opioid

System Approach

Opioid Analgesics

Dr Lokendra SharmaDepartment of Pharmacology,SMS Medical College

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What is the mechanism of action of medications that activate presynaptic opioid receptors?Inhibits calcium influx through voltage-gated ion channels, thereby inhibiting neurotransmitter releaseWhat is the mechanism of action of medications that activate postsynaptic opioid receptors?Increases potassium efflux from cells leading to membrane hyperpolarization and thereby inhibition of neurotransmitter releaseOpioid receptors are coupled to what type of proteins?Inhibitory G-proteins (inhibits adenylyl cyclase)What is the prototype opioid analgesic?MorphineWhy must caution be taken when using opioids in patients with head injuries?Opioids may increase intracranial pressureWhere in the midbrain are opioid receptors located?Periaqueductal gray region (binding to these receptors leads to activation of descending pathways to the raphe nuclei, thereby decreasing transmission throughoutpain pathways)Where in the dorsal horn of the spinal cord are opioid receptors located?Primary afferent fibers (binding to these receptors leads to inhibition of substance P release)Are opioid analgesics better at relieving intermittent or persistent pain?Persistent painWhat is the mechanism of morphine-induced hypotension and pruritus?Increased histamine release from mast cellsDo opioid analgesics increase or decrease gastrointestinal (GI) peristalsis?Decrease (they cause constipation)Which two opioids are used specifically to treat diarrhea?1. Loperamide2. DiphenoxylateWhich opioid analgesic does not increase the tone of the biliary tract, bladder, and ureter?Meperidine (antagonizes muscarinic receptors)Do opioid analgesics increase or decrease uterine contractions during pregnancy?T hey decrease uterine contractions, thus a good contraction pattern should be achieved before placement of an epidural catheter during labor.Do opioid analgesics cause miosis or mydriasis of the pupils?Miosis (common sign of opioid overdose is pinpoint pupils)What is the mechanism of opioid-induced miosis?Increased parasympathetic (cholinergic) activity in the pupilary constrictor musclesWhich opioid analgesic does not cause miosis?Meperidine (antagonizes muscarinic receptors)Which two opioids are used specifically to treat cough?1. Codeine2. DextromethorphanOpioids suppress the cough reflex.SyntheticIs dextromethorphan a natural or synthetic opioid?SyntheticWhat is the mechanism of opioid-induced urinary retention?Increases antidiuretic hormone (ADH)Do opioid analgesics promote emesis or act as antiemetics?Promote emesisWhat is the mechanism of opioid-induced emesis?Activation of the chemoreceptor trigger zone (CT Z)Where is the CTZ located?Area postremaWhat is the mechanism of opioid-induced respiratory depression?Reduced sensitivity of respiratory center to carbon dioxide levelsWhat is the most common cause of death in opioid overdose?Respiratory depressionWhat are the two most lipophilic opioids?1. Heroin2. FentanylT hese two medications rapidly cross the blood-brain barrier (BBB) to produce euphoric effects.Which opioid is the least lipophilic?MorphineIs morphine metabolized via phase I or phase II reactions?Phase II metabolism (glucuronidation)Does morphine-3-glucuronide have analgesic activity?NoDoes morphine-6-glucuronide have analgesic activity?YesWhich two opioid-induced effects do patients not develop tolerance to?1. Constipation2. MiosisWhat are the signs and symptoms of opioid withdrawal?Lacrimation; rhinorrhea; diaphoresis; yawning; goose bumps; anxiety; muscle spasms; diarrhea; increased pain sensationWhich medication is used to counteract the respiratory depression seen in opioid overdose?IV naloxone (may need to give multiple doses as naloxone has a shorter half-life than morphine)What is the mechanism of action of naloxone?,-Receptor antagonistWhich opioid antagonist is given orally to decrease cravings in alcoholism?NaltrexoneWhich opioid analgesic is used to prevent withdrawal symptoms in patients discontinuing heroin use?MethadoneWhich central-acting 2-agonist is used to prevent withdrawal symptoms in patients discontinuing heroin use?ClonidineGive examples of strong opioid agonists:Morphine; fentanyl; heroin; methadone; meperidine; hydrocodone; hydromorphoneGive examples of weak opioid agonists:Codeine; propoxypheneGive examples of partial opioid agonists:Buprenorphine; pentazocinePropoxyphene is a derivative of which opioid analgesic?MethadoneName two synthetic opioid analgesics:1. Meperidine2. MethadoneFentanyl is chemically related to which synthetic opioid analgesic?MeperidineDoes morphine have a high or low oral bioavailability?LowWhich two opioids should not be given in combination with monoamine oxidase inhibitors (MAO Is)?1. Meperidine2. DextromethorphanT hese combinations may produce serotonin syndrome.What drug do you get by acetylating morphine?HeroinIs codeine itself an active opioid analgesic?No (must be metabolized via cytochrome -450 2D6 to active morphine)Which medication is commonly given in combination with codeine for the treatment of pain?Acetaminophen

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Objectives of Opioid Analgesics

2Dr. Lokendra Sharma, SMS Medical College, Jaipur

Opioid Analgesics (against algesia) some important termsQ Analgesics: The Drugs which selectively relieves pain by acting in the CNS or on peripheral pain mechanisms without significantly altering the consciousness Opioids and NSAIDS


3Narcotic is a greek term meanig stupor(deficiency of mental and physical alertness)pethidine, fentanyl, sufentanyl and alfentanyl are synthetic.

Opioids:

Any drug which binds to the opioid receptors (Pharmacologically related) in the CNS and antagonized by Naloxone . They may be Natural, Synthetic and semi-synthetic



Opiates: Drugs derived from opium Natural or semi-syntheticQ Narcotics: Drugs derived from opium or opium like compounds, with potent analgesic effects associated with significant alteration of mood and behavior, and with the potential for dependence and tolerance following repeated administration.




Opioids - OpiumA dark brown, resinous material obtained from poppy Q (Papaver somniferum) Capsules. * OPIUM

PHENANTHRENEMorphine 9-14%Codeine 0.5-2%Thebaine 0.2-1%BENZYLISOQUINOLINEPapaverine 0.8-1% Q (least Narcotic opioid)Noscapine 3-10%Narcine 0.2-0.4%


7Papavarine is least narcotic opiod

Phenanthrene is apolycyclic aromatic hydrocarboncomposed of three fusedbenzenerings--as the above formula shows. Phenanthrene has fiveresonance structures, given below.Reactions of phenanthrene typically occur at the 9 and 10 positions.

Many benzylisoquinolines have amethylatednitrogen atom as well as functional groups containing oxygen (-OH,-OCH3, -OCH2O-) in positions 6, 7, 3' and 4'

Poppy Plant - image


Poppy to Opioids


HistoryFriedrich Wilhelm Serturner A German PharmacistIsolated Morphine in 1803 and named it after the Q Greek god of Dreams MORPHEUS


Presynaptic Neuron(mu,kappa,delta) G protein coupled receptor Gi/GoActivation of Opioid RInhibit Adenyl CyclDecrease cAMPBlock N type Ca2+ ChInhibit NT releaseNT(Ach,NA,DA,5HT)


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What is the mechanism of action of medications that activate postsynaptic opioid receptors?Increases potassium efflux from cells leading to membrane hyperpolarization and thereby inhibition of neurotransmitter release


What is the mechanism of opioid-induced miosis?Increased parasympathetic (cholinergic) activity in the pupilary constrictor muscles


What is the mechanism of opioid-induced urinary retention?Increases antidiuretic hormone (ADH)


What is the mechanism of opioid-induced respiratory depression?Reduced sensitivity of respiratory center to carbon dioxide levels



MORPHINE : PA Analgesia:Strong analgesicQ Visceral pain is relieved better than somatic painDegree of analgesia increases with doseNociceptive pain is better relieved than Neuretic painQ Associated reactions to pain are also relieved apprehension, fear and autonomic effectsTolerance to pain is better


MORPHINE Analgesia actionTwo components spinal and supraspinalInhibits release of excitatory transmitters from primary afferents at Substantia gelatinosa of dorsal horn (Q opioid receptor location)Exerted through Interneurones gating of painAt supraspinal level in cortex, midbrain and medulla - alter processing and interpretation and send inhibitory impulses through descending pathway



Sedation:

Drowsiness and indifference to surroundingsInability to concentrate and extravagant imagination colorful day dreamApparent excitementLarger doses produce sleep EEG resembles normal sleep


Mood effects:

In Normal persons calming effect, mental clouding, feeling of detachment, lack of initiative etc. - unpleasant in absence of painQ Sometimes DYSHORIA( Kappa)But in persons with pain & addicts sense of wellbeing, pleasurable floating feelings kickEUPHORIA


Morphine Depression:Respiratory centre depression Both rate and depth of respiration are diminishedQ Dangerous in Head injury and asthmaticsCough Centre DepressedTemperature regulating centre depressedVasomotor centre high doses cause fall in BP

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Morphine Stimulation:Q CTZ sensitize CTZ to vestibular & other impulsesQ Edinger Westphal Nucleus miosis Vagal centre Bradycardia Q Hippocampal cells convulsions (inhibition of GABA release)

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Neuro-endocrine:

GnRH and CRH inhibited FSH, LH and ACTH levels are lowered only short term tolerance developsDecrease in levels Sex hormone and corticosteroids, but no infertilityIncreases ADH release oliguria


Neuro-endocrine:GnRH and CRH are inhibited FSH, LH and ACTH levels are lowered only short term tolerance developsDecrease in levels of Sex hormone and corticosteroids, but no infertilityIncreases ADH release oliguriaCVS: NO DIRECT EFFECT ON HEARTVasodilatation histamine release, depression of vasomotor centre and directly on blood vessels decreasing the toneCardiac work reduction due to consistent vasodilatation

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Neuro-endocrine:

CVS: NO DIRECT EFFECT ON HEARTVasodilatation histamine release, depression of vasomotor centre and directly on blood vessels decreasing the toneCardiac work reduction due to consistent vasodilatation


Neuro-endocrine:GnRH and CRH are inhibited FSH, LH and ACTH levels are lowered only short term tolerance developsDecrease in levels of Sex hormone and corticosteroids, but no infertilityIncreases ADH release oliguriaCVS: NO DIRECT EFFECT ON HEARTVasodilatation histamine release, depression of vasomotor centre and directly on blood vessels decreasing the toneCardiac work reduction due to consistent vasodilatation

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GIT:CONSTIPATIONDirect action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretionsSmooth Muscles:Billiary Tract: Billiary colic closure of sph. Of OddiBladder: Urinary urgency but difficultyBronchi - Bronchospasm


GIT: CONSTIPATIONDue to direct action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretionsSmooth Muscles:Billiary Tract: Billiary colic closure of sph. Of OddiBladder: Urinary urgency but difficultyBronchi - Bronchospasm

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Morphine - PharmacokineticsAbsorption and Distribution:Variable orally (usually not given orally 1st pass metabolism, given IM or IV)Widely distributed liver, spleen, kidney etc.Enters Brain slowlyQ crosses placental barrier dependence in fetus


Absorption and Distribution:Variable orally (usually not given orally 1st pass metabolism, given IM or IV)Widely distributed liver, spleen, kidney etc.Enters Brain slowlycrosses placental barrier dependence in fetusMetaboloism:Liver by glucoronidation water soluble metabolites Morphine-6- Glucoronide analgesic in renal failure prolong analgesiaMorphine-3-glucoronide No analgesia neuroexcitatory

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Morphine - Pharmacokinetics

Metaboloism:Liver by glucoronidation water soluble metabolites Morphine-6- Glucoronide analgesic in renal failure prolong analgesiaMorphine-3-glucoronide No analgesia neuroexcitatory


Absorption and Distribution:Variable orally (usually not given orally 1st pass metabolism, given IM or IV)Widely distributed liver, spleen, kidney etc.Enters Brain slowlycrosses placental barrier dependence in fetusMetaboloism:Liver by glucoronidation water soluble metabolites Morphine-6- Glucoronide analgesic in renal failure prolong analgesiaMorphine-3-glucoronide No analgesia neuroexcitatory

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Dr. Lokendra Sharma, SMS Medical College, Jaipur 29PharmacokineticsOPIOIDMORPHINEMETHADONEPlasma life~3 hr24 hrDuration - analgesia~5 hr~6 hrStored in bodyLimitedSignificantIM/oral potency6/12/1EliminationKidney>>GutKidney=Gut

AMSP29

Stored=accumulation29

Morphine - PharmacokineticsExcretion: Via Urine, Plasma t1/2 = 2-3 HrsAction lasts for 4-6 HrsCompletely eliminated in 24 HrsPreparation: 10, 15, and 20 mg. (IV: 2 10 mg)Q No sublingual route ,no subarachnoid route,Rectal route is established


Excretion: Via Urine, Plasma t1/2 = 2-3 HrsAction lasts for 4-6 HrsCompletely eliminated in 24 HrsPreparation: 10, 15, and 20 mg. (IV: 2 10 mg)Q no sublingual route ,no subarachnoid route,Rectal route is established

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Adverse EffectsRespiratory Depression: Infant and OldVomitingSedation, Mental Clouding sometimes Q Dysphoria (Kappa)Hypotensive effect Rise in Intracranial PressureApnoea: Newborn


31Tolerance and dependence is the most comon problem with morphine. Tolerance is exhibited in most action except constipation and miotic action. It produces psychological and physical dependenceBecause of this abuse potential increases. Mostly medical and paramedical persons go for morphine abuse. This is the major drawback of morphine. Withdrawal may lead to Drug seeking behaviour and may turn to Morphine withdrawal syndrome. It is characterized by anxiety, fear, restlesness, diarrhoea, abdominal coli, delirium and convulsion - treatment is methadone.

Adverse Effects7. Urinary retention8. Idiosyncrasy and allergy9. Acute Morphine Poisoning: occurs if >50 mg (Lethal dose 250 mg), Gastric lavage with KMNO4, Specific antidote: Q Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up10 Tolerance(No tolerance to miosis) and dependence


32Tolerance and dependence is the most comon problem with morphine. Tolerance is exhibited in most action except constipation and miotic action. It produces psychological and physical dependenceBecause of this abuse potential increases. Mostly medical and paramedical persons go for morphine abuse. This is the major drawback of morphine. Withdrawal may lead to Drug seeking behaviour and may turn to Morphine withdrawal syndrome. It is characterized by anxiety, fear, restlesness, diarrhoea, abdominal coli, delirium and convulsion - treatment is methadone.

Morphine Therapeutic usesAnalgesic:Long Bone FractureMyocardial Infarction Q (IHD contraindicated)Terminal stages of cancerBurn patientsPostoperative patientsVisceral pains pulmonary embolism, pleurisy, acute pericarditisBiliary colic and renal colicObstetric analgesiaSegmental analgesia


Morphine Other Therapeutic usesPreanaesthetic MedicationBalanced anaesthesia and surgical analgesiaAcute Left ventricular failure Cardiac asthmaQ Cough not used but Codeine is usedDiarrhoea colostomy - Loperamide, Diphenoxylate


Morphine - Contraindications Two Extremes of AgeBronchial asthma Respiratory insufficiency - empysemaQ Head InjuryShock HypotensionUndiagnosed acute abdomenBHPQ Renal Failure, Liver diseases and hypothyrodismUnstable personalities


Opioids - ClassificationNatural Opium Alkaloids: Morphine and CodeineSemi-synthetic: Diacetylmorphine (Heroin) and PholcodeineSynthetic Opioids: Phenylpiperidines: Pethidine (Mepiridine) and its congeners Diphenoxylate and LoperamideFentanyl and its congeners sufentanil, remifentanil and alfentanilPhenyl-heptylmines: Methadone and congeners like Propoxyphene and DextropropoxypheneBenzomorphans: PentazocineMorphinan compounds and congeners: Levorphanol and Butorphanol


Natural Opium Alkaloids: Morphine and CodeineSemi-synthetic: Diacetylmorphine (Heroin) and PholcodeineSynthetic Opioids: Phenylpiperidines: Pethidine (Mepiridine) and its congeners Diphenoxylate and LoperamideFentanyl and its congeners sufentanil, remifentanil and alfentanilPhenyl-heptylmines: Methadone and congeners like Propoxyphene and DextropropoxypheneBenzomorphans: PentazocineMorphinan compounds and congeners: Levorphanol and Butorphanol

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Classification of Opioids

Opiumpapaverine morphinecodeine

Full AgonistsSemi-synthetic HeroinhydromorphoneOxycodonepholcodeineSyntheticFentanyl(Al;su)Meperidine / pethidineHydrocodoneMethadone Pentazocine

Partial Agonists

BuprenorphineButorphanol

Non-synthetic

Antagonist naltrexone . Naloxone Nalmefene


37LAAM

.DrugsMorphineCodeinePethidinDextropPentazosineBuprinorphineRouteO,iv,I T,sc,Reoo.imoO,injSL,injt1/23-42-442-412Analgesic11/6-1/101/8-1/10MildLower25xCoughmore1/2RD++/-+Less1/2constipation+++lessLessLessLessAbuse Potential ++/-+LessLessLess

Dr. Lokendra Sharma, SMS Medical College, Jaipur 38

.DrugsMorphineCodeinePethineDextro-PhanPentazoBuprinorphineMiosis+LessLessMydrisisUR&Bs+LessLessTolerence &Phy D+SlowMildLowerS/E/w++LesslessDosemg10-156060-100Intranasal butrophanol Oral transmucosal Fentanyl citrate lozenges Trans dermal patch(TTS) & Iontophoresis Fentanyl


Synthetic opiatesMeperidine: Shorter-actingMethadone: Orally effectivePentazocinePropoxypheneBuprenorphine Partial agonistOxycodone Hydrocodone40Dr. Lokendra Sharma, SMS Medical College, Jaipur

Morphine Vs PethidineSN Q 1/10th potent Morphine, but Efficacy is similarProduces as much sedation, euphoria and respiratory depression in equianalgesic dose and similar abuse potentialQ Less spasmodic action in smooth muscles less miosis, constipation and urinary retentionRapid short duration of action (2-3 Hrs)Vagolytic effect - Tachycardia


SN Q 1/10th as potent as Morphine, but Efficacy is similarProduces as much sedation, euphoria and respiratory depression in equianalgesic dose and similar abuse potentialQ Less spasmodic action in smooth muscles less miosis, constipation and urinary retentionRapid but short duration of action (2-3 Hrs)Vagolytic effect - TachycardiaQ Devoid of antitussive actionQ Less histamine release safer in asthmaticsBetter oral absorption

Q Pethidine alkaloid associated with seizure

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Morphine Vs PethidineSN Q Devoid of antitussive actionQ Less histamine release safer in asthmaticsBetter oral absorption



SN Q 1/10th as potent as Morphine, but Efficacy is similarProduces as much sedation, euphoria and respiratory depression in equianalgesic dose and similar abuse potentialQ Less spasmodic action in smooth muscles less miosis, constipation and urinary retentionRapid but short duration of action (2-3 Hrs)Vagolytic effect - TachycardiaQ Devoid of antitussive actionQ Less histamine release safer in asthmaticsBetter oral absorption


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Pethidine contd.PharmacokineticsWell absorbed orally, bioavailability 50%Effects appear in 10-15 min. after oral absorptionOn parenteral administration action lasts for 2-3 HrsMetabolized in liver mepiridinic acid and norpethidineNorpethidine accumulates on chronic useExcreted in urine


Pethidine contd.Adverse Effects:Similar to MorphineAtropine like effects dry mouth, blurred vision, tachycardiaOverdose tremors, mydriasis, delirium and Q convulsion due to norpethidine accumulationUses: Analgesic as substitute of MorphinePreanaesthetic medicationAs analgesic during labor less fetal respiratory depressionDose 50-100 mg IM/SC, oral 50-100 mg tabs.


MethadoneChemically dissimilar but similar pharmacological actions.High action orally as well as parenterallySingle dose effect same with Morphine including duration of actionCumulation on repeated administration (t1/2 24-36 Hrs)Highly bound to plasma protein 80 to 90%Metabolized in liver by demethylation and cyclizationExcreted in urineSlow action and less subjective effect abuse potential is lowQ Used as substitution therapy as opioid dependence: 1:4mg and 1:20 mg of Morphine and Pethidine respectivelyQ Codeine is used as substitution in Methadone addiction


Chemically dissimilar similar pharmacological actions.High action orally as well as parenterallySingle dose effect is same with Morphine including duration of actionCumulation on repeated administration (t1/2 24-36 Hrs)Highly bound to plasma protein 80 to 90%Metabolized in liver by demethylation and cyclizationExcreted in urineSlow action and less subjective effect abuse potential is lowQ Used as substitution therapy as opioid dependence: 1:4mg and 1:20 mg of Morphine and Pethidine respectivelyQ Codeine is used as substitution in Methadone addiction

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TramadolQ Centrally acting analgesicVery low action on opioid receptors Q Other mechanisms involved in analgesic action 5-HT and NA reuptake inhibition spinal inhibition of painEffective both orally and IV (100mg = 10 mg Morphine)Side effects are similar to Morphine but less prominentQ Well tolerated and low abuse potentialQ Only Partially reversed by NaloxoneQ Used in chronic neuropathic pain and short diagnostic proceduresDose: 50-100 mg IM/IV/Oral (Contramol)


Opioid ReceptorsMainly 3 (three) types (mu), (kappa) and (delta)Subtypes: 1, 2, 1, 2, 3, 1 and 2 Location: Peripheral Nerve endings, SG in spinal chord, Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala Opioids agonists, partial agonist or competitive antagonists of these receptorsOverall effect depends on nature of interaction and affinity to theseMorphine is agonist of all but affinity is higher for mu


Mainly 3 (three) types of receptors (mu), (kappa) and (delta)Subtypes: 1, 2, 1, 2, 3, 1 and 2 Location: Peripheral Nerve endings, SG in spinal chord, Periaqueductal gray (PAG) in midbrain and Brain stem (medulla, hypothalumus and also amygdala Opioids are agonists, partial agonist or competitive antagonists of these receptorsOverall effect depends on nature of interaction and affinity to theseMorphine is agonist of all but affinity is higher for mu

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receptor receptor receptorQ Location1 supraspinal2 - spinal1 spinal3 -supraspinalSpinalsupraspinalEffectsAnalgesiaRespiratory depressionSedationEuphoriaMiosisPhysical dependenceLoss of GI motilitySpinal analgesiaQ DysphoriaSedationPsychomimeticPhysical dependence (nalorphine type)Spinal analgesiaAffective behaviour (Supraspinal) Respiratory depressionReduced GI motilityAgonistsMorphine, Codeine, Fentanyl and pentazocine weaklyPentazocine

Effects of Different Opioid Receptor Stimulation:


Opioid Receptors Intracellular mechanismAll are G-protein coupled receptorsLocated on prejunctional neuronesInhibits release of transmitters NA, DA, 5-HT, GABA and GlutamateActivation reduces intracellular cAMP formation - Opening of K+ channel via and . and supression of N type of Ca++ channelsUltimately Hyperpolarization and reduced intracellular Ca++ Reduced Neurotransmitter release


Q Opioid AntagonistsPure antagonists: Naloxone, Naltrexone and NalmefeneAffinity for all receptors (, and )Can displace opioids bound to -receptorsQ No action on Normal person but reverses poisoning and withdrawal symptoms in addictsMixed Agonist-antagonists: Nalorphine, Pentazocine, Butorphanol and NalbuphinePartial/weak agonist and antagonist: Buprenorphine


NalorphineQ Not used anymorePreviously used as Opioid antagonistBut, antagonism is restricted to -receptor only and agonist of -receptorQ Drawbacks - dysphoria and psychomimetic effects


PentazocineWeak -receptor antagonist, but agonist of -receptorOne of the commonly used agents, given orally and IMQ Low abuse liabilityPharmacokinetics: High 1st pass metabolism but effective orallyHalf life = 3-4 HrsMetabolized in liver by glucoronide conjugationDose: orally 50-100 mg and parenterally 30-60 mg IMQ Uses:Moderately severe pain in Injury, Burns, Fracture Trauma, Cancer and Orthopaedic manuevers


Pentazocine Vs MorphineSpinal analgesia via kappa receptorDose is 30 mg Vs 10 mg and low ceiling effectSedation and Respiratory depression at lower dosesQ Tachycardia and rise in BP dangerous in MILesser smooth muscle spasmsVomiting and other side effects are lessQ Subjective effects lower ceiling (psycomimetic effects)Q Tolerance develops on repeated use, but lesser than MorphineWithdrawal symptoms both Morphine and Nalorphine likeGood analgesic in subjects not exposed to MorphinePrecipitate withdrawal in Morphine addicts


BuprenorphineQ Synthetic thebaine congener and highly lipid solubleGiven Sublingually or parenterally but not oral high 1st pass metabolismSelective -agonist analgesicQ 20-30 times more potent than MorphineSlow but longer duration of action upto 24 HrsPharmacological effects are similar to MorphineQ Has ceiling effect in analgesic and respiratory depression Good analgesic for naive patients but addicts precipitates withdrawal syndromeQ Lower tolerance and physical dependence than Morphine and abuse liabilityWithdrawal syndromes are similar to Morphine


Buprenorphine contd.Adverse Effects:Hypotension (Postural)Q Respiratory depression (fatal in neonates) and cannot be reversed by NaloxoneUses:Long lasting painful conditions cancerPostoperative painMyocardial infarctionPreparations: Norphine, Tidigesic0.3 mg/ml injections and 0.2 mg sublingual tablets


NaloxoneQ Competitive antagonist of all types of opioid receptorsBut, blocks -receptors at much lower doseAlways injected IV (0.4 t0 0.8 mg) - All symptoms of Morphine action are antagonized respiratory stimulationQ At higher doses 4-10 mg: antagonizes actions of Nalorphine and Pentazocine dysmorphic and psychomimetic effects are not suppressed ()Withdrawal symptoms: 0.4 mg doses Morphine and 4-5 mg doses Nalorphine and Pentazocine


Naloxone contd.Q Buprenorphine actions are prevented but not reversed fully tight bond with receptorsAlso acts on endogenous opioidsQ Antagonizes respiratory depression of Diazepam and N2OUses:Q Acute Morphine Poisoning (0.4 0.8 mg IV 2-3 min, maximum 10 mg.New Born opioid poisoningReverse respiratory depression intraoperativelyQ Diagnosis of Morphine addictionQ Alcohol intoxication


Differences between naloxone and naltrexoneNaloxoneNaltrexoneEffective by i.v. routeOrally effectiveShort actionLong actionLess potentMore potentUsed for opioid induced respiratory depression and opioid poisoningUsed for prevention of opioid and alcohol dependenceNo hepatotoxicityMay cause hepatoxicity at higher dose


Pupil size Morphine - miosis (pinpoint pupils) kappa receptor effect pinpoint pupils - responsive to bright light oculomotor nerve (CN3)-stimulated by kappa receptor site kappa receptor -blocked, mydriasis from sigma effect will resultatropine partially blocks effect indicating parasympathetic system involved


morphine causes miosis (pinpoint pupils) kappa receptor effect pinpoint pupils still responsive to bright light oculomotor nerve (CN3) is stimulated by kappa receptor site kappa receptor is blocked, mydriasis from sigma effect will resultatropine partially blocks effect indicating parasympathetic system involved

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Endogenous Opioid PeptidesEndorphins: Derived from POMC-endorphins: 2 Types - -endorphin1 and -endorphin-2Primarilty agonist and also has actionEnkephalins: Derive from ProenkephalinMet-ENK and leu-ENKMet-ENK - Primarily and agonist and leu-ENK agonistDynorphins:Derive from Prodynorphin: DYN-A and DYN-BPotent agonist and also have and action


60 proopiomelanocortin (POMC) geneDifferent tissues in human body produces substances which behave like opium Pharmacologically but chemically peptides. Remember opium is alkaloid. These re called endogenous opioid peptides. They are located in Brain, Pituitary, Spinal Chord which can modulate pain.

Fentanyl (Sublimaze)

Synthetic drug Different structure than morphine Q- 80 to 100 times more potent than morphine Rapidly acting drugQ-Used as preoperative medication Short acting (30-45 min) Onset of action is 5 minutes Very high potency Q-Highly abused ,known as china white as street name


NalmefeneQ Nalmefene-pure antagonist long duration of actionGreater bioavailabilityLack of dose dependent problemMore potent than naloxoneDr. Lokendra Sharma, SMS Medical College, Jaipur 62

Opioid withdrawal SignsYawningLacrimation, mydriasisDiaphoresisRhinorrhea, sneezingTremorPiloerectionDiarrhoea and vomiting SymptomsAnorexia and nauseaAbdominal pain or crampsHot and cold flushesJoint and muscle pain or twitching InsomniaDrug cravingsRestlessness / anxietyDr. Lokendra Sharma, SMS Medical College, Jaipur 63

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Courtesy of Dr. John Sherman, St. Kilda Medical CentreDr. Lokendra Sharma, SMS Medical College, Jaipur 64

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Acute Intoxication/OverdoseDisruption of central control of peripheral sympathetic activity.- Respiratory depression => apnea=> DEATH- Circulatory depression => BP- Pupils constricted (may be dilated with meperidine)- Convulsions with propoxyphene and meperidine.- Arrhythmias with propoxyphene.- Pulmonary edema- Reflexes


Enkephalinase inhibitor BL-2401A novel enkephalinase inhibitor, its antinociceptive and antidepressant-like activities

the antinociceptive effect being antagonized by naloxone hydrochloride. Dr. Lokendra Sharma, SMS Medical College, Jaipur 66

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Enkephalinase inhibitorRelieved arthritis-induced hyperalgesia. . As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 selectively inhibited enkephalinase in vitro orally active enkephalinase inhibitor Produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems


EpibatidineEpibatidine alkaloid found in the skin of a neotropical poisonous frog, Epipedobates tricolor, found in modern Ecuador.a powerful analgesic, about 200 times more potent than morphine.[1] Dr. Lokendra Sharma, SMS Medical College, Jaipur 68

Epibatidinenot opioidsimilar to nicotine and appears to act by binding and activating nicotinic acetylcholine receptors. Too toxic to use in clinical practice, The compound represents a new lead in the drug design of new analgesics.[3]


not an opioidIt is similar to nicotine and appears to act by binding and activating nicotinic acetylcholine receptors. While epibatidine may be too toxic to use in clinical practice, The compound represents a new lead in the drug design of new analgesics.[3]

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ABT-594 (Tebanicline) Tebanicline is the most promising reported to date. 50 times more potent than morphine, It completed Phase II clinical trials in EuropeFurther research in this area is ongoingDr. Lokendra Sharma, SMS Medical College, Jaipur 70

Tebanicline is the most promising reported to date. 50 times more potent than morphine, It completed Phase II clinical trials in EuropeFurther research in this area is ongoing

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What is LAAM.L-@ acetyl methenance, long action congener of methadone. used in maintenance program for treatment of heroin addicts


What is thiorphan?It is an enkephalinase inhibitor; acts by inhibiting metabolic degradation of endogenous opioid peptides-produces analgesia.


What are the therapeutic uses of opioid antagonists?opioid induced toxicity.To diagnose physical dependence on opioids (be careful, not to precipitate severe withdrawal syndrome).Treatment of compulsive opioid users.To decrease neonatal respiratory depression secondary to maternal opioid administration.Naloxone is used in septicemic shock where opioid peptides are released by stress and may produce hypotension.


LofexidineAlpha 2 agonist similar to clonidineLess hypotensive effectsCurrent Phase III trial of 3.2 mg lofexidine versus placebo in an opiate dependent population undergoing withdrawalMay be tested for prevention of relapse Dr. Lokendra Sharma, SMS Medical College, Jaipur 74

General CommentsOPIOID withdrawal is NOT fatal, person won't die; but with barbiturates, withdrawal can be fatalQ-Withdrawal from OPIOID is called going cold turkey (goose bumps on skin) and also called kicking the habit due to leg motionsdrug that is more potent as analgesic than morphine will have more intense drug withdrawal symptoms


goose bump - reflex erection of hairs of the skin in response to cold or emotional stress or skin irritation75

OxycodoneOxycodone is synthesized from thebaineLike morphine and hydromorphone, Oxycodone is used as an analgesic. Prescribed for the treatment of moderate to severe pain. Crushing the tablet and swallowing, snorting, or injecting the drug product for a more rapid and intense high



opioid

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