NEWER NARCOTIC DRUGS ROUTES OF ADMINISTRATION OF NARCOTIC DRUGS SPINAL NARCOTIC DRUGS

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NEWER NARCOTIC DRUGS ROUTES OF ADMINISTRATION OF
NARCOTIC DRUGS SPINAL NARCOTIC DRUGS

• Dr. S. Sai Janani

University College of Medical Sciences GTB
Hospital, Delhi
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INTRODUCTION

• NARCOTIC (Greek) stupor
• OPIUM (Greek) juice
• OPIATE Drugs derived from opium
• OPIOID all exogenous substances, natural and
  synthetic, that bind specifically to any of
  several subpopulations of opioid receptors and
  produce atleast some agonist (morphine-like)
  effects.
• Plant Papaver Somniferum (poppy)

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OPIOID TIMELINE

• c.3400 B.C. - poppy the joy plant
  mesapotamia
• 1803 Friedrich Sertürner- discovers active
  ingredient of opium- Morphine
• 1874 C R Wright discovers Heroin or
  diacetylmorphine by boiling morphine

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Timeline

• 1960 Janssen Pharmaceuticals- synthesise
  Fentanyl
• 1976 Janssen Pharmaceutica Alfentanil
• 1980s Janssen Pharmaceutica Remifentanil

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CLASSIFICATION OF OPIOIDS

• NATURALLY OCCURING
• Phenanthrenes
• Morphine
• Codeine
• Benzylisoquinoline
• Papaverine
• Thebaine

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Classification.

• SEMI-SYNTHETIC
• Heroin
• Dihydromorphone
• Thebaine derivatives
• Etorphine
• Buprenorphine

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Classification contd.

• SYNTHETIC
• Morphinan series
• Levorphanol
• Butorphanol
• Diphenylpropylamine series
• Methadone
• a- propoxyphene

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Classification contd

• Benzomorphan series
• Pentazocine
• Phenazocine
• Phenylpiperidine series
• Meperidine
• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

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CLASSIFICATION OF OPIOIDS ACC. TO THEIR ACTIVITY

• PURE AGONISTS
• Morphine
• Morphine-6-glucouronide
• Meperidine
• Fentanyl
• Sufentanil
• Alfentanil
• Remifentanil

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Pure Agonists.

• Codeine
• Hydromorphone
• Oxymorphone
• Oxycodone
• Hydrocodone
• Propoxyphene
• Methadone
• Heroin

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Pure Agonists..

• AGONISTS WITH DUAL ACTIVITY
• Tramadol
• Tapentadol

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AGONIST ANTAGONISTS

• Pentazocine
• Butorphanol
• Nalbuphine
• Buprenorphine
• Nalorphine
• Bremazocine
• Dezocine
• Meptazinol

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ANTAGONISTS

• CENTRAL ANTAGONISTS
• Naloxone
• Nalmefene
• Naltrexone
• PERIPHERAL ANTAGONISTS
• Methylnaltrexone
• Alvimopan

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MECHANISM OF ACTION

• Opioids bind to the opioid receptor
• G- protein coupled receptor (GPCR)
• Spinal cord, CNS and periphery

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G- protein COUPLED RECEPTOR
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SITES OF OPIOID RECEPTORS
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LOCATION OF OPIOID RECEPTORS - SUPRASPINAL
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Mu (µ)1 Mu (µ) 2 Kappa (?) Delta (d)
Analgesia (supraspinal spinal) Analgesia (spinal) Analgesia (supraspinal spinal) Analgesia (supraspinal spinal)
Euphoria Vent.depression Dysphoria Vent.dep
Miosis Phy. dep sedation Phy.dep
Bradycardia constipation miosis Constipation(minimal)
Hypothermia diuresis Urinary retention
Urinary retention
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OPIOID RECEPTORS
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STRUCTURE ACTIVITY RELATIONSHIP
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STRUCTURE OF THE FENTANYL FAMILY
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FENTANYL
N-(1-(2-phenylethyl)-4-piperidinyl)-N-phenyl-propa
namide
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FENTANYL

• Synthetic opioid agonist
• Phenylpiperidine derivative
• Structurally similar to pethidine
• 75 to 125 times more potent than morphine

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PARAMETER FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
pKa 8.4 8.0 6.5 7.26
nonionised(pH 7.4) 8.5 20 89 58
?ow 816 1757 128 17.9
Protein binding() 84(40 rbcs 75 lungs) 93 92 66-93
Clearance (ml/min) 1530 900 238 4000
Vdss 335 123 27 30
t1/2pmin 1.2-1.9 1.4 1.0-3.5 0.4-0.5
T1/2amin 9.2-19. 17.7 9.5-17 2.0-3.7
T1/2ß h 17.7 2.2-4.6 1.4-1.5 0.17-0.33
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Fentanyl conc and EEG spectral edge
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ALFENTANIL
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Redistribution of fentanyl after a single
intravenous bolus
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Recurrent fentanyl-induced respiratory depression
evidenced by changes in slope of CO2 ventilatory
response curve
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Pharmacokinetics..

• CONTEXT SENSITIVE HALF LIFE
• Defined as the time required for the drug
  concentration in the central compartment to
  decrease by 50 after an intravenous infusion.
• f( infusion rate)
• Except remifentanil----- independent of inf rate
  (rapid ester hydrolysis and short t1/2)

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Context sensitive t1/2 of the fentanyl group vs
rate of infusion
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Pharmacokinetics Remifentanil

• Unique features
• Small Vd
• Rapid clearance
• Lower interindividual variability
• Hence it accumulates less than other opioids
• PKinetic similar in lean obese- Hence dose
  should be based on ideal body mass rather than
  total body weight.

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Pharmacokinetics

• Rapid effect site equilibration-
• Reaches steady state after 10 min of infusion
• Context sensitive t1/2 nearly independent of
  rate of infusion because-
• small Vd rapid clearance
• Prompt changes in affect with infusion rate

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Pharmacokinetics
FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Metabolism in liver- CYP3A N- demethylation Principle metabolite Norfentanyl Minimally active O-demethylation N-desmethyl sufentanil (10 active) ? pl.conc in CRF Metabolism dep on hepatic blood flow Piperidine dealkylation ---noralfentanil Amide N- dealkylation ---phenylpropionamide Inter individual variability in disposition d/t CYP450 isoforms Principal metabolite- remifentanil acid 300 -4,600 fold less potent Excreted by kidneys Not substrate for pseudocholinesterase Not affected by renal or hepatic failure Hypothermic cardio pulm. bypass reatrds metab. by 20
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Pharmacokinetics..

• METABOLISM

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PHARMACODYNAMICS
FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Reduces MAC in a dose- dependent manner (i.v. or epidural) Opioids propofol TIVA Required pl. conc of fentanyl to reduce CP50 of propofol to 50 1.2 ng/ml skin incision 1.8 ng/ml peritoneal incision 2.8ng/ml abd. retraction Analgesia 0.1 -0.4 mcg/kg longer period of analgesia and lesser R.D than fentanyl ?MAC requirement by 70 to 90 (dose dependent) Cardiac surgery 10-30 mcg/kg with O2 and ms. Relaxants ?cerebral O2 requirement Analgesia to acute and transient noxious stimuli like endotracheal intubation or retrobulbar block. 15 mcg/kg i.v 90 sec before direct laryngoscopy Lower incidence of PONV than fentanyl or sufentanil Profound analgesic when needed transiently- retrobulbar nerve block endotracheal intubation Intermittent remifentanil- labor analgesia Long surgeries where rapid recovery is needed- neurologic assessment, wake up test Less post op resp depression
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Pharmacodynamics.

• STRESS FREE ANESTHESIA
• At very high doses, fentanyl reduces
  neuro-endocrine response to various surgical
  stimuli
• Requires high doses of fentanyl- 50 to 150
  mcg/kg to achieve a pl conc of 20-30 ng/ml
• Blunts the stress response hemodynamic and
  endocrinologic
• Minimal cardiovascular depression
• Disadvantages awareness, muscle rigidity,
  biphasic post-op resp.depression (EEG monitoring,
  ms.relaxants)

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SIDE EFFECTS

• CNS Effects
• Muscle rigidity
• Seen in doses from 7 8 mcg/kg i.v during
  induction
• Mechanismµ receptor at nucleus pontis raphe
• Depends on dose, speed of administration, use of
  N2O and ms. Relaxant, age

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Muscle rigidity

• Problems due to ms. Rigidity
• Hemodynamic - ? CVP,? PAP,?PVR
• Respiratory - ? compliance, ? FRC, ? ventilation,
  hypoxia, hypercarbia
• Miscellaneous- ?O2 consumption, ?ICP,
• Flexion of extremities, tonic- clonic movements.
• Reduced by pre med.with NDMRs, induction doses
  of thiopentone,diazepam and midazolam

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CNS Effects..

• Pruritus
• Central mechanism due to µ receptor.
• gt facial itching d/t opioid triggered neural
  tranmission at a distal site.
• t/t- nalbuphine or butorphanol ( partial antag at
  µ Rc and ag at ? Rc.hence, antipruritic and
  analgesic)
• -ondansetron
• -teroxicam

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Pharmacodynamics..

• Respiratory system
• Respiratory depression
• Similar to equianalgesic dose of morphine.
• For Fentanyl-
• At plasma conc 1.5 -3.0 ng/ml - ?CO2 response
  to ventilation
• At high doses (50 -100 mcg/kg) R.D for several
  hours
• At mod doses (30 -50 mcg/kg) post op.
  mechanical ventilation is needed.
• Factors? high dose,sleep ,old age, CNS
  depressants
• ? with pain

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• Seen as-
• ? ETCO2
• ? slope of CO2 response curve
• minute ventilation at ETCO2 50 mmHg increases
  rapidly reaching a peak at 5min f/b depression
  
• ? in R.R gt ? T.V
• Hence R.R can be used to used to monitor fentanyl
  induced respiratory depression
• Biphasic recurrent with secondary peaks in pl.
  fentanyl levels.

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Pharmacodynamics..

• Cardiovascular effects
• Causes bradycardia
• ? baroreceptor reflex more in neonates since
  cardiac output is mostly rate dependent.
• Responds to atropine
• Also ? AV nodal conduction,?RR interval , ?QTc
  interval.(?ß blockade and CCBs)

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Acute Opioid Tolerance

• ? post op analgesic requirement with high dose
  remifentanil
• Delayed hyperalgesia
• Dose dependent tolerance
• ?NMDA receptors
• Blocked by ketamine, Mg

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ROUTES OF ADMINISTRATION- INTRAVENOUS
FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Available as fentanyl citrate injection 2 ml ampoules 50 mcg/ml 10 ml vials Available as sufentanil citrate 2 ml amp 50mcg/ml Available as Alfentanil citrate 0.5 mg/ml Available as Remifentanil citrate 2 mg/ml (glycinated)
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I.V ROUTE
I.V FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Pre- medication 25-50 mcg 2-5 mcg 250-500 mcg
Induction with hypnotic- 1.5-5 mcg/kg 0.1-1 mcg/kg 10-50 mcg/kg 0.5-1.0 mcg /kg bolus or 0.25- 0.5 mcg/kg/min
with 60-70 N2O- 8-23 mcg/kg 1.3-2.8 mcg/kg
high dose opioid- 50 mcg/kg 10-30 mcg/kg 120 mcg/kg 2-5 mcg/kg bolus and/or 2 mcg/kg/min
Maintenance int.bolus 25-100 mcg 5-20 mcg 250-500 mcg 5-50 mcg
infusion 0.033mcg/kg/mi 0.005-0.015 mcg/kg/min 0.5 -1.5 mcg/kg/min 0.25-0.05 mcg/kg/min
high dose opioid- 0.5 mcg/kg/min 1.0-3.0 mcg/kg/min
MAC int.bolus- 12.5-50 mcg 2.5-10 mcg bolus 125 250 mcg bolus 12.5- 25 mcg bolus 0.01-0.2 mcg/kg/min
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TARGET CONTROLLED INFUSION (TCI)

• Computer controlled infusion pumps (CCIP)
• Target conc. Set instead of infusion rate
• CCIP calculates infusion rate from target
  concentration and delivers required volume
• Therapeutic pl. conc for a particular opioid for
  a particular effect needs to be known

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TCI DOSES
FENTANYL SUFENTANIL ALFENTANIL REMIFENTANIL
Moderate to strong analgesia- 1.5 5 ng/ml 0.05-0.10ng/ml 40-80ng/ml
50 MAC reduction- 0.5-2 ng/ml 0.0145ng/ml 200 ng/ml 1.3ng/ml
Surgical analgesia with 50N2O- 15-25 ng/ml N.A 300 -600 ng/ml
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PATIENT CONTROLLED ANALGESIA (PCA)

• Combine the advantages of cont infusion with
  flexibilty of bolus doses acc to patients need
• Activating a switch ------delivers bolus dose
• Lockout interval- minimum time that would have to
  elapse between two activations
• Bolus dose- 0.015 mg
• Cont.infusion- 0.02-0.1mg/hr
• Lockout interval-3-10 min
• 4 hr limit- 0.2-0.4 mg

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Disposable PCA Pump with a switch

• Delivers bolus dose according to patients
  analgesic need
• Specific pre set rate only

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Newer PCA Pump

• Administration of background infusion
  superimposed on patient controlled boluses
• Help to maintain plasma concentration in between
  boluses

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BUCCAL- TRANSMUCOSAL

• Oral transmucosal fentanyl (fentanyl lollipop)
• Delivers 5 -20 mcg/kg
• Goal- to decrease pre op anxiety and facilitate
  inductionin children
• Dose 15-20 mcg/kg 45 min before induction
• S/E dec.RR, PONV
• Self medication to adequate analgesia in cancer
  patients.

Buccallozenge200 mcg 300 mcg 400 mcg
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TRANSDERMAL FENTANYL

• Ideal drug fo transdermal delivery because
• High solubility in water and oil
• LMW
• High potency
• Minimal skin irritation
• Advantages
• No 1st pass metab
• Better compliance
• Convenience and comfort
• Consistent analgesia

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TRANSDERMAL FENTANYL PATCH

• Marketed as Duragesic
• 25 mcg/h 50 mcg/h 75 mcg/h 100 mcg/h
• Peak pl. fentanyl conc at 18 hrs after
  application
• Conc.stable as long as patch is in place
• Decrease 17 hours after patch is removed
• Each patch lasts 3 days
• Prescribed with patient instructions about
• heartbeat that is faster than normal
• chest pain
• rash
• seizure
• coughing up blood
• fever
• Not recommended for post op analgesia d/t R.D

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Iontophoretic transdermal patch

• Skin patch in which drug passes through the skin
  into circulation augmented by external electric
  current
• Available as IONSYS
• When in need of pain medication, pt. double
  clicks the button.40 mcg of fentanyl delivered
  over 10 minutes

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CENTRAL NEURAXIAL ADMINSTRATION- FENTANYL

• Spinal fentanyl
• Dose 5-25mcg
• Onset5-10 min
• Duration 1-4 hrs
• Epidural fentanyl bolus
• Fentanyl 0.001- 100mcg bolus
• Onset 4-10 min
• Peak- 20 min
• Duration 2.6-3hrs
• Continous epidural infusion( fentanyl 0.001
  bupivacaine 0.1)
• range- 4-12ml/hr
• base- 5ml/hr
• patient assisted bolus- 1ml
• lock out interval- 12 min

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SUFENTANIL

• Sufentanil 0.0001- bolus- 10-60 mcg
• onset- 7.3 min
• peak- 26.5 min
• duration- 3.9-6.9 hrs
• Continous infusion rate 10 ml/hr

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ALFENTANIL

• Bolus 15 mcg/kg
• Onset 15 min
• Duration 1-2hr

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SPINAL INFUSION PUMP

• Consists of spinal catheter and infusion pump
• Screening test- dose titration- pump pocket-
  implantation- periodic assessment.
• Delivers drug at set rate
• (not FDA approved for fentanyl yet)
• Lesser systemic side effects.
• Used mostly in cancer pain

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CONTINOUS SPINAL PUMP

• Spinal catheter placed
• Subcutaneous pocket for pump in the abd
• Catheter tunneled to pump s/c
• External programmer for communication dose
  adjustments

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CONTINOUS EPIDURAL INFUSION PUMPS

• NON ELECTRIC ELASTOMERIC PUMPS
• WORKING PRINCIPLE
• mechanical restriction within the flow path
  determines the speed of pressurized fluid
• Pressurised by elastomer
• Mechanical restriction by narrow bore of tube.
• This pump 50-250 ml/hr
• Different designs- different flow rates.
• Flow rate is higher in beginning and end of
  infusion

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Pediatric considerations

• Oral (lollipop)- 15-20 mcg/kg
• Parenteral- 0.5-1mcg/kg
• PCA(gt 5 yrs old)-
• bolus- 0.25-0.5mcg/kg
• lockout 10 min
• basal rate- 0.15 mcg/kg/hr
• hourly limit-0.005 mg/kg
• Epidural infusion-
• 0.1bupivacaine with fentanyl 2 mcg/ml
• (3 months to 5 yrs)-
• cath tip below T10- 0.2-0.3ml/kg/h
• cath tip above T10- 0.1-0.2ml/kg/h

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SUFENTANIL

• 10- 15 times more potent than fentanyl

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ALFENTANIL

• Tetrazole derivative of fentanyl
• ¼ to 1/10th potent as fentanyl
• Effect- site equilibration lt1 min
• Because of low pKa

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REMIFENTANIL
methyl 1-(2-methoxycarbonylethyl)-4-(phenyl-propan
oyl-amino) -piperidine-4-carboxylate
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REMIFENTANIL

• 4- anilidopiperidine with a methyl ester side-
  chain
• Ultra short acting opioid
• Potent µ- agonist

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Pharmacokinetics..

• Context sensitive t1/2- 4 min
• Independent of infusion rate

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DRUGS WITH DUAL MODE OF ACTION

• Centrally acting agonist on µ- opioid receptor
• Norepinephrine uptake inhibitor
• Tramadol
• Tapentadol

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TRAMADOL

• Centrally acting
• µ receptor- moderate affinity
• ? receptor- weak affinity
• d receptor- weak affinity
• 5-10 times less potent than morphine
• Racemic mixture of 2 enantiomers-
• inhibits NE uptake
• inhibits 5HT uptake opioid
  receptor effects

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Tramadol

• Pharmacokinetics-
• metabolised by CYP 450 to O-
  desmethyltramadol
• Uses-
• Treatment of mod to sev pain( 3mg/kg)
• ?post op shivering with min. effects on
  breathing
• in chr. Pain- no tolerance or addiction
• no major organ toxicity
• S/E-
• Drug related seizures ( avoid in
  seizures)
• nausea and vomitting (ondansetron
  interferes with its analgesic action)
• D/I
• coumarin derivatives
• anti- depressants (? seizure threshold)

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Tapentadol
3-(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylprop
ylphenol hydrochloride
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Tapentadol.

• Johnson Johnson Pharmaceutical and Grunenthal
  Pharmaceutical
• FDA approval 21 November 2008
• Potency between morphine and tramadol

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Mechanism Of Action

• Agonist at µ receptor
• Inhibitor of noradrenaline uptake
• Modify sensory and affective aspects of pain
• Inhibit pain pathways at spinal cord and brain

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Pharmacokinetics

• Administered orally
• Bioavailabilty - 31.96.8
• Peak plasma concentration after 0.83 hrs.
• Metabolism in liver Phase II glucouronidation
• No active metabolite
• Oral tablets approved 50 mg,75 mg 100 mg
• Extended release 100 mg , 200 mg

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Uses..

• In moderate to severe pain
• Has been studied in patients who underwent
  bunionectomy and in pts of end stage joint
  disease, pts with dental pain
• Provided acceptable pain relief

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Pain relief with tapentadol in patients who
underwent bunionectomy
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Contraindications

• ? ICP
• Impaired consciousnesss
• Coma
• Caution in
• head injury
• Pancreatic, biliary and hepatic disease
• Elderly
• Pts with respiratory compromise- COPD, asthma,
  cor-pulmonale,sev.obesity,sleep apnea
  syndrome(resp. depression)
• Patients with risk of abuse

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Adverse effects

• Nausea,
• Vomitting
• Somnolence
• Headache

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OPIOID AGONIST-ANTAGONISTS

• Butorphanol
• Buprenophine
• Antagonist at µ-receptor
• Agonist at ?-receptor

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PARAMETER BUTORPHANOL BUPRENORPHINE
Structure Benzomorphan derivative Thebaine derivative
Receptors Mu receptor-antagonist (low) ? receptor agonist-analgesia,antishivering s receptor agonist-dysphoria(low) Agonist-antagonist at µ receptors (high affinity slow dissociation resitance to naloxone Displaces opioid ag from receptor site)
Pharmacokinetics Completely absorbed from i.m.route Elimination t1/2-2.5-3.5hr Metabolism-hydroxybutorphanol excreted in bile Onset-30 min Duration-2 hrs 2/3 excreted unchanged in bile Rest- inactive metabolites in urine
Side-effects Sedation, nausea,diaphoresis, Vent.depression ?SBP Drowsiness,nausea,vomitting Vent depression (prolonged resis to naloxone)
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OPIOID ANTAGONISTS CENTRAL

• NALOXONE
• Non- selective antagonist at all 3 opioid
  receptors
• Pharmacokinetics
• Short duration of action-30-45 min
• (d/t rapid redistribution)
• Elimination t1/2 60/90 min
• Metabolism naloxone -3- glucouronide
• Dose- 1-4 mcg/kg iv
• Infusion- 5mcg/kg/hr
• Uses- reversal of opioid-induced vent.
  Depression
• -vent depression in neonates after
  maternal opioid adminstration
• - opioid overdose
• -detect physical dependence
• S/E- nausea, vomitting,CVS stimulation,?sympatheti
  c activity

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CENTRAL OPIOID ANTAGONISTSNaltrexone and
Nalmefene

• NALTREXONE
• Similar to naloxone, but longer duration of
  action (24 hrs)
• NALMEFENE
• 6-methylene analogue of naltrexone
• Equipotent to naloxone
• Longer t1/2- 6.8 hrs
• Dose- 15 25 mcg i.v (max- 1mcg/kg)

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PERIPHERAL OPIOID ANTAGONISTS

• Either Quarternary opioid receptor antagonists
  or highly selective for receptors.
• TWO COMPOUNDS
• Methylnaltrexone
• Alvimopan

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METHYLNALTREXONE

• 17(Cyclopropylmethyl)17methyl-4,5-epoxy-3,14-dihyd
  roxymorphinanium-6-one

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Methylnaltrexone

• Manufactured by Progenics Pharmaceuticals and
  Wyeth Pharmaceuticals.
• Quarternary Nitrogen group
• Cannot cross BBB

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Pharmacodynamics

• Reverses peripheral opioid effects such as
  opioid-induced constipation
• nausea/vomiting( by dec delay in gastric
  emptying and acting on the CTZ which is outside
  the BBB)
• cough suppression
• urinary retention.

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ALVIMOPAN
2-((2S)-2-((3R,4R)-4-(3-hydroxyphenyl)-3,4-dimet
hylpiperidin-1-ylmethyl) -3-phenylpropanoylamino
)acetic acid
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Mechanism Of Action

• Competitively binds to µ-opioid receptor in GIT.
• Peripheralcentral opioid receptor 2001
• Acts on entero- enteric and myentereic plexuses

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Pharmacokinetics

• Poor oral absorption
• Bioavailability 30
• Cpss 2 hrs after oral dose
• Vd 30 l
• 80 90 pl protein binding
• Metabolism- Metabolised by gut flora- inactive
  metabolite
• Excretion- gt60- biliary excretion
• Elimination t1/2 10-17 hrs.

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Adverse Effects

• Dyspepsia
• Hypokalemia
• Back pain
• Delayed micturition

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Contraindications

• Severe hepatic failure
• ESRD
• Dialysis
• Not preferred in comlete bowel obstruction
• Pts gt7 days of opioid therapy (opioid t/t leads
  to gut sensitisation- antagonist can lead to
  withdrawal)

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Doses

• Oral 6 mg and 12 mg tab
• Studies 12 mg BD
• Approved by FDA- May 20, 2008

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Drug Interactions

• P- glycoprotein substrate
• Interactions with P- glycoprotein inhibitors
• amiodarone, depridil, diltiazem, cyclosporine,
  itraconazole, quinine, quinidine, spironolactone,
  and verapamil.

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Bibliography

• Millers Anesthesia 6th edition Edited by
  Ronald D.Miller
• Clinical Anesthesia- 5th edition
  Barash,Cullen,Stoelting
• Pharmacology Physiology in anesthetic practice-
  Edited by Stoelting, Hillier
• The Massachusetts General Hospital Handbook of
  Pain Management- 3rd edition edited by Jane
  C.Ballantyne

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• Marion D, Datta S Opioid Pharmacology Pain
  Phyisician Opioid special issue11133-53,2008.

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THANK YOU