Analgesics Lecture 2022/2023 PDF

Analgesics Opioid receptor agonists Coanalgesics Non-opioid analgesics Morphine...

Analgesics Opioid receptor agonists Coanalgesics Non-opioid analgesics Morphine Groups of drugs: Paracetamol Codeine Antiepileptic drugs Fentanyl Metamizol Antidepressants Tramadol Central alpha-adrenoceptor agonists Buprenorphine 5-HT receptor agonists Opioid receptor antagonists * Non-steroidal anti-inflammatory Sumatriptan Naloxone drugs (NSAIDs) Diclofenac Ibuprofen ** CGRP receptor antagonists CGRP antagonists Erenumab Galcanezumab **CGRP calcitonin gene related peptide * See details in theme Rheumatology. Steroidal and non-steroidal anti- inflammatory drugs RSU Farmakoloģijas katedra 1 2022/2023  Analgesics Pain Classification: Malignant and non-malignant pain Non-malignant pain classification: Acute (nociceptive) pain Nociceptive pain - Pain caused by nociceptor activation. This activation is caused by * damage to various tissues other than nerve tissue. (in this situation, somatosensory nervous system functionality is maintained). * eg internal organs, skin, muscles, connective tissue Chronic pain Inflammatory pain (such as arthritis) Musculoskeletal pain (back pain) Headache Neuropathic pain Neuropathic Pain - Pain that is caused by somatosensory nerves system damage or disease (postosteric neuralgia, diabetic neuropathy, trigeminal neuralgia) RSU Farmakoloģijas katedra 2 2022/2023  Analgesics Neuropathic pain (NP) NP is characterized by excessive sensitization of neurons and formation of ectopic signals foci. NP – pain caused by the somatosensory nervesystem damage or disease (post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia). One of the main reasons for the occurrence of ectopic signal foci is the overexpression of Na+ channels. Based on the pathogenetic differences in pain, there is a different therapeutic approach in the treatment of NP. In cases of NP, antiepileptic drugs or tricyclic antidepressants are more often used, while for nociceptive pain - NSAIDs or paracetamol. RSU Farmakoloģijas katedra 3 2022/2023  Analgesics The structure of the nociceptive system Pain stimulus irritates nociceptors in primary afferent neurons, which are located in the dorsal horns of the spinal cord then switches to interneurons. They connect to the ascending tract - spinothalamic (STT) and spinomedullary tract neurons see pictures in subsequent slides RSU Farmakoloģijas katedra 4 2022/2023  Analgesics Antinociceptive regulation Lejupejošā modulācija Antinociceptive regulation is effected by downward modulation Due to neuron stimulation in the periaqueductive efferent tract, in the spinal cord, the release of serotonin (5-HT), norepinephrine (NE) and encephalins (Enk) is stimulated and thus primary afferent pain impulse (SP, Glu) transmission is blocked Glu - glutamate, LC - locus ceruleus, NMR - nucleus magnus raphe, SP - Substance P (Substance P - a neuropeptide involved in the transmission of pain impulses) RSU Farmakoloģijas katedra 5 2022/2023  Analgesics Mechanisms of action used in analgesia Realized at different levels of the nervous system - starting from the initial pain stimulus nociceptor (in the case of nociceptive pain) or damaged nerve fibers to central pain perception in the cerebral cortex 1. NSAIDs response to peripheral stimuli Downward modulation (inflammation) - modulation of signal transduction by reducing hyperalgesia and sensitization of nociceptive neurons. 2. Na + channel blockers reduce action potential transmission in nociceptive fibers. 3. Opioid and non-opioid analgesics, antidepressants, antiepileptics and α2-adrenoceptor agonists affect signal transduction in the ascending and / or descending pathways (peripheral to CNS or vice versa) RSU Farmakoloģijas katedra 6 2022/2023  Analgesics Endogenous ligands of the opioid system: endorphin, enkephalin, dynorphin, Opioids endomorphine Nowadays, the best studied are three subtypes of opioid receptors mu (OP3 or MOP), delta (OP1 or DOP), kappa (OP2 or KOP) Opioid receptor agonists cause: 1. presynaptic Ca2 + channel blockade, thus inhibiting the excitable release of neurotransmitters (e.g. glutamate, substance P, CGRP) and 2. opening of postsynaptic K + channels, leading to hyperpolarization and non- excitability of the postsynaptic pole Spinal analgesia reduces signal transduction in afferent fibers Supraspinal analgesia - reduces neuronal activity in Thalamus RSU Farmakoloģijas katedra 7 2022/2023  Analgesics Pharmacological effects associated with the main types of opioid receptor Receptor µ δ κ Analgesia Supraspinal +++ +++ +++ Spinal +++ +++ +++ Respiratory depression +++ __ — Pupil constriction ++ — - Reduced gastrointestinal ++ __ ++ motility Euphoria +++ — — Dysphoria and — — +++ hallucinations Sedation ++ — ++ Long-term administration of morphine in a patient with chronic pain can cause down-regulation of δ opioid receptors in the brain and spinal cord. Receptor down-regulation is one of the primary mechanisms of PD drug tolerance. RSU Farmakoloģijas katedra 8 2022/2023  Analgesics Pharmacological effects of opioid receptor agonists The most important therapeutic effects ▪Analgesia (relieves acute and chronic pain) ▪Sedation RSU Farmakoloģijas katedra 9 2022/2023  Analgesics Opioids Morphine µ, δ, k receptor agonists Analgesic and sedative effects Traumatic pain relief Postoperative pain (multimodal analgesia) Tumor-induced pain (basic pain) CHF with pulmonary edema (morphine only) Codeine Weak µ receptor agonists Analgesic and sedative effects Moderate intensity pain RSU Farmakoloģijas katedra 10 2022/2023  Analgesics Fentanyl Opioids µ, δ receptor agonist, partial receptor agonist for the k receptor Analgesic activity stronger than morphine, sedative effect (lipophilic, short acting) Tumor pain (breaktrough cancer pain) Tramadol Weak receptor affinity for µ Analgesic effect enhanced by * SNRI (especially SSRI) Analgesic and sedative effects Pretsāpju un sedatīva iedarbība Moderate intensity pain * explanation of the role of antidepressants in analgesia, e.g. amitriptyline, duloxetine, etc. See above. image Descending modulation RSU Farmakoloģijas katedra 11 2022/2023  Analgesics Opioids Buprenorphine Partial agonist of µ receptors, antagonist of k Very strong µ receptor affinity, low intrinsic activity and very slow dissociation. Mild k receptor antagonist. The effect on δ receptors is unclear Analgesic and sedative effects Applicable to addiction reduction programs in the detox phase Abstinence of potent opioid receptor agonists or opiates Severe to moderate pain RSU Farmakoloģijas katedra 12 2022/2023  Analgesics Side effects of opioids ▪Respiratory depression (possible at therapeutic doses) (children and the elderly are very sensitive to morphine!) ▪Nausea, vomiting (~ 40% of cases cause temporary irritation of the vomiting center) ▪Suppression of cough reflex (interferes with evacuation of bronchial secretion) ▪Pupil constriction (miosis) (differential diagnosis, barbiturates dilate pupil) ▪Increase in GI tone (constipation) ▪Bradycardia, hypotension ▪Itching (histamine induced) ▪Increasing the tone of the Oddi Sphincter ▪Increasing urinary tone (urinary retention) ▪Muscle rigidity ▪Euphoria (if the disease is painful - reduces anxiety) ▪Tolerance (increase the dose gradually to produce an effect) ▪Addiction (propensity to use) ▪Abstinence (pain, epileptic seizures after discontinuation) RSU Farmakoloģijas katedra 13 2022/2023  Toxicology of opioid receptor agonists Clinical manifestations Symptoms triad: miosis, coma, respiratory depression Lethargy is often observed in mild to moderate overdoses. Pinpoint pupils are noted. Possible hypotension and bradycardia, hypoperistalsis.Skeletal muscle tone is weakened, body temperature is lowered, skin is cold and moist. Skin color cyanotic. At higher doses, coma with respiratory depression may develop, and apnea may cause sudden death. In some cases, convulsions are possible See additional informationIn the lecture of the CNS 3rd class. Medicinal toxicology. Toxic syndromes RSU Farmakoloģijas katedra 14 2022/2023  Toxicology of opioid receptor agonists Treatment Basic therapy 1. If necessary, artificial ventilation and additional oxygenation should be performed. 2. If necessary, treat coma, convulsions, hypotension, ventricular arrhythmia. Specific drugs and antidotes Specific opioid antagonist - naloxone IV, with pronounced antagonism of µ, δ, k opioid receptors. Naloxone rapidly reverses respiratory depression. The action of the drug is short, so it must be re-administered if necessary. Other uses of naloxone: Limiting abuse of buprenorphine Reducing the risk of opioid-induced constipation RSU Farmakoloģijas katedra 15 2022/2023  Analgesics Algorithms for Opioid SE Neutralization 1.GI SE Reduction (uses * PAMORA concept) The concept is based on peripheral µ opioid receptor blockade, which does not interfere with central opioid function but at the same time reduces the risk of constipation. Example, the combination of oxycodone and naloxone O is well absorbed by the GI tract, providing central pharmacological effects, whereas N is subject to first-pass metabolism. Thus, N does not affect the central effects of O but, due to the higher affinity of the µ receptor for the GI tract,as well as being a µ receptor antagonist, it reduces the adverse effects of O on GI functions 2. Limiting the misuse of medicines Buprenorphine (sublingual tablets) is used for opioid drug dependence in substitution therapy. To reduce abuse of buprenorphine (IV administration), buprenorphine is commercially manufactured in combination with naloxone. B is absorbed from the oral mucosa providing the desired pharmacological effect, while N bioavailability is very low following subcutaneous administration without affecting B activity. In cases where the drug is administered i / v, N blocks the central µ receptors, thereby interrupting B exposure 3. In the case of respiratory depression, the µ receptor antagonist naloxone is administered *Peripherally acting mu-opioid receptor antagonists (PAMORA) RSU Farmakoloģijas katedra 16 2022/2023  Analgesics Non-opioid analgesics Paracetamol Prostaglandin H2 synthetase inhibitor Inhibition of COX2 / COX3 in the CNS Inhibition of PG synthesis centrally Has a central effect on the proinflammatory cytokine release Acetaminophen = Paracetamol COX - cyclooxygenase RSU Farmakoloģijas katedra 17 2022/2023  Acetaminophen The prevailing hypothesis on the mechanism of action of acetaminophen. The enzyme responsible for synthesis of prostnoids has been given several names, including prostaglandin H2-synthase (PGHS), but is now most commonly referred to as cyclooxygenase (COX). This bifunctional enzyme contains two separate catalytic domains that are responsible for converting arachidonic acid to PGH2: i) a cyclooxyginase domain that produces an unstable peroxide intermediate (PGG2), and ii) a peroxidase (POX) domain containing a heme group that converts the unstable intermediate to PGH2. Experiments published by Boutaud et al (2002, 2010) and Aronoff et al (2009) indicate that acetaminophen acts as a PGG2 cosubstrate & heme reducing agent that inhibits the POX catalytic step by converting its heme group to an inactive reduced state (as illustrated in the box, bottom right). Because acetaminophen acts as a heme reducing agent, its effects are nearly abolished in the presence of high levels of lipid hydroperoxides (such as inflammatory HETEs) that oxidize the heme back to its active state. As a result, acetaminophen is ineffective in tissues with high peroxide tone, such as in platelets or activated lymphocytes (e.g. inflammatory conditions). However, acetaminophen is effective in inhibiting prostanoid synthesis in vascular endothelial cells and neurons that have a low basal https://tmedweb.tulane.edu/pharmwiki/doku.php/acetaminophen peroxide tone, which can account for its antipyretic and (central) analgesic effects. RSU Farmakoloģijas katedra 18 2022/2023  Analgesics Paracetamol / acetaminophen Para- (acetylamino) phenol N acetyl - P aminophenol (APAP) Analgesic and antipyretic with a slight anti-inflammatory effect (unable to block COX in locally where acidic environment is determined by peroxides) Short-term treatment of moderate intensity postoperative pain i / v Symptomatic treatment of mild to moderate pain p / o Fever Overdose: Lethal dose for adults 7-10 g Symptoms progress within 4-6 days - liver failure (hepatic cytolysis), encephalopathy and coma RSU Farmakoloģijas katedra 19 2022/2023  Paracetamol toxicology Paracetamol metabolism and toxicity mechanism There are two major metabolic pathways for paracetamol: Pathway 1 - Conjugation to form glucuronides and sulfates Pathway 2 - CYP450 induced metabolism In case 2 the active intermediate metabolite is formed NAPQI (N-acetyl-p-benzoquinone imine), which is rapidly neutralized by glutathione at therapeutic doses. Increasing the dose of paracetamol depletes glutathione reserves, NAPQI levels increase and liver failure develops IA: Ethanol enhances paracetamol toxicity RSU Farmakoloģijas katedra 20 2022/2023  Paracetamol toxicology Clinical manifestations Manifestations of an overdose depend on how much time has passed since the drug has entered the body. Anorexia, nausea, vomiting and abdominal pain are usually possible in the first 24 hours after an acute paracetamol overdose. A transient prolongation of the prothrombin time/international normalized ratio (PT/INR) is observed in the absence of signs of hepatitis. Some, but not all, of these patients develop liver damage. After 24-48 hours, when AST and ALT levels begin to rise, hepatocellular damage becomes more apparent. Hyperbilirubinemia is also possible. Severe liver damage and poor prognosis indicated by encephalopathy, metabolic acidosis, hypoglycemia and progressive increase in prothrombin time. Along with liver failure, acute kidney failure can also develop. If acute liver failure develops, death may occur. RSU Farmakoloģijas katedra 21 2022/2023  Paracetamol toxicology Treatment Clinical symptoms of liver damage – liver failure (hepatic cytolysis), encephalopathy (coma) usually peaks after 4-6 days. In fulminant liver failure may be necessaryliver transplantation. Specific medicines and antidotes Treatment should be adjusted according to the concentration of paracetamol in plasma. An antidote that restores glutathione reserves - acetylcysteine IV. Recommended time of administration of antidote - within 10 hours after paracetamol ingestion.The effectiveness of the antidote depends on early treatment, before the toxic metabolite has accumulated. If necessary, other symptomatic therapy. RSU Farmakoloģijas katedra 22 2022/2023  Analgesics Non-opioid analgesics Metamizol Inhibition of COX in CNS (Inhibition of PG synthesis centrally) Additional antispasmodic effect SE: agranulocytosis Severe to moderate intensity postoperative or post-trauma pain IV Severe to moderate intensity acute pain p/o Fever RSU Farmakoloģijas katedra 2022/2023  Analgesics Chronic headache Migraine (hemicrania simplex) - pain usually unilateral, pulsating, in the forehead and temples. Headaches are moderate to very severe, usually 1-6 attacks per month. Therapy depending on the severity of the attack. In case of mild attacks, it is possible to use NSAIDs or non-opioid analgesics. If migraine attacks are frequent and/or long-lasting, it is recommended to use medication to prevent migraine attacks Tension headache The most common type of chronic headache (~60% of the population 1x per month) RSU Farmakoloģijas katedra 24 2022/2023  Analgesics Origin of migraine type headache 5HT1b, 5HT1d are presynaptic receptors that localize at endings of n. trigeminus. Their stimulation inhibits the release of CGRP CGRP induces neurogenic inflammation and vasodilation of cerebral vasculature. CGRP concentration reduction prevents migraine type headache RSU Farmakoloģijas katedra 25 2022/2023  Analgesics Serotonin (5HT1) receptor agonists Sumatriptan 5HT1d agonists, 5HT1b partial agonists, vasoconstriction of blood vessels of brain sheath, analgesic effect Migraine attack therapy Galcanezumab Erenumab CGRP antagonist CGRP receptor antagonist Migraine attack prophylaxis RSU Farmakoloģijas katedra 26 2022/2023  Co-analgetics (adjuvants) ▪Medicines whose primary indications are not related to analgesia. Co-analgesics can be used in monotherapy as well as in combination with opioid receptor agonists (ORAs) or NSAIDs because they: ▪may increase ORA or NSPL analgesic activity ▪are distinguished by independent pain killer or analgesic activity ▪can neutralize or reduce side effects of ORA and NSPL Clonidine Adjuvant opioid therapy Carbamazepine N. trigeminus neuralgia Valproic acid Prevention of migraine attacks Gabapentin Postherpetic neuralgia Amitriptyline Fibromyalgia RSU Farmakoloģijas katedra 27 2022/2023