L14 Analgesics PDF

14 ANALGESICS ILOs By the end of this lecture, students will be able to 1. Determine principles of pain management 2. Categorize analgesics based on their mechanism of action & clinical indications. 3. Classify opiate analgesics into subtypes & select their use priorities. 4. Appr...

14 ANALGESICS ILOs By the end of this lecture, students will be able to 1. Determine principles of pain management 2. Categorize analgesics based on their mechanism of action & clinical indications. 3. Classify opiate analgesics into subtypes & select their use priorities. 4. Appraise their acute risks versus their chronic abuse and addiction. 5. Determine non - opiate analgesics acting on descending tracts PRE-REQUISITS: 1. Terminologies linked to pain, its incidence, types, nature, etiology, distribution ascending pathways to perception and descending inhibitory facilitatory modulation. 2. Different approaches to induce analgesia with final stress on pharmacotherapeutic modulation by narcotic opioid analgesics, non-narcotic analgesics & others as α2 adrenergic agonists NARCOTICS OPIOID ANALGESICS Opioid Receptors: mu [] [MOR]; Supraspinal / delta []; Supraspinal / kappa []; Spinal Study details from book + slides CLASSIFICATION of OPIOIDs [Acting on different opioid receptors] A. Depending On Their Source: Endogenous Opioids; in our body as Endorphins, Dynorphins, Enkephalins Exogenous opioids; a. Natural: extracted from opium [poppy plant]. These are opiates as Morphine & Heroin b. Semisynthetic: naturally modified: Codeine c. Synthetic; Manufactured: Meperidine, Heroin, Methadone, Fentanyl, Tramadol B. Depending On Their Action a. Agonists; Morphine, Meperidine, Methadone, Fentanyl, Tramadol b. Agonist / Antagonists; buprenorphine. NB.: Antagonists; are not analgesics but are used as antidotes in acute narcotic toxicities. MECHANISM OF OPIOID ACTION I. In Induction of Analgesia: A. Inhibit Pain Transduction: By attenuating pain stimuli via activation of MOR to  excitation of peripheral nociceptive afferent neurons B. Reduce Pain Transmission & Supraspinal Processing & Perception: Whether along ascending supraspinal pathways or at cortex, thalamus & limbic system. So nociceptive sensation even if perceived is no longer unpleasant or threatening. By Direct Presynaptic Inhibition via binding to MOR [a Gi GPCR] that –ve AC & cAMP   Ca2+ influx via closing Ca2+ channels  excitatory transmitter release; Glutamate & SP in ascending pathways By Direct Postsynaptic Inhibition via binding to MOR so  K+ efflux via opening of K+ channels   neuronal membrane hyperpolarization   generation of action potential at postsynaptic fibers. C. Facilitate Descending Pain Inhibitory Modulation: By facilitating the inhibitory inputs at PAG to RM & LC through inhibition of GABA-ergic release by activation of MOR. This will exert a 1  modulatory action via the supraspinal descending inhibitory serotonergic & noradrenergic axons. That indirectly will activate the inhibitory MOR interneurons at dorsal horn cells  suppressing pain signaling. II. In Inducing Euphoria: Dopamine is dominating the reward pathway that gives rise to pleasurable sensation & happiness. This is checked by higher central control, specially from the frontal lobe to keep a balanced mood and to prevent over excitement and euphoria. Such higher check signals are dominated by GABA-ergic inhibitory transmission. However, opioids through MOR activation cans disinhibit such GABA-ergic signals leaving dopamine unrestrained to fully activate the reward centres with development of intense pleasure excitement & euphoria. III. In Development of Withdrawal Manifestations: As MOR belong to GPCR of the Gi type, so continuous opioid occupancy in addicts will always exert suppression on adenyl cyclase (AC). As an adaptive process, cells will begin to synthesize more and more adenyl cyclase as a compensation. But with the maintenance of opioid occupancy, cAMP production remains at a low pace. Once opioids are withdrawn, cAMP production shoots up secondary to the overexpressed AC already present. Such cAMP shooting is responsible for the withdrawal manifestation that peaks immediately on withdrawal and takes days to way off. __________________________________________________________ INDIVIDUAL OPIOID ANALGESICS Morphine Commonest route of administration is IM every 4 hours but can be given subcutaneous or with dose adjustment IV to prevent adverse effects. It is now rarely taken orally as it undergoes extensive 1st pass metabolism and has low bioavailability. Intrathecal or epidural is given by anesthetist in smaller doses. It is indicated in: ▪ Control of pain; after trauma, severe burns, cancer pain, visceral pain (not renal/biliary colic, acute pancreatitis) < neuropathic < musculoskeletal. ▪ In distressful conditions; even if are not painful; acute pulmonary edema, AMI, acute HF… ▪ In pre-anesthetic medication and in post-operative pain control Its Relevant ADRs; Pupillary constriction. Nausea & vomiting (activates CRTZ), constipation and gall bladder contraction. Itching due to histamine release. Sedation and respiratory Depression (> if renal impairment). Tolerance and Dependence (Physical & Psychological) is common on chronic use. It is contraindicated in; ▪ Head Injury; as the pin point pupil may mask the pupillary signs of head injury. Also morphine tends to increase the intracranial pressure. ▪ Pregnancy & Labor: as it may induce respiratory depression to delivered neonate. ▪ Neonates/ Infancy; as morphine toxicity may develop because the neonatal metabolism is not fully developed [i.e., decreased drug conjugation]. ▪ Elderly; being very sensitive to it as they have poor metabolism and body functions. ▪ Asthmatics; as histamine released may precipitate an attack. ▪ Renal & Biliary colic; as there is contraction of their sphincters. Heroin Is a strong addicting drug of abuse, not used in medical profession [fast acting / highly lipophilic]. It is injected, sniffed, snorted, or smoked 2 Fentanyl It is [50-100] times more potent than morphine. It is short acting (lasts 2 hrs) but because it is highly lipophilic there exist a transdermal patch preparation to be changed every 72 hours. It is the commonest used during anaesthesia IV, as infusion, or intrathecal during induction & maintenance. Also used in severe breakthrough in cancer pain & severe postoperative pain Meperidine [Pethidine] It is tenth the potency of morphine, with rapider onset and & shorter duration. It has less respiratory depression and possess atropine-like action. It is used in obstetric analgesia (safest on respiration) and in severe visceral pain and in renal and biliary colic (atropine-like). Has good pre - anesthetic profile. Toxicity develops more in patient with renal disorders as may appear as Atropine Toxicity with Tremors, Hyperthermia, Hypotension, Dilated pupil & blurred vision, Dry mouth, Urine retention Tramadol A weaker analgesic given in moderate pain. Also affect monoaminergic transmissions. Given orally, has good oral bioavailability, less respiratory depression, tolerance and addiction yet can induce seizers & sedation. Codeine A weaker analgesic (20% morphine) used in moderate pain. Present currently as over the counter, oral preparations in combination with paracetamol or aspirin. Also it is antitussive but induce constipation. Methadone Firmly occupies MOR with high affinity. It also has NMDA antagonism that adds to its analgesic action. It has good oral bioavailability but hard to titrate. It has very long action (dissociates very slow from receptors) with (30-55 hrs). Buprenorphine It has a µ agonist &  antagonist action. It is half the potency of morphine but with higher affinity and lower efficacy and with longer duration of action. It is used in severe pain but can induce more emesis & sedation. BOTH methadone and buprenorphine are used as analgesic in severe pain in non-addicts but still can induce dependence especially psychological dependence. In ADDICTS they are both used in opioid detoxication programs as both are drugs of high affinity lower efficacy and longer duration than that or more addicting opioids as heroin & morphine. Buprenorphine being more rapid in inducing detoxication than methadone. __________________________ Naloxone Competitive antagonist to all opioid receptors with high affinity at MOR. Used as an antidote to rapidly reverse acute opioid toxicity in non-addicts. If used in ADDICTS, it can precipitate withdrawal manifestations. It is short acting, may need repeated administration or given as infusion __________________________ 3 STRATEGIES USED TO CONTROL PAIN A general rule, narcotic analgesics are given in moderate to severe pain while Non-opioid Analgesics are given in mild to moderate pain. Opioids as morphine, fentanyl, pethidine methadone, buprenorphine …. etc. are strong opioids so are used in severe pain while weaker opioids as tramadol and codeine are prescribed in pain of moderate intensity. The NSAIDs are only used when there is mild to moderate pain only. All analgesics can be used with adjuvant analgesics depending on the etiology inducing the pain. WHO has suggested the LADDER APPROACH for pain treatment, which eencourages the escalation of analgesia when pain increases with progression of a disease like in cancer. While currently most pain clinics adopt MULTIMODAL APPROACH which suggests the combination of two or more analgesics or techniques to ensure a better control with least side effects. __________________________ OTHER ANALGESICS 2 – Agonists Dexmedetomedine Highly selective α2-AR agonist: Sedative (by acting on Locus coeruleus) Analgesic (by acting on spinal cord via the descending inhibitory pathways). Used specially in perioperative analgesia or in pain not well controlled by adding adjunctive analgesics Also, successfully in the treatment of withdrawal from benzodiazepines, opioids, alcohol, and other recreational drugs. But it is not recommended in patients with advanced heart block and ventricular dysfunction. It is given cautiously in pregnancy. __________________________ 4