OPIOIDS- SHOEIB

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JJM MEDICAL COLLEGE, DAVANGERE. DEPT OF ANAESTHESIA:

JJM MEDICAL COLLEGE, DAVANGERE. DEPT OF ANAESTHESIA SEMINAR ON OPIOIDS & OPIOID RECEPTORS CHAIR PERSON PRESENTED BY Dr. M.J.M SHARMA Dr. SHOEIB M.D,D.A PROFESSOR DATE- 24/08/2010

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‘Among the remedies which it was pleased almighty god to give to man to relieve his sufferings, non is so universal and so efficacious as opium’ Sydenham-1680

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OPIUM ' Opos ’  Greek word for juice. papavera somniferum . Opiates Narcotic ’ Narcos ’ ( ‘Numb’)

HISTORY :

HISTORY First undisputed reference to opium is seen in writings of ‘Theophrastus ’ in 3rd century BC. Arabian physician were well versed in uses of opium. Arabian traders introduced drug to the orient

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1806 Serturner Morphine  Morpheus (Greek god of dreams)

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1832 Robiquet isolated codeine. 1848 Merck isolated papaverene . 1970 Endogenous opioids. 1973 Opiate receptors in the brain were identified.

Classification :

Classification I) Naturally occurring a) Phenanthrenes (5 ring structure) Codeine Morphine b)Benzyl isoquinolenes (3 ring structure) Papaverine Noscapine 2) Semisynthetic (morphine derivatives) - Heroin ( estrification of both hydroxyl groups) - Dihydromorphine / morphinone - Thebaine derivatives ( eg . etorphine , buprenorphine )

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3) Synthetic opioids (4 groups) - Morphinon series ( levorphanol , butorphanol ) - Diphenyl propylamine series or methadone derivatives ( eg . methadone, d- propoxyphene ) - Benzomorphan series ( pentazocine , phenazocine ) - Phenylpiperidine series ( meperidine , fentanyl , sufentanil , alfentanil , remifentanil )

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Compound Major Receptor Types μ κ δ * AGONIST Morphine (and codeine, oxycodone , meperidine , hydromorphone , and the like) Agonist (Ag) Agonist MIXED AGONISTS/ANTAGONISTS Buprenorphine ( Buprenex ) Partial Ag Antagonist Ant Pentazocine ( Talwin ) Partial Ag Ag Nalbuphine ( Nubain ) Partial Ag Ag Butorphanol ( Stadol ) Partial Ag Ag ANTAGONISTS Naloxone ( Narcan ) Ant Ant Ant Naltrexone ( ReVia ) Ant Ant Ant

Chemical structure of the opioid receptor :

Chemical structure of the opioid receptor These are G-protein coupled receptors.

M or µ - for morphine type :

M or µ - for morphine type μ 1, μ 2, μ 3 BRAIN Cortex (lamina II & IV) Thalamus Periaqueductal Grey SPINAL CORD Substansia gelatinosa μ 1 Dependence Analgesia ( Supraspinal ) μ2 Depression Miosis Euphoria ↓ GI motility Dependence μ3 ?

ƙ or K- ketocyclazocine type :

ƙ or K- ketocyclazocine type Epsilon receptor – was proposed as binding site for  -endorphin in rat vas deferens. Ƙ1,ƙ2, ƙ3 BRAIN Hypothalamus Periaqueductal Grey Claustrum SPINAL CORD Substansia gelatinosa Spinal analgesia Sedation Miosis Inhibition of ADH release. ( dysphoria )

δ-D receptor:

δ -D receptor σ -sigma receptor Dysphoria (opposite of euphoria) Hallucination(both visual & auditory) Respiratory and vasomotor stimulation Mydriasis (Ref : GG) δ 1, δ 2 BRAIN Pontine nuclei Amygdala Olfactory bulb Deep cortex Analgesia Antidepressant effects Physical dependence

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In 1994, nociceptin / orphanin FQ has been cloned. ORL1 ( Opioid Receptor Like)/ Nociceptin BRAIN Cortex Amygdala Hippocampus Septal nuclei Habenula Hypothalamus SPINAL CORD Anxiety Depression Appetite Development of tolerence to μ agonist.

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Actions of opioids on targets other than opioid receptors : Inhibition of voltage dependent Na+ current in a naloxone insensitive manner in cardiac myocytes by morphine. Agonistic activity  2B adrenoceptor subtype by meperidine . Direct inhibition of NMDA receptor by meperidine , morphine, fentanyl and naloxone . (Ref : Miller)

Location of opioid receptors :

Location of opioid receptors Periaqueductal gray matter (PAG), Pontine reticular formation median raphe , Nucleus raphe magnus , Adjacent gigantocellular reticular nucleus in the rostral ventral medulla (RVM), Amygdala .

SPINAL CORD:

SPINAL CORD Substantia gelatinosa (SG) which constitutes lamina II of the Rexed laminae .

Endogenous ligands for opioid receptor:

Endogenous ligands for opioid receptor 3 distinct families of endogenous opioid peptides have been identified. Enkephalins , Endorphins, Dynorphins . The precursors are Pre-pro- opio - melanocortin (POMC) Pro- dynorphin Pro- enkephalin Pre-pro- nociceptin

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Each of these are derived from separate precursors, encoded by separate genes. The opoids peptides share a common amino-terminal sequence of Tyr- Glye - Gly - Phe (Met or Leu ) which has been called an opioid motif.

POMC:

POMC Gives rise to  -endorphin, ACTH,  -MSH,  - lipotropin . POMC producing cells are relatively distributed within CNS occurring mainly in the arcuate nucleus and nucleus tractus solitarus . These neurons project widely to limbic and brain stem areas and spinal cord.

POMC producing cells are also seen in anterior & intermediate lobe of pituitary and in islets of pancreas :

POMC producing cells are also seen in anterior & intermediate lobe of pituitary and in islets of pancreas

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Pro- enkephalin  met- enkephalin (multiple copies) + 1 leu-enkephalin . Present in areas of CNS that are presumed to be related to the perception of pain. Eg . Lamina I and II of spinal cord, trigeminal nucleus and peri-aqueductal area. Prodynorphin : 3 peptides begining with leu-enkephalin sequence, dynorphin A, B and neoendorphin .

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Orphanin FQ/ nociceptin – a novel endogenous opioid peptide that was cloned in 1995, bearing a significant sequence homology to dynorphin A with identical length of 17 aminoacids The search for an endogenous ligand that binds to the µ receptor with high affinity and high selectivity led to discovery of a class of novel endogenous peptides termed endomorphin-1 and 2.

Mechanism of action of opioid receptors:

Mechanism of action of opioid receptors

Pharmacokinetics of opioids ::

Pharmacokinetics of opioids : To reach effector site in CNS, opioids should cross BBB which is determined by 1) Molecular size 2) Ionization 3) Lipid solubility Protein binding. Ionization and lipid solubility are important.

Drug elimination:

Drug elimination

CNS EFFECTS:

CNS EFFECTS Mechanism of Analgesia Inhibit directly the ascending transmission of nociceptive information from the spinal cord dorsal horn. Activate the pain control circuits.

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µ receptors  analgesic K receptor agonists  either analgesic or anti analgesic. Spinal mechanism  Opioids act at synapses either pre or post synaptically and inhibit subs-P release from the primary sensory neuron.

Muscle rigidity :

Muscle rigidity Increases muscle tone and rigidity. Begins just as or after the patient looses consciousness. Hoarseness is seen in conscious patient. Mechanism Central mechanism. Nucleus ponteraphe integrates this phenomenon acting in concert with Basal Ganglia.

Problems associated with opioid induced rigidity:

Problems associated with opioid induced rigidity Hemodynamic Respiratory Miscellaneous ↑CVP ↓Compliance ↑O2 consumption ↑PAP ↓FRC ↑ICP ↑PVR ↓Ventilation ↑ fentanyl plasma levels Hypercarbia Hypoxemia

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Factors affecting the incidence : Difference in the speed and dose of opioid administration Concomitant use of N ₂ 0. Presence or absence of muscle relaxants Patient age. Treatment Pre treatment with NDMR Use of induction agents Serotonin antagonist- Ketanserin α2 adrenergic agonist

Neuroexcitatory phenomenon of opioids :

Neuroexcitatory phenomenon of opioids Fentanyl  delirium to grand mal seizure Remifentanil  GTCS activity in healthy adults, stimulates cingulate cortex. Meperidine  CNS excitation and convulsions ( N- desmethyl metabolite, normeperidine ) Excitatory opioid actions may be related to their coupling to mitogen activated protein kinases .

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Treatment : Midazolam , Naloxone and phenytoin prevent seizure activity on the EEG and histologically evident brain damage PUPIL SIZE Mediated by µ and  receptor . Excitatory action on the parasympathetic nerve innervating the pupil (short ciliary nerve) Opioids release cortical inhibition of the Edinger-Westphal nucleus resulting in pupillary constriction.

Thermoregulatory and shivering :

Thermoregulatory and shivering Reduces thermoregulatory threshold. Meperedine effectively terminates shivering in 70-80% of patients, Mediated by ƙ receptor. Meperedine activity at  2B adrenoceptor subtype  anti-shivering mechanism.

Pruritis:

Pruritis Earlier thought to be due to histamine release. µ receptor mediated. Stimulation of trigeminal nucleus  possible mechanism. Treatment Naloxone . Ondensetron Tenoxicam Droperidol 1.25 mg, Propofol 20mg, Alizapride 100mg

Respiratory Effects:

Respiratory Effects Causes respiratory depression  μ 2 mediated. Incidence of 0.1-1% in perioperative period. They ↓ responsiveness of ventilatory centres to CO2. Depressant effect on muco-ciliary flow in trachea. Prevent hyperventilation induced by pain & anxiety. Anti- tussive action of opoids  centrally mediated Blunting of somatic & autonomic responses to intubation. Treatment  Naloxone / Physostigmine .

CARDIOVASCULAR EFFECTS:

CARDIOVASCULAR EFFECTS Modulates stress response by action on H-P-O axis. Reduce sympathetic & enhances vagal & parasympathetic tone. HR  induced bradycardia  secondary to stimulation of Vagal nucleus (exception- Pethidine ). Depress cardiac function ↑RR int. AV refractory period & purkinje fibre action potential duration.

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Cardio-protective mechanism  mediated through δ 1 receptors, adenosine A1 receptors & protein kinase C. No significant effect on coronary circulation. Cause histamine release  dilatation of terminal arterioles  hypotension & ↓ SVR. Mechanism ↓ calcium transients & enhance calcium sensitivity  δ 1 mediated. Dose dependant + ve inotropic effect causing catecholamine release/ direct myocardial adrenergic activation.

RENAL EFFECTS:

RENAL EFFECTS μ receptor activation  anti-diuresis & ↓electrolyte excretion. Ƙ receptor activation diuresis & little change in electrolyte excretion. ADH & ANP  secretions altered. Ureter  ↑ tone & peristalsis. Bladder  ↑ tone of detrusor muscle & sphincter urethra  urinary retention. Rx  Methylnaltrexone 0.3mg/kg, Naloxone 0.01mg/kg.

GI EFFECTS:

GI EFFECTS ↓ GI motility  constipation Should be considered full stomach regardless of NPO status (pt on previous Opioid therapy) LES relaxed Gastric transit time ↑ ↑ in secretions Rx  Naloxone 0.01mg/kg. Metoclopramide 0.2mg/kg.

HEPATOBILIARY EFFECTS:

HEPATOBILIARY EFFECTS ↑ biliary duct pressure Spasm of sphincter of Oddi Reversible by Naloxone NAUSEA & VOMITING CTZ stimulation ↑ ed secretions Delayed gastric emptying Rx :- Serotonin antagonists / Dexamethasone / CBI receptor agonists

OPIOIDS & OBSTETRICS:

OPIOIDS & OBSTETRICS Placental transfer  Neonatal depression Exaggerate hypotension. Neonatal abstinence syndrome. Oocyte retrieval  Alfentanil / Pethidine are safe. Intra uterine foetal surgery  Intra amniotic Sufentanil

MORPHINE:

MORPHINE From Greek, Morpheus, god of dreams. Isolated from opium by F.W.A Sertuener in 1806. It produces analgesia, sedation, euphoria.

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Chemical structure : Phenanthrene compound. Mechanism of actions: Agonist at µ and  opioid receptor. Pharmacokinetics : Pka - 8.0, 10-20% is unionized portion. Distribution: 20 - 40% protein bound, albumin predominantly. V D – 3.4 – 4.7 L/kg. Absorption : Well absorbed orally,

Preparations :

Preparations Tab  5/10/30/60/100/200 mg Syrup  2/10/20 mg/ml Suppositories  15/30 mg Injection  10/15/30 mg/ml solution Preservative free morphine must be used for intrathecal use.

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Metabolism :

Dose :

Dose Analgesia: IV - 2.5 - 15mg (children 0.05 - 0.2 mg/kg max - 15mg) SC/IM - 2.5 - 20mg. Peak effect in 30-60 min after IM use. PO - 10-30mg q4h for pain. Rectal - 10 - 20mg q4h. Induction: IV - 1 mg/kg. Epidural: (Bolus) 2-5mg(40- 100 µg/kg) (Infusion) 0.1 – 1mg/hr (2 -20 µg/kg/hr) Spinal: 0.2 – 1 mg (4 - 20 µg/kg/hr) preservative free. PCA - IV (bolus) 0.5 - 3 mg (infusion) 0.5 - 2 mg/hr

MEPEREDINE (Pethidine) :

MEPEREDINE ( Pethidine ) Phenylpiperidine derivative. Described in 1939 by Eisleb and Schanmann . 1/10 potency of that of morphine. Duration : 2-4 hours  short acting. Opioid with anticholinergic and weak LA properties. Mechanism - µ and  agonist.

Metabolism : :

Metabolism :

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Dose : IM/IV/PO  25-75mg (0.5 -2 mg/kg) Epidural  (bolus) 1-2 mg/kg. (infusion) 10-20mg/hr. Spinal  (bolus) 0.2 - 1mg/kg. (infusion) 5-10mg/hr. PCA  IV/epidural (bolus) 5 - 30mg. (infusion) 5 - 10mg/hr.

SIDE EFFECTS:

SIDE EFFECTS Orthostatic hypotension. Rarely causes bradycardia . Less constipation, urinary retention, biliary spasm & miosis . Serotonin syndrome with MAO inhibitors and fluoxeitine . Nor meperidine  convulsions.

FENTANYL:

FENTANYL Synthesized in 1960, tertiary amine related to phenyl piperidine . 75-125 times more potent than morphine. Effect site equilibration time-6.8 min. MOA - Highly selective µ, agonist.

Preparations :

Preparations 50 μ g/ml ampoules. Transdermal patch- delivering 25-100 μ g/hr Fentanyl citrare lozenges- 200-1600 μ g

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Pharmacodynamics : Fentanyl and sufentanil - modest ↑in ICP (6 - 9mmHg) Peak of action 2-5 min after IV Duration of action is 30-60 min. Pharmacokinetics : Absorption : Oral bioavailability is 33%, 47% - 97% by Transdermal route. Distribution : 80-95% protein bound. 75% absorbed by lungs. 40% taken up by RBC`s .

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Metabolism  Cyt P 450 3A4 plays important role. Fentanyl  Norfentanyl . Doses: Induction- IV 5 - 30 µg/kg. Analgesia: IV / IM - 0.7 - 2 µg/kg, Infusion 0.05 - 0.2 µg/kg/min. Oral - 5 - 20 µg/kg

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Spinal - (Bolus) 0.1-0.4 µg/kg Epidural - 1 - 2 µg/kg (bolus). 0.5 - 0.7 µg/kg/hr (Infusion). Transdermal - 75 - 100 µg/ hr. PCA IV - bolus 15-75 µg. Infusion 15-25 µg/ hr .

SUFENTANIL:

SUFENTANIL Thienyl derivative of fentanyl. 5-10 times more potent than fentanyl and 1000 - 2000 times more potent than morphine. Effect site equilibration time is 6.2 min.

Dose :

Dose Analgesia : IV/IM 02 - 0.6 µg/kg. Infusion 0.01 - 0.05 µg/kg/min. Intranasal - 1.5-3 µg/kg. Induction - 2 - 10 µg/kg. Epidural - Bolus - 0.2 - 0.6 µg/kg. Infusion - 5 - 30 µg/hr. Spinal Bolus - 0.2-0.08 µg/kg

ALFENTANIL:

ALFENTANIL Tetrazole derivative of fentanyl . 1/5 - 1/10 less potent than fentanyl and 1/3 the duration of action of fentanyl . 10-20 times more potent than morphine

Metabolism :

Metabolism Hepatic clearance  96%. Clearance is 300-500ml/min. Elimination half life  100 minutes. Acute dystonia  Parkinsons disease. Erythromycin, fluconazole , diltiazem  inhibits clearance of Alfentanil .

Doses:

Doses Analgesia : IV - 10-25 µg/kg, peak effect seen in 90 sec. after IV admn . Infusion - 0.1 - 3 µg/kg/min. Duration of action 5-10 min. Induction : 50 - 150 µg/kg Epidural  bolus 10-20 µg/kg. Infusion 100 - 250 µg/kg.

REMIFENTANIL :

REMIFENTANIL Anildopiperidine derivative Analgesic potency similar to fentanyl Ultrashort acting  1.1 min Smaller V D , rapid clearance (3 litres /min) Context sensitive half time  4 min. T ½  10 – 20 mins

Metabolism:

Metabolism Ester hydrolysis by nonspecific plasma esterases to a carboxylic acid derivative Unique pathway of metabolism imparts to remifentanil : Brevity of action. Rapid recovery after discontinuation of its administration. Not influenced by pseudocholinesterase deficiency. Clearance independent of hepatic and renal function.

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Dose: Analgesia: IV/IM 0.05 - 0.3 µg/kg/min Infusion 0.5 - 2 µg/kg/min. Induction : 1.0 µg/kg. Contains glycine hence avoided by spinal / epidural route.

TRAMADOL :

TRAMADOL Synthetic opioid : Aminocylohexonol group. Racemic mixture of 2 enantiomers (+) (-) tramadol . Similar to pethidine (1/10 potency of morphine). Has potential to cause seizures and possibly exacerbate seizures in patient with predisposing factors.

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STRUCTURE METABOLISM

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Dose : Oral, I.M, IV  3 mg/kg. IM50-I00mg, 4-6hrly. IV(Slow)400mg24hr. Paediatric l-2mg/kg4-6hrly. Uses : Treatment of post-operative shivering. (0.5 mg/kg) Precipitated when mixed with, diazepam and midazolam. Useful for chronic pain does not cause tolerance or addiction.

Disadvantages :

Disadvantages Precipitated when mixed with diazepam and midazolam. Should not be used with MAO inhibitors since it precipitate serotonin syndrome. Drug is not licensed for intraoperative use as it may enhance intraoperative recall during enflurane/nitrous oxide anaesthesia.

OPIOID AGONIST - ANTAGONISTS:

OPIOID AGONIST - ANTAGONISTS PENTAZOCINE (FORTWIN) Benzomorphan derivative Agonist at delta and kappa receptors. Antagonized by naloxone . Withdrawal symptom can be precipitated in opioid addicts. CVS  ↑ in HR, BP, PAP, LVEDP

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Extensive first pass metabolism  80% 60-70% protein bound Urinary excretion T1/2  2-3 hrs DOA  4-6 hrs Dose  10 to 30 mg IV or 50 mg orally Ceiling effect occurs after 30-70 mg. Side effects  sedation, diaphoresis, dysphoria

BUTORPHANOL:

BUTORPHANOL Parenteral route only Low affinity for μ , moderate for ƙ. T1/2  2- 3 hrs Peak analgesia seen in 1 hr Ceiling effect seen at high doses (10mg) Pharmacodynamic actions similar to Pentazocine . Analgesic dose 2-3mg

BUPRENORPHINE:

BUPRENORPHINE Derivative of Thebaine . 33 times more potent than morphine. Affinity to μ receptor 50 times greater T1/2 166min DOA  8 hrs V D  2.8 l/kg Side effects  Pulmonary edema Respiratory depression . Dose  0.3- 0.6 mg IM /IV/ Epidural.

USES OF OPIOIDS:

USES OF OPIOIDS Analgesia Sedation TIVA Balanced anaesthesia Opioid anaesthesia for cardiac surgery Neurolept analgesia- anaesthesia Transdermal therapeutic systems Iontophoresis Trans mucosal drug delivery

OPIOID ANTAGONIST:

OPIOID ANTAGONIST NALOXONE: N-alkyl derivative of oxymorphone introduced in 1960.

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Mechanism of a action : Pure opioid antagonist with no agonist activity . High affinity for u receptor. NO subjective/ autonomic symptoms are seen in individual not having received opioids. NO psychological dependence is seen

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PHARMACOKINETICS : Absorption : Bioavilability is only 2% orally Distribution : 46% protein bound VD 2l/kg Metabolism : In liver by conjugation to glucuronide Excretion : Clearance 25 ml/min/kg

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“Re- narcotiziation ”  with longer acting opioids such as morphine. ‘Clinical paradox’ T1/2  60-90 min DOA  30-45 min Dose : IV/ IM/ S.C : 0.5 - 1 µg/kg every 2-5 min. IV infusion dose  4-5 µg/kg/hour. Side effects  Pulmonary oedema , VF

NALTREXONE:

NALTREXONE µ,  ,  opioid receptor antagonist 3 advantages compared to naloxone . Longer acting (plasma half-life 8-12 hr) Active orally More potent than naloxone

Constant plasma concentration upto 24 hours:

Constant plasma concentration upto 24 hours Dose : 50-100 mg tag/day in opioid addicts. Side effects : Nausea, headache, hepatotoxicity . Uses : i) Post addiction therapy in opioid addicts. ii) To reduce alcohol craving

NALMEFENE :

NALMEFENE 6 methylene analogue to naltrexone Equipotent to naloxone . Longer duration of action Dose  0.5 -3 mg/kg PO 0.2 -2 mg/kg IV T1/2  8.5 hrs

INTRATHECAL OPIOIDS / NEURAXIAL OPIOIDS :

INTRATHECAL OPIOIDS / NEURAXIAL OPIOIDS Drugs used : Non- lipohilic : Morphine (commonest) Lipophilic : Fentanyl (commonest) Sufentanil , Alfentanil , Pethidine , Hydromorphine , diacetylmorphine , Buprenorphine , Butorphanol .

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DRUG SINGLE DOSE (mg) INFUSION RATE (mg/hr) ONSET (min) Duration Of Effect Of Single Dose(hr) EPIDURAL Morphine 1 – 6 0.1 – 1.0 30 6 – 24 Pethidine 20 -150 5 – 20 5 4 – 8 Methadone 1 – 10 0.3 – 0.5 10 6 – 10 Fentanyl 0.025 - 0.01 0.025 – 0.1 5 2 – 4 Sufentanil 0.01 – 0.06 0.01 – 0.05 5 2 – 4 Alfentanil 0.5 – 1 0.2 15 1 – 3 SPINAL Morphine 0.1 – 0.3 15 8 – 24+ Pethidine 10 – 30 ? 10 – 24+ Fentanyl 0.005 – 0.025 5 3 - 6

TOLERANCE:

TOLERANCE High degree of tolerance develops for 1) Sedation 2) Euphoria, dysphoria . 3) Analgesia, 4) Antidiuretic action 5) Respiratory depression, 6) Cough suppression, 7) Nausea and Vomiting.

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Moderate degree tolerance Bradycardia 2) Hypotension No tolerance \ minimal 1) Miosis 2) Constipation 3) Convulsions 4) Antagonists actions

OPIOID WITHDRAWAL :

OPIOID WITHDRAWAL Initial period (3-4 hr) Early (8-12 hr later) Overt (1-3 days of abstinence from drug) Treatment: Detoxification and stabilization

REFERENCEs:

REFERENCEs Miller’s Anaesthesia – 7 th ed Pharmacology & Physiology In Anaesthetic Practice, Stoelting - 3 rd ed Textbook Of Pharmacology, Goodman and Gilman – 11 th ed Barash Textbook Of Anaesthesia – 6 th ed

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Thank you

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