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Pharmacotherapy of pain

Pharmacotherapy of pain. Types of pain 1. Acute pain preventive function localised has vegetative sympthomatology and doesn´t cause severe psychological changes clearly defined beginning and ending analgesics are usually effective in treatment. Chronic pain without preventive function

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Pharmacotherapy of pain

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  1. Pharmacotherapy of pain

  2. Types of pain 1 • Acute pain • preventive function • localised • has vegetative sympthomatology and doesn´t cause severe psychological changes • clearly defined beginning and ending • analgesics are usually effective in treatment • Chronic pain • without preventive function • lasts 3-6 months • often associated with severe psychological changes • without clearly defined beginning • malignant (caused by cancer)or non-malignant

  3. Types of pain 2 • Nociceptive • somatic • superficial • deep • visceral (diffuse) • Neuropatic • central • deafferentational • peripherial • neuropaties • Idiopatic • Psychogenic

  4. Types of pain 2 • SOMATIC: often well localised to specific dermal, subcutaneous or musculosceletal tissue • VISCERAL: often poorly localized and can irradiate to somatic structures (myocardial infarction), originating in thoracic or abdominal structures • NEUROPATHIC: nerve damage (compression, inflammation, diabetes), e.g. trigeminal neuralgia, postherpetic neuralgia, fibromyalgia (antidepressants, anticonvulsives)

  5. (According to: Stahl's Essential Psychopharmacology, 4th Edition)

  6. Therapy of pain • Analgesics and co-analgesics • Non-opioidanalgesics • Analgesics/antipyretics • Non-steroidalanti-inflammatorydrugs (NSAIDs) • Opioidanalgesics • Natural (morphine, dihydrocodeine) • Synthetic (fentanyl, buprenorphine) • Co-analgesics(Antidepressants, Anxiolytics, Myorelaxants, Anticonvulsives,Neuroleptics, Glucocorticoids, Anesthetics, 2-sympaticomimetics, H1-antihistamines)

  7. Non-opioid analgesics • Analgesics/antipyretics(no anti-inflammatory) • aspirin (acetylsalicylicacid- ASA) • paracetamol (USA- acetaminophen) • metamizole • Non-steroidalanti-inflammatorydrugs (NSAIDs) (used to treatinflammation in rheumatoidarthritis) • Non-selectiveinhibitors of COX-1 and COX-2 (ibuprofen, diclofenac, ASA) • Preferentialinhibitors of COX-2 (nimesulide, meloxicam) • Selectiveinhibitors of COX-2/coxibs (celecoxib, rofecoxib (dereg.))

  8. Analgesics/antipyretics

  9. Paracetamol (Acetaminophen) Derivate of anilin • Mechanism of action – unknown, possibly inhibition of COX-3 in CNS • Goodabsorptionfrom GIT • Biologicalhalflife - 1,5-3 h  • Only a smallpercentage of thedrugbinds on plasmaproteins (10%) • Elimination – through the kidnies in the form of glucuronides and sulfates • In doses over 5 g/daycancauseHEPATAL DAMAGE • In theworld, approximately 200 differentpreparatescontainingparacetamol are beingused • Antidote: N-acetylcysteine(mucolyticdrug– used in thetherapy of productivecough)

  10. (according to: dailyem.wordpress.com/2014/01/07) NAC = N-acetylcysteine)

  11. Metamizole (Dipyrone) Derivate of pyrazolone • Mechanism of action: complex;  inhibition of a central COX-3 and activation of the opioidergic system and cannabinoid system • Has spasmolytic properties • Serious adverse effect:depression of bone marrow leading to AGRANULOCYTOSIS • Good absorption in the case of both peroral and rectal administration. • More than 50 % binds onto plasmatic proteins; short plasmatic half-life (i.v. metamizole - 14 min); elimination mostly through kidneys

  12. Non-steroidal anti-inflammatory drugs (NSAIDs)

  13. Properties Cyklooxygenase 1 Cyklooxygenase 2 Localisation cytoplasmatic in ER perinuclear Regulation constitutive inducible / constitutive Presence intissues GIT mucosa, renal parenchyma, endothelium, Tr Mf, Mo, CNS, kidneys, uterus, seminiferous Predicted function Integrity of stomach mucosa, kidney perfusion, Tr function Patogenesis of inflammation andgenesis of pain

  14. Non-steroidal anti-inflammatory drugs Division according to COX selectivity:

  15. Acetylsalicylic acid (Aspirin) • in a dose of 30- 300 mg/day (secondary prevention if atherosclerosis) • in a dose of 500 mg (pain, fever) • high doses (antiinflammatory effect; high risk of gastrotoxicity) • not in children: Reye´s syndrome

  16. Effects of NSAIDs • Analgesic effect • Antipyretic effect • Antiflogistic effect (mainly higher doses) • Antiaggregatory effect (not every NSAID, most important is ASA because of irreversible blocade of COX-1- be careful with combination of ASA for anti-aggregation and other NSAIDs- mostly ibuprofen) • Other effects- for example reduced incidence of some tumors (for example colorectal carcinoma), uricosuric effect ...

  17. NSAIDs– oneofthe most widelyuseddruggroups→theirADRsrepresent a seriousmedical / publichealth / economicalproblemthere are big differencesbetweenvariousNSAIDsin thelevel risk ofparticularpossibleADRs

  18. Adverseeffects of NSAIDs • GIT-erosions and ulcersofthegastricmucosa (also in otherlocalisationsinthe GIT), nausea, vomitus, meteorism, diarrhoea, constipation... (mainlyinhibitionof COX-1) • kidney-reductionofglomerularfiltration, retentionof Na and fluids, edema, hyperkaliemia, kidneyfailure, interstitialnephrits...(inhibitionof COX-1 and 2) • CVS-thromboticevents, increaseofbloodpressure, heartfailure...(mainly COX-2 (mostly in thromboticevents)) • CNS- cephalea, weakness, sleep disorders, dizziness, epileptic seizures... • other-hepatotoxicity, bleeding, provocationofasthmaticattack, Ray´ssyndrom, prolongedchildbirth, urticaria, decreasednumberofwhitebloodcells...

  19. Gastrointestinal ADRs (inhibition of COX-1) • most serious – ↓ productionofprostaglandins in thegastricmucosa→ pepticulcer(most often in thestomach and duodenum; themucosacan get damaged by NSAIDsalso in otherplacesinthe GIT) • roughly 25 % ofchronic NSAID usersmightdeveloperosions and ulcers, in 2-4 % perforation or bleedingcanoccure

  20. Kidney ADRs • Decreasedproductionofprostanoids→negativeeffect on theperfusionofthekidneys, glomerularfiltration, excretionofsodium and waterand on productionofrenin→circulationoverload, oedemas, hypertension ; hyperkalemia; in severe casessymptomsofacutekidneyfailure • seriouscomplication– interstitialnephritis(immunologicalreasons) • Incidence of kidney ADRs is approx. 18%, severe cases- roughly 1%

  21. CardiovascularADRs(inhibition of COX-2) • Increased blood pressure- mostly in hypertensive patients treated with antihypertensives (mainly ACEIs, ARBs, beta blockers), there are big differences between various NSAIDs • Development/worsening of heart failure- the risk is highest during the first weeks of treatment, mainly in patients with preexisting congestive heart failure; possibly 19% of all cases of congestive heart failure could be caused (at least partially) by NSAID therapy • Thrombotic events- acute myocardial infarction, stroke, thromboembolic disease

  22. Opioid analgesics • Dampen strong somatic and visceral pain – strongest analgesics • Dampen algognostic (perception and localisation) and algothymic(psychical and emotional) part of pain • Tolerance – results from down-regulation of opioid receptors (not to miosis and constipation) • Physical dependence – a person´s continued use of drug is required for his or her well being (in therapy is used methadone, buprenorphine)

  23. HYDROCODONE

  24. Opioid analgesics – strong opioids • NO CEILING (´ROOF´) EFFECT • The Ceiling effect: when the dosage of a drug is increased, its effect increases proportionally; but after a certain dosage, any amount of increase in the dosage of the drug shows no additional effect

  25. Opioid analgesics Strongagonists: morphine (trauma, myocardialinfarction, cancer),heroine (diamorphine), fentanyl, meperidine, methadon, oxycodone Weakagonists: tramadol (´atypicalopioid´), codeine (antitussive), hyddrocodone Partialagonistsor agonists/antagonists: buprenorphine,butorfanol, pentazocine Antagonists:naloxone, naltrexone (antidotes)

  26. Influence of pain transmission

  27. Pharmacological effects • Depressor • Analgesia • Depression of breathing • Antitussive effect • Decreased secretion and motility in the GIT – constipation • Sedation • Stimulatig • Vomiting • Miosis • Increased tonus of smooth muscles, sphincters • Induction of histamine release • Euphoria

  28. Adverse effects of opioids Neuropsychiatric • Sedation, cloudedconsciousness, euphoria, sleepdisorders Cardiopulmonal • Depression of breathing centre (the most feared ADR), bronchoconstriction (highdoses), orthostatichypotension, bradycardia (highdoses) Gastrointestinal • Nausea, vomiting, constipation, gastrointestinal or gallbladdercolics Urinarysystem • Retentionofurine Endocrine • Decreasedlevelsoftestosterone, problemswithmenstrualcycle Allergic and immunologic • Pruritus, immunosupression

  29. Morphine Prototypical opioid • Isolated from sap from unriped skulls of poppy (1803) • Fast resorption after p.o. application, bioavailabilityis only 30% (significant first pass effect) • Most common adverse effects- nausea, vomiting, constipation, gallbladder and uretral spasms • Depression of breathing is the most common cause of death in case of intoxication. • Most common signs of intoxication – unconstiousness, bradypnoea a miosis

  30. Synthetic derivate of phenylpiperidine Strong agonist of  receptors 80-100 times more potent than morphine Lipophilic character – rapid onset of action, but the effect lasts only for a short time Contraindicated in pregnancy Derivates of fentanyl- sufentanyl and alfentanyl are used in anestesiology Big advantage – availability of fentanyl in the form of TRANSDERMAL PATCHES – „Durogesic“ The second most widely used opioid Fentanyl

  31. Atypical opioid (dual-action opioid: agonist at µ receptors + inhibits the neuronal reuptake of serotonin and norepinephrine) For moderate pain High bioavailability is an advantage In therapeutic doses lacks most of the adverse effects of opioids The most common adverse effects are sweating, nausea and dry mouth Suitable for treatment of mild to severe pain in adults and children Available in different drug forms. It is cheap Tramadol

  32. In case of long term treatment, analgesics should be administered regularly, not only when the patient feels pain.

  33. Muscle Relaxants

  34. Cholinergic Transmission • CNS • neuromuscular junction • ganglia of the autonomic nervous system (sympathetic and parasympathetic) • postganglionic parasympathetic neurons

  35. Receptors for Ach • muskarinic: M1 = CNS, ganglions, stomach M2 = heart M3 = glands, smooth muscles M4,5 = CNS • nicotinic: NM (muscular) = neuromuscular junction NN (neuronal) = veg. ganglions

  36. Degradation of Ach = acetate + choline • Ach esterase– synapsis • Butyrylcholinesterase – plasma, tissues (atypic form of BCh esterase = ↓ activity !!!)

  37. Muscle Relaxants • Peripheral – acting on the neuromuscular plate • non-depolarising • depolarising • Centrallyacting

  38. kurare - tubokurarine

  39. Muscle Relaxants = relaxation of skeletal muscles structure similar to Ach, peripheral + central 1. Peripheral: a. nondepolarising • competitive blockade of nicotinic (N) receptor on neuromuscular junction • fast elimination (kidneys, ↓ liver) • effect starts quickly, lasts about 1 hour after administration (i.v. injection, contin. infusion) • always OT intubation !!!

  40. Muscle Relaxants – peripheral, non-depolarising • muscle relaxation: mimic, chewing, oculomotory muscles, than head, neck, limbs, belly, at last diaphragma and intercostal muscles • Ind.: anestesiology (abdominal operations) • ADR: hypotension, tachycardia, release of histamine • interactions: potentiation of myorelaxation after inhalatory anesthetics and aminoglycosides • antidote:inhibitors of Ach esterase (neostigmine) + atropine

  41. Muscle Relaxants – peripheral, non-depolarising • examples: atracurium, pancuronium, vecuronium, pipecuronium = less ADR as original d-tubocurarine (release of histamine, blockade of N recept. of veget. ganglions) • atracurium, cis-atracurium:spontaneous nonenzymat. cleavage through Hoffmann´s elimination (independently from kidney and liver function) • pancuronium:action till 60 min.

  42. MuscleRelaxants – peripheral, depolarising b. depolarising sukccinylcholine (suxamethonium) = depolarisation of neuromuscular junction, i.v. administration • effect: fast and short (cca 5 min.) • on the beginning fasciculations and spasms – always general anesthesia before administration !!! • degradation = butyrylcholinesterase • genet. defect of Bch esterase = long lasting paralysis of muscles and breathing • no antidote – assisted breathing !!!

  43. MuscleRelaxants – peripheral, depolarising • Ind.:short lasting manipulations (OT intubation, reposition of fractures and luxations, electroconvulsive therapy in psychiatry) • ADR: fasciculations, spasms, hypotension, bradycardia, ↑ intraocular pressure, hyperkalemia

  44. Botulotoxine cervical dystoniastrabismusblepharospasmushyperhidrosisspastic bladder

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