opioid analgesics 2014
DESCRIPTION
opioid analgesics-dr.G.Vishnupriya,MD pharmacologyTRANSCRIPT
OPIOID ANALGESICS
Dr. G.vishnupriya M.D
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Pain –
Unpleasant & emotional experience associated with tissue
damage such as injury , inflammation or cancer.
Analgesics – Opioid/narcotic/Morphine like analgesics. Non opioid/non narcotic/Aspirin like antipyretics/analgesics.
Pathophysiology of pain -
1- Nociceptive component - ascending pathway
2- Affective component - descending pathway
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CLASSIFICATION OF PAIN - Somatic Visceral Superficial Vascular Referred Neuropathic Phantom Cancer Psychogenic Central
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Peripheral and Central Pathways for PainAscending TractsAscending TractsDescending TractsDescending Tracts
Cortex
Midbrain
Medulla
Spinal Cord
Thalamus
Pons
Ascending pathway – From primary afferent neurons relays impulses to the cortex
from cortex it relays signals to the organ ,it alerts the person to
Use withdrawal reflexes to avoid noxious stimuli. This is called
sensory discriminative component via A delta fibres C fibres causes motivational affective response These nociceptors are present in lamina I & II
Descending pathway – It possess inhibitory effect on dorsal horn transmission.
PAG → RVM & NRM → SG Inhibits ascending pain transmission via STT neurons Met encephalins are released to inhibit pain .
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described by Melzack and Wall in 1965
Gate control Mechanism.
• Stimulation of the large fibers inhibits the transmission of pain, thus “closing the gate.” Whereas, when smaller fibers are stimulated, the gate is opened.
• When the gate is closed signals from small diameter pain fibres do not excite the dorsal horn transmission neurons.
• When the gate is open pain signals excite dorsal horn transmission cells.
• The gating mechanism is influenced by nerve impulses that descend from the brain.
Wind up – in event of repeated firing synaptic potential
increases amplitude & results in wind up shows activity
dependent facilitation .
NMDA, substance P, Nitric oxide, ↑ NGF causes
facilitation by tissue damage results in hyperalgesia. 6
MODULATION OF PAIN –
Peripheral modulators & neuromodulators- capsacin →TRPV1→Depolarisation → initiation of action
potential. Capsacin is obtained from bell peppers it irritates skin on
applying used in incontinence of bladder in patients with spinal
injury & stroke.
TRPV1- Polymodal, closely matches nociceptive neurons Modulated by phosphorylation, TRPV1-4 are thermosensitive, non-selective cation channels that exist as tetrameric
complexes7
They are activated by a range of stimuli including heat, protons, lipids and changes in osmolarity or pressure.
TRPV5-6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and renal epithelia.
cannabinoids are endogenous ligands for vanilloid receptors. adenosine has been shown to be an endogenous TRPV1
ligand and TRPV4 is activated by anandamide and arachidonic acid.
Kinins – Bradykinins & kallidin produced during tissue injury. Potent pain producing substance Releases prostaglandins
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Kinins contd… Act on B2 receptors on nonciceptive neurons Opens TRPV1 channels
Prostaglandins- Enhances 5HT& bradykinins Sensitizes nerve terminal by inhibiting k channels
Other peripheral mediators –ATP, Protons, 5HT, Histamine, K ions, Substance P, Glutamate,
GABA, Noradrenaline, Adenosine
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History of opioids – First reference of opium by Theophrastus 3rd century BC.
Arab physician used it for control of dysentry
1806, Frederich Serturner a pharmacist assistant isolated by
crystallization of pure substance in opium named Morphine
after Morpheus – Greek god of dreams.
middle of 19th century – use of pure alkaloids coincided with
development of hypodermic syringe and hollow needle.
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They used in a civil war in U.S named as soldiers disease.
C.R Alder Wright in 1874 – heroin
Early 1970 – effect of Morphine, Heroin and other opioids as anti nociceptive and addictive agents were well described.
Martin and Goldstein discovered receptors.
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F. SERTURNER (1783–1841)
Morphine
Papaver somniferumL.•Opium-morphine (1806)-codeine-papaverine
..Afghanistan PakistanThailand
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ENDOGENOUS OPIOID PEPTIDES –
In 1973 researchers determined the existence of opiate binding
sites in the brain through the use of radioligand-binding assays
Have Morphin like actions & μ receptor binding activity
– Endorphins,
Encephalin
Dynorphins &
Nociceptin
share a common terminal amino acid sequence of five amino
acids joined to MET/LEU
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β Endorphins It has Met at the last +26 amino acids Has greater affinity to μ Derived from POMC found in Pituitary, Hypothalamus, Limbic area & Medulla These project from Hypothalamus, Thalamus, Arcuate
Nucleus & brain stem
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ENCEPHALINS- 2 encephalins (Leu/Met) derived from preproencephalin Both have high affinity to δ Present- Hypothalamus, cortex, limbic system , PAG &Pain
areas of spinal cord.
DYNORPHINS- It has Leu terminal amino acid sequence Dynorphin A,B,α neo endorphin & β neo endorphin possess
extension of additional amino acids. Greater affinity to κ
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Dynorphins contd… Derived from preprodynorphin Present in dorsal horn of spinal cord Binds to activate NMDA receptors.
ENDOMORPHINS - Endomorphin 1&2 found in brain during stress High affinity μ receptors Precursors not known Short amino acid sequence.
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NOCICEPTIN – Orphan receptors Derived from pro orphanin Found in hippocampus, cortex, many sensory neurons 17 amino acid sequence it is termed as ORL-1 In reward , reinforcement, learning, memory & parkinsons
Disease It causes hyperalgesia.
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Opioid Receptors-
types of receptors - μ, δ, κ & NOP. μ- μ1, μ2 Delta- δ1, δ2 κ-κ1, κ2, κ3.
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Functional effects and opioid receptorsMu Delta Kappa
Analgesia
Supraspinal +++ - -
Spinal ++ ++ ++
Peripheral ++ - ++
Resp. depression
+++ ++ -
Miosis ++ - +
GI motility ++ ++ +
Euphoria +++ - -
Dysphoria - - +++
Sedation ++ - ++
Dependence
+++ - +21
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Selectivity of Opioid Drugs for receptor subtypes
Mu Delta Kappa
Morphine, Codeine
+++ + +
Methadone ++ - -Pethidine ++ + +Pentazocine + + ++Buprenorphine
+++ - ++
Naloxone +++ + ++Naltrexone +++ + +++
Agonist + Antagonist + 23
MECHANISM OF ACTION OF OPIOID
RECEPTORS-
STRUCTURE OF RECEPTOR
These are G protien coupled receptorsSeven hydrophobic regionThree intracellular loopsThree extracellular loopsIntracellular carboxy-terminal tailExtracellular amino-terminal tail
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MECHANISM OF ACTION OF OPIOID
RECEPTORS-The mu-receptor opens ion channel allowing K ions to
flow
out of the cell → hyperpolarisation. it become extremely difficult
for an action potential to be reached and the neurons excitability
decreases.
also causes less calcium ions to enter the terminal end of the
neuron where neurotransmitters are stored and as a result this
significantly reduces neurotransmitter release26
MOA of opioid recep Contd…
It inhibits the membrane bound enzyme adenyl cyclase and
prevents the synthesis of cAMP.
Action at supra spinal level –
Opioids binds at μ opioid receptor & blocks pain which is
Naloxone reversible
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Action at supra spinal level Cont…
Action at spinal level – Opioids depress discharge from spinal dorsal horn neurons by
C Fibers. Prevents opening of Ca, preventing transmitter release.
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Action at spinal cord level Cont… Post synaptic action is demonstrated by ability of opioids to block
excitation of dorsal horns evoked by Glutamate..
Peripheral actions-These agents acts centrally
Direct application produces Local anesthetic like action at high
conc. which is not Naloxone reversible
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OPIOID ANALGESICS Opioids are drugs derived from or related to the Opium Opium is derived from the juice of the opium poppy, Papaver
somniferum Opium contains over twenty distinct alkaloids (morphine was the
first alkaloid of opium to be isolated in 1806). The unripe seed capsule of poppy plant
are incised ,milky exudates collected, dried
& powdered
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Based on the chemical structure opium alkaloid are
classified into two types:
Phenanthrene derivatives
Morphine
Codeine
Thebaine
Benzoisoquinoline derivatives
Papaverine, Noscapine, Narcine
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CLASSIFICATION:
NATURAL-Morphine, Codeine
SEMI SYNTHETIC-Diacetyl Morphine, Pholcodeine, Hydromorphone, oxymorphone,
SYNTHETIC –
Pethidine , Fentanyl, Methadone, Dextropropoxyphene, Tramadol
Levorphanol, Dextromoramide, Alfentanyl, Sufentanyl, Remifentanil 32
Phenanthrene group –
8%- 20% of morphine
0.5 – 2.5% of codeine along with thebaine(0.2 – 0.4).
MORPHINE – Phenanthrene derivative with 2 planar ring & 2 aliphatic ring
Prototype analgesic used as sulfate or hydrochloride, both salts are soluble in water
Acts on μ receptors ,↓ release of glutamate from nociceptive
nerve terminals & also acetylcholine,NA,5HT& Substance P
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Pharmacokinetics – Oral morphine extensive first pass effect hence bioavailability
is 20-40%,sustained release have a longer duration of action.
various routes of administration are -
Oral, intrathecal ,epidural, rectal, I.V, I.M & S.C- effect within 15-20 mins, persist 3-5hrs.
It circulates in plasma partly protein bound &
partly in free Form.
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Morphine Cont.. It enters the blood brain barrier, placental barrier, secreted in
breast milk
It metabolized by liver & kidney
Conjugated with Glucuronic acid to form morphine-6-
Glucuronide active and more potent than morphine,t1/2 is longer
Eliminated in urine 90% of the dose, biliary excretion
accounts for 7-10% of dose
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EFFECTS OF MORPHINE –
Analgesia- Acts on μ receptor Acute & chronic pain ↓ affective component of pain – reflects supra spinal
level at limbic system involved in euphoria producing action
Euphoria,sedation,convulsion – With therapeutic doses causes sense of well being ,
Agitation & anxiety associated with pain ↓ - acts on μ
receptors
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Actions Cont.. κ receptors activation produces dysphoria & hallucinations
even in the absence of pain. Causes drowsiness, difficulty in concentration & mental
apathy, thoughts lack logic produces vivid & daydreams Large dose induces sleep, normal NREM & REM cycle
disrupted ↑ monosynaptic responses via supra spinal stimulation causes
convulsions.
Respiratory depression- Due to↑ PCO2 with normal analgesic doses mediated by μ
receptors
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Actions CONT.. This effect is due to ↓ sensitivity of respiratory centers to ↑
plasma CO2 concentration. Direct depressant action on respiratory center (μ2). In later stages hypoxic drive tends to maintain minute volume
despite ↓ sensitivity of respiratory center to accumulate CO2. broncho constriction → Histamine Toxic doses breathing is maintained by hypoxic drive
mediated through carotid & aortic body chemoreceptors results
in cheyne stokes respiration - in this case, controlled assisted
Ventilation & O2 induced tolerance can develop.
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cough suppression – Direct depressant at cough center, causes this action at lower
than the doses required to produce analgesia, tolerance will
develop Codeine & pholcodeine suppress cough but causes
constipation.
Nausea & vomiting – Directly stimulates CTZ produces emesis, later depresses
vomiting center abolished by Nalorphine& Prochlorperazine &
Haloperidol. In case of poisoning vomiting is absent.
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Pupillary constriction- μ & κ receptor mediated stimulation of occulomotor nucleus. Pin point pupils is important diagnostic feature in opioid
Poisoning. tolerance does not develop.
Vagus stimulation –
Bradycardia & hypotension occurs due to action on medulla
Spinal cord-
depression of higher centers in
CNS → significant ↑ CSF pressure .
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Miscellaneous actions – Release of ADH with resultant ↓ in urinary output, Morphine reduces the efficacy of diuretics in CHF patients ↓ body temperature in larger doses by central actions.
GIT – Induces spasm of smooth muscle of gut,ileocolic & anal
sphincter ↓ propulsive peristaltic movement,spasmogenic action in
duodenum & large intestine ↓ in saliva, gastric acid & intestinal secretion, spasm of
sphincters.
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Action Cont… Inattention to normal sensory stimuli from loaded rectum
causes constipation Atropine antagonizes the action in biliary spasm, patient
should receive laxatives Senna regularly. In mice morphine produces severe spasm of anal sphincter
causes erection of tail- straub’s test formerly employed to detect morphine in biological fluids.
It can be used in treatment of diarrhoea
Smooth muscles – ↑ tone of ureter & detrusor muscle of the bladder Vesical sphincter is contracted ,effects are augmented by
inattention to stimuli arising from bladder -urinary retention ↑ tone of bronchi & bronchioles – bronchoconstriction
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Actions Cont..
Inhibitory release of GnRH ↓ plasma concentration FSH, LH
& ACTH, plasma Prolactin ↑. Suppress the various immune function -↑ susceptibility to
infection in experimental animals . Release of Histamine causes urticaria , Asthmatics should not
be given morphine.
TOLERANCE/DEPENDENCE/ADDICTION –
Tolerance – it develops when large amount of dose of drug is
needed to produce the effect ordinarily produced by its normal
therapeutic dose.
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Mechanism of development of tolerance Tolerance to opioids is cellular adaptive type – long term
desensitisation of receptor effector coupling mechanism
Or it may be due to ↑ Ca levels in the cells,↑ production of
cAMP, ↓efflux of k and resultant release of neurotransmitters to
normal levels
Development of tolerance begins with first dose of
opioids, repeated administration at shorter interval results in loss
of effectiveness with intermittent use of morphine.
Tolerance develops to respiration, depression, emetic,
hypotensive, euphoriant & urinary retention action but not to
miotic & constipation.
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Tolerance cont.. Cross tolerance can occur with other opioid analgesic to
prevent this opioid rotation should be done another approach is to
recouple opioid receptor function via use of adjunctive non
opioid agents. Does not develop tolerance to antagonist action of mixed
agonist antagonist. Remifentanyl induces tolerance within hours
ketamine prevents or reverses opioids induced tolerance
Novel use of δ receptor antagonist with μ receptor agonist –
Useful in emergency condition.
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Dependence –
WHO definition- A state of psychic & sometimes also physical, resulting from the interaction between a living organism & a drug, charecterized by behavioural & other responses that always include a compulsion to take the drug on continuous or periodic basis in order to experience its psychic effect and sometimes to avoid the discomfort of its absence. Tolerance may or not be present. A person may be dependent on more than one drug.
Morphine produces physical dependences, life threatening
withdrawal symptoms are produced with exaggerated rebound
from acute effects of the drug.There is some psychological
dependence also46
Signs &Symptoms –morphine & heroin signs starts within 6-10hrs of last dose, by 5 days most of signs & symptoms disappear some persists for months. Increased craving for drug, lethargy & weakness Weight loss Pupil dilation Chills,rhinorrhea Excessive sweating Abdominal cramps Muscle spasms Hyperirritability Lacrimation Tremor Increased heart rate Increased blood pressure
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Dependence cont.. Buprenorphine & Clonidine are treatments for opioid
detoxification. Babies born to opioid addicted women also exhibit withdrawl
signs because of slower metabolism of opioids in newborn. It facilitate DA transmission in mesocortical or mesolimbic
Pathways and thus activate endogenous reward pathway in the
brain. In order to prevent morphine dependence , morphine should
not be prescribed readily for chronic pain except in terminal
Cancer pain
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Treatment – gradual withdrawal of morphine with substitution of
another opioid analgesic to ↓ severity of withdrawal syndrome. Methadone orally is often used for replacement as it has longer
duration of action than Morphine.
1mg of Methadone will substitute for 4mg of Morphine. Once
it is stabilized, dose is gradually ↓ by 10-20% daily. Drug can be
completely stopped from 6-10th day.
Acute opiate withdrawal symptoms & signs can be controlled
to certain extent by drugs like Chlorpromazine, Propranolol &
clonidine which counter non adrenergic activity49
Morphine poisoning – Due to overdosage, accidental overingestion in an addict or
From suicidal or homicidal intention.
60mg is usually toxic but rarely fatal in normal adult who is
not in pain. Doses 250mg usually fatal.
Larger doses are generally required to produce toxicity in
individuals with pain, whereas in addicts the toxic as well as the
fatal doses are much higher.
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Pin point pupils
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Characterized by – Respiratory depression, pin point pupils, Cyanosis, Reduced body temperature & urinary output, Hypotension, Shock & coma.
Convulsions may occur in infants, Death due to respiratory
depression or shock & pulmonary embolism
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Treatment Naloxone & Nalorphine are specific morphine antagonists
should be administered since they produce severe withdrawal
syndrome.
Drug interactions :
CNS depressants, Phenothiazines, MOA inhibitors & Tricyclic
antidepressants enhances the sedative effects of Morphine &↑
respiratory depression
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Therapeutic uses of Morphine –
Pain relief – Acute MI, fracture of long bones, burns, terminal
stage of malignancy, pulmonary embolism, acute pericarditis &
spontaneous pneumothorax, renal & biliary colic Morphine is administered I.V to↓ shock ,S.C not
advocated because absorption is hampered. If repeated S.C may
result in sudden absorption of toxic quantities into systemic
circulation . Parentral morphine ↓ Post operative pain it ↓ coughing and
Mask signs of recovery & of its complication.
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Pain relief cont.. morphine produces long lasting analgesia -segmental Used following thoracic & upper abdominal surgery
Actions in acute LVF & pulmonary edema –
Morphine induced peripheral vasodilatation → shunting of
Blood to dilated peripheral vasculature - ↓preload thus it ↓
cardiac work load & relieves dyspnoea, provided oxygenation is
Maintained.
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presence of severe pain
Morphine routinely for sedating patients in haematemesis,
Diazepam is safer. Preanesthetic medication Control diarrhoea Anaesthetic – morphine I.V produce general anaesthesia
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DOSAGE.
10 mg / ml inj.
10,30,60,100 mg CR Tabs; 60 mg SR Tabs, 10,20 mg Tab.
2-3 mg epidural / intrathecal
10-15 mg IM or SC
0.1 – 0.2 mg / kg – children.
2-6 mg IV
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Precautions & Contraindications
Infants & elderly
Respiratory insufficiency
Bronchial asthma
Head injury
Hypotension / hypovolemia
Undiagnosed acute abdominal pain
Hypothyroidism, liver & kidney disease
Unstable personalities.
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Other drugs
Oxycodone - acts on κ receptors
Alphaprodine –
Relief of pain in first stage of labour.
Diphenoxylate, Difenoxin, Loperamide- treatment of diarrhoea
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FENTANYL -
1959-Fentanyl first synthesized by Paul Janssen under Janssen
Pharmaceuticals 1960s-Introduced as intravenous anesthetic 1990’s-same company produced Duragesic patch Next came flavored lollipop of fentanyl citrate Present-Effervescent tab for buccal absorption and buccal
spray device patient controlled infusion systems, Advantage in
breakthrough pain Causes Post operative muscle rigidity
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NEUROLEPTANALGESIA•Fentanyl 100 mcg +•Droperidol 5 mg i.m.
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Alfentanil - an ultra-short acting (5-10 minutes) analgesic
Sufentanil – a most potent analgesic (5 to 10 times more potent than fentanyl) for use in heart surgery
Remifentanil - currently the shortest acting opioid, has the benefit of rapid offset, even after prolonged infusions
Carfentanil - is an analogue of fentanyl with an analgesic potency 10,000 times that of morphine and is used in veterinary practice to immobilize certain large animals such as elephants
Fentanyl, Sufentanil, Alfentanyl –truncal rigidity on rapid I.V
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Apomorphine-
Obtained from acid catalyzed rearrangement
Of Morphine, stimulates CTZ –potent emetic-
activation of DA receptors-
blocked by Chlorpromazine Produces a variety of behavioural,
neuro- pharmacological & endocrine effects.
In larger doses in rats causes stereotyped behaviour
syndrome
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Apomorphin cont.. It is used to evaluate actions of psychotropic drug actions in
experimental animals. Dose- 0.1mg/kg S.C – causes vomiting Other effects- nausea, dizziness, hypotension & bradycardia.
Pethidine : 25-100mg oral, I.M/S.C 25-100mg I.V Potent as morphine as analgesic Not suitable in Asthmatics ↑ heart rate, ↓B.P –depression vasomotor system &release
Histamine anti cholinergic property – tachycardia, C/I – M.I
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Pethidine contd.. Preferred in labour does not reduce the force of uterine
Contraction
Naloxone is needed to reverse respiratory depression
50% bioavailability, analgesic effect occur within 10-15 mins,
crosses placental barrier, secreted in milk, metabolized by liver , product Norpethidine shows excitatory effects on CNS.
Treatment to Pethidine addiction is similar to morphine ,Methadone 1mg for 20 mg Pethidine 68
Drug Interactions- Phenytoin ↑ biodegradation of pethidine Cemetidine ↓ clearance of pethidine /morphine is given as
alternative Administered in patient with MAOI → Confusion, excitement,
collapse, Causes seizure in renal failure patient due to accumulation of
Norpethidine
Methadone -5-10 mg/ml oral/ I.M/S.C/rectal
In chronic visceral pain can be given, substitute for Morphine &
Pethidine & used in opioid abstinence.
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Methadone contd… Acts on inhibiting Noradrenaline & 5HT reuptake Blocks NMDA receptors that modulate pain – in neuropathic
& cancer pain Long t1/2 24-36hrs ,bioavailability 80% ,high protein & tissue
bound. Development of tolerance & dependence is slow- useful
for opioid rotation therapy. causes cumulative toxicity Crosses placental barrier Codeine is used as a substitute – Methadone addiction.
Methadone congeners –
Levomethadyl acetate – slow onset ,prolong action in long term
management of heroin addicts to prevent withdrawal syndrome
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d-propoxyphene – Few G.I side effect less respiratory depression, analgesic Potentiates action of Warfarin Dose- 65mg t.i.d .
Morphinan compounds –
Levorphanol - More potent analgesic than Morphine Cause drug dependence Oral/I,M/I.V – 2mg ,intranasally
Butorphanol- Partial agonist I.M/I.V- 2mg, intranasal. Psychomimetic effects
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Pentazocine – Action at κ receptors in spinal cord ,weak opioid
antagonist activity in μ receptor- dysphoria. ↑ systemic & pulmunory arterial blood pressure -↑cardiac
load ,C/I – M.I Dose-25mg-30mg ,Given orally, rectally, S.C, I.M & I.V. Causes hallucinations & unpleasant dreams, precipitates withdrawal syndrome in morphine addicts –
antagonist action μ receptors Naloxone is useful antidote to Pentazocine
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Nalbuphine – Related to Oxymorphone & Naloxone Both agonist & antagonist property Causes psychomimetic effects S.C,I.M,I.V, dose 10 – 20mg every 3-6hrs Ceiling effect to its respiratory depressant action
Meptazinol –
Partial agonist ,Oral or by injection
Buprenorhine – High lipophilic,synthetic derivative of Thebaine Mainly partial μ agonist weak antagonist at κ receptors Dissociates slowly from μ receptors resistant to Naloxone reversal
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Buprenorphin cont..
Not precipitate withdrawal symptoms in morphine addicts
cause respiratory depression , can be used in M.I
Given during induction of anesthesia with nitrous oxide &
Fentanyl, it reverses anaesthetic and respiratory depressant
effects of Fentanyl prolongs analgesia.
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Buprenorphin cont..
Adverse Effects -
drowsiness, nausea, vomiting, constipation, miosis, bradycardia available 0.2mg tablets, 0.3 mg/ml inj & transdermal patches
0.2-0.4 mg sublingually every 8hrs & 0.3-0.6 mg I.M or slow I.V
Every 6-8hrs
Tapentadol-μ receptor agonist NA reuptake inhibiting action
Ziconotide -for intrathecal analgesia,blocks voltage gated N type
Ca channels
OPIOID ANTAGONISTS –
Competitive antagonism
Pure antagonist – Naloxone
- Naltrexone75
Partial agonist of Nalorphine type-
Nalorphine
Levallorphan
Cyclazocine
Partial agonist of morphine type-
Propiram & Profadol
Naloxone- Pure antagonists Antagonizes respiratory depressant effect of opioids D.O.A :3 -4 hrs, Given parenterally ,short acting
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Naloxone cont… treatment of opioid poisoning – I.V bolus 0.8-2.0mg every 2-
3mins – max of 10mg children – 10 mcg/kg bolus
If no response inject 100 mcg/kg bolus Reverses respiratory depression of opioid analgesic post
Operatively Naloxone I.V given correct hypotension in septic shock, Treat adverse drug reactions of epidural opioids Used in neonatal resuscitation to reverse effect of opioids if
used during labour, but should not be used if mother is dependent
on opioids since baby is also dependent in utero Naloxone can
precipitate withdrawal77
Naltrexone – effective opioid antagonist Maintenance drug for opioid poisoning repeatedly given Decreases craving in chronic alcoholics Prevents relapse after opioid deaddiction Long acting well tolerated no euphoric effect No physical dependence Blocks heroin and other opiates upto 4 days, 25mg is used
50mg available ,drug causes difficulty in sleeping, muscular pain
Methylnaltrexone –
Used S.C treat morphine induced constipation
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Nalmefene –
Pure μ receptor antagonist, more potent than naltrexon
Given parenterally longer1/2 life
Nalorphine – 10mg/ml S.C or I.V Semisynthetic compound of morphine Treat acute morphine poisoning It acts as partial agonist produce analgesia & respiratory
Depression,displaces Morphine from receptor site & abolishes its
effects
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Nalorphin contd…
Dysphoric symptoms may be present
Do not produce dependence, less effective against Pethidine
When 1-3 mg given to morphine addict it precipitates
Withdrawal syndrome within 3-5min lasting 2 hrs, pupil dilates
or fail to produce effects
Withdrawal syndrome is precipitated in Heroin & Methadone
80
Nalorphine cont… Diagnosis of morphine addiction Given to morphine addicts.
Levallorphan- More potent than Nalorphine I.V - 0.2mg, fails to reverse Pethidine induced respiratory
depression.
Alvimopan – Selective opioid μ receptor antagonist Blocks G.I effects of opioids Treating post operative ileus after bowel resection Given 30 min -5 hrs before surgery continued for 7 days Does not be useful unless started before paralytic ileus
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SCREENING METHODS-
Principle: record the response of animal to a painful stimulus before & after administration of analgesic
CLASSIFICATION
In Vivo Studies
In Vitro Studies
Neuropathic Pain Models
In Vivo screening methods
Chemical Stimulation Methods
Electrical Stimulation Methods
Mechanical Stimulation Methods
Thermal Stimulation Methods
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Thermal –Tail flick test
hot-plate test
Mechanical-Haffner’s tail clip method
Randall & selitto test
Chemical –Formalin test (intradermal injection)
writhing test (intraperitoneal injection)
chemical stimulation of visceral organs
Electrical – Tail stimulation
Tooth pulp test
Monkey shock titration test
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Hot plate method
Principle-
Animals should be individually placed on hot plate at constant
temperature (55ºc)reaction of animal such as paw licking or
Jumping response is taken as end point. analgesic ↑ reaction time
Drugs:
• Morphine -5mg/kg s.c
• Unknown
– Instruments: Cages Stop watches Thermostatically controlled hot plate Thermometer
– Animals: 30 mice84
Method-
Group I, 6 mice (20-25 g) should be taken
Test sensitivity of animal to heat (not exceed 10 sec.)
Morphine (IP) 0.2ml/10 gm should be given
Test sensitivity of animal to heat every 10 min for 60 min
results should be recorded in table.
Procedure
Mouse should be weighed and numbered
Basal reaction time observing hind paw licking noted
Normal response 6-8 sec,cut off 15 sec observed
Drug should be given react. time of 15,30,60&120 min
Calculate % ↑ in reac time as index of analgesia at each interval
85
Table 1 Change in the reaction time (sec.) over 60 min. in group injected with morphine using hot-plate method
Animal #
0 min.
10 min.
20 min.
30 min.
40 min.
50 min.
60 min.
1
2
3
4
5
6
Mean
86
Tail flick method
Material
• Animal: Mouse
Instrument: Tail-flick analgesiometer
Drug used: 5mg/kg Morphine hydrochloride via s.c route
Procedure-
mouse should be weighed and number
Basal reaction time gap of 5mins should be taken to radiant heat by
placing the tip of tail on heat source, tail withdrawal from heat is end
point. Normal withdrawal time 3-5 sec,cut off 10-12 sec noted
Inj morphine should be given & reaction time of 5,15,30 & 60min is
Noted %↑ in reaction time at each interval is noted
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in vitroμ opiate receptor binding assayAssay to study Cannabinoids activityRole of vasoactive intestinal polypeptide &
pituitary adenylate cyclase activating peptide&
nociceptin in analgesia
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Newer drug in clinical trials NKTR-192, A New Short-Acting Mu-Opioid Analgesic
Molecule, Achieves Desired Pharmacokinetic Profile in First
Phase 1a Clinical Study NKTR-192 is a new mu-opioid agonist molecule designed to
have a short-acting profile and onset of pain relief suitable for
the treatment of acute pain, but with a reduced rate of entry into
the CNS as compared to other fast-acting opioids used to treat
acute pain. Reduce the euphoria, or rush, that can drive opioid abuse and
dependence, while at the same time reducing other unwanted
CNS side effects, such as sedation
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H.L Sharma & K.K Sharma – The Principles of Pharmacology
second Edition.
Goodman & Gilman- pharmacological basis of therapeutics -12th edition
R.S.Satoskar - Pharmacology &Therapeutics
-Twentieth Edition. Rang & Dale - Pharmacology –sixthEdition
H.L Sharma & K.K Sharma – The Principles of Pharmacology
second Edition.
Goodman & Gilman- pharmacological basis of therapeutics -12th edition
R.S.Satoskar - Pharmacology &Therapeutics
-Twentieth Edition. Rang & Dale - Pharmacology –sixthEdition
91
92