OPIOID ANALGESICS (ANALGESICS – ANODYNES) Department of Pharmacology MU Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slides is against the law. Adobe Systems Pain nDefinition: „subjective unpleasant sensory or emotional experience accompanied by real or potential damage of tissues, with motoric and vegetative responses “ Adobe Systems A) by duration B) according to pathophysiology Pain – types and classification [USEMAP] Adobe Systems A) According to length of experience 1) acute: sign of and disease, danger or damage to organism... 2) chronic: more than 3 months / unusually long for a given disease or disorder Pain – types and classification [USEMAP] Adobe Systems A) According to length of experience 1) acute: physiological sensory perception, -tissue damage, -mobilizes defensive forces of the organism in order to remove the inducing cause of the pain 2) chronic: pathological, pain may persists even after the removal of the causes → difficult to determine whether the pain arose as a result of persistent pathological activity in the nerve endings in the periphery, or is the source of the CNS Pain – types and classification [USEMAP] Adobe Systems B) According to pathophysiology 1) nociceptive – irritation of nociceptors Therapy: „analgesic ladder“ according WHO (see below; not used for aggressive procedure in the treatment for cancer or breakthrough pain) 2) neurological and neuropathic pain Therapy: antidepressants and anticonvulsants (in combination with opioids or some muscule relaxants; neuroprotective vitamins – thiamine; antimigraine drugs from the group of the so-called triptans; antipsychotics = neuroleptics) Pain – types and classification Adobe Systems B) According to pathophysiology 3) psychogenic pain somatization, hypochondric and somatoform disorder Therapy: psychopharmac drugs (antidepressants – TCA, SSRI, anxiolytics, antipsychotics) Pain – types and classification Adobe Systems nneuralgia sharp, paroxysmal pain, affects peripheral or cranial nerves (often the trigeminus, facialis) → after traumatological damage, compression, viral infects (herpetic), metabolic (DM) npain in the chronic compression of peripheral nerves and nerve roots hernia of the intervertebral discs, compression of the nerve in the spinal cord → pain + paresthesia, pain acquires a hot character Special types of pain [USEMAP] Adobe Systems nischemic pain due to disorders of blood circulation in the myocardium, smooth or skeletal muscle nmigraine migraine is characterized by attacks of pulsating, mostly unilateral headache lasting typically 4-72 hours with nausea, possible vomiting, photofobia and phonofobia, suffering from 12% of the adult population Special types of pain [USEMAP] Adobe Systems nphantom pain surgically or traumatically removed parts of the human body, most commonly the lower limb or other parts of the body (ablation of the breast, as well as after the removal of the visceral organs - the colon); apply pathophysiological influences peripheral, central and psychogenic; nbreakthrough pain sudden, transient, mostly short-term worsening of pain in patients who have well-controlled baseline pain; usually in patients treated with opioids for cancer diagnosis; typically in progression of cancer Special types of pain Adobe Systems ndelivery pain - belongs to the strongest pain reliever, nevertheless, that before the birth are rising thresholds for somatic and visceral pain - the tissue is developed by excessive pressure, they are strongly being pushed and lacerations occur - tissues are under influence of bradykinin, H+, K+, histamine and serotonin - induction of stress → ↑ cortisol, epinephrine, norepinephrine, dopamine → somatic and psychological reactions Special types of pain Adobe Systems ONCOLOGICAL PAIN SOMATIC MANIFESTATIONS sharp or dull pain Inflammatory response colic pain neuralgia EMOTIONAL MANIFESTATIONS anxiety depression SOCIO-ECONOMIC IMPACT personality changes care of the security of the family the breakdown of the family loss of friends EXISTENTIAL CONCERNS concerns about the course of the disease general uncertainty the fear of death [USEMAP] Adobe Systems VAS: Visual analogue scale Diagnostics of Pain NO PAIN THE WORST PAIN YOU CAN IMAGINE [USEMAP] Adobe Systems Process of pain perception algognostic component algothymic component [USEMAP] Adobe Systems Pain – causes and mechanism Mediators of pain (act on the nociceptors = pain receptors) „algogenic substances“ bradykinin + ↑PGE (mediators of inflammation), increase sensitivity of nociceptors histamine acetylcholine substance P (pain) tissue damage  production of prostaglandines and other substances  effects on the free nerve endings  transduction of signal up to the brain neurons  PAIN [USEMAP] Adobe Systems Endogenous pain suppressing (analgesic) substances: endorphins enkephalins dynorphins Pain – causes and mechanism [USEMAP] Adobe Systems Pain transduction – 3 neuron`s tract tractus spinothalamicus (spinothalamic tract) vs. tractus spinoreticulothalamicus (spinoreticulothalamic tract) MAIN PAIN PATHWAYS the tracks leading from the spinal cord (spinal ganglia) to specific areas of the brain (finally to the cerebral cortex) information about pain is received and processed Adobe Systems Pain transduction – 3 neuron`s tract → spinothalamic tract – 3 neuron`s phylogenetically younger pathway – sharp, well localized pain → spinoretikulothalamic tract – phylogenetically older polysynaptic system, impulses are transmitted to the higher centres through short axonal pathways – dull, poorly localized pain nvegetative response: blood pressure change, tachypnea, mydriasis, diaphoresis, increased muscle tone,... [USEMAP] Adobe Systems Analgesics – anodynes (opioids) Non-opioid analgesics (analgesics – antipyretics  NSAIDs) Local anaesthetics General anaesthetics Adjuvant therapy (antidepressants, neuroleptics - antipsychotics, antiepileptics - anticonvulsants, antimigrenics, central/peripheral myorelaxants, corticoids, bisphosphonates, caffeine…) Pharmacological modulation of pain Adobe Systems analgesics – anodynes (opioids) Analgesics – suppress perception of pain (increase the pain threshold) selectively without influencing perception of other stimuli non-opioid analgesics act on spinal and supraspinal level, cause effects on somatic and visceral pain, strong effects on consciousness, act substantially more strongly than non-opioid analgesics mostly peripheral effects (some have central effects!), effects on inflammation, weaker effects in general, no effects on visceral pain, no addiction Pharmacological modulation of pain [USEMAP] Adobe Systems Analgesics - anodynes Opiates substances similar structurally to morphine with analgesic effect (natural origin, currently produced synthetically) Opioids + synthetic, semisynthetic and endogenous opioid peptides + exogenous opioid analgesics blocking transmission of pain signals between cells of the CNS (in the spinal cord, brain), as well as endogenous opioids: endorphins, enkephalins, dynorphins → binding to opioid receptors (agonists) Adobe Systems Opioid receptors - μ κ δ (σ) • G-protein coupled •the interaction of the opioid with receptor → G- protein inhibition → reduction of neurotransmitter release + inhibition of neuronal activity •adenylylcyclase inhibition, facilitation of K+ channels opening postsynaptically, inhibition of Ca2+ channels opening presynaptically n µ n κ n δ n(σ) [USEMAP] Adobe Systems nμ – supraspinal analgesia, euphoria, sedation, miosis, breath depression, addiction, GIT effects nκ – spinal + peripheral analgesia, sedation, dysphoria, miosis, GIT effects, (somatic addiction) nδ – spinal analgesia, breath depression, inhibition of GIT motility n[σ] – dysphoric effect, psychotomimetic effect [(hallucinations, perception disturbances), anxiety] Opioid receptors - μ κ δ (σ) [USEMAP] Adobe Systems Opioid receptors - μ κ δ (σ) FOR ANALGESIC EFFECT IS CRUCIAL ESPECIALLY ACTIVATION OF RECEPTORS: μ – supraspinal analgesia κ – spinal + peripheral analgesia [USEMAP] Adobe Systems Opioid receptors - μ κ δ (σ) FOR ANALGESIC EFFECT IS CRUCIAL ESPECIALLY ACTIVATION OF RECEPTORS: FOR ADDICTION IS CRUCIAL ESPECIALLY ACTIVATION OF RECEPTORS: μ – supraspinal analgesia, euphoria κ – spinal + peripheral analgesia [USEMAP] Adobe Systems Pharmacological influence on opioid receptors Atypical opioids agonists (strongly effective, moderate/weakly effective) partial agonists – dualists mixed agonists - antagonists antagonists [USEMAP] Adobe Systems Pharmacological effects of analgesics - anodynes CENTRAL: analgesic suppression of respiratory center sedation (+-) suppression of anxiety euphoria/dysphoria antitussive effect nausea and vomiting  tendency to convulsions/cramps miosis secretion of ADH,  GnRH, corticotropine, FSH, LH, ACTH, cortisol, testosterone) [USEMAP] Adobe Systems TOLERANCE !!! (to all effects of opioids except constipation and miosis!) ADDICTION !!! Pharmacological effects of analgesics - anodynes [USEMAP] Adobe Systems PERIPHERAL: •decrease intestinal motility, slowdown propulsion of GIT content •increase muscle tone of GIT and urinary bladder •increase sphincter tone of gall bladder and urinary bladder •constriction of pyloric sphincter, delayed gastric emptying •vasodilation, orthostatic hypotension •histaminoliberation •inhibition of ciliated epithelium • Pharmacological effects of analgesics - anodynes [USEMAP] Adobe Systems PERIPHERAL: •urological tract – increase tone of renal pelvis, ureter, m. detrusor and sphincter of bladder…urine retention, especially in post-operative conditions •uterus - ↓ tone and motility, may prolong labor Pharmacological effects of analgesics - anodynes Adobe Systems ABSORPTION DISTRIBUTION parenteral oral („first pass effect“ !!!) perrectal transdermal sublingual transmucous (nasal) parenchymatous organs muscles adipose tissue (lipophilic drugs ➙ e.g. fentanyl) pass well across BBB ➙ brain (fentanyl, heroin,..) Can cross placental barrier !!! Pharmacokinetics of analgesics - anodynes [USEMAP] Adobe Systems BIOTRANSFORMATION EXCRETION primarily in liver polar metabolites • inactive metabolites • active metabolites (codeine, tramadol, morphine…) • kidneys - urine • liver - bile Pharmacokinetics of analgesics - anodynes [USEMAP] Adobe Systems Opioid agonists morphine • 10 % of opium content, together with codeine, thebaine + other phenanthrene alkaloids • isolated in 1803 (Sertürner) • high affinity to µ receptors – selective µ agonism [USEMAP] Adobe Systems morphine Ø see above effects Ø application routes: Ø orally (also p.o. with sustained release) Ø parenterally (i.v., i.m., s.c., epidural,… ) Ø perrectally Indications: chronic cancer pain, pain after surgery, injuries, (pain during acute myocardial infarction → today, given preference to other opioids) Opioid agonists [USEMAP] Adobe Systems Other strong opioid analgesics methadone • less sedation and euphoria than in morphine • ↑ bioavailibility after oral administration, ↑t ½ • acts on opioid + NMDA receptors • Use: addiction treatment (heroin) ➙ 2 benefits ➙ change from injection application to oral administration ➙ ↑t ½ decreases plasmatic fluctuation of methadone ➙ less withdrawal symptoms [USEMAP] Adobe Systems Other strong opioid analgesics heroin (= diacetylmorphine) • not used in clinical medicine (in Czech Republic) (but in Great Britain can be therapeutically used!) • causes severe addiction; abused! • heroin belongs to the most health and personality devastating substance!!! [USEMAP] Adobe Systems fentanyl, sufentanil, remifentanil,… • pass well across HEB (↑ concentrations in CNS) • strong, short analgesia (fentanyl 100 x more potent than morphine, sufentanil 1000 x more potent than morphine) • strong respiratory depression!, ↓ emetogenic potency, CAVE ➙ can cause muscle rigidity • risk of serotonin syndrome in combination with 5-HTergic drugs Other strong opioid analgesics [USEMAP] Adobe Systems fentanyl, sufentanil, remifentanil,… • Indications, use: • in anaesthesiology ➙ neuroleptanalgesia (= neuroleptic (AP) + opioid) ➙ analgosedation (e.g. opioid + BZD) • therapy of strong pain – acute myocardial infarction, cancer pain,… • fentanyl in TTS (↑ duration of action – can be used in chronic cancer pain), transmucous (can be used in breakthrough pain) Other strong opioid analgesics [USEMAP] Adobe Systems piritramid • less respiratory depression than morphine • less emetogenic potency • usually well tolerated parenteral administration • Use: therapy of acute strong pain, e.g. after surgery (PCA), acute myocardial infarction, pain after injuries,… Others: oxycodone, hydromorfone (not registered in Czech Rep.), oxymorphone (not registered in Czech Rep.) CAVE: all strong opioids are prescribed to forms with blue band („opiate forms“), very strict accounted and subjected to the rules for handling with narcotics and psychotropic drugs and their precursors!!! Other strong opioid analgesics Adobe Systems Other strong opioid analgesics pethidine (=meperidine) •↓suppression of respiratory center than morphine •↓analgesic potency than morphine (5-10 x weaker) •metabolite norpethidine is proconvulsive and causes hallucinations •administration orally and parenterally Indications: cancer pain, pain after injuries, pain during acute myocardial infarction, pain after surgery, premedication before general anaesthesia…today not often used (high risk of abuse, hallucinations!) Adobe Systems codeine • 10 % mtb. to morphine • antitussive effect in subanalg. doses • analgesic effect in combinations (paracetamol, ASA) analgesic potency: codeine 50mg ~ ASA 1g • ↓ risk of addiction than strong opioids • CAVE ↑ risk of addiction of combined (compositive) analgesics • causes obstipation • not used in children!!! Opioid agonists (moderate and weak potent) [USEMAP] Adobe Systems dihydrocodeine • suitable in pains combined with cough (this co-incidency is not necessary for dihydrocodeine indication) • in Czech Rep. dihydrocodeine in sustained release drug form (effect 12 h) ➙ indication for chronic moderate and strong pain Side effects: obstipation, ↑liver tests, histaminoliberation Opioid agonists (moderate and weak potent) CAVE: codeine and dihydrocodeine are prescribed to normal forms - without blue band! Adobe Systems Partial agonists + mixed agonists - antagonists • lower affinity to μ receptors, high affinity to κ rec., • respectively κ-agonists - μ-antagonists or partial μ receptor agonists (buprenorphine) • less potential for addiction, but exists! • lower analgesic effect than full agonists • less side effects than full agonists [USEMAP] Adobe Systems buprenorphine • partial μ rcp. agonist • ↓tolerance in comparism with other opioids • ↓abuse potential, obstipation and other GIT effects •↑ „first pass effect“ ! Do not administer orally!!! • Use: 1) strong chronic pain (TTS!) 2) substitution therapy of opioid (heroin) addiction ➙ combined with opioid antagonist naloxone in one drug form (sublingual) ➙ in injection application naloxone antagonizes effects of buprenorphine (in sublingual administration naloxone does not act!) Partial agonists + mixed agonists - antagonists [USEMAP] Adobe Systems Partial agonists + mixed agonists – antagonists – other representatives •mixed agonists – antagonists •usually μ-antagonists and κ-agonists (event. also δ-agonists) •possibility of σ-receptor activation → psychotomimetic and hallucinogenic effects) •analgesic effects are weaker than full agonists •today minimal use •pentazocin, butorfanol – in Czech Rep. not registered Adobe Systems nalbuphine • for short-term therapy of moderate and strong pain • unsuitable for long-term therapy • parenteral administration (i.v., i.m., s.c.) • causes respiratory depression comparable to morphine, but suppression of respiratory center has drug ceiling effect • Use: perioperative pain, suppression of pain in obstetrics (BE AWARE: in newborns risk of breathing depression, bradycardia, cyanosis and hypotension → newborn`s monitoring necessary!) Partial agonists + mixed agonists – antagonists – other representatives [USEMAP] Adobe Systems Atypical opioids tramadol low affinity to μ receptors + norepinephrine and serotonin reuptake inhibition (= atypical mechanism of action, similar to some antidepressants from SSRI group; effect of tramadol can not be fully antagonized by opioid antagonists) • approximately 1/6 – 1/10 of morphine analgesic potency • very suitable combination with paracetamol • less side effects (minimal respiratory depression) • risk of serotonin syndrome • in Czech Rep. very often prescribed analgesic, prescription to normal forms without blue band; more drug forms • RISK OF ADDICTION!!! Use: therapy of moderate and strong pain (acute and chronic) [USEMAP] Adobe Systems tapentadol • dual mechanism of action - μ agonist + NRI (+ σ agonist) NEW GROUP – MOR-NRI (μ receptor agonism – noradrenaline reuptake inhibitor) • more effective than tramadol, analgesia comparable with oxycodone, but less adverse effects • suitable for the treatment of acute (but also chronic pain – e.g. vertebrogenic; also effective in diabetic neuropathy - neuropathic pain!!!) • relatively few adverse effects (compared to classical strong opioids, e.g. oxycodone) • p.o. administration (also tbl. with sustained release) Atypical opioids CAVE: tapentadol is prescribed to forms with blue band („opiate forms“), very strict accounted and subjected to the rules for handling with narcotics and psychotropic drugs and their precursors!!! [USEMAP] Adobe Systems Antagonists of opioid receptors naloxone, naltrexone Indications: treatment of opioid intoxication, treatment of respiratory depression induced by opioids, addiction diagnostics (withdrawal symptoms) TRIAD: coma, respiratory depression, miosis [USEMAP] Adobe Systems Opioid-induced side effects nrespiratory depression (suppression of breathing) nnausea and vomiting nsedation, inhibition of cognitive functions nconstipation (solution = oxycodone + naloxone) nADDICTION nbe carefull in pro-convulsive states! (e.g. epilepsy – proconvulsive action – decrease of the threshold for seizures) n intracranial pressure [USEMAP] Adobe Systems Intoxication by opioid agonists nausea, „flush“, tinnitus apathy, sedation, sleep, miosis superficial breathing cyanotic, cold skin, tachycardia asphyxia TRIAD: coma, respiratory depression, miosis Treatment: naloxone i.v. ventilation, vital functions, parenteral liquids in unconsciousness [USEMAP] Adobe Systems Withdrawal symptoms „craving“ („drogenhunger“), „craving“ for the another dose (psychic addiction arises easiest to heroin, oncology patients treated with opioids ➙ < 1% of patients) unrest, depression anxiety, weakness, nervousness, mydriasis lacrimation, ↑ nose secretion, frisson (goosebumps), ↑ perspiration, pain, stenocardia occur approximately after 3-4 weeks of opioid administration [USEMAP] Adobe Systems Rotation of opioids nSwitch in case of AE nSometimes even in equianalgesic dose increase of effect [USEMAP] Adobe Systems Other indications of opioids nantitussive effect ncan be induced by codeine and dextromethorphan in dry non- productive cough nconstipative effect ncan be induced by loperamide and diphenoxylate in functional diarrhea np r e m e d i c a t i o n before anaesthesia and surgery under general anaesthesia nleads to calm the patient and based on the synergism of drugs reduces the total dose of narcotics (thereby increasing the safety of anaesthesia) nparticularly fentanyl and its derivatives are used ncombination of opioid analgesic with neuroleptic (fentanyl + droperidol) within neuroleptanalgesia nr e p l a c e m e n t (substitution) therapy of addiction to heroin or other opioids – methadone, buprenorphine [USEMAP] Adobe Systems General rules of pain pharmacotherapy management nWHO's pain relief ladder ºStep 1 (VAS 0-4) nnon-opioid analgesics ± adjuvant treatment ºStep 2 (VAS 4-7) npain persists, intensifies, no change in the objective finding nweak/moderate opioid analgesics ± non-opioid analgesics ± adjuvant treatment ºStep 3 (VAS 7-10) npain persists, intensifies, there is no indication for another treatment nstrong opioid analgesics ± non-opioid analgesics ± adjuvant treatment ± weak/moderate opioid analgesics [USEMAP] Adobe Systems NSAIDs, Antipyretics Antigout drugs Department of Pharmacology MU Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slides is against the law. [USEMAP] Adobe Systems ̶Analgesics-antipyretics (A-A) drugs against fever and pain ̶ ̶Nonsteroidal antiinflammatory drugs (NSAIDs) - against inflammation, fever and pain A-A and NSAIDs overlap partially [USEMAP] Adobe Systems Mechanism of action ̶all of them have similar mechanism of action– inhibition of eicosanoids synthesis (with higher or lower selectivity and strength) ̶ ̶NSAIDs differ in the strength of COX1/COX2 inhibition and the incidence of typical AE (ulcer disease, bleeding) [USEMAP] Adobe Systems Cyclooxygenases •COX-1 – constitutive – prostanoids involved in physiological processes (gastroprotective effects, platelet activities) •COX-2 – inducible – activity enhanced by proinflammatory factors (IL-1, IL-2, TNF-a, oncogenes,..) –prostanoids à inflammation, fever, pain •COX-3 ? – central mechanism of analgesic and antipyretic effect (localization: heart + CNS) [USEMAP] úči Adobe Systems Classification by COX1/COX2 inhibition 1.Nonspecific inhibitors •ASA, ibuprofen, diclofenac, … • 2.Preferential inhibitors of COX-2 •meloxicam, nimesulid • 3.Specific inhibitors of COX-2 •coxibs ̶ [USEMAP] Adobe Systems mechanismus 3 Classification 1.Salicylic acid derivatives 2.Aniline derivatives 3.Propionic acid derivatives 4.Pyrazolones 5.Acetic acid derivatives 6.Oxicams 7.Coxibs 8.Other [USEMAP] Adobe Systems 1. Salicylates Effects: ̶analgesic ̶antiinflammatory ̶antipyretic ̶antirheumatic ̶antiaggregation à inhibition of platelet function [USEMAP] Adobe Systems NSAIDs: ̶ASA (acetylsalicylic acid) ̶sodium salicylate ̶cholinsalicylate Therapy of inflammatory bowel desease: ̶sulfasalazine à sulfapyridine + 5-aminosalicylic acid ̶mesalazine ̶ Salicylic acid derivatives – drugs [USEMAP] Adobe Systems Acetylsalicylic acid ̶efficiency standard of AA and NSAIDs ̶selective inhibitor of COX1 (100-200 : 1) ̶irreversible acetylation of COX-1 active centre ̶pharmacokinetics: ̶weak acid, complete and rapid absorption in stomach and proximal part of intestine ̶salicylic acid (SA) is product of metabolisation ̶T1/2 ASA 15-20 min, T1/2 SA 30 hrs depending to dose ̶80-95% binding to plasma proteins, elimination and exkretion via kidneys ̶higher doses – risk of cumulation in a body ̶ ̶ [USEMAP] Adobe Systems Usual dosages ̶ ̶antipyretic 500 mg ̶ ̶analgesic 500 mg (4 - 6 hrs) ̶ ̶anti-phlogistic, -rheumatic, -uratic 3,6 – 4 g/day ̶ ̶antiaggregative 30 –100 mg ̶ ̶total daily dose 4 g/day [USEMAP] Adobe Systems ASA – adverse effects ̶salicylism (d.) – hearing impairment, tinnitus, deafness, vertigo ̶allergy - itching, rash, anaphylaxis,… ̶aspirin-induced asthma - LT ̶GIT - nausea, dyspepsia, bleeding, ulcer disease ̶„analgetic“ nephropathy – reversible decrease of glomerular filtration ̶increased bleeding ̶ CAVE ̶pregnancy- differs in trimesters ̶children- Rey‘s syndrome ̶elders- more sensitive to AE [USEMAP] Adobe Systems ASA interactions ̶anticoagulants ̶NSAIDs and other analgesics (except of opioids) ̶other ̶valproate, sulfonylureas – competition on plasma proteins – increase of efficacy ̶SSRI – potentiate ASA antiaggregative effect (citalopram, fluoxetine) ̶glucocorticoids decrease ASA plasma levels, but increase the risk of GIT bleeding and ulceration [USEMAP] Adobe Systems ASA - contraindications ̶hemophilia and other diseases influencing blood coagulation ̶administration prior to surgery ̶gastroduodenal ulcers, gastritis ̶children to 12 years ̶Rey‘s syndrome (hyperpyrexia, acidosis, seizures, vomiting, psichiatric disorders, hepatopathy) ̶pregnancy (only temporary) ̶asthma, allergy, nasal polyps [USEMAP] Adobe Systems 2. Aniline derivatives Paracetamol (=acetaminophen) ̶analgesic, antipyretic, is not antiinflammatory active ̶does not influence blood coagulation or uric acid levels ̶mechanism of action is unclear: ̶central mechanism due to COX-3 inhibition ̶indirect effect on 5-HT3 spinal receptors ̶elevates PGG2 to PGH2conversion in peripheral tissues ̶influencing the endocannabinoid and vanillin system and Ca2+ channels ̶ [USEMAP] Adobe Systems Usual doses ̶comparable effect to ASA, but better tolerance ̶ ̶drug of choice to ¯ fever and pain in children younger than 12 years ̶ ̶pain in adults ̶300 to 500 mg every 3-4 hrs ̶650 mg every 4 to 6 hrs ̶1000 mg every 6 hrs ̶ ̶total daily dose up to 4 g [USEMAP] Adobe Systems Pharmacokinetics: •p.o. good absorbtion, maximum in 30-60 min, low plasma protein binding, hepatic metabolism •production of hepatotoxic mtb. – binding to gluthathione •overdose (10 – 15 g) à antidote N-acetylcysteine AE, CI: ̶allergy ̶hepatotoxicity after ↑ doses ̶comorbidities: ̶alcohol addiction ̶nephropathy ̶hepatopathy ̶ [USEMAP] Adobe Systems 3. Pyrazolones Propyphenazone ̶in combinations (with paracetamole and caffein) ̶AE: GIT intolerations, rash, bronchospasm, hematopoetic disorders ̶ Metamizole ̶analgetic, antipyretic + spasmolytics effect ̶combined with spasmolytics (pitofenone, fenpiverine) ̶AE: rare but serious - the most serious are agranulocytosis and pancytopenia ̶ ̶ [USEMAP] Adobe Systems 4. Propionic acid derivatives Ibuprofen ̶good analgesic and antiinflammatory effect ̶used often for acute pain therapy ̶low AE incidence, well tolerated NSAID, indicated for children Ketoprofen ̶phototoxicity Dexketoprofen [USEMAP] Adobe Systems Naproxen ̶longer T1/2 (12-15 hrs) ̶low gastro- and cardiovascular toxicity compared to other NSAIDs Tiaprofenic acid ̶good penetration to synovial fluid à joints diseases Flurbiprofen ̶ 4. Propionic acid derivatives [USEMAP] Adobe Systems 5. Acetic acid derivatives Diclophenac ̶antiinflammatory, analgesic, weak antipyretic ef. ̶bioavailability 30-70% ̶short biological halftime à retarded DDF ̶more AE than ASA, less than indomethacin ̶mild: cephalgia, insomnia, GIT disorders, photosensitivity ̶significant risk of cardiovascular AE ̶ ̶ Aceclofenac [USEMAP] Adobe Systems 5. Acetic acid derivatives Indomethacin ̶very strong nonselective COX inhibitor ̶toxic à short-time treatment of acute states ̶urikosuric effectsà used in gout attacks ̶AE in 30 % of pacients ̶GIT, cephalgia, depression, confusion, hallucinations, hematoxicity, cartilages destruction [USEMAP] Adobe Systems 6. Oxicams ̶high plasma protein binding (interactions!) ̶long biological halftime (once daily dosing) ̶different COX affinity Meloxicam ̶COX-2 more selective ̶lower AE incidence Lornoxicam ̶nonselective COX inhibitor ̶low occurence of GIT adverse effect Piroxicam ̶nonselective COX inhibitor, high toxicity [USEMAP] Adobe Systems 7. Coxibs ̶100 x more selective to COX-2 (specific COX-2 inhibitors) ̶lower AE in GIT ̶do not influence thrombocyte aggregation or renal perfusion ̶good analgesic effect, not suitable for treatment of acute or transient pain à effect is progressing slowly ̶prescription and indication restrictions ̶I: osteoarthritis, rheumatoid arthritis, ankylosing spondylitis ̶AE: increase of thrombembolisms (myocardial infarction, strokes) after chronic use ̶ [USEMAP] Adobe Systems Celecoxib Parecoxib – only inj. Etoricoxib ̶ Pharmacokinetics: ̶after p.o. administration good absorption from GIT, but not too fast, max levels reach in 2-4 hours ̶fat diet slows down absorption 7. Coxibs [USEMAP] Adobe Systems 8. Other Nimesulide ̶preferential inhibitor of COX-2 ̶inhibits enzymes destroys cartilage (elastases, collagenases), due to occurrence of AE, indication of treatment of painful osteoarthritis has been taken ̶is not the first choice medicine in any of indications ̶PK: lipophilic, short elimination half-life (1,5-5 hrs), analgesia up to 12 hrs ̶AE: hepatotoxicity (max duration of therapy 15 days) ̶ [USEMAP] Adobe Systems Adverse effects ̶because of COX-1 inhibition: ̶GIT - ¯ cytoprotective PGE2, PGI2 Þ erosions, ulcerations ̶thrombocytes - ¯ TXA2: inhibition of thrombocytes aggregation Þ increased bleeding ̶PGE2, PGI2 regulation of renal functions Þ renal failure ̶ LT production induces in predisposed people bronchoconstriction Þ asthma attack ̶uterus - ¯ PGE/F: inhibition of constriction Þ prolongation and complications during delivery ̶coxibs: ̶thromboembolic cardiovascular and cerebrovascular complications [USEMAP] Adobe Systems Prevention of AE ̶dose reduction or DDF change ̶combination with protective drugs ̶proton pump inhibitors (lansoprazole, omeprazole) ̶prostaglandine analogues (misoprostol) ̶H2 antihistamines (ranitidine, famotidine) ̶ ̶think about preferential or specific COX-2 inhibitors [USEMAP] Adobe Systems NSAIDs for local aplication ̶ketoprofen, ibuprofen, naproxen, indomethacin, diclophenac, nimesulide, piroxicam ̶flurbiprofen (lozenges), choline salicylate (oral gel) ̶DDF: creams, gels, solutions (sprays), patches, lozenges ̶AE: hypersensitivity reaction, phototoxic reaction [USEMAP] Adobe Systems Treatment of gout [USEMAP] Adobe Systems Drugs 1.Acute gout attack ̶strong anti-inflammatory action ̶pain-killers ̶inhibition of leucocyte migration to the joint 2.Hyperuricemia therapy / prevention of gout attack ̶increase of uric acid excretion ̶block of synthesis + diet ̶ [USEMAP] Treatment of acute gout attack NSAIDs higher doses (i.m., p.o., p.r.) some have preferably uricosuric effect indometacine, diclofenac, piroxicam colchicine alcaloid obtained from Colchicum autumnale p.o. every 2-4 hrs mitotic poison, inhibits phagocytosis and leukocyte migration AE: severe diarrhea – rehydratation! glucocorticoids local adm. (i.a.) – triamcinolone systemic (p.o., i.m., i.v.) – prednison, methylprednisolon canakinumab IL-1 inhibitor, human monoclonal antibody patients who do not tolerate NSAIDs and GC s.c. aplication [USEMAP] Adobe Systems Chronic treatment of gout 1.Uricosurics ̶inhibit reabsorption of uric acid in primary tubulus Lesinurad ̶only in combination with xantin oxidase inhibitors Probenecide ̶sometimes used with antibiotics or antivirotics to make them stay longer in the body ̶Not registered in Czech Rep. [USEMAP] Adobe Systems 2.Antiuratics ̶inhibit syntesis of urine acid by inhibition xantin oxidase (XO) ̶ Allopurinol ̶isomer of hypoxanthin, competitive inhibition of xanthin oxidase ̶inhibits de novo syntesis of purines •not combine with cytostatics of purine structure (azathioprin, 6-mercaptopurin) – allopurinol their toxicity! •AE: usually well tolerated, most common: ̶rash, GIT intoleration, hypersensitive reaction hypoxanthin xanthin uric acid XO XO [USEMAP] Adobe Systems Febuxostat ̶MA: non-purine inhibitor of xantinoxidase ̶clinical trials proved higher efficacy than allopurinol ̶AE: gout attacts, liver function abnormalities, diarrhoea, nausea, headache Pegloticase (recombinant uricase) ̶MA: transforms uric acid to alantoin with better solubility ̶AE: anaphylactic shock, reaction to infusion, gout attacts at the beginning of therapy ̶i.v. aplication (only to inpatient) [USEMAP]