Opioid Analgesics PDF

Opioid Analgesics Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University  Opiates Vs Opioids Opiates ❑ Substances with active ingredients naturally derived from Seed capsule of poppy plants (Opium) or obtained by semi synthesis f...

Opioid Analgesics Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University  Opiates Vs Opioids Opiates ❑ Substances with active ingredients naturally derived from Seed capsule of poppy plants (Opium) or obtained by semi synthesis from morphine. ❑ Morphine (16%), codeine (4%), thebaine. Opioids ❑ Natural, semisynthetic, fully synthetic & endogenous substances that mimic the pharmacological effects of morphine. 2 Opioids Centrally acting analgesics that bind to opioid receptors which are found principally in CNS & GIT (Compounds with morphine – like action in the body). Opioids Semi- Fully Endogenous Natural synthetic synthetic Opioids Opiates Opiates Opioids peptides N CH3 N CH3 Endorphins COOC2H5 Enkephalins HO O Dynorphins OH O H3C OC O OCOCH3 N Morphine Heroin CH3 Meperidine 3 Opioids Receptors Receptor type Location Effects Analgesia (central), constipation, respiratory Brain, spinal depression, euphoria, miosis, inhibition of μ cord diuresis, tolerance, physical dependence, addiction. Analgesia (peripheral), sedation, dysphoria, Brain, spinal minor respiratory depression, minor miosis, κ cord less-addictive, stimulation of diuresis, hallucination. Analgesia (spinal), antidepression, δ Brain dependence. 4 Opioids Side effects ❑ Respiratory depression ❑ Nausea & vomiting ❑ Pupil constriction ❑ Constipation ❑ Euphoria ❑ Itching ❑ Tolerance & dependence 5  Tolerance Dependence Psychological Withdrawal dependence symptoms The same Physical need Euphoria may amount of the for the ongoing provoke a Occur with drug produces supply of the strong desire sudden less effect over drug. for further cessation of time application of the drug after More drug is the compound regular use or needed to (addiction). application of have the same an antagonist. effect. 6 Endogenous Opioid Peptides ❑ Two endogenous pentapeptides, (Met-enkephalin) & (Leu-enkephalin), cause opioid activity. ❑ They are produced by the body to relief pain. ❑ Discovery of the enkephalins was soon followed by the identification of other endogenous opioid peptides, including β-endorphin, the dynorphins, & the endomorphins. ❑ Endorphin boosters? 7  Morphium after the Greek god Morpheus Morphine (The god of dreams). E NH B ❑ Principle alkaloid in opium. A C ❑ Responsible for analgesic activity. Morphinan ❑ Because of morphine’s poor oral BA→ little use in medicine until the hypodermic syringe was invented in 1853. ❑ Morphine was used during the American Civil War. ❑ It acts in the brain and appears to work by ↑ Prototype the pain threshold → ↓ the brain's awareness of pain. 8 Morphine 17 16 N CH3 ❑ Most effective pain killer (severe pain either acute or chronic). 10 E 9 1 11 14 8 15 B ❑ Morphine itself is poorly soluble in water used as HCl or SO4 2 A 12 13 C 7 D salts. 3 4 5 6 HO O OH ❑ Used in cancer, postoperative pain & in serious accidents. ❑ Natural: levo (-) which has the analgesic effect. ❑ Synthetic: dextro (+) with no analgesia but still have antitussive effect. +3 +1 +2 9 Morphine Metabolism N-demethylation Normorphine N CH3 Minor pathway (↓ activity) HO O OH Morphine-3-glucuronide Morphine-6-glucuronide (Inactive) (2x more active than morphine) 10 11 Aims of opioid drug design→ Analogues ❑ They should retain analgesic activity of morphine which requires the presence of : 1- The important binding groups. 2- The ability to cross BBB. ❑ Have fewer side effects/ less addiction power. ❑ Can be administrated orally ( increase oral BA). Analogues Removal of ring Removal of ring Removal of ring Removal of ring Ring A Ring C D C&D B, C, & D B, C, D, & E 12 Ring A 3-OH → OCH3 Codeine Morphine. OH 20% of morphine activity 10-15% Slow ❑ 3-methoxy derivative of morphine. ❑ ↑ oral activity. ❑ Used for mild to moderate pain & as an antitussive. ❑ Weaker analgesic but weaker side effects. ❑ Lower risk of abuse & addiction. 13 Ring A & C 3- &6- OH → OCOCH3 Heroin N CH3 Diacetyl morphine 2-3X more potent H3C OC O O OCOCH3 ❑ More potent analgesic than morphine because : 1- It is less polar than morphine (A lipophilic morphine derivative) → ↑ penetration of BBB→ Once in the brain, esterases hydrolyze the acetyl goup to produce morphine & 6- acetylmorphine which has μ agonist activity more than morphine. 2- Rapid brain access & rapid conversion into a potent μ agonist → a quick onset of action & high abuse potential (a more exaggerated euphoria when the drug is taken by injection). ” Euphoric rush” 14 Synthesis of Codeine & Heroin N CH3 H3C O O OH N CH3 Codeine N CH3 HO O OH Morphine H3C OC O O OCOCH3 3,6- Diacetylmorphine Semi-synthetic derivative 15 Opioid Agents Used as Cough Suppressants (Antitussives) ❑ Many of the rigid-structured opioids have cough suppressant activity. ❑ This action is not a true opioid effect in that it is not always antagonized by opioid antagonists. ❑ The 3-OCH3 derivatives of morphine are nearly as effective antitussive agents as free phenolic agents. ❑ Incorporation of the 14α-OH into the structure greatly→ ↑ analgesic activity & ↓ antitussive activity. The ↑ oral activity & ↓ abuse potential of the methoxy derivatives make them preferred as antitussive agents. 16 Ring C 7,8-dihydro + 6-keto Hydromorphone Hydrocodone 8-10X more potent ❑ 7,8-dihydro-6-keto derivative of morphine. ❑ 3-methoxy derivative of hydromorphone, ❑ More potent & better absorbed than ❑ Midway between codeine & morphine in morphine. analgesic action. ❑ ↑ Lipid solubility→ Orally active, Higher ❑ It acts primarily on μ-opioid receptors. penetration of BBB. ❑ More effective than codeine as antitussive ❑ It acts primarily on μ-opioid receptors. ❑ Orally active. ❑ More addictive. ❑ Low frequency of S.E. 17 Ring C 7,8-dihydro + 6-keto + 14β-OH Oxomorphone Oxocodone 10X more 2X more potent potent orally Equipotent parenterally ❑ Bind to & activate the μ-opioid receptor &, ❑ Oxycodone has activity at opioid receptors to a lesser extent, the delta opioid μ & κ. receptor. ❑ Better oral BA than morphine ❑ ↑ analgesic activity & ↓antitussive activity. ❑ Used mainly as analgesic. ❑ Oxycodone appears to have a significant antidepressant effect. (illegal). The 14α-hydroxy group generally ↑ μ agonist properties & ↓ antitussive activity, 18 Removal of Ring D (Morphinans) Dextromethorphan More potent & longer acting than morphine Removal of 4,5-epoxide bridge in the morphine ❑ Only the levo-(–) isomers possess opioid activity. ❑ The dextro + (-) isomers have useful antitussive activity. ❑ It lacks the analgesic, respiratory depressant, & abuse potential of μ-opioid agonists but retains the centrally acting antitussive action. ❑ More lipophilic→ Oral BA & long duration. 19 Removal of Ring C & D (Benzomorphans) Phenazocine N CH2 CH2 10X more potent CH3 CH3 HO ❑ Synthetic compounds that lack both the epoxide ring and the C ring of morphine with retaining opioid activity. ❑ Used as analgesic. ❑ It has the same addictive properties as morphine. 20 Removal of Ring B, C & D 4-Phenylpiperidines Meperidine (Pethidine) COOC2H5 Weak analgesic action Convulsions 20-25% activity N NH Normeperidine CH3 ❑ The 1st fully synthetic analgesic with morphine like activity. ❑ Short duration of action because of esterases hydrolysis to a Zwitter ionic metabolite → extensively used in obstetrics (Childbirth) due to its rapid onset & short duration of action. (given I.V in small doses), the respiratory depression in the newborn child is minimized. ❑ µ- opioid receptor agonist. ❑ The same side effects of morphine + Abuse potential + Dependence. 21 Removal of Ring B, C & D Anilidopiperidines Fentanyl Powerful analgesic: 80-100X more potent ❑ Fentanyl & its derivatives are μ- opioid agonists. Carfentanil 10,000 X more potent than morphine ❑ Typical morphine-like analgesia & side effects. ❑ For unknown reasons, the compounds produce analgesia at much lower doses than is necessary to cause respiratory depression (Safer than morphine). ❑ Highly lipophilic absorbed from skin & pass BBB also. ❑ Used for chronic pain management & in cancer patients' pain (1st Choice). 22 Removal of Ring B, C, D & E Diphenylheptanone Full opioid agonist Active OH Methadone NH2 Active CH3 H3C Equipotent to morphine N O CH3 C2H5 C 2 Antidiarrheal derivatives: Diphenoxylate Loperamide ❑ Methadone is marketed as a racemic mixture, but the R (–)- isomer possesses almost all of the analgesic activity. ❑ Synthetic, orally active with long duration of action (85% PPB with half-life= 15-22 hrs). ❑ Used in maintenance therapy for opioid addicts (controlled withdrawal) as (morphine or heroin substitute) & for pain suppression in the terminally ill patients. ❑ Less side effects than morphine (e.g., emesis, euphoria, sedation & constipation). 23 Removal of Ring B, C, D & E Centrally acting Tramadol analgesic 10-20% activity Dual action ❑ A centrally acting μ-opioid receptor agonist & SNRI (serotonin/norepinephrine reuptake-inhibitor). ❑ Tramadol binds weakly to κ- & δ-opioid receptors & to the μ-opioid receptor with 6000-fold less affinity than morphine. 24 Removal of Ring B, C, D & E Centrally acting Tramadol analgesic 10-20% activity Dual action OH ❑ A racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol & its primary metabolite (+)-O-desmethyl-tramadol (6X more potent than parent drug) are agonists of the μ opioid receptor. ❑ Non opioid action→ ↓ spinal pain transmission, 1R, 2R (+)-tramadol inhibits 5-HT reuptake & 1S, 2S (-)-tramadol inhibits NE reuptake. 25 N- Extension (N-substituted morphines) Nalorphine Nalbuphine N CH2 C CH2 H Mixed N OH κ agonist - μ antagonist HO O OH HO O OH ❑ Weak agonist/Antagonist. ❑ Rapid onset of action. ❑ Used to treat morphine overdose. ❑ ↓ dependence & ↓ hallucinations ❑ Non-addictive analgesic. ❑ Uses : ❑ First indication of a safe opioid analgesic. ❑ To treat moderate to severe pain. ❑ Hallucinogenic side effects. ❑ As adjunct to anesthesia. ❑ No longer used due to its side effects. 26 N- Extension (N-substituted morphines) Naloxone Naltrexone N CH2 C CH2 H N OH OH Pure Opioid Antagonists HO O O (slightly selective to μ receptor) HO O O ❑ Potent antagonist ❑ 8x more active than naloxone as an ❑ ↓ oral BA due to extensive 1st pass antagonist. metabolism in liver (parenteral). ❑ ↑ oral BA. ❑ Short acting. ❑ Longer duration (8-12 hrs). ❑ Uses ❑ Uses : Blocks the euphoria 1. Treat opioid overdose. Treat opioid & alcohol dependence (for 2. Antagonize opioid side effects. addicts, weaned off morphine or heroin). 3. Reverse opioid-induced anesthesia. 27 Structure-Activity Relationship N-substitution: N- methyl→ good activity. N- ethyl, N-propyl → ↓ activity, N-butyl→ zero activity. N-CH2CH2Ph→ ↑ activity N-CH2CH=CH2 , N-CH2- cyclopropyl, N-CH2- cyclobutyl → μ- antagonist Pharmacophore: N: EFA 17 1) 3ry amine. Ring E 2) Qry Center Carbon. 16 N CH3 ✓ 14-OH → ↑ analgesic activity, ↓ 10 E antitussive 9 3) 2 carbon bridge between Center C & amine. 14 1 11 8 4) Phenyl ring attached to center C. Ring A 15 B ✓ 7,8-dihydro → ↑ analgesic 12 activity 2 A 13 C 7 Especially when C6 is C=O D 3 4 5 6 ✓ 3-OCH3 → ↓ analgesic activity, O ✓ 6-OCOCH3 → ↑ analgesic HO OH ↑ antitussive activity Ring D: is not EFA ✓ 3 & 6- OCOCH→ ↑ analgesic activity 28 Break 29 Analgesic & Antipyretic Drugs Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University Acetaminophen (Paracetamol) & Related Analogues Paracetamol The only one currently in the market. Oral, rectally, & I.V. No Anti- inflammatory NOT NSAID Aromatic amines which cause Methemoglobinamia/nephropathy. Acetanilide Phenacetin 31 Acetaminophen (Paracetamol) & Related Analogues ❑ They have similar analgesic & antipyretic efficacies to the conventional NSAIDs such as aspirin & ibuprofen. ❑ However, unlike the conventional NSAIDs, they lack the antiplatelet effects of aspirin & the GIT side effects associated with NSAIDs. ❑ Acetaminophen & its related analogues are analgesic/antipyretic agents but NOT NSAIDs (No clinical usefulness as anti-inflammatory agents/ no or little anti-inflammatory properties). 32 Mechanism of Action of Acetaminophen The exact mechanism of action of acetaminophen still unknown: 1st hypothesis It inhibits central COX isozyme in the brain (COX-3). 2nd hypothesis It is actively competing with PGG2 for its conversion to PGH2 catalyzed by COX enzymes. (Active only in intact non-inflamed tissue). 3rd hypothesis It depletes glutathione (GSH) stores in body which is an essential co- factor for PGE synthase → decrease PGE production. 33 Acetaminophen Metabolism (Toxicity) Glutathione adduct Excretable Non-toxic Reactive N-acetylcysteine Toxicity antidote hepatotoxic metabolite Hepatic necrosis Excretable non-toxic Liver failure conjugate 34 Acetaminophen Metabolism (Toxicity) Acetaminophen hepatotoxicity is significantly increased by: 1) High dose (> 4 gm /day = 1 gm every 6 hrs). 2) Alcohol intake (Induce CYP1E2). N.B: paracetamol can be used during pregnancy, for children 3) Heavy intake of caffeine. & peptic ulcer patients. 4) Elderly/ Malnutrition. Acetaminophen Synthesis Acetylation with acetic anhydride P-amino phenol Acetaminophen 35 Drugs used in the Management of Gout & Hyperuricemia Dr. Rawda Mahmoud Lecturer of Pharmaceutical Chemistry Faculty of Pharmacy, Cairo University Gout ❑ Gout is an inflammatory disease characterized by elevated levels of uric acid (as urate ion) in the plasma (Hyperuricemia) & urine. ❑ Gouty arthritis is also more prevalent in men than in women by a ratio of approximately 6 to 1. Acute gouty arthritis Chronic gout symptoms Results from the accumulation of Chronic gout symptoms develop as needle-like crystals of monosodium permanent erosive-joint deformity. urate within the joints. Associate with recurrent attacks of gouty arthritis due to hyperuricemia. 37 Uric acid Biosynthesis: In mammals other than human Urea Allontoin Uricase Urate Anion Transporter-1 38 Uric acid Metabolic Problem ❑ Blood levels of urate are maintained by a careful balance between its formation & excretion. When levels of uric acid in the body increase (hyperuricemia), either as a result of ↓ excretion or ↑ formation → the solubility limits of sodium urate are exceeded, & pptn. of the salt from the resulting supersaturated solution → causes deposits of urate crystals to form. The formation of these urate crystals in joints & connective tissue that initiate attacks of gouty arthritis (acute). 39 Uric acid Metabolic Problem ❑ In addition to hyperuricemia, other factors that may also increase the risk of development of gout include: Hypertension. Renal insufficiency. Obesity. The use of thiazides or loop diuretics. High intake of alcoholic beverages & purine rich foods such as meat, liver, bacon, fish, & beans. 40 Gout Treatment: In mammals other than human Urea Allontoin Uricase Uricase analogues Xanthine oxidase inhibitors Uricosuric drugs 41 Gout Treatment Ӏ. Control of the acute attacks: by drugs that reduce pain & inflammation caused by the deposition of urate crystals (Colchicine (anti-inflammatory), NSAIDs (anti- inflammatory & analgesic), Intra-articular injection of glucocorticoids (anti- inflammatory). ӀӀ. Uricosuric drugs (increasing the rate of uric acid excretion) as Probenecid & Sulfinpyrazone. ӀӀӀ. Xanthine oxidase inhibitors (inhibiting the biosynthesis of uric acid) as Allopurinol & Febuxostat. ӀV. Uricase analogues (enhance degradation (metabolism) of uric acid) as Pegloticase (IV administered PEGylated recombinant mammalian uricase enzyme). 42 Colchicine ❑ It is an alkaloid obtained from various species of Colchicum. ❑ Treatment of acute gouty arthritis. ❑ It’s recommended only as a second-line therapy when NSAIDs & glucocorticoids are contraindicated or ineffective due to its side effects & drug-drug interactions. 43 Colchicine M.O.A. ❑ It doesn't alter uric acid serum levels, but retard inflammation process initiated by the deposition of urate crystals. ❑  the phagocytosis: ▪ Inhibit the production of lactic acid leading to  pH of synovial tissue →  solubility of uric acid →  urate needles deposition. ▪ Inhibit the release of lysosomal enzymes during phagocytosis ( inflammation). Colchicine Side effects ❑ Long term therapy → Bone marrow depression & aplastic anemia. 44 Chronic Gout Symptoms Treatment  Excretion  Synthesis Xanthine oxidase 01 Uricosuric drugs. 02 inhibitors. Drugs that increase uric acid Drugs that decrease uric acid secretion by  the reabsorption of biosynthesis. uric acid in the proximal tubules. 45 1) Uricosuric drugs 1) Probenecid M.O.A. ❑ Exhibits a high affinity for URAT-1 (urate anion transporter-1) (URAT-1 inhibitor). ❑ So  uric acid reabsorption from the renal proximal tubules. ▪ Only effective in patients with normal kidneys. ▪ Used for the prophylaxis for patients with severe recurrent gout. 46 2) Sulfinpyrazone ❑ Produces its uricosuric action in a similar manner to that of probenecid. ❑ Exhibits a high affinity for URAT-1 (URAT-1 CYP2C9 inhibitor). ❑ So  uric acid reabsorption from the renal proximal tubules. 47 2) Xanthine oxidase inhibitors 1) Allopurinol M.O.A. Competitive inhibitor of xanthine oxidase ( uric acid synthesis). Allopurinol & its active metabolite, oxypurinol, compete with the Hypoxanthine Xanthine Uric acid substrate hypoxanthine & xanthine, respectively, for xanthine oxidase, thus blocking uric acid formation Allopurinol Alloxanthine (oxypurinol) from adenine, & guanine. 48 2) Febuxostat ❑ A selective, non-purine inhibitor of xanthine oxidase. ❑ Non-competitively inhibits the access to the enzyme’s catalytic site by the endogenous hypoxanthine & xanthine substrates. 49  NSAIDs or GCs Acute Colchicine Gout Probenecid ↑ Uric acid excretion Sulfinpyrazone Chronic Allopurinol ↓ Uric acid biosynthesis Febuxostat 50  Thanks! You can find me at: [email protected] 51