BIMM118Drugs against Pain• Anesthesia• Narcotic Analgetics• Local Anesthetics• NSAIDsBIMM118General AnestheticsState of drug-induced absence of perception of all sensations:Unconciousness, analgesia, amnesia and muscle relaxationGeneral anesthesia is usually induced with intravenous anesthetics,and maintained with inhalation anesthetics 1846 - first surgery under ether-anethesia; 1847 - introduction of chloroformOriginally, anesthesia was achieved with a single agent (e.g ether, nitrous oxide).However, to satisfy all four anesthesia requirements with one agent necessitateshigh dosage => increased risk of suppression of vital functions.BIMM118General AnestheticsInhalation anesthetics:• Very diverse drugs: ether, nitrous oxide, halogenated hydrocarbons• Mechanism of action largely unknown (probably inhibition of glutamate receptors andincreased activity of GABA receptors)• Actions are affected by cardiac output and ventilation rate• Elimination predominantly through exhalation of the unchanged gasPotency and speed of induction/recovery depend on two properties of the anesthetic:• Solubility in blood (blood:gas partition coefficient)– Speed of onset is inversely correlated with the solubility in blood (more soluble => sloweronset): blood acts as a reservoir that “needs to be filled”• Solubility in lipid (oil:gas partition coefficient)– Determines the potency of the anesthetic– Minimal alveolar concentration (MAC)= alveolar concentration at 1 atm that produces immobilityin 50% of the patients exposed to a painful stimulus(usually expressed in Vol%)– More lipophilic anesthetics have higher potency– Lipophilic anesthetics gradually accumulate in body fat=> prolonged “hang-over”BIMM118General AnestheticsInhalation anesthetics:• Ether– Obsolete (except in underdeveloped regions)– Slow onset and recovery– Post-operative nausea, vomiting– Highly explosive• Nitrous oxide– Low potency (must be combined with other agents)– Rapid induction and recovery– Good analgesic properties• Halothane– Widely used agent– Potent, non-explosive and non-irretant– 30% metabolized in liver=> repeated use can cause liver damage– No analgetic properties– Causes hypotension (vasodilation, cardio-suppression)BIMM118General AnestheticsInhalation anesthetics:• Enflurane– Similar to halothane– Less metabolized => smaller risk of liver damage• Isoflurane• Desflurane• SevofluraneBIMM118General AnestheticsIntravenous anesthetics:• Thiopental– Barbiturate with very high lipid solubility– Rapid action, but accumulates in fat with extended use– No analgesic effect– Narrow therapeutic range• Propofol– Rapidly metabolized => quick recovery– Drug of choice for day-case surgery– Used as continuous infusion• Ketamine– Phencyclidine analogue– Good analgesia and amnesia– High incidence of hallucinations during recovery• Midazolame– BenzodiazepineBIMM118General AnestheticsModern anesthesia:Employs a combination of drugs to achieve the goals of a “balanced anesthesia”:– Anxiolytic premedication (Diazepines)– Autonomic stabilization (Atropin: prevents visceral reflexes)– Analgetics (Opioids: Fentanyl)– Muscle relaxant (Pancuronium)BIMM118Opioid AnalgesicsOpiates:– Alkaloids derives from Papaver somniferum– Already used 4000 B.C. (opius greek: “little juice”)– 1805: Morphine isolated (morpheus: Greek god of dreams)– 1874: synthesis of heroin (introduced in 1898 by Bayer as a cough medicine)– Opium tincture heavily used during civil war– Opiates freely available in the US until 1914– 1914: Harrison ActPrevented physicians from maintaining addictionBIMM118Opioid AnalgesicsOpiates:– Act through receptors (7TM, coupled to Gαi or ion-channels) for endogenous opioids:Enkephalins, endorphines,…– Reduce cAMP, but countereffect: upregulation of adenylate cyclase => toleranceEndorphine Morphin– Three receptor subtypes:• mu (µ): account for most of the morphin effects• delta (δ): mediate reduced GI motility and respiratory suppression (in addition to µ)• kappa (κ): mediate dysphoria and contribute to sedation, weak analgesic effect– Most opiods are full agonists for all receptors(exception: Pentazocine, buprenorphine, which are mixed a(nta)gonists based on receptor type)BIMM118Opioid AnalgesicsOpiates:Mechanism of analgesic action:– Spinal analgesia:Activation of presynaptic opioid receptors => decreased Ca++ flux => decreasedneurotransmitter (Substance P) release => decreased transmission of pain signal fromnocireceptors– Supraspinal analgesia:Activation of postsynaptic opioid receptors in the medulla and midbrain => increased K+flux => hyperpolarization => inhibition of neurons in the pain pathway– Oral opioids are subject to first-passelimination => low oral bioavailability– Morphine is metabolized and eliminatedvia glucuronidation– Heroin, Fentanyl: very lipophilic =>rapid accumulation in the CNSBIMM118Opioid AnalgesicsOpiates:Morphine:– CNS:• Sedation and drowsiness• Nausea (direct stimulation of the chemoreceptor trigger zone)• Cough suppressant (suppressive effect on medulla; independent of analgesic effect)– Eyes:• Pupillary constriction (stimulate parasympathetic portion of the oculomotor nucleus)– Respiratory system:• Strongly suppressive on all phases (frequency; volume)• Also depression of hypoxic drive– GI:• Increases resting tone of the smooth muscle of the entire GI tract => segmentation• Decreased peristaltic movements, increased sphincter tonus => constipation– Urinary tract:• Increased smooth muscle cell tone => urinary retentionWithdrawal symptoms:– Mostly autonomic hyperactivity: diarrhea, vomiting, chills, cramps, pain…BIMM118Opioid AnalgesicsCodeine (3-methoxy-morphine):– Better oral absorption than morphine– Only 20% of analgesic effect of morphine(does not increase significanly by increasing the dose)– Prodrug: Converted into morphine by demethylation via CYP2D6(mutated in ~10% of the population => resistance to the analgesic effect)– CYP2D6 inhibitors (e.g. Fluoxetine) reduce efficacy of Codeine– Little euphoria => rarely addictive– GI and respiratory effects similar to morphine(=> codeine and dihydrocodeine are widely used as antitussiva)Dextromethorphane (DXM):– Synthetic morphine derivative– Equally antitussive as codeine– Does not act through opioid receptors– No analgesic or GI
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