ANALGESICS PART 1.pptx

Analgesics ABENAA OWUSUWAA ADU HND 3 MEDICINAL CHEMISTRY 1 WEEK ACTIVITIES ACTION PLAN(S) Week 1 Overview of Semester’s Work Week 2 Analgesics Further discussion of Analgesics Week 3...

Analgesics ABENAA OWUSUWAA ADU HND 3 MEDICINAL CHEMISTRY 1 WEEK ACTIVITIES ACTION PLAN(S) Week 1 Overview of Semester’s Work Week 2 Analgesics Further discussion of Analgesics Week 3 Analgesics Try Sample questions Assignment Week 4 Anti-infective agents: Antibiotics Further discussion of antibiotics Week 5 Sulphonamides Seek and tackle students’ needs that will be presented Week 7 Anti Protozoal agents: Antimalarial agents Discussion on the subject Assignment Try Sample Questions Week 8 Antifungal and antihelmintics Discussion on topic Assignment Week 9 Antiviral agents Discussion on topic HND 3 MEDICINAL CHEMISTRY 2 Steroids Assignment INTRODUCTION Pain Pain is an uncomfortable /Unpleasant physical or physiological sensation in the body. Pain is a good thing. It warns us of something damaging our body so we take proper medical care. However, constant pain can reduce quality of life HND 3 MEDICINAL CHEMISTRY 3 HND 3 MEDICINAL CHEMISTRY 4  INTRODUCTION How do we feel pain? Pain receptors or Nociceptors are found on the free nerve endings of primary sensory fibres that detect unpleasant stimuli and pass the information to the CNS to be interpreted as pain They are distributed all over the body( skin, muscles, joint joints, internal organs but not brain) When tissue gets damaged by certain (mechanical, thermal and chemical) stimuli, it releases inflammatory mediators (e.g. bradykinin, serotonin, prostaglandins, cytokines, and H+) which can activate primary nociceptors When thesee neurons reach the spinal cord, they pass the pain signal to secondary sensory fibres located around the spinal cord where the key neurotransmitter is substance P. The secondary sensory fibres transmits information to the brain where it is interpreted as pain. HND 3 MEDICINAL CHEMISTRY 5  INTRODUCTION Pain can be categorized into various types based on different factors, including its source, duration, and underlying mechanisms. Types of Pain according to duration Acute pain: Sharp, short term pain - Surgery, broken bones, burns, sprain, labor It is cured if the cause of the pain is removed or treated. Chronic pain: dull, long term pain - Cancer, arthritis, chronic back pain and knee pain, migraine Pain exists for months even when the injury is healed. Cause not well understood HND 3 MEDICINAL CHEMISTRY 6 Types of Pain Nociceptive Pain: This is the most common type of pain and occurs when specialized nerve endings, called nociceptors, detect tissue damage or potential injury. Nociceptive pain can be somatic or visceral: 1.Somatic Pain: Originates from the skin, muscles, bones, joints, or connective tissues. It is often described as a sharp, localized pain. 2.Visceral Pain: Arises from internal organs such as the abdomen, chest, or pelvis. Visceral pain is often described as a deep, dull, or cramp-like sensation. HND 3 MEDICINAL CHEMISTRY 7 Types of Pain Neuropathic Pain: This type of pain results from damage or dysfunction in the nervous system, specifically the peripheral nerves or the central nervous system (brain and spinal cord). Neuropathic pain is often chronic and characterized by shooting, burning, tingling, or electric shock-like sensations. Radicular Pain: Also known as radiculopathy, it occurs when a nerve root is compressed or irritated, leading to pain that radiates along the nerve's pathway. This type of pain often follows a specific pattern, such as sciatica, where pain radiates down the leg due to compression of the sciatic nerve. Referred Pain: Referred pain is felt in a location different from the actual source of the problem. For example, during a heart attack, pain may be felt in the left arm or jaw rather than the chest. HND 3 MEDICINAL CHEMISTRY 8 Types of Pain Psychogenic Pain: This type of pain has a psychological origin and is not associated with any physical damage or injury. It may be caused by emotional distress, depression, anxiety, or somatization disorders. Phantom Pain: Phantom pain occurs after the amputation or removal of a body part, where the person continues to experience pain in the absent limb. The exact cause is not fully understood, but it is believed to involve complex changes in the nervous system. HND 3 MEDICINAL CHEMISTRY 9 INTRODUCTION Ways to relieve pain General Anaesthetics (GA): affects chemical component of neuro transmission (GABA and NMDA receptors General Anaesthetics (LA); blocks electrical component of neuro transmission ( Voltage Gated Na+ channel) (especially for pain) Non- Steroidal Anti- Inflammatory Drugs(NSAIDs) – Blocks local pain messenger such as prostaglandin Opioids: Blocks both chemical and electrical component of nerve transmission. Except NSAIDS, all three are CNS depressants. HND 3 MEDICINAL CHEMISTRY 10 Uses of Opioids They are therefore used for the symptomatic relief of pain. Choice of drugs for managing chronic pain as with cancer or rheumatoid arthritis Used as inducing agent (Fentanyl) or analgesic supplement with General anesthetics They have clinical use as anti-diarrheal and antitussive e.g. Loperamide and Dextromorphan Some opioids such as methadone and buprenorphine are used to counter addiction of more potent opioids such as heroin HND 3 MEDICINAL CHEMISTRY 11 Analgesics In modern times new anesthetic agents, analgesics, hypnotics, nerve sections, and laboratory studies on the physiology and psychology of pain have gone a long way toward making the relief of pain a widely studied and thoroughly investigated scientific problem. The word "analgesia" entered the medical, chemical, and related literature with the discovery and isolation of morphine by Serturner in 1803. It is by definition the absence of sensibility to pain which is physiologically due to a raising of the pain threshold. Anesthesia—pain relief by loss of feeling—was introduced into the medical literature with the discovery of ether by Sir Humphrey Davy, C. W. Long, Morton and others in the early part of the 19th century. HND 3 MEDICINAL CHEMISTRY 12 ANALGESICS Analgesics are substances that relieve pain. Analgesics are selective central nervous system (CNS) depressants and they are grouped into: Centrally acting narcotics (e.g. morphine) Peripherally acting non-narcotics (e.g. salicylates) Centrally acting non-narcotics(e.g. d-proxyphene) Their major sites are the cerebrum and medulla; therefore their ability to pass the blood brain barrier is extremely important. Analgesics are drugs that can relief pain without causing narcosis (loss of consciousness) Anaesthetics are drugs that produce insensivity to pain with loss of consciousness. HND 3 MEDICINAL CHEMISTRY 13 Opium Opium – is a Greek word meaning “juice,” or the extract of seeds from the poppy Papaver somniferum. It is a white milky exudate from the incised unripe seed capsules of the poppy Papaver somniferum. The dried opium contains the following alkaloids: morphine 10%, codeine 0.5%, narcotine 6.0% and papaverine 1% Morphine was the first Narcotic analgesic isolated from opium which contains over twenty distinct alkaloids Opiates : synthetic/ natural compounds both structurally and pharmacologically similar to Morphine Opioids : synthetic/ natural compounds not structurally similar but only pharmacologically similar to morphine HND 3 MEDICINAL CHEMISTRY 14  Naturally occurring analgesics are found among the opium alkaloids and are of two main groups with different pharmacological activities: 1. The morphine group, e.g. morphine, codeine and thebaine – these have the phenanthrene nucleus. 2. The papaverine group, e.g. narcotine and papaverine. They have the isoquinoline nucleus Phenanthrene ring Isoquinoline ring system HND 3 MEDICINAL CHEMISTRY 15 system Opioids - Classification 1. Natural Opium Alkaloids: Morphine and Codeine 2. Semi- synthetic: Buprenorphine, Oxycodone, Diacetylmorphine(Heroin) 3. Synthetic opioids 4 – Phenylpiperidines: Loperamide and Fentanyl and Meperidine Diphenylpropylamine derivatives: Loperamide and Methadone Benzomorphans: Pentazocine, Phenazocine Morphinans: Levorpanol and Butorphanol 4. Endogenous opioids: Natural pain relieving peptides of the body, such as endorphins, enkephalins and dynorphins 5. Miscellaneous: Tramadol, Meptazinol HND 3 MEDICINAL CHEMISTRY 16 Analgesic receptors Body has mechanism to naturally relief pain There are three types in the CNS μ (mu): most widely occurring and target of most drugs Κ (Kappa): lack respiratory drepressing effect and can counter analgesic effect of mu agonist δ (Delta) : Reduced GIT motility, respiratory depression, convulsant effect, limited clinical use Only μ and Κ have clinical use HND 3 MEDICINAL CHEMISTRY 17 Mechanism of action Opioid analgesics agonize opioid receptors μ,κ and δ which are G-protein coupled receptors. This leads to a series of events which ultimately block neuronal pain transmission by: 1. Inhibition of activation of voltage gated Ca2+ channel which depresses NT release 2.Increases K+ conductance outside the cell to cause hyper polarization of cell thus reducing its excitability 3. Inhibition of adenyl cyclase (adenyl cyclase Camp PKA phosphorylation of ion channels increases chances of channel opening) HND 3 MEDICINAL CHEMISTRY 18 Three effects of opioid receptors HND 3 MEDICINAL CHEMISTRY 19 NARCOTIC ANALGESICS Narcotic analgesics have the main stay of pain treatment for decades and remain so today. They exert their therapeutic effects by mimicking naturally occurring substances termed endogenous opioid peptides or endorphins at opioid receptors. The narcotic analgesics are centrally acting and may conveniently be divided into the following groups: A. Morphine and related substances B. Morphinans C. 6,7- Benzomorphans D. Phenylpiperidines E. Diphenylpropylamines HND 3 MEDICINAL CHEMISTRY 20 Morphine and related substances Morphine was isolated by Seturner (1805) from opium and it was the first plant base to be isolated. Its structure was proposed in 1925 by Guillard and Robinson and total synthesis was achieved by Gates and Tschud in 1952, while Kavolda and co-workers established its absolute configuration in 1955. The natural substance is (-)morphine whilst the (+) isomer has no analgesic activity. It is insoluble in water, soluble in base (phenolic hydroxyl group present). It forms water soluble salts with most acids and is used preferrably as the sulphate and hydrochloride. It has a very high ability to relieve pain but its dependence liability has HND 3 MEDICINAL CHEMISTRY 21 limited its clinical use.  SAR Modification to Morphine Structure of Morphine HND 3 MEDICINAL CHEMISTRY 22 SAR 1. Morphine has 5 chiral centres. Only the Levo( - ) rotatory isomer is active. HND 3 MEDICINAL CHEMISTRY 23  2. The OH group in the phenolic ring and basic Nitrogen is needed for activity and seen in all potent μ agonist. Activity can be preserved or enhanced by removing other rings. Changing –OH to just -H or –OCH3 lowers activity as seen with codeine R = C3 substituent Activity effect -H 10X Decrease - OH Morphine - OCH3 Decrease HND 3 MEDICINAL CHEMISTRY 24  Loss of other rings does not affect CHEMISTRY HND 3 MEDICINAL analgesic activity 25 How many chiral centres? HND 3 MEDICINAL CHEMISTRY 26  3. The Nitrogen is mostly tertiary with a methyl substitution in morphine. The size of substituent on Nitrogen dictates potency and agonist or antagonist activity. a) Increasing size from methyl ( ie one carbon) to 3 or 5 carbon (especially with double bonds or small cyclic / aromatic ring) results in antagonist activity b) Still larger substitution restores agonist activity in more potent form. HND 3 MEDICINAL CHEMISTRY 27  If R = 3-5 carbons then mu antagonist effect (more valid if presence of double bond or small carbo-cyclic ring) If R = > 5 carbon ( in chain or ring) then increased mu agonist effect R= Nitrogn effect substituent CH2CH=CH2 ( 3C Becomes mu with double bond) antagonist CH2CH2Ph Mu agonist 10x (Total 8C) more potent than morphine) HND 3 MEDICINAL CHEMISTRY 28  4. Reduction of 7,8 double bond increases activity 5. Inclusion of Hydroxyl group at 14 increases activity HND 3 MEDICINAL CHEMISTRY 29  6. Removal of Hydroxyl group at 6 increases activity 7. Oxidation of Hydroxyl to jeto group at 6 increases activity, if there is also reduction of 7,8 double bond e.g.hydrocodone 8. Acetylation of Hydroxyl at 6 increases activity R = C6 substituent Effect in activity H Increase = O (keto) Decreases =O (keto) with 7,8 Increases (10X reduction ( change more potent than double bond to morphine single) H3CC=O 9 acetyl) Increase HND 3 MEDICINAL CHEMISTRY 30  9. Removal of the ether linkage produces compounds called morphinans that have increased activity HND 3 MEDICINAL CHEMISTRY 31 1. Methylmorphine(Codeine): It is prepared by methylation of the phenolic hydroxyl group of morphine. It is less potent that morphine than morphine and it is widely used as an antitussive. It is prescribed in numerous combinations for the relief of pain and the suppression of cough. 2. Dimethylmorphine (Thebain): Methylation of both hydroxyl groups of morphine yields thebaine. It has no analgesic but convulsant action. HND 3 MEDICINAL CHEMISTRY 32 SUMMARY OF CONVERSIONS HND 3 MEDICINAL CHEMISTRY 33 Summary of SARs HND 3 MEDICINAL CHEMISTRY 34 Morphine It is a naturally occurring analgesic alkaloid extracted from opium of poppy plant Modification to kits structure has resulted in more potent compound. Used in chronic pain management Its 3-O- glucuronidation form is inactive However, its 6-0- glucuronidation form is active and thus does reduction is needed in case of renal damage (cos its rate of clearance is reduced) It is potent enough that its 60mg oral dose has analgesic effect equal to parenteral administration MOA: agonizes mu receptor which depresses pain signals by: Inhibiting VGCC and prevents release of neurotransmitters Opening VGPC and hyperpolarization of nerve cells Inhibiting adenyl acyclase Codeine It is prepared by methylation of of the phenolic OH group of morphine. It is a weak μ agonist formed by modification of 3OH in morphine into H3CO. This results in loss of activity. Thus codeine is used in moderate to mild pain only. It is a colourless, efflorescent and light sensitive alkaloid used as the sulphate or phosphate salt. It is less potent than morphine and is widely used as an antitussive. Its metabolic product is morphine and thus abused by addicts. The dose required to produce analgesia after parenteral dose causes release of histamine that in turn causes allergic responses; thus not used parenterally. Morphine derivatives cont’d Dimethylmorphine(Thebaine):Methylation of both hydroxyl groups of morphine produces thebaine. It has no analgesic but convulsant action. Diacetylmorphine(Heroin): Acetylation of both phenolic and alcoholic hydroxyl groups of morphine gives diacetylmorphine but it is forbidden in most countries because of its intense dependency liability. Dihydromorphinone(Dilaudid): It is obtained from morphine by oxidation of alcohol hydroxyl group to a ketone and reduction of the C7- C8 double bond. It is more potent than morphine and has equal addicting liability. Methyldihydromorphinone or hydrocodone: It is prepared by conversion of the phenolic group of dihydromorphinone to methoxy group.It is used as an antitussive and for the relief of pain. Its analgesic potency is midway between morphine and codeine Morphinans The morphinans are more potent and longer acting than their morphine counterparts but have higher toxicity and comparable dependence characteristics. The N-methylmorphinans differ from the morphine nucleus in the lack of the ether bridge between C4 and C5 as well as the absence of phenolic and hydroxyl groups. Structural modifications of this group have provided highly potent and useful antitussives: Levorphanol(a synthetic analgesic), yhe levo form of racemorphan, is five times more potent than morphine. Dextrorphan(the + isomer): This is totally devoid of analgesic properties ; useful a s an antitussive and is in the form of its methyl ether (dextromethorphan) 6,7 Benzomorphans (or Benzazocines) In this group, one or two methyl groups replace the acyclic ring of morphine. They are mostly used as antagonist- type analgesics. Examples are pentazocine and cyclazocine Pentazocine A mixed agonist/antagonist effect( mu antagonist and kappa agonist) Weak analgesic effect -1/6 as potent as morphine Phenylpiperidines Pethidine (Meperidine) It is a 4-Phenylpiperidines based derivative of morphine. A weak mu agonist, 1/10th as potent as morphine. Does not inhibit cough Rapid onset of action but high 1st pass metabolism Thus used in obstetrics, where given in small dose to mother will not cause respiratory depression to the newborn  Fentanyl It is a 4-(Phenylpropionamido) piperidines based derivative of morphine It is about 80 times more potent than morphine. It does not cause histamine release on iv injection (ie no skin inflammation) It inhibits p-glycoprotein mediated efflux of digoxin (ie increases concentration of digoxin in blood) Tramadol Not a true opioid analgesic (+) isomer has activity 1/3800 that of morphine (-) isomer blocks norepinephrine Tramadol Not a true opioid analgesic (+) isomer has activity 1/3800 that of morphine (-) isomer block norepinephrine and serotonin (excitatory NT) reuptake and thus show some analgesic activity. But the effect is weak. Its metabolite is active and 1/35 as effective as morphine Non-addictive, no respiratory depression or constipation. Used with other analgesic for synergistic effect. NSAIDs  They are a class of medications commonly used for their analgesic (pain-relieving), anti-inflammatory, and antipyretic (fever-reducing) properties. NSAIDs work by inhibiting the enzymes called cyclooxygenases (COX), which are involved in the production of prostaglandins, substances that contribute to pain, inflammation, and fever.  They can be referred to as non- narcotic analgesics and they differ from the narcotic type analgesics in that they do not: A) cause addiction or euphoria or tolerance B) Cause respiratory depression C) Relieve the severe pains of burns, cancer and heart attack. They are antipyretic and anti-inflammatory ( except paracetamol) agents  They can be divided into 7 classes: Derivatives of phenol e.g. salicylic acid and derivatives Derivatives of aniline e.g. phenacetin and paracetamol Derivatives of pyrazolone and pyrazolidinediones; eg phenazone, phenylbutazone Arylacetic and arylpropionic acid derivatives e.g. indomethacin, ketoprofen Anthranilic acids, e.g. mefenamic acid Derivatives of substituted furanone and pyrazole, eg vioxx and celecoxib respectively Adrenocortical steroids e.g. cortisone, prednisolone Classes A-E are referred to as NON- steroidal anti-inflammatory drugs(NSAIDS) REFERENCES 1.Katzung, B. G., Trevor, A. J., & Kruidering-Hall, M. (2020). Basic & Clinical Pharmacology. McGraw-Hill Education. 2."Essentials of Medicinal Chemistry" by Thomas L. Lemke and David A. Williams. 3."Wilson and Gisvold's Textbook of Organic Medicinal and Pharmaceutical Chemistry" by John M. Beale Jr. and John H. Block. 4.Brunton, L. L., Hilal-Dandan, R., & Knollmann, B. C. (2018). Goodman & Gilman's The Pharmacological Basis of Therapeutics. McGraw-Hill Education. 5.Rang, H. P., Dale, M. M., Ritter, J. M., Flower, R. J., & Henderson, G. (2020). Rang & Dale's Pharmacology. Elsevier. 6.Schumacher, M. A., Basbaum, A. I., & Way, W. L. (2018). Opioids: Basic Mechanisms and Clinical Aspects. Lippincott Williams & Wilkins. 7.Chou, R., Korthuis, P. T., McCarty, D., Coffin, P. O., Griffin, J. C., & Davis-O'Reilly, C. (2020). Management of Suspected Opioid Overdose with Naloxone by Emergency Medical Services Personnel. Annals of Internal Medicine, 172(2), S66-S73. HND 3 MEDICINAL CHEMISTRY 48