatly narrows the possibilities.
- #25 1. activated charcoal (1 g/kg in children and 50-100 gin adults) 2. Abortion of any seizures - Correction of hypoxia, hypoglycaemia or electrolyte imbalance.
- #26 Competitive antagonists and and can reverse all the receptor-mediated actions of opioids. Naloxone - Excellent safety profile Nalmefene – longer T1/2 (8 to 11)hrs = IV 0.5 to 1.5 mg (stop when clinical response has been achieved) IM or intranasal naloxone. Clinical reversal occurs within 5-10 minute
- #28 ad
- #31 Although opioid withdrawal can be uncomfortable, it is not life-threatening