opioids & nonopioids

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Pharmacology of opioids and NSAIDS


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ANALGESICS Pain- Unpleasant sensory & emotional experience described in terms of tissue damage pain: nociceptive , as sensation & as suffering Pain pathway modulators Substance-p, neurokinins , opioid peptides and descending pain inhibitory pathway Opioid receptors Attack causative mechanisms

Pain receptors:

Pain receptors Mechanoheat receptors- respond to high intensity stimuli, produce sharp, rapid localized pain- myelinated A delta fibers Polymodal receptors: respond to mechanical /thermal/chemical insults/cytokines, produce dull, aching, poorly localized pain with slower onset, un-myelinated-C fibers

Clinical types:

Clinical types Acute – associated with trauma/disease, accompanied by tachycardia, hypertension, sweating, mydriasis Chronic: experience with physical, psychological social deterioration- contributes for exacerbation of pain Nociceptive: somatic/visceral Neuropathic: dysfunction of peripheral nerves/ receptors in CNS ,difficult to treat

Classification :

Classification 1.Opioids : narcotics – legal word A. natural opioids : morphine codeine B. semisynthetic : heroin, pentazocine C. synthetic : pethidine, methadone, sufentanil, tramadol, dextropropoxyphene fentanyl, buprenorphine, Non opioids- NSAIDS

Opioid peptides:

Opioid peptides Enkephalins, endorphins & dynorphins Each has characteristic distribution Synthetic: Morphiceptin Related : Nociceptin & Orphanin N/OFQ: behavioral & pain modulating role Leu-enkephalin, met-enkephalin Beta endorphin ligand for opioid receptors

Natural opioids:

Natural opioids Papaver somniferum- extract Opium Opiates -naturally occurring Opium - brownish extract from unripe seed capsule Opium alkaloids : Phenanthrene type- morphine, codeine, thebaine others: noscopine, papaverine


Opioids Effective Easily titrated Have favorable benefit risk ratio Alter pain perceptive mechanisms Suitable for excruciating, severe, emergency painful conditions Parenteral- s. c., im. Iv, transdermal, sublingual, oral, rectal & intraspinal

Opioid receptors:

Opioid receptors MU; supra spinal analgesia,euphoria, RSPd constipation, sedation, dependence Kappa : spinal analgesia, sedation, miosis Delta : dysphoria, hallucination, spinal analgesia N/OFQ : now NOP –nociceptin & nocistatin –agonist & antagonist

Opioid drugs:

Opioid drugs MU agonists- morphine, meperidine, spiradoline, etorphine, sufentanil Partial MU- buprenorphine Kappa agonists-nalbuphine, butorphanol MU antagonist & kappa agonist-pentazocine (mu. partial agonist) Fentanyl- Mu+++, K. delta

Mechanism of action:

Mechanism of action Act at one /more opioid receptors-open K+ channel, inhibit adenyl -cyclase & n-type Ca++ channels Substance-p release & action inhibited Augment descending pain inhibitory pathway Induce changes in mood-rewarding-nucleus accumbens

Descending pain inhibitory path:

Descending pain inhibitory path cortex (N/OFQmRNA peptides) TMS Peri-aqueductal Grey Matter HPS (MU-receptors) NRPG Nucleus Raphe Magnus LC Dorsal horn cells


Morphine Analgesia, relief of distress Affect mood & rewarding behavior Alter RSP,CVS,GIT & neuro-endocrine systems Crucial effect on locus ceruleus to affect feelings of alarm, panic, fear & anxiety Truncal rigidity during anesthesia Miosis, emesis, bradycardia & spasmogenic

Morphine contd..:

Morphine contd.. Tolerance & dependence Not predictors of addiction NMDA receptors antagonists block tolerance to Mu agonist opioids Morphine-6 glucuronide- active & potent Cause histamine release- fentanyl X s.c, i.m. i.v., rectal, sublingual, t1/2 2hrs epidural, PO-first pass metabolism

Adverse reactions:

Adverse reactions Side effects: vomiting, urinary retention, RSP depression, truncal-rigidity, hypotension constipation Acute poisoning: pin point pupil. RSP, hypoxia, relaxed Jaw, Non-cardiogenic pulmonary edema, convulsions, 30-120mg Treatment: naltrexone

Contraindications :

Contraindications Children & elderly Head injury Bronchial asthma Pregnancy Undiagnosed acute abdomen Hepatic failure secondary to lung disease cyanosis

Meperdine & Methadone:

Meperdine & Methadone Action on CNS & GIT Not for chronic use Orally effective Rapid onset Short acting Less spasmogenic CNS excitation Post-anesthetic chill Less RSP depression in neonate Oral opioid Long acting Suppress withdrawal symptoms Cough suppressant T1/2 15-40 hrs Binds to brain proteins Tolerance develop slowly-partial Not for labor

Codeine & Tramadol:

Codeine & Tramadol Less effective-60% High-oral-to parenteral potency Converted into morphine CYP2D6 Chinese x caucasians With NSAIDS Cough suppressant Addictive constipation Synthetic codeine analogue Inhibit NE & 5HT uptake Mild to moderate & labor pain Oral & t1/2 6 hrs Constipation & RSP depression less Seizures with naloxone

Clinical summary – 0pioids:

Clinical summary – 0pioids Underlying disease remains Physical dependence-frequency of administration Judicious use for chronic pain Too small dose; infrequent use both should be curbed Terminal illness & cancer pain Cross tolerance Patient control analgesia

Opioid antagonists:

Opioid antagonists Naloxone, naltrexone & nalmefene Im iv. 1mg x 25mg of heroin High oral efficacy & longer acting Antidote for acute opioid poisoning Treatment of opioid addict Shock ,stroke, spinal cord & brain trauma Alcoholism


NSAIDS-classification Salicylates : diflunisal Indole : indomethacin , sulindac , etodolac Propionic acid derivatives : IBu,keto , flurbiprofen Phenylacetic acid : diclofenac , aceclofenac fenmates : Mefanamic acid, flufenamic acid Oxicam : piroxicam , tenoxicam Pyrrole : tolmetin , ketorolac Selective COX2 : nimesulide . Valdecoxib , etoricoxib , rofecoxib , lumiracoxib paracetamol & DMARDS

Prostaglandin synthesis :

Prostaglandin synthesis





NSAIDS(non-opioid analgesics):

NSAIDS(non-opioid analgesics) Anti- inflammatory mechanisms include : PG synthesis inhibition Inhibit chemotaxis- reduce IL-2 production Bradykinin antagonism scavenge free radicals Reverse vasodilation, increase apoptosis Reduce pro-inflammatory cytokines Liberate corticosteroids

NSAIDs as antipyretics:

NSAIDs as antipyretics Block the action of endogenous pyrogens-IL1beta, IL-6, TNFs, PGE2 Promote heat dissipation Reset the ‘thermodynamic’ center Reduce elevated body temperature Brain COX-3 inhibition


Aspirin….dynamics RSP: hyperventilation, alkalosis, acidosis GIT: irritant, increase acid secretion-ulcer hemorrhage, microcytic, hypochromic anemia Platelet : no TXA2 production Kidney : interstitial nephritis Blood : hypo- prothrombinemia Pregnancy : premature closure of ductus arteriosus

Metabolic effects of aspirin:

Metabolic effects of aspirin Metabolic acidosis Hypoglycemia- hyperglycemia Negative nitrogen balance Enhanced oxidation of FFA Stimulate steroid secretion Uricosuric at high doses


Aspirin…kinetics Acidic pH rapid absorption-disintegration & dissolution rates 90% bound, t1/2 20mts, crosses placenta Mitochondrial & hepatic pathway Glycine, glucuronide conjugation, oxidized-gentisic acid


ASPIRIN Anti-rheumatic-acute rheumatic fever Chemoprophylaxis of colonic cancer Cardio-protective Headache Kawasaki disease (muco-cutaneous lymph node syndrome) with immuno-globulins Cataract ? Interfere with thyroid function tests

Aspirin -ADR:

Aspirin -ADR CNS: headache, vertigo, tinnitus Gastric mucosa erosion, ulceration, hematemesis & malaena Hypersensitivty -rhinitis/asthma-history of atopy/nasal polyps-’aspirin triad’ Reye’s syndrome -acute encephalopathy & fatty liver-influenza, chikenpox Salicylism: tinnitus, vomiting , confusion Nephrtoxicity ; haematuria, interstitial nephritis

Aspirin interactions:

Aspirin interactions Blunt anti-HBP action of ACEI, diuretics, beta blockers, + dipyridamole & CCBs anti-platelet action augmented + probenecid - antagonism + mifepristone decreases efficacy + steroids, alcohol-increased GIT effects

Ibuprofen :

Ibuprofen Better tolerated than aspirin/indomethacin Rapid absorption t1/2 2hrs. Thrombocytopenia 5-15% GIT toxicity Rash Fatal asthmatic attack Dental pain, topical gel / spray

Diclofenac :

Diclofenac Widely used more potent COX-2 (-) Accumulates in synovial fluid + misoprostol, suppository PO, IM GIT 20% 2% discontinue Increase hepatic transaminase Not for children, pregnant & nursing mother Chronic therapy prone for CVS hazards

Piroxicam :

Piroxicam Long acting t1/2 50hrs. Slow acting (-) activation of neutrophils, collagenase , proteoglycanase CYP2c PO. PR, topical 99% bound Used in Rheumatoid arthritis, osteoarthritis

Indomethacin :

Indomethacin Non selective COX-(-) poorly tolerated Distinct analgesic both central & peripheral PO, PR, excellent oral –F, t1/2 2hrs. For closure of patent ductus arteriosus Acute gout, ankolysing spondylitis GIT, ADR 50%. 20% discontinue +furosemide & thiazides antagonism


Paracetamol Acetaminophen; COX3 -antipyretic Non inflammatory pain Low GIT effects Peroxidases rich inflammatory sites no PG synthesis inhibition Toxic metaboliteN-ac-p-’benzoquinoneimine’- glutathione depleter- hepatotoxicity Methionine & N-acetylcysteine

COX2 inhibitors:

COX2 inhibitors REDUCED GASTROTOXICITY Efficacy Advantage? IMPAIR RENAL FUNCTIONS CARDIOTOXICITY ?- patient underlying risk profile & dose, duration, frequency HEPATOTOXICITY! PROTHROMBOTIC


DMARDS Methotrexate Hydroxy chloroquine D-penicillamine Leflunamide -immunomodulator, t 1/2 14d, Gold salts- high toxicity; G. nephritis Azathioprine, cyclosporine, sulfasalazine Anti-TNF-alpha antagonists IL-1 receptor antagonist : Anakinra

NSAIDS as anti-rheumatic agents:

NSAIDS as anti-rheumatic agents Acute rheumatic fever- tolmetin, naproxen Rheumatic carditis – steriods + NSAIDS Rheumatoid arthritis: +DMARDS Ankylosing spondylitis; indomethacin Osteoarthritis: tolmetin diclofenac

Leflunomide :

Leflunomide Immunosuppressant & anti-proliferative (-) dihydro- orotate dehydrogenase to block purine synthesis PO. First pass t 1/2 2weeks teriflunomide active Hypertension, reduced BW, leucopenia, hypersensitivity, acute hepatic necrosis

Anti gout drugs:

Anti gout drugs NSAIDS; indomethacin Uricosurics : Probenecid, sulphinpyrazone,benzbromarone UA synthesis inhibitors : allopurinol-not for acute attack: febuxostat Coticosteroids : for acute attacks Alkalization of urine –xanthine stone +6MP, Azathioprine, increase toxicity

Pain management:

Pain management Analgesic ladder Step-1—non opioid + adjuvant agent Step-2 pain uncontrolled by step one method-short acting opioid + NSAID +adjuvant Step -3 severe pain- long acting opioid+ NSAID+ adjuvant- sustained release/ transdermal

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