opioids

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Opioids:

Opioid s

pain:

pain Unpleasant subjective signal Warning signal Pain relief means business Pain types - acute,chronic -somatic -Visceral -Referred Neuropathic/nociceptive Components of pain- sensation &reaction (nociceptive &affective )

Types of Pain – contd.:

Types of Pain – contd.

Types of Pain – contd.:

Types of Pain – contd. Transduction Transmission Perception Modulation

opioids:

opioids Main stay of pain treatment for thousands of years. naturally occurring substances called endogenous opioid system or endorphins. Three major types of receptors - µ, δ , and κ receptors. forth one nociception/ orphanin FQR

Opioids - Opium:

Opioids - Opium A dark brown, resinous material obtained from poppy ( Papaver somniferum ) Capsules. OPIUM PHE N AN T HRE N E Morphine 9-14% Codeine 0.5-2% Thebaine 0.2-1% BENZYLISOQUINOLINE Papaverine 0.8-1% Noscapine 3-10% Narcine 0.2-0.4%

Poppy Plant - image:

Poppy Plant - image

Poppy to Opioids:

Poppy to Opioids

ANALGESICS:

ANALGESICS Relieves pain without loss of consciousness No effect on underlying cause 2 classes- 1)Opioid or morphine type 2)Non-opioid or aspirin like Endogenous opioid peptides- Enkephalins - delta>mu- preproenkephalin -met & leuENK Endorphins — mu-good analgesics Dynorphins – k>mu or delta receptors-A& B dyn Endomorphins –mu R-End 1 &2 Nociceptin /OFQ –NOP rec-biphasic hyperalgesic -analgesic response-reward&reinforcement

Opioid Receptors:

Opioid Receptors Mainly 4 receptors – μ (mu), κ (kappa) and δ (delta) ,N/OFQ MOP,KOP,DOP,NOP Subtypes: μ1, μ2, κ1, κ2, κ3, δ1 and δ2 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 receptors Morphine is agonist of all but affinity is higher for mu PERIPHERAL OPIOID RECEPTORS- endogenous opioid peptides released from immunocytes-knee surgery analgesia

Effects of Different Opioid Receptor Stimulation::

Location E ff e cts t y p e) δ receptor Spinal s u p r a s p i n al Spinal analgesia Affective behaviour (S u p r a s pi n al ) R e s pir a t o r y depression Reduced GI motility Agonists μ receptor μ1 – supraspinal μ2 - spinal Analgesia R e s pi r at o r y depression - μ2 S e d at ion Euphoria Miosis Physical de pendence Constipation- μ2 Morphine,Fentanyl and pentazocine weakly κ receptor κ1 – spinal κ3 -supraspinal Spinal analgesia Dysphoria Sedation Psychomimetic Physical d e p e n d e n c e (nalorphine Pentazocine Effects of Different Opioid Receptor Stimulation:

Opium - History:

Opium - History Friedrich Wilhelm Serturner A German Pharmacist Isolated Morphine in 1803 and named it after the Greek god of Dreams “MORPHEUS”

Classification-:

Classification- 1. Agonists Natural opium alkaloids Morphine, codeine Synthetic opioids Pethidine, methadone, oxycodone,oxymorphone , fentanyl, diphenoxylate, loperamide, dextropropoxyphene, tramadol, tapentadol 2. Mixed agonist- antagonists Pentazocine, nalbuphine,butorphanol , buprenorphine, nalorphine 3. Antagonists Naloxone, naltrexone, nalmephene , naloxegol

classification:

classification can also be classified depending on their source as: 1. Natural opium alkaloids: Morphine, codeine, noscapine 2. Semisynthetic derivatives: Heroin, oxymorphone, pholcodeine 3. Synthetic opioids: Pethidine, methadone, fentanyl, oxycodone, oxymorphone, diphenoxylate loperamide, dextropropoxyphene, tramadol, tapentadol

MORPHINE (Pharmacological actions) - CNS:

MORPHINE (Pharmacological actions) - CNS Analgesia: Strong analgesic Visceral pain is relieved better than somatic pain Degree of analgesia increases with dose Nociceptive pain is better relieved than Neuretic pain Associated reactions to pain are also relieved – apprehension, fear and autonomic effects , euphoria sedation contribute Perception & reaction both are altered Tolerance to pain is better

Slide16:

GPCRs-Gi 1)Decrease cAMP 2)K channel open 3)Ca channel close- decrease intracellular calcium Decrease NT release ( DA,glutamate,GABA,NA , 5HT,SubstanceP ( TRANSMIT PAIN IMPULSES ) 1)Direct inhibition of transmission in dorsal horn ascending pathway 2)Stimulate descending pain control pathway

MORPHINE – Analgesia action:

MORPHINE – Analgesia action 2 components – spinal and supraspinal Inhibits release of excitatory transmitters from primary afferents – at Substantia gelatinosa of dorsal horn Exerted through Interneurones – gating of pain At supraspinal level in cortex, midbrain and medulla - alter processing and interpretation and send inhibitory impulses through descending p a thway

Morphine -The Gate Theory:

Morphine - The Gate Theory Excitatory connection Met -ENK

Pharmacological actions:

Pharmacological actions 2. EUPHORIA(mu1),SEDATION&HYPNOSIS Distressed>chronic dull pain- Pain is there but dsnt hurt Affective>sensory Dysphoria(k)

Pharmacological actions of Morphine (CNS) – contd.:

Pharmacological actions of Morphine (CNS) – contd. Depression: Respiratory centre ( mu ) depression – Both rate and depth diminished Indifference to breathing Dangerous in Head injury and asthmatics Cough Centre – Depressed Temperature regulating centre – depressed Vasomotor centre – high doses cause fall in BP Stimulation: CTZ – sensitize CTZ to vestibular and other impulses Edinger Westphal Nucleus – miosis - mu,k -pin point pupil-central actn -D/D Vagal centre – Bradycardia Hippocampal cells – convulsions ( - of GABA release)

Pharmacological actions of Morphine – contd- .peripheral actions:

Pharmacological actions of Morphine – contd - . peripheral actions CVS: NO DIRECT EFFECT ON HEART HYPOTENSION Peripheral Vasodilatation – histamine release, depression of vasomotor centre - not much Inhibition of baroreceptor reflex Cardiac work reduction due to consistent vasodilatation Increased pco2-cerebral vasodilatation-raised ICP

Pharmacological actions of Morphine – contd.:

Pharmacological actions of Morphine – contd. GIT: CONSTIPATION (mu2)- tolerance never develops Stomach –decreased gastric motility Due to direct action on intestine reducing propulsive movement, spasm of sphincters, decrease in all GIT secretions Sphincters –tone increased Inattention to defaecation reflex Smooth Muscles: Billiary Tract: Biliary colic – spasm of sph. Of Oddi Bladder: Urinary urgency but difficulty Bronchi - Bronchospasm

Slide26:

Renal function- decrease RBF- depress renal function-antidiuretic effect Neuroendocrine effects-inhibit release of GnRH,CRF -decrease FSH,LH ACTH &beta endorphins- tolerance &reversible Pruritis- Tolerance-RASE-Depressant effects Not to constipation &miosis Cross tolerance Dependence-physical>psychological-withdrawal-symptoms opposite to pharmacological actions except emesis

DEPENDENCE:

DEPENDENCE Withdrawal symptoms-opposite to pharmacological actions Psychological dependence<physical dependence – Reward system activation Going Cold turkey – Noradrenergic storm t/t-1) SUBSTITUTION THERAPY METHADONE- Dose-1mg methadone for every 4mg of Morphine longer acting, no kick Orally affective Cross tolerance Tapered LAAM - levo alfa acetyl methadol -alt day dosing-prolongs QT Buprenorhine

DEPENDENCE T/T:

DEPENDENCE T/T 2) OPIOID ANTAGONIST USE In detoxified patient- atleast 10 days Naltrexone 150 mg thrice weekly or depot inj. 3) CLONIDINE/LOFEXIDINE- Central sympatholytic Decrease NA outflow Reduces severity of withdrawal effects 4) REHABILITATION- COUNSELLING Educate-prevent HIV inf, hepatitis,endocarditis

Morphine - Pharmacokinetics:

Morphine - P h a r ma c o k i n e t i cs Absorption and Distribution: Variable orally (usually not given orally – 1 st pass metabolism, given IM or IV) - controlled release oral tablet-chronic cancer pain Widely distributed – liver, spleen, kidney etc. Enters Brain slowly Readily crosses placental barrier – dependence in fetus Metabolism : In Liver by glucoronidation – water soluble metabolites Morphine-6- Glucoronide – analgesic – in renal failure prolong analgesia Excretion: Via Urine, Plasma t 1/2 = 2-3 Hrs Action lasts for 4-6 Hrs Completely eliminated in 24 Hrs Preparation: 10, 15, and 20 mg. (IV: 2 – 10 mg)

Morphine - Pharmacokinetics:

Morphine - P h a r ma c o k i n e t i cs

MORPHINE:

MORPHINE

Morphine – Adverse Effects:

Morphine – Adverse Effects Respiratory Depression : Infant and Old Vomiting Sedation, Mental Clouding – sometimes dysphoria Hypotensive effect Rise in Intracranial Pressure Apnoea: Newborn Urinary retention Idiosyncrasy and allergy Acute Morphine Poisoning : Tolerance –pharmacodynamic mainly D ependence -psychological and physical-acute withdrawal- ‘ Cold turkey’

Slide33:

WITHDRAWAL IN NEWBORN- Treatment- Tincture opium0.2 ml/kg/3-4 hours started at birth and withdrawn gradually

SPEEDBALl:

SPEEDBALl Heroine +cocaine

Morphine – Therapeutic uses:

Morphine – Therapeutic uses An algesic: Moderate to severe visceral pain- MI,renal colic,traumatic,post op pain,cancer pain CR Morphine,oxycodone -oral Parenteral route for severe pain Patches-fentanyl Buccal transmucosal patch Nasal Intra articular-peripheral analgesia PCA

Morphine – Other Therapeutic uses:

Morphine – Other Therapeutic uses 2) Preanaesthetic Medication – pethidine,fentanyl (CABG) Balanced anaesthesia and surgical analgesia Intrathecal/epidural –no resp dep 3) Acute Left ventricular failure – Reduce anxiety, preload,afterload 4) Cough – Codeine 5) D ia r rh o ea – c o l o sto my - Lo p e r amid e, Diphenoxylate

Slide39:

occurs if >50 mg (Lethal dose –250 mg), Gastric lavage with KMNO4, Specific antidote: Naloxone: 0.4 to 0.8 mg IV repeatedly in 2-3 minutes till respiration picks up

-Contraindications:

- Contraindications 5H 3Bs H ypotension H epatic damage H ypertrophy of prostate H ead injury H ypothyroidism B ronchial asthma B iliary colic B abies

Pethidine/meperidine:

Pethidine /meperidine Morphine Vs Pethidine: 1/10th as potent as Morphine, but Efficacy is similar Produces as much sedation, euphoria and respiratory depression in equianalgesic dose and similar abuse potential less miosis, constipation and urinary retention Rapid but short duration of action (2-3 Hrs) Vagolytic effect - Tachycardia Less histamine release – safer in asthmatics Doctor’s choice Escape detection

Pethidine – contd.:

Pethidine – contd. P harmacokinetics Effects appear in 10-15 min. after oral absorption Metabolized in liver – mepiridinic acid and norpethidine Norpethidine accumulates on chronic u se

Pethidine – contd.:

Pethidine – contd . Adverse Effects: Similar to Morphine Atropine like effects – dry mouth, blurred vision, tachycardia Overdose – tremors, mydriasis, delirium and convulsion due to norpethidine accumulation Uses: Analgesic as substitute of Morphine Preanaesthetic medication Post anesthetic shivering Dose 50-100 mg IM/SC

Slide44:

Dangerous opioid from India-tramadol Fentanyl is at the center of the opioid crisis in the United States . It is used as a direct substitute for heroin, but it is 50 times more powerful than heroin. Fentanyl is a synthetic opioid, meaning it requires precursor chemicals to manufacture, and it is prescribed as a pain medication. In the past two years, however, illicit manufacturing and importing of fentanyl has skyrocketed. The death rate from synthetic drug use reflects this trend

Tramadol:

T r am a dol Other mechanisms involved in analgesic action – 5-HT and NA reuptake inhibition – spinal inhibition of pain Effective both orally and IV (100mg = 10 mg Morphine) Only Partially reversed by Naloxone Used in chronic neuropathic pain ,chronic neuropathic pain Dose: 50-100 mg IM/IV/Oral (Contramol)

Pentazocine:

Pentazocine Mixed agonist-antagonist Weak mu- receptor antagonist, but agonist of κ-receptor One of the commonly used agents, given orally and IM Low abuse liability -dysphoric Pharmacokinetics: High 1 st pass metabolism but effective orally Dose: orally 50-100 mg and parenterally 30-60 mg IM Uses : Moderately severe pain in Injury, Burns, Fracture Trauma, Cancer and Orthopaedic manuevers (Fortwin, Fortagesic ) C/I –MI, epilepsy , psychosis head injury

Effects of Opioid Receptor Stimulation:

Effects of Opioid Receptor Stimulation

OTHER MIXED AG ANTAGONISTS&PARTIAL AG:

OTHER MIXED AG ANTAGONISTS&PARTIAL AG Nalbuphine - mu antag,k partial ag -obstetric analgesia Butorpahanol -mu partial ag,k strong ag- Buprenorphine- mu ag,k antag NOP ag-30 times potent than morhine,resp dep >-not reversed fast by Naloxone, used for opioid withdrawalLong lasting painful conditions – cancer Postoperative pain Myocardial infarction

Opioid Antagonists:

Opioid Antagonists Pure antagonists: Naloxone, Naltrexone and Nalmefene Affinity for all receptors (μ, δ and κ) No action on Normal person reverses poisoning and withdrawal symptoms in addicts

Naloxone:

Naloxone Competitive antagonist of all types of opioid receptors blocks μ-receptors at much lower dose Always injected IV (0.4 t0 0.8 mg) - All symptoms of Morphine action are antagonized – respiratory stimulation At higher doses 4-10 mg: antagonizes actions of Nalorphine and Pentazocine – dysmorphic and psychomimetic effects are not suppressed (δ) Withdrawal symptoms: 0.4 mg doses – Morphine and 4-5 mg doses –

Naloxone – contd.:

Naloxone – contd. Buprenorphine actions are prevented but not reversed fully – tight bond with receptors Also acts on endogenous opioids Antagonizes respiratory depression of Diazepam and N 2 O Uses: Acute Morphine Poisoning (0.4 – 0.8 mg IV 2-3 min, maximum 10 mg. New Born – opioid poisoning Reverse respiratory depression intraoperatively Differential Diagnosis

Slide52:

Nalmefene - Onset of action-within 2 min Longer DOA-10 hrs Use- Opioid overdose Cholestatic pruritis Naltrexone- Opioid dependence after detoxification Decrease craving in alcoholics Alvimopan - peripheral mu rec blockade relieve constipation in addicts & post op paralytic ileus

Slide53:

Antitussives- Dextromethorphan,noscapine Antidiarrhoeals - mu rec in gut Diphenoxylate,loperamide

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