Analgesics2009
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Transcript of Analgesics2009
Pharmacology of
Analgesia
Opium is a narcotic formed from the latex(juice) released by lacerating the immature seed pods (fruits) of Papaver Papaver somniferum.somniferum.
Opium contains up to 12% morphine, an opiate alkaloid, which is most frequently processed chemically to produce heroin for the illegal drug trade.
Opioid AnalgesicsOpioid AnalgesicsOpioid AnalgesicsOpioid Analgesics
Opioid AnalgesicsOpioid AnalgesicsOpioid AnalgesicsOpioid Analgesics
µ- receptors are most important
CNS contains opioid peptides – enkephalins, endorphins, dynorphins, orphanin/nociceptin
Four receptors subtypes – µ, κ, ∂, N/OFQ
(Gi-coupled - AC inhibition - decrease cAMP)
Presynaptic and postsynaptic inhibition
OpioidOpioidss
pharmpharmacologyacology
AnalgesiaAnalgesia An analgesicanalgesic (also known as a painkiller) is any drug used to relieve pain (achieve analgesia)
Tissue injury lead to activation of nociceptors (pain receptors) by differrent substances released by injured tissues.
Thermal Chemical
MechanicalElectrical
Activated pain receptors generate impulses that go into spinal cord through primary afferent neurons.
Opioid ReceptorsOpioid Receptors
Opioid agonists inhibit the release of excitatory transmitters from these primary afferents, and they directly inhibit the dorsal horn pain transmission neuron. Thus, opioids exert a powerful analgesic effect directly on the spinal cord.
It is well established that the analgesic effects of opioids arise from their ability to directly inhibit the ascending transmission of nociceptive information from the spinal cord dorsal horn and to activate pain control circuits that descend from the midbrain to the spinal cord dorsal horn.
Morphine inhibits the release of:gonadotropin-releasing hormone (GnRH)corticotropin-releasing hormone (CRH) thus decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and b-endorphin; As a result plasma concentrations of testosterone and cortisol decline.
Convulsions• With most opioids, convulsions occur only at doses
far in excess of those required to produce profound analgesia.
• High doses of morphine and related opioids produce convulsions
SedationDrowsiness and clouding of mentation are common effects of opioids. There is little or no amnesia. Sleep is induced by opioids more frequently in the elderly than in young, healthy individuals. Ordinarily, the patient can be easily aroused from this sleep.
Respiratory depressionAll of the opioid
analgesics can produce significant respiratory
depression by inhibiting brainstem respiratory mechanisms acting on
receptors. The respiratory depression is
dose-related. Opioid-induced respiratory
depression remains one of the most difficult
clinical challenges in the treatment of severe pain.
Cardiovascular system
Most opioids have no significant direct effects on the heart
and, other than bradycardia, no major effects on cardiac rhythm.
Smooth muscles• Longitudinal relaxes• Circular constricts:- GI: peristalsis, constipation, cramping- GU: urinary retention- Bile duct : pressure(OA contraindicated - in biliary colic)- Pupils: miosis
Morphine and related opioids also depress the cough reflex at least in part by a direct effect on a cough center in the medulla.
When we use OA for cough suppression?
Cough is due to foreign body in the lungs
Cough is due to lung cancer Cough is due to pleura
irritation by broken ribs parts after trauma
The opioid analgesics can activate the brainstem chemoreceptor trigger zone to produce nausea and vomiting(action on dopamine receptors)
Histamine releaseMorphine and some other opioids provoke release of histamine, which sometimes plays a large role in the hypotension.
Morphine pharmacokinetics• Glucoronidation• Morphine-6-glucuronide is highly active• Caution in renal dysfunction
Type Drug name PropertiesFull agonist Mepiridine
Methadone
MorphineFentanyl subgroupLevorphanol
Antimuscarinic action(atropine-like action), no miosis, tachycardia, no spasm of smooth muscles.
Long half-life, use for maintenance of opiate addicts
Partial agonists
Codeine
PropoxypheneHydrocodone
AntitussiveAnalgesic in combination with NSAIDsand other drugs (Solpadeine)
Type Drug name PropertiesMixed opioid agonist-antagonists
Nalbuphine k-agonist – spinal analgesia, dysphoriam – antagonist – precipitation of withdrawal
Antagonists Naltrexone
NaloxoneNalmefene
IV, reversal of respiratory depression, used in opiate addiction
Problems with opioid therapyProblems with opioid therapy1.1. Acute toxicity(classic triad):Acute toxicity(classic triad):- ComaComa- Pinpoint pupilsPinpoint pupils- Respiratory depressionRespiratory depressionManagement of acute toxicity:Management of acute toxicity:- SupportiveSupportive- IV naloxoneIV naloxone2.Tolerance(pharmakodynamic)2.Tolerance(pharmakodynamic) – decrease of drug efficiency over time with
multiple administrations. This is due to increased cAMP production in cells. Tolerance can be overcome by dose increasing . Marked tolerance may develop to the analgesic, sedating, and respiratory depressant effects, but not to the miotic, convulsant, and constipating actions.
3.Dependence3.Dependence(psychological and physical symptoms on withdrawal)
4.Withdrawal: 4.Withdrawal: sweating, lacrimation, rhinorrhea, anxiety, restlessness, insomnia, dilated pupils, tachycardia, hypertension, nausea/vomiting, abdominal pain, diarrhea,muscle aches. Opioid withdrawal is not life threatening. Emergence of withdrawal symptoms varies with half-life of the particular opioid; within 6-12 hours after the last dose of morphine/hydromorphone/oxycodone or 72-96 hours following methadone. Duration and intensity of withdrawal symptoms can be variable and are related to clearance of the drug; withdrawal from morphine is short (5-10 days) but more protracted with methadone.
Management of withdrawal
•Supportive•Clonidine•Methadone
Drug with specific action
Loperamide (Imodium) – antidiarrheal agentDextromethorphan – antitussive agentBoth are over-the-counter (OTC) drugs
NSAIDs• Non-steroidal anti-inflammatory drugs• NAIDs have analgesic, antipyretic and, in higher doses, anti-
inflammatory effects• Term "non-steroidal" is used to distinguish these drugs from
steroids, which have a similar anti-inflammatory action• NSAIDs are non-narcotic analgesics
BurnsChemical irritantsFrostbiteToxinsInfection by pathogensPhysical injuryImmune reactionsIonizing radiationForeign bodies
Tissue Injury
Activation of the arachidonic acid cascade
through membrane bound phospholipase A2 (PA2).
o Arachidonic acid is a polyunsaturated fatty acid that is present in the phospholipids of membranes of the body's cells.
o Enzyme phospholipase A2 (PLA2) release arachidonic acid from a phospholipid molecule
PLA2
Arachidonic
acid
NSAIDsInhibition
-vasoconstrictor - platelet aggregation.
- inhibit platelet aggregation-vasodilation
-↓ gastric acid secretion- ↑ gastric mucus secretion- hyperalgesia- pyrogenic
COX-1 is expressed in most tissues including platelets and GICOX-2 is inducible; is expressed in brain, kidney and in sites of inflamation.COX-1 generates prostanoids for "housekeeping" such as gastric epithelial cytoprotection, COX-2 is the major source of prostanoids in inflammation and cancer.
This distinction is overly simplistic, however; there are both physiologic and pathophysiologic processes in which each enzyme is uniquely involved and others in which they function coordinately. For example, endothelial COX-2 is the primary source of vascular prostacyclin (PGI2), whereas renal COX-2-derived prostanoids are important for normal renal development and maintenance of function.
COX-1- selective Non-selective COX-1,2
COX-2- selective
- Low-dose aspirin
- (up to 325 mg per day),
- 75 mg as therapeutic agent for MI prevention
All other:-Indomethacin-Ibuprophen-Naproxen-Diclofenac-Ketorolac-Piroxicam-Meloxicam
COXIBs:-rofecoxib-celecoxib-lumaricoxib-parecoxib-valdecoxib-etoricoxib
Nimesulide
1)Antipyretic2)Analgesic3)Anti-inflammatory
All NSAIDs, including selective COX-2 inhibitors, are antipyretic, analgesic, and antiinflammatory, with the exception of acetaminophen(paracetamol), which is antipyretic and analgesic but is largely devoid of antiinflammatory activity.
• Alleviate pain of low-to-moderate activity• Have no opioid-like effects on CNS• Pain arising from inflammation is controlled particularly well by
NSAIDs• Effective for menstrual pain• Lower body temperature by inhibiting PGE2 synthesis in
hypothalamic thermo regulating centers• Do not lower normal body temperature
Antiplatelet action Most notable for aspirin.Unlike other agents Aspirin is
irreversible inhibitor of COX(COX should be resynthesized)
No nucleus – no new COX synthesis – no new TXA2- no platelet activation- no thrombus formation
Acetaminophen(Tylenol, Panadol)• No inhibition of COX in peripheral tissues• Lack of significant anti-inflammatory action• Analgesic and antipyretic activity due to COX inhibition in CNS• No antiplatelet action• Not increase bleeding• Not cause Reye syndrime• Minimal GI distress
Adverse effectsHepatotoxicity in high dose
Adverse effects are generally quite similar for all of the NSAIDs:Central nervous system: Headaches, tinnitus(aspirin), and dizziness.
Cardiovascular: Fluid retention hypertension, edema, and rarely, congestive heart failure.
Gastrointestinal: Abdominal pain, dysplasia, nausea, vomiting, and ulcers or bleeding.(2,5% incidence in clinical trials)
Hematologic: Rare thrombocytopenia, neutropenia, or even aplastic anemia.
Hepatic: Abnormal liver function tests and rare liver failure.Pulmonary: Asthma.Rashes: All types, pruritus.Renal: Renal insufficiency, renal failure, hyperkalemia, and
proteinuria.
Coxibs controversy• Rofecoxib and valdecoxib was withdrawn from the
market because of increased cardiovascular mortality in chronic drug users• Overall mortality was higher in patients on coxibs in
clinical trials
NSAIDs cannot be used (are contraindicated) in the following cases: • Allergy to aspirin or any NSAID • Aspirin should not be used under the age of 16 years (associated
with Reye syndrome)• During pregnancy • During breast feeding • On blood thinning agents (anticoagulants) • Suffering from a defect of the blood clotting system (coagulation) • Active peptic ulcer
1)Salicylates Salicylic acidAspirin(ASA)Methyl salicylateSalsalateDiflunisalOlsalazineSulfasalazine.
5)Heteroayl acetic acid derivatives
TolmetinKetorolacDiclofenac
2)Para-aminophenol derivatives
Acetaminophen(paracetamol)
6)Propionic acid derivatives
IbuprofenNaproxenFenoprofenFlurbiprofenKetoprofen
3)Acetic acid derivates
IndomethacinSulindacEtodolac
6)Enolic acid derivates(oxicams)
PiroxicamMeloxicamLornoxicamothers
4)Fenamates Mefenamic acidFlufanamic acidMeclofenamic acid
7)Pyrazolon derivatives AnalgineAntipyrine Phenybutazone