HOMEWORK 2

HOMEWORK 2PHARMACOLOGY OF ANALGESIC ERLIN IRAWATIOPIOID ANALGESICSOPIOID ANALGESIC

FARMAKOKINETIK (ABSORBSI)Rute pemberian bisa secara subkutan, intramuskular, oral, intravena, nasal insufflation, mukosa oral via lozenges, transdermal via transdermal patches.Rute pemberian oral membutuhkan dosis yang lebih tinggi agar dapat menimbulkan efek terapeutik karena metabolisme lintas pertama (first-pass metabolism).FARMAKOKINETIK (DISTRIBUSI)Obat-obatan opioid berikatan dengan protein plasma dengan afinitas yang bervariasi.Konsentrasi tertinggi obat ini adalah di otak, paru, hati, ginjal, dan limpa.Konsentrasi di otot rangka juga cukup tinggi karena sebaran otot rangka yang luas di tubuh.FARMAKOKINETIK (METABOLISME)Opioid dimetabolisme menjadi konjugat glukuronida (metabolit yang lebih polar).Morphine, which contains free hydroxyl groups, is primarily conjugated to morphine-3-glucuronide (M3G), a compound with neuroexcitatory properties.Approximately 10% of morphine is metabolized to morphine-6-glucuronide (M6G), an active metabolite with analgesic potency four to six times that of its parent compound.FARMAKOKINETIK (EKSKRESI)Konjugat glukuronida analgesik opioid yang merupakan metabolit polar sebagian besar di ekskresikan di urin. Sebagian kecil dari analgesik opioid diekskresikan tanpa perubahan bentuk (unchanged drug).Sebagian kecil konjugat glukuronida diekskresikan di empedu.

farmakodinamik

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. This spinal action has been exploited clinically by direct application of opioid agonists to the spinal cord, which provides a regional analgesic effect 11MECHANISM OF ACTIONOpioid agonists produce analgesia by binding to specific G protein-coupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain.The opioids have two well-established direct G protein-coupled actions on neurons: (1) they close voltage-gated Ca2+ channels on presynaptic nerve terminals and thereby reduce transmitter release, and (2) they hyperpolarize and thus inhibit postsynaptic neurons by opening K+ channels.

Sites of action on the afferent pain transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on inflamed or damaged peripheral tissues B: Inhibition also occurs in the spinal cord. C: Possible sites of action in the thalamus.

Brainstem local circuitry underlying the modulating effect of-opioid receptor (MOR)mediated analgesia on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord

Opioid analgesic action on the descending inhibitory pathway. Sites of action of opioids on pain-modulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus caeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C).CLINICAL USED OF OPIOID ANALGESICSAnalgesiaSevere, constant pain is usually relieved with opioid analgesics with high intrinsic activity; whereas sharp, intermittent pain does not appear to be as effectively controlled.The pain associated with cancer and other terminal illnesses must be treated aggressively and often requires a multidisciplinary approach for effective management.Such conditions may require continuous use of potent opioid analgesics and are associated with some degree of tolerance and dependence.Opioid analgesics are often used during obstetric labor.The acute, severe pain of renal and biliary colic often requires a strong agonist opioid for adequate relief. Acute pulmonary edemamorphine can be particularly useful when treating painful myocardial ischemia with pulmonary edema.Proposed mechanisms include reduced anxiety (perception of shortness of breath), and reduced cardiac preload (reduced venous tone) and afterload (decreased peripheral resistance). BATUKSuppression of cough can be obtained at doses lower than those needed for analgesia.DIAREDiarrhea from almost any cause can be controlled with the opioid analgesics. Now synthetic surrogates with more selective gastrointestinal effects and few or no CNS effects, eg, diphenoxylate or loperamide, are usedSHIVERINGMeperidine is reported to have the most pronounced anti-shivering properties. Meperidine apparently blocks shivering mainly through an action on subtypes of the 2 adrenoceptor.

Applications in Anesthesia

The opioids are frequently used as premedicant drugs before anesthesia and surgery because of their sedative, anxiolytic, and analgesic properties. They are also used intraoperatively both as adjuncts to other anesthetic agents and, in high doses (eg, 0.020.075 mg/kg of fentanyl), as a primary component of the anesthetic regimen Opioids are most commonly used in cardiovascular surgery and other types of high-risk surgery in which a primary goal is to minimize cardiovascular depression.Because of their direct action on the superficial neurons of the spinal cord dorsal horn, opioids can also be used as regional analgesics by administration into the epidural or subarachnoid spaces of the spinal column.NSAIDNSAID USED:To suppress the signs and symptoms of inflammation. Exert antipyretic and analgesic effects,But it is their anti-inflammatory properties that make them most useful in the management of disorders in which pain is related to the intensity of the inflammatory process.PHARMACOKINETICAll but one of the NSAIDs are weak organic acids as given.Most of these drugs are well absorbed, and food does not substantially change their bioavailability.NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver. While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). Most of the NSAIDs are highly protein-bound (~98%), usually to albumin.

PHARMACODYNAMICThe anti-inflammatory activity of the NSAIDs is mediated chiefly through inhibition of biosynthesis of prostaglandins.Various NSAIDs have additional possible mechanisms of action, includingInhibition of chemotaxis,Down-regulation of interleukin-1 productionDecreased production of free radicals and superoxideInterference with calcium-mediated intracellular events.